Quinazoline derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

 

The present invention relates to 1H-hinzelin-2,4-diones, their reception, their use as pharmaceuticals and pharmaceutical compositions containing them.

In particular, the present invention provides compounds of formula (I)

where

G means NR3R4or or5

where

R3, R4and R5means independently hydrogen, aryl, aralkyl, acyl or alkyl, optionally substituted aryl, heterocyclyl, arroceros, aralkylamines or alkoxycarbonylmethyl, or

R3and R4form together with the adjacent nitrogen atom heteroaryl or heterocyclyl group containing at least one ring nitrogen atom and is attached via the ring nitrogen atom, where the heteroaryl and heterocyclyl group optionally substituted aryl, aralkyl, aryloxyalkyl, aminocarbonyl, mono - or dialkylaminoalkyl or morpholinosydnonimine,

R1means nitrogroup or triptorelin group, and

R2means alkyl, aryl or aralkyl,

and their salts.

As mentioned above, the alkyl, heteroaryl and heterocyclyl are optionally substituted, preferably unsubstituted, mono-, di - or tizamidine mentioned substituents, more prefer is Ino unsubstituted or monosubstituted mentioned substituents.

Unless otherwise specified, expressions used in this invention have the following values.

Acyl means alkylsulphonyl, arylcarbamoyl or aralkylamines.

Alkyl means a linear, branched or cyclic, saturated or unsaturated, preferably saturated alkyl, preferably (C1-C8)alkyl, more preferably (C1-C6)alkyl, most preferably (C1-C4)alkyl. Alkyl is optionally substituted by one or more substituents, preferably from one to three substituents. The substituents are preferably halogen, hydroxyl, lagrappe, (C1-C4)alkoxygroup, (C1-C4)alkoxycarbonyl, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)alkoxycarbonylmethyl or (C1-C4)alkylcarboxylic.

Alkane (for example, in alkanesulfonyl) and Ala (e.g., alkoxy) are defined similarly to alkyl, particularly in terms of linearity, saturation, preferred size, and an optional replacement.

Aryl means preferably phenyl, naphthyl or a 5-10 membered heteroaryl, more preferably phenyl or 5-6-membered heteroaryl. Aryl is optionally substituted, preferably unsubstituted, mono-, di - or triseme the military. The substituents are preferably halogen, more preferably fluorine or chlorine, nitro-group, lagrappe, formyl, carboxamido, hydroxyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)alkyl, (C1-C4)alkoxygroup, (C1-C4)alkoxycarbonyl, (C1-C4)alkanesulfonyl, (C1-C4)alkylsulphonyl, (C1-C4)alkoxycarbonylmethyl or (C1-C4)alkylcarboxylic.

Aralkyl means alkyl substituted by aryl.

Halogen means preferably bromine, chlorine or fluorine.

Heteroaryl means a mono - or polycyclic, preferably mono - or bicyclic, most preferably monocyclic aromatic residue containing one or more, preferably from one to three ring heteroatoms, preferably selected from nitrogen atoms, oxygen and sulfur, most preferably nitrogen. Heteroaryl means preferably 5-10-membered heteroaryl, more preferably 5-6-membered heteroaryl. Heteroaryl is optionally substituted, preferably unsubstituted, mono-, di - or tizamidine. The substituents are preferably halogen, more preferably fluorine or chlorine, nitro-group, lagrappe, formyl, carboxamido, Hydra is KSIL, amino group, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)alkyl, (C1-C4)alkoxygroup, (C1-C4)alkoxycarbonyl, (C1-C4)alkanesulfonyl, (C1-C4)alkylsulphonyl, (C1-C4)alkoxycarbonylmethyl or (C1-C4)alkylcarboxylic.

Heterocyclyl means a mono - or polycyclic, preferably mono - or bicyclic, most preferably monocyclic, saturated or partially unsaturated cyclic residue, containing three or more ring atoms, preferably from three to ten ring atoms of which one or more, preferably one to three, are heteroatoms, preferably selected from nitrogen atoms, oxygen and sulfur. Heterocyclyl is optionally substituted, preferably by halogen, langroup, carboxamido, hydroxyl, amino, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, (C1-C4)alkyl, (C1-C4)alkoxygroup, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarboxylic, (C1-C4)alkoxycarbonylmethyl or (C1-C4)alkylcarboxylic.

Salt means preferably fisiologicas is acceptable salt, educated as corresponds to the addition of acid or base.

Mentioned optional substituents listed in the definition of alkyl, aryl, heteroaryl and heterocyclyl, should be understood as the substituents in addition to those listed in the General formula, ie, for example, the alkyl may have substituents listed in the General formula and/or definitions.

Tautomeric forms of the compounds of formula (I) are also covered by the invention. In cases where you have one or more asymmetric atoms, particularly carbon atoms, the compounds exist in individual optically active isomeric form or as mixtures thereof, e.g. as racemic or diastereomeric forms. The present invention encompasses the individual optically active isomers and their mixtures, e.g. racemic or diastereomeric mixture.

Preference is given to compounds of the formula (Ia)

where R1, G, and R2have such values that are defined in this specification.

Additional preference is given to compounds of the formula (Ib)

where R2, R3and R4have such values that are defined in this specification.

Further preference is given to compounds of the formula (1C)

where R1, R2and R5have such values that are defined in this specification.

Further preference is given to compounds of the formula (Id)

where G and R2have such values that are defined in this specification.

Further preference is given to compounds of the formula (Ie)

where R1and R2have such values that are defined in this specification.

Further preference is given to compounds of the formula (Ih)

where G and R2have such values that are defined in this specification.

Preferably G implies R3R4N.

Preferably R3means hydrogen, aryl, aralkyl, acyl or alkyl, optionally substituted by heterocyclyl, arroceros, aralkylamines or alkoxycarbonylmethyl, and R4means hydrogen or alkyl, or R3and R4form together with the adjacent nitrogen atom heteroaryl or heterocyclyl containing at least one ring nitrogen atom and is attached by means of this ring nitrogen atom, where heteroaryl and heterocyclyl are optionally substituted by aryl, aralkyl, aryloxyalkyl, aminocarbonylmethyl or morpholinosydnonimine. Preferably R3and R4clicks the form together with the adjacent nitrogen atom a 5-membered heteroaryl, containing at least one ring nitrogen atom and is linked via the ring nitrogen atom, most preferably imidazol-1-yl.

Preferably R1is the nitro-group.

Preferably R2represents methyl, ethyl, phenyl, benzyl, nitrophenyl or pyridyl, most preferably methyl, ethyl or fined.

In another variant embodiment of the invention provides compounds of formula (I),

where

G means NR3R4or or5,

where

R3means hydrogen, aralkyl or alkyl, optionally substituted aryl, heterocyclyl, arroceros, aralkylamines or alkoxycarbonylmethyl,

R4means hydrogen or alkyl, or

R3and R4form together with the adjacent nitrogen atom heteroaryl or

heterocyclyl containing at least one ring nitrogen atom and is linked via the ring nitrogen atom, where heteroaryl and heterocyclyl are optionally substituted by aryl, aminocarbonyl, mono - or

dialkylaminoalkyl or morpholinosydnonimine, and

R5means alkyl,

R1means the nitro-group or trifluoromethyl, and

R2means alkyl,

and their salts.

Especially preferred are the compounds of formula (Ia)where R1is is nitrogroup and R 2represents methyl.

Especially preferred are the compounds of formula (Ia)where R1

is trifluoromethyl and R2represents methyl.

Especially preferred are the compounds of formula (Ia)where R1is the nitro-group, and R2represents ethyl.

Especially preferred are the compounds of formula (Ia)where R1is trifluoromethyl and R2represents ethyl.

Especially preferred are the compounds of formula (Ia)where R1is the nitro-group, and R2represents phenyl.

Especially preferred are the compounds of formula (Ia)where R1is trifluoromethyl and R2represents phenyl.

Especially preferred are the compounds of formula (I), where G is saturated the unsubstituted heterocycle.

Especially preferred are the compounds of formula (I), where R3represents methyl and R4is hydroxyethyl.

Preferred, particularly preferred ranges and formulas can be mapped at the discretion. Definitions applicable to compounds of formula (I) and the corresponding starting materials and intermediate compounds.

In a further aspect the present invention provides methods for producing compounds according to the invention.

Method 1

The connection is of formula (Ib)

where R2, R3and R4have the meanings specified above,

can be obtained by the coupling of compounds of formula (II)

where R2has the meaning specified above,

with the compound of the formula (III)

,

where R3and R4have the values specified above.

To this end, the mixture of the compounds of formula (II) with an excess of the compounds of formula (III), preferably 1.5 to 30 equivalents, most preferably 2 to 10 equivalents, pure or dissolved in an appropriate inert solvent such as 1,3-dimethylimidazolidin-2-it, dimethylsulfoxide, acetic acid or ethanol, can be heated in a closed vessel at high temperatures, for example 150°C using an oil bath or a microwave reactor, within the required time, for example 5 min to 1 h, or alternatively in the relevant high-boiling inert solvent like dimethyl sulfoxide, in an open system to a lower temperature, for example 120°C, for longer periods of time, for example 16 hours If necessary secure connection parts, such as hydroxyl or amino group, may be released in the reaction product or the reaction product may be further transformed, for example, recovery or oxidation.

Obedinenie formula (II) can be obtained by using common methods of amine (IV).

where R6means alkyl,

the conversion of the isocyanate (V)

where R6has the meaning specified above,

for example, by reaction with phosgene and subsequent cyclocondensation with sulfonylhydrazide (VI)

where R2has the meaning specified above,

in an appropriate inert solvent such as tetrahydrofuran, followed by addition of a base, for example aqueous sodium hydroxide, or organic bases such as triethylamine or base Hunya (N,N-diisopropylethylamine). Compounds of formulas (IV) and (V) are known or can be obtained by known literature methods or by analogy with them.

The following reaction scheme is illustrative for the way 1.

Scheme 1

Method 2

The compounds of formula (Ic)

where R1, R2and R5have the values specified above can be obtained by the reaction of the compounds of formula (VII)

where R1and R5have the meanings indicated above and R7means alkyl, with a compound of formula (VI) in an appropriate inert solvent such as tetrahydrofuran, optionally in the presence of an appropriate base, such to the to an aqueous solution of sodium hydroxide, or organic bases such as triethylamine or base Hunga. The appropriate temperature for this reaction are in the range of 0-40°C., preferably 22°C.

Isocyanate (VII) can be obtained from the amine (VIII)

where R1and R7have the meanings specified above,

the reaction of the alcoholate (IX)

where R5has the meaning specified above, and M+means a metal, preferably alkali metal ion, in an appropriate inert solvent, for example an appropriate alcohol R5HE, with subsequent hydrolysis of ndimethylacetamide, for example with 98% sulfuric acid, amine (X).

where R1and R7have the meanings specified above,

and conversion of the isocyanate (VII), for example, with phosgene or triphosgene. The compounds of formula (VIII) are known or can be obtained by known literature methods or by analogy with them.

The following reaction scheme is illustrative for the way 2.

Scheme 2

Method 3

The compounds of formula (Id)

where G and R2have the meanings specified above,

can be obtained by reaction of compounds of formula (XI)

where G is the value specified above,

co is an Association of the formula (VI).

The reaction is carried out in an appropriate inert solvent such as tetrahydrofuran, followed by the action of a base, for example aqueous sodium hydroxide, or organic bases such as triethylamine or base Hunga.

Isocyanate (XI) can be obtained by nucleophilic substitution of fluoride (XII)

with the amine (III) or alkoxide (IX), giving nitrosoaniline (XIII),

where G is the value specified above,

subsequent reduction in the amine (XIV),

where G is the value specified above,

with the appropriate regenerating agent, for example, by hydrogenation with hydrogen using palladium on coal as a catalyst, and the conversion of the isocyanate (XI), for example, with phosgene or triphosgene.

The compounds of formula (XII) are known or can be obtained by known literature methods or by analogy with them.

The following reaction scheme is illustrative for the way 3.

Scheme 3

Method 4

The compounds of formula (Ie)

where

R1and R2have the meanings specified above, and

G' means R3'R4'N or R5'O,

where

R3', R4'and R5'have the values of R3, Rsup> 4and R5accordingly, as described above, provided that the carbon atoms of R3', R4'and R5'adjacent to nitrogen and oxygen

R3'R4'N and R5'O, respectively, are primary or secondary carbon atoms

can be obtained by condensation, alkylation or reductive alkylation of compounds of formula (If),

where

R1and R2have the meanings specified above, and

R8means an amino group or a hydroxyl,

with the appropriate halide or aldehyde precursors R3', R4'or R5'in the presence of a condensation catalyst, a base or a reducing agent, such as nitrobenzamide, respectively.

The compounds of formula (If) can be obtained by release of the compounds of formula (Ig)

where

R1and R2have the meanings specified above, and

R9means is substituted by an amino group or a hydroxyl,

which, in turn, can be obtained one of the following methods 1-3. The corresponding halide or aldehyde precursors of R3', R4'or R5'known or can be obtained by known literature methods or by analogy with them.

The following reaction scheme is illustrative for method 4.

Scheme 4

Method 5

The compounds of formula (Ih)

where G and R2have the meanings given above are obtained by reaction of compounds of formula (XVI)

where

G is the value specified above,

R11represents phenyl which is optionally substituted by halogen or (C1-C4)alkyl, with a compound of formula (VI).

The reaction is preferably carried out in an appropriate inert solvent such as tetrahydrofuran, followed by addition of a base, for example aqueous sodium hydroxide, or organic bases, such

as triethylamine, ethyldiethanolamine or base Hunga.

The reaction is particularly preferred for compounds of formula (If), in which G

is in position 6, and triptorelin group is in position 7.

Carbamate (XVI) can be obtained by the reaction of substitution of the corresponding

the amino compounds of the formula (XVII)

with chloroformiate (XVIII)

where R11matter mentioned above, in the presence of a diluent, such as dioxane, giving carbamate (XVI).

Compounds of formula (XVIII) and (XVII) are known or can be obtained by known literature methods or by analogy with them./p>

The following reaction scheme is illustrative for the way 5.

Scheme 5

The following considerations may apply depending on the circumstances to all methods in the context of, and to receive the appropriate starting materials and intermediates.

One or more functional groups, such as carboxypropyl, the hydroxy-group, amino group or mercaptopropyl, may need to block in the original compounds with protective groups. Used protective groups may already be present in the precursors and must protect reactive functional group from undesired secondary reactions, such as alkylation reaction, the formation of ethers, education esters, solvolysis and similar reactions. The hallmark of the protective groups is that they are easily, i.e. without undesired secondary reactions are removed, usually by solvolysis, recovery, photolysis or also by means of enzymatic activity, for example, in conditions similar to physiological conditions, and that they are not present in the final products. The expert knows or can easily determine which protective groups correspond to the reactions mentioned previously and in the future.

The protection of such functional groups is akimi protective groups, themselves of the protective group and the reaction of their removal are described, for example in standard reference publications, such as J.F.W.McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York, 1973, in .W.Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1981, in "The Peptides"; volume 3 (editors: E.Gross and J.Meienhofer), Academic Press, London and New York, 1981, in "Methods der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th the third edition, volume 15/1, Georg Thieme Verlag, Stuttgart, 1974, in H.-D.Jakubke and H.Jescheit, "Acids, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel, 1982 and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart, 1974.

Acid additive salts can be obtained from the free bases in a known manner, and Vice versa. The compounds of formula (I) in optically pure form can be obtained from the corresponding racemates according to well-accepted procedures, such as HPLC with chiral matrix. Alternatively can be used optically pure starting compound.

Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated into the respective isomers generally accepted basically by means of appropriate methods of separation. Diastereomer mixture, for example, can be separated into their individual diastereoisomers by fractional crystallization, chromatography, the distribution between solvents and similar procedures. This section is tion may occur either at the level of the parent compound, or at the level of the compounds of formula (I). Enantiomers can be separated through education diastereoisomeric salts, for example by salt formation with enantiomerically pure chiral acid, or by chromatography such as HPLC, using chromatographic substrates with chiral ligands.

In a further aspect, the connections provide new intermediate compounds, as defined above. Data intermediate compounds applicable for producing compounds of formula (I) and also possess interesting pharmaceutical properties. These compounds are also the object of the present invention.

Compounds according to the invention possess pharmacological activity and are therefore suitable as pharmaceutical drugs. In particular, the compounds are potent competitive antagonists of the receptor AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) with some activity against kainite-induced receptor.

Compounds according to the invention is particularly effective as pharmaceuticals in the treatment of epilepsy, especially partial seizures (simple, complex and partial evolving to secondary generalized seizures) and generalized epileptic seizures [small epileptic pripad is a (typical and atypical), myoclonic, clonic, tonic, tonic-clonic and atonic].

Compounds according to the invention is particularly effective as pharmaceuticals in the treatment of psychosis in schizophrenia, bipolar violation, Parkinson's disease and induced by drugs psychosis, and improving positive and negative symptoms and is effective in the treatment of patients resistant to both drugs (cf ..Kalkman, E. GAD67: the link between GABA-deficit hypothesis and the dopaminergic and glutamatergic theories of psychosis. J. Neural. Transm. 2003, 1110, c.c.803-812).

In addition, the compounds according to the invention is suitable as pharmaceuticals for the treatment of any diseases, disorders or clinical condition, including mediated by AMPA receptor neural damage, such as neurodegenerative disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease or Alzheimer's disease, schizophrenia, especially chronic schizophrenia, anxiety, depression, bipolar mood disorders, sleep disorders, disorders of cognitive abilities, vomiting, tinnitus, pain, neuronally pain, migraine, tumor growth, symptoms of autism, ischemic and hypoxic conditions such as stroke, subarachnoid hemorrhage, perinatal hypoxia, brain injury and possono is nick, head injury, high intracranial pressure with any surgical procedure, potentially associated with hypoxia of the Central nervous system, and conditions caused by the actions of the environment, exogenous neurotoxins, including those caused by infections and those caused by metabolic changes and hepatoencepholopathy associated with liver failure.

For all these indications, the appropriate dosage will, of course, vary, depending, for example, by compounds according to the invention, the patient, the route of administration and the nature and severity to be processed States. However, in General, satisfactory results in animals, as shown, are obtained at daily dosages from about 0.1 to about 30 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 mg to about 2 g of compound according to the invention, it is convenient to introduce for example, in separate doses up to four times per day.

Active preparations according to the invention can be introduced by any conventional means, especially enterline, preferably orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions.

According to the aforementioned present invented the e provides compounds for use as pharmaceuticals, in particular, for use in treating any of the diseases, disorders or clinical condition, including the etiology of AMPA receptors or including mediated by AMPA receptors neuronale damage, and especially for use under any specific conditions listed above.

The present invention also provides a pharmaceutical composition that includes compounds in combination with at least one pharmaceutical carrier or diluent. Such compositions can be obtained in the usual way. Standard dosage forms contain, for example, from about 1 mg to about 400 mg of active agent according to the invention.

In addition, the present invention provides the use of compounds according to the invention for obtaining a medicinal product for the treatment of any diseases, disorders or clinical condition, including the etiology of AMPA receptors or including mediated by AMPA receptors neuronale damage.

Moreover, the present invention provides a method of treating any of the diseases, disorders or clinical condition, including the etiology of AMPA receptors or including mediated by AMPA receptors neuronale damage to the subject in need of such treatment, which includes an introduction to this subject a therapeutically effective what about the number of compounds according to the invention.

In addition, the compounds according to the invention can be combined with other drugs that are suitable for a variety of indications, for example, in the case of epilepsy with other anti-epileptic drugs, such as barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, suktinimida, valproic acid and other derivatives of fatty acids, other antagonists of AMPA. Compounds according to the invention can also be combined with antipsychotic drugs, selected from the list consisting of atypical antipsychotic drugs such as clozapine, olanzapine, risperidone and typical antipsychotics such as haloperidol.

This application discloses in an additional aspect, the use of compounds of formula (I) for the treatment of pathological States which are responsive to blockade of excitatory amino acid receptors, such as AMPA receptors, such as neurodegenerative disorders, stroke, epilepsy, anxiety, and pain.

Currently, it has been unexpectedly found that the compounds are also useful in the treatment of neuropathic pain.

Activity of compounds in the treatment of neuropathic pain is confirmed, for example, the following model of neuropathic pain in rats.

The Wistar rats were given General anesthesia with enflurane and made a small incision at the top of the middle one is edra, to highlight the sciatic nerve. The nerve was freed from connective tissue and silk suture thread was injected into the nerve, using a 3/8 curved surgical cutting mini-needle, and tightly ligated so that 1/3-1/2 of the back thickness of the nerve was kept inside ligatures. The muscle and the skin was closed with sutures and staples and wound sprinkled powder antibiotic. This procedure creates mechanical hyperalgesia that develops in the interval of 2-3 days and sustained for at least 4 weeks. Mechanical hyperalgesia is assessed by measuring thresholds twitching legs on one side (legirovannoi), and on the opposite side (religiouns) hind legs in response to the increasing impact of the stimulus applied to the foot using analgesiometer (Ugo-Basile) with a wedge-shaped probe (area of 1.75 mm2) and the interrupt threshold 250, the End point is taken as the first sign of pain response (resistance, beep or twitching paws). On hyperalgesia indicates the difference thresholds twitching on one side and the opposite side. The reversibility of established hyperalgesia using the introduced compounds measured 12-14 days after surgery using 6 animals per group processing. Thresholds twitching feet measured before the introduction is then up to 6 h after injection of the drug or excipient. Statistical analysis is performed in terms of threshold twitching, using analysis of variance ANOVA and then Tukey test plausible significant differences (HSD), comparing animals treated with the drug, and agreed on a time filler.

On this model the connection was largely paid neuropathic mechanical hyperalgesia at 10 mg/kg orally. With selected compounds of the formula (I) maximum treatment of neuropathic mechanical hyperalgesia 35% achieved within 3 h after injection of 10 mg/kg orally.

The activity of compounds of the formula I in the treatment of neuropathic pain can be confirmed in clinical trials, for example in the following study to assess the effectiveness of the compounds in the treatment of chronic pain in patients with diabetic neuropathy.

Patients randomizers in the ratio of 1:1 to receive 2400 mg/day of a compound or a placebo.

The study consists of a phase prior to randomization (1 week), and the double-blind phase (5 weeks). A double-blind phase consists of three periods: a one-week period of dose titration, a three-week period of maintenance therapy and one-week follow-up period.

During a one-week phase before randomization evaluated the suitability of patients. Patients who tocause criteria inclusion/exclusion of studies, was randomizirovannoe to obtain or compounds, or placebo in the double-blind phase of the study. During a 1 week period of dose titration study drug was titrated from 800 mg/day (twice a day) up to 2400 mg/day (twice a day). Patients who had completed a one-week period of dose titration, then went into a three-week period of maintenance therapy. Patients who completed the three-week period of maintenance therapy or prematurely stopped treatment double-blind method, then entered into a one-week follow-up period. A study destination medicines completely stopped or passed in the follow-up period. During the double-blind phase of the received serial evaluation of efficacy and safety.

Ambulatory patients, 120 men and women aged 18-65 years with a clinical diagnosis of diabetes (type I or type II) and a history of pain associated with diabetic neuropathy within 6 months to 3 years before entering the study, randomly distributed in the ratio of 1:1 to obtain compound or a placebo.

The total score of the brief pain McGill questionnaire (SF-MPQ) at the end of the period of maintenance therapy is used as the primary parameter of efficacy. Average weekly assessment of severity of pain (daily day the IR pain patient) from the start of randomized treatment until the end of the period of maintenance therapy, the use of "rescue" drug therapy during the period of dose titration and maintenance therapy, and the average assessment of the severity of pain during the follow-up period (recurrent pain) are used as secondary performance parameters.

Total pain score SF-MPQ at the end of the period of maintenance therapy is analyzed using the analysis of variance model, adjusted for the effect of processing on points after treatment using the baseline total pain score SF-MPQ as covariant. Weekly average pain severity analyzed using analysis of variance model with repeated measurements using weekly processing and the average severity of pain during the phase prior to randomization, as covariant. The use of "rescue" drug therapy during the double-blind phase is analyzed using control using the criterion of the Cochran-Mantel-Hansel for the center. The average severity of pain during the follow-up period (recurrent pain) is analyzed using the analysis of variance model, adjusted for the effect of treatment on the average severity of pain the follow-up period with average severity of pain during the period preceding randomize the AI, as covariant.

In this study, we found that the connection

N-{6-[(2-hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide,

N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide and

N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide

the most specific and statistically significantly lower rates of severity of pain relative to placebo during periods of maintenance therapy and follow-up.

Therefore, the compound suitable for the treatment of neuropathic pain and associated hyperalgesia, including trigeminal neuralgia and herpes, diabetic neuropathic pain, migraine, causalgia and deafferentation syndromes, such as avulse of the brachial plexus.

In a further aspect of the invention it has been unexpectedly found that the compounds suitable for the treatment of emotional disorders and disorders of attention.

Activity of compounds in the treatment of emotional disorders, including bipolar disorders, such as manic-depressive psychosis, extreme psychotic States such as mania, confirmed by, for example, in the following analyses, suitable for the determination of drugs that turn psychomotor stimulation is yousie effects.

Analysis 1: locomotion induced by antagonist of N-methyl-D-aspartate (NMDA)

Used male rats of Wistar Kyoto (Iffa Credo, Lion, France) weighing between 250 and 310, In principle formed 4 groups of treatment: 1) connection (doses of 1, 3 or 10 mg/kg), then the competitive NMDA receptor antagonist, (S)-2-amino-3-(2'-chloro-5-phosphonomethyl-3-yl)propionic acid, henceforth assuming your 220-581 (10 mg/kg), 2) pre-treatment solvent, then assuming your 220-581 (10 mg/kg), 3) solvent, accompanied by the solvent, 4) connection (1, 3, 10 mg/kg), then the solvent. Rats were randomly distributed across these groups pre-treatment (n=10/dose group). The drugs were injected subcutaneously 15 minutes before assuming your 220-581. Immediately after the animals were obtained assuming your 220-581, they were placed in the activity monitor for a period of 60 minutes Locomotor activity was analyzed during the first 30 minutes

The locomotion was recorded with videoslady system (VideoMot2, TSE Technical and Scientific Equipment GmbH, Bad Hombourg, Germany), using a digital camera with a closed circular reference (WV-BP.330/GE, Panasonic, Osaka, Japan). The video signal from the camera was translated into digital form and used for data analysis. The animals were housed under normal light cycle of 12 h day/12 h night light lit at 6 o'clock the Experiments were conducted in a dimly lit room between 7 h and 15 h, Animals were placed in a circular arena (diameter 42 cm, wysota cm), made from grey PVC plastic. The camera was placed so that the four animals (one in the arena) could be recorded simultaneously.

In this analysis, the compound (1-10 mg/kg subcutaneously) was not significantly alter locomotor activity compared to animals treated filler, at any time within a period of 30 minutes, However, a competitive antagonist of the NMDA receptor-assuming your 220-581 (10 mg/kg subcutaneously) induces a strong locomotor response. So, while control animals are approximately 8-10 m for 30 min, the animals treated assuming your 220-581, are approximately 30 meters This locomotor response decreases dose-dependent manner by means of connections. With selected compounds of the formula (I) (for example, when 10 mg/kg) effect of NMDA antagonist-assuming your 220-581 almost normal.

Analysis 2: channel blocker of the NMDA induces rocking and circling the head

Used adult male rats of Wistar Kyoto (340-380 g; Iffa Credo. Lyon, France). Animals were randomly distributed into the following groups treatment (n=10): connection (at a dose of 0.3 or 10 mg/kg), then phencyclidine (PCP; blocker of the NMDA channel at a dose of 0 or 10 mg/kg). Connection (at time t=-15 min) and PCP (at time t=0 min) was administered subcutaneously in a volume of 1 ml/kg of Videos of animal behavior during 0-30 min after RFA was evaluated in points by the observer, not knowing about the pre is the prior treatment of animals. Head nodding (repeated swinging of the head of at least 2 cm left and right) and spinning (turning around using the front paws, while his hind legs remained more or less on the source position was estimated in points as presence (1) or absence (0) of the effect every 5 min for the duration of 1 min. Scores for individual animals summarized and group scores were used for statistical analysis (t-test with correction of Bonferroni).

In this analysis, PCP (10 mg/kg subcutaneously) induced a weak shake of the head and circling. Pre-treatment compounds (3 and 10 mg/kg subcutaneously) was greatly enhanced these behavioral reactions to PCP (p<0,05).

Induced by the NMDA antagonist locomotor responses reflect a state similar mania. Blockade of this activity indicates antigenically activity. In addition, the strengthening of the swing head and whirling involves behavioral disinhibition (anxioliticeski-/antidepressantsattorney) and azeotroping activity. Therefore, the compounds useful in the treatment of emotional disorders, including bipolar disorders, such as manic-depressive psychosis, extreme psychotic States such as mania and excessive mood swings where desirable behavioral stabilization. In addition to the CSO, connections shown disorders attention deficit and hyperresponsiveness (ADHD) and other violations of attention, such as autism, States of fear, generalized fear and agoraphobia, as well as with those behavioral States, which are characterized by social syndrome, such as negative symptoms.

In a further aspect of the present invention it has been unexpectedly found that the compounds are also suitable in the treatment of schizophrenia and other psychosis symptoms in other cases, such as Parkinson's disease.

Antihistaminics activity of the compounds shown in standard tests, for example in the analysis of amphetamine-induced hyperlocomotion. Blockade induced by amphetamine of hyperlocomotion well known as a screening paradigm for antihistaminics activity.

Used male Wistar rats (Iffa Credo, Lion, France) weighing between 215 and 315, In principle formed 4 groups of treatment: 1) connection (doses of 1, 3 or 10 mg/kg), followed by amphetamine (1 mg/kg), 2) pre-treatment solvent, then amphetamine (1 mg/kg), 3) solvent, accompanied by the solvent, 4) compound (10 mg/kg), then the solvent. Rats were randomly distributed across these groups pre-treatment (n=10/dose group). The drugs were injected subcutaneously 15 minutes before amphetamine. Direct Politova, as animals received amphetamine, they were placed in the activity monitor for a period of 60 minutes Locomotor activity was analyzed during the first 30 minutes

The locomotion was recorded with videoslady system (VideoMot2, TSE Technical and Scientific Equipment GmbH, Bad Hombourg, Germany), using a digital camera with a closed circular reference (WV-BP.330/GE, Panasonic, Osaka, Japan). The video signal from the camera was translated into digital form and used for data analysis. The animals were housed under normal light cycle of 12 h day/12 h night light lit at 6 o'clock the Experiments were conducted in a dimly lit room between 7 h and 15 h, Animals were placed in a circular arena (diameter 42 cm, height 32 cm), made of gray PVC plastic. The camera was placed so that the four animals (one in the arena) could be recorded simultaneously.

Amphetamine was dissolved in saline at a concentration of 1 mg/ml and was injected subcutaneously in a volume of 1 ml/kg of the Compound was dissolved in a few drops of sodium hydroxide solution (0.1 N.) and then diluted in saline solution, as required, to obtain solutions with concentrations of 10, 3 and 1 mg/ml was injected subcutaneously in a volume of 1 ml/kg

Comparison between groups was performed using t-test, t-test, adjusted for multiple analyses using procedures Bonferroni.

