13-substituted derivatives milbemycin, acaricidal and insecticidal composition and method of protecting plants from damage by parasites

 

(57) Abstract:

13 - Substituted derivatives milbemycin having the formula I

< / BR>
where R1is methyl, ethyl, isopropyl or sec-butyl; R2- hydrogen and alkyl; X is ( - hydroxyimino - or-alkoxyimino-substituted)-arylmethyl or (hydroxyimino - or-alkoxyimino-substituted)-heterocyclyl, N-substituted AMINOPHENYL or N-substituted aminophenoxy; m is 0 or 1, and n is 0 or 1, are suitable as anthelmintic, acaricidal and insecticidal preparations for agriculture and horticulture. 3 C. and 20 C.p. f-crystals, 12 tab., 7 Il.

The invention relates to a series of new derivatives of compounds known as "milbemycin", which are derivatives, substituted in position 13. The invention also provides new methods and compositions for the use of these compounds in agriculture and horticulture, as well as methods for their preparation.

There are several classes of known compounds with the structure on the basis of 16-membered macrolide ring, which is produced by fermentation of various microorganisms or get by a semi chemical processing products such natural fermentation and who show acaricide, which measures two classes of such known compounds, but there are also various other compounds that are identified in the technique of different names or code numbers. The names of these various macrolide compounds usually form from names or code numbers of microorganisms that produce naturally occurring compounds in each class, and these names are then expand to encompass chemical derivatives of the same class, resulting in, as a rule, there is no standardized system of nomenclature for these compounds.

To avoid confusion, here is used a standardized system of nomenclature, which follows the normal rules for naming derivatives of organic compounds, which are recommended by the International Union of pure and applied chemistry (IUPAC). Department of organic chemistry. Commission on nomenclature of organic chemistry, which is based primarily on the hypothetical parental connection, defined here as "milbemycin", and represented by the formula A

,

where

Raand Rbare both hydrogen atoms.

For the avoidance of doubt in the formula A also lists the numbering of the provisions in the system of the macrolide ring, napoleonville, produced naturally represent a range of macrolide compounds, known for its anthelmintic, acaricidal and insecticidal action. Milbemycin D is disclosed in U.S. patent 4346171, where it is called "connection V-41D", and milbemycin A3and A4disclosed in U.S. patent 3950360. These compounds can be represented by the above formula A, in which Rain position 13 represents a hydrogen atom, and Rbin position 25 represents a methyl group, ethyl group or isopropyl group, and these compounds are referred to as milbemycin A3milbemycin a and milbemycin D, respectively. Analogues milbemycin containing a hydrogen atom in position 13 and substituted in position 25 second-butilkoi or ISO-propyl group, are disclosed, respectively, in U.S. patent 4173571 as the aglycone 13-deoxy-22,23-dihydroavermectin B1aand the aglycone 13-deoxy-22,23-dihydroavermectin B1b"; and the corresponding 13-gidroksilirovanii compounds known as 22,23-dihydro-avermectin B1aand 22,23-dihydro-avermectin B1b".

Subsequently received various derivatives of the original milbemycin and avermectins and investigated their activity. For example, mi, 4579864 and 4547491, in publications of European patents 8184, 102721, 115930, 180539 and 184989 and applications for the Japan patent Kokai (i.e., open display) 57-120589 and 59-16894.

Derivatives of 13-hydroxy-5-kelimelerin disclosed in U.S. patent 4423209. Derivative milbemycin-5-oxime disclosed in U.S. patent 4547520 and in the publication of the European patent 203832. Derivative milbemycin-23-oxime disclosed in the published European patent 259779; and derivatives milbemycin containing oximino Deputy in position 13, are disclosed in the publications of the European patents 165029 and 341972 and in PCT publication WIPO 93/18041.

Some compounds, in which 13-esterified hydroxy-group, are disclosed in U.S. patent 4959386, which describes esters of various carboxylic acids. No part of carboxylic acids at position 13 in these compounds prior art has no heterocyclic substituents. Derivatives of 13-acetoxypiperidine in which acetoxygroup may contain various heterocyclisation as substituents are disclosed in the published European patent 549273. Publication of the European patent 246739 reveals 13-alonetime milbemycin, which can be substituted in position alcoholedu.

None of the groups of carboxylic acids at position 13 in these compounds prior art does not contain alkoxyimino Deputy, or does not contain aryl or heterocyclyl Deputy with substituents containing aminosilane ring.

Opened some milbemycin containing in position 13 simple ester group. Milbemycin containing in position 13 fenilalanina, are disclosed in the publications of the European patents 448243, 444964, 357460 and 594291.

On prior art not disclosed milbemycin with simple ether group at position 13, in which alkoxygroup contains arylacetylenes or geterotsiklicheskikh Deputy.

Different classes related milbemycin macrolide compounds belonging to the above-mentioned compounds, all as disclosed means having one or more types of activity, i.e. as antibiotics, deworming drugs, ectoparasiticide, acaricide or other pesticide means. However, there is still a need to provide such means with increased activity relative to one or more classes of agricultural or garden pests.

Now ofhis selection of combinations of substituents for the system macrolide ring, especially substituents in position 13. In particular, it was found that the activity of the compounds can be improved by appropriate selection of some very typical ester groups ethers in position 13, as will be described below. In General, the compounds of the present invention tend to have higher pesticide activity than compounds of the prior art, and many of the compounds of the invention have significantly higher activity.

The aim of the invention is to provide a macrolide compounds with increased activity. Another object of the invention is to provide methods for obtaining such compounds. And another aim of the invention is to provide pesticidal compositions and methods of using these compounds.

In accordance with these objectives, the invention proposes a 13-substituted derivatives milbemycin General formula I

< / BR>
where R1is methyl, ethyl, ISO-propyl or sec-bucilina group;

R2is a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms;

X - (a) a group of formula II

< / BR>
where R3is a hydrogen atom or alkyl gli two heteroatoms in the ring, selected from nitrogen, oxygen or sulfur, and these phenyl and heterocyclyl groups are unsubstituted or substituted by 1 or 2 substituents (which may be the same or different) selected from the following substituents A; or

X - (b) a group having formula III

,

where

p = 0 or 1;

Z - alcoolica group containing 2 to 3 carbon atoms; alkylsulfonyl group containing 1 to 3 carbon atoms; alkoxycarbonyl group containing 2 to 5 carbon atoms; aminoadenosine group containing 2 to 7 carbon atoms and linoprint mentioned aminoalkanoic group substituted by 1 or 2 substituents, which may be the same or different and which are selected from the following substituents B, alcoholly fragment mentioned aminoalkanoic group not substituted or substituted phenyl group or alkylthiol containing 1 to 3 carbon atoms); a saturated 5 - or 6-membered heterocyclic carbonyl group, containing ring nitrogen atom or containing in the ring nitrogen atoms and sulfur, in which the said nitrogen atom of the ring may be unsubstituted or substituted by alkoxycarbonyl having 2 to 5 carbon atoms, and in which the carbonyl group PREROLL carbonyl group attached to an atom, other than the nitrogen atom of the lactam; -alkoxyimino- -geterotsiklicheskikh, in which CNS fragment contains 1 to 3 carbon atoms, and heterocyclyl fragment is a 5 - or 6-membered aromatic heterocyclic group containing one or two ring heteroatoms selected from nitrogen or sulfur, which may not be substituted or replaced by alkoxycarbonylmethyl having 2 to 5 carbon atoms or haloalkaline having 2 to 3 carbon atoms;

among the substituents A are: a halogen atom; a nitro-group; hydroxyl group; alkoxygroup containing 1 to 4 carbon atoms; arancelaria containing 7 to 11 carbon atoms; the amino group; alkanolamines containing 1 to 4 carbon atoms; halogenoaluminate containing 2 to 4 carbon atoms; alkylsulfonamides containing 1 to 3 carbon atoms; alkoxycarbonyl containing 2 to 5 carbon atoms; halogenocarboxylic containing 3 to 5 carbon atoms; aminoalkylindole containing 2 to 7 carbon atoms, in which the amino group in aminoalkanoic fragment may not contain substituents or contain one or two substituent (which may be the same or different), carbon; and (saturated 5 - or 6-membered heterocyclyl) carbylamine containing ring nitrogen atom, in which the said nitrogen atom may not be substituted or replaced alkoxycarbonyl group having 2 to 5 carbon atoms, and in which carbonylation attached to an atom other than the nitrogen atom of the ring;

the deputies are an alkyl group containing 1 to 3 carbon atoms; alcoolica group containing 2 to 3 carbon atoms; alkoxycarbonyl group containing 2 to 5 carbon atoms; phenylcarbonylamino group containing 7 to 11 carbon atoms; aracelikarsaalyna group containing 8 to 10 carbon atoms; alkoxycarbonylmethyl group containing 1 to 4 carbon atoms in its CNS side and 2 to 3 carbon atoms in alkanoyloxy part; and alkoxycarbonylmethyl group containing 1 to 4 carbon atoms in the CNS;

m = 0 or 1; and n = 0 or 1;

provided that when X is a group of the aforementioned formula (II), R2is a hydrogen atom, and m and n are both cannot be zero;

and provided that when X is a group of the above formula III, R2is an alkyl group containing 1 to 3 carbon atoms, and m and n are both equal to 1.

Predpochtitel is s, nitro, hydroxyl group, alkoxygroup containing 1 to 4 carbon atoms, aralkylated containing 7 to 11 carbon atoms, an amino group, alkanolamines containing 1 to 4 carbon atoms, and halogenosilanes containing 2 to 4 carbon atoms, and compounds in which X is a group having the formula III, in which the Deputy Z-NH-attached paraprotein phenyl ring.

Another group of preferred compounds are compounds where

X is a group having the formula II; and

Y is a phenyl group which is substituted in paraprotein: 1) alkylsulfonamides containing 1 to 3 carbon atoms, (2) alkoxycarbonylmethyl containing 2 to 5 carbon atoms, (3) halogenocarboxylic containing 3 to 5 carbon atoms, 4) aminoalkylindole containing 2 to 7 carbon atoms in which the amino group aminoalkanoic part may not be replaced or substituted by one or two substituents selected from alkoxycarbonyl group having 2 to 5 carbon atoms and alkanoyloxy group having 2 or 3 carbon atoms, or Y - (saturated 5 - or 6-membered heterocyclyl) carbylamine containing ring nitrogen atom (where HC carbon and in which carbonylation attached to an atom other than the above-mentioned nitrogen atom ring);

as well as connection 1, in which

X is a group having the formula II;

R1is methyl, ethyl, ISO-propyl or sec-bucilina group;

R3is a hydrogen atom or a methyl or ethyl group;

Y is phenyl, perederina, furilla, thienyl, oxazolidinyl or thiazolidine group which may have substituents, or have 1 or 2 substituent selected from substituents (A1defined below.

Vice-A1include 1 fluorine atom, 2 chlorine atom, 3 bromine atom, 4 the nitrogroup, 5 hydroxyl group, 6 alkoxygroup containing 1 to 3 carbon atoms, 7 aralkylated containing 7 to 10 carbon atoms, 8 amino group, 9 alkanolamines containing 1 or 2 carbon atoms, fluorine-, chlorine - or 10 posledney alkanolamines containing 2 or 3 carbon atoms, 11 alkylsulfonamides containing 1 to 3 carbon atoms, 12 alkoxycarbonylmethyl containing 2 or 3 carbon atoms, 13 aminoalkylindole, containing 2 to 5 carbon atoms ( in which the amino group aminoalkanoic part may be unsubstituted or substituted group, the cat is; what do Y - (6-membered saturated heterocyclyl) carbylamine containing one ring nitrogen atom ( in which the nitrogen atom may not be substituted or may be substituted by alkoxycarbonyl having 2 to 5 carbon atoms, and carbonylation replaces an atom other than the nitrogen atom of the ring).

Of the latter the preferred connection, where

R1is a methyl or ethyl group;

R3is a methyl or ethyl group;

Y - furilla, thienyl, thiazolidine, perederina or phenyl group which may be unsubstituted or substituted by 1 or 2 substituents selected from substituents AND2, which are defined below;

Vice-A2include fluorine atom, chlorine atom, bromine atom, hydroxyl group, methoxy group, ethoxypropan, benzyloxy, amino group, acetylamino, monochloroethylene, monobromoacetate, triptoreline, alkylsulfonamides containing 1 or 2 carbon atoms, aminoalkylindole containing 2 or 3 carbon atoms ( in which the amino group mentioned aminoalkanoic part may not be replaced or substituted by a group which is selected from alkanoyloxy group, the soda is nlaminer (in which the nitrogen heteroatom may not be substituted or replaced alkoxycarbonyl group, having 2 or 3 carbon atoms, and carbonylation attached to any other atom, in addition to the nitrogen atom), as well as connections, where

Y is a phenyl group which may contain substituents or contain in paraprotein Deputy selected from fluorine atom, chlorine atom, bromine atom, hydroxyl group, metoxygroup, ethoxypropan, benzyloxy, amino, acetylamino, monochloroethylene, monobromoacetate, triptoreline, alkylsulfonamides containing 1 or 2 carbon atoms, acetylaminofluorene, and alkoxycarbonylmethyl containing 1 or 2 carbon atoms in its alkyl portion, and 2 or 3 carbon atoms in its alkanolamine part.

Preferred are also compounds, where

R1- ethyl group;

R3is a methyl group;

Y is a phenyl group or a phenyl group substituted in paraprotein methylsulfonylamino or methoxycarbonylaminophenyl; and

m = 0 and n=1.

Another group of preferred compounds of formula 1 are compounds where

X is a group having the formula III;

Z - alcoolica group containing 2 or jada 2 or 3 carbon atoms; aminoadenosine group containing 2 to 6 carbon atoms (in which the amino group may be unsubstituted or substituted by 1 or 2 substituents, which may be the same or different, selected from substituents B1, which are defined below, and alcoolica group may not be substituted or substituted phenyl group or alkylthiol containing 1 or 2 carbon atoms); (5 - or 6-membered heterocyclyl) carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl group having 2 to 5 carbon atoms and a carbonyl group attached to an atom other than the nitrogen atom); (5-chinua - lactam) carbonyl group in which a carbonyl group attached to an atom in position 5, -alkoxyimino- -geterotsiklicheskikh in which heartilly component represents a 5-membered aromatic heterocyclic group that caution be not substituted or substituted alkoxycarbonyl group having 2 to 5 carbon atoms, or haloalkaline having 2 or 3 carbon atoms, and in which part alkoxyimino contains 1 or 2 carbon atoms; and

Deputy B1include alkyl is onilne group, containing 2 to 5 carbon atoms, phenylcarbonylamino group containing 7 to 11 carbon atoms, and alkoxycarbonylmethyl group, in which alkoxycarbonyl component contains 2 to 5 carbon atoms, and alcoolica part contains 2 or 3 carbon atoms.

and of these more preferred compounds, where

R1is a methyl or ethyl group;

Z - alcoolica group containing 2 or 3 carbon atoms; alkylsulfonyl group containing 1 to 3 carbon atoms; aminoadenosine group containing 2 to 5 carbon atoms ( in which the amino group may be substituted by 1 or 2 substituents selected from substituents B2, which are defined below, and alcoolica group may have substituents or be replaced by methylthioribose), and (5 - or 6-membered heterocyclyl) carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl group having 2 to 5 carbon atoms);

Deputy B2include alkyl group containing 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, alkoxycarbonyl group containing 2 to 5 carbon atoms, and phenylcarbonylamino grunge ring group mentioned formula III, and Z - alkylsulfonyl group containing 2 or 3 carbon atoms; aminoadenosine group containing 2 to 4 carbon atoms ( in which the amino group optionally may be substituted by 1 or 2 substituents selected among the deputies of the B2, which are defined below), and (5-membered heterocyclyl) carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl group containing 2 to 5 carbon atoms); and

Deputy B2include alkyl group containing 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, alkoxycarbonyl group containing 2 to 5 carbon atoms, and phenylcarbonylamino group containing 7 to 11 carbon atoms.

The most preferable of the above, characterized in that

R1- ethyl group;

R2is a methyl group;

p is 0;

Deputy Z-NH - is paraprotein phenyl ring;

Z - aminoadenosine group containing 2 or 3 carbon atoms (in which the amino group may contain substituents or contain the Deputy selected from substituents B3, which are defined below); or (us who may not be substituted or replaced alkoxycarbonyl group, having 2 or 3 carbon atoms);

and the deputies of the B3include: alkyl group containing 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, and alkoxycarbonyl group containing 2 or 3 carbon atoms.

In the group of most preferred compounds of the present invention includes:

1) 13-( -methoxymethylethoxy)milbemycin A4(isomer A);

2) 13-( -methoxymethylethoxy)milbemycin A4(isomer B);

3) of 13-[2-methoxyimino-2-(4-acetylaminofluorene)-ethoxy]- milbemycin A4;

4) 13-[ -methoxyimino-(4-methanesulfonylaminoethyl)acetoxy]- milbemycin A4;

5) 13-[ -methoxyimino-(4-acetylaminofluorene)-acetoxy]- milbemycin A4;

6) 13-[ -methoxyimino-(4-methoxycarbonylaminophenyl)- acetoxy]milbemycin A3;

7) 13-[ / -methoxyimino-(4-methoxycarbonylaminophenyl)- acetoxy]milbemycin A4;

8) 13-[2-(4-methoxycarbonylaminophenyl)-2-methylpropionate] milbemycin A3;

9) 13-[2-(4-methoxycarbonylaminophenyl)-2-methylpropionate] milbemycin A4;

10) 13-[2-(4-benzylaminocarbonyl)-2-methylpropionate] milbemycin A4;

[4-{2-(methoxycarbonylamino}propionamido)-phenyl]-2 - methylpropionate]milbemycin A4;

13) 13-[2-[4-{2-(methoxycarbonylamino)-2-methylpropionamide}- phenyl]-2-methylpropionate]milbemycin A4and

14) 13-[2-[4-[(1-ethoxycarbonylpyrimidine-2-carbylamine]- phenyl]-2-methylpropionate]milbemycin A4.

Another aspect of this invention is the acaricidal and insecticidal composition comprising an active substance - derived milbemycin and target additives, characterized in that, as specified derived milbemycin it contains [13-substituted derivative of the formula I

,

where

R1is methyl, ethyl, ISO-propyl or sec-bucilina group;

R2is a hydrogen atom or an alkyl group containing 1-3 carbon atoms;

X - (a) a group of formula II

,

where

R3is a hydrogen atom or an alkyl group containing 1-4 carbon atoms; and

Y is a phenyl group or 5 - to 6-membered heterocyclyl group with 1 or two heteroatoms in the ring selected from nitrogen, oxygen or sulfur, and these phenyl and heterocyclyl groups are unsubstituted or substituted by 1 or 2 substituents (which may be the same or different) selected from the following substituents A; or

X - (b) group formonline group, containing 1 to 3 carbon atoms; alkoxycarbonyl group containing 2 to 5 carbon atoms; aminoadenosine group containing 2 to 7 carbon atoms (amino part of these aminoalcohols group is substituted by 1 or 2 substituents, which may be the same or different and which are selected from the following substituents B, and alcoolica part of these aminoalcohols group is unsubstituted or substituted phenyl group or alkylthiol containing 1 to 3 carbon atoms); a saturated 5 - or 6-membered geterotsiklicheskikh group containing a ring nitrogen atom, with the said nitrogen atom of the ring can be substituted or replaced by alkoxycarbonyl having 2 to 5 carbon atoms, and in which the carbonyl group attached to an atom other than the nitrogen atom of the ring; a 5 - or 6-membered lactalbumine group in which a carbonyl group attached to an atom other than a nitrogen atom of the lactam; -alkoxyimino- -geterotsiklicheskikh, in which CNS part contains 1 to 3 carbon atoms, and heterocyclyl part is a 5 - or 6-membered aromatic heterocyclic group containing one or two annular heteroatoms, selected and the carbon:

among the substituents A are: a halogen atom; a nitro-group; hydroxyl group; alkoxygroup containing 1 to 4 carbon atoms; arancelaria containing 7 to 11 carbon atoms; the amino group; alkanolamines containing 1 to 4 carbon atoms; alkylsulfonyl group containing 1 to 3 carbon atoms; aminoalkylindole containing 2 to 7 carbon atoms in which the amino group in aminoalkanoic fragment may not contain substituents or contain one or two substituent (which may be the same or different) selected from alkoxycarbonyl groups, having 2 to 5 carbon atoms and alkanoyl groups having 2 or 3 carbon atoms; and saturated 5 - or 6-membered heterocyclyl)carbylamine containing ring nitrogen atom, in which the said nitrogen atom may not be substituted or may be substituted alkoxycarbonyl group having 2 to 5 carbon atoms, and in which carbonylation attached to an atom other than the nitrogen atom of the ring.

