New nitromethylene, method for their production and compositions containing them


C07D333/70 - attached in position 2
C07C311/60 - having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings

 

(57) Abstract:

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1. Also described is a method of obtaining these compounds and pharmaceutical composition for inhibiting alsoreported based on them. The technical result obtained new compounds with useful biological properties. 7 C. and 10 C.p. f-crystals, 8 PL.

The invention relates to new nitromethylene, to receive them and their use as pharmaceuticals, particularly in the treatment and prevention of complications in diabetes.

Diabetes is characterized by high concentration of glucose in the blood. During normal metabolism in the first stage of glycolysis this glucose by the enzyme hexokinase undergoes transformation, leading to the breakdown to pyruvate. To the threat passes through the second path, which is paleology path, comprising the sequential action of two enzymes, i.e., alsoreported, which converts glucose into sorbitol and sarbadhikary that turns sorbitol into fructose. In the case of diabetes, the excess glucose accelerates the formation of sorbitol, which tends to accumulate. The result is a serious metabolic disorder, such as, for example, the increase in osmotic pressure, which can lead to degeneration of the tissue. Thus, for the treatment or prevention of some complications of diabetes, can be used inhibitors alsoreported.

The literature describes a number of such products as inhibitors alsoreported who are action both in vitro and in vivo.

They are mainly derivatives of hydantoins, suktinimidov and derivatives of acetic acid, and the later derivatives of sulfonylmethane.

The present invention relates to nitromethylene derived and their additive salts with physiologically acceptable bases corresponding to General formula (I):

< / BR>
where And denotes6-C10aryl or naochnih heteroatoms, selected from O, S and N,

X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy - or cryptometer,

R1and R2may be the same or different and each represents hydrogen, C1-C7alkyl, C3-C12cycloalkyl, trifluoromethyl or1-C7alkoxygroup or R1and R2together form alkylenes chain type -(CH2)r- where the value r is chosen from 2, 3 and 4

p is chosen from 0, 1, 2, 3, 4 and 5,

Z represents a bond, divalent radical-CO-NH-, in which the carbonyl group is linked to R3, the divalent radical-SO2-NH-, in which sulfonylurea group associated with R3WITH2-C7alkenylamine radical, a sulfur atom, sulfinyl group or sulfonyloxy group

R3denotes hydrogen, halogen, three(C1-C7alkyl)silyl,1-C7alkyl, optionally substituted by one or more identical or different radicals Y6-C10aryl, optionally substituted by one or more identical or different radicals Y6-C10alloctype, optionally substituted by one or more of the same and which are all the same or different radicals Y, optional aromatic three-deletechannel a heterocycle, containing from one to four identical or different heteroatoms selected from O, S and N, and the heterocycle optionally substituted by one or more identical or different radicals Y, or R3means of indanyl, 1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl, 1,3-benzodioxolyl, 2-oxopiperidine or 2-[(4-nitromethylene-3-chlorophenyl)aminocarbonyl]-1-(phenyl)ethyl,

Y represents halogen, C1-C7alkyl, C1-C7alkoxygroup, trifluoromethyl, carboxy, carbarnoyl,1-C7allylcarbamate, di(C1-C7)allylcarbamate,1-C7alkoxycarbonyl, amino, C1-C7alkylamino-, di(C1-C7)alkylamino-, nitro-, cyano, hydroxyl, cryptometer,3-C12-cycloalkyl, sulfo-FROM1-C7allylthiourea,1-C7alkylsulfonyl,1-C7alkylsulfonyl, C2-C8alkylsulphonyl,2-C8alkylthiomethyl,2-C8alkylcarboxylic or6-C10aryl,

E denotes a divalent radical selected from the group including

(I) a radical-CO-NR4- which carbonyl is ybiraut from 0 and 1 and where R5denotes hydrogen, or including next1-C7alkyl, C6-C10aryl or optionally aromatic three - deletechannel a heterocycle, containing from one to four identical or different heteroatoms selected from O, N and S, or R5and R3together form a bond,

(II) the radical-SO2-NR4- which sulfonylurea group is associated with -(CR1R2)p- and the values of R4above,

(III) a radical-NR4- which values of R4above,

(IV) a radical-CH=N-, in which the nitrogen atom is linked to A, and

(V) oxygen,

n denotes 0 or 1,

provided that-A(X)-(E)n-(CR1R2)p-Z-R3doesn't mean haloethanol, were, dichlorophenyl, dimetilfenil, 4-ethoxy-2-methylaminophenol, methylindolin, dimethylindole, 2-hydroxyphenyl substituted by a group X, 2-methoxyphenyl, substituted by a group X and optionally substituted 2-forfinal, as described above, and provided that when a represents pyridyl, X denotes methyl, n is 1, and E does not denote a radical-NR4-.

These compounds are inhibitors of the enzyme alsoreported and can be used in the treatment or prevention of complications is SNA, such as cataract and retinopathy.

Physiologically acceptable salts of the compounds of formula (I) include salts formed with metals (such as sodium, potassium, calcium, magnesium, aluminum), bases such as ammonium hydroxide and substituted amines (e.g., diethylamine, triethylamine, piperidine, piperazine, morpholine), basic amino acids (such as lysine, arginine), asaminami (such as meglumine) or aminoalcohols (such as 3-aminobutanol, 2-aminoethanol).

The term "aryl" means an aromatic mono - or bicyclic group containing 6-10 carbon atoms, such as phenyl or naphthyl.

The term "heterocycle" refers to a mono - or bicyclic aromatic ring or otherwise, containing 3 to 10 ring carbon atoms, 1-4 of which are the same or different heteroatoms selected from oxygen, sulfur and nitrogen, such as, for example, aziridinyl, oxiranyl, oxazolyl, furyl, tetrahydrofuranyl, thienyl, imidazolyl, pyridyl, pyrazinyl, benzothiazyl, benzopyranyl, benzofuran, benzothiazole, pyrimidinyl, pyridazinyl, piperidinyl, hinely, tetrahydropyranyl, tetrazolyl, phthalazine, purinol, indolyl, bromanil, bromanil, isopropanol and pyrrolyl.

The term "halogen" is used to denote an atom of fluorine, chlorine, bromine or iodine.

The term "alkyl" is used to denote a linear or branched hydrocarbon radical, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl.

The term "alkoxygroup" refers to an alkyl group attached to an oxygen atom. Her examples are methoxy, ethoxy, isopropoxy, butoxy, hexyloxymethyl.

Similarly, the term "alloctype" refers to aryl radical, as defined above linked to an oxygen atom, such as phenoxy and naphthalocyanines.

In the context of the present invention, the term "alkenylamine" radical is understood to mean, inter alia, the divalent hydrocarbon radical bearing one or more ethylene double bonds, such as, for example, -CH= CH-CH2- or-CH=CH-CH=CH-.

The concept of "carbamoyl" radical denotes a monovalent radical of the formula-CO-NH2. Radical "(1- 1-C7)allylcarbamate" mean carbamoyl radical substituted on the nitrogen atom WITH two1-C7alkyl groups.

Radical "(1-C7)alkoxycarbonyl" called the radical R-O-CO-, in which R denotes a1-C7alkyl group.

Radical "(1-C7)alkylamino" is called the amino group, substituted on the nitrogen atom WITH1-C7alkyl radical, and radical "di(C1-C7)alkylamino" means the amino group, the nitrogen atom is substituted by two (C1-C7)alkyl radicals.

The terms "allylthiourea", "alkylsulfonyl" and "alkylsulfonyl" refers to an alkyl group attached to the sulfur atom, which respectively is oxidized, minoocycline or dicyclanil such as methylthiourea, methylsulfinyl or methylsulphonyl.

Some compounds of this type are known. For example, in DE 2415350 described antiallergic compounds of the formula

< / BR>
where R1, R2, R3and R4may be the same or different and each may denote a hydrogen atom or the halogen, alkyl, alkoxy, aryl or arylalkyl group gets the e compounds of General formula

< / BR>
in which Rodenotes hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, (C3-C6)alkenyl or (C3-C6)quinil or a radical of the formula

< / BR>
In EP 0574231 described with antibiotic action nitromethylene derivatives associated with polyamidine the naphthirydines and quinoline.

The literature describes other nitromethylene derivatives, for example, as intermediate products of the synthesis, but in previously published sources do not contain information about the possibility of therapeutic applications of these compounds. You can mention, for example, J. SETER, Israel J. Chem. (1966) 4, 7-22, BAKER D. C. and PUTT S. R., Synthesis (1978) 678-9, FIELD G. F. and ZALLY W. J., Synthesis (1979) 295-6, and Yasumasa HAMADA and others, Chem. Pharm. Bull. (1981) 29, 259-61.

Known nitromethylene derivatives do not meet the formula (I), which correspond to the compounds according to the invention. Moreover, it is not described none of these compounds as having any inhibitory effect on alsoreported.

Preferred compounds according to the invention are those in which in formula (I):

And denotes phenyl, n and p represent 0, Z OPP-CO-NR4- in particular, those for which p represents 1, R1and R2denote hydrogen, and Z represents a bond, or

And denotes phenyl, n is 1, E denotes the group-SO2-NR4- or

And denotes phenyl, n is 1, E represents a group-CO-NR4-, p is 0, and Z represents the group-SO2-NH-, or

And refers to an aromatic heterocycle, such as benzothiazyl or thienyl, or

And denotes naphthyl, or

n denotes 1, and E denotes the oxygen.