In this and the Alize the compounds of formula (I) reduced amphetamine-induced the locomotion in doses of about 1 mg/kg to about 10 mg/kg subcutaneously.

In another additional aspect of the invention it was unexpectedly found that the compounds can be used in the treatment of tinnitus.

The effect of compounds on the activity of tinnitus shown in standard tests, for example, on the model of tinnitus induced by salicylate.

It was shown [Saheeh and others, Hearing Research 147 (2000) SS-182]that chronic exposure to salicylate causes in the lower mound (IC) rats sverhregulyatsiyu expression of glutamic acid decarboxylase (GAD)is associated with the development of tinnitus. Moreover, electrophysiological registration of neurons of the auditory nerve using the method of fixation potential [D.Peruzzi and others, Neuroscience, 101 (2000) SS-416, X.Lin, and others, Journal of Neurophysiology, 79 (1998) c.c.2503-2512] and registration of single neuron [J.J.Eggermont and .Kenmochi, Hearing Research, 117 (1998) SS-160]showed that neuronal excitability changes after treatment with salicylate and quinine.

Introduction salicylate or quinine caused an increase in the share of working neurons of the auditory nerve, measured using the technique of extracellular electrophysiological registration. Using in vitro electrophysiological recording techniques hypothermia with salicylate increases the excitability of the recorded neurons. With the introduction of compounds in concentrations from about 1 nm to 100 μm, the effects of salicylate turn.

For the treatment of the Oia, the above-mentioned indications, the appropriate dosage will, of course, to change, for example, depending on the connection of the patient, the route of administration and the nature and severity of the condition to be treated. However, in General, satisfactory results in animals, as indicated, are obtained at a daily dosage of from about 1 mg/kg to about 50 mg/kg of body weight. In larger mammals, for example humans, shows the daily dose is in the range from about 10 mg to about 1000 mg of the compounds according to the invention, it is convenient to introduce for example, in separate doses up to four times per day.

In a further aspect of the present invention it has been unexpectedly found that the compounds suitable for the treatment of myopia and other eye disorders.

Such violations include, but without limitation, associated with age-related macular degeneration, diabetic retinopathy, cestoidea macular Eden (CME), pathological myopia, hereditary optic neuropathy Leber's, pigmentary pigmentosa and other inherited retinal degeneration.

Activity of compounds against myopia shown in standard tests, for example, on the model according R.A.Stone and others [Proc. Natl. Acad. Sci. (USA) 86, SS-706 (1989)], where experimental myopia is on the Chicks with the introduction of from about 0.1 mg/kg to about 1 mg/kg in eye drops.

Efficiency described in the audience who's violations could be installed on the following animal models.

1) Spontaneous development of secondary forms of glaucoma (e.g., pigment dispersion, angle-closure glaucoma or angular dysgenesia) in mice (for example, but not limited to, strains DBA/2J DBA/2Nnia and mouse AKXD28/Ty, as described by Anderson and others, Navy Genetics, 2001; 2:1, Chang and others, Nature Genetics, 1999; 21:405-409, John and others, Invest. Ophthalmol. Vis. Sci., 1998; 39:951-962, Sheldon and others, Lab. Animal Sci., 1995; 15:508-518).

2) Genetic animal model for retinal degeneration, such as a mouse

with retinal degeneration (rd) (as described by Li and others, Invest. Ophthalmol. Vis. Sci., 2001; 42:2981-2989), Rpe65-deficient mice (Van Hooser and others, PNAS, 2000; 97: 8623-8628), the RCS rat (Faktorovich and other, Nature 1990; 347:83-86), mouse slow retinal degeneration (rds) (Ali and others, Nature Genetics, 2000, 25:306-310), the dog with degeneration of type 1 retinal cells (rcd1) (Suber and others, PNAS, 1993; 90:3968-3972).

3) Experimental retinal degeneration induced:

- light exposures in mice (as described by Wenzel and others, Invest. Ophthalmol. Vis. Sci., 2001; 42:1653-1659) or rats (Faktorovich, etc., J. Neurosci, 1992; 12:3554-3567),

- the introduction of N-methyl-N-nitrosoanatabine (kiuchi's etc., Exp. Eye Res., 2002, 74:383-392) or sodium Iodate (Sorsby and Harding, Vision Res., 1962, 2:139-148).

4) Experimental model of the optic nerve (ON):

by crushing the optic nerve in mice ((Levkovitch-Verbin and others, Invest. Ophthalmol. Vis. Sci., 2000, 41:4169-4174) and rats (Yoles and Schwartz, Exp. Neurol., 1998, 153:1-7),

- by dissection of the optic nerve in rats (as described by Martin and others, Inest. Ophthalmol. Vis. Sci., 2002, 43:2236-2243, Solomon and others, J. Neurosci. Methods, 1996, 70:21-25),

through experimental temporary (acute) retinal ischemia in rats after stitching the eye of the vessel (as described by Lafuente et al., Invest. Ophthalmol. Vis. Sci., 2001, 42:2074-2084) or kanalirovaniya front camera (Buchi, etc., Ophthalmologica, 1991, 203:138-147),

by intraocular injection of endothelin-1 in rats (Stokely and others, Invest. Ophthalmol. Vis. Sci., 2002, 43:3223-3230) or rabbits (Takei and others, Graefes Arch. Clin. Exp.Ophthalmol., 1993, 231:476-481).

For treatment of myopia and other eye disorders appropriate dose, of course, will depend, for example, connections in use, the patient, the route of administration and the nature and severity of myopia. However, in General, it is shown that satisfactory results in animals are obtained at a daily dosage of from about 0.01 mg/kg to about 1 mg/kg animal body weight. In larger mammals, for example humans, shows the daily dose is in the range from about 0.25 mg to about 10 mg of the compounds according to the invention, is conveniently introduced, for example, in separate doses up to four times per day.

For the above indications compounds may be entered in any conventional manner, for example orally, for example in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions.

For the treatment of myopia and other vision impairments compounds may be centuries is found locally in the eye or around the eye, for example, in the form of eye drops, ophthalmic suspensions or ointments, subconjunctival, peribulbar, retro-bulbar or intravitreal injection, possibly with the use of slow release devices such as conjunctival inserts, microspheres or other periocular or intraocular depot-fixture.

The compounds are preferably applied in the eye approximately in the form of 0.002% to about 0.02% of ophthalmic solutions. Filler eye medication is such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal eye area. Pharmaceutically acceptable excipients for ocular drug can be, for example, ointment, vegetable oil, or encapsulating material.

Such compounds to treat the aforementioned conditions include

N-{6-[(2-hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide,

N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,

N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide

and their pharmaceutically acceptable salts.

The present invention also provides pharmaceutical preparations is practical composition, comprising the compound of formula (I) in combination with at least one pharmaceutical carrier or diluent, for use in the treatment of neuropathic pain, emotional disorders, and disorders of attention, schizophrenia, tinnitus, myopia and other eye disorders. Such compositions can be obtained in the conventional way. Standard dosage forms for the treatment of neuropathic pain, emotional disorders, and disorders of attention, schizophrenia, tinnitus can contain, for example, from about 2.5 mg to about 500 mg of the compounds of formula (I). Standard dosage forms for the treatment of myopia and other vision disorders can include, for example, from about 0.05 mg to about 5 mg of the compounds of formula (I).

The invention also provides the use of compounds of formula (I) to obtain a pharmaceutical composition for the prevention, treatment or delay of progression of neuropathic pain, emotional disorders, and disorders of attention, schizophrenia, tinnitus, myopia and other eye disorders.

Moreover, the invention provides a method for the prevention, treatment or delay of progression of neuropathic pain, emotional disorders or attention, schizophrenia, tinnitus, myopia and other eye disease of the subject, under easigo such treatment, the method, which includes the introduction referred to the subject a therapeutically effective amount of the compounds of formula (I).

In a further aspect the present time it has been unexpectedly found that the compounds can be used in the treatment of multiple sclerosis and related diseases associated with demyelination, such as neuromyelitis optic nerve.

Activity of compounds in the treatment of multiple sclerosis confirmed by, for example, the following model of experimental autoimmune encephalomyelitis (EAE), the primary animal model for symptom of multiple sclerosis (MS), autoimmune diseases of the Central nervous system.

Female rats Dark Agouti (DA-rats) contain in a room with controlled climate at 12-hour cycle of light/dark is placed in full of sawdust cells 4-5 rats per cage and receiving standard food for rodents and water at the discretion of the contractor. Severely paralyzed animals specially provides an easier approach to forage and water. Rats given at least one week to adapt to their surroundings, then they randomly divided into experimental group (10 rats per group) and receive individual digital label on the tail. The age of the rats is 8-9 weeks (approximately 135 g) during immunization in den is 0. For optimal induction of experimental autoimmune encephalomyelitis (EAE) for immunization procedures used freshly isolated brain and spinal cord (the ratio of 40:60) from adult-DA rats as a source of syngeneic encephalitogenic of neuroantigen. Samples of tissue from the Central nervous system (CNS), also called as DA-b/sc, stored in Eppendorf tubes at -70°C until needed.

Rats receive light anaesthesia with isoflurane and are immunized with a single intradermal (i.d.) injections in the dorsal part of the tail with 200 μl of inoculum containing 1 part (volume:volume) CNS tissue emulsified in an appropriate diluent to 1 part incomplete adjuvant's adjuvant (IFA), supplemented by a strain of Mycobacterium tuberculosis H37RA (Difco, Detroit, MI). The mixture IFA-Mycobacterium below indicated CFA (complete beta-blockers). More specifically, DA-b/sc emulsify in the syringe And containing 0.9% NaCl, using a homogenizer transmitter station PT 3100 (Kinematica, Lucerne, Switzerland) at 28000 rpm for about 3 minutes, the Emulsion of the antigen gradually added to the CFA in syringe B" as homogenization. All solutions are on the ice, and they were not allowed to overheat with high speed mixing.

Additional control animals were injected with one complete Freud's adjuvant (CFA) (1.6 mg M. tuberculosis in the rat) and treated filler. Animal is x in the other experimental groups were injected with the emulsion neuroantigen-CFA (65 mg DA-b/sc 1.6 mg of mycobacteria in the rat) and was treated with a single filler or filler, containing the analyzed compound. The study usually ends at day 63, nine weeks after immunization on day 0.

Clinical scoring of experimental autoimmune encephalomyelitis (EAE)

Animals were examined daily for neurological symptoms and change in body mass. Clinical degree EAE is measured using the scale of the disease from 0 to 4:

0 - no disease,

1 - complete loss of tail tone,

2 - the weakness of the hind limbs (extremities) or ataxia,

3 - complete paralysis or both rear limbs, or legs,

4 is a lethal condition with paralysis of both fore limbs and hind limbs; (deaths associated with the disease).

Scores of 3-4 were often accompanied by urinary incontinence. Mortality associated with EAE, recorded the maximum score of 4. Other recorded data include the day of the beginning EAE and % of cases in the group.

The use of connections: connections are accepted within 14 to 21 days, starting from day 0 (preventive treatment) or day 12 after immunization (therapeutic treatment). The connections twice a day or three times a day and was administered orally, intraperitoneally or subcutaneously.

Statistical analysis: because the severity of disease and duration - both are the camping key parameters for consideration in the study of drug clinical scores are analyzed as area under the curve (AUC) points in time.

In this model, EAE 10-20% of the immunized antigen control animals may be killed for reasons related to the disease. To explain this important information in the statistical analysis it was used the method of Gould (A.L.Gould. A new approach to the analysis of clinical drug trials with withdrawals. Biometrics, 1980; 36:721-727). Animals in each group were classified according to their AUC value (increased severity of the disease). Dead rats were positioned in accordance with the time of their death, thereby giving them a higher score than the survivors. Assessments were compared using the nonparametric Wilcoxon and Mann-Whitney. The confidence factor p≤0.05 is considered statistically significant.

In this model, compounds reduce the severity of symptoms of EAE. For selected compounds of formula (I) effect occurs when 2×10 mg/kg intraperitoneally.

Such compounds for the treatment of multiple sclerosis:

N-{6-[(2-hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide,

N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,

N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide

and their pharmaceutically acceptable salts.

Present from Britanie also provides pharmaceutical compositions comprising the compound of formula (I) in combination with at least one pharmaceutical carrier or diluent for use in the treatment of multiple sclerosis and related diseases associated with demyelinating, such as neuromyelitis optic nerve. Such compositions can be obtained in the conventional way. Standard dosage forms for the treatment of multiple sclerosis and related demyelination diseases such as neuromyelitis optic nerve may contain, for example, from about 2.5 mg to about 500 mg of the compounds of formula (I).

The invention also provides the use of compounds of formula (I) to obtain a pharmaceutical composition for the prevention, treatment or delay of progression of multiple sclerosis or associated with demyelination diseases such as neuromyelitis optic nerve.

Moreover, the invention provides a method for prevention, treatment or delay of progression of multiple sclerosis and related demyelination diseases such as neuromyelitis optic nerve in a patient in need of such treatment, the method which comprises introducing said patient a therapeutically effective amount of the compounds of formula (I).

In a further aspect the present invention relates to a method and to connect enum for the treatment of dementia.

It has been unexpectedly found that dementia can be treated by introducing receptor antagonist α-amino-3-hydroxy-5-methylpropionic acid (AMPA). Therefore, the present invention relates to a method of treatment and/or prevention of dementia, including an introduction warm-blooded animal, including man, in need, an effective amount of an antagonist of the AMPA receptor.

The term "AMPA receptor antagonist," as it is used in context, refers to compounds of the formula (I).

Particularly suitable compounds for the treatment of dementia are:

N-{6-[(2-hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide,

N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,

N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide

and their pharmaceutically acceptable salts.

The term "dementia"as it is used in a context that includes, but without limitation, dementia Alzheimer's disease with psychotic symptoms or without them. In particular, the methods and compounds described in the context suitable for the treatment of behavioral disorders observed in these types of symptoms.

It will be clear that when discussing ways to reference the active ingredients imply the inclusion pharmaceutically is active salts. If the data of the active ingredients are, for example, at least one basic center, they can form acid additive salt. The corresponding acid additive salts may also be formed having optionally present basically the center. Active ingredients having an acid group (for example COOH)can also form salts with bases. The active ingredient or its pharmaceutically acceptable salt can also be used in the form of hydrates or include other solvents used for crystallization.

The pharmacological activity of the compounds of formula (I) may be, for example, demonstrated in a clinical study. Such clinical trials are preferably randomized, conducted double-blind method clinical studies of patients with Alzheimer's disease. Beneficial effects on Alzheimer's disease can be determined directly through the results of these studies or by changes in planning studies, which are as such well-known specialist in this field.

One purpose of this invention is the provision of a pharmaceutical composition comprising a quantity that is therapeutically effective against dementia, composition, comprising what about the at least one AMPA receptor antagonist and at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention may be obtained generally accepted as fact by the way and those suitable for enteral administration, such as oral or rectal, and parenteral administration mammals (warm-blooded animals), including humans, the method comprising therapeutically effective amount of at least one pharmacologically active ingredient, one or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. The preferred route of administration dosage form of the present invention is oral.

New pharmaceutical compositions contain, for example, from about 10% to about 100%, preferably from about 20% to about 60% of the active ingredients. Pharmaceutical preparations for the treatment for enteral or parenteral administration are, for example, drugs in standard dosage forms, such as tablets coated with sugar coating of tablets, capsules or suppositories, and also ampoules. Unless otherwise noted, they are generally accepted as fact by the way, for example by conventional mixing, granulation, coating sugar coating, dilution and freeze-drying. It will be recognized that the standard Dol the active ingredient or ingredients, contained in an individual dose of each dosage form itself is optional effective amount since the necessary effective amount can be achieved by introducing multiple dosed shares.