The substituents B are: an alkyl group containing 1 to 3 carbon atoms; alcoolica group containing 2 to 3 carbon atoms; alkoxycarbonyl group containing 2 to 5 carbon atoms; phenylcarbonylamino xtermination group, containing 1 to 4 carbon atoms in its CNS side and from 2 to 3 carbon atoms in alkanoyloxy part; and alkoxycarbonylmethyl group containing 1 to 4 carbon atoms in the CNS;

m = 0 or 1; and n = 0 or 1;

provided that when X is a group of the above formula II, R2is a hydrogen atom, and m and n are both not equal to zero;

and provided that when X is a group of the above formula III, R2is an alkyl group containing 1 to 3 carbon atoms, and m and n are both equal to 1.

Preferred is a composition, where the connection I

X is a group having the above formula II; and the substituents A are selected from a halogen atom, nitro group, hydroxyl group, alkoxygroup containing 1 to 4 carbon atoms, aralkylated containing 7 to 11 carbon atoms, an amino group, alkanolamines containing 1 to 4 carbon atoms, and

composition, where the connection I

X is a group having the formula III, in which the Deputy Z-NH - attached paraprotein phenyl ring.

Even more preferred composition, characterized in that

X is a group having the formula II;

and Y is a phenyl group which is substituted in paraprotein: aggered (in which the amino group aminoalkanoic part may not be replaced or substituted alkoxycarbonyl group, having 2 to 5 carbon atoms), or Y is a 5 - or 6-membered saturated heterocyclyl)carbylamine containing one ring nitrogen atom (in which the nitrogen atom may not be a substituent or may be present Deputy, choose from alkoxycarbonyl having 2 to 5 carbon atoms, and carbonylation attached to an atom other than the nitrogen atom of the ring).

The most preferred compositions containing as an active ingredient the above-mentioned compounds 1-14.

The next aspect of the present invention is a method of protecting plants from damage by parasites selected from the group consisting of mites and insects by treating the plants or the locus an effective amount of an active compound, characterized in that active compound is used as a compound of General formula I.

In a preferred variant of its embodiment the active compound is a compound selected from the above compounds 1-14.

Compounds of the invention can contain in their molecules several asymmetric carbon atoms and thus can form optical isomers. Although they are all represented here by a single toolsour methods stereospecific synthesis or used as starting compounds are optically active substances, then you can directly obtain the individual isomers; on the other hand, if you get a mixture of isomers, the individual isomers can be obtained by conventional methods of separation. In particular, the compounds of the invention may exist in or configuration, in regard to the stereochemistry at position 13 of the skeleton milbemycin. Although all such isomers and mixtures thereof are part of the invention, the preferred configuration is the configuration.

Milbemycin derivatives containing oximino Deputy in position 13, in accordance with the invention can exist in the form of SYN - and anisomerous relative to the nitrogen atom of the oxime group transformation of. When these isomers of the oxime share column chromatography, milbemycin derived with less polarity indicate in experiments as isomer A, and more polar derivative is designated as isomer B.

Specific examples of the compounds of the invention are given below in table. 1, 2 and 3.

Connection table. 1 are all compounds having formula I in accordance with the above definition, in which X is a group having the formula II.

Connection table. 2 all are compounds of the formula I, in which sooty with 2-1 on 2-96 inclusive Y - group 4-(A-NH)-phenyl-, in which A has the values specified for these compounds in the table. 2;

(b) in connection with 2-97 on 2-106 inclusive, Y is A group-NH-thiazole-4-yl-, in which A has the values specified for these compounds in the table. 2; and

(c) in connection with 2-107 on 2-114 inclusive, Y is A group-NH-phenyl-, in which A has the values set for these compounds in the table. 2, and the prefix number in front of each group A indicates the position of the substituent A-NH - phenyl ring.

Connection table. 3 are all compounds of formula I, in accordance with the definition above, in which X is a group having formula III, and preferably a group having the formula 4-(Z-NH)-C6H4-(O)p- in which Z and p have the foregoing significance.

In the following tables are used abbreviations have the following meanings: Ac is acetyl, AcNH - acetylamino, BAc - bromacetyl, BAcNH - bromoacetamide, Bn is benzyl, Bu is butyl, BuO - butoxy, airport BZO - benzyloxy, CAc - chloroacetyl, CAcNH - chloracetamide, Et is ethyl, EtO - ethoxy, Fo - formyl, Fu - furyl, Hex - hexyl, Lac - lactam, Me is methyl, MeO is methoxy, Oxa - oxazolyl, Pen - pencil, Ph is phenyl, PhenO - penetrate, Pip - piperidyl, Pr is propyl, PrO - propoxy, Pro - propionyl, ProNH - propionyl - the zo, S - secondary (Deut. ), t - tertiary (tert.).

The preferred compounds among the compounds represented in table. 1, are compounds NN 1-11, 1-12, 1-38, 1-72, 1-73, 1-74, 1-75, 1-77, 1-78, 1-79, 1-80, 1-81, 1-89, 1-90, 1-91, 1-92, 1-93, 1-98, 1-100, 1-102, 1-107, 1-111, 1-114, 1-147 and 1-186. More preferred compounds are compounds NN 1-38, 1-72, 1-73, 1-77, 1-78, 1-79, 1-80, 1-89, 1-92, 1-93 and 1-98. Especially preferred compounds are compounds NN 1-72 1-73 and.

The preferred compounds among the compounds represented in table. 2, are compounds NN 2-7, 2-16, 2-22, 2-39, 2-43, 2-45, 2-60, 2-61, 2-62 and 2-65. More preferred compounds are compounds NN 2-7, 2-22, 2-39, 2-43, and 2-45.

The preferred compounds among the compounds represented in table. 3, are compounds NN 3-1, 3-11, 3-19, 3-26, 3-27, 3-33, 3-34, 3-36, 3-37, 3-38, 3-39, 3-40, 3-43, 3-46, 3-47, 3-48, 3-49, 3-56, 3-58, 3-61, 3-64, 3-65, 3-68, 3-69, 3-70, 3-71, 3-72, 3-76, 3-77 and 3-78. More preferred compounds are compounds NN 3-11, 3-26, 3-27, 3-36, 3-37, 3-38, 3-39, 3-47, 3-48, 3-56, 3-68, 3-69 and 3-71. Especially preferred compounds are compounds NN 3-26, 3-27, 3-36, 3-37, 3-47, 3-56 and 3-69.

In accordance with the invention the compounds of formula I can be obtained by a process comprising the following stages:

(a) the interaction of the compounds of formula IV is the group of formula V

B-(CR22)m-(C=O)n-OH ,

(where

R2, m and n have the same meanings as in formula I, and B is a group of formula (II) according to the definition above (or a group of the formula VI

,

where

p has the same meaning as in formula I, to obtain the compounds of formula VII

,

(b) recovering the said compounds of formula VII to obtain the compounds of formula VIII

,

and optional stages, or,

(c1when the group B in the compound of formula VIII represents a group of the above formula II (where Y is nitrosamine aryl group containing 6 to 10 carbon atoms, or nitrosamino heterocyclic group) or a group of formula VI, the recovery of the said compounds of formula VIII to the compound of formula IX

,

where

R1, R2m and n have the same meanings as in formula I and D is a group of formula II (in accordance with the above definition, in which the Y-aminosilane aryl group containing 6 to 10 carbon atoms, or aminosilane heterocyclic group), or a group of the formula X

,

in which

p has the values set for the formula I, or,

(c2when the group B in the compound of formula VIII represents the Kai group, moreover, the aforementioned aryl or heterocyclic group contains at least one alkanolamines containing 1-4 carbon atoms, halogenoaluminates containing 2-4 carbon atoms, alkoxycarbonylmethyl containing 2-6 carbon atoms, or halogensilberemulsionen containing 3-5 carbon atoms), diallylamine mentioned the compounds of formula VIII to the compound mentioned formula IX in which Y - aminosilane aryl group containing 6-10 carbon atoms, or aminosilane heterocyclic group, and also optional

(d) interaction of the mentioned compounds of formula IX with the compound of the formula XI

E - OH,

[where

E - alcoolica group containing 1 to 4 carbon atoms, halogenalkyls group containing 2 to 4 carbon atoms, alkylsulfonyl group containing 1 to 3 carbon atoms, alkoxycarbonyl group containing 2 to 5 carbon atoms, halogenocarboxylic group containing 3 to 5 carbon atoms, aminoalkyl group containing 2 to 7 carbon atoms (in which the amino group optionally may be substituted by 1 or 2 substituents, which may be identical or different, chosen among replaces the em to be, optionally substituted phenyl group or alkylthiol containing 1 to 3 carbon atoms), (saturated 5 - or 6-membered heterocyclyl)carbonyl group containing a ring nitrogen atom (in which the above-mentioned nitrogen atom, optionally, may be present Deputy, choose among the substituents C, which are defined above, and in which the carbonyl group is attached to any atom, but not to the nitrogen atom), or a group of formula Z, in accordance with its determination to formula I]

or its reactive derivative with the formation of compounds of formula XII

,

(where

R1, R2, m and n have the values set in the definition of formula I; and G is the group of formula III, as defined above; or G is a group of formula II, as defined above, in which Y - aryl group containing 6 to 10 carbon atoms, or heterocyclic group in which the aforementioned aryl group or the heterocyclic group has at least one Deputy formula XIII

E1- NH-,

where E1- the same groups as those mentioned above in the definition of group E with the choice of Z).

More compounds of formula I of the invention in which X is IU reactions A, shown in Fig. 1, 2.

In shown in Fig. 1, 2 formulas, R1, R2, R3, m and n have the foregoing significance; Y1- any of the groups Y, the value of which is set out above, except that any aminosilane aryl or aminosilane heterocyclic component replaces the corresponding nitrosamines aryl or nitrosamines heterocyclic component; Y2- aminosilane aryl or aminosilane heterocyclic group in accordance with their definition for group Y, which is given above; and Y3- aryl or heterocyclic group, which are defined above for the group Y, with the aforementioned aryl or heterocyclic group substituted by a group E1NH (XIII), the definition of which is given above.

15-Gidroksilevamizola derivative of the formula IV which are used as starting compound at the stage of A1in reaction scheme A, can be obtained in accordance with methods described in the published European patent 147852.

Another source substance on the stage of A1in reaction scheme A is a substance represented by formula Va

Y1-(C=N-OR3)-(CH2)m-(C=O)equal to 1, -alkoxybenzoiloxy acid can be obtained by using as the starting material commercially available ethylvinylacetate in accordance with the methods described in U.S. patent N 4024133.

-Alkoxyimino-2-prilocaine acid can be obtained using as starting compounds are commercially available 2-fullcarbon acids in accordance with the method described in published UK patent 1557423.

-Alkoxyimino-2-tirelessly acid can be obtained by using as the starting material commercially available 2-tanygrisiau acid according to the method described in U.S. patent N 4024133. -Alkoxyimino-(2-amino-4-thiazolyl)acetic acid and its derivatives can be obtained using as the starting material commercially available 2-amino-4-triethylchlorosilane acid according to the method described in U.S. patent 4024133.

-Alkoxyimino (substituted phenyl)acetic acid can be obtained by using as starting material 2-(substituted phenyl)-1,2-ethanediol (which is described in J. Med. Chem. 24, 1360 (1981)) using the method described in chem. Lett 1350 (1985), for simple tert-butyldimethylsilyl-2-about the people, and get 2 alkoxyimino-2-(substituted phenyl) ethanol, which is then oxidized in the usual way and get alkoxyimino-(substituted phenyl)acetic acid. For example, 2-alkoxyimino-2-(4-nitrophenyl )acetic acid can be obtained according to the method described in J. med. chem. 24, 1360 (1981). The method consists in transforming the original substance - 2-(4-nitrophenyl)-1,2-ethanediol - tert-butyldimethylsilyl-2-oxo-2-(4-nitrophenacyl)new ether (this reaction is described in Chem. Lett. 1358 (1985), the interaction of the above-mentioned ether 0-alkoxysilanes with the formation of 2-alkoxyimino-2-(4-nitrophenyl)ethanol and then oxidizing the obtained substances in the usual way.

2 Alkoxyimino-2-(4-nitrophenyl)acetic acid can also be obtained in an alternative way, in which ethyl-4-nitrophenylglyoxylate (described in Synthesis, 850 (1990) injected into the interaction with O-alkoxysilanes with subsequent hydrolysis of the thus obtained ether complex.

2 Hydroxyimino-2-(4-nitrophenyl)acetic acid can be obtained by the above method using hydroxylamine instead of O-alkoxysilane.

When m is 1 and n is 0, derivatives of 2-alkoxyimino-2- (substituted or unsubstituted phenyl)this is a 2-alkoxyimino-2-(2-amino-4-thiazolyl)ethanol can be obtained as described above, when such compounds are intermediate compounds in the synthesis of derivatives-alkoxyimino acid.

When m is 1 and n is equal to 1, derivatives of 3-alkoxyimino-3-(substituted or unsubstituted phenyl)propionic acid can be obtained using the above-described methods for the synthesis alkoxybenzoiloxy acid, using as the starting material commercially available ethylbenzylamine or ethyl(substituted benzoyl)acetate, which receive the usual way.

3 Alkoxyimino-3-(4-nitrophenyl)propionic acid can be obtained by using as the starting material ethyl(4-nitrobenzoyl)acetate obtained in a known manner, by the method similar to that described above for the synthesis of 2-alkoxyimino-2-(4-nitrophenyl)acetic acid. 3 Hydroxyimino-3- (4-nitrophenyl)propionic acid can be obtained from the corresponding propionic acid derivative in a manner similar to that described above.

Derivatives of 3-alkoxyimino-3-(3-furyl)propionic acid derivatives of 3-alkoxyimino-3-(2-thienyl)propionic acid and derivatives 3-alkoxyimino-3-(2-amino-4-thiazolyl)propionic acid can be obtained according to the method oade A1in the reaction scheme A includes obtaining compounds of General formula VIIa by reacting compounds of General formula IV with a carboxylic acid or alcohol of General formula Va in the presence of a strong acid, such as sulfuric acid, hydrochloric acid, metasulfuron, triftormetilfullerenov, benzolsulfonat, 4-chlorobenzenesulfonate or triperoxonane acid, preferably in the presence of triftormetilfullerenov acid.

The number triftormetilfullerenov or another used a strong acid can vary considerably depending on the reactivity of carboxylic acid or alcohol (Va), which is used, but is not more than 1 equivalent, and usually it is a catalytic amount.

The reaction can sometimes be accelerated by adding to the reaction system inorganic compounds. Examples of such inorganic compounds include metal salts, such as triftorbyenzola copper, copper iodide, zinc iodide, cobalt iodide or iodide Nickel, celite, silica gel, aluminum oxide or the like; preferred are salts of copper, such as triftorbyenzola copper or copper iodide, and the most preferred is copper iodide.

on the solvent has no adverse effect on the reaction and can dissolve the original substance at least to a certain extent. Carboxylic acid or alcohol of General formula Va, they can serve as solvents. Examples of preferred solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform; esters, such as ethyl acetate or propyl; ethers, such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; sulfoxidov, such as dimethyl sulfoxide; and NITRILES, such as acetonitrile.

The reaction can be carried out in a wide range of temperatures and the precise temperature is not critical to the present invention, but usually the reaction is carried out at a temperature of from -10 to 100oC, preferably at 0 to 50oC.

The time required for the reaction varies depending on many factors - from the reaction temperature and the nature of the reagents and solvent, but usually under suitable reaction conditions, the reaction time from 5 min to 6 h, in particular from 10 min to 2 h

Stage A2the scheme of reactions A includes obtaining compounds of General form is PPI in position 5 to a hydroxyl group.

There is no specific limitation concerning the reductant provided that he is able to restore the carbonyl group in position 5, and provided that does not affect other functional groups in the compounds of formula VIIa, when the carbonyl group is restored. Examples of such reducing agents include reducing agents capable of generating a hydride anion, such as borohydride sodium or DIBORANE, and preferred is borohydride sodium.

There is no specific limitation concerning the nature of the solvent used in the reaction, provided that the solvent does not have adverse effects on the reaction. When the reductant use borohydride sodium, examples of particularly preferred solvents include lower alcohols, such as methanol, ethanol or propanol.

Although the reaction can be carried out in a wide temperature range and the temperature is not critical to the present invention, the reaction is usually carried out at 0 - 50oC. the Time required for the reaction may also vary widely and is not critical to the invention. However, under suitable reaction conditions are usually sufficient period of time the organisations General formula Ib, in which Y2represents aminosilane aryl or heterocyclic portion, which are defined above for Y. This can be achieved in two different ways. The first of these methods involves the restoration of the nitro group of compounds of General formula Ia where Y1represents nitrosamino aryl or heterocyclic group.

The restoration of the nitro group of compounds of formula Ia can be performed by any conventional method, provided that the above recovery method is not valid for any other functional group of compounds of formula Ia. One example of such methods is a catalytic reduction using a catalyst made of noble metal. Examples of preferred catalysts for use in the reaction are palladium-on-charcoal, palladium-on-barium sulphate and oxide of platinum.

The reaction is normally and preferably performed in the presence of a solvent. There is no specific limitation regarding the nature of the solvent, provided that it has no adverse effect on the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable for skin and dioxane; and esters such as ethyl acetate.

The reaction can occur in a wide range of temperatures and the precise temperature is not critical to the present invention. The reaction is usually carried out at 10 - 80oC. the Time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. As a rule, under suitable conditions, the period from 10 min to 5 h

Another method proposed nitrogroup reduction is the interaction of compound Ia with powdered zinc in the presence of acetic acid. The reaction may proceed in a wide range of temperatures and the precise temperature is not critical to the present invention. But usually the reaction is carried out at a temperature of from 0oC to room temperature. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. Under suitable conditions, is usually sufficient period of from 30 minutes to 12 o'clock

Another alternative method is auroy Y1represents an aryl or heterocyclic group, substituted by at least one alkanolamine Deputy containing 1 to 4 carbon atoms, alkoxycarbonylmethyl Deputy containing 2 to 5 carbon atoms, or halogenocarboxylic Deputy containing 3 to 5 carbon atoms.

Suitable alkanolamines are formylamino and acetylamino. Suitable halogenoaluminates are monochloroethylene and monobromoacetate. Suitable alkoxycarbonylmethyl include tert-butoxycarbonylamino, and to appropriate halogenguidesrealestate is trichlorocarbanilide.

Diallylamine alkanolamine, halogenosilanes, alkoxycarbonyl or halogenocarboxylic the compounds of formula Ia can be carried out in any conventional manner, provided that the above diallylamine no effect on other functions of the group of the compounds of General formula Ia.

Diallylamine tert-butoxycarbonylamino can be carried out, for example by reaction of compounds of formula Ia with hydrochloric acid in dioxane. The reactions to the present invention. However, the reaction is conveniently carried out at room temperature. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvents. As a rule, under suitable conditions, a sufficient reaction time is between 1 - 3 hours

Diallylamine formylamino can be carried out, for example, by reacting the compounds of formula Ia with hydrochloric acid in methanol. The reaction can be carried out in a wide range of temperatures and the precise temperature is not critical to the present invention. However, the reaction is conveniently carried out at a temperature of approximately 10oC. the Time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent. As a rule, under suitable reaction conditions sufficient period of time the reaction is between about 1 o'clock

Diallylamine trichlorocarbanilide can be carried out, for example, by reacting the compounds of formula Ia with a powder of cadmium in the presence of dimethylformamide. the rum for the present invention. However, the reaction can be suitably carried out at room temperature. The time required for the reaction may also vary widely and is not critical to the present invention, and depends on many factors, notably the reaction temperature and the nature of the reagents and solvent. However, under suitable reaction conditions is usually sufficient period of 1 - 3 hours

Another example of a suitable method diallylamine trichlorocarbanilide is the treatment of compounds of formula Ia zinc and acetic acid. The reaction may proceed in a wide range of temperatures and the precise temperature is not critical to the present invention. However, the reaction can be conveniently carried out at room temperature. The time required for the reaction may vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent, and is not critical to the present invention. However, under suitable conditions, a sufficient reaction time is between 30 min to 1 h

Diallylamine monochloroethylene or monobromoacetate can be in order to place in a wide temperature range, and the precise reaction temperature is not critical to the present invention. However, the reaction can be suitably carried out at a temperature from room temperature up to 50oC. the Time required for the reaction may vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent. Usually, when conditions are sufficient is the reaction time is 1 - 3 hours

Optional step A4reaction scheme A includes obtaining compounds of General formula Ic by reacting amino compounds of General formula Ib with an acid of the formula E1-OH (where E1has an established higher values) or its reactive derivative.

