Derivatives finokalia, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Derivatives finokalia General formula I, where A is nitrogen or CH; R1, R2- alkyl, halogen or CF3; R4- N, cycloalkyl or alkyl, possibly substituted by hydroxy, alkoxy, phenyl, pyridinyl, morpholinyl, benzimidazolium, pyrazolyl, isoxazole or phthalimido,2-6alkenyl, C2-6the quinil,2-6alkanoyl, carboxy, aminocarbonyl, alkylamino, dialkylamino, NHSO2CF3, CONR5R6, O(CH2)nNR5R6, NHCO-NR5R6; R5, R6Is h, alkyl or together with the nitrogen atom form pyrrolidino or morpholinopropan; n = 2, 3, or 4, and pharmaceutically acceptable salts, possess anxiolytic, anticonvulsant, analgesic or neuroprotective activity. 4 C. and 11 C.p. f-crystals, 4 PL.

The invention relates to the derivatives of cinoxacin used in therapy.

L-Glutamic acid is an excitatory amino acid neurotransmitter, whose physiological role in the brain is associated with the interaction of four receptors, three of which were later called selective agonists: NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5 - Metalmania to the site for binding glutamic acid NMDA receptor has a high affinity sites for attachment dissociative anaesthetics (for example, ketamine), polyamines (e.g., spermine), glycine, and some metal ions (e.g., Mg2+), Zn2+. Because the NMDA receptor is an absolute requirement for the occurrence of the initiation is the binding of glycine, glycine antagonists can act as a functional NMDA antagonists.

For example, in the area of cerebral infarction, hypoxia triggers the release of abnormally high concentrations of glutamic acid, which leads to increased stimulation of the NMDA receptor, leading to degeneration and death of neurons. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo , can be useful in the treatment and/or prevention of pathological conditions, which poses a significant activation of NMDA receptors. Examples of such conditions include neurodegenerative disorders, including senile dementia and Alzheimer's disease, and diseases of the brain and spinal cord, resulting from such cases as stroke, transient ischemic stroke associated with surgery ischemia and head trauma. They can also be useful when the state of the th spot.

In addition, it is shown that NMDA antagonists possess anticonvulsant and anxiolytic activity and therefore can be used in the treatment of epilepsy and anxiety. They can also be useful for the treatment of pain.

NMDA antagonists may also reduce the impact of the syndrome of alcohol in animals with physical dependence (K. A. Grant et al. J. Pnarm. Exp. Ther. (1992), 260, 1017) and thus NMDA antagonists may be useful in the treatment of chronic alcoholism.

Describes the various derivatives of 1,2,3,4-tetrahydroquinoline-2,4-dione as NMDA (glycine site)-antagonists (see EP-A-0459561 and EP-A-0481676), whereas WO-A-91/13878 and JP-A-3220124 describe 1,4-dihydroquinoxaline-2,3-diones as antagonists of glutamic acid.

WO-A-94/00124 describes 1,4-dihydro-cinoxacin - 2,3-dione (including 6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3 - dione) with high affinity for the glycine binding site and used to treat shock and related disorders.

According to this invention features a compound of formula 1

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where A Is N or CH;

R1and R2independently C1-4-alkyl, halogen or CF3;

R3- C1-4alkyl (optionally substituted C3-7cycloalkenyl [optional substituted for IT, C1-4alkoxy, aryl (optionally substituted by up to 3 substituents, which are independently selected from C1-4of alkyl, C1-4alkoxy, halogen and CF3), heterocycle (optionally substituted by up to 3 substituents, which are independently selected from C1-4of alkyl, C1-4alkoxy, HE, halogen, CF3and oxo, and optionally benzododecinium), C2-6alkenyl, C2-6the quinil, C2-6alkanoyl, CO2H, C1-4alkoxycarbonyl, NH2C1-4alkylamino, di(C1-4alkyl)amino, NHSO2CF3, CONR5R6, NHCONR5R6or O(CH2)nNR5R6];

R5and R6independently - H or C1-4alkyl, or together with the nitrogen atom to which they are attached, may represent pyrrolidino-, piperidino or morpholinopropan; and

n = 2, 3, or 4

or its pharmaceutically acceptable salt (referred to here as the "compounds of the invention").

Pharmaceutically acceptable salts include the salts of the basic or acid groups which can be represented (for example, sodium salts of carboxylic acids and hydrochloric salts of amino groups).

Preferably, A represents H.

"Halogen" denotes fluorine, chlorine, bromine or y independently denote R1and R2are halogen and C1-4alkyl. For example, they both can denote chlorine or one can refer to chlorine, and the other may represent methyl or ethyl.

"Aryl" means an aromatic hydrocarbon, such as naphthyl or, more preferably, phenyl.

Preferably, R3represents C1-4alkyl, more preferably methyl.

"Heterocycle" refers to an aromatic or nonaromatic a heterocycle containing one or more heteroatoms which are selected from O, S and N. It can be connected with C1-6-alkyl group via a nitrogen or, more preferably, the carbon atom. As the heterocyclic group can be mentioned pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. Heterocyclic groups containing condensed benzene include benzimidazolyl.

Preferably, R4represents C1-6alkyl, substituted by OH or CO2H, more preferably, it represents CH2CH2OH or CH2CO2H.

The appropriate alkyl, alkoxy, Alchemilla and alcoolica group can be linear or razvetvlennogo atom, cannot be sufficiently stable in order to use them as medicines. Some of these unstable compounds are not part of the invention.

In some cases, the compounds according to this invention can exist as tautomers and all of these tautomers are included in the scope of the invention and the attached items, regardless of whether separately or not. In addition, compounds containing asymmetric centers may exist as enantiomers and diastereoisomers and the invention includes the individual isomers as well as mixtures of isomers.

In particular, may be limited rotation between A and 1,4-dihydro-2,3-dioxoimidazolidin cycle and thus may be atropisomers. Preferably, when A represents N, R4in the formula I is located above the plane of the sheet, a SO2R3is located behind the plane of the sheet, as shown below in formula IA:

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For example, when R1- C1, we have (R) - stereochemical assignment of this communication, and (S) - when R1is methyl.

Optical isomers (including atropisomers) can be separated by conventional means, such as fractionated crystallization di the teachings of the compounds according to the invention, including the removal of the protective groups of the compounds of formula II

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where A and R1-4such as defined above; P1and P2are protective groups for hydroxyl groups associated with aromatic cycles, and where it is desirable or necessary transformation of the compounds obtained into pharmaceutically acceptable salt or Vice versa. Protective groups which can indicate P1and P2include benzyl and C1-6alkyl, in particular methyl. These protective groups can be removed using conventional methods unprotect (see "Protective Groups in Organic Syntnesis" by T. W. Greene and P. G. M. Wuts, Jonn Wiley and Sons Inc, 1991). For example, when they denote methyl, they can be removed by acid hydrolysis using dilute aqueous hydrochloric acid (for example, 2 molar.). The reaction is usually carried out by heating the compounds of formula II, preferably to the boiling point under reflux in a mixture of dilute aqueous hydrochloric acid and a suitable organic solvent, such as dioxane or acetone, for example, for 2 to 48 hours to complete the reaction. The connection according to the invention can be isolated and purified by using common methods.

The compounds of formula II, as defined above, ostavlyayuthaya, can be obtained by interaction of the corresponding compounds of formula II in which R4denotes H, with the corresponding halide of formula R4aX, where X Is Cl, Br or I, and R4ahas the same values as defined for R4as described above, except that it cannot denote H, in the presence of a base, such as tert-butyl potassium. Usually the base is added to a solution of the compounds of formula II, where R4denotes H) in a suitable organic solvent, such as dimethylformamide. After stirring for a few minutes add the halide R4X and the mixture is stirred for several hours at approximately room temperature [see, for example, example 7(a)]. The desired intermediate compound can then be isolated and purified by using common methods.

In addition, the compounds of formula II can be obtained from other compounds of formula II using conventional methods. For example, compounds in which A is CH, and R4- allyl, can be converted into compounds in which R4- 2-hydroxyethyl, by ozonolysis and subsequent reduction. The compounds of formula II in which A is CH, and R4- allyl, can also be obtained from shooter 93).

Alternatively, the above method of alkylation, when A represents N, can be used in the Mitsunobu reaction. It includes the interaction of the alcohol of formula R4aOH (where R4ais as defined above) with diethylazodicarboxylate, triphenylphosphine and a compound of formula II in which R4- H. the Reaction is usually carried out in a suitable organic solvent, for example tetrahydrofuran, at about room temperature under stirring, for example, within 6 - 12 hours [see, for example, example 49(a)].

The compounds of formula II, where R4represents C1-C6alkyl group substituted, hydroxyl, can also be obtained by the methods, or similar preparative examples 8 to 10, which include education alkanolamines derived either to restore, for example, diisobutylaluminium, or subjected to interaction with alkalinisation.

The compounds of formula II, where R4- hydrogen and A - N, can be obtained by sulfonylamine corresponding finokalia formula III,

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where R1, R2, P1and P2such as defined above,

using the corresponding sulphonylchloride R3SO2the substituents may be deleted by the interaction of di-sulfonylamino product with aqueous sodium hydroxide (see, for example, preparative example 3). The compounds of formula III can be obtained by using common methods such as the methods illustrated by preparative examples 1 and 2.

The compounds of formula II, where R4is hydrogen and A is CH, can be prepared by the interaction of the compounds of formula IV,

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where R1, R2, P1and P2as described above, with mercaptides NaSR3in which R3is as defined above, followed by oxidation using nagkalat, such as 3-chlormadinone acid (see, for example, preparative example 29). The compounds of formula IV can be obtained by conventional methods (see, for example, preparative example 28).

In the syntheses of the compounds according to the invention mu. Ways of conducting such operations known to experts in the relevant field of synthesis and described in "Protective Groups in Organic Synthesis" mentioned above.

The compounds of this invention are useful because they possess pharmacological activity in animals (including humans). In particular, the compounds are useful in the treatment or prevention of neurodegenerative disorders (including senile dementia, Alzheimer's disease and diseases of the brain and spinal cord, resulting from such cases as stroke, transient ischemic stroke associated with surgery imeche and head trauma; and retinal degeneration and macular degeneration), seizures, pain and anxiety. In particular, the interest is the treatment of shock.

In addition, according to another aspect of the invention, given anxiolytic, anticonvulsant, analgesic or neuroprotective treatment method comprising introducing the compound according to the invention to a patient in need of such treatment. Also provides the use of compounds according to the invention in the form of pharmaceutical preparations and the use of compounds according to the invention in the manufacture of anxiolytic, protivosudorojnami according to the invention it is possible to demonstrate the following to the following examples:

(a). The ability of binding at the glycine site of the NMDA receptor.

It can be measured by testing the ability of the compound to displace radioligand with selective glycine sites of the membranes of rat brain as described in Brit. J. Pharm. (1991), 104, 74. In the used version of this method thoroughly washed membrane protein incubated with [3H]-L-689,560 for 90 minutes, using triacetate buffer (pH 7,4). The displacement radioligand when using the range of concentrations of the test compounds is used to produce IC50values (concentration of 50% inhibition).

(b). The binding ability of AMPA-receptor.

Can be measured by testing the ability of compounds to displace radioligand [3H] -AMPA from membranes of rat brain. The membrane homogenate was incubated with radioligand (10 nm) in the presence or in the absence of compounds at various concentrations at 4oC for 45 minutes Free and associated radioactive label share by rapid filtration and radioactivity measured using a liquid scintillation counter.

(c). Functional NMDA antagonism in vitro.

Demonstrates the ability of compounds Med. Chem. (1990), 33, 789 and Brit J. Pharm. (1985), 84, 381. In this embodiment of the method, evaluate the response to a standard concentration of NMDA in the presence of a range of concentrations of the test compounds and the results obtained are used to derive values for the IC50(concentration of 50% inhibition).

(d). NMDA Antagonism in vivo.

Can be demonstrated by the compound's ability to inhibit NMDA-induced chaotic bustle mice, varying the method described in Brit. J. Pharm " Proceedings Supplement (1992), 107 58P. In this model, groups of mice treated with test compounds at various doses before the introduction of NMDA (60 mg/kg, intravenously). Register latent period of onset of chaotic bustle and the presence or absence of such behavior is used to assess ED50. The analysis unit of probability is used to determine the dose at which 50% of mice do not exhibit the ability to erratic running 10 minutes after NMDA injection.

(e). Blocking cortical growing depression.

The potency of the compound in vivo can also be demonstrated by measuring its ability to block the spread of electroniciens cortical growing depression in anastasiav the brain to a depth of 0.5 to 1 mm for registering brain activity. In addition, the meninges before microelectrodes placed bipolar stimulating electrode. Then Dura subjected to stimulation with 10-minute intervals, and using microelectrodes recorded waves growing depression, reinforced and reproduced by using a tape recorder. Compound is dissolved in water in the form of their sodium salts or hydrochloric salts (where possible) and administered by intravenous injection at different doses to determine the minimum dose, blocking the spread of growing depression.

Compounds according to the invention it is possible to enter a patient in need of treatment, a variety of conventional routes of administration, including oral and intravenous administration. Joints have the ability to be adsorbed in the gastrointestinal tract and due to this it is also possible introduction by trains delayed allocation.

Basically therapeutically effective oral dose is approximately in the range of from 0.1 to 100 mg/kg body weight, requiring treatment of the patient, and intravenous dose is approximately in the range of 0.01 - 10 mg/kg body weight treatment is revenage infusion, at the dose being approximately in the range of 0.01-1 mg/kg/hour. In practice, the physician determines the actual dose, the most suitable for a particular patient and it will vary with age, weight and response of the individual patient. Of course, the above doses are typical average values, but there may be some cases when you need a higher or lower intervals of doses, and they are included in the scope of the invention and the attached items.

Although the compounds according to the invention can be entered separately, they are usually injected in a mixture with a pharmaceutical carrier which is selected depending on the intended route of administration and standard pharmaceutical practice. For example, oral administration can take the form of tablets containing such excipients as starch or lactose, capsules, either in pure form or in a mixture with excipients, or in the form of elixirs or suspensions containing perfumes or dyes. Connections can be entered in parenteral injection, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution of the corresponding salt of the compound, and the solution can contain also provides a pharmaceutical composition, including a connection according to the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The compounds of this invention have the advantage that they are more potent, more soluble, more selective [for example, are potent antagonists of NMDA(glycine site) - receptor, but have a weak affinity, or lack the affinity for AMPA-receptor] , less toxic or have other more desirable properties than the compounds known from the prior art.

The invention is illustrated in the following examples. The intermediate compound can be obtained, as described in the following preparative examples.

The melting temperature determined using the device Buchi'a, in glass capillaries and do not adjust. Spectroscopic data are obtained on the devices. Perkin Elmer 983 (UK), Fisons, The 1000 (mass spectrometer, thermal spray, using as a carrier of ammonium acetate in aqueous methanol ), and Bruker AC 300 and Varian Uniti 300-NMR (both 300 MHz), and they correspond attributed to structures. Column chromatography is carried out on Kieselgel 60, (230-400 mesh mesh) from E. Merck Darmstadt. For thin-layer chromatography (TLC) using Cedida sodium. In cases where the compounds analyzed in the form of hydrates, in the proton NMR spectrum clearly the presence of water in a rugged, thanks to the water peak. The purity of the compounds carefully evaluated using analytical TLC and proton NMR (300 MHz), the method of the proton NMR is used to calculate the amount of solvent in solvated samples. In multistage successive transformations of the purity and structure of the intermediate compounds is confirmed by a spectroscope by proton NMR. The shifts of the proton NMR are given in ppm in the lower region of the spectrum relative to tetramethylsilane was.

In the preparative examples and examples used some well-known experts in the relevant field designations, for example, Me (methyl), Et (ethyl). Ac (acetyl), h (hour), m (with respect to silica gel mesh.)