Another group of preferred compounds includes compounds of formula

< / BR>
in which

And denotes phenyl, naphthyl, benzothiazyl or thienyl,

X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy - or cryptometer,

R1and R2each denotes hydrogen or R1and R2together form alkylenes chain type -(CH2)r- where the value r is chosen from 2, 3 and 4

p is chosen from 0, 1, 2 and 3

Z represents a bond, divalent radical-CO-NH-, in which the carbonyl group is linked to R3or the divalent radical-SO3-NH-, in which sulfonylurea group associated with R3,

R3denotes a hydrogen atom, a C13-C12cycloalkyl group, optionally substituted by one or more identical or different radicals Y, benzothiazyl, benzofuran, or R3denotes 1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl or 2-oxopiperidin,

Y represents halogen, C1-C7alcohop, trifluoromethyl, carboxy, cryptometer or phenyl,

E denotes a divalent radical selected from the group including

(I) a radical-CO-NR4- whose carbonyl group is associated with -(CR1R2)p-, a R4represents the radical -(CH2)qR5where the value of q is chosen from 0 and 1, a R5denotes hydrogen, and includes WITH1-C7alkyl or phenyl group,

(II) the radical-SO2-NR4- which sulfonylurea group is associated with -(CR1R2)p- and the values of R4above,

(III) a radical-NR4- which values of R4above,

(IV) a radical-CH=N-, in which the nitrogen atom is linked to A, and

(V) hydrogen

n abonl, were, dichlorophenyl, dimetilfenil, 4-ethoxy-2-methylaminophenol, methylindolin, dimethylindole, 2-hydroxyphenyl substituted by a group X, 2-methoxyphenyl, substituted by a group X and optionally substituted 2-forfinal, as described above, and provided that when a represents pyridyl, X denotes methyl, n is 1, and E does not denote a radical-NR4- as well as their additive salts of pharmaceutically acceptable bases.

Among the preferred compounds according to the invention can be mention

(1) the nitro methyl-2-triftormetilfullerenov;

(2) nitro methyl-2-cyanovinylene;

(3) a nitro methyl-2-ethylphenidate;

(4) a nitro methyl-2-triftormetilfullerenov;

(5) a nitro methyl-2-ethoxyphenylacetic;

(6) nitro methyl-2-isopropylacetanilide;

(7) nitro methyl-2-methyl-1-nafcillin;

(8) a nitro methyl-3-chloro-2-nafcillin;

(9) a nitro methyl-3-chlorobenzo[b]Tien-2-Ilkeston;

(10) a nitro methyl-6-methoxy-5-trifluoromethyl-1-nafcillin;

(11) 4-methyl-N-[2-nitromethylene-3-methylbenzo[b] Tien-5-yl]-benzosulfimide;

(12) N-(3-chloro-4-nitromethylene)ndimethylacetamide;

(13) nitro methyl-4-amino-2-chlortrimaton;

(14) N-(3-chloro-4-nitromethylene)benzamide;

(15) N-(3-chloro-4-micrometeorological)-4-methoxybenzamide;

(18) N-(3-chloro-4-nitromethylene)-2-cryptomelane;

(19) N-(3-chloro-4-nitromethylene)-2,2,3,3-tetramethylcyclopropanecarboxylate;

(20) N-(3-chloro-4-nitromethylene)hexanamide;

(21) N-(3-chloro-4-nitromethylene)cyclopentylacetic;

(22) N-(3-chloro-4-nitromethylene)-3-phenylpropanamide;

(23) N-(3-chloro-4-nitromethylene)-2-phenylpropanamide;

(24) N-(3-chloro-4-nitromethylene)phenylacetamide;

(25) N-(3-chloro-4-nitromethylene)benzo[b]thienyl-2-carboxamide;

(26) N-(3-chloro-4-nitromethylene)benzofuran-2-carboxamide

(27) N-(3-chloro-4-nitromethylene)-4-chlorophenoxyacetate;

(28) 2-chloro-N-(3-chloro-4-nitromethylene)phenylacetamide;

(29) N-(3-chloro-4-nitromethylene)-1-(4-chlorophenyl)-cyclopropanecarboxamide;

(30) N-(3-chloro-4-nitromethylene)-2-triftormetilfullerenov;

(31) N-(3-chloro-4-nitromethylene)-4-chlorobenzenesulfonamide

(32) N-(3-chloro-4-nitromethylene)benzosulfimide;

(33) the nitro methyl-4-[N,N-di(phenylmethyl)amino]-2-chlortrimaton;

(34) N-(2-chloro-3-nitromethylene)ndimethylacetamide;

(35) N-(2-chloro-3-nitromethylene)-2-methylphenylacetic;

(36) N-(>/BR>(38) N-(4-chloro-3-nitromethylene)benzosulfimide;

(39) 2-[(3-chloro-4-nitromethylene)aminocarbonylmethyl]benzoic acid;

(40) N-(3-chloro-4-nitromethylene)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-ylacetamide;

(41) 1-(3-chloro-4-nitromethylene)-3-vinylsulfonylacetamido;

(42) the nitro methyl-3-methyl-2-titillation;

(43) N-(3-chloro-4-nitromethylene)-2-methylphenylacetic;

(44) N-(3-chloro-4-nitromethylene)-2-oxopiperidin;

(45) N-(3-chloro-4-nitromethylene)-1-(4-chlorophenyl)-cyclopentanecarboxylic;

(46) N-(3-chloro-4-nitromethylene)indan-2-ylacetamide;

(47) N-(3-chloro-4-nitromethylene)-4-chlorophenylacetic;

(48) N-(3-chloro-4-nitromethylene)-3-chlorophenylacetic;

(49) N-(3-chloro-4-nitromethylene)-3,4-dichlorophenylacetamide

(50) N-(3-chloro-4-nitromethylene)-4-methylphenylacetic;

(51) N-(3-chloro-4-nitromethylene)-3-methylphenylacetic;

(52) N-(3-chloro-4-nitromethylene)-3,4-dimethylphenylacetate;

(53) N-(3-chloro-4-nitromethylene)-4-triftormetilfullerenov;

(54) N-(3-chloro-4-nitromethylene)-4-methoxyphenylacetamide;

(55) N-(3-chloro-4-nitromethylene is-chloro-4-nitromethylene)-4-perforated;

(58) N-(3-chloro-4-nitromethylene)-3-phenyl-2-propenamide;

(59) N-(3-methyl-4-nitromethylene)-2-methylphenylacetic;

(60) N-(2-bromo-4-nitromethylene)-2-methylphenylacetic;

(61) a nitro methyl-2-chloro-4-methoxyphenylacetone;

(62) the nitro methyl-2-isopropylaniline;

(63) N-(4-chloro-2-nitromethylene)-2-methylphenylacetic;

(64) a nitro methyl-2-chloro-4-phenylthiophene;

(65) N-(3-chloro-4-nitromethylene)-4-(3-chloro-4-nitratecontaminated)-3-phenylbutane;

(66) a nitro methyl-2-chloro-4-phenylsulfonylacetate;

(67) the nitro methyl-4-chloro-2-triftormetilfullerenov;

(68) N-[2-(3-chloro-4-micrometeorological)] -2-methyl-benzosulfimide;

(69) N-(3-bromo-4-nitromethylene)-2-methylphenylacetic;

(70) N-(3-chloro-4-nitromethylene)-N-isopropylbenzenesulfonyl.

Compounds according to the invention receives, for example, in accordance with the following choices (a) and (B) of the method.

(A) the Products of formula (I) can be obtained from the carboxylic acids of the formula (II)

< / BR>
in the result of the interaction of di(C1-C7)alkylsulfonate and nitromethane in the presence of a base in a solvent that is inert in relation to conentration. Acceptable molar ratio between the carboxylic acid of formula (II) and nitromethane ranges from 0.6: 1 to 2:1, preferably in the range from 0.8:1 to 1.2:1. Preferred used is based on Amin, alkylate, a hydride of an alkali metal, a carbonate of an alkali metal, an alkali metal hydroxide or alcoholate of an alkali metal, in particular triethylamine, pyridine, utility, sodium hydride, potassium carbonate, potassium hydroxide or tert-piperonyl potassium, the ratio between the carboxylic acid of formula (II) and the base in the range of 0.2:1 to 0.5:1, preferably at a ratio of 0.4:1.

Usually the reaction temperature ranges from -78oC to the boiling point of the solvent (under reflux), preferably in the range from -5 to 80oC. Typically, the duration of reaction is 2-72 h, preferably 2-18 h

(B) alternatively, the product of formula (I) can be obtained from the carboxylic acids of the formula (II) by pre-transformation phenyl ether of the formula (III) according to reaction scheme 1 (see the end of the description).

a) the Process of obtaining phenyl ester (III) can be done by conducting sequential or simultaneous Rhea components of the reaction mixture. When using solvent, they in the preferred embodiment, serves as an aprotic solvent, such as dichloromethane, benzene or toluene. At this first stage, the preferred molar ratio between SOCl2or l3and carboxylic acid of formula (II) ranges from 1/1 to 50/1, more preferably is 10/1. Equally preferred molar ratio between the carboxylic acid and phenol is from 1/0,9 to 1/1,2, more preferably is 1/1,05. The reaction is preferably carried out at a temperature ranging from -78oC to the boiling point of the solvent (under reflux), preferably in the range of 0oC to the boiling point of the solvent. The duration of this reaction is equal 1-48 hours, preferably 1-8 hours

b) Next, the thus obtained phenyl esters of the formula (III) is treated with nitromethane in the presence of a base at a temperature in the range of 20oC to the boiling point of the solvent, preferably in the range from 20 to 40oC. the Duration of the reaction, it is expedient to vary within 2-72 hours, preferably within 2-48 hours At this stage created the molar ratio between the compound is avno 1/3. As an acceptable base is usually used, for example, a hydroxide of an alkali metal, a carbonate of an alkali metal, alkali metal hydride, alkylate, amine or alcoholate of an alkali metal. Thus, the base can be, for example, from tert-butoxide potassium, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, utility and pyridine. The preferred molar ratio of phenyl ether of the formula (III) and the base is usually in the range from 1/1 to 1/5, and in the preferred embodiment, this molar ratio is 1/3.

The compounds of formula (I) can be obtained in other ways.

When in the above formula (I) the value of n equal to 1 and E represents a group-CO-NR4the compounds according to the invention can be obtained by the reaction of galodamadruga acid of formula R3-Z-(CR1R2)p-CO-hal, where R1, R2, R3, Z and p have the above values, a, hal denotes a halogen atom, with an amine of formula (IV)

< / BR>
in which a and X have the meanings indicated above.

This method is carried out in the presence of a base, preferably an amine, such as pyridine, triethylamine and dimethylaminopyridine, dissolve the reflux), for example, in the range from 0 to 40oC. the Duration of the reaction is 2-48 h

Examples of preferred solvents are dichloromethane, tetrahydrofuran, benzene or toluene.