Suitable reactive derivatives of the acid of formula E1-OH are compounds that are usually used in the condensation reactions, such as, for example, galoyanized (usually, the acid chloride or bromohydrin), acid anhydride, mixed anhydride, activated ester or an activated amide.

When using acid represented by the formula E1-OH, the reaction is carried out in the presence of a dehydrating agent, that is, and sulfuric acid, and preferred is 2-chloro-1-methylpyridinium. The amount of reagent used is not critical to the invention the size, but usually it is used from 1 to 5 equivalents, preferably 1 to 2 equivalents, per mole of acid of formula E1-OH.

There is no specific limitation concerning the nature used in the reaction solvent, provided that the solvent does not have adverse effects on the reaction and can dissolve the original substance to some extent. Examples of preferred solvents are hydrocarbons, such as hexane, petroleum ether, benzene or toluene; halogenated hydrocarbons such as chloroform, dichloromethane or 1,2-dichloroethane; ethers, such as diethyl ether or tetrahydrofuran; amides such as N,N-dimethylformamide; sulfoxidov, such as dimethyl sulfoxide; NITRILES such as acetonitrile; and mixtures of one or more types of these solvents. Especially preferred are dichloromethane or 1,2-dichloroethane.

The reaction may proceed in a wide range of temperatures and the precise temperature is not critical to the present invention. The reaction can conveniently be the main way from the reaction temperature and the nature of the used starting compounds, reagents and solvents and is not critical for the invention. Under suitable reaction conditions sufficient reaction time is usually from 30 minutes to a full day, usually from 30 minutes to 6 o'clock

When used haloganated acid represented by the formula E1-OH, the reaction is carried out preferably in the presence of a base. Used the base is not critical to the present invention. Examples of preferred bases are organic bases, such as, for example, triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5,4.0]undec-7-ene (DBU).

The exact number of galodamadruga and base used in the reaction are not critical values for the invention. However, the reaction can be carried out appropriately when using 1 to 10 equivalents of galodamadruga acid of the formula E1-OH and 2 - 8 equivalents of base relative to the compound of General formula Ib.

The solvent, the reaction temperature and the time required for the reaction with halogenerator acid of the formula EoC during the period of time from 5 min to 2 h

After completion of each stage of the reaction, the desired compounds of formula VIa, Ia, Ib and Ic can be isolated from the reaction mixture by conventional means and, if necessary, purified by conventional means such as column chromatography.

Milbemycin and similar natural products that can be used as starting substances in the synthesis of compounds of formula IV, are usually obtained in the form of individual compounds or as mixtures at various ratios related compounds, and they can be introduced into the reaction after separation of the different fractions, or they can be used in the above reactions in the form of mixtures. Therefore, the connection used at each stage in the above-mentioned reactions can be either a single compound or mixture of compounds. Accordingly, the compounds of formula Ia, Ib or Ic can be obtained in the form of single compounds or mixtures of compounds and can be used as such or can be separated into individual compounds before use.

Compounds of the invention of formula I in which X is a group of formula III, Oprah is 4).

In formulas in the reaction scheme B, R1, R2, p and z have the foregoing significance.

Derivatives of 15-hydroxymelatonin formula IV which are used as starting substances at the stage of B1are known compounds disclosed in published European patent 147582.

The connection that is used as the other starting substances at the stage of B1, is represented by the formula Vb

[NO2C6H4- (O)p- C (R2)2- COOH],

(where

R2and p have established higher values), and can be obtained by using as starting substances commercially available reagents well known methods.

When p is equal to 1, the desired compound Vb can be obtained by hydrolysis of the ester(nitrophenoxy)- -alkylamino acid (for example, ether -(4-nitrophenoxy)- -alkylamino acid), which can be obtained through the following stages:

(a) alkylation in position commercially available ether alanovoy acid using galodamadruga in the presence of a base;

(b) halogenoalkane in the position thus obtained ether-alkylamino acid; and

(c) interaction obtained (for example, with 4-NITROPHENOL in the presence of a base.

When p is equal to 0, the desired compound Vb can be obtained by hydrolysis -(nitrophenyl)- , -dialkylamino (for example, -(4-nitrophenyl)- , -dialkylamino), which can be obtained by alkylation of commercially available nitrophenylacetate (for example, 4-nitrophenylacetate) alkylhalogenide in-position in the presence of a base.

Stage B1reaction scheme B includes obtaining compounds of General formula VIIb by treating compounds of General formula IV carboxylic acid of General formula Vb in the presence of a strong organic acid, such what was used at the stage of A1reaction scheme A, for example triftormetilfullerenov acid. The number of strong organic acids, the preferred conditions, such as the use of inorganic accelerator, a solvent, time and temperature of reaction are suitable are the same as those written for the stage of A1reaction scheme A.

Stage B2reaction scheme B includes obtaining compounds of General formula VIIIa in the interaction of compounds of General formula VIIb with a reducing agent to restore the carbonyl group in position 5 to a hydroxyl group.

Neraly VIIb are not affected by the reduction of carbonyl groups. Examples of such reducing agents are reducing agents capable of generating a hydride anion, such as borohydride sodium or DIBORANE, and the preferred borohydride sodium.

Solvent used, the interval of reaction temperature and reaction time are appropriate, when they are the same as for stage A2the above reaction scheme A.

Stage B3reaction scheme B includes obtaining compounds of General formula IXa, containing aminosalicylic, by restoring microsatelites phenyl or fenoxaprop compounds of General formula VIIIa, obtained in stage b2.

The restoration of the nitro group of compounds of General formula VIIIa can be carried out by usual methods described for an arbitrary stage of A3reaction scheme A. Examples of suitable reducing agents, solvents, reaction temperature and reaction time are described above for the optional stage of A3the scheme of reactions A.

Stage B4includes obtaining compounds of General formula Id, the definitions for which are given above, by reacting ring aminosalicylates compounds of General formula IXa, obtained in stage B3with LASS="ptx2">

Suitable reactive derivatives of the acid of formula Z-OH are derived, which are used in conventional reactions of condensation, such as, for example, galoyanized (usually, the acid chloride or bromohydrin), anhydride, mixed anhydride, activated ester or an activated amide.

When using acid represented by the formula Z is OH, the reaction is carried out preferably in the presence of a dehydrating agent such as, for example, dicyclohexylcarbodiimide (DCC), 2-chloro-1-methylpyridinium, p-toluensulfonate acid or sulfuric acid, and the preferred 2-chloro-1-methylpyridinium. The amount of reagent used is not critical for the invention, but typically use 1 to 5 equivalents, preferably 1 to 2 equivalents of the reagent per mole of acid of formula Z-OH.

There is no special limitation to the nature of the solvent, provided that it has no harmful effect on the reaction and can dissolve the ingredients, to some extent. Examples of preferred solvents are hydrocarbons, such as hexane, petroleum ether, benzene or toluene; halogenated hydrocarbons, such as chlorof as N,N-dimethylformamide; the sulfoxidov, such as dimethyl sulfoxide; NITRILES such as acetonitrile; and mixtures of one or more types of these solvents. Especially preferred are dichloromethane or 1,2-dichloroethane.

The reaction can occur in a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. Suitably the reaction is carried out at a temperature of from -70 to 90oC, preferably at 0 to 60oC. the Time required for the reaction depends mainly on the reaction temperature and the nature of the reagents, starting compounds and solvents and is not critical for the invention. Under suitable reaction conditions, the reaction period is from 15 minutes to a full day, usually from 30 minutes to 6 o'clock

When using galoyanized acid represented by the formula Z is OH, the reaction is carried out preferably in the presence of a base. Used the base is not critical for the invention. Examples of preferred bases include organic bases, such as, for example, triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo value for the invention. However, suitably the reaction can be carried out using 1 to 10 equivalents of galodamadruga acid of the formula Z-OH and 2 - 8 equivalents of base relative to the compound of General formula IXa.

The solvent, the reaction temperature and the time required for the reaction, which is used in the interaction of compounds of formula IXa with halogenide acids of the formula Z-OH, are essentially the same as in the reaction with the carboxylic acid. Typically, the reaction is carried out at a temperature of 0 - 50oC, and is usually sufficient reaction time from 5 min to 2 h

After completion of the reaction at each stage of the desired compounds of formula VIIb, VIIIa, IXa and Id can be extracted from the reaction mixture by conventional means and, if necessary, purified by conventional means such as column chromatography.

Milbemycin and similar natural products that can be used as starting substances for the synthesis of compounds of formula IV, are usually obtained in the form of individual compounds or as mixtures with various proportions related compounds and can be introduced into the reaction after divided into various factions, or they can be used in the above reaction is made either as a single connection, or a mixture of compounds. Accordingly, the compound of formula Id can be obtained in the form of individual compounds or mixtures of compounds, and, if preferred, a mixture of compounds, it can be used as such or it can be separated into individual compounds before use.

Compounds of the invention possess a strong acaricidal activity against adult insects and eggs of spider mites belonging to the families Tetranycnidae, Eriophyidae, etc. that are parasitic on fruit trees, vegetables and flowers. They are also active against ticks families Ixodidae, Dermanyssidae, Sarcoptidae, etc. that are parasitic on animals. In addition, they are effective against resistant ticks that may be difficult to fight known acaricides, and which cause a lot of trouble.

Compounds of the invention also possess strong insecticidal activity and, therefore, can be used as insecticides. Active compounds of the invention show a certain preventive effect against insect pests, but have no phytotoxicity, and therefore agricultural and garden plants nikosh insect pests, including pests that damage plants by sucking or eating them, pests that are parasitic on plants, pests, which damage the material during storage, insects that are considered pests for reasons of hygiene, etc.

Examples of harmful insects that are sensitive to the compounds of the invention are insects units Coleoptera, for example weevil bean (azuki bean weevil) (Callosobruchus chinensis), rice weevil (Sitophilus zeamais), garden chafer chestnut (Tribolium castaneum), dvadtsativosmiletny Ladybird (Epilachna vigitioctomaculata), wireworm barley (Agriotes fuscicollis), beetle soybean (Soybean beetle (Anomala rufocuprea), Colorado potato beetle (Leptinotarsa decemkineata), beetle blaska (Diabrotica spp.) (hereinafter spp. - types), barbel black (Monochamus alternatus), the rice weevil water (Lissorhoptrus oryzophilus) and kapusany (Lyctus bruneus); Lepidoptera, for example, the Gypsy moth (Lymantria disper), econopred (Malacosoma neustria); caterpillar cabbage ordinary (Pieris rapae), scoop ordinary (Spodoptera litura), cabbage "marching worms" (Mamestra brassicae), a scoop of rice (Chilo suppressalis), oriental corn borer (Pyrausta nubilalis) and Mediterranean Ognevka (Ephestia cautella), tea tortrix (Adoxophyea orana), Codling moth (Carpocapsa pomonella), a noctuid moth (Agrotis fucosa), mol large wax (Galleria mellonella), cabbage moth (Plutella Iowa (Nilaparvata lugens), mealybug powdery (Pseudococus comstocki), San Jose scale (Unaspis yanonensis), peach aphid (Myzus persicae), Apple aphid sheet (Aphis pomi), cotton aphid (Aphis gossypii), aphids lookupentry (Rhopalosiphum pseudobrassicas), lace pear (Stephanitis nashi), aphid vegetable ordinary (Nazara spp.), the bed bug (Cimex lectularius), the greenhouse whitefly (Trialeurodes vaporariorum), and listblock (Psylla spp.); Orthoptera, for example, the red cockroach (Blatella germanica), American cockroach (Reriplaneta americana), the African mole cricket (Gryllotalpa africana), and locust (Locusta migratoria, migratorioides). Isoptera, for example termite Yamato(Deucotermes speratus) and the termite Coptotermes formosamus; Diptera, such as the fly room (Mucus domestica), the larva of a fly germ (Hylemia platura), aegypti mosquito (Aedes aegypti), the ordinary mosquito (Culex pipiens), the mosquito Anopheles (Anopheles slnensis) and small ordinary mosquito (Culex tritaeniorhynehus).

In addition, in the field of veterinary compounds of the invention are effective against various gulmetov animals (as against endo-and against Astarita), such as insects and worms. Examples of harmful worms of animals are the gadfly gastric great (Gastrophilus spp.), gigalo autumn (Stomoxys spp. ), flashed (Trichodectes spp.), bug-jimnez (Rhodnius spp.) and the dog flea (Ctenocephalides canis).

The compounds are also effective against various nematodes, od which are parasites on livestock, poultry, pet animals, such as pigs, sheep, goats, cows, horses, dogs, cats or chickens and against which the compounds of the invention are effective are Haemonohus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Binostomum, the recommended dose rate, Chabertia, Trichuris, Storongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, Parascaris.

Some species are parasites of the genera Nematodirus, Cooperia and the recommended dose rate affecting the intestines, while some species of the genera At and Ostertagia parasites in the stomach, and parasites belonging to the genus Dictyocaulus found in the lungs. Parasites belonging to the families Filariidae and Setariidae found in internal tissues and organs, such as heart, blood vessels, subcutaneous tissues and lymph vessels. Compounds of the invention act on all of these parasites.

Compounds of the invention are also effective against other parasites, such as parasites of the genera Ancylostoma, Necator, Ascaris, Strongyloides, Trechinella, Capillaria, Trichuris and Enterobius.

The compounds are also effective against parasites of the genera Wuchereria, Brugia, Onchoceca and Loa family Fillaridae (which are found in the blood, tissues and organs other than the gastrointestinal tract, and which are important to medicine which particularly affect activestrategy channel.

When the compounds of the invention are used as anthelmintic for animals, they can be administered orally in the form of a liquid for drinking. Drink may contain a solution or suspension or dispersion of active compound in a suitable non-toxic solvent or in water, and mixed with suspenders agent such as bentonite, wetting agent or other excipients. Drinking, in General, may also contain protivovspenivayushchie tool. The active compound is usually present in water in an amount of 0.01-5 wt.%, preferably 0.01 to 0.1 wt.%.

Compositions can be administered orally in the form of dry solid preparations, preferably in the form of a standard dose, such as capsules, pills or tablets containing the desired amount of active compound. These compositions can be obtained by mixing the active compound until smooth with suitable powdered carriers, diluents, disintegrating agents and/or binders, for example starch, lactose, talc, magnesium stearate and vegetable resin. The weight and content of the preparations can vary within wide limits, depending on the type of animal that is being treated, the degree of contamination, nature of the parasite and animal body weight, which is the case of these compounds can be evenly distributed in the stern, used as a seasoning or in the form of granules. The content of active compounds in the feed to achieve anthelminthic action is preferably of 0.0001 to 0.02%.

Compounds of the invention, when it is dissolved or dispersed in a liquid carrier, can be administered parenterally to animals by injection pocelui, muscles, or trachea, or can be administered by subcutaneous injection. For parenteral administration the active compound is mixed preferably with a suitable vegetable oil, such as peanut oil or cottonseed oil. The content of active compound in the composition is usually from 0.05 to 50 wt.%.

Compounds of the invention can also be administered topically in a mixture with a suitable carrier, such as dimethylsulfoxide or a hydrocarbon solvent. These drugs are applied directly to the animal, externally, by spraying or bathing.

The dose of the active compound may vary depending on the type of animal that is being treated, and the nature and extent of infection by parasites. However, the best results with a dose achieved at the dose of 0.01 - 100 mg, preferably 0.5 to 50 mg per 1 kg body weight of the animal. The connection may be entered in

When the compositions of the invention are intended for use in agriculture and horticulture, there are various forms and compositions. For example, the composition can be in the form Farrukh Dustov, powders, soluble powders, micro granules, fine micro granules, wettable powders, dilute emulsions, concentrates, emulsions, aqueous or oily suspensions or aqueous or oil solutions (which can directly be used for spraying or which can be used for dilution), aerosols or capsules made of polymeric materials. Used media can be of natural origin or synthetic, organic or inorganic, and is generally used in order to promote active compound to reach the goal, which is to be processed, and to facilitate storage, transport or handling of the active connection. Solid, liquid and gaseous media can be selected from among well known in the art platforms for songs such.

Such compositions can be prepared by conventional means, for example by co-mixing and/or grinding the active ingredient (ingredient) with the carrier or rasb the>

Examples of suitable solvents are aromatic hydrocarbons, in particular faction C8-C12the refining of oil, such as a mixture of xylenes or substituted naphthalenes; esters of phthalic acid, such as dibutil or dioctylphthalate; aliphatic or alicyclic hydrocarbons such as cyclohexane or alkanes; alcohols, such as ethanol, ethylene glycol, onomatology ether of ethylene glycol or monotropy ether of ethylene glycol; glycols or their ethers; ketones, such as cyclohexanone; polar solvents such as N-methyl-2-pyrrolidone, dimethylsulfoxide or dimethylformamide; arbitrarily epoxydecane vegetable oils, such as epoxydecane peanut oil or soybean oil; and water.

Examples of media that can be used, for example, in doctah and dispersible powders, are natural mineral fillers such as calcite, talc, kaolin, montmorillonite or attapulgite. To improve the physical properties of the composition, it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Examples of suitable granular absorbent carriers are porous substances such to calitatea a variety of pre-granulated materials organic and inorganic, signs which are dolomite and crushed the remains of plants.

When using one or more surface-active substances, such substances may be cationogenic, anionic and nonionic compounds having good emulsifying, despeyroux and wetting properties, which per se are conventional in the formulations of agrochemicals, etc., May be a single such surface-active substance, as well as mixtures of such surfactants.

To nonionic surface-active substances which can be used include simple polyoxyethylenesorbitan esters; complex polyoxyethylenesorbitan esters; simple polyoxyethylenesorbitan esters; polyoxyethylenesorbitan esters; arbitrarily esters; esters of fatty acids and sugars; glycerol or PENTAERYTHRITE esters of fatty acids; surfactants of the type pluronic; acetylaspartic, acetylindole and their ethyleneoxide adducts; silicone surfactants and Alkylglucoside.

For anionic surface-active substances, which can use; the Oli alkylmercury; anionic surfactants obtained by esterification sulfuric or phosphoric acid mentioned above ethylenoxide the adducts - nonionic surfactants, followed, if necessary, by neutralization with a suitable alkali, salts of lignosulfonic acids, salts alkylnaphthalenes acids; salts phenolsulfonate and their condensates; polymeric detergents from polycarboxylic acids of the Il polysulfonic acids in the form of salts or condensates, for example, acrylic acid, maleic acid, styrelseledamot acid or vinyl radical; surface-active substances such as starch, containing addition products of starch or dextrin with 1-(2-octenoyl)-nutrisytem; salts of carboxymethyl cellulose; Soaps, such as sodium or potassium salts of higher fatty acids; and salts - olefin-sulfonic acid.

Cationogenic surfactants that may be used include surfactants, which aminosilane or salts of Quaternary ammonium, and ethyleneoxide adducts of higher aliphatic amines or fatty acid amides.

Amphoteric surface-act the PA betaine or lecithin.

Discovered that various derivatives of the above-mentioned surfactants, in which one or more hydrogen atoms substituted by fluorine atoms, greatly reduce the surface tension and can be successfully used in the compositions of the present invention.

Compositions of the invention can also contain one or more additives selected from the group consisting of stabilizers, antifoaming agents, viscosity regulators, binders and adhesives, or any of their combinations, as well as fertilizers and other active ingredients to achieve a special effect.

Insecticidal and acaricidal compositions generally contain from 0.01 to 99%, preferably 0.1 to 95% active compound; 1-99,99% solid or liquid additive and 0-25%, preferably 0.1 to 25% surfactant. When commercial products are sold, usually in the form of concentrated compositions, they are usually diluted for final use to a concentration of 0.001 and 0.0001 wt.% (10-1 ppm).

All the above percentages are weight percent.

Compounds of the invention can be formulated in a mixture or used in combination with other active compounds, e.g. plants or herbicides. Examples of the above-mentioned organophosphorus insecticides are chemicals, urethane chemicals, carboxylate drugs, chlorinated hydrocarbons and insecticides produced by microorganisms.