The following NMR spectra, the following notation:

m - multiplet,

s - singlet,

kV - Quartet

t - triplet,

user. - broadened signal,

d - doublet,

DD: double doublet,

dt - double triplet

Example 1. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-econsultant.

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A mixture of N-(6,7-dichloro-dimethoxyquinazolin-5-yl) is the boiling point under reflux for 2.5 hours, cooled and concentrated under reduced pressure. The solid residue is suspended in water, filtered and washed with water and diethyl ether, obtaining mentioned in the title compound (90 mg, 98%) as a white solid product, so pl. 297oC (decomp.).

Analysis%:

Found: C 33,97; H 2,97; N 11,68; for C10H9Cl2N3O4S

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a). tert-Butyl potassium (67.5 mg, 1.1 mmol) is added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyaniline-5 - yl)acanaloniidae (preparative example 4) (200 mg, 0.55 mmol) in dry dimethylformamide (3 ml) in a nitrogen atmosphere at 20oC. After 5 minutes add methyliodide (38 μl, 1.1 mmol) and the mixture stirred at 20oC for 2 hours. The mixture is concentrated under reduced pressure, distributed between ethyl acetate and water and the combined organic extracts washed with dilute aqueous sodium hydroxide. The solution is dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (elution with dichloromethane) to give N- (6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N- (methyl)econsultant (150 mg, 79%).

1H-NMR (300 MHz, CDCl3): =is 1.51 (3H, t, J 7 Hz), at 3.35 (3H, s), 3,37 (2H, square, J 7 Hz); 4,14 (3H, s), 4,20 (3H, s), 7,92 (1H, s), m/z (thermal spray) 380 (b), 2 M hydrochloric acid (4 ml) and dioxane (8 ml) is heated to the boiling temperature under reflux for 16 hours, cooled and concentrated under reduced pressure. The remaining solid product is suspended in water, filtered and washed with water and diethyl ether, obtaining mentioned in the title compound (140 mg, 99%) as a white solid product, so pl. > 300oC.

Analysis%:

Found: C 37,69; H 3,09; N 11,84. For C11H11Cl2N3O4S calculated: C 35,51; H 3,15; N 11,93%.

Examples 8 to 48. Compounds of the following examples in table 2, receive according to the method of example 7, using the corresponding 2,3-dimethoxyisoquinoline derived (preparative examples 3, 4, 6, 7, 11 - 14) and the appropriate alkyl halide [for example, methyliodide, ethyliodide, n-butylbromide, 3- (N,N-dimethylamino)propylchloride, benzylchloride, finitevolume, 2 - propyl bromide, 2-methoxyethylamine, allylbromide, Cyclopentanone, 2-(morpholine)ethylchloride, 4-picolylamine, 2-hydroxyethylamide, n-propyl bromide, 2-picolylamine, 3 - hydroxypropylamino, chlorate, propylbromide and 2-(methyl bromide)-6 - methoxypyridine (compound of preparative example 22)].

Notes to table 2:

a)1H-NMR (300

b) Obtained by the method of example 7 (b) using N-(6, 7-dichloro-2,3-dimethoxyaniline-5-yl)-N-[(6-methoxy - pyridine-2 - yl)methyl] methanesulfonamide (preparative example 22). During hydrolysis of dimethoxyaniline, methoxypyridine turn in 2 - pyridone.

c)1H-NMR (300 MHz, DMSO-d6) = 0,95 (3H, t, J 8 Hz), of 1.18 (3H, t, J 8 Hz), 2,70 (2H, q, J 8 Hz), 3,20 (3H, s), 3,71 (2H, m), 7,05 (1H, s), is 10.75 (1H, user. C) 12,09 (1H, user.C) m/z (thermal spray) 357 (MNH4+),max(KBr) 3300, 2950, 1720, 1330, 1150 cm-1.

d)1H-NMR (300 MHz, DMSO-d6) = 0,80 (3H, t, J 8 Hz), of 1.30 (2H, m), are 2.19 (3H, s), 2,22 (3H, s), 3,19 (3H, invisible), to 3.49 (2H, m), 6,98 (1H, s) 9.95 (1H, user.C) 11,83 (1H, user.C).

m/z (thermal spray) 326 (MH+), 343 (MNH4+), max(KBr) 3380, 3220, 1720, 1680, and 1150 cm-1.

e)1H-NMR (300 MHz, DMSO-d6) = 2,19 (3H, s), of 2.21 (3H, s), and 3.16 (3H, s), to 6.95 (1H, s), 10,67 (1H, user.c). 11,82 (1H, user.C).

m/z (thermal spray 298 (MH+), 315 (MNH4+,max(KBr) 3225, 1700, 1325, 1140 and 750 cm-1.

f)1H-NMR (300 MHz, DMSO-d6) = 1,00 (3H, t, J 8 Hz), to 2.35 (3H, s) to 3.58 (3H, s), and 3.72 (2H, m), 7,12 (1H, s), the 10.40 (1H, user.C) 12,01 (1H, user.C).

m/z (thermal spray) 349 (MNH4+) max(KBr) 3450, 3260, 2950, 1700, 1380, 1330, 1150 and 520 cm-1.

g)1H-NMR (300 MHz, DMSO-d6): = 2,3>SUP>+)

h)1H-NMR (300 MHz, DMSO-d6) = 1,00 (3H, t, J 7 Hz), is 2.30 (3H, s), 3,23 (3H, s), the 3.65 (2H, square J 7 Hz), 7,24 (1H, s), the 10.40 (1H, user.C) 11,93 (1H, user.C)

m/z (thermal spray) 349 (MNH4+)

i)1H-NMR (300 MHz, DMSO-d6) = 2,30 (3H, s), 3,19 (3H, invisible), to 3.34 (2H, m), 3,74 (1H, m), of 4.05 (1H, m), 5,98 (1H, user.C) of 7.23 (1H, s), 10.92 (1H, user.C) 11,91 (1H, user.C).

m/z (thermal spray) 348 (MH+), 365 (MNH4+).

j)1H-NMR (300 MHz, DMSO-d6) = 1,05 (3H, t, J 8 Hz), to 2.18 (3H, s), 2,22 (3H, s), 3,90 (2H, m), 7,10 (1H, c), was 10.82 (1H, user.C) 11,94 (1H, user.C).

m/z (thermal spray 383 (MNH4+).

k).1H-NMR (300 MHz, DMSO-d6) = to 2.18 (3H, s), 2,22 (3H, s) to 3.35 (1H, m), 3,50 (1H, m), 3,70 (1H, m) to 4.16 (1H, m), 6,10 (1H, user.C). 7,05 (1H, s), 10,85 (1H, user.C) 11,95 (1H, user.C)

m/z (thermal spray) 382 (MH+), 399 (MNH4+).

Or otherwise, the compound of example 17 can be obtained in the following way:

(RS)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxo-cinoxacin-5-yl)-N- (2-hydroxyethyl) methanesulfonamide

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a) a Mixture of potassium carbonate (25,81 g, 0,187 mol), 2-bromoethanol (13,26 ml, 0,187 mol) and N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl) methanesulfonamide (preparative example 3) (55,0 g, 0,156 mol) in acetone (2.5 l), heated to boiling point under reflux in decelerates sodium. Then the organic layer is dried (MgSO4), concentrated under reduced pressure and the residue is cleaned three times by recrystallization from methanol, which gives (RS)-N-(6,7-dichloro-2, 3-dimethoxyquinazolin-5-yl)-N-(2 - hydroxyethyl)methanesulfonamide (43,7 g, 70%) as a white solid, so pl. 240-242oC.

Analysis %:

Found: C 39,35; H Of 3.78; N 10,55. Calculated for C13H15N3O5Cl2: C 39,41; H 3,82; N 10,61%.

b) a Mixture of (RS)-N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2 - hydroxyethyl)methanesulfonamide (11,41 g 0,029 mol) and 2 M hydrochloric (300 ml) acid is heated to boiling point under reflux for 18 1/2 hours, then cooled in an ice bath. The solid product is filtered off and washed with water, giving specified in the title compound (9,65 g, 91%) as a white solid. So pl. 272 - 274oC.

Analysis %:

Found: C 35,82; H 3.04 from; H 11,37;

Calculated for C11H11N3O5Cl2S: C 35,88; H 3,01; N 11,41%.

Example 49. N-(1,4-Dialer-6,7-dichloro-2,3 - dioxopiperidin-5-yl)-N-(3-pyridylmethyl) methanesulfonamide, hydrochloride

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a) Diethylazodicarboxylate (90 µl, or 0.57 mmol) is added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxycinnamoyl) and triphenylphosphine (149 mg, of 0.57 mmol) in dry tetrahydrofuran (12 ml) in a nitrogen atmosphere at 23oC. After 8 hours the solvent is removed under reduced pressure and the residue clean flash chromatography (gradient elution with diethyl ether/methanol) to give N-(6,7-dichloro-2, 3 - dimethoxyquinazolin-5-yl)-N-(3-pyridylmethyl)methanesulfonamide (145 mg, 57%) as a white solid product, so pl. 217oC (decomp.).

1H-NMR (300 MHz, CDCl3): = 3,18 (3H, s), 4,10 (3H, s), 4,14 (3H, s), of 4.95 (2H, s), 7,17 (1H, DD. J 4 and 6 Hz), 7,68 (1H, dt, J 2 and 6 Hz), of 7.90 (1H, s), to 8.41 (1H, d, J 2 Hz), 8,48 (1H, DD, J 2 and 4 Hz).

m/z (thermal spray) 443 (MH+).

b) a Mixture of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(3 - pyridylmethyl)-methanesulfonamide (130 mg, 0,293 mmol), 2 M hydrochloric acid (2 ml) and dioxane (4 ml) is heated to the boiling temperature under reflux for 2.5 hours, cooled and concentrated under reduced pressure. The residue is suspended in water (1 ml), filtered and washed with water and diethyl ether, obtaining mentioned in the title compound (120 mg, 98%) as a white solid. So pl. 234 - 235oC (decomp).

Analysis %:

Found: C 39,67; H A 3.06; N 12,20; S, 7,05. For C15H12Cl2N4O4S = up 3.22 (3H, s), to 4.73 (1H, d, J 15 Hz), 4,89 (1H, d, J 15 Hz), 7.23 percent (1H, s), 7,47 (2H, with the oksipropil)methanesulfonamide

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The specified connection is obtained from (RS)-N-(6,7-dichloro - 2,3-dimethoxyaniline-5-yl)-N-(2-hydroxypropyl)methanesulfonamide (preparative example 9) according to the method of example 1: yield 81%, white solid product (a mixture of diastereoisomers), so pl. 291-292oC (from water).

Analysis %:

Found: C 37,77; H 3,15; N 10,63.

Calculated for C12H13Cl2N3O5S: C 37,71; H 3,43; N 10,99%.

Example 67. (N-(1,4-Dihydro-6,7-dichloro-2,3 - dioxopiperidin-5-yl)-N-(2-hydroxy-2-methylpropyl " methanesulfonamide

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The specified connection is obtained from N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-N-(2-hydroxy-2-methylpropyl)methanesulfonamide (preparative example 10) according to the method of example 1: yield 83%, white product, so pl. 252-253oC (decomp.).

Analysis %:

Found: C 39,32; H 3,71; N 10,55,

Calculated for C13H15Cl2N3O5S 39,40; H 3,81; N, 10.60% OF.

Example 68. N-(1,4-Dihydro-6-chloro-7-trifluoromethyl-2,3 - dioxopiperidin-5-yl)-N-ethylmethanesulfonate

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a) a Mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxy-cinoxacin - 5-yl)methanesulfonamide (preparative example 20, 73 mg, 0.2 mmol) and anhydrous potassium carbonate (33 mg, 0.24 mmol) in acetone was stirred under heating up to the boiling point of the hour. Add a further quantity of iodata (32 μl, 0.4 mmol) and continue heating for another 4 hours. The mixture is concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic solution is dried (MgSO4), concentrated under reduced pressure and the residue clean flash chromatogaphy (gradient elution dichloromethane/methanol) to give N-(3-amino-6-chloro-7 - trifluoromethyl-2-methoxyaniline-5-yl)-N-ethylmethanesulfonate (75 mg, 96%) as a white solid product.

1H-NMR (300 MHz, CDCl3) / = of 1.16 (3H, t, J 7 Hz, (3,20 (3H, s), 3,86 (2H, m), 4,16 (3H, s), of 5.50 (2H, user.C) of 8.06 (1H, s).

m/z (thermal spray) 399 (MH+).

b) a Mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyaniline-5-yl)-N-ethyl-methanesulfonamide (stage (a) above, 70 mg, 0.18 mmol), 2 M hydrochloric acid (3 ml) and dioxane (6 ml) is heated to the boiling temperature under reflux for 2 hours, cooled and concentrated under reduced pressure. The residue is suspended in water, filtered and the solid product washed with water. After drying specified in the title compound (33 mg, 48%) are obtained in the form of a white solid product, so pl. > 300oC.

Analysis %:

Found: C 37,61; H 2,73; N 10,80.

The expect iformity-2,3 - dioxopiperidin-5-yl)-N-(2-hydroxyethyl)methanesulfonamide

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Specified in the title compound, receive by way of example 68, replacing Iodate 2-bromoethanol. Specified in the title compound obtained as white solid (40 mg, 44% yield for two steps), so pl. 292-294oC.

Analysis %:

Found: C 36,17; H 2,73; H 10,26.

Calculated for C12H11ClF3N3O5S : C 35,88; H WAS 2.76; N 10,46%.

Example 70. (RS)-N-(Carboxymethyl)-N-(1,4-dihydro-6,7 - dichloro-2,3-dioxopiperidin-5-yl)methanesulfonamide

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A mixture of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N- (methoxycarbonylmethyl)methanesulfonamide (preparative example 21, 3,17 g of 7.48 mmol), 2 M hydrochloric acid (80 ml) and dioxane (80 ml) is heated to the boiling temperature under reflux for 18 h, cooled and concentrated under reduced pressure, obtaining a yellow solid product (2.85 g, 100%), so pl. 271oC (decomp).

Analysis %:

Found: C 33,98; H 2,64; N 10,50.

Calculated for C11H9Cl2N3O6S 1/2H2O: C 33,77; H 2,58; m a 10.74%.

Example 71. (RS)-N-(1,4-Dihydro-6,7-dichloro-2,3 - dioxopiperidin 5-yl)-N-(methoxycarbonylmethyl)methanesulfonamide

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A solution of N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro- -2,3-dioxopiperidin-5-yl)metangula to the boiling temperature under reflux for 3 hours, cooled and concentrated under reduced pressure, obtaining a yellow solid product (2,838 g, 96%), so pl. 301oC (decomp).

Analysis %:

Found: C 36,29; H 2,60; N 10,49.

Calculated for C12H11Cl2N3O6S: C 36,38, H 2,80; N 10,61%.

Example 72. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl) - N-(N-methylcarbamoylmethyl)methanesulfonamide

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A mixture of N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl) -N-(methoxycarbonylmethyl)methanesulfonamide (from example 71, 150 mg, 0.38 mmol), ethanol (3 ml) and methylamine (33% solution in ethanol, 3 ml) is heated in a closed vessel at 75oC for 1 hour, then at 90oC for 1.5 hour. The mixture is cooled and slowly poured into an excess of 2 M hydrochloric acid. A white precipitate filtered and dried, obtaining mentioned in the title compound (107 mg, 72%), so pl. 289oC.

Analysis %:

Found: C 36,24; H 2,99; N 13,98,

Calculated for C12H12Cl2N4O5S: C 36,47; H A 3.06; N 14,18%.

The compounds shown below in table 4, obtained from the compound of example 71 by way of example 72, using the corresponding amine instead of methylamine.