When in the above formula (I) the value of n is 1, and E denotes the group-SO2-NR4the compounds according to the invention can be obtained by the reaction of sulphonylchloride formula R3-Z-(CR1R2)p-SO2-hal, where R1, R2, R3, Z and p have the above values, a, hal denotes a halogen atom, with an amine of formula (IV), which is presented above. In this case, the method is carried out in the presence of a base in a solvent and at a temperature of from -20oC to the boiling point of the solvent (under reflux). Preferred process conditions such as these for interaction galodamadruga with the amine of the above formula (IV).

Alternatively, in the first case, a possible synthesis of the benzyl ether of formula (III)

< / BR>
in accordance with one of the reaction stages (I) to(VI) below, and then processing benzyl ether of formula (III) interaction with nitromethane in the presence of a base, as it presents the s formula R3-Z-(CR1R2)p-CO-hal, where R1, R2, R3, Z and p have the above values, a, hal denotes a halogen atom, with an amine of formula (V)

< / BR>
in which a and X have the meanings mentioned above,

- on stage (II), when n is 1, and E denotes the group-SO2-NR4- conduct the reaction sulphonylchloride formula R3-Z-(CR1R2)p-SO2-hal, where R1,

R2, R3, Z and p have the above meanings and hal denotes a halogen atom, with an amine of formula (V) given above,

- on stage (III) when n is 1, and E represents-NR4- conduct the reaction of the compound of formula R3-Z-(CR1R2)p-hal, where R1, R2, R3, Z and p have the above meanings and hal denotes a halogen atom, with an amine of formula (V) given above,

- on stage (IV), when the value of n equal to 1 and E represents-CH=N-, conduct the reaction of the aldehyde of the formula R3-Z-(CR1R2)p-CHO, where R1, R2, R3, Z and p have the above meanings, with an amine of formula (V) given above,

- on stage (V), when n is 1, and E represents-O-, conduct the reaction of the compound of formula R3-Z-(CR1R2)p-hal, where R1R<

in which a and X have the meanings mentioned above,

- on stage (VI), when n is 1, and E denotes-CO-NR4-, p denotes Oh, and Z represents the group-SO2-NH-, conduct the reaction of the isocyanate of formula R3-SO2-NH= C= O where R3have the above meanings, with an amine of formula (V) given above,

- on stage (VII), when n is 1, and E denotes-CO-NR4- conduct the reaction of the acid of formula R3-Z-(CR1R2)p-COOH, where R1, R2, R3, Z and p have the above meanings, with an amine of formula (V) given above.

Some compounds of formula (I) can be obtained from compounds of formula (I) implementation of simple stages of transformation.

For example, the compounds of formula (I) in which n is equal to 1, E represents a group-CO-NH-, p denotes 1, R1and R2denote hydrogen, Z represents a bond, a R3denotes 1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl, can be obtained from corresponding compounds (in which a and X have the same values), in which n is equal to 1, E represents a group-CO-NH-, p denotes 1, R1and R2denote hydrogen, Z represents a group-CO-NH-, a R3denotes 2-carboxyphenyl, by reaction with hydrochloric acid.

The compounds of formula (IV) can be easily synthesized from commercially available compounds by methods in the art known.

For example, the compounds of formula (IV) can be obtained from the corresponding amines of formula (VII)

NH2-A(X)COOPh (VII)

in accordance with a process comprising the following stages:

- protection of the amino group protecting group, such as (C1-C7)alkylcarboxylic group, for example acetyl,

- interaction protected amine with di(C1-C7-alkylsulfonates and nitromethane in the presence of a base, and then

- delete a group protecting the amino group, for example, the influence of sodium hydroxide, when the protecting group is acetyl group.

Shot down can be confirmed by the results presented below standard laboratory tests.

1) in vitro: inhibition alsoreported

Used alsoreported get from the lenses of male Wistar rats in accordance with a modified method of S. HAYMAN and others (Journal of Biological Chemistry 240. page 877, 1965). The enzyme extract was diluted with phosphate buffer in the presence of adenine dinucleotide phosphate and test products at various concentrations. L-glyceraldehyde initiate the reaction and the reaction rate is determined according to the observations of the disappearance of adenine dinucleotide phosphate by using a spectrophotometer at 340 nm. The speed of this reaction is calculated for each concentration of the product, and then by linear interpolation to determine the concentration required for 50% reduction of the reaction rate (IR50). Obtained in this experiment the results are presented in table 1 below.

2) in vivo: fewer cumulative sorbitol

In male Wistar rats weighing 200-250 g intravenous injection streptozotocin (at a dose of 60 mg/kg) to induce diabetes. Then after 4, 30 and 50 h after injection of streptozotocin rats orally administered test products in the form of suspension. Eighteen hours after the last perorally nerve. After extraction according to the enzymatic method described by H. U. BERGMEYER (Methods of enzymatic analysis. , edited by H. U. BERGMEYER, Academic Press, new York, 3, pp. 1323, 1974) define the content of sorbitol in the nerve.

The percentage degree of protection with each product for a group of diabetic animals count, whereas the content of sorbitol in the sciatic nerve of animals without diabetes.

As an example, in table.1 presents the results obtained for some of the tested products.

Compounds according to the invention can be used as drugs as inhibitors alsoreported, and they are particularly effective in the treatment of complications of diabetes such as cataract and retinopathy, a disease of the nervous system, nephropathy and some vascular diseases. The daily dose can be varied in the range of 5-200 mg of active substance.

These medicinal substances can be administered orally in the form of tablets, gelatin capsules or granules with immediate or controlled release of the active substance, intravenous injection in the form of solution for injection, transdermally in the form of adhesive means for percutaneous injection oral injection, comprising as active substance a compound according to the invention is prepared by adding to this connection of the filler, and optionally a binder, baking powder, lubricant, dye, corrigenda and manufacture of such a mixture of tablets, coated tablets, granules, powder or capsules.

Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of the binder include polyvinyl alcohol, polyvinyl simple ether, ethylcellulose, methylcellulose, acacia and tragacanth gum, gelatin, shellac, hydroxypropylcellulose, hypromellose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The dye may be any of the permitted for use in the composition of medicines. Examples corrigentov include cocoa powder, mint in the form of grass, in the form of a powder plants spicy, mint in the form of oil, borneol and cinnamon powder. A tablet or granule can, obviously, accordingly, apply a coating of sugar, W connection of the present invention, prepare, where appropriate, by mixing this compound with a pH regulator, a buffer, suspenders agent, a solubilizer, a stabilizer, a toning agent and/or preservative and transfer this mixture into a form suitable for injection intravenous, subcutaneous and intramuscular route, in accordance with the known method. If necessary, a translation into a form suitable for injection, it is possible to carry out drying, freezing by a known method.

Examples suspendida agents include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, gum Arabic, powdered tragacanth gum, sodium carboxymethyl cellulose and polyoxyethylene sorbitanoleat.

Examples of the solubilizer include castor oil, utverjdenie a polyoxyethylene, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanoleat and ethyl esters of fatty acids of castor oil.

Examples of the stabilizer include sodium sulfite, metasulfite sodium and diethyl ether, and examples of preservatives are methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

Below as non-limiting examples neshledala 100 mg, ingredients: lactose, wheat starch, polyvinylpyrrolidone, talc, magnesium stearate;

the composition in the form of tablets with controlled release of active substance 100 mg ingredients: lactose, polyvinylpyrrolidone, talc, magnesium stearate, polymer (cellulose, acrylic, methacrylic, vinyl or glycerine derived);

- composition gelatin capsules: active ingredient 100 mg ingredients: lactose, wheat starch, talc, magnesium stearate;

the composition of solution for injection in vials: active ingredient 200 mg ingredients: mannitol, water for injection;

- the cream composition (composition for 100 g of cream): active substance 2 g additives: promulgaretis cetylstearyl alcohol, tetraisostearate, nipazol, sorbic acid, propylene glycol, carbopol;

- composition lotions for the eyes: the active substance 15 mg, additives: sodium chloride, benzylaniline, water for injection.

Below the invention is illustrated in the examples, not limiting its scope.

When specifying the data of nuclear magnetic resonance (NMR) used the following abbreviations: s for singlet, d for doublet, t for triplet, q for quadruplet and m for unresolved complex signals, chemical shifts are expressed in the P CLASS="ptx2">

Example 1

Nitromethyl-2-triftormetilfullerenov

a) Phenyl-2-(trifloromethyl)benzoate

A mixture comprising 10 g (48.5 mmole) 2-(triptoreline)benzoic acid, 50 ml of thionyl chloride and a drop of dimethylformamide, maintained at the boiling point under reflux for 1.5 hours After cooling and concentrating the reaction mixture under vacuum to obtain the residue, which was stirred for 2 h at 100oWith the presence of 4.75 g (50 mmol) of phenol. After cooling, the reaction mixture is dissolved in dichloromethane, washed with saturated solution of NaHCO3and then water, dried over Na2SO4and concentrate. After distillation of 11 g of colorless liquid (yield: 80%).

tKip100-110o(Under a residual pressure of 1 mm RT.CT.)

NMR (CDCl3): 7,15 to 7.4 (7H, m), 7,55 (1H, m), with 8.05 (1H, dd, J=7.8 and 1.8 Hz).

b) nitro methyl-2-triftormetilfullerenov

of 4.2 ml (75 mmol) of nitromethane is introduced into the solution, which includes 8.5 g (75 mmol) of tert-butoxide potassium and 115 ml of dimethyl sulfoxide and the temperature of which is supported on the 15oC. the Mixture is stirred for 1 h at 15oWith, and then added dropwise 7 g (25 mmol) of phenyl ether, obtained on opican the th ice water and 6.8 ml of concentrated hydrochloric acid, and then poured into 500 ml of a mixture of ice water. The formed precipitate is dried, washed with water and hexane, followed by drying. After recrystallization from a mixture of ethyl acetate with hexane get 3 grams of white as wool solid substance (yield: 48%), tPL35-36oC.

NMR (DMSO-d6): 6,3 (2H, s, is able to exchange with CF3COOD), 7,55 (2H, m), and 7.8 (1H, m), 7,95 (1H, dd, J=7,7 and 1.6 Hz).

Examples 2-6

Analogously to example 1 (a and b) in examples 2-6 obtain compounds shown in table.2.

Examples 7-9

Analogously to example 1 (a and b) in examples 7-9 obtain compounds shown in table.3.

Examples 10 and 11

Analogously to example 1 (a and b) in examples 10 and 11 receive connections, are presented in table.4.