Compounds of the invention can also be formulated in a mixture or used in combination with synergists. It is necessary that such chemicals and forms intended application available commercially. The synergist is present regardless of the activity in the connection, is able to enhance the action of active compounds.

Further, the invention is illustrated, but not limited to, examples, preparative examples and examples of compositions that illustrate, respectively, the receipt of some compounds of the invention, the starting substances used to produce compounds of the invention, the agrochemical compositions containing compounds of the invention. Compounds of the invention are numbered, assigned to them in the above table. 1-3.

Example 1. 13-( -Methoxymethylethoxy)milbemycin A4(isomer A).

(Stage A). 13-( -Methoxymethylethoxy)-5 - kelimelerin A4.

When ohlord is droxy-5-kelimelerin A4, and 64.5 mg (0.36 mmol) is methoxykynuramine acid (less polar isomer) and 68 mg of copper iodide (I) in 5 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1 h By the end of this period the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% aqueous solution of sodium bicarbonate, then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off and the resulting residue is purified column chromatography on silica gel, elute with ethyl acetate in hexane with step gradient (10 to 50%), and obtain 53 mg named the title compound (yield 41%).

Mass spectrum (m/Z): 717 (M+), 659, 539, 520, 502.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,46 - rate of 7.54 (2H, multiplet); 7,31 - 7,41 (3H, multiplet); 6,55 (1H, singlet); 5,78 - to 5.93 (2H, multiplet); 5,38 - 5,57 (3H, multiplet); 5,20 (1H, doublet, J = 10,9 Hz); 3,99 (3H, singlet); of 3.96 (1H, singlet).

(Stage B). 13-( -Methoxymethylethoxy)milbemycin A4(isomer A) (compound N 1 - 72).

While cooling with ice add to 3.0 (0.08 mmol) of sodium borohydride to a solution of 43.2 mg (0.06 mmol) of 13-( -methoxymethylethoxy)-5-cytomel. what about the end of this time the reaction mixture was poured into water and then extracted with ethyl acetate. The extract is washed with water, then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the resulting residue is purified column chromatography on silica gel, elute with ethyl acetate in hexane with stepped gradient (25 - 50%), and obtain 38 mg (64%) named in the connection header.

Mass spectrum (m/Z): 719 (M+), 591, 540, 412, 394, 279.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: of 7.48 - rate of 7.54 (2H, multiplet); 7,31 - 7,42 (3H, multiplet); 5,78 - by 5.87 (2H, multiplet); the 5.51 (1H, doublet of doublets, J = 8,0, 12.0 Hz); 5,31 - 5,47 (3H, multiplet); 5,20 (1H, doublet, J = 10,9 Hz); 3,99 (3H, singlet); 3,98 (1H, singlet) .

Examples 2 to 27. The compounds of examples 2 to 27 are synthesized by methods similar to the method described above in example 1. As in example 1, first stage receive A 5-keto-derivatives need milbemycin compounds, and the compound obtained is then converted into the final product on stage B. Output (%) at each stage is indicated after the number of connections. An asterisk in parentheses (*) indicates that the resulting product is used in subsequent reactions without Ino-2-phenylacetate)milbemycin A4.

[Connection N 1-11: stage A ( * ) phase - B (48%)].

Mass spectrum (m/Z): 750 (M+), 687, 656, 554, 540, 504.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,60 - of 7.69 (2H, multiplet); 7,28 - 7,39 (3H, multiplet); 5,63 - of 5.81 (2H, multiplet); 5,13 - 5,46 (4H, multiplet); to 4.46 (2H, singlet); 3,98 (3H, singlet); 3,21 - 3,30 (3H, multiplet).

Example 3. 13-[2-Methoxyimino-2-(2-chlorophenyl)ethoxy]milbemycin A4.

[Connection N 1-12: stage A ( * ) phase - B (74%)].

Mass spectrum (m/Z): 739 (M+), 721, 690, 540, 460.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,25 - 7,40 (4H, multiplet); 5,57 - 5,78 (2H, multiplet); 5,14 - 5,42 (4H, multiplet); 4,37 and 5,54 (2H, AB-Quartet, J = 15.7 Hz); 3.96 points (3H, multiplet); and 3.16 (1H, doublet, J = 9.9 Hz).

Example 4. 13-[2-Methoxyimino-2-(3-forfinal)ethoxy]milbemycin A4.

[Connection N 1-13: stage A ( * ) phase - B (55%)].

Mass spectrum (m/Z): 723 (M+), 674, 572, 540, 444, 414.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,28 - 7,46 (3H, multiplet); 6,99 - 7,07 (1H, multiplet); 5,67 - of 5.81 (2H, multiplet); 5,14 - 5,46 (4H, multiplet); 3,98 (3H, singlet).

Example 5. 13-[2-Methoxyimino-2-(3-chlorophenyl)ethoxy]milbemycin A4.

[Connection N 1-14: stage A ( * ) phase - B (61%)]., 200 MHz), ppm: the 7.65 (1H, singlet); 5,52 - to 5.58 (1H, multiplet); 7,25 was 7.36 (2H, multiplet); 5,65 - 5,80 (2H, multiplet); 5,15 - of 5.45 (4H, multiplet); was 4.42 (2H, singlet); 3,98 (3H, singlet).

Example 6. 13-( -Methoxymethylethoxy)milbemycin A4(isomer B).

[Connection N 1-73: stage A ( * ) phase - B (55%)].

Mass spectrum (m/Z): 719 (M+), 591, 540, 458, 412, 394.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,30 - 7,46 (5H, multiplet); 5,70 - of 5.89 (2H, multiplet); from 5.29 - 5,48 (4H, multiplet); 5,10 (1H, doublet, J = 10.5 Hz); Android 4.04 (3H, singlet).

Example 7. 13-( -Methoxymethylethoxy)milbemycin A3.

[Connection N 1-38: stage A (78%) stage B (75%)].

Mass spectrum (m/z): 705 (M+), 577, 526, 398, 380.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,45 - of 7.55 (2H, multiplet); 7,28 - 7,40 (3H, multiplet); 5,71 - 5,91 (2H, multiplet); from 5.29 - ceiling of 5.60 (4H, multiplet); 5,19 (1H, doublet, J = a 10.6 Hz); 3,98 (3H, singlet).

Example 8. 13-( - Methoxyimino-2-chlorophenylacetic)milbemycin A4.

[Connection N1 - 74 phase A (*) - phase B (20%)].

Mass spectrum (m/z): 753 (M+), 625, 540.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,55 - of 7.60 (2H, multiplet); 7,25 - 7,41 (3H, multiplet); 5,78 - 5,91 (2H, multiplet); ethoxy)milbemycin A4.

[Connection N1 - 75: stages A (*): stage B (60%)].

Mass spectrum (m/z): 737 (M*), 680, 609, 552, 522.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 5,77 is 5.98 (2H, multiplet): 5,30 - 5,61 (4H, multiplet); 5,20 (1H, doublet, J = a 10.6 Hz); 4,00 (3H, singlet).

Example 10. 13-( / -Methoxyimino-3-chlorophenylacetic)milbemycin A4.

[Connection N1 - 76: stage A (*) - stage B (55%)].

Mass spectrum (m/z): 753 (M+), 625, 540, 456, 412, 394.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,25 - of 7.55 (4H, multiplet); 5,72 - by 5.87 (2H, multilet); and 5.30 - 5,49 (4H, multiplet); 5,20 (1H, doublet, J = 10.4 Hz); 4,01 (3H, singlet).

Example 11. 13-( )-Methoxyimino-4-chlorophenylacetic)milbemycin A4(isomer A).

[Connection N1 - 77: stage A (*) - stage B (34,0%)].

Mass spectrum (m/z): 753 (M+), 625, 522, 456, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: 7,42 - 7,46 (2H, multiplet); 7,31 and 7.36 (2H, multiplet); of 5.82 - 5,90 (2H, multiplet); of 5.34 - 5.54 (4H, multiplet); 5,19 (1H, doublet, J = 10.5 Hz); 3,99 (3H, singlet); of 3.97 (1H, doublet, J = 6.0 Hz);

Example 12. 13-( -Methoxyimino-4-chlorophenylacetic)milbemycin A4(isomer B).

[Connection N1 - 78: stage A (55,8%) stage B (70,8%)].

Example 13. 13-( -Amoxiillin-4-chlorophenylacetic)milbemycin A4(isomer A).

[Connection N1 - 79: stage A (45%) stage B (44%)].

Mass spectrum (m/z): 767 (M+), 639, 554, 522, 412.

Range nuclear magnetic resonance (CDCl3, 270 MHz), ppm : 7,43 - of 7.48 (2H, multiplet); 7,30 - 7,37 (2H, multiplet); 5,79 - 5,90 (2H, multiplet); 5,34 - 5,54 (4H, multiplet); 5,20 (1H, doublet, J = 10.5 Hz); 4,24 (2H, Quartet, J = 5,2 Hz); of 3.96 (1H, doublet, J = 6.4 Hz); of 1.28 (3H, triplet, J = 7,3 Hz).

Example 14. 13-( -Amoxiillin-4-chlorophenylacetic)milbemycin A4(isomer B).

[Connection N1 - 80: stage A (33%) stage B (65%)].

Mass spectrum (m/z): 767 (M+), 639, 540, 444, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm : 7,32 - 7,44 (4H, multiplet); 5,75 - 5,88 (2H, multiplet); 5,30 - 5,46 (4H, multiplet); 5,09 (1H, doublet, J = 10,9 Hz); or 4.31 (2H, Quartet, J = 7,1 Hz); of 3.96 (1H, doublet, J = 6.5 Hz); of 1.30 (3H, triplet, J = 7,1 Hz).

Example 15. 13-( - Methoxyimino-4-nitrophenylacetate)milbemycin A4.

[Connection N1 - 81: stage A(*) - phase B (40%)].

Mass spectrum (m/z): 746 (M+), 540, 504.

Range nuclear is; ,26 - 5,51 (4H, multiplet); 5,11 (1H, doublet, J = 10,7 Hz); 4,08 (3H, singlet).

Example 16. 13-( -Methoxyimino-2-hydroxyphenylacetate)milbemycin A4.

[Connection N1 - 89: stage A (*) phase - B (24%) ].

Mass spectrum (m/z): 735 (M+), 703, 634, 556, 540.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm : 9,96 (1H, singlet); 7,38 - of 7.48 (1H, multiplet); 6,91 - to 7.18 (3H, multiplet); 5,90 - 6,03 (2H, multiplet); 5,63 - 5,71 (1H, multiplet); 5,40 - 5,58 (3H, multiplet); of 5.34 (1H, doublet, J = 10.0 Hz); 4,12 (3H, singlet).

Example 17. 13-( - Methoxyimino-2-methoxyphenylacetate)milbemycin A4(isomer A).

[Connection N1 - 90: stage A (*) - phase B (20%)].

Mass spectrum (m/z): 749 (M+), 634, 600, 558, 506, 472, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: of 7.82 (1H, doublet of doublets, J = 1,7 and 7.6 Hz); 7,46 (1H, doublet of triplets, J = 1,7 and 7.6 Hz); 7,06 (1H, triplet, J = 7,6 Hz); to 6.95 (1H, doublet, J = 7,6 Hz); 5,85 of 5.99 (2H, multiplet); 5,41 - 5,64 (4H, multiplet); the 5.25 (1H, doublet, J = 10.4 Hz); 4,08 (3H, singlet); 3,76 (3H, singlet).

Example 18. 13-( - Methoxyimino-2-methoxyphenylacetate)milbemycin A4(isomer B).

[Connection N1 - 91: stage A (*) phase - B (15%)].

Mass spectrum (m/z): 749 (M+), 621, 522, 412, 394, 355.

Range let); is 6.78 (1H, doublet, J=8.1 Hz); 5,74-of 5.89 (2H, multiplet); 5,23-of 5.45 (4H, multiplet); 5,09 (1H, doublet, J=10.4 Hz); a 4.03 (3H, singlet), and 3.72 (3H, singlet).

Example 19. 13-( )-Methoxyimino-2-ethoxyphenylacetic)milbemycin AND4(isomer A).

[Connection N 1 - 92: stage A (*) phase - B (15%)].

Mass spectrum (m/z): 763(V+), 586, 540.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm : to 7.64 (1H, doublet of doublets, J = 1,7, 7.5 Hz); 7,34 (1H, doublet, triplet, J=1,7, 7.5 Hz); of 6.96 (1H, triplet, J=7.5 Hz); 6,85 (1H, doublet, J=7.5 Hz); 5,71-5,90 (2H, multiplet); 5,31-of 5.53 (4H, multiplet); 5,10 (1H, doublet, J=10.4 Hz); 3,99 (3H, singlet); 3,90-of 4.05 (3H, multiplet).

Example 20. 13-( -Methoxyimino-2-ethoxyphenylacetic) milbemycin AND4)isomer B).

[Connection N1-93: stage A(*) - stage B (12%)].

Mass spectrum (m/z):763 (M+), 634, 540, 506, 442, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm:7,25-7,39 (1H, multiplet); 6,72-7,14 (3H, multiplet); 5,70 - 5,90(2H, multiplet); 5,28-5,50 (4H, multiplet); to 5.08 (1H, doublet, J=10,7 Hz); a 4.03 (3H, singlet); 3,89-4,11 (3H multiplet).

Example 21. 13-( )-Methoxyimino-2-benzyloxybenzoate) milbemycin AND4.

[Connection N 1 - 98 : stage A (*) phase - B (15%)].

Mass spectrum (m/z):825 (M+), 697, 630, 540, ltiple); 6,75-6,94 (2H, multiplet); 5,72-5,88 (2H, multiplet); from 5.29-5,42 (4H, multiplet); 5,22 (1H, doublet, J=10.3 Hz); 5,01-5,09 (2H, multiplet); 4,00 (3H, singlet).

Example 22. 13-[ -Methoxyimino-(2-pyridyl)acetoxy] milbemycin AND4.

[Connection N 1-111: stage A (15%) stage B (78%)].

Mass spectrum(m/z):720 (M+), 702, 540, 522, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm:8,66-8,68 (1H, doublet, J=4,8 Hz); 7,73-7,79 (1H, multiplet); to 7.59 to 7.62 (1H, doublet, J= 8.1 Hz); 7,28-7,33 (1H,multiplet); 5,74-to 5.85 (2H, multiplet); 5,20-5,44 (4H, multiplet); 5,11 (1H, doublet, J=10.5 Hz); 4,06 (1H, singlet); of 3.96 (1H, doublet, J=6.0 Hz).

Example 23. 13-(3-Methoxyimino-3-phenylpropionylamino)milbemycin AND4.

The compound N 1 - 186: stage A (61%) stage B (74%)].

Mass spectrum (m/z):733 (M+), 702, 605, 586, 572, 554, 540.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm:7.68 per-to 7.77 (2H, multiplet); 7,41 is 7.50 (3H, multiplet); of 5.84-5,91 (2H, multiplet); 5,39-5,51 (4H, multiplet); to 5.03 (1H, doublet, J=10.5 Hz); 4,07 (3H, singlet); a 3.83 (2H, broad singlet).

Example 24. 13-( )-Hydroxyindolacetic)milbemycin A4.

[Connection N 1-70: stage A (61%) stage B (41%)].

Mass spectrum (m/z):705 (M+), 577, 540, 522, 504, 412, 394, 279.

Spectrum of nuclear magnetic resonance (2H, broad singlet); 4,30 (1H, triplet, J=7.4 Hz); 4,10 (1H, singlet); of 3.97 (1H, doublet, J=6.2 Hz).

Example 25. 13-( )-Methoxyimino-2-teeniesex)milbemycin A4.

The compound N 1-102: stage A(*) phase - B (93%)].

Mass spectrum (m/z):725 (M+), 597, 554, 522.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,32-7,38 (1H, multiplet); 6,95? 7.04 baby mortality (4H, multiplet); 5,74-of 5.92 (2H, multiplet); 5,27-to 5.58 (4H, multiplet); by 5.18 (1H, doublet, J=10.5 Hz); 4,69 (2H, broad singlet); 4,30 (1H, multiplet); 4.09 to (1H, singlet); 3.96 points (4H, broad singlet).

Example 26. 13-[ -Methoxyimino-(2-chloroacetylation-4-yl)acetoxy]- milbemycin A4.

Compound 1-108 N: stage A (*) phase - B (60%)].

The mass spectrum with the bombardment of accelerated atoms (mM/z): 967 (M++ 150, C40H52ClN3O11S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm(1H, broad singlet); 7,07 (1H, singlet); 5,76-to 5.93 (2H, multiplet); 5,28-5,69 (4H, multiplet); by 5.18 (1H, doublet, J=10.4 Hz); 4,69 (2H, broad singlet); the 4.29 (3H, broad singlet); 4.09 to (1H, singlet); a 4.03 (2H, singlet); of 3.97 (1H, doublet, J=6.2 Hz).

Example 27. 13-( )-Methoxyimino-3-uranylacetate)milbemycin A4.

[Connection N 1-100: stage A(*) - a hundred, multiplet); 5,78-of 5.92 (2H, multiplet); from 5.29-5,54 (4H, multiplet); 5,16 (1H, doublet, J=a 10.6 Hz); 4,69 (2H, broad singlet); 4,30 (1H, multiplet); 4,08 (1H, singlet), 3,99 (4H, broad singlet)Yu

Example 28. 13-[ -Methoxyimino)-(2-aminothiazol-4-yl)acetoxy) milbemycin A4.

[Compound 1-107 N].

At room temperature add 340 mg of the powder of cadmium to a solution of 92 mg (0.1 mmol) of 13-[2-methoxyimino-{ 2-(2,2,2 - trichlorocarbanilide)thiazol-4-yl} acetoxy]milbemycin A4obtained by the method of example 37 below, dimethylformamide and acetic acid (1:1 by volume), and the resulting mixture is stirred for 2 hours, the Reaction mixture was then poured into a mixture of 5 ml of ethyl acetate and 5 ml of water and stirred for several minutes. The insoluble is filtered off and the filtrate is divided into an ethyl acetate layer and water layer. The aqueous layer was extracted several times with several ml of ethyl acetate. Collect and connect all an ethyl acetate extracts are washed their first 4% aqueous solution of sodium bicarbonate and then saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent is evaporated under vacuum, and the residue is purified column chromatography on silica gel, alumroot 45%).

The mass spectrum with the bombardment of accelerated atoms (M/z): 891 (M++ 150, C38H51N3O10S + triethanolamine +H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 6,56 (1H, singlet); 5,73-5,90 (2H, multiplet); from 5.29-of 5.55 (4H, multiplet); 5,20 (2H, singlet); further 5.15 (1H, doublet, J=a 10.6 Hz); 4,69 (2H,broad singlet); the 4.29 (1H, multiplet); 4.09 to (1H, singlet); 3,99 (4H, broad singlet).

Example 29. 13-[ - Methoxyimino-(4 - methoxycarbonylaminophenyl)-acetoxy]milbemycin A4.

[Connection N 2 - 45].

(Stage A): 13-( -methoxyimino-4-nitrophenylacetate)-5 - kelimelerin AND4.

In a stream of argon and while cooling with ice, add one drop triftormetilfullerenov acid to the solution 843 mg (of 1.52 mmol) of 15-hydroxy-5-kelimelerin A4, 694 mg (3.03 mmol), methoxyimino-4-nitrophenylarsonic acid and 289 mg of copper iodide (I) in 5 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1 h, then the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed first with 5% aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent of natim gradient (20-40%) and receive 663 mg (yield 57%) named in the workpiece connection.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: of 8.27 (2H, doublet, J= 9.0 Hz); 7,56 (2H, doublet, J=9.0 Hz); is 6.54 (1H, multiplet); 5,74-5,94 (2H, multiplet); 5,32-5,54 (3H, multiplet); 5,12 (1H, doublet, J= 10.5 Hz); 4,74 (2H, broad singlet); 4,08 (3H, singlet); 4,01 (1H, singlet); 3,88 (1H, singlet).

(Stage B). 13-( - Methoxyimino-4-nitrophenylacetate)-milbemycin A4.

While cooling with ice added 87 mg (0.44 mmol) of sodium borohydride to a solution of 337 mg (0.44 mmol) of 13-( - methoxyimino-4-nitrophenylacetate)-5-kelimelerin A4in 40 ml of methanol, and the resulting mixture was stirred at 0oC for 30 minutes the Reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed in turn with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with stepped gradient (30 - 50%), and receive 332 mg (yield 98%) named in the connection header.