Example 79. (RS), (RS)-N-(1-Carboxyethyl)-N-(1,4-dihydro - 6,7-dichloro-2,3-dioxopiperidin-5-yl)metanil)-methanesulfonamide (preparative example 23, 1.40 g, 32 mmol), 2 M hydrochloric acid (40 ml) and dioxane (40 ml) is heated in an autoclave at 130oC for 48 hours and at 150oC for 24 hours. The mixture is cooled, concentrated to small volume under reduced pressure and the solid product filtered off and washed with diethyl ether. The product is dissolved in 1 M aqueous sodium hydroxide (40 ml) and periostat by adding 2 M hydrochloric acid (to pH 3), the White solid product is filtered off and dried in vacuum, obtaining mentioned in the title compound (1.13 g, 89%), in the form of a mixture of diastereoisomers, so pl. 282oC (decomp.).

Analysis %:

Found: C 33,68; H 3,17; N Being 9.61.

Calculated for C12H11Cl2N3O6S

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i) a Mixture of potassium carbonate (42,37 g, 0.3 mol), methylpropanoate (48,4 ml, 0.51 mol) and N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl) methanesulfonamide (preparative example 3) (90 g, 0,256 mol) in acetone (1.75 l), heated to boiling point under reflux for 8 1/2 hours, cooled and remove the acetone under reduced pressure. The residue is stirred with water (1.5 l) for 1/4 hour, filtered and the solid product washed with water and then diethyl ether, to obtain (RS)-N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-N-(UB>N3O6S calculated: C 39,63; H of 3.56; N 9,90%.

ii) a Mixture of (RS)-N-(6,7-dichloro-2,3-dimethoxyaniline - 5-yl)-N-(methoxycarbonylmethyl)methanesulfonamide from stage (i) above, 2 M hydrochloric acid (1 l) and dioxane (1 l) was heated to the boiling temperature under reflux for 18 hours, cooled and concentrated under reduced pressure. The solid residue suspended in water (1.5 l), filtered and washed with water and diethyl ether, obtaining mentioned in the subtitle compound (95 g, 92%) as a white solid product, so pl. 271oC. (decomp. ).

Analysis %:

Found: C 33,98; H 2,64; N 10,50.

Calculated for C11H9Cl2N3O6S

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Quinine (25,48 g 0,078 mol) in ethanol (300 ml) are added to the heated to the boiling temperature under reflux a solution of (RS)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3 - dioxopiperidin-5-yl)methanesulfonamide (from stage (a), 30 g 0,078 mol) in ethanol (2.1 liters). After 1/2 hour of heating up to the boiling temperature under reflux, the suspension is filtered hot and the solid product washed with ethanol, getting mentioned in the subtitle compound (S) stereochemistry in the form of a quinine salt (23,2 g, 41,3%).

[]2D

[]2D5= -98.7 (=0,15, MeOH)

Quinine salt separately suspended in water (1.3 l) and treated with concentrated hydrochloric acid (22 ml) with vigorous stirring, getting two of these in the subtitle compound (after filtering).

Specified in the subtitle compound (R)-stereochemistry receive in the form of a white solid product (9.8 g, 95%) so pl.>218oC (decomp.).

[]25D/= +19,4 (C = 0.18, MeOH).

Analysis %:

Found: C 33,51; H 2,32; N 10,46.

Calculated for C11H9Cl2N3O6S

A mixture of (R)-N- (carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl) methanesulfonamide (from stage (b), 20,34 g, 0,053 mol) and methanol (266 ml) saturated with gaseous hydrogen chloride, stirred for 18 hours at room temperature, evaporated to dryness and the residue suspended in methanol (300 ml). After stirring for 1/2 hour, the solid product is filtered off, getting mentioned in the subtitle compound as atropisomers (17.5 g, 83%), so pl. 290oC (decomp.).

[]2D5= -1,7o, 2,2 (1H, user. C). m/z (thermal spray) 396 (MH+).

d) (R)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin - 5-yl)-N- (2-hydroxyethyl)methanesulfonamide

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Alumoweld lithium (39,4 ml, 1 molar. in THF, to 39.4 mmol) are added to (R)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N- (methoxycarbonylmethyl)methanesulfonamide (from stage (C) of 9.75 g, 24.6 mmol) in tetrahydrofuran (590 ml), cooled in an ice bath to a temperature of between 0 - 5oC. Through 1/4 hours add an additional amount of lithium aluminum hydride (2.4 ml, of 2.46 mmol), the mixture is stirred for another 1/2 hour and add methanol in tetrahydrofuran (60 ml).

The mixture is evaporated to dryness under reduced pressure and the residue distributed between ethyl acetate and 2 M hydrochloric acid. The organic extracts are dried over sodium sulfate and concentrate under reduced pressure. The remainder of the clean flash chromatography using gradient elution (CH2Cl2:MeOH mixture containing 10% AcOH 100:0 ---> 95:5), receiving first mentioned in the title compound in the form of individual atropisomers, (6.0 g, 66%), so pl. 293 - 294oC.

[]2D5= +49,0 (C = 0,1, 1 M aqueous sodium hydroxide)

Analysis %:

Found: C 35,89; H 2,83; N 11,42.

Calculated for C11H11
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Specified in the subtitle compound produced from (S)-N-carboxymethyl-N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)methanesulfonamide (stage (b)) according to the method of stage (c); yield 78% in the form of a white solid.

1H-NMR (300 MHz, DMSO-d6): = 3,30 (3H, in), 3.75 (3H, s), 4,32 (1H, d), is 4.85 (1H, d), 7,35 (1H,s), 10,85 (1H, s), 12,60 (1H, s).

m/z (thermal spray) 396 (MH+).

f) (S)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin - 5-yl)-N-(2-hydroxyethyl)methanesulfonamide

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The second is mentioned in the title compound is obtained from (S)-N-(1,4-dihydro-6,7-dihydro-2,3-dioxopiperidin-5-yl)-N- (methoxycarbonylmethyl)methanesulfonamide (stage (e)) according to the method of stage (d): output. 60% in the form of a white solid

product, so pl. >300oC.

[]2D5= -45,0 (C = 0.1 and 1 M aqueous sodium hydroxide).

1H-NMR (300 MHz, DMSO-d6): / = 3,21 (5H, m), the 3.65 (1H, m), a 4.03 (1H, m), of 6.02 (1H, user. C) to 7.32 (1H, s) 11,00 (1H, user. C), 12,12 (1H, user. C).

m/z (thermal spray) 369 (MH+).

Example 81. (RS), (RS)-N-(1,4-Dihydro-6,7-dichloro-2,3 - dioxopiperidin-5-yl)-N-(1-methoxycarbonylethyl)methanesulfonamide

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N-(1-Carboxyethyl)-N-(1,4-dihydro-6,7-dichloro - 2,3 - dioxopiperidin-5-yl)methanesulfonamide (from example 79, 1 g of 2.53 mmol) in methane is 8 hours at 60oC. the Solid product is filtered off, getting mentioned in the title compound as a mixture of diastereoisomers (431 mg, 42%).

1H-NMR (300 MHz, DMSO-d6): = 1,70 (3H, d), 3,17 (3H, s), of 3.77 (3H, s), and 4.75 (1H, square), 7,39 (1H, s), 11,46 (1H, s), 12,20 (1H, s).

m/z (thermal spray) 413, 415 (MNH4+).

Example 82. (RS),(RS )-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N- (1-(N'-methylcarbamoyl)ethyl)methanesulfonamide

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N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N- (1-methoxycarbonylethyl)methanesulfonamide (from example 81, 110 mg, 0.27 mmol) in 33% methylamine in ethanol (6 ml) is heated at 100oC for 5 hours in a sealed ampoule, cool and add to 2 M hydrochloric acid (400 ml). The obtained solid product is filtered off, dissolved in 1 M sodium hydroxide, precipitated with 2 M hydrochloric acid and filtered, obtaining mentioned in the title compound as a mixture of diastereoisomers (63 mg, 57%), so pl. 250oC (decomp.).

Analysis %:

Found: C 37,98; H 3,37; N 13,19.

Calculated for C13H14Cl2N4O5S: C 37,66; H 3,55; N 13,51.

Example 83. N-(1,4-Dihydro-7-chloro-6-fluoro-2,3-dioxopiperidin-5-yl)- N-(2-hydroxyethyl)methanesulfonamide

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a) N- (7-Chloro-6-fluoro-2,3-dimethoxyaniline-5-yl)N-(2-hydroxyethyl) methanesulfonamide. The product is obtained as a white solid (91% yield), so pl. 209 - 210oC.

1H-NMR (300 MHz, CDCl3): = 3,18 (3H, s), 3,32 (1H, m), 3,50 (1H, m), 3,74 (2H, m), 4,08 (1H, m), 4,14 (3H, s), 4,20 (3H, s), of 7.90 (1H, d, J 8 Hz).

m/z (thermal spray) 380 (MH+).

b) N- (7-Chloro-6-fluoro-2,3-dimethoxyaniline-5-yl)-N-(2 - hydroxyethyl)-methanesulfonamide [from stage (a)] transform by way of example 17 (b) N-(1,4-dihydro-7-chloro-6-fluoro-2,3 - dioxopiperidin-5-yl)-N-(2-hydroxyethyl) -methanesulfonamide. The product is obtained as a white solid (86%), so pl. 298 - 300oC.

Analysis %:

Found: C 37,44; H 3,00; N To 11.79.

Calculated for C11H11ClFN3O5S: C 37,56; H 3,15; N 11,95%.

Example 84. N-(1,4-Dihydro-6-chloro-7-fluoro-2,3 - dioxopiperidin-5-yl)-N-(2-hydroxyethyl)methanesulfonamide

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a) N- (6-Chloro-7-fluoro-2,3-dimethoxyaniline-5-yl)methanesulfonamide (preparative example 26) transform according to the method of example 17(a) N-(6-Chloro-7-fluoro-2,3-dimethoxyaniline-5-yl)-N-(2-hydroxyethyl) methanesulfonamide. The product is obtained as a white solid (68% yield).

1H-NMR (300 MHz, CDCl3): / = 3,26 (3H, s), 3,50-4,10 (4H, m), 4,16 (3H, s), 4,20 (3H, s), 7,60 (1H, d, J 10 Hz).

m/z (thermal spray) 380, 382 (MH+).

the teaching of example 17(b) N-(1,4-dihydro-6-chloro-7-fluoro-2, 3-dioxopiperidin-5 - yl)-N-(2-hydroxyethyl)methanesulfonamide. The product is obtained as a white solid (75% yield), so pl. 290-291oC.

Analysis %:

Found: C 37,62; H 3,10; N 11,88.

Calculated for C11H11ClFN3O5S: C 37,56; H 3,15; N 11,95%.

Example 85. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N- (2-amino-ethyl)methanesulfonamide

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Specified in the title compound is obtained from N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-N-(2-amino-ethyl)methanesulfonamide (preparative example 27), 40 mg, 0,101 mmol) by the method of example 7(b) in the form of a white solid of compound (18 mg, 48%), so pl. >300oC.

Analysis %:

Found: C 31,85; H 3,74; N 13,15.

Calculated for C11H12Cl2N4O4S 2/5H2O1/10 CH2Cl2: C 31,79; H 3,36; N MADE 13.36%.

Example 86. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)- N-(2-phthalimidomethyl)methanesulfonamide

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Specified in the title compound, receive by way of example 85 N-(6,7-dichloro-2,3-dimethoxyaniline-5- -5-yl)-N-(2-phthalimidomethyl)-methanesulfonamide (from preparative example 27 (a), 150 mg, 0,285 mmol) as a white solid (131 mg, 92%), so pl.>300oC.

1H-NMR (300 MHz, d6- DMSO); = 3,25 (3H, "ptx2">

Example 87. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N-(2- (N'-trifloromethyl)aminoethyl)methanesulphonamide

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a) Triethylamine (13 μl, 0,139 mmol) and then anhydride triftormetilfullerenov acid (23 μl, 39 mg, 0,139 mmol) is added dropwise to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyaniline - 5-yl)-N-(2-amino-ethyl)-methanesulfonamide (from preparative example 27, 50 mg, 0,126 mmol) in dichloromethane (1.5 ml) at -78oC in nitrogen atmosphere. The mixture is stirred for 30 minutes and then allowed to warm to room temperature. The mixture is washed with water, saturated aqueous sodium bicarbonate and salt solution and then dried (MgSO4). Concentration under reduced pressure gives N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2-(N'-trifloromethyl) aminoethyl)methanesulphonamide in the form of a pale yellow solid (50 mg, 75%).

1H-NMR (300 MHz, CDCl3): = 3,20 (3H, s), 3,20-3,30 (1H, m), 3,52-3,62 (1H, m), 3,86-of 3.96 (1H, m), 4.04 the-4,17 (1H, m), 4,18 (3H, s) to 4.23 (3H, s), of 8.00 (1H, s).

1 m/z (thermal spray) 527 (MH+).

(b) Specified in the title compound, receive by way of example 7(b) from N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2-(N'- trifloromethyl)aminoethyl)methanesulphonamide [from stage (a)] itano for C12H11N4S2O6Cl2F3H2O3/10 Et2O: C 29,39; H 2,99; N 10,38.

Example 88. N-(1,4-Dihydro-6,7-dichloro-2, 3-dioxopiperidin-5-yl)-N-(2-[methylaminomethyl]aminoethyl) methanesulphonamide

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a) methyl isocyanate (8,2 μl, 8.0 mg, 0.14 mmol) are added to a solution of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2 - amino-ethyl)methanesulfonamide (from preparative example 27, 50 mg, to 0.127 mmol) in dichloromethane (2 ml) at room temperature and under nitrogen atmosphere. After 30 minutes the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and concentrated under reduced pressure, obtaining N-(6,7-dichloro-2,3-dimethoxyaniline - 5-yl)-N-(2-[methylaminomethyl]aminoethyl)methanesulphonamide in the form of a pale yellow foam (52 mg, 91%).

1H-NMR (300 MHz, CDCl3): = is 2.74 (3H, d, J 2 Hz), 3,18 (3H, s) to 3.36 (2H, m) to 3.92 (2H, m), 4,15 (3H, s), 4,17 (3H, s), 4.2V (1H, user.C) 5,14 (1H, user, C) of 7.96 (1H, s).

m/z (thermal spray) 452 (MH+).

(b) Specified in the title compound, receive by way of example 7(b) from N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2- [methylaminomethyl] aminoethyl)methanesulphonamide [from stage (a)] as a pale yellow foam (60%).

Analysis %:

Found: C 32,90; H 3,90; N 14,50.

The caters the(1H,s).

Example 89. N-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N-(5-tetrazolyl) methanesulfonamide

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a) Chloroacetonitrile (233 μl, 279 mg of 3.69 mmol) are added to the heated to the boiling temperature under reflux a mixture of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)methanesulfonamide (from preparative example 3, and 1.00 g, 2,84 mmol) and potassium carbonate (0.47 in) to 3.41 mmol) in acetone (50 ml) under nitrogen atmosphere. The mixture is heated to boiling point under reflux for 18 hours and then allowed to cool and distributed between ethyl acetate (500 ml) and water (500 ml). The organic phase is dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (elwira 0-100% ethyl acetate in hexane and then with 5% methanol in dichloromethane) to give N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(cyanomethyl) methanesulfonamide as not quite white solid product (600 mg, 54%).

1H-NMR (300 MHz, DMSO-d6): = and 3.31 (3H, s) 4,07 (3H, s) 4,08 (3H, s), 4,84 (1H, d, J = 19 Hz), 5,10 (1H, d, J = 19 Hz), 8,11 (1H, s).

b) a Mixture of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N- (cyanomethyl)methanesulfonamide (100 mg, 0,256 mmol) and tributylamine (170 mg, 0,512 mmol) (Synthesis, 1976, 329) in toluene (10 ml) is heated to the boiling point of the reverse haladas chromatography (gradient elution of a mixture of from dichloromethane to 90:10:1 dichloromethane: methanol: ammonia), that gives N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-N-(5-tetrazolyl) methanesulfonamide as not quite white solid (78 mg, 70%).