In preparing the compositions for oral dosage forms may be used any conventional media, such as, for example, water, glycols, oils or alcohols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating drugs, lubricants, binders drugs, dezintegriruetsja drugs and the like in the case of oral solid preparations such as powders, capsules and tablets. Because of the ease of introduction of tablets and capsules represent the most favorable standard oral dosage form, in which case, of course, are for solid pharmaceutical carriers.

Moreover, the present invention relates to the use of compounds of formula (I) for drugs for treatment of dementia.

Additionally, the present invention provides a method of treating warm-blooded animals with dementia, including the introduction of animal compounds of formula (I) in an amount which combined therapeutically effective against dementia and in which the compounds can also risedronate in the form of their pharmaceutically acceptable salts.

The effective dose of each active ingredient used in the compound of formula (I)may vary depending on the specific compounds or used in the pharmaceutical composition, the method of administration, the severity of the condition to be treated. So, dose mode of the compounds of formula (I) is selected according to various factors, including route of administration and the kidneys and liver of the patient. A physician, Clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the same active ingredient that is required to prevent, counter or arrest the progression of the condition. Optimal precision in achieving concentration of active ingredients in the range that provides efficacy without toxicity requires a regime based on the kinetics of the availability of the active ingredients to the target. This includes consideration of the distribution, equilibrium, and delete the active ingredients from the body.

The invention is illustrated, but without limitation, the following examples.

Working examples

Abbreviations:

CNQX7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-carbonitrile,
DMSO dimethyl sulfoxide,
HVhigh vacuum,
HEPES4-(2-hydroxyethyl)piperazine-1-econsultancy acid,
HPLCHigh performance liquid chromatography
IRinfrared spectroscopy
tPLthe melting point
GHSDliquid chromatography medium pressure
PFreversed phase
SPLthe sound pressure level
TFKtriperoxonane acid,
TLCthin-layer chromatography.

Example 1

N-(6-Imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A solution of 15 ml of phosgene in toluene (20%) was added dropwise to a suspension of 1 g of methyl ester of 2-amino-5-fluoro-4-nitrobenzoic acid in 20 ml of anhydrous toluene at -15°C. was Introduced slow current of the phosgene and the reaction is mesh was heated to boiling. After 45 min of argon was blown yellow solution and the solvent drove away, thus obtaining 1.1 g of methyl ester of 5-fluoro-2-isocyanato-4-nitrobenzoic acid in a solid yellow color, pure enough for use in the next stage. IR (CHCl3): 2240 cm-1.

To a solution of 1.1 g (4,58 mmole) of methyl ester of 5-fluoro-2-isocyanato-4-nitrobenzoic acid in 20 ml of anhydrous tetrahydrofuran was added 0,504 g (4,58 mmole) methysulfonylmethane in 7 ml of anhydrous tetrahydrofuran. The resulting suspension was stirred for 1 h, then was treated 4,58 ml of 1 M sodium hydroxide solution and stirred for 3.5 hours After acidification of 5.7 ml of 2 M HCl solution and the mixture was concentrated until the sediment was filtered and the residue washed with water and recrystallized from tetrahydrofuran, getting 0,774 g specified in the connection header in the form of a powder beige tPL240-255°C (decomp.).

A mixture of 530 mg (1,665 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 567 mg (8,325 mmole) of imidazole and 7.7 ml of anhydrous 1,3-imidazolidinone was heated at 140°C. (oil bath temperature) for 90 min in a closed vessel. After cooling, the dark solution was poured into 130 ml of water and brought the pH to ~5 added the eat 2 M acetic acid. Formed precipitate was separated by filtration and recrystallized four times from a mixture of dimethyl sulfoxide/water, receiving 214 mg specified in the connection header in the form of a powder red, tPL>270°C.

Example 2

N-[6-(4-Hydroxymethylimidazole-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 100 mg (0,314 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 333 mg (1.57 in mmole) of 4-(tert-butultimately-silyloxy)-1H-imidazole and 1 ml of anhydrous 1,3-dimethyl-2-imidazolidinone was heated at 140°C. (oil bath temperature) in a closed vessel for 4 hours After cooling, the orange solution was diluted with ethyl acetate and the organic phase is washed with water and saturated saline and dried over sodium sulfate. Evaporation of the solvent gave an oil which was purified by medium pressure chromatography on silica gel with a mixture of ethyl acetate/acetic acid (98:2) as eluent, receiving 53 mg of N-{6-[4-(tert-butyldimethylsilyloxy)-imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide, tPL>270°C.

A mixture of 1 g (a 1.96 mmole) of N-{6-[4-(tert-butyldimethylsilyloxy)-imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide, 0,738 g (2,34 mmole) of frigid the ATA tetrabutylammonium and 20 ml of tetrahydrofuran was stirred at 50°C for 18 hours The reaction mixture was concentrated to dryness and the residue was fractionally by medium pressure chromatography on a column of reversed phase RP-C18 (sorbent 20 μm) with a mixture of acetonitrile/water (1:1) as eluent. The residue obtained by evaporation of the fractions 2-5, was dissolved in water and brought the pH to ~5 with dilute ammonium hydroxide solution. The product was besieged and was separated by filtration. The residue obtained from fractions 6-13, fractionally by medium pressure chromatography on a column of RP-C18 (sorbent 20 μm) with a mixture of acetonitrile/water (1:2) as eluent. During concentration, the product was precipitated and collected by filtration. Crystallization of all of the combined product fractions from a mixture of dimethyl sulfoxide/water gave 0,328 g of N-[6-(4-hydroxymethylimidazole-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in the form of a yellow powder, tPL>300°C.

Example 3

N-(6-Morpholine-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A mixture of 100 mg (0,314 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and 0,274 ml (3,14 mmole) of the research was heated at 140°C. (oil bath temperature) for 1 h in a closed vessel. After cooling, the residue was dissolved in water, the solution was acidified with 2 M acetic acid to pH~5 and left at room temperature. Education which was avivasa orange precipitate, which was separated by filtration and recrystallized from a mixture of dimethyl sulfoxide/water, receiving 81 mg specified in the connection header in the form of a powder orange, tPL>260°C.

Example 4

N-(6-Dimethylamino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A mixture of 100 mg (0,314 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and 0,185 ml (0,925 mmole) of dimethylamine (33% in ethanol) in a closed vessel was heated in a microwave reactor at 150°C for 15 minutes After cooling, the reaction mixture was concentrated to dryness and the residue was led from a mixture of tetrahydrofuran/water, receiving 90 mg specified in the connection header in the form of a powder orange, tPL245-260°C (decomp.).

Example 5

N-[6-(2-Hydroxy-1-hydroxyethylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 100 mg (0,314 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and 142 mg (1,55 mmole) of 2-amino-1,3-propane diol in a closed vessel was heated in a microwave reactor at 150°C for 20 min. After cooling, the reaction mixture was concentrated to dryness and the product was purified HPLC column reversed-phase RP-C18, using as eluent a gradient of water/acetonitrile/0.1% of triperoxonane Isleta. Received 35 mg specified in the connection header in the form of a powder red, tPL126-145°C (decomp.).

In a manner analogous to that described in the previous example, received the following connection.

Example 6

N-[6-(2-Hydroxy-2-thiophene-2-ylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

Powder, red, tPL110°C (decomp.).

Example 7

N-[7-Nitro-2,4-dioxo-6-(2,2,2-triptoreline)-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 200 mg (0,628 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and 1.08 ml (13,68 mmole) of 2,2,2-triptorelin in a closed vessel was heated in a microwave reactor at 140°C for 20 hours After cooling, the reaction mixture was distributed between ethyl acetate and water, the organic phase was dried and concentrated, obtaining a residue, which was separated by filtration and subjected to purification by medium pressure chromatography on a column of reversed phase RP-C18 (sorbent 20 μm) with a mixture of tetrahydrofuran/water (4:3) as eluent, containing 0.1% triperoxonane acid. During concentration of the product fractions were precipitated, was collected by filtration, receiving 63 mg powder red, tPL250°C (decomp.).

Example 8

N-(6-Amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-IU is unsulfonated:

To the yellow solution of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (500 mg, of 1.57 mmole) in ethanol (0.5 ml) was added 2,4-dimethoxybenzene (4.72 in ml, of 31.4 mmole) in argon atmosphere. The solution was heated at 150°C in a closed vessel in a microwave reactor for 4 minutes After removal of the solvent and 2,4-dimethoxyaniline by evaporation in high vacuum on a rotary evaporator, the remaining oil intense purple color was treated with diethyl ether to obtain a suspension, which was filtered, the precipitate was dried, obtaining mentioned in the crude title compound in the form of solids intense purple color, tPL232-237°C.

To a solution of N-[6-(2,4-dimethoxyaniline)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide (725 mg, and 1.56 mmole) in dichloromethane (4 ml) was added triperoxonane acid (0.5 ml) and the mixture was stirred at room temperature for 30 minutes Then the solvent was removed by evaporation on a rotary evaporator, getting a solid orange color, which is suspended in diethyl ether, filtered and the residue washed three times with diethyl ether and twice with ethyl acetate, receiving specified in the title compound in the form of a pure solid orange, tPL 326-335°C (decomp.).

Example 9

N-(7-Nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (90 mg, 0,285 mmole) and 2,5-dimethoxytetrahydrofuran (0,038 ml, 0,291 mmole) in acetic acid (0.5 ml) was heated at boiling for 80 minutes the resulting suspension was filtered and the precipitate washed with ethyl acetate. The filtrate was concentrated in vacuum, obtaining a solid brown color, which is suspended in diethyl ether and filtered, obtaining a solid brownish-orange color as desired pure product, tPL243-250°C.

Example 10

N-[6-(3-Formylphenol-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (470 mg, 1,49 mmole) and 2,5-dimethoxytetrahydrofuran-3-aldehyde (796 mg, 4,47 mmole) in acetic acid (0.5 ml) was heated at boiling for 5 hours the Solvent was removed by evaporation on a rotary evaporator, obtaining a brown oil, which was dissolved in ethyl acetate and washed three times with water. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed by evaporation on a rotary evaporator, the of learn almost pure compound, specified in the header, in the form of a solid brown, tPL230-245°C (decomp.).

Example 11

N-[6-(3-Hydroxymethylfurfural-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a solution of N-[6-(3-formylphenol-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide (580 mg, about 1.47 mmole, crude from previous step) in methanol (5 ml) was added sodium borohydride (112 mg, 2,95 mmole) at 0°C and left to mix for 30 minutes was Added a small amount of acetic acid to destroy excess sodium borohydride. The reaction mixture was diluted with ethyl acetate and washed twice with water, and the organic solvent layer was removed by evaporation on a rotary evaporator, getting oil red-brown color, which was purified flash chromatography with a mixture of dichloromethane/methanol 98:2 to 95:5, receiving specified in the title compound in the form of solid orange, tPL260-270°C (decomp.).

Example 12

N-[6-(2-Methoxy-1-methylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 200 mg (to 0.63 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, with 0.27 ml of 2.51 mmole) of 2-methoxy-1-methylethylamine and 3 ml of ethanol was heated at 150°C in a closed vessel in a microwave the reactor for 15 minutes After cooling to room temperature was added 1 M aqueous christoforidou acid until then, until it reached pH 5-6. The resulting suspension was filtered, the precipitate washed with water and dried at 60°C. Crystallization from a mixture of ether-hexane gave 82 mg (34%) indicated in the title compound as red crystals, tPL103-111°C.

Example 13

N-[6-(2-Benzyloxyaniline)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 318 mg (1 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 605 mg (4.0 mmole) of 2-benzyloxyaniline and 3.2 ml of ethanol was heated at 120°C in a closed vessel in a microwave reactor for 10 minutes After cooling to room temperature was added 1 M aqueous hydrochloric acid until then, until the pH value has not reached ~3. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, washed with water and saturated saline solution, dried over magnesium sulfate and evaporated. Chromatography of the residue on silica with elution with a mixture of dichloromethane-methanol (93:7) and crystallization from a mixture of tetrahydrofuran-hexane gave 261 mg (58%) indicated in the title compound as red crystals, tPL204°C (decomp.).

Example 14

N-(6-Cyclopentyl the Mino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A mixture of 140 mg of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 0.17 ml (1,76 mmole) of cyclopentylamine and 3 ml of ethanol was heated at 150°C in a closed vessel in a microwave reactor for 5 min After cooling to room temperature, water was added and the resulting suspension was filtered. To the filtrate was added concentrated aqueous hydrochloric acid until then, until the pH value has not reached 2-3, and the formed suspension was filtered. The residue was led from a mixture of ether-hexane, receiving 52 mg (31%) indicated in the title compound as red crystals, tPL146-155°C.

Example 15

N-(6-Methoxy-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

Added to 2.06 ml (4,12 mmole) of 2 M solution of desmethylselegiline in hexane at low cooling at 20°C to a solution of 1.0 g (4,13 mmole) of 2-acetylamino-5-fluoro-4-nitrobenzoic acid in 15 ml of methanol and 35 ml of benzene. Analysis by HPLC after 15 min showed that there is about 50% of the source material. Added additional 2.4 ml (4.8 mmole) of desmethylselegiline. After standing for about 16 hours no starting material could not be determined using HPLC. Was added 0.5 ml of glacial acetic acid and the reaction see what camping was evaporated to dryness. Was added toluene and the mixture is again evaporated. The resulting residue was dissolved in boiling ethyl acetate, hexane was added, the formed crystals were separated by filtration, washed with hexane and dried at about 0.01 mm Hg and 50°C receives 912 mg (86%) of methyl ester of 2-acetylamino-5-fluoro-4-nitrobenzoic acid, tPL124-126°C.

Dissolved 256 mg (1.0 mmol) of methyl ester of 2-acetylamino-5-fluoro-4-nitrobenzoic acid 5.1 ml of boiling absolute methanol and cooled to 23°C, thus a number of substances precrystallization. Was added 81 mg (1.5 mmole) of sodium methylate and the mixture was stirred in an argon atmosphere for 16 hours was Added acetic acid until then, until the pH value reached 5, the resulting mixture was distributed between ethyl acetate and water, the organic phase was separated, washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated. The residue was chromatographically on 100 g of silica gel (0.04 to 063 mm), elwira a mixture of toluene-ethyl acetate (3:1), the volume fractions of 12 ml Fractions 37-46 were combined and evaporated, receiving 77 mg (28%) of methyl ester of 2-acetylamino-5-methoxy-4-nitrobenzoic acid in the form of yellowish crystals, tPL141-143°C.

Was added dropwise to 0.12 ml of 98% with the nuclear biological chemical (NBC acid at 0° (exothermic reaction) to a suspension of 69 mg (0,257 mmole) of methyl ester of 2-acetylamino-5-methoxy-4-nitrobenzoic acid, 0,69 ml of methanol and 0.12 ml of water. Then the mixture was heated at 70°C for 30 min, cooled to room temperature, poured into a mixture of ice, water and ethyl acetate and brought the pH to 6 with concentrated solution of potassium bicarbonate. The organic phase was separated, washed with saturated saline solution, dried over sodium sulfate, filtered and evaporated, receiving 46 mg (79%) of methyl ester of 2-amino-5-methoxy-4-nitrobenzoic acid in the form of crystals red-brown, tPL127-129°C.