Mass spectrum (m/z): 764 (M+), 540, 504.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: of 8.27 (2H, doublet, J=8.6 Hz); 7,56 (doublet, J = 8.6 Hz); 5,72-5,90 (2H, multiplet); 5,26-5,51 (4H, multiplet); 5,11 ( 4
.

At room temperature add 1.19 g of powdered zinc to a solution of 1.98 g (2,59 mmol) of 13-( -methoxyimino-4-nitrophenylacetate)milbemycin A4in 20 ml of acetic acid, and the resulting mixture is stirred for 2 hours, the Reaction mixture was then mixed with ethyl acetate and filtered insoluble. The filtrate is diluted with water and extracted with ethyl acetate. The extract is washed with 4% aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elute with ethyl acetate in hexane with stepped gradient (40-100%), and receive 789 mg (yield 41%) named in the workpiece connection.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,30 (2H, doublet, J = 7,1 Hz); is 6.61 (2H, doublet, J = 7,1 Hz); 5,78-5,88 (2H , multiplet); 5,28-5,54 (4H, multiplet); to 5.17 (1H, doublet, J = a 10.6 Hz); 4,66 and 4,70 (2H, AB-Quartet, J 15,5 Hz); 4,30 (1H, triplet, J = 7.0 Hz); 3,93 (3H, singlet).

(Stage D). Phase acylation 13-[ -Methoxyimino-(4-methoxycarbonylaminophenyl)-acetoxy] milbemycin A4.

To a solution of 0,815 g (6.12 mmol) of N-methoxycarbonylamino in 10 ml of dichloromethane was added queue 1.50 g (2.04 mmol) of 13-( -methoxyimino-iodide, and the resulting mixture was stirred at room temperature for 1.5 hours after this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated. The concentrate is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with step gradient of 30-100%), and obtain 268 mg (yield 92%) named in the connection header.

The mass spectrum with the bombardment of accelerated atoms: 999 (M++ 150, C45H59N3O13+ triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,13 is 8.25 (1H, broad singlet); at 7.55 (2H, doublet, J = 8.7 Hz); 7,47 (2H, doublet, J = 8.7 Hz); 5,75-of 5.92 (2H, multiplet); 5,27-5,69 (4H, multiplet); 5,19 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); 4,50 (1H, multiplet); 4,11 (1H, singlet); of 3.97 (3H, broad singlet); 3,76 (3H, singlet)

Examples 30-36. Compounds of examples 30-36 synthesized by methods similar to the method described above in example 29. Output (%) obtained at the stage of acylation /stage D/ is indicated after the number of each connection.

Example 30. 13-( -Methoxyimino-4-acetylaminobenzoic)milbemycin A4.

[Connection N 1-83: stage D (70%)].0 MHz), , ppm: 7,42-to 7.59 (4H, multiplet); 7,29 (1H, singlet); 5,75-to 5.93( 2H, multiplet,); 5,28-5,59 (4H, multiplet); 5,20 (1H, doublet, J = 10.5 Hz); 4,70 (wide singlet); or 4.31 (1H, multiplet); 4,11 (1H, singlet).

Example 31. 13-[ -Methoxyimino-(2-acetylaminophenol-4-yl)acetoxy]-milbemycin A4.

[Connection 1-204 N: stage D (55%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 933 (M++ 150, C40H53N3O11S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 9,37 (1H, singlet); 7,00 (1H, singlet); 5,74-5,90 (2H, multiplet); from 5.29-5,59 (2H, multiplet); to 5.17 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); 4,34(1H,1 multiplet); 4,12 (1H, singlet); 3,99 (4H, broad singlet).

Example 32. 13-[2 - Methoxyimino-2-(4-acetylaminofluorene)ethoxy] milbemycin A4.

[Connection N 2-7, stage D (65%)].

The mass spectrum with the bombardment of accelerated atoms: 912 (M+), 150, C43H58N2O10+ triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: a 7.62 (2H, doublet, J = 8,8 Hz); 7,50 (2H, doublet, J=8,8 Hz); 5,64-5,80 (2H, multiplet, ); 5,18-5,43 (4H, multiplet); of 4.66 (2H, broad singlet); was 4.42 (2H, broad singlet); to 4.28 (1H, multiplet); 3,99 (1H, singlet); 3.96 points (4H, broad Shin is>/P>[Connection N 2-16: stage D (70%)].

The mass spectrum with the bombardment of accelerated atoms: 948 (M++ 150, C42H58N2O11S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: the 7.65 (2H, doublet, J = 8.7 Hz); 7,21 (2H, doublet, J = 8.7 Hz); 6,83 (1H, singlet); 5,64 - of 5.82 (2H, multiplet); 5,17 - 5,43 (4H, multiplet); of 4.66 (2H, broad singlet); 4,43 (2H, broad singlet); 4,30 (1H, broad singlet); of 3.97 (3H, singlet); to 3.92 (1H, doublet, J = 3.8 Hz).

Example 34. 13-[ -Methoxyimino-(4-methanesulfonylaminoethyl)acetoxy] milbemycin A4.

[Connection N 2-22: stage D (75%)].

Mass spectrum (m/z): 812 (M+), 522.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz) / ppm: 7,51 (2H, doublet, J = 8.6 Hz); for 7.12 (2H, doublet, J = 8.6 Hz); to 6.67 (1H, singlet); 5,77 - 5,94 (2H, multiplet); 5,28 - 5,59 (4H, multiplet); 5,20 (1H, doublet, J = 10,7 Hz); 4,69 (2H, broad singlet); 4,30 (1H, doublet, J = 6.2 Hz); 3,98 (4H, broad singlet).

Example 35. 13-[ -Methoxyimino-(4-acetylaminofluorene)acetoxy] milbemycin A4.

[Connection N 2-39: stage D (45%)].

The mass spectrum with the bombardment of accelerated atoms: 938 (M++ 150, C45H59N3O12+ triethanolamine + H).

Spectrum of nuclear magnetic is C); 5,76 - of 5.92 (2H, multiplet); 5,28 - 5,59 (4H, multiplet); 5,19 (1H, doublet, J = 10,7 Hz); 4,69 (2H, broad singlet); 4,30 (1H, multiplet); 4,12 (3H, broad singlet); 3,98 (4H, broad singlet).

Example 36. 13-[ -Methoxyimino-(4-methoxycarbonylaminophenyl)acetoxy]milbemycin A3.

[Connection N 2-43, stage D (85%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,14 (1H, broad singlet); at 7.55 (2H, doublet, J = 8,8 Hz); 7,47 (2H, doublet, J = 8,8 Hz); 5,72 - 5,91 (2H, multiplet); 5,27 (4H, multiplet); 5,20 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); 4,30 (1H, multiplet); 3,85 - 4,12 (4H, multiplet); of 3.97 (3H, singlet).

Example 37. 13-[ -Methoxyimino-(2-(2,2,2-trichlorocarbanilide)thiazol - 4-yl)acetoxy]milbemycin A4.

[Connection N 2-101: stage A ( * ) phase - B (65%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 1065 (M++ 150, C41H52Cl3N3O12S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,07 (1H, singlet); 5,77 - of 5.92 (2H, multiplet); 5,28 - 5,49 (4H, multiplet); to 5.17 (1H, doublet, J = 10.5 Hz); 4,88 (2H, singlet); 4,69 (2H, broad singlet); or 4.31 (1H, multiplet); 4,00 (4H, broad singlet).

Example 38. 13-[ -Methoxyimino-(2-methoxycarbonylamino-4-yl)ACE the accelerated atoms (m/z): 949 (M++ 150 C40H53N3O12S + ethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,39 (1H, broad singlet); of 6.96 (1H, singlet); 5,76 - 5,91 (2H, multiplet); 5,27 - to 5.58 (4H, multiplet); to 5.17 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); 4,30 (1H, multiplet); 4.09 to (1H, singlet), of 4.00 (4H, broad singlet).

Example 39. 13-[ - Methoxyimino-(2-ethoxycarbonylmethyl-4-yl)acetoxy]milbemycin A4.

[Connection N 2-100: stage D (55%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 963 (M++ 150, C41H55N3O12S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,24 (1H, broad singlet); 6,98 (1H, singlet); 5,76 - 5,91 (2H, multiplet); 5,28 - 5,57 (4H, multiplet); to 5.17 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); 4,32 (3H, Quartet, J = 7.0 Hz); 4.09 to (1H, singlet); 4,00 (3H, singlet); of 3.97 (1H, doublet, J = 3,7 Hz).

Example 40. 13-[ -Methoxyimino-(2-isopropoxycarbonyloxymethyl-4-yl)acetoxy]milbemycin A4.

[Connection N 2-105: stage D (60%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 977 (M++ 150 C42H57N3O12S + triethanolamine + H).

Spectrum of nuclear magnetic J = 10.4 Hz); 5,08 (multiplet, J = 6.3 Hz); 4,69 (2H, broad singlet); or 4.31 (1H, triplet, J = 6.2 Hz); 4,10 (1H, singlet); 4,00 (3H, singlet); 3,98 (1H, doublet, J = 6 Hz).

Example 41. 13-[ -Methoxyimino-[2-(1-ethoxycarbonylpyrimidine - 2-yl-carbylamine)triazole-4-yl]acetoxy]milbemycin A4.

[Connection N 2-106: stage D (50%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 1046 (M++ 150, C45H60N4O3S + triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 10,22 (1H, broad singlet); 7,05 (1H, singlet); 5,74 - 5,91 (2H, multiplet); 5,28 - 5,57 (4H, multiplet); to 5.17 (1H, doublet, J = 10.4 Hz); 4,69 (2H, broad singlet); a 4.53 (1H, broad); 4,30 (1H, triplet, J=6,1 Hz); 4.09 to (1H, singlet); was 4.02 (3H,singlet); of 3.97 (1H, doublet, J=6 Hz).

Example 42. 13-[ -methoxyimino-(2-methoxycarbonylaminophenyl 4-yl)acetoxy]milbemycin A4.

[Connection N 2-103: stage D (45%)].

The mass spectrum with the bombardment of accelerated atoms (m/z): 1006 (M++150, C42H56N4O13S+triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 9,8 (1H, broad singlet); 7,03 (1H, singlet); 5,76-5,91 (2H, multiplet); 5,27-5,66 (4H, multiplet); 5,27-5,66 (4H, multiplet); to 5.17 (1H, doublet, J=a 10.6 Hz); 4,69 (2H, the">

Example 43. 13-[2-(4-Methoxycarbonylaminophenyl)-2-methylpropionate] milbemycin A4.

(Stage A). 13-[2-(4-nitrophenyl)-2-methylpropionate]-5-kelimelerin A4.

Under ice cooling and argon flow add 15 ál triftormetilfullerenov acid to a solution of 188 mg (0.34 mmol) of 15-hydroxy-5-kelimelerin A4and 212 mg (1.01 mmol) of 2-(4-nitrophenyl)-2-methylpropionic acid in 8 ml of dichloromethane. The resulting mixture was stirred at room temperature for 30 minutes At the end of this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed first with 5% aqueous sodium bicarbonate solution, then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with stepped gradient (10-35%), and obtain 502 mg (yield 58%) named in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: 7,16 (2H, doublet, J=9.8 Hz); is 6.54 (1H, triplet, J=1.8 Hz); 5,69-5,91 (2H, multiplet); from 5.29-5,47 /3H,multiplet/; 4,91 (1H, doublet, J=10.5 Hz); 4,70 (2H, broad singlet); a-3.84 (1H, singlet); and 1.63 (6H, singlet).4
in 5 ml of methanol, and the resulting mixture was stirred at 0oC for 30 minutes the Reaction mixture was then poured into water and extracted with ethyl acetate. The extract is washed first with water, then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with stepped gradient (20 - 40%), and receive 300,4 mg (yield 60%) named in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,17 (2H, doublet, J=9.0 Hz);7,46 (2H, doublet, J=9.0 Hz); 5,66-of 5.81 (2H, multiplet ); the 5.25-5,48 (3H, multiplet); the 4.90 (1H, doublet, J=a 10.6 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J=6,1 Hz); 4,07 (1H, singlet); of 3.94 (1H, doublet, J=6,1 Hz).

(Stage C). 13-[2-(4-AMINOPHENYL)-2-methylpropionate]-milbemycin A4.

Add at room temperature, 10 mg of zinc dust to the solution of 23 mg (0,0307 mmol) of 13-[2-(4-nitrophenyl)-2-methylpropyloxy)milbemycin A4in 1 ml of acetic acid, and the resulting mixture is stirred for 2 hours, the Reaction mixture was then diluted with ethyl acetate, and the diluted mixture is filtered to remove insoluble. The filtrate mixture is then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with step gradient of 30-100%), and gain of 14.7 mg (yield 67%) named in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,08 (2H, doublet, J=8.6 Hz); 6,62 (2H, doublet, J=8.6 Hz); 5,68-of 5.81 (2H, multiplet); to 5.21-5,44 (4H, multiplet); 4,85 (1H, doublet, J=a 10.6 Hz); of 4.66 (2H, broad singlet); 4,79 (1H, broad singlet); 4,07 (1H, broad singlet); of 3.95 (1H, doublet, J=6,1 Hz).

(Stage D). 13-[2-(4-Methoxycarbonylaminophenyl)-2-methylpropionate] milbemycin A4.

[Connection N 3-27].

Add queue 3,61 g (5.0 mmol) of 13-[2-(4-AMINOPHENYL)-2-methylpropionate] milbemycin A4, 1,012 g (10.0 mmol) of triethylamine and of 2.56 g (10.0 mmol) of 2-chloro-1-methylpyridinium to a solution of 2.0 g (15.0 mmol) of N-methoxycarbonylamino in 20 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1.5 hours after this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, the solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in Gex Mass spectrum with the bombardment of accelerated atoms: 984 (M++ 150, C26H62O12N2+ triethanolamine + H).

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: of 8.25 (1H, broad singlet); 7,46 (2H, doublet, J=8,9 Hz); of 7.25 (2H, doublet, J=8,9 Hz); 5,70 of 5.84 (2H, multiplet); 5,61 (1H,broad singlet); to 5.21-5,41 (4H, multiplet); a 4.86 (1H, doublet, J=10,8 Hz); 4,63 and to 4.68 (2H, AB-Quartet, J= 15,0 Hz); the 4.29 (1H, triplet, J=6.0 Hz); 4,12 (1H, singlet); 4,01 (1H, doublet, J = 5.6 Hz); of 3.94 (1H, doublet, J = 6.0 Hz); 3,74 (3H, singlet).

Examples 44 - 78. The compounds of examples 44 - 78 synthesized by methods similar to the method described in example 37. In order to illustrate the method of the present invention, which is used to specify the outputs (%) stage D after the number of each connection.

Example 44. 13-[2-(4-Acetylaminophenol)-2-methylpropionate]milbemycin A4.

[Connection N 3 - 1 (69%)].

Mass spectrum (m/z): 777 (M+), 759, 741, 540, 522, 412.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: 7,29 (2H, doublet, J = 9.8 Hz);? 7.04 baby mortality (1H, broad singlet); 6.75 in (2H, doublet, J = 9.8 Hz); 5,75 - by 5.87 (2H, multiplet); 5,28 - 5,46 (4H, multiplet); free 5.01 (1H, doublet, J = 10.5 Hz); with 4.64 and 4,70 (2H, AB-Quartet, J = 15,0 Hz); the 4.29 (1H, doublet, J = 6.0 Hz); 4,07 (1H, broad singlet); of 3.96 (1H, doublet, J = 6.0 Hz); of 2.15 (3H, singlet).

Example 45. 13-[2-(4-Acetyll the resonance (CDCl3, 200 MHz), ppm: the 7.43 (2H, doublet, J = 8.7 Hz); 7,19 (2H, doublet, J = 8.7 Hz): 5,75 - of 5.83 (2H, multiplet); 5,23 - of 5.45 (4H, multiplet); a 4.86 (1H, doublet, J = 10.5 Hz); the 4.65 (2H, broad singlet); the 4.29 (1H, triplet, J = 6.2 Hz); 4,07 (1H, singlet); of 3.95 (1H, doublet, J = 6.2 Hz).

Example 46. 13-[(4-Methanesulfonylaminoethyl)-2-methylpropionate]-milbemycin A4.

[Connection N 3-11 (72%)].

Mass spectrum (m/z): 813 (M+), 685, 540, 412, 394.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm : 7,08 (2H, doublet, J = 9.8 Hz); 6,77 (2H, doublet, J = 9.8 Hz); to 6.39 (1H, singlet); 5,72 - 5,88 (2H, multiplet); from 5.29 - 5,46 (4H, multiplet); 4,99 (1H, doublet, J = 10,8 Hz); with 4.64 and 4,69 (2H, AB-Quartet, J = 15,4 Hz); the 4.29 (1H, doublet, J = 6.5 Hz); 4,08 (1H, broad singlet); of 3.96 (1H, doublet, J = 6.5 Hz), 2,95 (3H, singlet).

Example 47. 13-[2-(4-Ethoxycarbonylmethoxy)-2-methylpropyloxy]-milbemycin A4.

[Connection N 3-19 (80%)].

Mass spectrum (m/z): 807 (M+) 633, 522, 504.

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm : 7,18 (2H, doublet, J = 9.6 Hz); 6,74 (2H, doublet, J = 9.6 Hz); 6.48 in (1H, broad singlet); 5,71 - 5,88 (2H, multiplet); 5,27 - 5,48 (4H, multiplet); free 5.01 (1H, doublet, J = 10.4 Hz); 4,65 and 4,71 (2H, AB-Quartet, J = 15,5 Hz); 4,28 (1H, broad singlet); 4,18 (2H, Quartet, J = 6.9 Hz); 4,08 (1H, broad singlet); of 3.96 (1H, doublet, J = 6.5 Hz).

[Connection N 3-26 (79%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm : 8,02 (1H, broad singlet); 7,45 (2H, doublet, J = 8.6 Hz); 7,26 (2H, doublet, J = 8.6 HZ); 5,67 - of 5.82 (2H, multiplet); to 5.21 - 5,55 (5H, multiplet); a 4.86 (1H, doublet, J = a 10.6 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J = 6.2 Hz); 4,08 (1H, singlet); of 4.00 (2H, doublet, J = 6.0 Hz); of 3.94 (1H, doublet, J = 6.2 Hz); of 3.75 (3H, singlet).

Example 49. 13-[2-(4-Methoxycarbonylaminophenyl)-2-ethylbutyrate] milbemycin A4.

[Connection N 3-28 (45%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm : a 7.92 (1H, broad singlet); 7,44 (2H, doublet, J = 8.5 Hz); to 7.18 (2H, doublet, J = 8.5 Hz); 5,71 - of 5.75 (2H, multiplet); to 5.21 - 5,46 (4H, multiplet); the 4.90 (1H, doublet, J = 10.5 Hz); with 4.64 (2H, broad singlet); 4,12 - 4,34 (1H, multiplet); 4,10 (1H, singlet); 3,99 (2H, doublet, J = 5,9 Hz); of 3.94 (1H, doublet, J = 6.2 Hz).

Example 50. 13-[2(4-Methoxycarbonylaminophenyl)-2-methylpropionate] milbemycin A4.

[Connection N 3-29 (23%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm : a 7.85 (1H, broad singlet); to 7.32 (2H, doublet, J = 9.1 Hz); 6.75 in (2H, doublet, J = 9.1 Hz); 5,72 - 5,90 (2H, multiplet); the 5.25 - 5,52 (5H, multiplet); free 5.01 (1H, doublet, J = a 10.6 Hz); of 4.67 (2H, broad singlet); the 4.29 (1H, triplet, J = 6.0 Hz); 4,08 (1H, singlet); 3,98 (2H, Geminiani)-2 - methylpropyloxy)milbemycin A4.

[Connection N 3-33 (76%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm : with 8.05 (1H, broad singlet); 7,44 (2H, doublet, J = 8.7 Hz); 7,26 (2H, doublet, J = 8.7 Hz); 5,67 of 5.84 (2H, multiplet); 5,14 - 5,95 (4H, multiplet); to 4.87 (1H, doublet, J = 10.5 Hz); of 4.66 (2H, broad singlet); to 4.28 (1H, triplet, J = 6.0 Hz); 4,08 (1H, singlet); of 3.95 (2H, doublet, J = 6.2 Hz); to 3.92 (1H, doublet, J = 6.0 Hz).