1H-NMR (300 MHz, CDCl3): =3,30 (3H, s), 4,14 (3H, s), 4,18 (3H, s), 5,12 (1H, d, J 16 Hz), 5,31 (1H, d, J 16 Hz), to 7.99 (1H, s),

m/z (thermal spray) 434 (MH+).

s) Specified in the title compound, receive by way of example 7(b) from N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(5-tetrazolyl) methanesulfonamide, but rubbing with water instead of diethyl ether, giving a white solid product (66%), pl. > 300oC.

Analysis %:

Found: C 32,79; H 2,15; N 23,25.

Calculated for C11H9N7O4Cl2S

A mixture of 6,7-dichloro-2,3-dimethoxyaniline-5-yl)-methyl methyl sulfone (80 mg, 0,228 mmol) (preparative example 29), 2 M hydrochloric acid (1 ml) and dioxane (3 ml) is heated to the boiling temperature under reflux for 3 hours, cooled and concentrated under reduced pressure. The residue is diluted with water and the resulting white solid product is collected by filtration, washed with water and diethyl ether, and dried under reduced pressure at 60oC, getting mentioned in the title compound (58 mg, 79%) as a white solid product, so pl. > 300o< 4
Cl2S: C 37,17; H 2,50; N 8,67%.

Example 91. (1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl) methyl-ethyl sulfon

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Specified in the title compound is obtained from (6,7-dichloro-2,3 - dimethoxyaniline-5-yl) methyl-ethyl sulfone (preparative example 30) according to the method of example 90 in the form of a white solid product (65%), so pl. > 300oC.

Analysis %:

Found: C 39,21; H 2,99; N 8,25; S 9,70.

Calculated for C11H10N2O4Cl2S: C 39,18; H 2,99; N 8,31; S 9,51%.

Example 92. (1,4-Dihydro-6,7-dichloro-2,3 - dioxopiperidin-5-yl)methylbenzyl sulfon

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Specified in the title compound is obtained from (6,7-dichloro-2,3-dimethoxyaniline-5-yl) methylbenzyl sulfone (preparative example 31) by the method of example 90 in the form of a white solid (92%), so pl. > 300oC.

Analysis %:

Found: C 48,30; H 3,12; N Of 6.65.

Calculated for C16H12N2O4Cl2S

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a) a Solution of (6,7-dichloro-2,3-dimethoxyaniline-5-yl)-methyl methyl sulfone (50 mg, 0,142 mmol) (preparative example 29) and diallyl carbonate (41 μl, 40 mg, 0,285 mmol) in dry tetrahydrofuran (0.8 ml) is added via cannula to a mixture of Tris(dibenzylideneacetone) dipalladium(O)chloroform-adduct (7.4 mg, to 0.007 mmol) and 1,2-bis (the round. The mixture is stirred at room temperature for 5 minutes and then heated to the boiling temperature under reflux for 2 hours. The mixture is allowed to cool, diluted with dichloromethane and concentrated under reduced pressure. The remainder of the clean flash chromatography (elution 3:1 hexane:ethyl acetate) to give 1-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-3-butenyl methyl sulfone in the form of a mixture of diastereoisomers (approximately 20:11H-NMR) as a white foam (29 mg, 52%).

1H-NMR (300 MHz, CDCl3): = (basically, only diastereoisomer) of 2.93 (3H, s) to 3.36 (1H, m), a-3.84 (1H, m), 4,16 (3H, s), 4,25 (3H, s) 5,00 (2H, m), the 5.45 (1H, m), the ceiling of 5.60 (1H, m), of 7.96 (1H, s).

m/z (thermal spray) 391 (MH+).

b) a Mixture of 1-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-3-butenyl methyl sulfone (from stage (a), 27 mg, 0,069 mmol), 2 M hydrochloric acid (0.5 ml) and dioxane (1 ml) is heated at 90oC for 15 hours, cooled and concentrated under reduced pressure. The residue is treated with ultrasound with diethyl ether and a few drops of methanol and the resulting white solid product is collected by filtration, washed with diethyl ether and dried, obtaining mentioned in the title compound (17 mg, 68%) as a white powder, so pl. 270,5 - 272oC.

Example 94. 1-(1,4-Dihydro-6,7-dichloro-2,3 - dioxopiperidin-5 - yl)-3-hydroxypropyl-methyl sulfon

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a) Ozone is bubbled through a solution of 1-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-3-butenyl methyl sulfone (50 mg, 0,128 mmol) [(example 93(a)] in dry dichloromethane (1.3 ml) at -78oC until blue color. The mixture is stirred for 5 minutes and then rinsed with current of oxygen and then nitrogen. Add methanol (1.3 ml) and the mixture is allowed to balanced at -78oC before the addition of sodium hydroxide (12 mg, 0,319 mmol) in two portions. The mixture is stirred for 5 minutes and then allowed to warm to room temperature. The mixture is then poured into 2 M hydrochloric acid (20 ml) and extracted with dichloromethane (2 x 20 ml). The combined extracts washed with brine (20 ml), dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (elwira 1:1 hexane:ethyl acetate), giving 1-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-3-hydroxypropyl methyl sulfon (35.6 mg, 70%) as a white foam.

1H-NMR (300 MHz, CDCl3): = 2,96 (3H, s), 3,05 (2H, m), 3,51 (1H, m), a 3.87 (1H, m), 4,15 (3H, s), 4,22 (3H, s), is 5.18 (1H, DD, J 6.8 Hz), 7,98 (1H, s).

m/z (thermal spray) 395 (MH+).

b) a Mixture of 1-(6,7-dichloro-2, is) and dioxane (1 ml) is heated at boiling temperature under reflux for 16 hours, cooled and concentrated under reduced pressure. The residue is treated with ultrasound and the resulting solid product is collected by filtration, washed with diethyl ether and dried under reduced pressure at 60oC, which gives specified in the title compound (24,7 mg, 82%) as a pale yellow solid product, so pl. 267 - 269oC.

Analysis %:

Found: C 39,12; H 3,21; N 7,81.

Calculated for C12H12N2Cl2O5S: C 39,25; H 3,29; N 7,63%.

Example 95. 1-(1,4-Dihydro-6,7-dichloro-2,3-dioxopiperidin-5 - yl)-4-hydroxybutylidene

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A solution of 9-borabicyclo[3.3.1] nonane in tetrahydrofuran (0.5 M, 1.07 ml, 0,537 mmol) is added to a stirred solution of 1- (6,7-dichloro-2,3-dimethoxyaniline-5-yl)-3-butylmethylamine (example 93 (a)) (200 mg, 0,511 mmol) at room temperature under nitrogen atmosphere. The mixture is stirred for 20 hours and then add portions of trimethylamine N-oxide (119 mg, was 1.58 mmol). The mixture is stirred at room temperature for 2 hours and then heated to the boiling temperature under reflux for 30 minutes, cooled and concentrated under reduced pressure. The remainder of the clean flash chromatography (elwira 1:1 hexane:ethyl acetate, then clean these diastereoisomers (1H-NMR).

1H-NMR (300 MHz, CDCl3): = (basically, only diastereoisomer) of 1.29 (1H, m) of 1.40 (1H, m) to 2.66 (1H, m), 2,89 (3H, s), 3,26 (1H, m), the 3.65 (2H, m), 4,15 (3H, s), 4,22 (3H, s), 5,42 (1H, DD, J 6.8 Hz), 7,98 (1H, s).

m/z (thermal spray) 409 (MH+).

(b) Specified in the title compound is obtained from 1-(6,7 - dichloro-2,3-dimethoxyaniline-5-yl)-4-hydroxyethylmethylcellulose (stage (a), 92 mg, 0,225 mmol) by the method of example 94 (b) and treated with ultrasound with a mixture of diethyl ether, methanol and diisopropyl ether, giving a pale grey solid product (43 mg, 53%), so pl. 306-307,5oC (NMR separate netnanny diastereoisomer).

Analysis %:

Found: C 41,06; H 3,76; N 7,26;

Calculated for C13H14Cl2N2O5S: C 40,96; H 3,70; N 7,35%

1H-NMR (300 MHz, d6-DMSO) = 1,15 (1H, m), 1,32 (1H, m), of 2.20 (1H, m), is 2.37 (1H, m), 3,30 (5H, invisible., m), 5,32(1H, DD, J 6.8 Hz), 7,38 (1H, s), 10,31 (1H, s), 12,12 (1H, s).

Example 96. The ability of some compounds of the examples to the glycine binding sites of the NMDA receptor determined by the above test (a), and the connections which have found that they have the IC50less than 50 nm, include compounds of the following examples: 1, 8, 17, 29, 40, 56, 70, 80(b) (first connection) and 80(d).


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a) a Mixture of 6,7-dichloro-1,4-dihydro-5-nitrophenoxy-2,3-dione (example 1 of WO-A-94/00124, 84 g, 0.34 mol), thionyl chloride (840 ml) and dimethylformamide (0.5 ml) is heated at the boiling point under reflux for 3 hours, cooled and concentrated under reduced pressure. Add ethyl acetate (300 ml) and removed under reduced pressure, and then petroleum ether (so Kip. 100 - 120oC). The solid residue is recrystallized from petroleum ether (so Kip. 100-120oC) receiving 2,3,6,7-tetrachloro-5-nitrophenoxy (78 g, 73%) as a pale yellow solid.

1H-NMR (300 MHz, CDCl3): = 8,6 (1H).

b) chloride Dihydrate tin (II) (346,3 g, 1.54 mol) are added to a solution of the product from stage (a) above (96,2 g, 0.31 mol) in ethyl acetate (1.8 l). The mixture is heated to boiling point under reflux for 4 hours, cooled and carefully poured into excess saturated aqueous sodium bicarbonate. The mixture is filtered through "Celite", (trademark), good washing with ethyl acetate. A dense precipitate on the filter is soaked in an additional amount of ethyl acetate and the solid product filtered off. United an ethyl acetate solution is dried (MgSO4) and concentrate under ponie>SUP>1H-NMR (300 MHz, CDCl3): = the 5.45(2H, user, C), 7,47 (1H, s), m/z (thermal spray) 385 (MH+).

C) a Solution of sodium methylate (25% solution in methanol, 274 ml, 1.28 mol) are added to a suspension of 5-amino-2,3,6,7-tetrachloronaphthalene (72.4 g, 0,256 mol) in dry methanol (1 l) and the resulting mixture is heated to boiling point under reflux for 30 minutes the Mixture is cooled, concentrated under reduced pressure and the residue partitioned between water and ethyl acetate (8 l). The organic solution is dried (MgSO4) and concentrate under reduced pressure. The crude product is clean, rubbing the powder with methanol, followed by dissolving in dichloromethane (2 l) and filtered. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title

compound as a yellow solid (55,0 g, 79%).

1H-NMR (300 MHz, CDCl3): = 4,13 (3H, s), 4,14 (3H, s), 5,07 (2H, user. C), 7,26 (1H, s).

m/z (thermal spray) 274 (MH+).

Preparative example 2. 5-Amino-2,3-dimethoxy-6,7-dimethylquinoxaline

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a) 1,4-Dihydro-6,7-dimethylquinoxaline-2,3-dione (10.0 g, for 52.6 mmol - see T. Liebigs Ann. Chem., 1982, 754-761) is added in portions over 10 minutes to concentrated nitric acid (density 1.4 the value of 7 hours using if necessary cooling. The solution is poured into ice water and the resulting solid product is filtered and dried in vacuum at 75oC, receiving 1,4-dihydro-6,7-dimethyl-5 - nitrophenoxy-2,3-dione (7,44 g, 60%) as a pale yellow solid, so pl. 280-290oC (decomp.) (from dimethylformamide/water).

1H-NMR (300 MHz, DMSO-d6): = 2,08 (3H, in), 2.25 (3H, s) 7,06 (1H, s), 11,70 (1H, user, C), 12,06 (1H, user, C)max(RBr) 3185, 1703, 1533, 1400, 1355 cm-1.

m/z (thermal spray) 253 (MNH4+).

b) a Mixture of 1,4-dihydro-6,7-dimethyl-5-nitrophenoxy-2,3-dione (from stage (a), 7,44 g of 31.6 mmol), thionyl chloride (69,2 ml, 0,949 mol) and dimethylformamide (0.25 ml, and 3.16 mmol) heated at boiling temperature under reflux for 3 hours and slowly added to vigorously stirred mixture of ice and water (1.2 l) for more than 15 minutes. The precipitate is filtered off and dried in vacuum at 80oC that gives 2,3-dichloro-6,7-dimethyl-5-nitrophenoxy (a 8.34 g, 97%) as a pale orange solid connection, so pl. 133-134oC.

1H-NMR (300 MHz, DMSO-d6): =of 2.38 (3H, s) to 2.54 (3H, s) to 8.12 (1H, s).

max(KBr) 1537, 1388, 1377, 1269, 1169 cm-1< / BR>
m/z (thermal spray) 289 (MNH4+).

C)ol) in ethyl acetate (300 ml) is heated to the boiling temperature under reflux for 11 hours. Add an additional portion of the chloride dihydrate tin (13,82 g, to 61.2 mmol) and the mixture is heated for 2 hours and diluted with ethyl acetate (500 ml). The mixture was added to saturated aqueous sodium bicarbonate (200 ml) and filtered, rinsing thoroughly dense precipitate on the filter with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (3 x 100 ml), dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (gradient elution methanol/dichloromethane) to give 5-amino-2,3-dichloro-6,7 - dimethylquinoxaline (x 6.15 g, 83%) as an orange solid product, so pl. 178-180oC.

1H-NMR (300 MHz, DMSO-d6): = of 2.38 (3H, s) to 2.54 (3H, s) to 8.12 (1H, s)max(KBr) 3475, 1613, 1267, 1178 cm-1.

m/z (thermal spray) 242 (MNH4+).

d) sodium Methylate (25% solution in methanol, to 13.9 ml, 61 mmol) is added over 12 minutes to a stirred solution of 5-amino-2,3-dichloro-6,7-dimethylquinoxaline (from stage (C), x 6.15 g, and 25.4 mmol) in dry tetrahydrofuran (250 ml) under nitrogen atmosphere at 0oC. the Mixture was stirred at 0oC for 20 minutes and at room temperature for 72 hours. The mixture is diluted with ethyl acetate (750 ml), washed with water (2 x 250 ml) and a solution of salt (250 is the second elution with hexane/dichloromethane), that gives specified in the title compound as a white solid product (4,55 g, 77%), so pl. 166 - 167oC.

1H-NMR (300 MHz, CDCl3): =2,32 (3H, s), 2,35-(3H, s), 4,14 (3H, s) to 4.15 (3H, s), is 5.06 (2H, user, C), 7,06 (1H, s).

max(KBr) 3540, 2950, 1600, 1535, 1395, 1335, 1240 cm-1< / BR>
m/z (thermal spray) 234 (MH+).