Was added dropwise 0.5 ml of a solution of phosgene in toluene (20%) to a suspension of 35 mg (0,155 mmole) methyl ester 2-amino-5-methoxy-4-nitrobenzoic acid in toluene at -15°C. the Mixture was allowed to warm to room temperature over 1 h and then heated at boiling. After 45 min of argon was blown through the boiling yellow solution for 30 min and for 2 h at room temperature. The reaction mixture was evaporated and the residue was dried at room temperature and a pressure of 9 mbar for 1 h, which resulted in 45 mg of the crude methyl ester 2-isocyanato-5-methoxy-4-nitrobenzoic acid. Added 43 mg of the substance in 0,91 ml of absolute tetrahydrofuran, was added 17 mg methysulfonylmethane and the suspension was stirred at room temperature for 1 h was Added 1.0 ml of absolute then it is carbonated is rufuran and of 0.045 ml base Hunga and continued stirring at room temperature for 18 hours The reaction mixture was evaporated, the residue was dissolved in a mixture of water and ethyl acetate and the aqueous layer was brought to pH~2 with the addition of 1 M aqueous hydrochloric acid. The organic phase was separated, washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated. The resulting substance was led out of tetrahydrofuran, was added 2 ml of toluene and 0.02 ml of base Chunga and the mixture was heated at boiling for 3 hours, the Reaction mixture was evaporated, was added 1 ml water and the pH was brought to 1 by addition of 1 N. aqueous hydrochloric acid. The suspension was stirred at room temperature for 1 h, then filtered and the residue washed with water. The remaining crystals were dissolved in boiling tetrahydrofuran, was added pentane, the resulting crystals were separated by filtration and dried in vacuum at 100°C, receiving 7 mg (13%) of N-(6-methoxy-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of crystals in a light beige color, tPL>280°C.

Example 16

N-[6-(4-Bromoimidazo-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

A mixture of 20 mg (0,062 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 56 mg (0,372 mmole) of 4-bromo-1H-imidazole and 0.1 ml of dimethyl sulfoxide was heated at 120°C is for 16 PM After cooling to room temperature the reaction mixture was distributed between ethyl acetate and water, the organic phase was separated, washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel using a mixture of dichloromethane-methanol (95:5), and the fractions containing the desired product were combined and evaporated, receiving 6 mg (21%) specified in the connection header. MS (electrospray ionization (ES), m/e): 445 (M+).

Example 17

N-[7-Nitro-2,4-dioxo-6-(4-phenylimidazol-1-yl)-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A mixture of 50 mg (0,156 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 139 mg (0,936 mmole) of 4-phenyl-1H-imidazole and 0.25 ml of dimethyl sulfoxide was heated at 120°C for 3.5 h, After cooling to room temperature the reaction mixture was distributed between ethyl acetate and water, the organic phase was separated, washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel using a mixture of tetrahydrofuran-hexane (80:20), and the fractions containing the desired product were combined and evaporated, receiving 53 mg (77%) specified in the connection header. MC(ES, m/e): 441 (M-1).

Example 18

N-{6-[4-(4-Methoxyphenyl)and idazole-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

A mixture of 75 mg (0,233 mmole) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 209 mg (1,165 mmole) of 4-(4-methoxyphenyl)-1H-imidazole and 0.3 ml of dimethyl sulfoxide was heated at 120°C for 3.5 h, After cooling to room temperature the reaction mixture was distributed between ethyl acetate and water, the organic phase was separated, washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel using a mixture of dichloromethane-methanol (95:5), and the fractions containing the desired product were combined and evaporated. The residue was led from dichloromethane, traces of methanol and isopropylacetate, receiving 56 mg (51%) indicated in the title compound, tPL268-271°C.

General procedure a (OMA)

To a suspension of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) in ethanol was added nucleophile (0,943 mmole, 10 EQ) at room temperature. The reaction mixture rapidly changed color to yellow-orange, and it was heated at 150°C for a period 6-40 min, corresponding to the disappearance of starting material (monitoring by HPLC). The solvent was evaporated, the crude material was dissolved in dimethyl sulfoxide or adsorbing on diatomaceous earth Isolute® sorbent HM-N and purified liquid chrome is cografya medium pressure on reversed phase C18.

General method B (BIP)

To a solution of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) in dimethyl sulfoxide was added nucleophile (0,471 mmole, 5 EQ) at room temperature. The reaction mixture was heated at 120°C. in a nitrogen atmosphere for 16 hours, the Crude solution was purified liquid chromatography (medium pressure reversed phase C18.

The specificity of HPLC: retention time (Rt) were obtained using system Waters® Alliance HT HPLC with column SS 70/4 .6 Nucleosil 100-3 C18, using a gradient of ADP + 0,1% TFA/acetonitrile + 0.1 to TFA (5:95) to (95:5) for 8 min, and current solvent of 1.4 ml/min

Example 19

N-(6-Benzylamino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with benzylamine according to OHMS, yielding 8 mg (31%) of red powder color. Rt=3,45 minutes

Example 20

N-[6-(4-Forbindelsen)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 4-tormentilline according to OHMS, giving 5 mg (12.5%) powder red. Rt=5,00 minutes

Example 21

N-[6-(2-Hydroxyethylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioc the o-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-aminoethanol according to OHMS, yielding 20 mg (58%) of red powder color. Rt=2,86 minutes

Example 22

N-[6-(2-Morpholine-4-ylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-morpholine-4-ylethylamine according to OHMS, yielding 21 mg (54%) of red powder color. Rt=2,33 minutes

Example 23

N-[6-(4-Methoxybenzylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 4-methoxybenzylamine according to OHMS, giving to 24.7 mg (60%) of red powder color. Rt=equal to 4.97 min

Example 24

N-{6-[(Benzo[1,3]dioxol-5-ylmethyl)amino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with benzo[1,3]dioxol-5-ylmethylamino according to OHMS, giving 9.1 mg (21,5%) powder red. Rt=4,86 minutes

Example 25

N-[7-Nitro-2,4-dioxo-6-(4-phenylpiperazin-1-yl)-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 1-phenylpiperazine according to OHM's giving of 28.6 mg (66%) of orange powder color. Rt=4,49 is in.

Example 26

N-[6-(2-Mei-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (25 mg, 0,0786 mmole) was reacted with 2-methyl-1H-imidazole according to OHMS, giving a 14.5 mg (49%) of yellow powder. Rt=1,98 minutes

Example 27

N-[7-Nitro-2,4-dioxo-6-(4-phenylbutyramide)-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 4-phenylbutyramide according to OMA, but because of the low solubility of the reaction product was subjected to purification preparative thin-layer chromatography (eluent: hexane-ethyl acetate-acetic acid (3:7:0,1), giving 5.4 mg (19%) powder red. Rt=5,93 minutes

Example 28

N-{6-[4-(4-Acetylphenyl)piperazine-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 1-(4-piperazine-1-ylphenyl)atenonol according to OHMS, yielding 14 mg (44%) of orange powder color. Rt=3,85 minutes

Example 29

N-(7-Nitro-2,4-dioxo-6-[1,2,4]triazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 1H-[1,2,4]triazole according to OMB, yielding 19 mg (83%) of the powder is elevatora color. Rt=2,87 minutes

Example 30

N-[7-Nitro-2,4-dioxo-6-(2-phenoxyethylamine)-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 2-phenoxyethylamine according to OHMS, yielding 14 mg (52%) of red powder color. Rt=5,25 minutes

Example 31

N-[6-(2-Methoxyethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 2-methoxyethylamine according to OHMS, giving 8.5 mg (36%) of red powder color. Rt=3,84 minutes

Example 32

N-(7-Nitro-2,4-dioxo-6-pyrazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 1H-pyrazole according to OMB, giving to 9.4 mg (27%) powder red. Rt=3,64 minutes

Example 33

N-[6-(4-Mei-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (25 mg, 0,0786 mmole) was reacted with 4-methyl-1H-imidazole according to OMB, giving 12.6 mg (43%) of yellow powder in the form of a mixture of regioisomers (5:1), Rt=2,11 minutes

Example 34

N-{6-[2-(1H-Imidazol-4-yl)ethylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (20 mg, 0,0628 mmole) was reacted with 2-(1H-imidazol-4-yl)ethylamine according to OHMS, giving 9.6 mg (37%) of red powder color. Rt=2,65 minutes

Example 35

N-(6-Cyclopropylamino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with cyclopropylamine according to OHMS, giving 10 mg (31%) of red powder color. Rt=3,15 minutes

Example 36

N-[6-(Cyclopropylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (33 mg, 0,1037 mmole) was reacted with cyclopropanemethylamine according to OMA, but with the purification of the reaction product liquid medium pressure chromatography (hexane-ethylacetat-acetic acid (95:5:0,1) to (40:60:0,1), yielding 11 mg (32%) of red powder color. Rt=4,66 minutes

Example 37

N-[6-(3-Hydroxypyrrolidine-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with pyrrolidin-3-I according to OHMS, yielding 21 mg (58%) of red powder color. Rt=4,22 minutes

Example 38

N-[6-(2-Hydroxypropylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

p> N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 1-aminopropan-2-I according to the OMA, the giving of 23.1 mg (65%) of red powder color. Rt=3,07 minutes

Example 39

N-(6-Isopropylamino-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with Isopropylamine according to OHMS, giving a 19.6 mg (58%) of red powder color. Rt=of 4.44 minutes

Example 40

N-(7-Nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with pyrrolidine according to OHMS, giving to 12.2 mg (35%) powder light orange color. Rt=4,37 minutes

Example 41

N-{6-[4-(2-Morpholine-4-yl-2-oxoethyl)imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-(1H-imidazol-4-yl)-1-morpholine-4-ratanana according to OMB, giving to 18.1 mg (39%) of yellow powder. Rt=4,37 minutes

Example 42

N-{6-[(2-Hydroxyethyl)methylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-meilani what metanolom according to OHM, giving 25 mg (71%) of yellow powder. Rt=2,98 minutes

Example 43

N-[6-(3-Hydroxypropylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 3-aminopropan-1-I according to OHMS, giving 24,1 mg (68,5%) of yellow powder. Rt=3,09 minutes

Example 44

N-[6-(2-Hydroxy-1-methylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-aminopropan-1-I according to OHMS, yielding 25 mg (71%) of red powder color. Rt=3,21 minutes

Example 45

N-[6-(2-Hydroxy-1,1-dimethylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-amino-2-methylpropan-1-I according to the OMA, the giving of 14.2 mg (39%) powder red. Rt=3,55 minutes

Example 46

N-[6-(4,5-Dimethylimidazole-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 4,5-dimethyl-1H-imidazole according to OMB, yielding 18 mg (48%) of white powder. Rt=2,43 minutes

Example 47

N-{6-[bis-(2-Hydroxyethyl)amino]-7-nitro-2,4-dioc the o-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-(2-hydroxyethylamino)-ethanol according to OHMS, yielding 21 mg (55%) of red powder color. Rt=2,36 minutes

Example 48

N-Allyl-2-[1-(3-methanesulfonamido-7-nitro-2,4-dioxo-1,2,3,4-tetrahydro-hinzelin-6-yl)-1H-imidazol-4-yl]ndimethylacetamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with N-allyl-2-(1H-imidazol-4-yl)ndimethylacetamide according to OHMS, giving 28 mg (52%) of yellow powder. Rt=2,36 minutes

Example 49

tert-Butyl ether [2-(3-methanesulfonamido-7-nitro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-ylamino)ethyl]carbamino acid:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with tert-butyl ether (2-amino-ethyl)carbamino acid according to OHMS, yielding 27 mg (62%) of red powder color. Rt=4,43 minutes

Example 50

N-[6-(2-Aminoethylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]-methanesulfonamide:

It chilled with ice to a solution of tert-butyl methyl ether [2-(3-methanesulfonamido-7-nitro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-ylamino)ethyl]carbamino acid (10 mg, of 0.022 mmole) in dichloromethane (0.5 ml) was added triperoxonane acid (0.25 ml). The reaction mixture was stirred at 0°C for 3 hours the Mixture was filtered and the floor is built in the solid red color was dried in vacuum, receiving 9 mg (87%) of red powder color. Rt=2,13 minutes

Example 51

N-[6-(1-Hydroxymethyl-2-methylpropylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-amino-3-methylbutane-1-I according to OHMS, yielding 17 mg (45%) of red powder color. Rt=4,00 minutes

Example 52

N-[6-(1-Hydroxymethylpropane)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-aminobutane-1-I according to the OMA, the giving of 14.5 mg (40%) powder red. Rt=3,60 minutes

Example 53

N-[6-((S)-2-Hydroxy-1-methylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (S)-2-aminopropan-1-I according to OHMS, giving to 21.4 mg (61%) of red powder color. Rt=3,20 minutes

Example 54

N-[6-((R)-2-Hydroxy-1-phenylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (R)-2-amino-2-phenylethanol according to OHMS, giving to 31.2 mg (75%) of red powder color. Rt=4,11 minutes

Example 55

N-[6-((S)-3-Hydroxyp Raiden-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (S)-pyrrolidin-3-I according to OHMS, yielding 26 mg (69%) of red powder color. Rt=3,11 minutes

Example 56

N-[6-((R)-3-Hydroxypyrrolidine-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (R)-pyrrolidin-3-I according to the OMA, the giving of 25.6 mg (60%) of red powder color. Rt=3,09 minutes

Example 57

N-(6-Azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with azetidine according to OHMS, yielding 15 mg (45%) of red powder color. Rt=3,92 minutes

Example 58

N-{6-[(R)-1-(3,4-Acid)-2-hydroxyethylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (R)-2-amino-2-(3,4-acid)ethanol according to the OMA, the giving of 24.8 mg (53%) of red powder color. Rt=3,80 minutes

Example 59

N-[6-(1-Hydroxymethylamino)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-AMI is Alexan-1-I according to OHM, giving 24 mg (61%) of red powder color. Rt=4,5 minutes

Example 60

N-(7-Nitro-2,4-dioxo-6-[1,2,3]triazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 1-H-[1,2,3]triazole according to OMB, giving 8.5 mg (25%) of white powder. Rt=4,5 minutes

Example 61

N-{6-[(S)-2-Hydroxy-1-(1H-imidazol-4-ylmethyl)ethylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (S)-2-amino-3-(1H-imidazol-4-yl)propan-1-I according to OHMS, giving 24,1 mg (46%) of red powder color. Rt=1,73 minutes

Example 62

N-[6-((S)-2-Hydroxy-1-phenylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (S)-2-amino-2-phenylethanol according to OHMS, giving, and 25.8 mg (76%) of red powder color. Rt=4,10 minutes

Example 63

N-[6-((R)-1-Hydroxymethyl-2-phenylethylamine)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (R)-2-amino-3-phenylpropane-1-I according to the OMA, the giving of 22.2 mg (65%) powder purple. Rt=4,40 minutes

Example 64

<> N-{6-[2-Hydroxy-1-(1H-indol-3-ylmethyl)ethylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with 2-amino-3-(1H-indol-3-yl)propane-1-I according to OHMS, giving 18,8 mg (33%) of red powder color. Rt=4,27 minutes

Example 65

N-{6-[(R)-2-Hydroxy-1-(1H-imidazol-4-ylmethyl)ethylamino]-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (R)-2-amino-3-(1H-imidazol-4-yl)propan-1-I according to OHMS, giving an increase of 22.7 mg (43%) of red powder color. Rt=1,73 minutes

Example 66

N-[6-(4-Cyanopyrimidine-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (30 mg, 0,0943 mmole) was reacted with (1H-imidazol-4-yl)acetonitrile according to OMB, giving 18.5 mg (47%) of yellow powder. Rt=2,56 minutes

Example 67

N-[6-(4-Ethoxymethyleneamino-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide (50 mg, of) 0.157 mmole) was reacted with 4-methoxymethyl-1H-imidazole according to OMB, yielding 36 mg (44%) of yellow powder. Rt=2,20 minutes

Example 68

N-(6-Morpholine-4-yl-2,4-dioxo-7-cryptomate the -1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

Was dissolved 70 mg (0,23 mmole) methyl ester 2-amino-5-morpholine-4-yl-4-triftorperasin acid in 5 ml of dichloromethane and treated 23 mg (0,076 mmole) of triphosgene. After 15 min the suspension was added to 0.025 ml of triethylamine. A clear solution was stirred for additional 3 h at room temperature (RT), after which was added by syringe a solution of 26 mg (0,23 mmole) methysulfonylmethane in 2.5 ml of anhydrous tetrahydrofuran. The resulting suspension was stirred for an additional hour at room temperature, was treated with 0.3 ml of 1 M aqueous sodium hydroxide solution and stirred over night. After evaporation of the solvent using a rotary evaporator, the residue was dissolved in dichloromethane and was purified preparative thin-layer chromatography using the solvent mixture dichloromethane/methanol (9:1)to give N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide with tPL255-260°C.