Example 52. 13-[2-(4-Benzyloxycarbonylamino)-2 - methylpropionate]milbemycin A4.

[Connection N 3 - 34: (69%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: to 7.84 (1H, broad singlet); 7,42 (2H, doublet, J = 8,8 Hz); 7,37 (5H, singlet); to 7.25 (1H, doublet, J = 8,8 Hz); 5,68 - 5,72 (2H, multiplet); 5,24 - 5,49 (6H, multiplet); by 5.18 (2H, singlet); to 4.87 (1H, doublet, J = 10.4 Hz); the 4.65 (2H, broad singlet); the 4.29 (1H, triplet, J = 6.2 Hz); 4,07 (1H, singlet); 4,00 (2H, doublet, J = 5,9 Hz); of 3.95 (1H, doublet, J = 6.2 Hz).

Example 53. 13-[2-(4-Benzylaminocarbonyl)-2 - methylpropionate] milbemycin A4.

[Connection N 3-36 (45%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 9,17 (1H, singlet); 7,89 (2H, doublet, J = 7,6 Hz); 7,41 - to 7.61 (2H, multiplet); to 7.25 (2H, doublet, J = 7,6 Hz); 5,66 of 5.84 (2H, multiplet); to 5.21 - 5,44 (4H, multiplet); a 4.86 (1H, doublet, J = 10.4 Hz); with 4.64 (2H, broad singlet); 4,Tyl)methoxycarbonylaminophenyl)-2 - methylpropionate]milbemycin A4.

[Connection N 3-37 (75%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: at 8.60 (1H, broad singlet); 7,45 (2H, doublet, J = 8.7 Hz); 7,26 (2H, doublet, J = 8,4 Hz); 5,68 - to 5.85 (2H, multiplet); to 5.21 - of 5.45 (4H, multiplet); to 4.87 (1H, doublet, J = 10.3 Hz); of 4.66 (2H, broad singlet); the 4.29 (1H, triplet, J = 6.2 Hz); 4,07 (1H, singlet); a 4.03 (2H, singlet); of 3.95 (1H, doublet, J = 6.2 Hz); of 3.78 (3H, singlet).

Example 55. 13-[2-(4-(N-Methyl)ethoxycarbonylmethylene] -2 - methylpropionate/milbemycin A4.

[Connection N 3-38 (89%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,15 (1H, broad singlet); 7,44 (2H, doublet, J = 8.7 Hz); of 7.25 (2H, doublet, J = 8.7 Hz); 5,68 - 5,88 (2H, multiplet); 5,23 - of 5.45 (4H, multiplet); to 4.87 (1H, doublet, J = 10.5 Hz); of 4.66 (2H, broad singlet); the 4.29 (1H, triplet, J = 6.2 Hz); 4,22 (2H, Quartet, J = 14,2 Hz); 4,07 (1H, singlet); was 4.02 (2H, singlet); of 3.95 (1H, doublet, J = 6.2 Hz).

Example 56. 13-[2-(4-Isopropoxycarbonyloxymethyl)-2 - methylpropionate]milbemycin A4.

[Connection N 3-39: (65%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,00 (1H, broad singlet); 7,44 (2H, doublet, J = 8.7 Hz); 7,26 (2H, doublet, J = 8.7 Hz); 5,68 - to 5.85 (2H, multiplet); 5,22 - of 5.45 (5H, multiplet); to 4.98 (1H, septuplet, J = 6.2 Hz); to 4.87 (1H, doublet, J = a 10.6 Hz); 4,66 (P> Example 57. 13-[2- -(4-Methoxycarbonylamino)- phenylacetylamino] -2-methylpropionate]milbemycin A4.

[Connection N 3-40 (76%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,29 - of 7.48 (7H, multiplet); 7,22 (2H, doublet, J = 8.6 Hz); of 6.02 (1H, doublet, J = 5,9 Hz); 5,67 - of 5.82 (2H, multiplet); 5,19 - of 5.45 (4H, multiplet); a 4.86 (1H, doublet, J = a 10.6 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J = 6.2 Hz); 4,08 (1H, singlet); of 3.95 (1H, doublet, J = 6.2 Hz); of 3.69 (3H, singlet).

Example 58. 13-[2-(4-Ethoxycarbonylmethylene)-2 - methylpropionate]milbemycin A4.

[Connection N 3-41 (53%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: scored 8.38 (1H, singlet); 7,51 (2H, doublet, J = 8,4 Hz); from 7.24 (2H, doublet, J = 8,4 Hz); 6,98 (1H, broad singlet); 5,68 - to 5.85 (2H, multiplet); 5,23 - 5,49 (5H, multiplet); a 4.86 (1H, doublet, J = 10.5 Hz); the 4.65 (2H, broad singlet); 4,06 is 4.36 (6H, multiplet); a 3.87 - to 3.99 (3H, multiplet);

Example 59. 13-[2-[4-(Methoxycarbonylamino)benzylaminocarbonyl]- 2-methylpropionate]milbemycin A4.

[Connection N 3-42 (69%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,71 (1H, singlet); of 7.82 (2H, doublet, J = 8.6 Hz); of 7.48 (doublet, 4H, J = 8,3 Hz); of 7.25 (2H, doublet, J = 8.6 Hz); 6,94 (1H, singlet); 5,69-to 5.85 (2H, mule is t); of 3.94 (1H, doublet, J = 6,1 Hz); 3,81 (3H, singlet).

Example 60. 13-[2-(4-Methoxycarbonylaminophenyl)-2 - methylpropionate]milbemycin A4.

[Connection N 3-43 (48%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,51 (1H, singlet); 7,51 (2H, doublet, J = 8,2 Hz); from 7.24 (2H, doublet, J = 8,2 Hz); 5,70 of 5.84 (2H, multiplet); 5,63 (1H, broad); 5,23 - 5,42 (5H, multiplet); the 4.65 (2H, broad singlet); 3,83 - 4,35 (7H, multiplet).

Example 61. 13-[2-[4-{ 3-(Methoxycarbonylamino)propionamido}phenyl]-2 - methylpropionate]milbemycin A4.

[Connection N 3-43 (66%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,44 (2H, doublet, J=8.6 Hz); of 7.25 (2H, doublet, J=8.6 Hz); 5,68-of 5.83 (2H, multiplet); 5,24-5,46 (5H, multiplet); to 4.87 (1H, doublet, J=10.3 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J=6,1 Hz); 4,07 (1H, singlet); of 3.95 (1H, doublet, J=6,1 Hz); to 3.67 (3H, singlet).

Example 62. 13-[2-[4-{2-(Methoxycarbonylamino)propionamido}- 2-methylpropionate]milbemycin A4.

[Connection N 3-47 (78%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,12 (1H, broad singlet); 7,46 (2H, doublet, J=8.6 Hz); of 7.25 (2H, doublet, J=8.6 Hz); 5,68-of 5.83 (2H, multiplet); 5,17-of 5.45 (5H, multiplet); to 4.87 (1H, doublet, J=a 10.6 Hz); of 4.66 (2H, broad singlet) is acetylamino)phenyl} -2 - methylpropionate]milbemycin A4.

The Compound N 3-48 (45%)].

Spectrum of nuclear magnetic resonance (CDCl3, 270 MHz), ppm: 8,72 (1H, broad singlet); 7,47 (2H, doublet, J=8.5 Hz); of 7.25 (2H, doublet, J=8.5 Hz); is 6.61 (1H, broad singlet); 5,66-5,80 (2H, multiplet); 5,26-5,41 (4H, multiplet); a 4.86 (1H, doublet, J=10.5 Hz); br4.61 and of 4.67 (2H, AB-Quartet, J= 15,5 Hz); 4,28 (1H, triplet, J=6.4 Hz); 4,12 (3H, singlet); of 3.95 (1H, doublet, J=6.4 Hz).

Example 64. 13-[2-[4-{ 3-(Ethoxycarbonyl)propionamido} phenyl]-2 - methylpropionate]milbemycin A4.

[Connection N 3-49 (66%].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,50 (1H, broad singlet); 7,45 (2H, doublet, J=8.6 Hz); of 7.25 (2H, doublet, J=8.6 Hz); 5,68-of 5.82 (2H, multiplet); 5,22-5,44 (5H, multiplet); to 4.87 (1H, doublet, J= a 10.6 Hz); the 4.65 (2H, broad singlet); the 4.29 (1H, triplet, J=6.2 Hz); 4,11 (2H, Quartet, J=7,1 Hz); 4,07 (1H, singlet); of 3.95 (1H, doublet, J=6.2 Hz).

Example 65. 13-[2-[4-{2-(Methoxycarbonylamino)-2 - methylpropionamide}-phenyl]-2-methylpropionate]milbemycin A4.

[Connection N 3-56 (51%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,63 (1H, broad singlet); 7,46 (2H, doublet, J=8.7 Hz); from 7.24 (2H, doublet, J=8.7 Hz); 5,68-of 5.82 (2H, multiplet); 5,24-5,43 (4H, multiplet); 5,10 (1H, singlet); 4,88 (1H, doublet, J=10.4 Hz); of 4.66 (2H, broad singlet); the 4.29 (1H, triplet, J= 6.2 Hz) is thio)- bucillamine}phenyl]-2-methylpropionate]milbemycin A4.

[Connection N 358 For (72%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm, 8,13 (1H, broad singlet); 7,46 (2H, doublet, J=8.7 Hz); 7,26 (2H, doublet, J=8.7 Hz); 5,69-of 5.83 (2H, multiplet); 5,26-5,49 (5H, multiplet); to 4.87 (1H, doublet, J= 10.5 Hz); of 4.66 (2H, broad singlet); 4,47 (4H, Quartet, J=8.1 Hz); the 4.29 (1H, triplet, J=6.2 Hz); 4,07 (1H, singlet ); of 3.95 (1H, doublet, J=6.2 Hz); of 3.73 (3H, singlet).

Example 67. 13-[2-[4-{2-(Methoxycarbonylamino)-3-methylbutylamine}-phenyl]- 2-methylpropionate]milbemycin A4.

[Connection N 3-61 (78%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,83 (1H, broad singlet); 7,47 (2H, doublet, J=8.7 Hz); from 7.24 (2H, doublet, J=8.7 Hz); 5,69-of 5.83 (2H, multiplet); 5,22-5,46 (5H, multiplet); to 4.87 (1H, doublet, J= 10.3 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J=6.2 Hz); 4,08 (1H, singlet); of 3.95 (1H, doublet, J=6.2 Hz); 3,71 (3H, singlet).

Example 68. 13-[2-[4-{ 2-(Ethoxycarbonyl)-3-methylbutylamine}phenoxy]- 2-methylpropionate]milbemycin A4.

[Connection N 3-62 (52%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,81 (1H, singlet), 7,33 (2H, doublet, J=9.0 Hz); 6,76 (2H, doublet, J=9.0 Hz); 5,72-5,90 (2H, multiplet); 5,18-5,50 (multiplet, 5H); free 5.01 (1H, doublet, J= a 10.6 Hz); and 4.68 (1H, broad singlet); the 4.29 (1H, triplet, J=6.2 Hz); 4,08 (1H, singlet) the}-phenyl]-2-methylpropionate]milbemycin A4.

[Connection N 3-64 (73%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,02 (1H, broad singlet); 7,46 (2H, doublet, J=8.6 Hz); from 7.24 (2H, doublet, J=8.6 Hz); 5,69-of 5.81 (2H, multiplet); 5,24-of 5.45 (4H, multiplet); 5,10 (1H, doublet, J=8,3 Hz); to 4.87 (1H, doublet, J=a 10.6 Hz); the 4.65 (2H, broad singlet); 4,20-4,34 (2H, multiplet); 4,08 (1H, singlet); of 3.95 (1H, doublet, J=6.3 Hz); and 3.72 (3H, singlet).

Example 70. 13-[2-[4-{2-(Methoxycarbonylamino)-3,3 - dimethylbutylamino} -phenyl [2-methylpropionate] milbemycin A4.

[Connection N 3-65 (61%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 5,90 (1H, broad singlet); 7,45 (2H, doublet, J=8.7 Hz); from 7.24 (2H, doublet, J=8.7 Hz); 5,67-of 5.83 (2H, multiplet); of 5.55 (1H, doublet, J=9.8 Hz); 5,24-5,44 (4H, multiplet); to 4.87 (1H, doublet, J = 10.4 Hz); the 4.65 (2H, broad singlet); to 4.28 (1H, triplet, J=6.2 Hz); 4,08 (1H, singlet); of 3.95 (1H, doublet, J=6.2 Hz); 3,70 (3H, singlet).

Example 71. 13-[2-[4-{1-(Methoxycarbonylamino)cyclohexane-1 - carbylamine}phenoxy]-2-methylpropionate]milbemycin A4.

[Connection N 3-66 (37%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,81 (1H, broad singlet); 7,34 (2H, doublet, J=8,8 Hz); 6.75 in (2H, doublet, J=8,8 Hz); 5,71-of 5.89 (2H, multiplet); 5,24-5,49 (4H, multiplet); free 5.01 (1H, doublet, J= 10.5 Hz); 4,89 (1H, singlet); 4,68 (2H72. 13-[2-[4-{1-(Ethoxycarbonyl)cyclohexane-1 - carbylamine}phenyl]-2-methylpropionate]milbemycin A4.

[Connection N 3-68 (55%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,98 (1H, broad singlet); 7,47 (2H, doublet, J=8.6 Hz); from 7.24 (2H, doublet, J=8.6 Hz); 5,68-to 5.85 (2H, multiplet); 5,23-5,46 (4H, multiplet); 4,88 (1H, doublet, J= 10.5 Hz); 4,87 (1H, singlet); of 4.66 (2H, broad singlet); to 4.28 (1H, triplet, J= 6.3 Hz); 4,07 (1H, singlet); of 3.95 (1H, doublet, J=6.3 Hz); and 3.72 (3H, singlet).

Example 73. 13-[2-[4-[(1-Ethoxycarbonylpyrimidine)-2-carbylamine] - phenyl]-2-methylpropionate]milbemycin A4.

The Compound N 3-69 (78%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,47 (2H, doublet, J=8,8 Hz); from 7.24 (2H, doublet, J=8,8 Hz); 5,67 - of 5.82 (2H, multiplet); 5,23-of 5.45 (4H, multiplet); 4,88 (1H, doublet, J=10.5 Hz); of 4.66 (2H, broad singlet); to 4.28 (1H, triplet, J= 6,1 Hz); 4,07 (1H, singlet); of 3.95 (1H, doublet, J=6,1 Hz); of 3.78 (3H, singlet).

Example 74. 13-[2-[4-(1-Ethoxycarbonylpyrimidine-2-carbylamine)phenyl]- 2-methylpropionate]milbemycin A4.

The Compound N 3-71 (65%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,94 (1H, broad singlet); 7,45 (2H, doublet, J=8.7 Hz); from 7.24 (2H, doublet, J=8,71 Hz); 5,68-of 5.82 (2H, multiplet); 5,23-5,46 (4H, multiplet); 4 the em J=6.2 Hz).

Example 75. 13-[2-[4-(1-Ethoxycarbonylpyrimidine-4-carbylamine)phenyl]- 2-methylpropionate]milbemycin A4.

The Compound N 3-72 (91%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,47 (2H, doublet, J=8.7 Hz); 7,26 (2H, doublet, J=8.7 Hz); 5,68-of 5.81 (2H, multiplet); 5,24-5,44 (5H, multiplet); 4,82-is 4.93 (2H, multiplet); 4,62-of 4.77 (3H, multiplet); to 4.38 figure-4.49 (1H, multiplet); the 4.29 (1H, triplet, J=6.2 Hz); 4,07 (1H, singlet); 3,95 (1H, doublet, J=6.2 Hz); a 3.83 (3H, singlet).

Example 76. 13-[2-[4-(3-Methoxycarbonyl-1,3-thiazolidin-4-carbylamine)- phenyl]-2-methylpropionate]milbemycin A4.

The Compound N 3-73 (60%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,47 (2H, doublet, J=8.7 Hz); 7,26 (2H, doublet, J=8.7 Hz); 5,68-of 5.81 (2H, multiplet); 5,24-5,44 (5H, multiplet); 4,82-is 4.93 (2H, multiplet); 4,62-of 4.77 (3H, multiplet); to 4.38 figure-4.49 (1H, multiplet); the 4.29 (1H, triplet, J=6.2 Hz); 4,07 (1H, singlet); 3,95 (1H, doublet, J=6.2 Hz).

Example 77. 13-[2-[4-(5-Clopyralid-2-carbylamine)phenyl] -2 - methylpropionate]milbemycin A4.

The Compound N 3-76 (29%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,16 (1H, singlet); 7,52 (2H, doublet, J=8.7 Hz); 7,27 (2H, doublet, J=8.7 Hz); 6,79 (1H, singlet); 5,68-5,74 (2H, multiplet); 5,22-5,43 (4H, multiplet); 4>Example 78. 13-[2-[4-{2-(2-Chloroacetylation-4-yl)-2 - methoxykynuramine}phenyl]-2-methylpropionate]milbemycin A4.

The Compound N 3-77 (68%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz) / ppm: 9,88 (1H, broad singlet); to 7.93 (1H, singlet); 7,56 (2H, doublet, J=8.7 Hz); 7,53 (1H, singlet); 7,31 (2H, doublet, J=8.7 Hz); 5,69-by 5.87 (2H, multiplet); 5,22-of 5.45 (4H, multiplet); the 4.90 (1H, doublet, J=10.5 Hz); of 4.66 (2H, broad singlet); the 4.29 (3H, broad singlet); 4,13 (3H, singlet); 4,10 (1H, singlet); of 3.95 (1H, doublet, J=6.2 Hz).

Example 79. 13-[2-[4-{2-(2-Methoxycarbonylamino-4-yl)-2 - methoxyimino}-acetylaminophenol]-2-methylpropionate]milbemycin A4.

The Compound N 3-78 (68%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: with 8.05 (1H, broad singlet); EUR 7.57 (2H, doublet, J=8.5 Hz); 7,37 (1H, singlet); 7,30 (2H, doublet, J=8.5 Hz); 5,68-5,88 (2H, multiplet); to 5.21-of 5.45 (4H, multiplet); 4,89 (1H, doublet, J= a 10.6 Hz); of 4.66 (2H, broad singlet); the 4.29 (1H, triplet, J= 6,1 Hz); 4.09 to (1H, singlet); of 4.05 (3H, singlet); of 3.95 (1H, doublet, J=6,1 Hz); 3,86 (3H, singlet).

Example 80. 13-[2-[4-(N-Methyl-N-methoxycarbonylaminophenyl)aminophenoxy]- 2-methylpropionate]milbemycin A4.

The Compound N 3-82 (56%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: of 7.97 (1H, dt, J= a 10.6 Hz); and 4.68 (2H, broad singlet); the 4.29 (1H, triplet, J=6.2 Hz); 4,07 (1H, singlet); was 4.02 (2H, singlet); of 3.96 (1H, doublet, J=6.2 Hz); of 3.77 (3H, singlet).

Example 81. 13-[2-[4-{ 1-(Ethoxycarbonylpyrimidine)-2-carbylamine} - phenoxy]-2-methylpropionate]milbemycin A4.

The Compound N 3-83 (26%)].

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 9,00 (1H, broad singlet); to 7.35 (2H, doublet, J=8,9 Hz); 6.75 in (2H, doublet, J=8,9 Hz); 5,71-5,90 (2H, multiplet); 5,26-5,51 (4H, multiplet); free 5.01 (1H, doublet, J= a 10.6 Hz); and 4.68 (2H, broad singlet); of 4.44 (1H, broad singlet); the 4.29 (1H, triplet, J=6.2 Hz); 4,07 (1H, singlet); of 3.96 (1H, doublet, J=6.2 Hz); of 3.77 (3H, singlet).

Preparative example 1. -Methoxymethylethoxy acid.

(a) Ethyl - methoxykynuramine.

Add 1.4 g (16,8 mmol) of the hydrochloride of O-methylhydroxylamine and of 1.16 g (8.4 mmol) of potassium carbonate to a solution of 0.50 g (2.8 mmol) of ethyl-phenylglyoxylate in N,N-dimethylformamide, and the resulting mixture was stirred at 90oC for 4 h At the end of this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue is purified of Kolonos,47 g (yield 67%) of the less polar isomer is named the title compound.