Preparative example 3. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)methanesulfonamide

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a) a Mixture of 5-amino-6,7-dichloro-2,3-dimethoxyaniline (see preparative example 1) (10.0 g, of 36.5 mmol), methanesulfonamide anhydride (31.8 g, 183 mmol) and pyridine (of 14.8 ml, 183 mmol) in dry dichloromethane (150 ml) was stirred at 20oC 16 hours. The solvent is removed under reduced pressure and the residue is dissolved in a mixture of water (5 ml) and tetrahydrofuran (50 ml). After stirring for 10 minutes the solution is distributed between ethyl acetate and 2 M hydrochloric acid. The combined organic solutions washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrate under reduced pressure. Purification of the residue flash chromatography (gradient elution with hexane/dichloromethane) to give 6,7-dichloro-5 - di(methanesulfonyl)amino-2,3-dimethoxyaniline as not quite white solid (12.3 g, 78%), so pl. 240-244tion) 430, 432 (MH+).

b) Aqueous sodium hydroxide (1 M, 145 ml, 145 mmol) are added to a suspension of 6,7-dichloro-5-di(methanesulfonyl)amino-2,3 - dimethoxyaniline (from stage (a) to 12.28 g, 28.6 mmol) and the mixture stirred at room temperature for 16 hours. The resulting organic solution is treated with 2 M hydrochloric acid (to pH 3) and usageprice solid product is filtered off, washed with water and diethyl ether, dried in vacuum at 80oC and get N-(6,7-dichloro - 2,3-dimethoxyaniline - 5-yl)methanesulfonamide (8,46 g, 84%) as a white solid, so pl. 225 - 227oC.1H-NMR (300 MHz, CDCL3) = 3,42 (3H, s) to 4.15 (3H, s), 4,20 (3H, s), to 7.15 (1H, user, C), 8,02 (1H,s).

m/z (thermal spray) 352 (MH+).

Preparative example 4. N-(6,7-Dichloro-2,3-dimethoxyaniline-5-yl)econsultant

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Specified in the title compound prepared as in preparative method of example 3 (a) and (b) using econsultancy anhydride. [J. Am.Chem. Soc., 76, 1222 (1954)] and 5-amino-6,7-dichloro-2,3 - dimethoxyphenoxy in the form of a pale yellow solid (47% yield), so pl. 174 - 176oC.

1H-NMR (300 MHz, CDCl3): =to 1.38 (3H, t, J 7 Hz), of 3.56 (2H, square, J 7 Hz), 4,13 (3H, s), 4,20 (3H, s), 6,97 (1H, user. C) a 7.85 (1H, s).

m/z (thermal spray) 366 (MH+).

In e the

Preparative example 5. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)-benzosulfimide

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A mixture of 5-amino-6,7-dichloro-2,3-dimethoxyaniline (preparative example 1) (548 mg, 2.0 mmol), benzosulfimide (1,28 ml, 10 mmol) and pyridine (0.8 ml, 10 mmol) in dry dichloromethane (30 ml) is stirred under heating up to the boiling temperature under reflux for 100 hours. The mixture was poured into ethyl acetate/water and the white solid product is filtered off, washed with water, ethyl acetate, diethyl ether and dried at 80oC in vacuum, obtaining mentioned in the title compound (250 mg, 30%), so pl. 292-293oC.

1H-NMR (300 MHz, DMSO-d6): = of 3.53 (3H, s), was 4.02 (3H, s) of 7.48 (2H, J 8 Hz), 7,63 (3H, m), of 8.00 (1H, s), 10,22 (1H, user, C), m/z (thermal spray) 414 (MH+).

Preparative example 6. N-(2,3-Dimethoxy-6,7-dimethylquinoxaline-5 - yl)-methanesulfonamide

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A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (from preparative example 2) (50 mg, 0,214 mmol), methanesulfonamide anhydride (187 mg, 1.07 mmol) and pyridine (87 ml, 1.07 mmol) in dry tetrahydrofuran (1 ml) was stirred at 20oC for 2.7 hours. Add water (0.3 ml) and the mixture is stirred for 40 minutes. The mixture is distributed between ethyl acetate (15 ml) and 2 M hydrochloric acid (5 ml). the t under reduced pressure, getting listed in the title compound (63 mg, 94%) as a white solid, so pl. 219oC.

1H-NMR (300 MHz, (CDCl3): = 2,46 (3H, s) to 2.55 (3H, s), 2,87 (3H, s), 4,16 (6H, s), 7,00 (1H, user.C), EUR 7.57 (1H, s).

max/(KBr) 3545, 1480, 1160 cm-1.

m/z (thermal spray) 312 (MH+).

Analysis %:

Found: C 50,02; H 5,48; N 13,35; S 10,51.

Calculated for C13H17N3SO4: C 50,15; H 5,50; N 13,50; S 10,30%.

Preparative example 7. N-(2,3-Dimethoxy-6,7 - dimethoxyquinazolin-5-yl)-econsultant

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A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (from preparative example 2) (50 mg, 0,214 mmol), acanaloniidae (138 mg, 1.07 mmol) and pyridine (87 μl, 1.07 mmol) in dry tetrahydrofuran (1 ml) was stirred at 20oC 3.5 hours. Add additional portions of acanaloniidae (138 mg, 1.07 mmol) and pyridine (87 ml, 1.07 mmol) and the mixture is stirred for an additional 4 days. Add water (0.6 ml) and the mixture is stirred for 40 minutes. The mixture is distributed between ethyl acetate (15 ml) and 2 M hydrochloric acid (5 ml). The organic solution was washed with water (5 ml), saturated aqueous sodium bicarbonate (5 ml), dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title of a joint who/SUB>): = is 1.35 (3H, t, J 7 Hz), 2,44 (3H, s) to 2.54 (3H, s), 3,03 (2H, square, J 7 Hz), 4,15 (3H, s) to 4.16 (3H, s). of 6.96 (1H, user, C), 7,56 (1H, s).

max(KBr) 3250, 2940, 1480, 1323, 1239, 1157 cm-1< / BR>
m/z (thermal spray) 326 (MH+).

Analysis %:

Found: C 51,88; H Of 6.02; N 12,43.

Calculated for C14H19N3SO40.15 ethyl acetate: C 51,79; H 6,01; N 12,41%.

Preparative example 8. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)-N-(2-oxopropyl)methanesulfonamide

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Tertbutoxide potassium (246 mg, 2.2 mmol) is added to a stirred solution of N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)methanesulfonamide (702 mg, 2.0 mmol, see preparative example 3) in dry dimethylformamide (10 ml) in a nitrogen atmosphere at 20oC. Add chloroacetone (175 ml, 2.2 mmol) and the mixture is stirred for 4 hours. The mixture is concentrated under reduced pressure and the residue partitioned between 1 M aqueous sodium hydroxide and ethyl acetate. The organic extracts are combined, washed with salt solution, dried (Na2SO4) and concentrated under reduced pressure, obtaining a white solid product, which was triturated in diethyl ether, filtered and dried, obtaining mentioned in the title compound (720 mg, 88%). so pl. 247-248oC.

1H-NMR (300 MHz, CDCl3): = 2UP>).

Preparative example 9. (RS)-N-(6,7-Dichloro-2,3 - dimethoxyaniline-5-yl)-N-(2-hydroxypropyl)methanesulfonamide

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Hydride diisobutylaluminum (1.0 M in dichloromethane, 1.0 ml, 1.0 mmol) is added dropwise to a stirred solution of N-(6,7 - dichloro-2,3-dimethoxyaniline-5-yl)-N-(2-oxopropyl)- methanesulfonamide (204 mg, 0.5 mmol - preparative example 8) in dry dichloromethane (10 ml) in a nitrogen atmosphere at 20oC. After 2 hours, add saturated aqueous solution of ammonium chloride (2 ml) and the mixture is stirred for 15 minutes before filtering through Arbocel" (Trade mark) accelerator filtering. A dense precipitate on the filter was washed with dichloromethane and the filtrate is dried (Na2SO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (gradient elution with hexane/diethyl ether), getting mentioned in the title compound (182 mg, 89%) as a white solid, so pl. 176 - 177oC.

Analysis %:

Found: C 40,67; H 4,07; N 10,06.

Calculated for C14H17Cl2N3O5S: C 40,99; H 4,18; N 10,24 %.

Preparative example 10. N-(6,7-Dichloro-2,3-dimethoxyaniline-5-yl)-N-(2 - hydroxy-2-methylpropyl " methanesulfonamide

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Methylanisole (1.4 mxarray)methanesulfonamide (143 mg, 0.35 mmol, see preparative example 8) in dry tetrahydrofuran (10 ml) in a nitrogen atmosphere at 5oC. the Mixture is allowed to slowly warm to room temperature and stirred for 5 hours. Add saturated aqueous ammonium chloride (1 ml) and the tetrahydrofuran removed under reduced pressure. The residue is distributed between water and ethyl acetate (3 portions). The combined extracts are dried (Na2SO4), concentrated under reduced pressure and the residue clean flash chromatography (gradient elution with hexane/diethyl ether), which gives specified in the title compound (105 mg, 75%) as a white solid product, so pl. 160oC.

1H-NMR (300 MHz, CDCl3): =0,97 (3H, s) of 1.30 (3H, s), up 3.22 (3H, s), of 3.56 (1H, s), with 3.79 (1H, d, J 15 Hz), of 3.96 (1H, d, J 15 Hz), 4,14 (3H, s), 4,19 (3H, s), of 7.96 (1H, s).

m/z (thermal spray) 424 (MH+).

Preparative example 11. N-(6,7-Dibromo-2,3 - dimethoxyaniline-5-yl)-methanesulfonamide

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a) 1,4-Dihydro-6,7-dibromo-5-nitrophenoxy-2,3-dione (see Example 33, WO-A-94/00124) make 6,7-dibromo - 2,3-dichloro-5-nitrophenoxy by the method of preparative example 1(a). The product is obtained in the form of not-quite-white solid (72% yield), so pl. 126-128oC (from hexane).

1H-NMR (300 MHz,enoxacin by the method of preparative example 1(b). The product is obtained as yellow solid (61% yield), so pl. 108-110oC (after clean flash chromatography).

1H-NMR (300 MHz, CDCl3): =5,55 (2H, user. C) to 7.68 (1H, s).

C) the Intermediate product of the above stage (b) is transformed into 5-amino-6,7-dibromo-2,3-dimethoxyphenoxy by the method of preparative example 1(C). The product is obtained in the form of a yellow solid product (59% yield), so pl. 148-150oC (after clean flash chromatography).

1H-NMR (300 MHz, CDCl3): =4,13 (6H, s), 5,20 (2H, user.C) 7,51 (1H, s).

m/z (thermal spray) 364 (MH+).

d) the Intermediate product of the above stage (C) transform according to the method of preparative example 3(a) of 6,7-dibromo-5-di(methanesulfonyl) amino-2,3-dimethoxyphenoxy (85% yield) of pale yellow solid product, so pl. 204-206 (after clean flash chromatography).

1H-NMR (300 MHz, CDCl3): = 3,61 (6H, s) to 4.15 (3H, s), 4,19 (3H, s), to 8.20 (1H, s).

m/z (thermal spray) 520 (MH+).

e) an Intermediate product of the above stage (d) is transformed into N-(6,7-dibromo-2,3-dimethoxyaniline-5-yl)- methanesulfonamide by the method of preparative example 3(b). The product is obtained in the form of a pale yellow solid (86% yield), so tx2">

m/z (thermal spray) 442 (MH+).

Preparative example 12. N-(2,3-Dimethoxy-6,7-dimethylquinoxaline - 5-yl)- triftormetilfullerenov

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Triftormetilfullerenov anhydride (126 ml, 0.75 mmol) is added dropwise to a solution of 5-amino-2,3-dimethoxy-6,7 - dimethylquinoxaline (preparative example 2) (170 mg, 0.73 mmol) and triethylamine (112 ml, 0.8 mmol) in dry dichloromethane (15 ml) in a nitrogen atmosphere at -50oC. the Mixture was stirred at -30oC for 2 hours, poured into water and extracted with three portions of dichloromethane. The product is then extracted from dichloromethane using a 1 M aqueous sodium hydroxide. The aqueous phase podkalyvayut excess of 2 M hydrochloric acid and the product extracted with dichloromethane (3 servings). The combined extract is dried (MgSO4) and concentrated under reduced pressure, obtaining a white solid product (260 mg, 98%).

1H-NMR (300 MHz, CDCl3): = 2,44 (3H, s), 2.49 USD (3H, s), 4,14 (3H, s) to 4.15 (3H, s), 7,13 (1H, user.C) to 7.61 (1H, s).

m/z (thermal spray) 366 (MH+).

Preparative example 13. N-(6-Chloro-7-ethyl-2,3 - dimethoxyaniline-5-yl) methanesulfonamide and N-(7-chloro-6-ethyl-2,3-dimethoxyaniline-5-yl)-methanesulfonamide

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a) 1,2-Diamino-4-chloro-5-ethylbenzene.

4) and concentrated under reduced pressure, obtaining a white solid product (2.70 g, > 100%), which is used directly without further purification.

1H-NMR (300 MHz, CDCl3) =1,19 (3H, t, J 7 Hz), 2.63 in (2H, square, J 7 Hz), 3,30 (4H, user.C) to 6.57 (1H, s) 6,70 (1H, s).

b) 1,4-Dihydro-6-chloro-7-utilisation-2,3-dione.

A mixture of 1,2 - diamino-4-chloro-5-ethylbenzene (from stage (a), 2.70 g, about 13 mmol), oxalic acid (1.65 g, and 18.3 mmol) and 4 M hydrochloric acid (66 ml) is heated to the boiling temperature under reflux for 4.6 hours, cooled, and gray solid product is collected by filtration and washed with water. The solid product is dried in vacuum at 50oC, getting mentioned in the title compound (2,34 g, 80%), so pl. > 315oC.

Analysis %:

Found, C 53,60; H A 3.87; N 12,40.

Calculated for C10H9ClN2O2: C 53.47 USD; H OF 4.04; N 12,47%.1

C) 1,4-Dihydro-6-chloro-7-ethyl-5-nitrophenoxy-2,3-dione and 1,4-dihydro-7-chloro-6-ethyl-5-nitrophenoxy-2,3-dione.

1,4-Dihydro-6-chloro-7-utilisation-2, 3-dione (from stage (b) of 2.34 g, 10.4 mmol) is added in small portions over 10 minutes to a vigorously stirred concentrated nitric acid (20 ml) at room temperature. The mixture is then heated at 40oC for 12 hours, cooled and poured into ice water. The resulting solid product is filtered off, washed with water and dried, obtaining mentioned in the title compound (2.55 g, 91%), in the form of a mixture (cootes. the 1.7:1).

1H-NMR (300 MHz, DMSO-d6) = 1,09-1,19 (3H, m), 2,56 (1, 3H, square, J 7 Hz), 2,71 (0,7, square J 7 Hz), 7,19 (0,4 H, s), 7,29 (0,6 H, C); 11,95-12,15 (2H, user.m).

m/z (thermal spray) 287 (MNH4+).

a) 2,3,7-Trichloro-6-ethyl-5-nitrophenoxy and 2,3,6-trichloro-7 - ethyl-5-nitrophenoxy.

A mixture of hinoksolinov from stage (C) above (2,75 g, 11 mmol), thionyl chloride (28,6 ml, 0,305 mol) and N,N - dimethylformamide (85 μl, 1.0 mmol) is heated under nitrogen atmosphere to boiling point under reflux for 24 hours. The solution is cooled and cautiously added dropwise to a stirred ice water (600 ml). After 1 hour, the solid product beige color otfi the mixture and flash chromatography (elution with hexane: dichloromethane =3:1) allows to obtain in pure form small amounts of isomers for their characterizatio. The first selected isomer has a melting point of 106-109oC.

Analysis %:

Found: C 39,21; H 1,99; N 13,71

Calculated for C10H6Cl3N3O2: C 39,18; H 1,97; N 13,71%.

1H-NMR (300 MHz, CDCl3) = of 1.41 (3H, t, J 7 Hz), 3,06 (2H, square J 7 Hz), 8,02 (1H, s).

m/z (thermal spray) 323 (MH+).

The second isomer has so pl. 88-92oC.

Analysis %:

Found: C 39,06; H To 1.87; N, 13.85 Per Cent.

1H-NMR (300 MHz, CDCl3) = 1,35 (3H, t, J 8 Hz), 2,98 (2H, q, J 8 Hz), 8,19 (1H, s).

m/z (thermal spray) 323 (MH+).

e) 5-Amino-2,3,7-trichloro-6-utilisation and 5-amino-2,3,6 - trichloro-7-utilisation.