Starting material, methyl ester 2-amino-5-morpholine-4-yl-4-trifluoromethyl-benzoic acid was prepared as follows.

A solution of 20 g (0,173 mmole) of potassium tert-butylate in 300 ml of anhydrous tetrahydrofuran was cooled to -78°C. in a nitrogen atmosphere. A solution of 10 g (46,87 mole) of 1-fluoro-4-nitro-2-cryptomelane and 8.1 ml of 0.1 mol) of chloroform is and 100 ml of anhydrous tetrahydrofuran was slowly added so that so that the temperature remained below -75°C. the Dark brown solution was treated successively additional 4 ml of chloroform and a solution of 10 g of potassium tert-butylate in 100 ml of tetrahydrofuran. After 3 h at -78°C. the solution was stirred until it reached room temperature and was evaporated to dryness. Was added 100 ml of a mixture (1:1) acetic acid and methanol. The residue was dissolved in 500 ml ethyl acetate and was extracted with three times 100 ml of a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. After chromatography on 400 g of silica gel and elution with a mixture of dichloromethane/methanol (9:1) was obtained pure 1-fluoro-4-nitro-5-trichlorophenyl-2-cryptomaterial in the form of a yellow oil.

To 300 ml of a mixture of solvents, carbon tetrachloride, acetonitrile and water (10:10:15) were added sequentially to 8.5 g (25 mmol) of 1-fluoro-4-nitro-5-trichlorophenyl-2-cryptomelane, 1 g (8 mol-%) monohydrate trichloride ruthenium and 23 g (0.1 mole) of periodate sodium. After stirring at 60°C for 16 h was added 1 g of the monohydrate of trichloride ruthenium and 23 g of periodate sodium and stirring at 60°C. was continued for 4 h the Cooled reaction mixture was filtered through a layer of celite and the filtrate was evaporated to dryness. Was added 150 ml of 1 M sodium hydroxide solution and was extracted with twice 150 ml of dichloromethane. In the dnow phase was acidified with concentrated hydrochloric acid and was extracted four times with 100 ml dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from a mixture of acetone/petroleum ether, receiving 5-fluoro-2-nitro-4-triftorperasin acid with tPL142-145°C.

A solution of 2 g (24.5 mmole) of 5-fluoro-2-nitro-4-triftorperasin acid in 250 ml of methanol was treated 9.28 are ml (73,5 mmole) of trimethylchlorosilane and heated at boiling for 6 days, during which every night was added additional 9.28 are ml trimethylchlorosilane. The cooled solution was evaporated in vacuum and was distributed between dichloromethane and water. The combined organic phases were extracted twice with 50 ml of 0.5 M sodium hydroxide solution and 50 ml of saturated salt solution. After drying over sodium sulfate, filtration and evaporation crystalline residue was recrystallized from a mixture of acetone/petroleum ether, obtaining the methyl ester of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid with tPL66-68°C.

A solution of 134 mg (0.5 mmole) of the methyl ester of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid in 5 ml of anhydrous tetrahydrofuran was treated with 0.05 ml (0.55 mmole) of the research and was heated at boiling for 90 minutes After evaporation of the solvent was obtained methyl ester 5-morpholine-4-yl-2-nitro-4-triftorperasin acid in the form of a yellow oil.

A solution of 140 ml (0,42 IMO is I) methyl ester 5-morpholine-4-yl-2-nitro-4-triftorperasin acid in 10 ml of methanol was treated with 30 mg of 10% palladium on coal and was first made at room temperature under a pressure of 5 bar for 23 hours After separation of the catalyst by filtration and evaporation of the solvent was obtained pure methyl ester 2-amino-5-morpholine-4-yl-4-triftorperasin acid in the form of a yellow oil.

Example 69

N-(2,4-Dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

A solution of 65.0 g (300 mmol) of N-(2-methyl-5-triptoreline)ndimethylacetamide in 520 ml of concentrated sulfuric acid was treated dropwise with a solution of 152.5 g (1.5 mmole) of potassium nitrate in 520 ml of concentrated sulfuric acid in a nitrogen atmosphere and the mixture was kept at room temperature in a bath of ice. Then the mixture was stirred for another 2 h at room temperature and then poured into ice. The suspension was filtered and the filter cake was dissolved in ethyl acetate, the solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified flash chromatography (silica, hexane/ethyl acetate (1:1))to give the product of nitration in the form of a mixture of regioisomers (62,44 g, 238 mmol). Dissolved 51,0 g (195 mmol) of the crude product in 1000 ml of water and heated at 100°C and the portions were treated with a mixture of 184 g (1167 mmol) of potassium permanganate and 70.4 g (585 mmol) monohydrate magnesium sulfate. The mixture was stirred at 100°C for additional 2 h and then was allowed to cool to room for the Noah temperature. The mixture is then filtered and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum, obtaining 19.3 g (27% over 2 stages) of 2-acetylamino-5-nitro-4-triftorperasin acid in the form of yellow crystals.1H-NMR (DMSO-d6, 400 MHz): 9,13 (s, 1H), 8,67 (s, 1H), up to 1.98 (s, 3H).

A solution of 49.5 g (169 mmol) of 2-acetylamino-5-nitro-4-triftorperasin acid in 600 ml of methanol and 100 ml of water was cooled to 0°C and added dropwise 71,1 ml of 1.33 mol) of concentrated sulfuric acid. Upon completion of addition, the mixture was heated at boiling for 1 h Then the mixture was cooled to 0°C, the pH was brought to 10 with 30% aqueous sodium hydroxide solution and stirred for 1 h, the Methanol was off and the remaining aqueous solution was diluted with water and was extracted with tert-butylmethylamine ether. The aqueous phase was acidified with concentrated HCl, the resulting yellow suspension was filtered and the precipitate washed with water. The solid was dried in vacuum at 100°C, getting to 28.3 g (67%) of 2-amino-5-nitro-4-triftorperasin acid, tPL237°C.

A solution of 28 g (112 mmol) of 2-amino-5-nitro-4-triftorperasin acid in 550 ml of methanol was cooled to 0°C in an atmosphere of nitrogen was added dropwise con is entirelynew sulfuric acid, to keep the temperature about 20°C. Upon completion of addition, the mixture was heated at boiling for 24 hours Then allowed to cool to room temperature and the mixture was concentrated in vacuo to a volume of about 50 ml the residue was poured on ice and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product is recrystallized from toluene, receiving 26.7 g (90%) of methyl ester of 2-amino-5-nitro-4-triftorperasin acid, tPL174-175°C.

A solution of 2.0 g (EUR 7.57 mmole) methyl ester 2-amino-5-nitro-4-triftorperasin acid in 20 ml of acetic anhydride was heated at boiling for 4 hours the Mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was taken in ethyl acetate and washed with water, aqueous saturated sodium bicarbonate solution and saturated saline solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuum. Purification with flash chromatography (silica, hexane/ethyl acetate (3:1)) gave 1,79 g (77%) of methyl ester of 2-acetylamino-5-nitro-4-triftorperasin acid in the form of yellow crystals, tPL75-80°C.

A solution of 1.7 g (of 5.55 mmole) of methyl ester of 2-acetylamino-5-nitro-4-triftorperasin acid in 29 ml of methanol was treated with 250 mg of Pd/C (10%) and the mixture was stirred under hydrogen pressure of 5 bar for 20 minutes the Mixture was filtered and the filtrate was concentrated in vacuum, obtaining 1,58 g (yield quantitative) methyl ester of 2-acetylamino-5-amino-4-triftorperasin acid in the form of yellow crystals, tPL143-152°C.

A solution of 1.55 g (5.6 mmole) of methyl ester of 2-acetylamino-5-amino-4-triftorperasin acid, 1.48 g (a 16.8 mmole) of 1,2-deformalization and 5.5 ml (329,2 mmole) of triethylamine in 40 ml of pyridine was treated dropwise with 10.8 ml (85,3 mmole) of tributyltinchloride. Then the mixture was heated at 100°C for 18 h and allowed to cool to room temperature. The mixture is then processed again 1.48 g (a 16.8 mmole) of 1,2-deformalization, 5.5 ml (39.2 mmole) of triethylamine and 10.8 ml (85,3 mmole) of tributyltinchloride and was heated at 100°C for 24 h the Mixture was cooled to room temperature, concentrated in vacuo and the residue was taken in water and extracted with ethyl acetate. The aqueous phase was acidified to pH 4-5 with 4 M aqueous hydrochloric acid solution and saturated sodium chloride. This aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, filtered and the concentration of Aravali in vacuum. The crude product is recrystallized from ethyl acetate, receiving of 1.34 g (76%) of 2-acetylamino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid. MS (ES, m/e): 315 (M+N].

A solution of 1.3 g (4,14 mmole) of 2-acetylamino-5-[1,2,4]triazole-4-yl-4-trifluoromethyl-benzoic acid in 15 ml of methanol was treated dropwise with 3.1 ml (6,21 mmole) of 2 M solution trimethylsilyldiazomethane in hexane. The mixture was stirred for 1 h at room temperature and again was added 1.5 ml (3,00 mmole) solution trimethylsilyldiazomethane in hexane (2 M). After 1 h the reaction was stopped by adding glacial acetic acid to until more was not observed gas evolution. The mixture was concentrated in vacuo and the residue was taken in ethyl acetate, the solution washed with water, dried over sodium sulfate, filtered and concentrated in vacuum. Purification with flash chromatography (silica, gradient 100% ethyl acetate to ethyl acetate/methanol (9:1)) gave 456 mg (34%) of methyl ester of 2-acetylamino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid in the form of yellow crystals, tPL180-184°C.

A solution of 450 mg (1,43 mmole) of methyl ester of 2-acetylamino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid in 5 ml of methanol and 1 ml of water was cooled to 0°C. and was treated dropwise 0.6 ml (11.3 mmole) of concentrated sulfuric acid. Then mesh was heated at boiling for 30 min and allowed to cool to room temperature. The mixture was poured on ice and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product is recrystallized from a mixture of ethyl acetate/hexane, getting 292 mg (71%) of methyl ester of 2-amino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid, tPL184-186°C.

A solution of 270 mg (0,94 mmole) methyl ester 2-amino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid in 5 ml of tetrahydrofuran at room temperature under nitrogen atmosphere was treated with 93 mg (0.31 in mmole) of triphosgene. The mixture was stirred for 10 min, was added to 0.13 ml (0,94 mmole) of triethylamine and stirring was continued for 3 hours Then was added 104 mg (0,94 mmole) methanesulfonanilide and the mixture was stirred for 1 h at room temperature. Then the mixture was treated with 2 ml of 1 M aqueous sodium hydroxide solution and was stirred for additional 2 hours, the pH Value of the mixture was brought to 4-5 with 4 M aqueous solution of HCl and the mixture was concentrated in vacuum. The residue was taken in ethyl acetate, the solution washed with water, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product is recrystallized from ethyl acetate, getting 219 mg (56%) of N-(2,4-dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)IU is unsulfonated in the form of colorless crystals, tPL231-237°C.

Example 70

(2,4-Dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)amide econsultancy acid:

A solution of 650 mg of 2.27 mmole) methyl ester 2-amino-5-[1,2,4]triazole-4-yl-4-triftorperasin acid in 15 ml of tetrahydrofuran at room temperature under nitrogen atmosphere was treated with 225 mg (from 0.76 mmole) of triphosgene. The mixture was stirred for 20 min, was added 0,32 ml of 2.27 mmole) of triethylamine and continued stirring for 3 hours was Added 282 mg of 2.27 mmole) acanaloniidae (obtained by analogy with the method described J.W.Powell and ..Whiting: The decomposition of sulphonylhydrazone salts - I, Tetrahedron, vol. 7 (1959) p.á305) and the mixture was stirred for 1 h at room temperature. Then the mixture was treated with 5 ml of 1 M aqueous sodium hydroxide solution and was stirred for 18 hours, the pH Value of the mixture was brought to 4-5 with 4 M aqueous solution of HCl and the mixture was concentrated in vacuum. The crude product was purified flash chromatography (silica, ethyl acetate/methanol (19:1)), giving colorless crystals which are recrystallized from a mixture of ethyl acetate/hexane, to obtain 462 mg (2,4-dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)amide econsultancy acid as colorless crystals, tPL185-195°C.

Example 71

Ethyl ester of 1-(3-methanesulfonamido-2,dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid:

The solution 613 mg (14.0 mmol) of sodium hydride in 10 ml of 1-methyl-2-pyrrolidinone was cooled to 0-5°C. and was treated dropwise with a solution of 1.74 g (12.4 mmole) ethyl ester 1H-[1,2,4]triazole-3-carboxylic acid in 10 ml of 1-methyl-2-pyrrolidinone within 8 minutes and the Mixture was stirred for 1 h at 0-5°C was added a solution of 3.00 g (11.2 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid in 10 ml of 1-methyl-2-pyrrolidinone. The mixture was let to slowly warm to room temperature and was stirred for 18 h under nitrogen atmosphere. The mixture was poured into water and was extracted with ethyl acetate. The organic phase was separated and dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified flash chromatography (silica, hexane/ethyl acetate (1:1)and mixed fractions was recrystallized from toluene, receiving a total of 3.12 g (71%) of ethyl ester of 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-[1,2,4]triazole-3-carboxylic acid, tPL190-192°C.

A solution of 3.00 g (7,73 mmole) ethyl ester 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-[1,2,4]triazole-3-carboxylic acid in 75 ml of methanol/tetrahydrofuran (1:1) was treated with 400 mg of Pd/C under hydrogen pressure of 5 bar for 30 minutes Then the mixture was filtered and the filtrate was concentrated in vacuum. The crude product is recristallization of isopropanol, getting 2,47 g (82%) of ethyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-[1,2,4]triazole-3-carboxylic acid as white crystals, tPL189-190°C.

A solution of 1.07 g (3,00 mmole) ethyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-[1,2,4]triazole-3-carboxylic acid in 9 ml of dichloromethane was treated with 296 mg (1.00 mmol) of triphosgene at room temperature in argon atmosphere. The mixture was stirred for 15 min and was added dropwise at 0.42 ml (3,00 mmole) of triethylamine. The mixture was stirred for 3 h and was added a solution of 330 mg (3,00 mmole) methysulfonylmethane 3.3 ml of anhydrous tetrahydrofuran. The mixture was stirred for 17 h at room temperature in argon atmosphere. The suspension was filtered, the precipitate washed with dichloromethane and water and dried in vacuum. Data colorless crystals were dissolved in 20 ml of anhydrous dioxane and treated 0,83 ml (a 4.86 mmole) of ethyldiethanolamine at room temperature in argon atmosphere. The mixture was stirred for 17 h and then concentrated in vacuum. The residue was taken in ethyl acetate and water and the pH brought up to 3-4 with 1 M aqueous HCl solution. The organic phase was separated, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product is PE is crystallizable from a mixture of tetrahydrofuran/hexane, getting 855 mg (62%) of ethyl ester of 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid as colorless crystals, tPL267-270°C.