Example 12

N-(3-chloro-4-nitromethylene)ndimethylacetamide

a) Phenyl-4-amino-2-chlorobenzoate

30 g of phenyl-2-chloro-4-nitrobenzoate obtained in accordance with the method described in Makoto Suzuki, Yakugaku Zasshi (1959) 79. 286-90 (SA 53 14991f), is introduced into a mixture of 800 ml of water, 60 ml of acetic acid and 96.5 g (1,728 mole) of iron. The reaction mixture was incubated for 1 h at boiling temperature under reflux. After cooling, the reaction mixture is filtered and the selected solid material washed AtlantNIRO and purified by column chromatography with silica using CH2CL2(yield: 82%), tPL127-128oC.

NMR (DMSO-d6): 6.35mm (2H, s, is able to exchange with CF3D), 6,55 (1H, dd, J= 8.6 and 2.2 Hz), 6,7 (1H, d, J=2.2 Hz), 7,1-7,3 (3H, m), 7,45 (2H, m), and 7.9 (1H, d, J=8.6 Hz)

b) Phenyl-4-(acetylamino)-2-chlorobenzoate

37 ml (266 mmol) of triethylamine is introduced into a mixture comprising 60 g (242 mmole) amine obtained in the above stage (a), and 280 ml of dichloromethane, and then add to 20.6 ml (290 mmol) of acetylchloride. After stirring for 2 h at room temperature the mixture was kept at boiling temperature under reflux for 2 hours After cooling, the reaction mixture is quickly poured into a mixture of ice / hydrochloric acid. The organic phase is removed by decantation and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, dried over Na2SO4and concentrate, getting the product in the form of an oil which crystallized (yield: quantitative), tPL84-86oC.

NMR (DMSO-d6): of 2.15 (3H, s), 7,35 (3H, m), and 7.5 (2H, m), and 7.7 (1H, dd, J= 8.7 and 2 Hz), with 8.05 (1H, d, J=2 Hz), and 8.2 (1H, d, J=8.7 Hz), and 10.5 (1H, s, is able to exchange with CF3D).

C) N-(3-chloro-4-nitromethylene)ndimethylacetamide

Specified in the header of the connection get analogously to example 1B and the d6): 2,3 (3H, s), 6,55 (2H, s, is able to exchange with CF3D), AND 7.8 (1H, dd, J=8.7 and 1.8 Hz), 8,1 (2H, m) and 10.7 (1H, s, is able to exchange with CF3D).

Example 13

The nitro methyl-4-amino-2-chlortrimaton

A mixture of 12.2 g (47,5 mmole) of N-(3-chloro-4-nitromethylene)ndimethylacetamide, obtained in example 12, 11 g (274 mmole) preformed sodium hydroxide and 161 ml of water maintained at 80oC for 1 h, After cooling, the reaction mixture is diluted with 900 ml of water and adding acidified with acetic acid to pH 5. The resulting precipitate out, washed with water and dried in air followed by recrystallization from ethyl acetate (yield: 27%), tPL131-133oC.

NMR (DMSO-d6): 6,1 (2H, s, is able to exchange with CFCD), 6,45 (3H, m, of which 2N are able to share with CF3D), 6,55 (1H, d, J=2 Hz), and 7.5 (1H, d, J=8,75 Hz).

Example 14

N-(3-chloro-4-nitromethylene)benzamide

a) Phenyl-2-chloro-4-[(benzoyl)aminobenzoate]

A solution of 2.27 g (16,1 mmole) of benzoyl chloride in 30 ml of dichloromethane dropwise introduced into the mixture, which includes 4 g (16,1 mmole) of the compound obtained in example 12A, and 2.26 ml (about 17.7 mmole) of triethylamine and 40 ml of dichloromethane and which is maintained at 0oC. the Reaction mixture is stirred for 1 water the solid material is filtered, washed with water and dried under vacuum at 80oWith obtaining 5 g not quite white powder (yield: 89%), tPL126-128oC.

NMR (DMSO-d6): to 7.3 (3H, m), of 7.5 to 7.7 (5H, m), and 8.0 (3H, m), and 8.2 (2H, m), 10,8 (2H, s, is able to exchange with CF3D).

b) N-(3-chloro-4-nitromethylene)benzamide

Get analogously to example 1B (yield: 57%).

tPL165-167oC.

NMR (DMSO-d6): 6,6 (2H, s, is able to exchange with CFCD), 7,7-7,8 (3H, m) and 8.1 (4H, m), and 8.3 (1H, d, J=0.8 Hz), or 10.9 (1H, s, is able to exchange with CF3D).

Examples 15-27

Of the amine obtained in example 12A, in examples 15-27 receive connections, are presented in table.5, when this process is carried out analogously to example 14.

Example 28

2-chloro-N-(3-chloro-4-nitromethylene)phenylacetamide

a) Phenyl-2-chloro-4-[(2-Chlorobenzyl)carbylamine]benzoate

1.54 g (8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide injected into a suspension of 2 g (8 mmol) of the compound obtained in example 12A, 1.28 g (of 10.4 mmole) of 4-dimethylaminopyridine and 80 ml of dichloromethane. The prepared solution is stirred for 15 min at room temperature, then added 1.45 g (8.4 mmole) 2-chlorophenylacetyl 200 ml of water and 20 ml of concentrated Hcl. Desantirovaniya the organic phase is washed with 1N. a solution of Hcl and then with sodium hydroxide solution and water until neutral, followed by drying over PA2S04and concentration. The residue is crystallized from ethanol (95o) to obtain 1.4 g of a white powder (yield: 43%), tPL160-163oC.

NMR (DMSO-d6): of 3.95 (2H, s), 7.3 to 7.4 (5H, m), and 7.5 (4H, m), and 7.7 (1H, dd, J=8.7 and 2.1 Hz), with 8.05 (1H, d, J=2.1 Hz), and 8.2 (1H, d, J=8.7 Hz), and 10.8 (1H, s, is able to exchange with CF3D).

b) 2-chloro-N-(3-chloro-4-nitromethylene)phenylacetamide

This connection get analogously to example 1B.

tPL154-156oC.

NMR (DMSO-d6): of 3.95 (2H, s), to 6.4 (2H, s, is able to exchange with CF3d), 7,35 (2H, m), 7,45 (2H, m), and 7.7 (1H, dd, J=8.7 and 1.9 Hz), 7,95 (2H, m), and 10.8 (1H, s, is able to exchange with CF3D).

Examples 29 and 30

In examples 29 and 30, working analogously to example 28, using as the starting material amine, obtained in example 12A, get connections, are presented in table.6.

Example 31

N-(3-chloro-4-nitromethylene)-4-chlorobenzenesulfonamide

A mixture comprising 2 g (9.3 mmole) amine, obtained in example 13, 1.5 ml (18.5 mmole) of pyridine, 2,95 g (13.9 mmole) of the acid chloride of 4-chlorbenzol 5 ml of concentrated hydrochloric acid followed by extraction with ethyl acetate. The organic phase is washed with diluted sodium hydroxide solution. Next, the aqueous phase is acidified model HC1 and extracted with ethyl acetate, and the extract is washed with water until neutral, dried over Na2SO4and concentrate under vacuum. The residue is purified by column chromatography with silica using a mixture of dichloromethane/methanol in the ratio of 98:2.

NMR (DMSO-d6): of 6.25 (2H, s, is able to exchange with CF3D), 7,0 IS 7.3 (3H, m), and 7.6 to 7.9 (4H, m), and 11.2 (1H, broad s, capable of exchanging with CF3D).

Example 32

N-(3-chloro-4-nitromethylene)benzosulfimide

a) Phenyl-2-chloro-4-(phenylcarbonylamino)benzoate

A mixture comprising 10 g (40,4 mmole) amine, obtained in example 12A, 6,5 ml (80,4 mmole) of pyridine, 10.7 g (60,5 mmole) of benzosulfimide acid and 200 ml of THF, at room temperature, stirred for 2 h, and then incubated at 40oWith over 14 hours After cooling, add 200 ml of water and 5 ml of concentrated Hcl. The reaction mixture is extracted with dichloromethane, then washed with water until neutral, dried over Na2SO4and concentrate under vacuum. The result of purification of the residue by column chromatography with silica to use the Mr (DMSO-d6): of 7.2 to 7.4 (5H, m), and 7.5 (2H, m), the 7.65 (3H, m), 7,8 (2H, dd, J= 7.5 and 0.8 Hz), and 8.1 (1H, d, J=7.5 Hz), 11,25 (1H, s, is able to exchange with CF3D).

b) N-(3-chloro-4-nitromethylene)benzosulfimide

This connection get analogously to example 1B.

NMR (DMSO-d6): 6,4 (2H, s, is able to exchange with CF3OD), 7,25 (2H, m), and 7.7 (3H, m), 7,9 (3H, m), and 11.2 (1H, broad s, capable of exchanging with CF3OD).

Example 33

The nitro methyl-2-chloro-4-[N,N-di(phenylmethyl)amino]phenylketone

a) Phenyl-2-chloro-4-[N,N-di(phenylmethyl)amino]benzoate

A mixture of 2.5 g (10 mmol) of the amine obtained in example 12A, 2.7 g (20 mmol) of potassium carbonate, 6.8 g (40 mmol) of benzylbromide, a few crystals of potassium iodide and 100 ml of dimethylformamide is maintained at 80oC for 6 hours After cooling, the reaction mixture is poured into 300 ml of water and extracted with ethyl acetate, after which the extract is washed with water, dried over Na2SO4and concentrate. Obtained in the form of oil residue triturated in hexane and eye-catching solid material is crystallized from ethanol to obtain 1.6 g not quite white solids (yield: 37%), tPL133-135oC.

NMR (DMSO-d6): 4,8 (4H, s), 6,7-6,85 (2H, m) and 7.1-7.5 (a 15 NM, m), and 7.9 (1H, m).

b) nitro methyl-2-chloro-4-[N,N-di(FeNi is 116-118oC.

NMR (DMSO-d6): 4.9m (4H, s), and 6.25 (2H, s, is able to exchange with CF3OD), 6.8 or 6.9 (2H, m), 7,2-7,5 (10H, m), and 7.7 (1H, d, J=9 Hz).