A mixture of hinoksolinov from stage (d) above (200 mg, 0,652 mmol), chloride dihydrate tin (II) (1,03 g of 4.57 mmol) and ethyl acetate (6.5 ml) is heated to the boiling temperature under reflux for 4 hours, cooled and diluted with ethyl acetate. The solution is washed with 10% aqueous sodium carbonate (25 ml). The aqueous layer was extracted with ethyl acetate (2 x 25 ml) and the combined organic solutions are washed with 10% aqueous sodium carbonate (2 × 25 ml), saturated aqueous sodium chloride (25 ml), dried (MgSO4) and concentrated under reduced pressure, getting listed in zaglaviv, CDCl3) =1,25 (1,5 H, t, J 8 Hz), 1,37 (1,5 H, t, J 8 Hz), 2,84 are 2.98 (2H, m), of 5.05 (1H, user. C), 5,28 (1H, user. C), 7,22 (0.5 H, s), 7,43 (0.5 H, s).

f) 5-Amino-6-chloro-7-ethyl-2,3-dimethoxyphenoxy and 5-amino-7-chloro-6-ethyl-2,3-dimethoxyphenoxy.

A mixture of trichloroethylene from stage (e) above (169 mg, 0,611 mmol) in anhydrous tetrahydrofuran (6 ml) is treated with a solution of sodium methylate (from 0.84 ml, 25% solution in methanol, to 1.47 mmol) at 0oC and under stirring. After 3.5 h, the solution was diluted with ethyl acetate, washed with water (2x10 ml), saturated aqueous sodium chloride (10 ml), dried (MgSO4) and concentrate under reduced pressure. Clean flash chromatography (elution with hexane/ethyl acetate 19:1) to give two fractions.

The first discharge connection, 5-amino-6-chloro-7 - ethyl-2,3-dimethoxyphenoxy (42 mg, 26%) are in the form of a white solid product.

1H-NMR (300 MHz, CDCl3) = 1,32 (3H, t, J 8 Hz), 2,87 (2H, square, J 7 Hz), 4,18 (6H, s), the 4.90 (2H, user. C) was 7.08 (1H, s). The second discharge connection, 5-amino-7-chloro-6-ethyl-2,3-dimethoxyphenoxy (57 mg, 35%), obtained as a pale green solid product.

1H-NMR (300 MHz, CDCl3) = 1,14 (3H, t, J 7 Hz), 2,84 (2H, square, J 7 Hz), 4,12 (3H, s), 4,14 (3H, s), 4,70 (2H, user.C), 7,22 (1H, s).

g) N-(6-chloro-7-ethyl-2,3-diseaseselena solution of 5-amino-6-chloro-7-ethyl-2,3 - dimethoxyaniline (207 mg, 0.77 mmol) and anhydrous pyridine (305 mg, of 3.85 mmol) in anhydrous tetrahydrofuran (7.7 ml) at room temperature. After 72 hours, add water (3 ml) and the mixture is stirred for additional 60 minutes. The mixture is diluted with ethyl acetate and washed with 2 M hydrochloric acid (50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml). The organic phase is dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound (206 mg, 77%).

1H-NMR (300 MHz, CDCl3) = to 1.37 (3H, t, J 8 Hz), 2,89-of 3.00 (2H, m), 3,39 (3H, s) to 4.16 (3H, s), 4,19 (3H, s), 7,01 (1H, s), 7,60 (1H, s).

m/z (thermal spray) 346 (MH+).

h) N-(7-Chloro-6-ethyl-2,3-dimethoxyaniline-5-yl)- methanesulfonamide

5-Amino-7-chloro-6-ethyl-2,3-dimethoxyphenoxy in turn derived methanesulfonamide by way of the above stage (g). Receive the product with 47% of the output.

1H-NMR (300 MHz, CDCl3) = a 1.25 (3H, t, J 8 Hz) of 3.00 (3H, s), or 3.28 (2H, q, J 7 Hz), 4,17 (3H, s), 4,27 (3H, s), 6.87 in (1H, s), 7,83 (1H, s).

m/z (thermal spray) 346 (MH+).

Preparative example 14. N-(6-chloro-2,3-dimethoxy-7 - methylpenicillin-5-yl) methanesulfonamide and N-(7-chloro-2,3-dimethoxy-6-methylphenoxy-5-yl) methanol the way, similar to that used for 6-chloro-7-ethyl - 7-chloro-6 - ethylphosphonic obtained in preparative example 13.

1,4-Dihydro-6-chloro-7-methylpenicillin-2,3-dione is obtained from 1,2-diamine-4-chloro-5-methylbenzene (obtained by Maybridge Chemicals) as a dark gray solid product, so pl. > 330oC.

Analysis %:

Found: C 51,58; H 2,98; N OF 13.27;

Calculated for C9H7ClN2O2: C 51,32; H 3,35; N 13,30%.

1,4-Dihydro-6-chloro-7-methyl-5-nitrophenoxy-2,3-dione and 1,4 - dihydro-7-chloro-6-methyl-5-nitrophenoxy-2,3-dione obtained as yellow solid product (1:2 ratio).

1H-NMR (300 MHz, CDCl3) =2,23 (2H, s), 2,35 (1H, s), 7,19 (0,3 H, s), 7,30 (0,7 H, s), 11,9-12,25 (2H, user. m).

2,3,7-Trichloro-6-methyl-5-nitrophenoxy and 2,3,6-trichloro-7-methyl-5-nitrophenoxy receive in the form of a powder straw color, the connection can hardly be separated for performance. Flash chromatography (gradient elution with hexane/dichloromethane) gives the first 6-methyl-7-chloro-isomer as a white solid, so pl. 164-165oC.

Analysis %:

Found: C of 36.76; H l,37; H 14,43.

Calculated for C9H4Cl3N3O2: C 36,96; H 1,38; N 14,37%.

Eluruumis second (7-methyl-6-chloro)-some is about: C 39,78; H 2,02; N 13,23;

Calculated for C9H4Cl3N3O2=2,41 (2H, s) to 2.55 (1H, s), 5,03 (1,3 H, usher. C) 5,08 (0,7 H, usher. s), 7.23 percent (0,3 H, s), 7,44 (0,7 H, C).

5-Amino-7-chloro-2,3-dimethoxy-6-methylphenoxy and 5-amino-6-chloro - 2,3-dimethoxy-7-methylpenicillin shared by repeated column chromatography on silica gel, elwira hexane/ethyl acetate = 1:1 and then dichloromethane.

The first discharge connection, 6-chloro-7-methyl-isomer is obtained in the form of not quite white solid connection, so pl. 169-170oC.

Analysis %:

Found; C 53,80; H 5,16; N 16,18;

Calculated for C11H12ClN3O2= 2,58 (3H, s) to 3.38 (3H, s) to 4.15 (3H, s), 4,18 (3H, s), 7,00 (1H, user.C), 7,60 (1H, s).

m/z (thermal spray) 322 (MH+)max/(KBr) 3230, 2950, 1480 and 1150 cm-1.

N-(7-chloro-2,3-dimethoxy-7-methylpenicillin-5-yl) methanesulfonamide receive in the form of a white solid product, so pl. 228 - 229oC.

Analysis %:

Found: C 43,51; H 3,98; N 12,60, C12H14ClN3O4S

Calculated: C 43,44; H 4,25; N 12,60%.

Preparative example 15. 4-Hydroxymethyl-2-(triphenylmethyl) -1,2,3-triazole

< / BR>
a) Methyl 1H-1,2,3-triazole-4-carboxylate [J. Org. Chem. 41, 1041 (1976)] (1,00 g, to 7.09 mmol) is added to a stirred suspension of hydride Noah temperature. After 20 minutes the mixture is cooled to 0oC and add trailhead (2.17 g, 7,80 mmol). The mixture is stirred for 4 hours at 0oC. Add water (100 ml) and the tetrahydrofuran removed under reduced pressure. The remaining mixture was extracted with ethyl acetate (100 ml). The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure, giving a solid product that clean flash chromatography on silica gel, elwira 5 to 30% ethyl acetate in hexane. Washed out the first product experimentally identified as methyl 1-(triphenylmethyl)- 1,2,3-triazole-4-carboxylate and obtained as a white solid (600 mg, 21%).

1H-NMR (300 MHz, CDCl3) =to 3.92 (3H, s), 7,11 (6H, m), 7,32 (9H, m), 8,15 (1H, s).

The product, washed out the second, tentatively identified as methyl 2-(triphenylmethyl)-1,2,3 - triazole-4-carboxylate and obtained as a white solid. (500 mg, 18%).

1H-NMR (300 MHz, CDCL3) =of 3.94 (3H, s), 7,11 (6H, m), of 7.36 (9H, m), 8,02 (1H, s).

b) a Solution of lithium aluminum hydride (1.04 million ml, 1 M in tetrahydrofuran, 1.04 mmol) is added dropwise with stirring to a solution of methyl 2- (triphenylmethyl)-1,2,3-triazole-4-carboxylate (from stage (a), 500 mg, 1.38 mmol) in anhydrous tetrahydrofuran (30 ml) at 0oC in CIS sodium (4 ml), and further, additional amount of water (4 ml). The resulting suspension was filtered through Arbocel accelerator filtration and the filtrate is dried (MgSO4) and concentrate under reduced pressure. The residue is partitioned between dichloromethane (150 ml) and water (150 ml). The dichloromethane layer was washed with water (600 ml) and then dried (MgSO4) and concentrated under reduced pressure, getting the balance specified in the title compound (401 mg, 85%).

1H-NMR (300 MHz, CDCl3) =2,05 (1H, t, J 7 Hz), to 4.81 (2H, d, J 7 Hz), 7,12 (6H, m), 7,35 (9H, m), 7,47 (1H, s).

Preparative example 16. 4-Hydroxymethyl-5-methyl-1- (triphenylmethyl)imidazol

< / BR>
a) sodium Hydride (900 mg, 80% oil dispersion, 30 mmol) is added in portions over 5 minutes to a stirred solution of ethyl 4-methyl-imidazole-5-carboxylate (of 3.85 g, 25 mmol) in dry tetrahydrofuran (100 ml) at room temperature under nitrogen atmosphere. After 10 minutes, add in one portion of Fritillaria (at 8.36 g, 30 mmol). After 1 hour the mixture is diluted with ethyl acetate (500 ml) and washed with water (200 ml). The washing water is extracted by etiracetam (2 x 75 ml) and the combined organic solutions dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (gradient suirou Agogo product.

1H-NMR (300 MHz, CDCl3) = to 1.38 (3H, t, J 6 Hz) and 1.83 (3H, s), 4,36 (2H, q, J 6 Hz), 7,14 (6H, m), 7,35 (10H, m).

b) a Solution of aluminum hydride - lithium (7.65 ml, 1 M in tetrahydrofuran, the 7.65 mmol) is added dropwise to a stirred suspension of ethyl-5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 2.55 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen atmosphere at 0oC for more than 1 minute. After 30 minutes, carefully add water (300 ml), then aqueous sodium hydroxide (1 M, 300 ml) and water (900 ml). The suspension is filtered using Arbocel accelerator filtering, and dense precipitate on the filter is washed with tetrahydrofuran (2 x 30 ml). The filtrate is concentrated under reduced pressure and the residue is dissolved in boiling methanol (50 ml). Add dichloromethane (200 ml) and anhydrous magnesium sulfate and the mixture is filtered through Arbocel accelerator filtering. The filtrate is concentrated under reduced pressure, obtaining a white solid product (325 mg, 36%).

1H-NMR (300 MHz, CDCl3) = 1,47 (3H, s), of 4.05 (2H, s), 7,14 (6H, m), 7,35 (10H, m).

Preparative example 17. 4-Hydroxymethyl-1-(triphenylmethyl)pyrazole

< / BR>
a) Ethyl 1H-pyrazole-4-carboxylate (1.50 g, is 10.7 mmol) is added in portions to a stirred suspension of sodium hydride (353 mg, 80% oil DISP mixture is cooled to 0oC and add trailhead (3.28 g, and 11.8 mmol). The mixture was stirred at 0oC for 4 hours and allowed to warm to room temperature over night. 3 Quiroga mixture is heated at 50oC for 3 hours, cool and add additional portions of sodium hydride (321 mg, about 10.7 mmol) and Fritillaria (1.0 g and 3.59 mmol). The mixture is heated at 50oC for 2 hours, cooled, treated with water (50 ml) and concentrate under reduced pressure. The product is extracted with ethyl acetate (200 ml), the solution is dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (gradient elution with hexane/ethyl acetate), giving ethyl 1-(triphenylmethyl)- pyrazole-4-carboxylate (2,273 g, 56%) as a white solid.

1H-NMR (300 MHz, CDCl3) = 1,31 (3H, t, J 7 Hz), 4,27 (2H, q, 7 Hz), 7,13 (6H, m), 7,32 (9H, m), 7,94 (1H, s), 8,02 (1H, s).

b) Alumoweld lithium (1 M solution in tetrahydrofuran, of 4.45 ml of 4.45 mmol) is added dropwise to a stirred solution of ethyl 1- (triphenylmethyl)pyrazole-4-carboxylate (2,27 g, to 5.93 mmol) in anhydrous tetrahydrofuran (300 ml) under nitrogen atmosphere at 0oC. After 1 hour, the mixture is treated successively with water (3 ml), 15% aqueous sodium hydroxide (3 ml) and water (6 ml). The mixture is filtered Ceres-hydroxymethyl-1-(triphenylmethyl)pyrazole (1,746 g, 86%), in the form of a white solid product.

1H-NMR (300 MHz, CDCl3) = 1,43 (1H, user. C) of 4.35 (2H, s), 7,16 (6H, m), 7,26 (9H, m), 7,37 (1H, s), to 7.68 (1H, s).

Preparative example 18. 3-Hydroxymethyl-1-(triphenylmethyl)- 1,2,4-triazole

< / BR>
The triethylamine (1.13 ml, 8,08 mmol) are added to a suspension of 3 - hydroxymethyl-1H-l, 2,4-triazole [J. Am. Chem. Soc, 77, 1538, (1955)] (400 mg, 4.04 mmol) in dry dichloromethane (8 ml) at 0oC. Add a solution of Fritillaria (1.24 g, of 4.44 mmol) in anhydrous tetrahydrofuran and the mixture is stirred for 3 hours at room temperature. The mixture was partitioned between water (75 ml) and dichloromethane (75 ml). The organic layer is dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound (1,547 g, > 100%), which is used without purification.

1H-NMR (300 MHz, CDCl3) / =of 4.77 (2H, s), 7,13 (6H, m), 7,32 (9H, m), 7,95 (1H, s).

Preparative example 19. 3-(Hydroxymethyl)-1-(triphenylmethyl)pyrazole

< / BR>
This compound is obtained from 3-(hydroxymethyl)-1H - pyrazole [J. Am. Chem. Soc, 71, 3996, (1949)] , Fritillaria and trimethylamine, using the method above preparative example 18. The crude product clean flash chromatography (gradient elution with hexane/ethyl acetate) to give white solid m). m/z (thermal spray) 341 (MH+).

Preparative example 20. N-(3-Amino-6-chloro-7-trifluoromethyl - 2-methoxyaniline-5-yl)methanesulfonamide

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
a) 1,2-Diamino-4-chloro-5-trifluoromethyl benzene.

The solution dithionite sodium (51,0 g, 293 mmol) in water (700 ml) is added to a stirred mixture of 5-chloro-4 - trifluoromethyl-2-nitroaniline [Khim. Geterotsikl. Soedin, 1136 (1976)] (23,5 g of 97.7 mmol) of potassium bicarbonate (51,0 g) in methanol (700 ml) at room temperature. After 30 minutes the mixture is concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The combined organic extracts dried (MgSO4) and concentrated under reduced pressure, obtaining an orange solid product (13.3 g, 65%).