The less polar isomer.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,55-to 7.64 (2H, multiplet); 7,32-7,46 (3H, multiplet); 4,43 (2H, Quartet, J=7.2 Hz); was 4.02 (3H, singlet); to 1.38 (3H, triplet, J=7,2 Hz).

The more polar isomer.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,42 (5H, singlet); 4,37 (2H, Quartet, J=7,1 Hz); 4,06 (3H, singlet); of 1.36 (3H, triplet, J=7,1 Hz).

(b) -Methoxymethylethoxy acid.

An aqueous solution of 0.90 g (to 22.6 mmol) of sodium hydroxide are added to a solution of 0.47 g (2.3 mmol) of ethyl - methoxykynuramine (obtained above the isomer of lesser polarity) in methanol. The resulting mixture is stirred over night at room temperature. The reaction mixture was poured into 1N hydrochloric acid, and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrate, get named in the title compound as a crude product, which is used in subsequent reactions without further purification.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 10,3 (1H, broad singlet); 7,60-7,72 (2H, multiplet); 7,32 was 7.45 (3H, multiplet); a 4.03 (3H, singlet).

Preparative example 2. -Methoxyimino-2-chlorophenylalanine acids is imidazole, and then 1.63 g (24 mmol) of tert-butyldimethylsilyloxy added under ice cooling to a solution of 3.45 g (20 mmol) 1-(2-chlorophenyl)-1,2-ethanediol in N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 20 minutes At the end of this time the reaction mixture was poured into water and extracted three times with portions of 50 ml ethyl acetate. The combined extracts washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with stepped gradient (10-20%), and receive 3.58 g (yield 63%) named in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,58-7,66 (1H, multiplet); 7,16-to 7.35 (3H, multiplet); 5,16 (1H, doublet of triplets, Jd=8.0 Hz, JT)=3.0 Hz); of 3.94 (1H, doublet of doublets, J=10,2, 3,0 Hz); 3.46 in (1H, doublet of doublets, J=8,0, 3,0 Hz); a 3.06 (1H, doublet, J=3.0 Hz); of 0.91 (9H, singlet); of 0.07 (3H, singlet); of 0.05 (3H, singlet).

(b) 2'-Chloro-2-tert-butyldimethylchlorosilane.

Add 70,0 g of manganese dioxide to a solution of 3.5 g (12.3 mmol) of 1-(2-chlorophenyl)-1,2-ethanediol-2-O-tert-butyldimethylsilyl ether in dichloromethane. The floor is trout through accelerating filtration diatomaceous earth. The filtrate is concentrated, and get 3,05 g (87%) of 2'-chloro-2-tert-butyldimethylchlorosilane in the form of a crude product.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,25-of 7.48 (4H, multiplet); at 4.75 (2H, singlet); of 0.87 (9H, singlet); 0,1 (6H, singlet).

(c) 2'-Chloro-2-hydroxyacetophenone-0-methyloxime.

Added 1.78 g of the hydrochloride 0-methylhydroxylamine to a solution of 3.05 g of the above 2'-chloro-2-tert-butyldimethylchlorosilane in a mixture of methanol, water and 1,4-dioxane. The resulting mixture was stirred at room temperature for 14 h and then the reaction mixture was poured into water and extracted with ethyl acetate three times with portions of 50 ml combined extracts washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with step gradient (10 - 40%), receive 691 mg (yield 32,4%) of isomer O-methyloxime 2'-chloro-2-hydroxyacetophenone with less polarity and 370 mg (yield of 17.3%) isomer with higher polarity specified in the connection header.

The isomer of lesser polarity

Spectrum of nuclear magnetic resonance polarity.

Spectrum of nuclear magnetic resonance (CDCL3, 200 MHz), ppm: 7,41 - 7,47 (1H,multiplet); 7,29 - 7,38 (1H,multiplet); 7,14 -7,20 (1H,multiplet); of 4.45 (2H,doublet, J=5.5 Hz); the 3.89 (3H, singlet).

(d) -Methoxyimino-2-chlorophenylalanine acid.

Add 10 ml of Jones reagent (Jones) chromic anhydride in dilute sulfuric acid to a solution of 0.40 g 0-methyloxime 2'-chloro-2-hydroxyacetophenone (the isomer of lesser polarity, obtained above). The resulting mixture was stirred at room temperature for one hour, and then, with ice cooling, add 10 ml of isopropanol. The reaction mixture was poured into 100 ml of water and extracted three times with ethyl acetate portions 10 ml combined extracts washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is distilled off, and get 320 mg (75%) named the title compound as crude product.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,28-to 7.50 (4H,multiplet); the 5.25 (1H, broad singlet); 4,14 (3H, singlet).

Preparative example 3. Derivatives 0-alkyloxy 2-hydroxyacetophenone.

The following derivatives 0-alkyloxy 2-hydroxyacetophenone, substituted phenyl group, received the of hydroxyacetophenone.

(1) 0-Methyloxan-2-hydroxyacetophenone.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,60-of 7.69 (2H, multiplet); 7,34-the 7.43 (3H, multiplet); 4,69 (2H, doublet, J=7.0 Hz); Android 4.04 (3H, singlet); 2,73 (1H, triplet, J=7,0 Hz).

(2) 0-Methyloxime-3'-fluoro-2-hydroxyacetophenone.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,30 was 7.45 (3H, multiplet); 7,01 for 7.12 (1H, multiplet); and 4.68 (2H, doublet, J=6,9 Hz); Android 4.04 (3H, singlet); to 2.65 (1H, triplet, J=6,9 Hz).

(3) On-Methyloxime-3'-chloro-2-hydroxyacetophenone.

Spectrum of nuclear magnetic resonance (CDCl3200 MHz), ppm: to 7.67(1H, multiplet); 7,49-7,56 (1H, multiplet); 7,31-7,40 (2H, multiplet); of 4.66 (1H, doublet, J=6,9 Hz); of 4.05 (3H, singlet); 2,60 (1H, triplet, J= 6,9 Hz).

Preparative example 4. Derivatives - methoxyimino-2-chlorophenylalanine acid.

The following derivatives - methoxykynuramine acid receive in a manner consistent with the method used above in preparative example 2, to obtain methoxyimino-2-chlorophenylalanine acid.

(1) - Methoxyimino-3-ftorhinolona acid.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 9,40 (1H, broad singlet); 7,76-of 7.97 (1H, multiplet); 7,15-7,58 (3H, multiplayermode magnetic resonance (CDCl3, 2-00 MHz), ppm: 7,94-8,10 (1H, multiplet); 7,25-of 7.70 (3H, multiplet): 4.09 to (3H, singlet).

(3) Methoxyimino-4-chlorophenylalanine acid.

The isomer of lesser polarity.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: to 7.59(2H, doublet, J=8,71 Hz); 7,38 (2H, doublet, J=8,71 Hz); 4,10 (3H, singlet).

The isomer with the higher polarity.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,50 (2H, doublet, J=8,91 Hz); 7,42 (2H, doublet, J= 8,91 Hz); 4,12 (3H, singlet).

(4) -Amoxiillin-4-chlorophenylalanine acid.

The isomer of lesser polarity.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: of 7.69(2H, doublet, J= 9,00 Hz); 7,39 (2H, doublet, J=9.0 Hz); 4,36 (2P, Quartet, J= 7,6 Hz); to 1.38 (3H, triplet, J=7,6 Hz).

The isomer with the higher polarity

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,54 (2H, doublet, J=6.6 Hz); 7,47 (2H, doublet, J=6.6 Hz); 4,37 (2H, Quartet, J= 7.0 Hz); of 1.37 (3H, triplet, J=7,0 Hz).

(5) - Methoxyimino-2-methoxyphenylalanine acid.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: the 7.65 (1H, doublet of doublets, J=1,6, 7,7 Hz); 7,41 (1H, triplet of triplets, J= 1,6, 8.0 Hz); 6,80 - 7,05 (2H, multiplet); 4,07 (3H, singlet); is 3.82 (3H, singlet).

(6) - Methoxyimino on resonance (CDCl3, 200 MHz), ppm : a 7.62 (1H, doublet of doublets, J = 1,7, 7,7 Hz); 7,39 (1H, doublet of triplets, J = 1,0, 7,0 Hz); 6,85 shed 8.01 (2H, multiplet); 4,08 (3H, singlet); 4,0-4,13 (2H, multiplet); of 1.40 (3H, triplet, J = 7,0 Hz).

The isomer with high polarity.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,25-7,40 (2H, multiplet); 6,88-7,05 (2H, multiplet); 4,08 (3H, singlet); 4,0-4,13 (2H, multiplet); of 1.33 (3H, triplet, J= 7,0 Hz).

(7) - Methoxyimino-2-benzyloxyaniline acid.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: to 8.70 (1H, broad singlet); 7,25-7,42 (7H, multiplet); 7,06 (2H, doublet, J = 8,3 Hz); 6,99 (2H, doublet, J= 8,3 Hz); 5,08 (2H, singlet); Android 4.04 (3H, singlet).

Preparative example 5. 3 Methoxyimino-3-phenylpropionate acid.

Named in the title compound, receive, following the method of obtaining-methoxykynuramine acid, described in preparative example 1, but using as the starting material ethylbenzylamine.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,60-7,71 (2H, multiplet); 7,34 was 7.45 (3H, multiplet); a 4.03 (3H, singlet); 3,81 (2H, singlet).

Preparative example 6. -Methoxyimino-4-nitrophenylarsonic acid.

Named in the title compound floor is as 1, but using as the starting material 4-nitrophenylglyoxylate described in Synthesis, 850 (1990).

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,13 (2H, doublet, J= 7.0 Hz); of 7.48 (2H, doublet, J= 7,0 Hz), of 3.95 (3H, singlet).

Preparative example 7. - Methoxyimino-2-hydroxyphenylarsonic acid.

Named in the header connection receive in accordance with the method of obtaining-methoxykynuramine acid, described in preparative example 1, but using as the starting material 2-hydroxyphenylglycine.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 7,17-7,38 (2H, multiplet); for 6.81-was 7.08 (2H, multiplet); 4,08 (3H, singlet).

Preparative example 8. - Methoxyimino-2-pyridyloxy acid.

Named in the header connection receive in accordance with the method of obtaining-methoxykynuramine acid, described in preparative example 1, but using as the starting material commercially available ethyl-2-pyridylacetate.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,50 (1H, doublet, J= 4,9 Hz); of 7.75 (1H, doublet of triplets, Jd= 1,6 Hz, Jt= 7,7 Hz); to 7.61 (1H, doublet of triplets, Jd= 7.7 Hz, Jt

(a) Ethyl - -methoxyimino-4-nitrophenylacetate.

Add 0.95 g to (11.4 mmol) of the hydrochloride of O-methylhydroxylamine to a solution of 1.18 g (5.7 mmol) of ethyl-4-nitrophenylglyoxylate (obtained according to the method described in Synthesis 850 (1990) in dimethylformamide, and the resulting mixture was stirred at room temperature for 24 hours after this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off. The residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with step gradient (10 - 40%), and obtain 0.40 g (yield 30%) named in the connection header.

Spectrum of nuclear magnetic connection (CDCL3, 200 MHz), ppm: 8,28 (2H, doublet, J= 9.0 Hz); 7,58 (2H, doublet, J= 9.0 Hz); of 4.38 (2H, Quartet, J= 7,1 Hz); 4.09 to (3H, singlet); to 1.37 (3H, triplet, J= 7,1 Hz).

(b) methoxyimino-4-nitrophenylarsonic acid.

Add 5 ml (10 mmol) of 2N aqueous sodium hydroxide solution to a solution of 1.28 g (5,07 mmol) ethyl-methoxyimino-4-nitrophenylacetate in methanol, and the resulting mixture is stirred over night at room temperature is a Ulfat magnesium, the solvent is distilled off, and get 1.0 g (yield 88%) named the title compound as crude product, which is used in subsequent reactions without further processing.

Spectrum of nuclear magnetic resonance (CDCl3, 200MHz), / , ppm: 8,13 (2H, doublet, J= 9.0 Hz); of 7.48 (2H, doublet, J = 9.0 Hz); 3,95 (3H, singlet).

Preparative example 10. O-methyloxime-4'-nitro-2-hydroxyacetophenone.

(a) 4-Nitrophenylglyoxylate acid.

Add 3 ml (6 mmol) of 2N aqueous sodium hydroxide solution to a solution of 651 mg (2,92 mmol) ethyl-4-nitrophenylglyoxylate in methanol, and the resulting mixture is stirred over night at room temperature. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off, and get 0.8 g (quantitative yield) of crude 4-nitrophenylglyoxylate acid.

(b) 1-(4-Nitrophenyl)-1,2-ethanediol.

At 0oC in a flow of nitrogen, add 7 ml of 1.0 M tertrahydrofuran ring solution of DIBORANE-tertrahydrofuran ring complex to a solution of 0.5 g of crude 4-nitrophenylglyoxylate acid in tetrahydrofuran, and obrazuemogo with ice and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off, and receive 0.56 g (quantitative yield) of crude 2-(4-nitrophenyl)-1,2-ethanediol.

(c) 1-(4-nitrophenyl)-1,2-ethanediol-2-0-tert-butyldimethylsilyloxy ether.

Take first of 0.23 g of imidazole, and then 0.50 g of tert-butyldimethylsilyloxy to a solution of 0.56 g of crude 1-(4-nitrophenyl)-1,2-ethanediol in dimethylformamide under ice cooling, and the resulting mixture was stirred at room temperature for 20 minutes At the end of this time the reaction mixture was poured into water and extracted three times with ethyl acetate portions of 50 ml combined extracts washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel, elwira with ethyl acetate in hexane with stepped gradient (0-30%), and gain of 0.58 g (yield 63%) of 1-(4-nitrophenyl)-1,2-ethanediol-2-0-tert-butyldimethylsilyl ether.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: by 8.22 (2H, doublet, J= 8.7 Hz); 4,84 (1H, multiplet); 3,82 (1H, doublet of doublets, J = 3,9, 10.1 Hz); 3,54 (1H, doublet of doublets, J=7,9, 10.1 Hz); 3,06 (vacation.

Add 3.5 g of manganese dioxide (IV) to a solution of 0.41 g (1,36 mmol) 1-(4-nitrophenyl)-1,2-ethanediol-2-0-tert-butyldimethylsilyl ether in dichloromethane, and the resulting mixture is stirred for 4 h at room temperature. The reaction mixture was then filtered through "Celite" /diatomaceous earth and the filtrate concentrated under vacuum. The residue is purified column chromatography, elwira with ethyl acetate in hexane with stepped gradient (0-25%), and gain of 0.16 (yield 40%) of 4'-nitro-2-tert-butyldimethylchlorosilane.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,32 (2H, doublet, J= 9.0 Hz); 8,11 (2H, doublet, J=9.0 Hz); 4,88 (2H, singlet); of 0.91 (9H, singlet); 0,12 (6H, singlet).

(e) 0-Methyloxime-4'-nitro-2-hydroxyacetophenone.

Add 69 mg of the hydrochloride of O-methylhydroxylamine to a solution of 0.12 g (0.41 mmol) of 4'-nitro-2-tert-butyldimethylchlorosilane (obtained above) in a mixture of methanol (1.2 ml), 1,4-dioxane (2.0) and water (2.0 ml). The resulting mixture is stirred for 1.5 hours at 80oC; then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The residue is purified chromatographytandem in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3, 200 MHz), ppm: 8,25 (2H, doublet, J=8,9 Hz); a 7.85 (2H, doublet, J=8,9 Hz); to 4.73 (2H, doublet, J=6.6 Hz); 4.09 to (3H, singlet); 2,44 (1H, triplet, J=6,6 Hz).

Preparative example 11.

(Stage A). 13-[2-Methoxyimino-2-(4-nitrophenyl)ethoxy]-5-keto-milbemycin A4.

Under ice cooling and argon flow type of 0.13 ml triftormetilfullerenov acid to a solution of 821 mg (1.5 mmol) of 15-hydroxy-5-kelimelerin A4, 1.08 g (5,16 mmol) 2-methoxyimino-2-(4-nitrophenyl)ethanol and 571 mg of copper iodide (I) in 10 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 1 h, the Reaction mixture was then poured into water, and extracted with ethyl acetate. The extract was washed first with 5% aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrate under vacuum, receive 824 mg of crude named in the title compound, which was used in subsequent reactions without further purification.

(Stage B). 13-[2-Methoxyimino-2-(4-nitrophenyl)ethoxy]-milbemycin A4.

Under ice cooling 200 mg (1.01 mmol) of sodium borohydride are added to a solution 824 mg (1.01 mmol) sitate the mixture was stirred at 0oC for 30 minutes the Reaction mixture was then poured into water and extracted with ethyl acetate. The extract is washed first with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrate under vacuum, to obtain 720 mg of crude named in the title compound, which was used in subsequent reactions without further purification.

(Stage C). 13-[2-Methoxyimino-2-(4-AMINOPHENYL)ethoxy]-milbemycin A4.

At room temperature, 130 mg of zinc dust are added to a solution of 150 mg (0.20 mmol) of the crude 13-[2-methoxyimino-2-(4-trienyl)ethoxy]milbemycin A4in 40 ml of 90% acetic acid, and the resulting mixture is stirred for 30 minutes, the Reaction mixture was then mixed with ethyl acetate, and filtered insoluble substances. The filtrate is diluted with water and then extracted with ethyl acetate. The extract is washed with 4% aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, the solvent is distilled, and the residue purified preparative high performance liquid chromatography (column UMC ODS (10 μm), h mm EXT. dia.; elute with a mixture of MeOH-H2O (6:1), 10 ml/min; UV-detection (240 nm)), and obtain 40 mg (yield 28%) named sagc); 6,24 (2H, doublet, J=8.7 Hz); 5,64-5,79 (2H, multiplet); 5,15-5,44 (4H, multiplet); and 4.68 (2H, singlet); however, 4.40 (2H, singlet); the 4.29 (1H, triplet, J=5.7 Hz); 3,98 (1H, doublet, J=5.7 Hz); of 3.94 (3H, singlet).

The product obtained in this way are used as starting substances at the stage of acylation of D in the above examples 32 and 33.

Agrochemical compositions.

When the compounds of the invention are intended for use in agriculture and horticulture, there are various forms and compositions, and their examples are given hereinafter in the examples of the compositions. In these examples, the compound of the invention, which is used, is present in a series of individual compounds are given below in table. 4 - 12. All percentages are mass, and compounds of the invention are numbered, assigned to them in the above table. 1 - 3.

Example composition 1. Wettable powder.

A mixture containing 10% of the compound of the invention (indicated in the table. 4 - 12), 2.5% dodecylbenzenesulfonate sodium 2,5% ligninsulfonate sodium and 85% of diatomaceous earth, mix thoroughly and spray, get a wettable powder.

Example composition 2. Emulsifiable concentrate.

A mixture of 5% of the compound of the invention (ukazyvaiut and get emulsifiable concentrate.

Example of composition 3. Granules.

A mixture containing 3% of the compound of the invention (indicated in the table. 4-12), % "white soot" (trade name for dehydrating agent is silicon dioxide), 5% ligninsulfonate sodium and 91% clay, thoroughly mixed and sprayed, mix well with water, and then to prepare granules, granularit and dried.

Example of composition 4. Emulsifiable concentrate.

Dissolve 2.5% of the compounds of the invention (indicated in the table. 4-12) and 1.0% BHT (antioxidant) in 26.5% of cyclohexanone. The solution is mixed with 50.0% of "Sylgard 309" (silicone surfactant from Dow Corning) and 20% "Excepal" (methyl ester of fatty acid, peanut oil from Kao Co., Ltd.) until smooth, and get emulsifiable concentrate.

Biological action.

The activity of compounds of the invention is illustrated by the following biological tests, the results of which are given in table. 4-12. Compounds of the invention are shown under the numbers used in the above table. 1-3. Connection (C1) to (C10) used as a control for comparison purposes, and their formulas are given (see Fig. 5-7). Connection (C1) to (C4) and (C6) to (C10) disclosed in the publication EB is eriment 1. Insecticidal activity against cabbage moths.

Concentrates of emulsions, obtained as described in example composition 2, and containing 1% of active ingredient, dilute with water to bring the final concentration to 1 ppm. The cabbage leaves were immersed in the mixture for 10 s and then air-dried, and then each sheet was placed in a polyethylene Cup with a diameter of 8 see ten caterpillars of cabbage moths in the third age stage are placed in each Cup, and the Cup is then closed. Cup set in terms thermostatic temperature control at 25oC for 3 days, and then determine the percentage of mortality (including disorders). In each case parallel conduct two tests. The results are shown in table. 4-6, in which the compounds of the invention are numbered, assigned to them above in the table. 1-3.