Example 72

Methylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid:

A solution of 150 mg (0,324 mmole) ethyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid in 0.8 ml of methanol was treated to 0.40 ml (3,24 mmole) ~8 M solution of methylamine in ethanol. The mixture was stirred for 22 h at room temperature and then concentrated in vacuum. The crude product was taken in water and the pH value of the solution was brought to 3 with 1 M aqueous HCl solution, and the mixture was stirred for 3 h at 0°C. the Crystals were separated by filtration, washed with cold water and dried in vacuum, obtaining 124 mg (86%) methylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid as white crystals, tPL257-260°C.

Example 73

N-(6-Imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

To a suspension of 100 mg (0,379 mmole) methyl ester 2-amino-5-nitro-4-triform what talentino acid in 1.5 ml of anhydrous toluene was added at -15°C, 1.5 ml of 20% solution of triphosgene in toluene. After heating to room temperature, the suspension was injected current of phosgene and at the same time started heating up. When boiling current of phosgene was maintained for 1 h, then was replaced by the current of argon for an additional hour. Toluene drove away, leaving 110 mg (100%) methyl ester 2-isocyanato-5-nitro-4-triftorperasin acid in a solid beige color. IR (CHCl3cm-1): 2260 (s).1H-NMR (CDCl3, 360 MHz): of 4.05 (s, 3H); at 7.55 (s, 1H); 8,65 (s, 1H).

To a solution of 110 mg (0,379 mmole) methyl ester 2-isocyanato-5-nitro-4-triftorperasin acid in 1.7 ml of anhydrous tetrahydrofuran was added at room temperature of 41.7 g (0,379 mmole) methysulfonylmethane in 0.6 ml of anhydrous tetrahydrofuran. The solution turned into a white suspension, which was stirred for 1 h, then was added 0,379 ml of 1 M sodium hydroxide solution and stirring a clear solution was continued for 4 h After addition of 0,472 ml of 2 M HCl solution and evaporation of the tetrahydrofuran, the residue was separated by filtration and dried at 50°C and 0.1 mm Hg, getting 114 mg (81%) of N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of powder light yellow color, tPL220-232°C (decomp.).1H-NMR (DMSO-d6, 400 MHz): 3.15 in (s, 3H); 7,66 (s, 1H); to 8.62 (s, 1H); 10,50 (s, 1H); 12,41 (s, 1H).

A solution of 109 mg of N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in 3 ml of ethanol and 3 ml of acetic acid was first made in the presence of 30 mg of 10% palladium on coal. After the disappearance according to TLC starting material, the reaction mixture was diluted with ethanol and acetic acid, and slightly warmed. The catalyst was separated by filtration and the filtrate was concentrated to dryness. Rubbing the residue with ethyl acetate gave 61 mg (61%) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of a yellow powder, tPL240°C (decomp.).1H-NMR (DMSO-d6, 400 MHz): 3,12 (s, 3H); to 5.66 (s, 2H); from 7.24 (s, 1H); 7,46 (s, 1H); 10,3 (ush. s, 1H); 11.4 in (ush. s, 1H).

A mixture of 500 mg (1,478 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 0,111 ml (1,478 mmole) of formaldehyde solution (37% in water), 0,170 ml (1,478 mmole) solution of glyoxal (40% in water) and 114 mg (1,478 mmole) of ammonium acetate in 3.7 ml of acetic acid was heated for 26 hours in an oil bath at 70°C. After 2 h, 7 h and 24 h added half equivalent (0,739 mmole) solution of formaldehyde solution of glyoxal and ammonium acetate. The reaction mixture was concentrated to dryness and the residue was fractionally using medium pressure chromatography on a column of reversed phase RP-18 (particle size 20 μm) with a mixture tetrahydrofuro the/water (3:4). After removal of tetrahydrofuran in a rotary evaporator faction liofilizirovanny, foam assembled and led from a mixture of ethanol/water (3:1)to give 217 mg of N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of powder light yellow, tPL282-301°C (decomp.).

Example 74

N-(2,4-Dioxo-6-thiomorpholine-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

A solution of 240 mg (from 0.90 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid and 0,189 ml (2.00 mmole) thiomorpholine in 2.5 ml of tetrahydrofuran was heated at boiling for 2 hours After evaporation of the tetrahydrofuran, the residue was distributed between water and ethyl acetate, the organic phase was separated and washed with water and saturated saline solution, dried over sodium sulfate and concentrated, gaining 310 mg of methyl ester of 2-nitro-5-thiomorpholine-4-yl-4-triftorperasin acid in the form of a brown powder, tPL68-82°C.

Was first made 300 mg of methyl ester of 2-nitro-5-thiomorpholine-4-yl-4-triftorperasin acid in 10 ml of anhydrous ethanol in the presence of 60 mg of Raney Nickel. After separation of the catalyst by filtration the solution was evaporated to dryness, obtaining 233 mg methyl ester 2-amino-5-thiomorpholine-4-yl-4-triftorperasin sour the s in the form of a yellow powder, tPL85-117°C (decomp.).

To a suspension of 100 mg (0,312 mmole) methyl ester 2-amino-5-thiomorpholine-4-yl-4-triftorperasin acid in 2 ml of anhydrous toluene at 0°C was added 1.5 ml of 20% solution of phosgene in toluene. After heating to room temperature, the suspension was injected current of phosgene and at the same time started heating up. When boiling current of phosgene was maintained for 2 h, then for an additional 1 h and replace it with the current of argon. Toluene drove away, leaving 126 mg (>100%) methyl ester 2-isocyanato-5-thiomorpholine-4-yl-4-triftorperasin acid in a solid brown color, pure enough for the next stage.1H-NMR (CDCl3, 360 MHz): 2,75 is 2.80 (m, 2H); 3,15-3,20 (m, 2H); 4,00 (s, 3H); 7,40 (s, 1H); to 7.95 (s, 1H).

To a solution of 120 mg (0,310 mmole) methyl ester 2-isocyanato-5-thiomorpholine-4-yl-4-triftorperasin acid in 1.5 ml of anhydrous tetrahydrofuran at room temperature was added 37.5 g (0,341 mmole) methysulfonylmethane in 0.5 ml of anhydrous tetrahydrofuran. After stirring for 2.5 h was added 0,340 ml of 1 M sodium hydroxide solution and stirring continued for 1.5 h followed by addition of 0,412 ml of 2 M solution model HC1. The tetrahydrofuran was evaporated and the aqueous phase was extracted three times with ethyl acetate. United organic the ski phase was washed with saturated saline solution, was dried over sodium sulfate and concentrated to dryness. The residue was purified by medium pressure chromatography on silica (particle size 20 μm) with a mixture of ethyl acetate/cyclohexane (2:1)to give N-(2,4-dioxo-6-thiomorpholine-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of powder light yellow, tPL245-260°C (decomp.).

The same sequence of reactions as in the previous example, based on the methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid and the appropriate amine were obtained the following compounds.

Example 75

N-(6-[1,4]Oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide

Powder light yellow, tPL198-203°C.

Example 76

N-[6-(4,4-Deformability-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide

Powder yellow tPL249-261°C (decomp.).

Example 77

N-[6-(1,4-Dioxa-8 azaspiro[4,5]Dec-8-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide

Powder yellow tPL253-262°C.

Example 78

N-[2,4-Dioxo-6-(4-oxopiperidin-1-yl)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

Was treated with 500 mg of N-[6-(1,4-dioxa-8-asasp the ro[4.5]Dec-8-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide 3.4 ml of 6 M HCl solution in 15 ml of dioxane for 26 h at room temperature. After dilution with water the aqueous phase was extracted with ethyl acetate, the organic phase was separated, washed with saturated saline solution, dried over sodium sulfate and concentrated to dryness, leaving 490 mg of yellow powder. From this powder 280 mg was fractionally by medium pressure chromatography on a column with a reversible phase RP-18 (particle size 20 μm) with a mixture of acetonitrile/water (1:2). The fractions containing the product were combined and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated, obtaining N-[2,4-dioxo-6-(4-oxopiperidin-1-yl)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in the form of powder light yellow, tPL238-242°C.

Example 79

N-(6-Azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A solution of 1.07 g (4.0 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid and 0,461 ml (6.8 mmole) of azetidine in 10 ml of tetrahydrofuran was heated at boiling for 90 minutes After evaporation of the tetrahydrofuran, the residue was distributed between water and ethyl acetate, the organic phase was separated and washed with water and saturated saline solution, dried over sodium sulfate and concentrated, obtaining 1.19 g of methyl ester of 5-azetidin-1-yl-2-nitro-4-triftorperasin acid in powder form Zheltov the color, tPL127-136°C.

Was first made 1.10 g of methyl ester of 5-azetidin-1-yl-2-nitro-4-triftorperasin acid in 12 ml of tetrahydrofuran in the presence of 200 g of palladium on coal. After separation of the catalyst by filtration the solution was evaporated to dryness, obtaining 0,99 g of methyl ester of 2-amino-5-azetidin-1-yl-4-triftorperasin acid in powder form yellow, tPL80-86°C.

A mixture of 129 mg (0,470 mmole) methyl ester 2-amino-5-azetidin-1-yl-4-triftorperasin acid, 0,082 ml (0,470 mmole) of ethyldiethanolamine, of 0.066 ml (0,470 mmole) of 4-chloroformate and 4 ml of dioxane was stirred for 45 min and then concentrated to dryness. The residue was distributed between water and ethyl acetate, the organic phase was separated and washed with water and saturated saline solution, dried over sodium sulfate and concentrated, leaving a viscous mass, which was subjected to medium pressure chromatography on silica with a mixture of ethyl acetate/cyclohexane (1:4). From the first fraction after evaporation was received 123 mg methyl ester 5-azetidin-1-yl-2-(4-chlorophenethylamine)-4-triftorperasin acid in the form of a yellow foam.1H-NMR (DMSO-d6+D2O): 7,20 d, J=10 Hz, 2H; 7,20 s, 1H; 7,15 s, 1H; of 6.75 (d, J=10 Hz, 2H; of 3.85, s, 3H; 3,75 t, J=7 Hz, 4H; 2,15 pent, J=7 Hz, 2H.

A solution of 115 mg (0,268 mmole) of the methyl ester 5-azetidin-1-yl-2-(4-chlorophenethylamine)-4-triftorperasin acid, 30 mg (0,268 mmole) methysulfonylmethane, 0,070 ml (0,402 mmole) of ethyldiethanolamine and 3 ml of dioxane was stirred for 24 h at 70°C. After evaporation to dryness the residue was fractionally by medium pressure chromatography on a column of reversed phase RP-18 (particle size 20 μm) with a mixture of acetonitrile/water (3:4). The fractions containing the product were combined and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated, leaving amorphous powder, which was led from a mixture of acetonitrile/water, receiving 47 mg of N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of a yellow powder, tPL266-283°C.

Example 80

N-[2,4-Dioxo-6-(pyridine-3-yloxy)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a suspension of 198 mg (4,53 mmole) of sodium hydride (65% in oil, washed with pentane) in 2.5 ml of anhydrous tetrahydrofuran was bury a solution of 356 mg (3,74 mmole) 3-hydroxypyridine in 5 ml of tetrahydrofuran and the mixture was stirred for 1 h at room temperature. After cooling to 0°C was added 1.0 g (3,74 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid, dissolved in 10 ml Tetra is drofuran, and stirring was continued for 7 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over sodium sulfate and evaporated, obtaining oil, which was fractionally by medium pressure chromatography on silica gel with a mixture of ethyl acetate/cyclohexane (1:1). The fractions containing the product were combined and evaporated, getting 977 mg of methyl ester of 2-nitro-5-(pyridine-3-yloxy)-4-triftorperasin acid in the form of a white powder, tPL98-100°C.

Was first made 919 mg of methyl ester of 2-nitro-5-(pyridine-3-yloxy)-4-triftorperasin acid in 20 ml of tetrahydrofuran in the presence of 227 mg of palladium on coal. After separation of the catalyst by filtration the solution was evaporated to dryness and the residue was purified by medium pressure chromatography on silica gel with a mixture of ethyl acetate/cyclohexane (1:2), receiving 611 mg methyl ester 2-amino-5-(pyridine-3-yloxy)-4-triftorperasin acid in powder form yellow, tPL132-134°C.

Was treated with 300 mg of 2-amino-5-(pyridine-3-yloxy)-4-triftorperasin acid with phosgene in accordance with the procedure described in example 74, receiving 291 mg of methyl ester of 2-isocyanato-5-(pyridine-3-yloxy)-4-triftorperasin acid in the form of oil coric autogo color. 1H-NMR (CDCl3): 8,50 ush. s, 1H; 8,40 s, 1H; 7,60 s, 1H; 7.50 for s, 3H; 3,95 s, 3H.

Was cyclically 288 mg of this oil with methysulfonylmethane in accordance with the procedure described in example 74, receiving 211 mg of N-[2,4-dioxo-6-(pyridine-3-yloxy)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in the form of a white powder, tPL194-196°C (acetonitrile).

Example 81

N-(6-Dimethylamino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide:

A mixture of 370 mg (1,094 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide, 0,083 ml of 1.02 mmole) of formaldehyde solution (37% in water), 0,0033 ml of acetic acid and 21 ml of tetrahydrofuran and 21 ml of water was first made in the presence of 100 mg of palladium on coal for 10 days. After day 1, 3, 4, 5 and 6 were added to a new batch of formaldehyde (0,083 ml) and acetic acid (0,0033 ml). After filtration of the reaction mixture, the tetrahydrofuran was evaporated and the remaining aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated to dryness leaving a yellow powder, which was fractionally by medium pressure chromatography on a column of reversed phase RP-18 (particle size 20 μm) with a mixture of acetonitrile/water (3:4). The fractions containing the product were combined and extracted what acetate, the organic phase was dried over sodium sulfate and concentrated, getting 277 mg of N-(6-dimethylamino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in the form of a yellow powder, tPL254-272°C.

Similar to the previous example method received the following connection.

Example 82

N-[6-(2-Hydroxyethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide

Powder yellow tPL240-246°C.

Example 83

N-{6-[(2-Hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

A mixture of 370 mg (0,968 mmole) of N-[6-(2-hydroxyethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide, 0,074 ml (0,912 mmole) of formaldehyde solution (37% in water)and 4 ml of acetic acid, 15 ml of tetrahydrofuran and 15 ml of water was first made in the presence of 115 mg of palladium on coal for 3 days. After days 1 and 2 were added to a new batch of formaldehyde (0,074 ml). After filtration of the reaction mixture, the tetrahydrofuran was evaporated and the remaining aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated to dryness leaving a brown oil, which was fractionally chromatography (medium pressure about ashenai phase RP-18 (particle size 20 μm) with a mixture of acetonitrile/water (1:2). The fractions containing the product were combined and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated, gaining 165 mg of N-{6-[(2-hydroxyethyl)methylamino]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide in the form of a yellow powder, tPL220-224°C.

Example 84

N-{6-[4-(4-Methoxyphenyl)imidazol-1-yl]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

A mixture of 1,200 g (4,49 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid and 0,861 g (4,94 mmole) of 4-(4-methoxyphenyl)-1H-imidazole in 15 ml of tetrahydrofuran was heated at boiling for 5 hours After cooling, the reaction mixture was distributed between ethyl acetate and water, the organic phase was separated and washed with saturated saline solution, dried over sodium sulfate and concentrated to dryness. The residue was purified flash chromatography on silica (particle size 20 μm) with a mixture of ethyl acetate/hexane (2:3), receiving 1,511 g methyl ester 5-[4-(4-methoxyphenyl)imidazol-1-yl]-2-nitro-4-triftorperasin acid in the form of a yellow powder.1H-NMR (DMSO-d6, 400 MHz): 3,80 s, 3H); 3.95 to s, 3H); 7,00 d, J=10.4 Hz, 2H; 7,78 d, J=10.4 Hz, 2H; 7,95 s, 1H; 8,00 s, 1H; 8,28 s, 1H; 8,72 s, 1H.