1H-NMR (300 MHz, CDCl3) =3,37 (2H, user.C), 3,70 (2H, user. C) is 6.78 (1H, s), 6,98 (1H, s).

b) 1,4-Dihydro-6-chloro-7-cryptometrics-2,3-dione.

A mixture of 1,2-diamino-4-chloro-5-triptoreline (13,4 g of 63.6 mmol) and diethyloxalate (100 ml) is heated to the boiling point under reflux in a nitrogen atmosphere with stirring for 5 hours. After cooling, the resulting solid product is filtered off and well washed with diethyl ether, obtaining a pale orange tardiv>3N2O2: C 40,85; H OF 1.52; N, 10.59 PER CENT.

C) 1,4-Dihydro-6-chloro-7-trifluoromethyl-5-nitrophenoxy-23-dione and 1,4-dihydro-7-chloro-6-trifluoromethyl-5-nitrophenoxy-2,3-dione.

1,4-Dihydro-6-chloro-7 - cryptometrics-2,3-dione (from stage (b), 14,06 g, 53,1 mmol) is added in portions to a stirred fuming nitric acid (100 ml) at 0oC. the Mixture is allowed to warm to 20oC for more than 30 minutes (after add) and the resulting solution was poured into ice-cold water and usageprice solid product is filtered off, washed with water and dried, obtaining a pale orange solid connection (15,06 g, 92%) as a mixture of 2 : 1 isomers.

1H-NMR (300 MHz, DMSO-d6) =7,42 (1H, less, (C), a 7.62 (1H, basic, C), of 12.33 (1H, major, 1H smaller, user.C), 12,51 (1H major, 1H smaller, user.C).

d) 2,3,6-Trichloro-7-trifluoromethyl-5-nitrophenoxy and 2,3,7-trichloro - 6-trifluoromethyl-5-nitrophenoxy.

The mixture khinoksalinona from stage (C) above, (14,7 g, and 47.5 mmol) of thionyl chloride (140 ml) and dry dimethylformamide (1.4 ml) is heated at boiling temperature under reflux for 30 minutes, cooled and added dropwise to ice water. The resulting solid product is extracted with ethylacetat (MgSO4) and concentrated under reduced pressure, obtaining a yellow oil (17.9 g, 100%).

1H-NMR (300 MHz, CDCl3) =8,33 (1H, less, (C), 8,58 (1H major, s).

e) 6-Chloro-7-trifluoromethyl-2,3-dimethoxy-5 - nitrophenoxy and 7-chloro-6-trifluoromethyl-2, 3-dimethoxy - 5-nitrophenoxy

Sodium hydride (0.95 g, 80% oil dispersion, and 31.7 mmol) is added in portions to a stirred solution of a mixture of trichloroethylene from above the stage (d) (5.0 g, 14.4 mmol) in anhydrous methanol (125 ml) at room temperature. After 18 hours the mixture was concentrated under reduced pressure, diluted with water and the resulting solid product is filtered off, washed with water and dried, obtaining a white solid compound (4.4 g, 90%), in the form of a mixture 2:1 isomers.

1H-NMR (300 MHz, CDCl3) =4,10 (3H, less, (C), 4,15 (main 3H, s), 4,20 (main 3H, 3H smaller) of 8.00 (1H, less (C) of 8.25 (1H major, s).

f) 3-Amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitrophenoxy and 3-amino-7-chloro-6-trifluoromethyl-2-methoxy-5-nitrophenoxy

The mixture dimethoxyisoquinoline isomers from stage (e) above (0.5 g, 1.5 mmol) and a saturated solution of ammonia in methanol (7 ml) is heated at 100oC in a closed vessel under pressure for 4 MgSO4) and concentrate under reduced pressure. The reaction is repeated in the same scale and raw foods are combined and clean flash chromatography (elwira hexane/ethyl acetate = 3:1). Washed out the first product is a 6-chloro-7-trifluoromethyl-isomer (590 mg, 61%) was obtained in the form of not quite white solid connection.

1H-NMR (300 MHz, CDCl3) =4,08 (3H, s), 7,88 (1H, user. C) 8,08 (1H, s), 8,43 (1H, user. C).

Washed out the second product is a 7-chloro-6-trifluoromethyl-isomer (205 mg, 21%) was obtained in the form of not quite white solid connection.

1H-NMR (300 MHz, CDCl3) =4,12 (3H, s), the 5.65 (2H, user. C), 7,80 (1H, s).

q) 3,5-diamino-6-chloro-7-trifluoromethyl-2-methoxyphenoxy.

Hydrazine hydrate (0,34 ml, 7.0 mmol) is added under stirring to a solution of 3-amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitroindoline (0.55 g, 17 mmol) in ethanol (25 ml) containing suspended 10% ruthenium-on-carbon (55 mg) in a nitrogen atmosphere by heating to the boiling temperature under reflux. After 20 minutes add a further quantity of hydrazine hydrate (0.17 ml, 3.4 mmol) and the mixture is stirred while heating to boiling point for 30 minutes, then allowed to stand at room washed with ethanol and dichloromethane. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound (0.50 g, 100%) as not quite white solid connection.

1H-NMR (300 MHz, CDCl3) = 4,13 (3H, s) 5,08 (2H, user. C), and 5.30 (2H, user, C), 7,47 (1H, s).

h) N-(3-Amino-6-chloro-7-trifluoromethyl-2-methoxyaniline-5-yl) methanesulfonamide.

Methanesulfonyl anhydride (2.9 g, of 16.6 mmol) is added under stirring to a solution of 3,5-diamino-6-chloro-2 - methoxy-7-triftormetilfosfinov (0,48 g of 1.64 mmol) and pyridine (1,34 ml of 16.6 mmol) in anhydrous tetrahydrofuran under nitrogen atmosphere at room temperature. After 18 hours the mixture was concentrated under reduced pressure, diluted with water and the products extracted with ethyl acetate (three servings). The combined organic solutions washed with 2 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (MgSO4) and concentrated under reduced pressure, obtaining a yellow product (0.9 g). This substance is suspended in a 25% solution of ethylamine in ethanol (20 ml) at 50oC for 2 hours. The mixture is concentrated under reduced pressure and distributed between ethyl acetate and 2 M hydrochloric acid. The extract is dried (MgSO4) and concentrate under reduced dative dichloromethane/ methanol = 98:2). Containing the product fractions are concentrated under reduced pressure, dissolved in ethyl acetate and extracted with 2 N. hydrochloric acid. Acid solution is alkalinized (pH 8) by adding saturated aqueous sodium bicarbonate and the product extracted with ethyl acetate. The organic solution is dried (MgSO4and concentrate, getting mentioned in the title compound (0.25 g, 41%), in the form of a white solid product.

1H-NMR (300 MHz, DMSO-d6) = 3,29 (3H, s) 4,07 (3H, s), of 7.70 (2H, user. C) of 7.90 (1H, s), a 9.35 (1H, s).

m/z (thermal spray) 371 (MH+).

Preparative example 21. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)-N-(methoxycarbonylmethyl)methanesulfonamide.

< / BR>
Anhydrous sodium carbonate (1.60 g, and 11.2 mmol) are added to a suspension of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl) methanesulfonamide (see preparative example 3, 3.0 g, 9.4 mmol) in acetone (70 ml) with stirring. The mixture is heated at the boiling point under reflux for 15 minutes, cool and add methylbromide (1.8 ml, to 18.7 mmol). 3 Quiroga mixture is heated at the boiling point under reflux for 2 hours, cooled, diluted with ethyl acetate (300 ml) and washed with water (I ml). The organic phase is dried (MgSO4) and concentrate p is the best specified in the title compound as a white solid (3,177 g, 80%).

1H-NMR (300 MHz, CDCl3) =3,44 (3H, s), 3,71 (3H, s), 4,14 (3H, s), 4,20 (3H, s), 4,37 (1H, d, J 8 Hz), 4,71 (1H, d, J 8 Hz), 7,95 (1H, s).

m/z (thermal spray) 424 (MH+).

Preparative example 22. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)-N-(6-methoxypyridine-2-yl)methyl]methanesulfonamide

< / BR>
This compound is prepared as in preparative method of example 21, above, using 2-(methyl bromide)- 6-methoxypyridine [(see Synth. Commun, 24, 1367 (1994)] instead of methylpropanoate. The compound obtained as white solid ( 299 mg, 84%).

1H-NMR (300 MHz, CDCl3) = 3,38 (3H, s). 3,68 (3H, s) 4,07 (3H, s) to 4.15 (3H, s), is 4.85 (1H, d, J 14 Hz), 4,99 (1H, d, J 14 Hz), to 6.58 (1H, d, J 8 Hz), 6.73 x (1H, d, J 7 Hz), 7,40 (1H, DD, J 8 and 7 Hz), 7,92 (1H, s).

m/z (thermal spray) 473 (MH+).

Preparative example 23. N-(6,7-Dichloro-2,3-dimethoxyaniline - 5-yl)-N-(1-methoxycarbonylethyl)-methanesulfonamide

< / BR>
Connection receive by way of preparative example 21, above, using methyl 2-bromopropane instead of methylpropanoate. The product is obtained as a mixture of two diastereoisomers who share flash chromatography (gradient elution with hexane/ethyl acetate). The first isomer receive in the form of a white solid product (1,456 g, 57%) (Rf,18 (3H, C) to 5.10 (1H, square, J 7 Hz), of 7.96 (1H, s).

m/z (thermal spray) 438 (MH+).

The second isomer is also obtained as a white solid (0.75 g, 29%) (Rf 0.45, and hexane/ethyl acetate = 1:1).

1H-NMR (300 MHz, CDCl3) = of 1.26 (3H, d, J 7 Hz), to 3.36 (3H, s), 3,61 (3H, s) to 4.15 (3H, s), is 4.21 (3H, s), to 4.98 (1H, q, J 7 Hz), of 7.97 (1H, s).

m/z (thermal spray) 438 (MH+).

Preparative example 24. 5-Amino-7-chloro-6-fluoro-2,3 - dimethoxyphenoxy and 5-amino-6-chloro-7-fluoro-2,3-dimethoxyphenoxy

< / BR>
a) 1,4-Dihydro-6-chloro-7-perinatally-2,3-dione (see example 17, W094/00124) (0,200 g of 0.93 mmol) is added by portions to fuming nitric acid (density of 1.5 fuel-3, 5 ml) at room temperature. After 30 minutes the mixture was added to water (50 ml). The resulting solid product is filtered off and dried in vacuum, obtaining a 6:1 mixture of 1,4-dihydro-6-chloro-7-fluoro-5-nitrophenoxy-2,3 - dione and 1,4-dihydro-7-chloro-6-fluoro-5-nitrophenoxy-2,3-dione (0,095 g, 39%) as a pale orange solid connections.

1H-NMR (300 MHz, DMSO-d6) = 7,24 (1H major, d, J 10 Hz), 7,39 (1H, main, d, J 8 Hz), 12,17 (1H, major, 1H lesser of user.C), 12,29 (1H major, 1H smaller, user.C).

m/z (thermal spray) 277, 279 (MH+).

b) a Mixture of intermediate products from preveden is on and 2,3,7-trichloro-6-fluoro-5 - nitroquinoline. The mixture of products obtained as a pale yellow solid (92% yield).

1H-NMR (300 MHz, CDCl3) =of 7.90 (1H major, d, J 10 Hz), of 8.28 (1H lesser, d, J 8 Hz).

(C) a Mixture of intermediate product from stage (b) above, make a 6:1 mixture of 5-amino-2,3,6-trichloro-7-forination and 5 - amino-2,3,7-trichloro-6-forination by the method of preparative example 1(b).

The mixture of products obtained as yellow solid (100% yield).

1H-NMR (300 MHz, CDCl3) =4,92 (2H smaller, user.C) the 5.45 (main, user. C) was 7.08 (1H major, d, J 10 Hz), 7,38 (1H lesser, d, J 8 Hz).

m/z (thermal spray) 267 (MH+).

d) a Mixture of intermediate products from stage (C), above, is converted into a mixture of 5-amino-6-chloro-7-fluoro-2,3-dimethoxyaniline and 5-amino-7-chloro-6-fluoro-2,3-dimethoxyaniline by the method of preparative example 1(C). The mixture of products is shared by flash chromatography (elwira toluene), which gives 5-amino-6-chloro-7-fluoro-2,3 - dimethoxyphenoxy in the form of a white solid (27% yield), so pl. 199-200oC.

1H-NMR (300 MHz, CDCl3) =4,15 (6H, s), 5,04 (2H, user. C) of 6.90 (1H, d, 10 Hz).

m/z (thermal spray) 258, 260 (MH+).

5-Amino-7-chloro-6-fluoro-2,3-dimethoxy is, CDCl3) =4,14 (3H, s), 4,18 (3H, s), to 4.62 (2H, user. C), 7,40 (1H, d, J 8 Hz).

m/z (thermal spray): 258, 260 (MH+).

Preparative example 25. N-(7-Chloro-6-fluoro-2,3-dimethoxyaniline-5-yl) methanesulfonamide

< / BR>
Methanesulfonyl anhydride (0.55 g, and 3.16 mmol) and pyridine (255 μl, of 3.15 mmol) is added to a stirred suspension of 5-amino-7-chloro - 6-fluoro-2,3-dimethoxyaniline (see preparative example 24) (0,274 g, 1.06 mmol) in dichloromethane (15 ml) at room temperature under nitrogen atmosphere. The mixture is stirred at room temperature overnight. Concentrate to dryness and suspended in tetrahydrofuran (30 ml). The reaction mixture was treated with 1 M sodium hydroxide (5.3 ml, 5.3 mmol) under ice cooling, followed by stirring at 5oC for 1.5 hours. The reaction mixture is acidified to pH 2 with 2 M hydrochloric acid, concentrated and partitioned between water and dichloromethane. The layers are separated and the aqueous layer was extracted twice with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated, obtaining a pale yellow solid product. Suspended in THF (30 ml) and treated with 1 M sodium hydroxide (5.3 ml, 5.3 mmol) in 5oC and subsequently stirred at room temperature for 2 ChessBase water and filtered. The filtrate is washed with water and chilled diethyl ether, obtaining a white solid product (0.32 g, 90%), so pl. 227-228oC.

1H-NMR (300 MHz, DMSO-d6) = 3,12 (3H, s), Android 4.04 (3H, s), of 4.12 (3H, s), of 7.90 (1H, d, J 8 Hz), 9,50 (1H, s).

m/z (thermal spray) 336, 338 (MH+).

Preparative example 26. N-(6-Chloro-7-fluoro-2,3 - dimethoxyaniline-5-yl)methanesulfonamide

< / BR>
5-Amino-6-chloro-7-fluoro-2,3-dimethoxyphenoxy (see preparative example 24) transform according to the method of preparative example 25 N-(6-Chloro-7-fluoro-2,3-dimethoxy cinoxacin-5-yl) methanesulfonamide. The product is obtained in the form of a white solid compound (30% yield).

1H-NMR (300 MHz, DMSO-d6) =and 3.16 (3H, s), Android 4.04 (3H, s), of 4.12 (3H, s), 7,72 (1H, d, J 10 Hz), a 9.60 (1H, s).

m/z (thermal spray) 336, 338 (MH+).

Preparative example 27.

N-(6,7-Dichloro-2, 3-dimethoxyquinazolin-5-yl)-N- (2-amino-ethyl)methanesulfonamide

< / BR>
a) N-(2-bromacil)phthalimide (1.73 g, for 6.81 mmol) are added to the heated to the boiling temperature under reflux a mixture of N-(6,7-Dichloro-2,3 - dimethoxy-cinoxacin-5-yl)methanesulfonamide (preparative 3, 2.00 g, of 5.68 mmol) and potassium carbonate (1.88 g, 13,63 mmol) in acetone (100 ml) under nitrogen atmosphere. After 48 hours add an additional number is up for 18 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is dissolved in dichloromethane. The resulting solution was twice washed with 1 N. solution of sodium hydroxide, water and salt solution and then dried (MgSO4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (elwira hexane:ethyl acetate), giving N-(6,7-dichloro-2,3 - dimethoxyaniline-5-yl)-N-(2-phthalimidomethyl)methanesulfonamide in the form of a pale yellow solid (2.55 g, 85%).