Example 34

N-(2-chloro-3-nitromethylene)ndimethylacetamide

a) Phenyl-3-amino-2-chlorobenzoate

This compound is obtained from phenyl-2-chloro-3-nitrobenzoate analogously to example 12A (yield: 97%).

tPL46-48oC.

NMR (DMSO-d6): 5,5 (2H, s, is able to exchange with CF3D), 6,85 (1H, dd, J=7,45 and 2.3 Hz), 7,0 (2H, m) and 7.1 (3H, m), and 7.3 (2H, m).

b) Phenyl-3-acetylamino-2-chlorobenzoate

This connection get analogously to example 12B (yield: 60%).

tPL120-122oC.

NMR (DMSO-d6): 2,2 (3H, s), and 7.4 (3H, m), 7,55 (3H, m), and 7.9 (1H, m), and 8.0 (1H, m), and 9.8 (1H, s, is able to exchange with CF3D).

C) N-(2-chloro-3-nitromethylene)ndimethylacetamide

This compound is obtained from phenyl-2-chloro-3-nitrobenzoate analogously to example 1B.

tPL140-142oC.

NMR (DMSO-d6): 2,2 (3H, s), and 6.5 (2H, s, is able to exchange with CF3D), and 7.6 (1H, m), and 7.8 (1H, dd, J=8 and 1.3 Hz), and 8.1 (1H, dd, J=8 and 1.3 Hz), and 9.8 (1H, s, is able to exchange with CF3D).

Example 35

N-(2-chloro-3-nitromethylene)-2-methylphenylacetic

a) Phenyl-2-chloro-3-[(2-methylbenzoyl)carbylamine the acid analogously to example 14a (yield: 78%).

tPL123-125oC.

NMR (CDCl3): 2,3 (3H, s in), 3.75 (2H, s), and 7.1 to 7.4 (10H, m), the 7.65 (1H, m), and 7.8 (1H, broad s, capable of exchanging with CF3D), AND 8.6 (1H, dd, J=8,3 and 1.55 Hz).

b) N-(2-chloro-3-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 1B (yield: 45%).

tPL130-132oC.

NMR (DMSO-d6): of 2.25 (3H, s), 3,8 (2H, s), to 6.4 (2H, s, is able to exchange with CF3OD), AND 7.1 (3H, m), 7,2 (1H, m), 7,45 (1H, m), and 7.6 (1H, dd, J=7.75, and 1,4 Hz), and 7.9 (1H, dd, J=8.1 and 1.3 Hz), and 9.8 (1H, broad s, capable of exchanging with CF3D).

Example 36

N-(4-chloro-3-nitromethylene)ndimethylacetamide

a) Phenyl-2-chloro-5-nitrobenzoate

This compound is obtained from 2-chloro-5-nitrobenzoic acid analogously to example 1A (yield: 92%).

tPL83-85oC.

NMR (DMSO-d6): of 7.4 (3H, m), 7,55 (2H, m), and 8.0 (1H, d, J=8,8 Hz), and 8.5 (1H, dd, J=8.8 and 2.7 Hz), of 8.95 (1H, d, J=2.7 Hz).

b) Phenyl-5-amine-2-chlorobenzoate

18 g of Raney Nickel are added to a solution of 59 g (212 mmol) of the compound obtained in stage a), in 600 ml of dioxane. The mixture hydrogenized under the pressure of 70 kg/sq. cm and 65oC. After filtering off the catalyst and concentrating removal of solvent the residue is purified by chromatography in a column dioxide crtridge substance (yield: 55%), tPL84-86oC.

NMR (CDCl3): 3,8 (2H, broad s, capable of exchanging with CF3D), 6,7 (1H, m), 7,2 (5H, m), 7,35 (2H, m).

C) Phenyl-5-acetylamino-2-chlorobenzoate

This compound is obtained from the amine obtained in stage b), analogously to example 12B (yield: 69%).

tPL141-143oC.

NMR (DMSO-d6): 1,95 (3H, s), 7,2 (3H, m), 7,35 (2H, m), and 7.5 (1H, d, J= 8.7 Hz), of 7.75 (1H, dd, J=8.7 and 2.6 Hz), of 8.25 (1H, d, J=2.6 Hz), of 10.25 (1H, broad s, capable of exchanging with CF3COOD).

g) N-(4-chloro-3-nitromethylene)ndimethylacetamide

This connection get analogously to example 1B (yield: 15%).

tPL122-124oC.

NMR (DMSO-d6): 2,2 (3H, s), 6,45 (2H, s, is able to exchange with CF3COOD), and 7.7 (1H, d, J=8.7 Hz), 7,9 (1H, dd, J=8.7 and 2.5 Hz), and 8.2 (1H, d, J=2.5 Hz), and 10.5 (1H, s, is able to exchange with CF3COOD).

Example 37

N-(4-chloro-3-nitromethylene)-2-methylphenylacetic

a) Phenyl-2-chloro-5-[(2-methylbenzyl)carbylamine]benzoate

This compound is obtained from the amine obtained in example 36B, and the acid chloride (2-were)acetic acid analogously to example 14a (yield: 94%).

tPL102-104oC.

NMR (CDCl3): of 2.25 (3H, s in), 3.75 (2H, s), 7,1-7,25 (N, m, of which 1H is able to exchange with CF3D), 7,

This connection get analogously to example 1B (yield: 38%).

tPL148-150oC.

NMR (DMSO-d6): 2,3 (3H, s), 3,8 (2H, s), to 6.4 (2H, s, is able to exchange with CF3D), 7,2 (4H, m), and 7.6 (1H, d, J=8.7 Hz), and 7.8 (1H, dd, J=8.7 and 2.5 Hz), and 8.2 (1H, d, J=2.5 Hz), or 10.6 (1H, s, is able to exchange with CF3D).

Example 38

N-(4-chloro-3-nitromethylene)benzosulfimide

a) Phenyl-5-(benzosulfimide)-2-chlorobenzoate

This compound is obtained from the amine obtained in example 36B, analogously to example 32A (yield: 97%).

tPLabout 50oC.

NMR (DMSO-d6): of 7.3 to 7.7 (10H, m), and 7.8 (3H, m), and 10.8 (1H, s, is able to exchange with CF3COOD).

b) N-(4-chloro-3-nitromethylene)benzosulfimide

This connection get analogously to example 1B.

tPL152-154oC.

NMR (DMSO-d6): 6,2 (2H, s, is able to exchange with CF3COOD), 7,2 (1H, m), 7,35-the 7.65 (5H, m), of 7.75 (2H, m), and 10.8 (1H, s, is able to exchange with CF3COOD).

Example 39

2-[(3-chloro-4-nitromethylene)aminocarbonylmethyl] benzoic acid

a) Phenyl-2-chloro-4-[(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)methylcobalamine]benzoate

This compound is obtained from the amine obtained in example 1 is the notes and SOCl2, tPL80-83oC) analogously to example 14a (yield: 54%).

tPL220-222oC.

NMR (DMSO-d6): 4,55 (2H, s), 7,25 (3H, m), and 7.4 (2H, m), and 7.6 (1H, m), 7,8-8,0 (5H, m) and 8.1 (1H, d, J=8.6 Hz), or 10.9 (1H, s, is able to exchange with CF3COOD).

b) 2-[(3-chloro-4-nitromethylene)aminocarbonylmethyl] benzoic acid

1,49 ml of nitromethane is introduced into a solution containing 2.9 g (25.5 mmole) of tert-butoxide potassium and 50 ml of DMSO, maintained at a temperature below 20oC. the Mixture is stirred for one hour at a temperature below 20oWith, and then added dropwise 3.7 g (8.5 mmole) of a compound phenyl ester obtained in stage (a) (b dissolved in 90 ml of DMSO. After stirring for 16 h at room temperature the reaction mixture is poured into 750 ml of water. The aqueous phase is washed with ethyl acetate and acidified with Hcl. The formed precipitate is filtered off, washed with water and dried under vacuum followed by recrystallization from acetonitrile, obtaining 2.2 g of white powder (yield: 61%), tPL206-209oC.

NMR (DMSO-d6): 4,0 (2H, d, J=5.6 Hz, CF3COOD converted into singlet), and 6.3 (2H, s, is able to exchange with CF3COOD), 7,4-8,0 (7H, m), is 8.75 (1H, t, J= 5.6 Hz, capable of exchanging with CF3D), AND 10.3 (1H, s4-nitromethylene)-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)ndimethylacetamide

Gaseous Hcl for 1.5 h bubbled through the suspension, including 2 g (4.8 mmole) of the compound obtained in example 39B, and 30 ml of methanol. Extract the mixture with approximately 60oWith the dissolution of solid material. After cooling, the formed precipitate is filtered off and recrystallized from acetonitrile to obtain 0.4 g not quite white powder (yield: 19%), tPL121oC (with decomposition).

NMR (DMSO-d6): 4,5 (2H, s), and 6.3 (2H, s, is able to exchange with CF3COOD), 7,55 (1H, dd, J=8.7 and 2 Hz), 7,8-8,0 (6N, m), or 10.9 (1H, s, is able to exchange with CF3COOD).

Example 41

1-(3-chloro-4-nitromethylene)-3-(phenylsulfonyl)urea

a) Phenyl-2-chloro-4-(vinylsulfonylacetamido)benzoate

1.5 g (8.2 mmole) phenylsulfonylacetate in 20 ml of dichloromethane dropwise introduced into the suspension of 2.08 g (8.4 mmole) amine, obtained in example 12A, in 40 ml of dichloromethane. Adding the first drops reach full solubilization followed by the formation of a thick precipitate. After stirring for 16 h at room temperature the precipitate is filtered off, washed with dichloromethane and dried at 80oWith under vacuum to obtain 2.2 g of a white powder (yield: 62%), tPL183-185oC.

b) 1-(3-chloro-4-nitromethylene)-3-(phenylsulfonyl)urea

This connection get analogously to example 1B (yield: 49%).

tPL168-169oC.

NMR (DMSO-d6): 6.35mm (2H, s, is able to exchange with CF3D), 7,35 (1H, m), of 7.5 to 7.7 (4H, m), and 7.8 (1H, d, J=8.7 Hz), and 8.0 (2H, m), and 9.5 (1H, s, is able to exchange with CF3COOD), and 11.3 (1H, broad s, capable of exchanging with CF3COOD).