Experiment 2. Insecticidal effect on well ordinary.

Concentrates of emulsions, obtained as described in example composition 2, and containing 1% of active ingredient, dilute with water to bring the final concentration to 10 ppm. In each of the obtained mixtures are loaded onto 20 with 5 g of artificial feed, and then the feed is dried in the air. Byknowing in the third age, and the cups are closed. Cups are in the conditions of a thermostatically controlled temperature at 25oC for 3 days, and then determine the percentage of mortality (including symptoms of disorders). Each test is carried out in parallel twice. The results are shown in table. 7-9.

Experiment 3. Insecticidal activity against Oriental tea leaf.

Concentrates of emulsions, obtained as described in example composition 2, and containing 1% of active ingredient, dilute with water to a final concentration of 10 ppm. In each of the resulting mixture was immersed in 5 g of artificial diet (Insecta L) at 20 C, and then the feed is dried in the air. It is put in a polyethylene Cup having a diameter of 8 see each Cup is placed on ten caterpillars Oriental tea leafroller in the fourth stage of growth, and the Cup is closed. Cup incubated at 25oC for 3 days, and then determine the percentage of mortality (including disorders). Each test is carried out in parallel twice. The results are shown in table. 10-12.

Experiment 4. Acaricidal activity against Tetranychus urticae.

The sheets of the first order of cow pea plant species Vigna sinensis Savi infect susceptible to orgolsa rotary atomizer Hizubo, 7 ml of the test solution containing the test compound at a concentration of 0.3 ppm, at a rate of 3.5 mg of the test solution on 1 cm2sheet. The condition of the plants evaluated in 3 days, checking out the adult ticks under a binocular microscope to determine live and dead individuals.

Two plants taken for each concentration and for each of the test compounds. During the test plants are kept in greenhouse conditions at 25oC. the Results are shown below.

The compound of example N - Mortality, %

1 - 72 - 100

1 - 73 - 100

1 - 77 - 95

1 - 78 - 95

1 - 79 - 95

1 - 80 - 95

3 - 26 - 90

3 - 27 - 95

3 - 56 - 95.

1. 13-Substituted derivatives milbemycin General formula I

< / BR>
where R1is methyl, ethyl, isopropyl or sec.bucilina group;

R2is a hydrogen atom or a C1- C3is an alkyl group;

X - (a) a group of formula II

< / BR>
where R3is a hydrogen atom or a C1- C4is an alkyl group;

Y is a phenyl group or 5 - to 6-membered heterocyclyl group with one or two heteroatoms in the ring selected from nitrogen, oxygen or sulfur, and these phenyl and heterocyclyl groups are unsubstituted or Casamicciola A;

or X - (b) a group of formula III

< / BR>
where p = 0 or 1;

Z - C2- C3-alcoolica group, C1- C3-alkylsulfonyl group, C2- C5-alkoxycarbonyl group, C2- C7-aminoadenosine group (and linoprint mentioned aminoalkanoic group substituted by 1 or 2 substituents, which may be the same or different and which are selected from the following substituents B, alcoholly fragment mentioned aminoalkanoic group not substituted or substituted phenyl group or a C1- C3-alkylthiophene), (saturated 5 - or 6-membered heterocyclyl)carbonyl group containing a ring nitrogen atom, or containing in the ring nitrogen atoms and sulfur, in which the said nitrogen atom of the ring may be unsubstituted or substituted C2- C5-alkoxycarbonyl, and in which the carbonyl group attached to an atom other than the nitrogen atom of the ring, (5 - or 6-membered lactam)carbonyl group in which a carbonyl group attached to an atom other than the nitrogen atom of the lactam, alkoxyimino- -geterotsiklicheskikh, in which CNS fragment contains from 1 to 3 carbon atoms and heterocyclyl fragment is a 5 - yl) - Rev. x from nitrogen or sulfur, which can be unsubstituted or substituted C2- C5-alkoxycarbonylmethyl, or C2- C3-haloalkaline, 2 to 3 carbon atoms;

the number of substituents And include a halogen atom, a nitro-group, a hydroxyl group, a C1- C4-alkoxygroup, C7- C11-arancelaria, amino group, C1- C4-alkanolamines, C2- C4-halogenoaluminate, C1- C3-alkylsulfonamides, C2- C5-alkoxycarbonylmethyl, C3- C5-halogenocarboxylic, C2- C7-aminoalkylation, in which the amino group in aminoalkanoic fragment may not contain substituents or contain one or two substituent (which may be the same or different) selected from alkoxycarbonyl groups having from 2 to 5 carbon atoms and alkanoyl groups having 2 to 3 carbon atoms, and saturated 5 - or 6-membered heterocyclyl)carbylamine containing ring nitrogen atom, in which the nitrogen atom may be unsubstituted or to be substituted C2- C5-alkoxycarbonyl group, and in which carbonylation attached to an atom other than Ola>3
-alcoolica group, C2- C5-alkoxycarbonyl group, C7- C11-phenylcarbonylamino group, C8- C10-aracelikarsaalyna group, alkoxycarbonylmethyl group containing from 1 to 4 carbon atoms in its CNS side and 2 to 3 carbon atoms in alkanoyloxy part, and alkoxycarbonylmethyl group containing from 1 to 4 carbon atoms in the CNS;

m = 0 or 1;

n = 0 or 1;

provided that when X is a group of formula II, R2is a hydrogen atom, and m and n are not both can be zero,

provided that when X is a group of formula III, R2- C1- C3is an alkyl group, and m and n are both equal to 1.

2. Connection on p. 1, characterized in that X represents a group having the above formula II, the substituents A are selected from a halogen atom, nitro group, hydroxyl group, C1- C4-alkoxygroup, C7- C11-aralkylated, amino, C1- C4-alkanolamines, C2- C4-halogenoaluminate.

3. Connection on p. 1, characterized in that X represents a group having the formula III, in which the Deputy Z-NH - preoedipal group, having the formula II and Y represents a phenyl group which is substituted in paraprotein C1- C3-alkylsulfonamides, C2- C5-alkoxycarbonylmethyl, C3- C5-halogenocarboxylic, C2- C7-aminoalkylindole, in which the amino group aminoalkanoic part may be unsubstituted or substituted by one or two substituents selected from alkoxycarbonyl group having from 2 to 5 carbon atoms, and alkanoyloxy group having 2 or 3 carbon atoms, or a saturated 5 - or 6-membered heterocyclyl)-carbylamines containing ring nitrogen atom (where the said nitrogen atom may not have substituents or may be substituted C2- C5-alkoxycarbonyl, and in which carbonylation attached to an atom other than the nitrogen atom of the ring).

5. Connection on p. 1, characterized in that X represents a group having the formula II where R' is methyl, ethyl, isopropyl or sec. bucilina group, R3is a hydrogen atom, or a methyl or ethyl group, Y is phenyl, perederina, furilla, thienyl, oxazolidinyl or thiazolidine group which may have substituents or to have 1 is fluorine, a chlorine atom, a bromine atom, a nitro-group, a hydroxyl group, a C1- C3-alkoxygroup, C7- C10-urlcategory containing the amino group, alkanolamines containing 1 or 2 carbon atoms, fluorine-, chlorine - or posledney alkanolamines containing 2 or 3 carbon atoms, C1- C3-alkylsulfonamides, alkoxycarbonylmethyl containing 2 or 3 carbon atoms, C2- C5-aminoalkylindole (in which the amino group aminoalkanoic part may be unsubstituted or substituted by a group which is selected from alkoxycarbonyl having 2 to 3 carbon atoms and alkanoyl having 2 or 3 carbon atoms, or 6-membered saturated heterocyclyl) carbonylation containing one ring nitrogen atom (in which the nitrogen atom may not be substituted or may be substituted by alkoxycarbonyl having from 2 to 5 carbon atoms, and carbonylation replaces an atom other than the nitrogen atom of the ring).

6. Connection on p. 5, wherein R1is a methyl or ethyl group, R3is a methyl or ethyl group, Y - furilla, thienyl, thiazolidine, perederina or phenyl group which may be nezamedin is; zamestitel A2include fluorine atom, chlorine atom, bromine atom, hydroxyl group, methoxy group, ethoxypropan, benzyloxy, amino group, acetylamino, monochloroethylene, monobromoacetate, triptoreline, alkylsulfonamides containing 1 or 2 carbon atoms, aminoalkylindole containing 2 or 3 carbon atoms (in which the amino group mentioned aminoalkanoic part may be unsubstituted or substituted by a group which is selected from alkanoyloxy group containing 2 or 3 carbon atoms, and alkoxycarbonyl group containing 2 or 3 carbon atoms), pyrrolidinecarboxamido (in which the nitrogen heteroatom may not be substituted or replaced alkoxycarbonyl group, having 2 or 3 carbon atoms, and carbonylation attached to any other atom, in addition to the nitrogen atom).

7. Connection on p. 5, wherein Y is a phenyl group which may contain substituents or contain in paraprotein Deputy selected from fluorine atom, chlorine atom, bromine atom, hydroxyl group, metoxygroup, ethoxypropan, benzyloxy, amino, acetylamino, monochloroethylene, monobromo is ethylaminoethanol and alkoxycarbonylmethyl, containing 1 or 2 carbon atoms in its alkyl part and 2 or 3 carbon atoms in its alkanolamines.

8. Connection on p. 5, wherein R1- ethyl group, R3is a methyl group, Y is a phenyl group or a phenyl group substituted in paraprotein methylsulfonylamino or methoxycarbonylaminophenyl, and m = 0, n = 1.

9. Connection on p. 5, wherein X is a group having formula III, Z is alkanoyloxy group containing 2 or 3 carbon atoms, alkylsulfonyl group containing from 1 to 3 carbon atoms, alkoxycarbonyl group containing 2 or 3 carbon atoms, aminoalcohols group containing from 2 to 6 carbon atoms (in which the amino group may be unsubstituted or substituted by 1 or 2 substituents, which may be the same or different, selected from substituents B2, which are defined below, and alcoolica group can be unsubstituted or substituted phenyl group or alkylthiol containing 1 or 2 carbon atoms), (5 - or 6-membered heterocyclyl)carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl the nitrogen atom), (5-membered-lactam)carbonyl group in which a carbonyl group attached to an atom in position 5, and alkoxyimino--geterotsiklicheskikh in which heterocyclyl component represents a 5-membered aromatic heterocyclic group which may be substituted or substituted alkoxycarbonyl group having from 2 to 5 carbon atoms or haloalkaline having 2 to 3 carbon atoms and in which part alkoxyimino contains 1 or 2 carbon atoms, and the substituents B1include alkyl group containing from 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, alkoxycarbonyl group containing from 2 to 5 carbon atoms, phenylcarbonylamino group containing from 7 to 11 carbon atoms, and alkoxycarbonylmethyl group, in which alkoxycarbonyl constituent contains from 2 to 5 carbon atoms and alcoolica part contains 2 or 3 carbon atoms.

10. Connection on p. 9, wherein R1is a methyl or ethyl group, Z - alcoolica group containing 2 or 3 carbon atoms, alkylsulfonyl group containing from 1 to 3 carbon atoms, aminoadenosine group containing from 2 to 5 and2, which are defined below, and alcoolica group may have substituents or be replaced by methylthioribose), and (5 - or 6-membered heterocyclyl) carbonyl group containing a heteroatom of nitrogen (in which the heteroatom nitrogen may be unsubstituted or substituted alkoxycarbonyl group having from 2 to 5 carbon atoms) substituents B2include alkyl group containing from 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, alkoxycarbonyl group containing from 2 to 5 carbon atoms, and phenylcarbonylamino group containing from 7 to 11 carbon atoms.

11. Connection on p. 9, characterized in that the Deputy Z-NH - is paraprotein phenyl ring group of the formula III, and Z represents alkylsulfonyl group containing 2 or 3 carbon atoms, aminoalcohols group containing from 2 to 4 carbon atoms (in which the amino group optionally may be substituted by 1 or 2 substituents selected among the deputies of the B2, which are defined below), and (5-membered heterocyclyl)carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl group, owls carbon alkanoyloxy group containing 2 or 3 carbon atoms, alkoxycarbonyl group containing from 2 to 5 carbon atoms, and phenylcarbonylamino group containing from 7 to 11 carbon atoms.

12. Connection on p. 9, wherein R1- ethyl group, R2is a methyl group, p = 0, the Deputy Z-NH - is paraprotein phenyl ring, Z - aminoadenosine group containing 2 or 3 carbon atoms (in which the amino group may contain substituents or contain the Deputy selected from substituents B3, which are defined below), or (saturated 5-membered heterocyclyl)carbonyl group containing a heteroatom of nitrogen in which the nitrogen heteroatom may be replaced or substituted alkoxycarbonyl group having 2 or 3 carbon atoms), and the substituents B3include alkyl group containing from 1 to 3 carbon atoms, alkanoyloxy group containing 2 or 3 carbon atoms, and alkoxycarbonyl group containing 2 or 3 carbon atoms.

13. Connection on p. 1, which is chosen from the group which includes:

13-(-methoxymethylethoxy)milbemycin AND4(isomer A),

13-(-methoxymethylethoxy)milbemycin AND4(isomer B),4-methanesulfonylaminoethyl)acetoxy]-milbemycin AND4,

13-[-methoxyimino-(4-acetylaminofluorene)-acetoxy] -milbemycin AND4,

13-[-methoxyimino-(4-methoxycarbonylaminophenyl)-acetoxy] -milbemycin AND3,

13-[-methoxyimino-(4-methoxycarbonylaminophenyl)-acetoxy] -milbemycin AND4,

13-[2-(4-methoxycarbonylaminophenyl)-2-methylpropionate] -milbemycin AND3,

13-[2-(4-methoxycarbonylaminophenyl)-2-methylpropionate] -milbemycin AND4,

13-[2-(4-benzylaminocarbonyl)-2-methylpropionate] -milbemycin AND4,

13-[2-(4-(N-methyl)methoxycarbonylaminophenyl) -2-methylpropionate]-milbemycin AND4,

13-[2-[4-{ 2-(methoxycarbonylamino)propionamido}-phenyl]-2-methylpropionate]-milbemycin AND4,

13-[2-[4-{ 2-(methoxycarbonylamino)-2-methylpropionamide} -phenyl]-2-methylpropionate] -milbemycin AND4and

13-[2-[4-[(1-ethoxycarbonylpyrimidine)-2-carbylamine] -phenyl] -2-methylpropionate]-milbemycin AND4.

14. Acaricidal and insecticidal composition comprising an active substance - derived milbemycin and target additives, characterized in that, as specified derived milbemycin it contains 13-C the th group;

R2is a hydrogen atom or a C1- C3is an alkyl group;

X - a) a group of formula II

< / BR>
where R3is a hydrogen atom or a C1- C4is an alkyl group;

Y is a phenyl group or 5 - to 6-membered heterocyclyl group with one or two heteroatoms in the ring selected from nitrogen, oxygen or sulfur, and these phenyl and heterocyclyl groups are unsubstituted or substituted by 1 or 2 substituents (which may be the same or different) selected from the following substituents;

or X - b) a group of formula III

< / BR>
where p = 0 or 1;

Z - C2- C3-alcoolica group, C1- C3-alkylsulfonyl group, C2- C5-alkoxycarbonyl group, C2- C7-aminoadenosine group (and aminocell mentioned aminoalkanoic group is substituted by 1 or 2 substituents, which may be the same or different and which are selected from the following substituents B, and alcoolica part of these aminoalcohols group is unsubstituted or substituted phenyl group or alkylthiol containing from 1 to 3 carbon atoms), (saturated 5 - or 6-membered heterocyclyl)carbonyl gr>-alkoxycarbonyl, and in which the carbonyl group attached to an atom other than the nitrogen atom of the ring, (5 - or 6-membered lactam)carbonyl group in which a carbonyl group attached to an atom other than the nitrogen atom of the lactam, alkoxyimino--geterotsiklicheskikh, in which CNS portion contains from 1 to 3 carbon atoms, and heterocyclyl part is a 5 - or 6-membered aromatic heterocyclic group containing one or two ring heteroatoms selected from nitrogen or sulfur, which can be not substituted or substituted C2- C5-alkoxycarbonylmethyl,

the number of substituents And include a halogen atom, a nitro-group, a hydroxyl group, a C1- C4-alkoxygroup, C7- C11-arancelaria, amino group, C1- C4-alkanolamines, C1- C3-alkylsulfonate group, C2- C7-aminoalkylation, in which the amino group in aminoalkanoic fragment may not contain substituents or contain one or two substituent (which may be the same or different) selected their alkoxycarbonyl groups having from 2 to 5 carbon atoms and alkanoyl groups, having the e a nitrogen atom, in which the said nitrogen atom may be unsubstituted or to be substituted C2- C5-alkoxycarbonyl group and in which carbonylation attached to an atom other than the nitrogen atom of the ring;

the substituents B are C1- C3is an alkyl group, a C2- C3-alcoolica group, C2- C5-alkoxycarbonyl group, C7- C11-phenylcarbonylamino group, C8- C10-aracelikarsaalyna group, alkoxycarbonylmethyl group containing from 1 to 4 carbon atoms in its CNS side and from 2 to 3 carbon atoms in alkanoyloxy part, and alkoxycarbonylmethyl group containing from 1 to 4 carbon atoms in the CNS part, m = 0 or 1 and n = 0 or 1;

provided that when X is a group of the above formula II, R2is a hydrogen atom and m and n are not both equal to zero;

provided that when X is a group of the above formula III, R2- C1- C3is an alkyl group, m and n are both equal to 1,

in an effective amount.

15. The composition according to p. 14, wherein X is a group having formula II, the substituents And selected from a halogen atom, nitro group, hydroxyl group, C1- C4

16. The composition according to p. 14, wherein X is a group having the formula III, in which the Deputy Z-NH - attached paraprotein phenyl ring.

17. The composition according to p. 14, wherein X is a group having formula II, and Y is a phenyl group which is substituted in paraprotein C1- C3-alkylsulfonamides, C2- C7-aminoalkylindole, (in which the amino group aminoalkanoic part may be unsubstituted or substituted by one or two alkoxycarbonyl group having from 2 to 5 carbon atoms or alkanoyloxy group having 2 or 3 carbon atoms), or Y is a 5 - or 6-membered saturated heterocyclyl)carbylamines containing one ring nitrogen atom (in which the nitrogen atom may not be a substituent or may be present Deputy, choose from alkoxycarbonyl having from 2 to 5 carbon atoms, and carbonylation attached to an atom other than the nitrogen atom of the ring).

18. The composition according to p. 14, characterized in that the compound is chosen from the group defined in paragraph 13.

19. Method of protecting plants from damage by parasites selected from the group consisting of mites and insects, by processing plants or alot compound of General formula I under item 14.

20. The method according to p. 19, characterized in that the active compound is selected from compounds of the formula I under item 15.

21. The method according to p. 19, characterized in that the active compound is selected from compounds of the formula I according to p. 16.

22. The method according to p. 19, characterized in that the active compound is selected from compounds of the formula I on p. 17.

23. The method according to p. 19, characterized in that the active compound selected from the group defined in paragraph 13.

Priority points:

01.04.94 - p. 2;

17.11.94 - p. 3;

25.01.95 - p. 4.

 

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The invention relates to a method of obtaining new compounds with antibiotic

The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture

The invention relates to a series of new derivatives of compounds known as "milbemycin", which are characterized by the presence of heterocyclic substituted mercaptoacetate group at the 13-position

The invention relates to certain 13-alkyl-23-imino - 13-halogen-23-imino-LL-F28249-compounds and to their use for combating endo - and ectoparasitic infections and infestations in warm-blooded animals

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

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whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

FIELD: agriculture.

SUBSTANCE: invention describes a method for feeding potato and tomato with 6-benzylaminopurine an aqueous solution taken in the concentration 10-4 M and growing pants up to preparing harvest according to technology accepted for the culture crop. Invention proposes 3-fold treatment of plants for vegetation: at the lateral branching phase, at onset of forming economically value organs and immediately after the growth termination. Method provides the effective enhancing the productivity of the most important vegetable crops - tomato and potato.

EFFECT: improved enhancing method.

6 tbl, 4 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

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