1H-NMR (300 MHz, CDCl3) =of 3.25 (3H, s) to 3.64 (2H, t, J 8 Hz), 3,90-was 4.02 (2H, m), of 4.12 (3H, s), 4,17 (3H, s), 7,65-7,80 (3H, m) of 7.82-a 7.92 (2H, m).

m/z (thermal spray) 525 (MH+)

b) 33% solution of methylamine in IMS (industrial denatured alcohol) (1.77 ml of 19.03 mmol) is added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N-(2 - phthalimidomethyl)methanesulfonamide (2.00 g, 3,81 mmol) in dichloromethane (38 ml) in a vessel filled with nitrogen, with a rubber gasket. The mixture is stirred for 72 hours and then add an additional amount of 33% solution of methylamine in IMS (1.77 ml of 19.03 mmol). The mixture is stirred for 18 hours and then concentrated under reduced pressure. The residue is dissolved in dichloromethane and twice extracted with 10% aqueous citric acid. The organic layer of CNIL] benzoyl)aminoethyl)methanesulphonamide in the form of solids (996 mg, 49%).

1H-NMR (300 MHz, CDCl3) =2,92 (3H, d, J 5 Hz), 3,20 (3H, s), 3,45-3,62 (2H, m), of 3.97 (3H, s), 3,98-4,10 (2H, m), 4,13 (3H, s), 6,60 (1H, user. d), 7,44 (1H, m), 7,60 (1H, m), 7,72 (1H, m), 7,82 (1H, m), 7,95 (1H, s).

m/z (thermal spray) 556 (MH+).

(C) Hydrazine hydrate (26 μl, 26 mg, mean HDI of 0.531 mmol) is added dropwise to a solution of N-(6,7-dichloro-2,3-dimethoxy-cinoxacin-5-yl)-N-(N' -([2-methylaminomethyl] benzoyl)amino-ethyl)methanesulfonamide (283 mg, mean HDI of 0.531 mmol) in dichloromethane (5 ml) and the mixture is heated to boiling point for 4 hours. Add methanol (1 ml) and heated to boiling point under reflux continued for 18 hours. After cooling, the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and extracted with 10% citric acid. The aqueous layer was brought to pH 8 with solid potassium carbonate and extracted twice with dichloromethane. The combined organic layers are dried (MgSO4) and concentrated under reduced pressure, obtaining N-(6,7-dichloro-2,3-dimethoxyaniline-5-yl)-N- (2-amino-ethyl)methanesulfonamide in the form of a pale yellow solid (138 mg, 66%).

1H-NMR (300 MHz, CDCl3) =2,70-is 2.88 (2H, m), 3,11 (3H, s), with 3.79 (2H, t, J 8 Hz), 4,17 (3H, s), 4,20 (3H, s), 7,95 (1H, s), m/z (thermal spray) 395 (MH+).

Preparative what linetramadol (Jpn. Kokai Tokyo Koho JP 81, 169, 651 (1980) Chem. Abstr. 1981, 96, 162307 g) (103 g, 0.46 mol) and tert-butyl CHLOROACETATE (79 ml, 0.55 mol) in dry tetrahydrofuran (400 ml) is added dropwise over 30 minutes to a solution of potassium tert-butylate (128 g, 1,14 mol) in dry tetrahydrofuran (800 ml) under stirring in nitrogen atmosphere and during curing temperature - 40oC. Upon completion of addition the resulting dark blue solution was stirred for an additional 30 minutes. The mixture is then poured into 0.5 M hydrochloric acid (2 l) and the product extracted with ethyl acetate (2.5 l and 1 l). The combined organic solutions dried (MgSO4) and evaporated on silica gel (70-200 mesh, 200 g). Silica gel is transferred into the upper part silikagelevye chromatographic column (800 g) and the product elute using a gradient of hexane/ethyl acetate. Containing the product fractions are combined and evaporated, receiving a yellow solid product, which is treated with hexane, giving tert-butyl 2-nitro-3,5,6 - trichlorophenylacetic (91,8 g, 59%) as a white solid. Found, 42,32; H, 3,50; N Is 4.03.

Calculated for C12H12Cl3NO4: 42,32; H 3,55; N 4,11%.1H-NMR (300 MHz, CDCl3) =of 1.42 (9H, s), of 3.73 (2H, s), 7,60 (1H, s).

m/z (thermal spray) 357 (MNH4+).

b) a Mixture of tert-butyl 2-nitro is anole (360 ml) is heated in an autoclave at 150oC for 72 hours. The resulting viscous black mixture was diluted with water (1 l) and ethyl acetate (1 l) and filtered through Arbocel accelerator filtering. Dark red filtrate was separated and the aqueous layer was extracted with ethyl acetate (2x1 l). The combined organic solutions are washed with salt solution (1 l), dried (MgSO4) and evaporated on silica gel (70-200 mesh, 200 g). Silica gel is transferred into the upper part of the chromatographic column containing silica gel (40-60 mesh, 800 g). Elution with hexane/ethyl acetate (98:2-92:8) gives 3-amino-5,6-dichloro-2-nitrotoluene (EUR. patent 385850) as a bright orange solid (and 39.7 g), contaminated with 5-amino-3,6-dichloro-2-nitrotoluene (14 %). This mixture is used in the next stage without additional purification.

1H-NMR (300 MHz, CDCl3) =2,48 (3H, s), 4,80 (2H, s), PC 6.82 (1H, s).

C) a Solution of dithionite sodium (94 g, 0.54 mol) in water (1 l) is added to a stirred mixture of 3-amino-5,6-dichloro-2-nitrotoluene (from stage (b), and 39.7 g, 0.18 mol) and potassium bicarbonate (94 g of 0.94 mmol) in methanol (1 l) at room temperature. After 30 minutes the mixture is concentrated under reduced pressure and the resulting suspension extracted with ethyl acetate (700 ml). The extracts are dried (MgSO4) and concentrate under reduced giving the

1H-NMR (300 MHz, CDCl3) =2,28 (3H, user, C) to 3.36 (2H, user.C) of 3.42 (2H, user.C) 6,72 (1H, s).

d) a Mixture of 2,3-diamino-5,6-Dichlorotoluene (from stage (C) of 21.6 g, 0,137 mol) and oxalic acid (of 18.45 g, 0,206 mol) in hydrochloric acid (4 M, 900 ml) is heated to the boiling point under reflux for 6 hours, cooled and filtered. Dark brown solid product is suspended in diethyl ether, filtered and washed with additional amount of diethyl ether, receiving 6,7-dichloro-5-methyl-cinoxacin-2,3-dione (representing 22.06 g, 66%).

1H-NMR (300 MHz, DMSO) =2,40 (3H, s), 7,14 (1H, s), 11,37 (1H, s) 11,94 (1H, s).

e) a Mixture of 6,7-dichloro-5-methylphenoxy-2,3-dione (from stage (d) representing 22.06 g, 90 mmol), thionyl chloride (300 ml) and dimethylformamide (1 ml) is heated to the boiling temperature under reflux for 3 hours, cooled and slowly poured into ice water. The obtained dark yellow precipitate is filtered off, giving 5-methyl-2,3,6,7 - tetrachloroaniline (24,42 g, 96%)

1H-NMR (CDCl3) = 2,85 (3H, s), 8,02 (1H, s).

f) a Solution of sodium methylate (38 ml, 25% solution in methanol, 175 mmol) is added over 10 minutes to a solution of 5-methyl-2,3,6,7-tetrachloronaphthalene (from stage (e), 21 g, 74 mmol) in dry tetrahydrofuran (200 mg) at 20oC. Protectton (3 l), washed with water (1 l), dried (MgSO4) and concentrated under reduced pressure, getting 6,7-dichloro-2,3-dimethoxy-5-methylphenoxy (20,3 g, 100%).

1H-NMR (300 MHz, CDCl3) =2,75 (3H, s) to 4.15 (3H, s), 4,18 (3H, s), 7,78 (1H, s).

m/z (thermal spray) 273 (MH+).

g) a Mixture of 6,7-dichloro-2,3-dimethoxy-5-methylinosine (from the stage (f), 22,0 g, 80,5 mmol), N-bromosuccinimide (17,2 g that 96.6 mmol) and azoisobutyronitrile (1.3 g, 8.0 mmol) is heated to the boiling point under reflux in 1,1,1-trichloroethane (400 ml) for 4 h under irradiation with a 500 W lamp daylight. The mixture is cooled, add silica gel (50 g, 60-230 mesh) and the solvent is removed under reduced pressure. The remainder of the load from above in a chromatographic column filled with silica gel and the product elute using a gradient of hexane/ethyl acetate. The product is triturated with hexane, receiving 5-methyl bromide-6,7-dichloro-2,3-dimethoxyphenoxy (25,3 g, 87%) friable white solid.

Found: C 37,72; H 2,40; N 7,40; for C11H9BrCl2N2O2< / BR>
calculated: C 37,53; H 2,58; N of 7.96%.

1H-NMR (300 MHz, CDCl3) =4,15(3H, s), 4,22 (3H, s), 5,20 (2H, s), 7,89 (1H, s).

Preparative example 29. (6,7-Dichloro-2,3-dimethoxyaniline-5 - yl)methyl methyl sulfon

< / BR>4) and concentrate under reduced pressure. The remainder of the clean flash chromatography (elwira 1:1 hexane: dichloromethane), which gives 6,7 - dichloro-2,3-dimethoxy-5-methyl-dimethylquinoxaline (79 mg, 87%) as a white solid, so pl. 143-5oC.

1H-NMR (300 MHz, CDCl3) = 2,10 (3H, s), of 4.12 (3H, s) to 4.15 (3H, s), 4,39 (2H, s), 7,81 (1H, s).

m/z (thermal spray) 319 (MH+).

b) 3-Chlorodeoxyadenosine acid (50%, 1,904 g, 5,52 mmol) is added in portions to a stirred solution of 6,7-dichloro-2,3 - dimethoxy-5-methyldiethanolamine (stage (a), 800 mg, 2.51 mmol) in dry dichloromethane at room temperature under nitrogen atmosphere. The mixture is stirred for 30 minutes and then the reaction being removed by adding 10% aqueous solution of sodium sulfite and the organic layer separated. The dichloromethane solution was washed with 10% aqueous potassium carbonate solution, dried (MgSO4) and concentrated under reduced pressure, obtaining a remainder of (6,7-dichloro-2,3-dimethoxy-Hino what about the product so pl. 161-3oC.

1H-NMR (300 MHz, CDCl3) =2,92 (3H, s), 4,13 (3H, s), 4,19 (3H, s), 5,16 (2H, s), 7,94 (1H, s).

m/z (thermal spray) 351 (MH+).

Preparative example 30. (6,7-Dichloro-2,3-dimethoxyaniline - 5-yl) methyl ethyl sulfon

< / BR>
Specified in the title compound is obtained from the compound of preparative example 28 by way of preparative example 29 (a) and (b) using etanercept sodium, in the form of not-quite-white solid (31% two steps), so pl. 150-2oC.

1H-NMR (300 MHz, CDCl3) =USD 1.43 (3H, t, J 8 Hz), is 3.08 (2H, q, J 8 Hz), 4,16 (3H, s), is 4.21 (3H, s), 5,14 (2H, s), of 7.96 (1H, s).

m/z (thermal spray) 365 (MH+).

Preparative example 31. (6,7-Dichloro-2,3 - dimethoxyaniline-5-yl)methyl benzyl sulfon

< / BR>
a) potassium Carbonate (108 mg, 0,781 mmol) and then benzylmercaptan (92 μl, 97 mg, 0,781 mmol) is added to a stirred solution of 5-methyl bromide-6,7-dichloro-2,3-methoxyaniline (preparative example 28) (250 mg, 0.71 mmol) in dry dimethylformamide (10 ml) under nitrogen atmosphere at room temperature. The mixture is stirred for 30 minutes and then partitioned between salt solution and ethyl acetate. The organic layer is separated and the aqueous phase is extracted twice with ethyl acetate. United extracted 2: 1 hexane: dichloromethane), that gives 5-benzyldimethyl-6,7-dichloro-2,3-dimethoxyphenoxy (268 mg, 96%) as a white solid, so pl. 121 - 122oC.

1H-NMR (300 MHz, CDCl3) =3,86 (2H, s), of 4.00 (3H, s), 4,14 (3H, s), 4,43 (2H, s), 7,25 (5H, m), 7,80 (1H, s).

m/z (thermal spray) 395 (MH+).

(b) Specified in the title compound is obtained from 5-benzyldimethyl-6,7-dichloro-2,3-dimethoxyaniline (stage (a)) by the method of preparative example 29 (b) in the form of a white solid (93%), so pl. 185-7oC.

1H-NMR (300 MHz, CDCl3) = a 4.03 (3H, s), of 4.12 (3H, s), 4,35 (2H, s), 5,12 (2H, s), 7,40 (5H, m), to 7.93 (1H, s).

m/z (thermal spray) 427 (MH+.

1. Derivatives finokalia General formula I

< / BR>
where A Is N, CH or n;

R1and R2independently - C1-4alkyl, halogen or CF3;

R3- C1-4alkyl, optionally substituted phenyl, CF3or phenyl;

R4is hydrogen, C3-7cycloalkyl or C1-6alkyl, [optionally substituted by hydroxy, C1-4alkoxy, phenyl, heterocyclic group selected from pyridinyl, morpholinyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazinyl, triazolyl, tetrazolyl, furil, isooxazolyl and phthalimide, which is optionally substituted up to 3 replace the Ohm, carboxy, amino, C1-4alkoxycarbonyl, C1-4alkylamino, di(C1-4alkyl)-amino, NHSO2CF3, CONR5R6, NHCONR5R6or O(CH2)nNR5R6], where R5and R6independently represent hydrogen or C1-4alkyl or together with the nitrogen atom to which they are attached, may represent pyrrolidino or morpholinopropan;

n = 2, 3, or 4

or their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that it denotes A n

3. Connection under item 1 or 2, characterized in that it R1- halogen or C1-4alkyl.

4. The compound according to any one of the preceding paragraphs, characterized in that it R2- halogen or C1-4alkyl.

5. The compound according to any one of the preceding paragraphs, characterized in that it R3- C1-4alkyl.

6. Connection on p. 5, characterized in that it R3is methyl.

7. The compound according to any one of the preceding paragraphs, characterized in that it R4- C1-6alkyl.

8. Connection on p. 7, characterized in that it R4- CH2CH2OH or CH2CO2H.

9. Connection on p. 2, characterized in that the om is such, as shown in the formula I

< / BR>
where R1-4such as defined in paragraph 1.

10. The compound according to any one of the preceding paragraphs, characterized in that it is (R)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)-N-(2-hydroxyethyl)-methanesulfonamide.

11. The compound according to any one of p. 1 - 9, characterized in that it is (R)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxopiperidin-5-yl)methanesulfonamide.

12. Anxiolytic, anticonvulsant, analgesic or neuroprotective pharmaceutical composition comprising a compound of formula I, as defined in paragraph 1 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. The compounds of formula I on p. 1 to obtain a pharmaceutical composition.

14. The method of obtaining derivatives of cinoxacin General formula I, as defined under item 1 or their pharmaceutically acceptable salts, characterized in that the compound of formula II

< / BR>
where A, R1- R4have the meanings given in paragraph 1;

P1and P2hidroxizina group,

remove the protective group and, if necessary, the compound obtained is transformed into its pharmaceutically nature>, P1and P2have the meanings given in paragraph 14.

 

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