Example 42

The nitro methyl-3-methyl-2-titillation

A solution of 10 g (70 mmol) of 3-methyl-2-thiophencarboxylic acid, 3.4 g (56 mmol) of nitromethane and 115 ml of DMF, cooled to 0oC. it successively added 11.9 g (72.8 mmole) diethylthiophosphate in 56 ml of DMF and then 18.2 g (180 mmol) of triethylamine in 56 ml of DMF. Next, the mixture is stirred for 2 h at 0oWith and for 21 h at room temperature. The reaction mixture is poured into 1 l of a mixture of toluene/ethyl acetate in a ratio of 1:1 and extracted with water. The aqueous phase was acidified with 40 ml of acetic acid, extracted with a mixture of toluene/ethyl acetate 1:1 ratio. The organic extracts washed with water and then with saturated solution of NaCl in water, followed by drying over Na2SO4and concentrate. The result of purification of the residue by column chromatography with silica with esportivo substance (yield: 19%), tPL59-61oC.

NMR ((CDCl3)): 2,6 (3H, s), 5,7 (2H, s, is able to exchange with CF3D), and 7.1 (1H, d, J=4.9 Hz), and 7.6 (1H, d, J=4,9 Hz).

Example 43

N-(3-chloro-4-nitromethylene)-2-methylphenylacetic

a) 2-chloro-4-[(2-methylbenzyl)carbylamine]benzoic acid

19,56 g (116 mmol) of the acid chloride (2-were) acetic acid for 1 h is introduced into a mixture of 20 g (116 mmol) of 4-amino-2-chlorbenzoyl acid and 12.9 g (127 mmol) of triethylamine and 150 ml of DMF, dried by passing through a molecular sieve. After stirring for 16 h at room temperature DMF is removed by evaporation under vacuum. The residue is washed with water and dichloromethane, getting after drying, 19 g not quite white powder (yield: 53%), tPL214-218oC.

NMR (DMSO-d6): of 2.25 (3H, s), 3,8 (2H, s), 7,1-of 7.25 (4H, m), 7,55 (1H, dd, J=8.6 and 2 Hz), and 7.8 (1H, d, J=8.6 Hz), and 7.9 (1H, d, J=2 Hz), or 10.6 (1H, s, is able to exchange with CF3COOD), 13,1 (1H, broad s, capable of exchanging with CF3D).

b) N-(3-chloro-4-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 42 using as source material 19 g (62.5 mmole) of 2-chloro-4-[(2-methylbenzyl)carbylamine] benzoic acid obtained in stage a), (3,18 g micrometres molecular sieve. After chromatography in a column of silica (eluent: dichloromethane/methanol in the ratio 95:5) and recrystallization from a mixture of hexane/ethyl acetate to obtain 0.2 g (yield: 1%) of pale yellow powder, tPL133-135oC.

NMR (DMSO-d6): 2,3 (3H, s), 3,8 (2H, s), 6,45 (2H, s, is able to exchange with CF3D), 7,2-7,3 (4H, m), of 7.75 (1H, dd, J=8.7 and 2 Hz), and 7.9 (2H, m), and 10.8 (1H, s, is able to exchange with CF3D).

Remove the wash liquids allows you to select 5,2 g (total yield: 30%) of the product, identical to the first portion of the product.

This compound is also obtained from the amine prepared in example 12A, similarly to example 28.

Difficult phenyl ether as an intermediate product (tPL120-123oC, yield: 56%) is converted into a compound-CO-CH2-NO2[tPL141-143oC (acetonitrile)] with the release of 43%.

Example 44

N-(3-chloro-4-nitromethylene)-2-oxopiperidin

a) Phenyl-2-chloro-4-(5-chlorphentermine)benzoate

This connection get analogously to example 14a using as starting material the compound obtained in example 12A, and the acid chloride of 5-chloropentane acid.

NMR (DMSO-d6): 1,8 (4H, m), and 2.5 (2H, t, J=6,7 Hz in), 3.75 (2H, t, J=6,7 Hz), and 7.3 and 7.6 (5H, m), and 7.7 (1H, dd)-2-oxopiperidin

This connection get analogously to example 1B (yield: 67%).

tPL119-120oC.

NMR (DMSO-d6): of 1.85 (4H, m), of 2.45 (2H, t, J=6.3 Hz), 3,7 (2H, t, J=5.5 Hz), 6,4 (2H, s, is able to exchange with CF3D), and 7.5 (1H, dd, J=8.5 and 2 Hz), and 7.7 (1H, d, J=2 Hz), and 7.9 (1H, d, J=8,5 Hz).

Examples 45 and 46

Using as the starting material amine, obtained in example 12A, get connections, are presented in table.7, where the method is carried out analogous to example 14.

Examples 47-57

Using as the starting material amine, obtained in example 12A, get connections, are presented in table.8, the process is carried out similar to that described in example 28.

Example 58

N-(3-chloro-4-nitromethylene)-2-propenamide

This connection get analogously to example 31, using as starting material amine, obtained in example 13, in the presence of triethylamine and dichloromethane, tPL140-144oC.

NMR (DMSO-d6): 6.35mm (2H, s, is able to exchange with CF3COOD), 6,8 (1H, d, J= 12 Hz), and 7.4 (3H, m), the 7.65 (4H, m), and 7.9 (1H, d, J=9 Hz), and 8.1 (1H, d, J=2 Hz), and 10.8 (1H, s, is able to exchange with CF3D).

Example 59

N-(3-methyl-4-nitromethylene)-2-methylphenylacetic
similar material 2-methyl-4-nitrobenzoic acid.

b) Phenyl-4-amino-2-methylbenzoate

A mixture containing 3.5 g (to 13.6 mmole) nitro-derivatives obtained in example 59A, 1 g of Raney Nickel and 35 ml of dioxane, treated with hydrogen under a pressure of about 100 ATM. for 2.5 h at 80oC. After cooling, filtration of the reaction mixture and concentrating obtain 2.7 g pasty solid.

NMR (DMSO-d6): 2,5 (3H, s), 6,1 (2H, s, is able to exchange with CF3D), AND 6.5 (2H, m), 7,2 (3H, m), and 7.4 (2H, m), and 7.8 (1H, d, J=8,3 Hz).

C) Phenyl-2-methyl-N-[(2-were)carbylamine]benzoate

This connection get analogously to example 14a using as starting material amine, obtained in example b, and the acid chloride (2-methyl) phenylacetic acid (yield: 86%).

NMR (DMSO-d6): 2,3 (3H, s), 2,6 (3H, s), 3,7 (2H, s), and 7.1 to 7.7 (11N, m) and 8.1 (1H, d, J=9 Hz), and 10.5 (1H, s, is able to exchange with CF3D).

g) N-(3-methyl-4-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 1B, using as source material phenyl ether obtained in example V, tPL159-160oC.

NMR (DMSO-d6): 2,1 (3H, s in), 2.25 (3H, s), 3,5 (2H, s), x 6.15 (2H, s, is able to exchange with CF3D), A 7.0 (4H, m), and 7.3 (1H, d, J=1.6 Hz), was 7.45 (1H, dd, J=8, ylcarbonyl)-2-methylphenylacetic

a) 3-bromo-4-[(2-were)carbylamine]benzoic acid

This connection get analogously to example 43A, using as starting material 4-amino-3-bromobenzoyl acid and the acid chloride 2-methylphenylacetic acid (yield: 86%).

NMR (DMSO-d6): 2,1 (3H, s), 3,6 (2H, s), 6,9 (3H, m), 7,0 (1H, m), of 7.75 (1H, m), and 7.9 (1H, d, J=1.3 Hz), and 9.3 (1H, s, is able to exchange with CF3D), 13,0 (1H, broad s, capable of exchanging with CF3D).

b) Phenyl-3-bromo-4-[(2-were)carbylamine]benzoate

This connection get analogously to example 1A (yield: 98%).

tPL139-141oC.

NMR (DMSO-d6): 2,4 (3H, s), 3,9 (2H, s), 7,2-7,5 (N, m) and 8.1 (2H, m), and 8.3 (1H, d, J=1,8 Hz), and 9.7 (1H, s, is able to exchange with CF3D).

C) N-(2-bromo-4-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 1B (yield: 41%).

tPL125-127oC.

NMR (DMSO-d6): 2,2 (3H, s), 3,7 (2H, s), and 6.3 (2H, s, is able to exchange with CF3D), AND 7.1 (4H, m), and 7.8 (1H, dd, J=9 and 2 Hz), and 7.9 (1H, m) and 8.1 (1H, d, J=2 Hz), and 9.5 (1H, s, is able to exchange with CF3D).

Example 61

The nitro methyl-2-chloro-4-methoxyphenylacetone

a) Phenyl-2-chloro-4-methoxybenzoate

This connection get analogously to example 1A, IP) and 3.8 (3H, s), 6,8 (1H, dd, J=9 and 2.5 Hz), to 6.95 (1H, d, J=2.5 Hz), to 7.15 (3H, m), and 7.3 (2H, m), and 8.0 (1H, d, J=9 Hz).

b) nitro methyl-2-chloro-4-methoxyphenylacetone

This connection get analogously to example 1B.

NMR (DMSO-d6): of 3.9 (3H, s), to 6.4 (2H, s, is able to exchange with CF3D), AND 7.1 (1H, dd, J=9 and 2.5 Hz), 7,2 (1H, d, J=2.5 Hz), and 7.9 (1H, d, J=9 Hz).

Example 62

The nitro methyl-2-isopropylaniline

a) Phenyl-2-isopropylbenzoic

This connection get analogously to example 1A, using as starting material 2-(1-methylethyl)benzoic acid (yield: 85%).

NMR (CDCl3): 1,2 (6N, m), and 3.8 (1H, m) and 7.1-of 7.25 (4H, m), 7,3-7,5 (4H, m), and 7.9 (1H, dd, J=8 and 1.5 Hz).

b) nitro methyl-2-isopropylaniline

This connection get analogously to example 1B (liquid).

NMR (CDCl3): 1,5 (6N, m), 3,4 (1H, m), 5,7 (1H, s, is able to exchange with CF3COOD), 7,2-7,5 (4H, m).

Example 63

N-(4-chloro-2-nitromethylene)-2-methylphenylacetic

a) 5-chloro-2-[(2-were)carbylamine]benzoic acid

This connection get analogously to example 43A, using as starting material 2-amino-5-chlorobenzoyl acid and the acid chloride 2-methylphenylacetic acid (yield: 75%).

tPL224-226oC.

NMR (DMSO-d6The D), 14,0 (1H, broad s, capable of exchanging with CF3D).

b) Phenyl-5-chloro-2-[(2-were)carbylamine]benzoate

This connection get analogously to example 1A (yield: 38%).

C) N-(4-chloro-2-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 1B.

tPL128-130oC.

NMR (DMSO-d6): 2,4 (3H, s), 3,9 (2H, s), and 6.5 (2H, s, is able to exchange with CF3COOD), AND 7.4 (4H, m), and 7.9 (1H, dd, J=9 and 2 Hz), and 8.1 (1H, d, J=2 Hz), and 8.3 (1H, d, J=9 Hz), or 10.9 (1H, s, is able to exchange with CF3D).

Example 64

The nitro methyl-2-chloro-4-phenylthiophene

a) Phenyl-2-chloro-4-(phenylthio)benzoate

A solution of 4.15 g (60,5 mmole) of sodium nitrite in 20 ml of water at 0oWith introducing a suspension of 15 g (60,5 mmole) amine, obtained in example 12A, 12.1 ml of 10 N. hydrochloric acid. After stirring for one hour at 0oThe mixture is neutralized with saturated solution of sodium acetate. The final mixture for 15 min then poured into the solution, whose temperature is 70-80oWith, including 8 g (72,6 mmole) of thiophenol, of 3.85 g (96 mmol) of sodium hydroxide and 25 ml of water. Upon completion of addition the reaction mixture was incubated for 1 h at 95oC. After cooling, the reaction mixture was extragonadal over Na2SO4and concentrate under vacuum. The residue is purified Express chromatography on silica (hexane) to give an orange-yellow liquid (yield: 31%).

NMR (DMSO-d6): of 7.3 to 7.7 (N, m) and 8.1 (1H, m).

b) nitro methyl-2-chloro-phenylthiophene

This connection get analogously to example 1B.

tPL77-78oC.

NMR (DMSO-d6): 6,5 (2H, s), and 7.3 (2H, m), and 7.7 (5H, m), 7,95 (1H, d, J=8,5 Hz).

Example 65

N-(3-chloro-4-nitromethylene)-4-[(3-chloro-4-nitromethylene)aminocarbonyl]-3-phenylbutane

a) Phenyl-2-chloro-4-{ {[[3-chloro-4-(phenoxycarbonyl)phenyl]amino]-1.5-dioxo-3-fenilpentil}amino}benzoate

This connection get analogously to example 14, using as starting material amine, obtained in example 12A, and 0.5 EQ. dichlorohydrin 3-phenylglutaric acid.

NMR (DMSO-d6): or 2.8 (4H, m), and 3.8 (1H, m) and 7.1 and 7.6 (17H, m), and 7.9 (2H, d, J=2 Hz), and 8.1 (2H, d, J=9 Hz), 10,4 (2H, s, is able to exchange with CF3D).

b) N-(3-chloro-4-nitromethylene)-4-[(3-chloro-4-nitromethylene)aminocarbonyl]-3-phenylbutane

This connection get analogously to example 1B.

tPL195-196oC.

NMR (DMSO-d6): or 2.8 (4H, m), 3,3D).

Example 66

The nitro methyl-2-chloro-4-phenylsulfonylacetate

a) Phenyl-2-chloro-4-(phenylsulfinyl)benzoate

5 ml (40 mmol) of a 70% aqueous solution of gidroperekisi tert-butyl in the water is introduced into a suspension of 2 g (5.9 mmole) of the compound obtained in example 64A, 60 ml of water. The reaction mixture was kept at 70oWith over 32 hours After cooling peroxide destroy the addition of a solution of 10 g of sodium metabisulfite in 100 ml of water. After stirring for 2 h, and a negative result of the analysis of peroxide, the reaction mixture is extracted with dichloromethane. The organic phase is washed with saturated NaCl solution in water and dried over Na2SO4. After concentration by removal of the dichloromethane and purification Express by column chromatography with silica (hexane/ethyl acetate in the ratio 4:1) as colourless oils are 0.1 g of product (yield: 4%).

NMR (DMSO-d6): 7,1 (3H, m), 7,2-7,4 (5H, m), and 7.7 (3H, m), and 7.8 (1H, d, J= 1.6 Hz), and 8.0 (1H, m).

b) nitro methyl-2-chloro-4-phenylsulfonylacetate

This connection get analogously to example 1B (in the form of oil).

NMR (DMSO-d6): 6,4 (2H, s, is able to exchange with CF3D), 6,8 (3H, m), 7,2 (2H, m), and 7.6 (3H, m).

Premarketing a closed steel vessel at 175oC for 6 h withstand mixture comprising of 21.5 g (112 mmol) of acid chloride of 4-chloro-2-hydroxybenzoic acid, to 59.8 g (336 mmol) of antimony TRIFLUORIDE, 3.2 g of PENTAFLUORIDE antimony and 258 ml CCl4. After cooling, the reaction mixture is dissolved in about 3 liters of dichloromethane. The organic phase is washed with water. The resulting precipitate was washed with dichloromethane. The combined organic phases are dried over Na2SO4and concentrate to obtain 19,2 black liquid, which is used without further purification.

of 19.2 g of compound obtained in the previous phase is mixed with 90 ml of toluene, 75 ml of thionyl chloride and a few drops of DMF and stirred for 2 h at room temperature. Next, the reaction mixture is concentrated under vacuum. The resulting residue is diluted with 200 ml dichloromethane, and then added to a mixture of 9.8 g of phenol, 16.2 g of triethylamine and 100 ml of dichloromethane. After stirring for 16 h at room temperature the reaction mixture was poured into a mixture of ice / Hcl. The final mixture is extracted with dichloromethane, after which the extract is washed with diluted sodium hydroxide solution and water and then dried over Na2SO4and concentrate. The residue is purified by chromatography on dioxi liquid (yield: 37%).

b) nitro methyl-4-chloro-2-triftormetilfullerenov

This connection get analogously to example 1B in the form of a pasty solid.

NMR (CDCl3): 5,7 (2H, s, is able to exchange with CF3D), 7,3-7,5 (2H, m), and 8.0 (1H, d, J=9 Hz).

Example 68

N-[2-(3-chloro-4-nitromethylene)ethyl]-2-methylbenzo-sulfonamide

a) Ethyl-2-chloro-4-(cyanomethyl)benzoate

3.1 g (11.2 mmole) of ethyl-4-(methyl bromide)-2-chlorobenzoate injected dropwise into a solution comprising 0,94 g (14.3 mmole) of potassium cyanide, 3,75 ml of water and 8.8 ml of ethanol, heated to boiling (under reflux). After boiling under reflux for 3 h the mixture was poured into 200 ml of water and extracted with ethyl acetate. The organic phase is washed with diluted aqueous Hcl, and then washed with saturated aqueous NaCl. The product oil obtained after concentration of the organic phase, clear Express chromatography on silica (hexane/ethyl acetate gradient ratio from 1:0 to 1:1). Obtain 0.4 g of a brown solid (yield: 16%), tPL60oC.

NMR (CDCl3): 1,4 (3H, t, J=7 Hz), 3,8 (2H, s), and 4.5 (2H, q, J=7 Hz), and 7.1 (1H, m), and 7.5 (1H, d), and 7.9 (1H, d).

6) Ethyl-4-(2-amino-ethyl)-2-chlorobenzoate

With the a few milliliters of liquid ammonia, treated with hydrogen under a pressure of about 60 kg/cm2at the 50oC for 5 h and then at 80oWith over 4.5 hours After filtration of the reaction mixture in the form of oil get 1.5 g of product (yield: 77%).

NMR (CDCl3): 1,3 (3H, t, J=7 Hz), 1,7 (2H, broad s, capable of exchanging with CF3D), of 2.6-3.0 (4H, m), a 4.3 (2H, q, J=7 Hz), 7,0 (1H, m), 7,2 (1H, m), and 7.6 (1H, d, J=6.3 Hz).

C) Ethyl-2-chloro-4-[2-(2-methylphenylsulfonyl)ethyl]benzoate

This connection get analogously to example 32V (yield: 43%) (oil).

NMR (CDCl3): 1,3 (3H, t, J=7 Hz), 2,4 (3H, s), 2,7 (2H, m), 3,1 (2H, m), a 4.3 (2H, q, J=7 Hz), 4,4 (1H, broad s, capable of exchanging with CF3D) AND 6.9 (1H, m), 7,0 (1H, m) and 7.1 to 7.4 (3H, m), and 7.7 (1H, m), and 7.8 (1H, dd, J=8 and 1.25 Hz).

g) 2-chloro-4-[2-(2-methylphenylsulfonyl)ethyl]benzoic acid

A mixture comprising 1 g (2.6 mmole) of prior complex ethyl ester, 18 ml of methanol and 18 ml of water and 0.2 g (5.2 mmole) preformed NaOH, incubated for 4 h at 40oC. After concentration by removal of methanol and add 30 ml of water the mixture was washed with CH2CL2. Next, the aqueous phase is acidified with getting 0,675 g of a white precipitate (yield: 72%), tPL122-124oC.

NMR (DMSO-d6): 2,3 (3H, s), 2,7 (2H, m), and 3.0 (2H, m), 7,0-7,2">

d) Phenyl-2-chloro-4-[2-(2-methylphenylsulfonyl)ethyl]benzoate

This connection get analogously to example 1A (yield: 61%) (oil).

NMR (CDCl3): 2,4 (3H, s), 2,7 (2H, m), and 3.2 (2H, m), 4,1 (1H, m, is able to exchange for D2O), 7,0-8,0 (N, m).

e) N-[2-(3-chloro-4-nitromethylene)ethyl]-2-methylbenzenesulfonamide

This connection get analogously to example 1B (in the form of oil).

NMR (CDCl3): 2,5 (3H, s), 2,7 (2H, t, J=5 Hz), and 3.2 (2H, t, J=5 Hz), 4,4 (1H, broad s, capable of exchanging with CF3COOD), AND 5.8 (2H, s, is able to exchange with CF3D), 7,0-7,5 (5H, m), and 7.6 (1H, m), and 7.9 (1H, m).

Example 69

N-(3-bromo-4-nitromethylene)-2-methylphenylacetic

a) 2-bromo-4-[(2-methylbenzyl)carbylamine]benzoic acid

This connection get analogously to example 43, using as starting material 4-amino-2-bromobenzoyl acid (yield: 23%), tPLdecomposition at 205oC.

NMR (DMSO-d6): 2,4 (3H, s), 3,9 (2H, s), 7,2 (4H, m), and 7.6 (1H, dd, J=9 and 2 Hz), and 7.9 (1H, d, J=9 Hz), and 8.2 (1H, d, J=2 Hz) and 10.7 (1H, s, is able to exchange with CF3D), 13,0 (1H, broad s, capable of exchanging with CF3D).

b) Phenyl-2-bromo-4-[(2-methylbenzyl)carbylamine]benzoate

This connection get analogously to example 14a (output: the number is 1H, d, J=2 Hz), and 10.5 (1H, s, is able to exchange with CF3D).

C) N-(3-bromo-4-nitromethylene)-2-methylphenylacetic

This connection get analogously to example 1B (in the form of oil).

NMR (DMSO-d6): 2,4 (3H, s), 3,8 (2H, s), and 6.5 (2H, s, is able to exchange with CF3D), 7,2-7,6 (4H, m), and 7.8 (1H, dd, J=9 and 2 Hz), and 8.0 (1H, d, J=9 Hz), and 8.3 (1H, d, J=2 Hz), or 10.9 (1H, s, is able to exchange with CF3D).

Example 70

N-(3-chloro-4-nitromethylene)-N-isopropylbenzenesulfonyl

a) Phenyl-2-chloro-4-[(isopropyl)(phenylsulfonyl)amino]benzoate

to 10.1 g (25.5 mmole) of sodium hydride (55% in oil) was injected into a solution of 9.9 g (25.5 mmole) of the compound obtained in example 32A, in 100 ml of DMF. After stirring for 1 h at room temperature add to 9.4 g (76.5 mmole) of 2-bromopropane and the mixture is stirred at room temperature for 16 h, followed by exposure at 60oWith over 34 PM on add to 5.1 ml (51 mmol) of 2-iodopropane. Then the reaction mixture was kept at 60oC for 4 h, then poured into a mixture of ice water and Hcl. The mixture is extracted with ethyl acetate, followed by drying and concentration of the extract receiving the product in the form of oil. In the purification by column chromatography dioxide cream is>is.

NMR (DMSO-d6): 1,0 (6N, d, J=6.5 Hz), 4,4 (1H, m) and 7.1-7,9 (N, m), and 8.0 (1H, d, J=8 Hz).

b) N-(3-chloro-4-nitromethylene)-N-isopropylbenzenesulfonyl

This compound (oil) are obtained analogously to example 1B with use as source material phenyl ester obtained in example 65A.

NMR (CDCl3): 1,0 (6N, d, J= 7 Hz), 4,5 (1H, q, J=7 Hz), and 5.8 (2H, s, is able to exchange with CF3D), 7,0 (1H, dd, J=9 and 2 Hz), to 7.15 (1H, m), 7,35 to 7.7 (6N, m).

1. Nitromethylene formula

< / BR>
where And denotes6-C10aryl, thienyl, benzothiazyl;

X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy or cryptometer,

R1and R2may be the same or different and each represents hydrogen, C1-C7alkyl, C3-C12cycloalkyl,

p= 0, 1, 2, 3, 4 or 5;

Z represents a bond, divalent radical-CO-NH-, in which the carbonyl group is linked to R3, the divalent radical-SO2-NH-, in which sulfonylurea group associated with R3, a sulfur atom, sulfinyl group or2-C7alkenylamine radical;

R3denotes hydrogen, halogen, C1-C7alkalmi Y, WITH6-C10alloctype, optionally substituted by one or more identical or different radicals Y3-C12cycloalkyl, optionally substituted by one or more identical or different radicals Y, benzothiazyl, benzofuran, 1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl, 2-oxopiperidine, 2-[(4-nitromethylene-3-chlorophenyl)aminocarbonyl]-1-(phenyl)ethyl;

Y denotes halogen, C1-C7alkyl, C1-C7alkoxygroup, trifluoromethyl, carboxy, nitro-, WITH6-C10aryl,

E denotes the divalent radical - CO-NR4- whose carbonyl group is associated with -(CR1R2)p-, -SO2-NR4- which sulfonylurea group is associated with -(CR1R2)p-, -NR4-, oxygen, and R4means a radical -(CH2)qR5where q=0 and R5denotes hydrogen, C1-C7alkyl; n = 0 or 1,

except 3,5-dimethyl-1-nitroacetophenone,

as well as additive salts of pharmaceutically acceptable bases.

2. Connection on p. 1, And which denotes phenyl, each of n and R = 0, Z represents a bond, and R3denotes hydrogen.

3. Connection on p. 1, And which indicates fidy of n and p = 1, E denotes the radical-CO-NR4- each of R1and R2denotes a hydrogen atom, and Z represents a bond.

5. Connection on p. 1, And which represents phenyl, n = 1, and E denotes the radical-SO2-NR4-.

6. Connection on p. 1, And which represents phenyl, n = 1, E denotes the radical-CO-NR4-, p = 0, and Z represents the divalent radical-SO2-NRH-, which group of SO2associated with R3.

7. Connection on p. 1, And which indicates thienyl or sensational.

8. Connection on p. 1, And which represents naphthyl.

9. Connection on p. 1, in which n = 1, and E denotes the oxygen.

10. Connection on p. 1, selected from the group including:

N-(3-chloro-4-nitromethylene)-2-methylphenylacetic,

N-(3-chloro-4-nitromethylene)-2-triftormetilfullerenov,

N-(3-chloro-4-nitromethylene)phenylacetamide,

N-(3-chloro-4-nitromethylene)-2-chlorophenylacetic,

N-(3-chloro-4-nitromethylene)-4-chlorobenzamide,

N-(3-chloro-4-nitromethylene)-4-chlorobenzenesulfonamide

N-(4-chloro-3-nitromethylene)benzosulfimide,

N-(3-chloro-4-nitromethylene)-benzosulfimide,

1-(3-what>the nitro methyl-3-methyl-2-titillation,

4-methyl-N-[2-nitromethylene-3-methylbenzo[b] Tien-5-yl] benzosulfimide,

the nitro methyl-2-methyl-1-nafcillin,

the nitro methyl-3-chloro-2-nafcillin,

the nitro methyl-6-methoxy-5-trifluoromethyl-1-afterelton.

11. The method of obtaining the compounds of formula (I) under item 1, comprising processing acid formula

< / BR>
in which R1, R2, R3, Z, E, n, p, A and X have the meanings specified in paragraph 1,

the mixture of nitromethane and di (C1-C7) alkylsulfonate in the presence of a base.

12. The method of obtaining the compounds of formula (I) under item 1, comprising (I) processing of the acid of formula (II)

< / BR>
in which R1, R2, R3, Z, E, n, p, A and X have the meanings specified in paragraph 1,

the thionyl chloride or phosphorylchloride in the presence of phenol to obtain the corresponding phenyl ether of the formula (III)

< / BR>
in which R1, R2, R3, Z, E, n, p, A and X have the meanings mentioned above,

further (II) processing phenyl ester obtained in stage (I) with nitromethane in the presence of a base to obtain the compounds of formula (I).

13. The method of obtaining the compounds of formula (I) under item 1, in which (I) when n = 1, and E denotes the g/SUB>-CO-hal, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, and hal denotes a halogen atom, with an amine of formula (IV)

< / BR>
in which a and X have the meanings specified in paragraph 1,

or (II) when n = 1, and E denotes the group-SO2-NR4- spend the interaction of sulphonylchloride formula R3-Z-(CR1R2)p-SO2-hal, where R1,

R2, R3, Z and R have the meanings specified in paragraph 1, and hal denotes a halogen atom, with an amine of formula (IV) given above.

14. The method of obtaining the compounds of formula (I) under item 1, in which Z represents the group-SO2-NH, R = 0, n = 1, and E represents a group-CO-NR4- including (a) the interaction of isocyanate of the formula R3-SO2-N=C=O, in which R3matter specified in paragraph 1, with an amine of the formula

< / BR>
in which a and X have the meanings specified in paragraph 1,

then (b) processing phenyl ester obtained in stage (a) with nitromethane in the presence of a base to obtain the compounds of formula (I).

15. The method of obtaining the compounds of formula (I) under item 1, comprising (a) obtaining a phenyl ether of the formula (III)

< / BR>
in accordance with one of the following stages (I) to(V):

(I) when n = 1, and E is denoted by/SUB>-CO-hal, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, and hal denotes a halogen atom, with an amine of formula (V)

< / BR>
in which a and X have the meanings specified in paragraph 1,

or

(II) when n = 1, and E denotes the group-SO2-NR4- spend the interaction of sulphonylchloride formula R3-Z-(CR1R2)p-SO2-hal, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, and hal denotes a halogen atom, with an amine of formula (V) given above, or

(III) when n = 1, and E represents-NR4- spend the interaction of the compounds of formula R3-Z - (CR1R2)p-hal, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, and hal denotes a halogen atom, with an amine of formula (V) given above, or

(IV) when n = 1, and E represents-CH=N-, spend the interaction of the aldehyde of the formula R3-Z-(CR1R2)pCHO, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, with an amine of formula (V) given above, or

(V) when n = 1, and E represents-O-, spend the interaction of the compounds of formula R3-Z-(CR1R2)p-hal, where R1, R2, R3, Z and R have the meanings specified in paragraph 1, and h
or

(VI) when n = 1, and E denotes-CO-NR4- spend the interaction of the acid of formula R3-Z-(CR1R2)p-COOH-, where R1, R2, R3, Z and R have the meanings stated above, with an amine of formula (V) given above, and then (b) processing phenyl ester obtained in stage (a) with nitromethane in the presence of a base to obtain the compounds of formula (I).

16. Pharmaceutical composition for inhibiting alsoreported comprising an effective amount of at least one of the compounds of formula (I) according to any one of paragraphs.1-10 in combination with at least one pharmaceutically acceptable excipient.

17. The composition according to p. 16 in the form of tablets with immediate-release tablets with controlled-release capsules, solution for injection, creams or lotions for the eyes.

 

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where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

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