Was first made 1,470 g of methyl ester 5-[4-(4-methoxyphenyl)imidazol-1-yl]-2-nitro-4-trifter what ethylbenzoic acid in 25 ml of tetrahydrofuran in the presence of 200 mg of palladium on coal. After separation of the catalyst by filtration the solution was evaporated to dryness and the residue was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of dichloromethane/methanol (98:2), receiving 1,270 g of methyl ester of 2-amino-5-[4-(4-methoxyphenyl)imidazol-1-yl]-4-triftorperasin acid in a solid beige color.1H-NMR (DMSO-d6, 400 MHz): 3,80 s, 3H); 3.95 to s, 3H); 6,95 d, J=10.4 Hz, 2H; 7,30 s, 2H; 7,40 s, 1H; 7,70 s, 1H; 7,75 s, 1H; 7,78 d, J=10.4 Hz, 2H; 7,80 s, 1H.

The mixture 0,923 g (2,31 mmole) methyl ester 2-amino-5-[4-(4-methoxyphenyl)-imidazol-1-yl]-4-triftorperasin acid and 0,976 ml (6,93 mmole) of triethylamine was treated with 1.04 g (3,47 mmole) of triphosgene and stirred at room temperature for 90 minutes was Added a solution of 0,520 g (4,62 mmole) methysulfonylmethane in 20 ml of dioxane and continued stirring at 80°C. After 2 and 3 h were added two additional servings, 400 mg and 200 mg, respectively methysulfonylmethane in dioxane. After 4 h the reaction mixture was concentrated, diluted with 80 ml of a mixture of dioxane/water (1:1) and treated with 4.5 ml of 1 M sodium hydroxide solution at room temperature for 1 h, the pH Value of the reaction mixture was brought to 5.5 with acetic acid, the mixture was concentrated and the residue was taken in ethyl acetate. The organic phase is washed with water and saturated saline solution, dried the hell sodium sulfate and evaporated to dryness. The residue was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of dichloromethane/methanol (95:5) and the obtained product was recrystallized from methanol/dichloromethane and of methanol/dichloromethane/diisopropyl ether, receiving 0,725 g of N-{6-[4-(4-methoxyphenyl)imidazol-1-yl]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide in the form of a white powder, tPL293-294°C.

Example 85

N-{6-[4-(4-Ethoxymethylene)imidazol-1-yl]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide:

To a suspension of 3.00 g (7,71 mmole) of 4-bromo-1-trityl-1H-imidazole in 30 ml of dioxane was added 1,58 g (9,23 mmole) 4-methoxymethylethoxy acid, 3,47 g (10.5 mmole) of cesium carbonate and 0,121 g (0,131 mmole) of Tris(dibenzylideneacetone)diplodia, then 0,315 ml (0,308 mmole) solution of 5 g of tri-tert-butylphosphine in 25 ml of dioxane. The mixture was heated at 80°C and was stirred for 6.5 h After cooling to room temperature, the suspension was diluted with dichloromethane and filtered, the filter cake was washed with ethyl acetate and the filtrate was concentrated to dryness. The residue was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of hexane/ethyl acetate (7:3), receiving 2,805 g of 4-(4-methoxymethyl)-1-trityl-1H-imidazole, Rt=4,659 min according to HPLC on a column of Nucleosil C18HD with eluent of Aceto ITIL is + 0.05% TFA/water + 0.05% of TFA (20:80) to (100:0) for 6 min, the flow rate of the solvent of 1.0 ml/min MS (ionization at atmospheric pressure (API-ES positive scan, e/m): 431 (M+1).

The mixture 2,800 g of 4-(4-methoxymethyl)-1-trityl-1H-imidazole in 50 ml triperoxonane acid was stirred at room temperature for 3 hours the Reaction mixture was concentrated, taken into ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and saturated saline and dried over sodium sulfate. Evaporation of the solvent gave a residue, which was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of dichloromethane/methanol (93:7), receiving 1,169 g of 4-(4-methoxymethyl-phenyl)-1H-imidazole in the form of a powder beige. Rt=2,906 min according to HPLC on a column of Nucleosil C18HD with eluent acetonitrile + 0.05% of TFA/water + 0.05% of TFA (20:80) to (100:0) for 6 min, the flow rate of the solvent of 1.0 ml/min MS (API-ES positive scan, e/m): 189 (M+1).

A mixture of 1.00 g (3,74 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid and 0,775 g (4,12 mmole) of 4-(4-methoxymethyl-phenyl)-1H-imidazole in 10 ml of tetrahydrofuran was heated at boiling for 2 hours After cooling, the reaction mixture was distributed between ethyl acetate and water, the organic phase was separated and washed with saturated saline solution, dried the over sodium sulfate and concentrated to dryness. The residue was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of ethyl acetate/hexane (2:3)to give 1.55 g of the methyl ester 5-[4-(4-methoxymethyl)-imidazol-1-yl]-2-nitro-4-triftorperasin acid in powder form yellow, tPL135-137°C.1H-NMR (DMSO-d6, 400 MHz): 3,30 s, 3H); 3.95 to s, 3H); 4,42 s, 3H; to 7.35 (d, J=10.4 Hz, 2H; of 7.82 (d, J=10.4 Hz, 2H; 8,02 s, 1H; 8,05 s, 1H; 8,30 s, 1H; 8,72 s, 1H.

Was first made of 1.00 g of methyl ester 5-[4-(4-ethoxymethylene)imidazol-1-yl]-2-nitro-4-triftorperasin acid in 20 ml of tetrahydrofuran in the presence of 200 mg of platinum on coal. After separation of the catalyst by filtration the solution was evaporated to dryness, obtaining 0,661 g of methyl ester of 2-hydroxyamino-5-[4-(4-ethoxymethylene)imidazol-1-yl]-4-triftorperasin acid in a solid yellow color.1H-NMR (DMSO-d6, 400 MHz): 3,30 s, 3H); 3,82 s, 3H); 4,40 s, 2H; to 7.35 (d, J=10.4 Hz, 2H; 7,62 s, 1H; 7,80 d, J=10.4 Hz, 2H; a 7.85-of 7.90 m, 3H). MS (API-ES positive scan, e/m): 422 (M+1).

The mixture 0,519 g (1,23 mmole) methyl ester 2-hydroxyamino-5-[4-(4-ethoxymethylene)imidazol-1-yl]-4-triftorperasin acid and 0,530 ml (3,76 mmole) of triethylamine were processed 0,564 g (of 1.88 mmole) of triphosgene and stirred at room temperature for 105 minutes was Added a solution of 0,282 g (of 2.51 mmole) methysulfonylmethane in 20 ml of Oksana and continued stirring at 80°C for 1 h The reaction mixture was cooled to room temperature, diluted with 25 ml of water and was treated with 2.5 ml of 1 M sodium hydroxide solution for 30 minutes After acidification of 1 M acetic acid to pH 5.5 and the mixture was concentrated, the residue was taken in ethyl acetate and the organic phase is washed with water and saturated saline solution, dried over sodium sulfate and concentrated to dryness. The residue was purified flash chromatography on silica (particle size 40-63 μm) with a mixture of dichloromethane/methanol (95:5), receiving 0,196 g of N-{6-[4-(4-ethoxymethylene)imidazol-1-yl]-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl}methanesulfonamide in the form of a powder beige tPL252-257°C.

Example 86

N-[2,4-Dioxo-6-(2-oxo-2H-pyridin-1-yl)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide

The HPLC analyses were carried out using the system, including pumps, Gilson 331 connected to the detector Gilson UV/VIS 152 and spectrometer Finnigan AQA (electrospray ionization (ESI)), relief valve in the loop input 50 ál and HPLC column Waters XTerra MS size 4,6h50 mm stationary phase 18 and a particle size of 3.5 μm and a flow gradient from 5 to 90% acetonitrile containing 0.05% triperoxonane acid. The retention time (Rt) were recorded for all new connections.

To a suspension of sodium hydride (315 mg, 1.4 EQ) in 50 ml tetrahed is furana was added dropwise a solution of 2-hydroxypyridine (801 mg, 1.5 EQ) in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 30 min before addition of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid (1.5 g, 5,61 mmole) in 10 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 16 hours the Solvent was removed in vacuum and the crude oil was dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuum, obtaining the crude yellow oil. The crude product was purified flash chromatography (ethyl acetate/hexane (0:100 to 100:0)to obtain methyl ester of 2-nitro-5-(2-oxo-2H-pyridin-1-yl)-4-triftorperasin acid in a solid yellow color (1.3 g, yield 68%). MS (ES, m/z): 328 [M+H+CH3SP]+, Rt4,67 minutes

Methyl ester of 2-nitro-5-(2-oxo-2H-pyridin-1-yl)-4-triftorperasin acid (1.3 g, 3.8 mmole) was first made over Ni-Raney (400 mg) under hydrogen pressure of 3 bar for 6 hours Then the mixture was filtered through a layer of celite and washed it with methanol and dioxane. The solvent was removed in vacuum, obtaining after drying in high vacuum, methyl ester 2-amino-5-(2-oxo-2H-pyridin-1-yl)-4-triftorperasin acid in a solid white color (1.2 g, 100%). MS (S, m/z): 313 [M+H]+, Rt4,45 minutes

To a solution of methyl ester 2-amino-5-(2-oxo-2H-pyridin-1-yl)-4-triftorperasin acid (500 mg, 1.6 mmole) in 20 ml of dioxane was added 4-chlorophenylalanine (0,273 ml, 1.25 EQ). The resulting mixture was stirred at 100°C for 1 h Then the solvent was removed in vacuum. The crude oil was dissolved in 20 ml of dioxane was added ethyldiethanolamine (0,550 ml, 2 EQ) and methysulfonylmethane (177 mg, 1 EQ). The resulting mixture was stirred at 100°C for 2 h the Solvent was removed in vacuum to dryness and the resulting crude residue was dissolved in 10 ml of dichloromethane, the solution was left at room temperature for 24 h Formed in the end the precipitate was separated by filtration, washed with dichloromethane and dried in high vacuum, obtaining N-[2,4-dioxo-6-(2-oxo-2H-pyridin-1-yl)-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in a solid white color (100 mg, yield 15%). MS (ES, m/z): 458,3 [M+H+CH3SP]+, Rtto 3.73 min1H-NMR (DMSO-d6, 400 MHz): 8,02 (s, 1H), 7,66 (s, 1H), 7,49-to 7.50 (m, 2H), 6,46 (d, 1H, J=7.8 Hz), of 6.31 (t, 1H, J=7,8 Hz)and 3.15 (s, 3H).

Example 87

N-(3-Methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-hinzelin-6-yl)-N-methylacetamide

The HPLC analyses were carried out using the system, including pumps, Gilson 33, connected to the detector Gilson UV/VIS 152 and spectrometer Finnigan AQA (ESI)), relief valve in the loop input 50 ál and HPLC column Waters XTerra MS-4.6×50 mm with a stationary phase and C18 particle size of 3.5 μm and a flow gradient from 5 to 90% acetonitrile containing 0.05% triperoxonane acid. The retention time (Rt) were recorded for all new connections.

Methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid (300 mg, 1.12 mmole) was dissolved in dioxane and, after addition of methylamine (0,490 ml, 3.5 EQ) yellow mixture was stirred at room temperature for 2 days. The mixture was evaporated to dryness. Was added dichloromethane and the suspension was filtered. Evaporation of the filtrate gave the methyl ester of 2-nitro-5-methylamino-4-triftorperasin acid in a solid yellow color (291,3 mg, yield 95.4 percent). The product was used in the next stage without further purification.

Methyl ester of 2-nitro-5-methylamino-4-triftorperasin acid was dissolved in methanol/tetrahydrofuran and after the addition of 10% Pd/C and the mixture was stirred for 45 min at room temperature in a hydrogen atmosphere. The mixture was filtered through a layer of celite, the solution was evaporated under reduced pressure, obtaining the methyl ester of 2-amino-5-methylamino-4-triftorperasin acid VI is e orange oil (240 mg, the output 103%). The product was used in the next stage without further purification.

Dissolved methyl ester 2-amino-5-methylamino-4-triftorperasin acid (26 mg, 0.96 mmole) in dioxane and, after addition of acetylchloride (54 μl, 1 EQ) and the mixture was stirred for 2 h (monitoring by TLC) at 80°C. Then was added acetylchloride (0.9 EQ) and stirring continued at 80°C for 18 hours the Mixture was evaporated to dryness. The residue was dissolved in dichloromethane, the solution was filtered, evaporated and the residue was dried in high vacuum. The crude product was purified flash chromatography (silica gel, gradient hexane to ethyl acetate), was obtained methyl ester 5-(acetylecholine)-2-amino-4-triftorperasin acid in a solid yellow color (36 mg, yield of 12.8%) (MN+291, Rt5.0 min). Allocated other monoacetyl derivative (50 mg) and diacetylpyridine (92 mg).

To a solution of methyl ester 5-(acetylecholine)-2-amino-4-trifluoromethyl-benzoic acid (36 mg, 0.12 mmole) in dioxane (0.2 ml) was slowly added 4-chlorophenylalanine (26 mg, 1.1 EQ). The solution was stirred at 80°C for 2 h, the Solution was evaporated, obtaining methyl ester 5-(acetylecholine)2-(4-chlorophenethylamine)-4-triftorperasin acid after repeated trituration with hexane. IP who was olovely such which is, at the next stage.

To a solution of methyl ester 5-(acetylecholine)2-(4-chlorphenoxy-carbylamine)-4-triftorperasin acid (55 mg, 0.12 mmole) in dioxane (0.5 ml) was added methysulfonylmethane (15 mg, 1.1 EQ) and ethyldiethanolamine (0,042 ml, 2 EQ). The mixture was stirred for 18 h (monitoring by TLC) at 85°C. the Mixture became white turbid yellow. Then the mixture was evaporated to dryness. The residue was dissolved in dichloromethane, the solid substance was separated by filtration and dried in high vacuum was 32.8 mg, yield 67,3%) (MH+395, Rtto 3.58 min.)

Example 88

Methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid:

A solution of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid (1 g, 3,74 mmole) and methyl ester 1H-imidazole-4-carboxylic acid (0,53 g, 4,12 mmole) in 10 ml of tetrahydrofuran and 2 ml of dimethyl sulfoxide was heated at boiling for 90 hours the Solution was allowed to cool to room temperature and was evaporated. The residue was led from dichloromethane and hexane, obtaining 1.12 g (3 mmole, 80%) of methyl ester 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-imidazole-4-carboxylic acid, tPL136-138°C. MS (ES, m/z): 374 [M+H]+.

A solution of 1.1 g (95 mmole) of methyl ester 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-imidazole-4-carboxylic acid in 400 ml of methanol was treated with 163 mg of 10% palladium on coal and was first made at room temperature under hydrogen pressure 5 bar for 16 hours After separation of the catalyst by filtration and evaporation of the solvent the residue was chromatographically on silica gel using dichloromethane and increasing to 15% of methanol. Recrystallization of the residue from dichlormethane and hexane gave 932 mg (2,715 mmole, 92%) of methyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-imidazole-4-carboxylic acid, tPL206-208°C. MS (ES, m/z): 344 [M+H]+.

A solution of methyl ester 1-(4-amino-5-methoxycarbonyl-2-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid (932 mg, 2,715 mmole) in dioxane (500 ml) was treated with triphosgene (814 mg, 2,715 mmole) and the mixture was stirred at 80°C for 3 hours was Added methysulfonylmethane (302 mg, 2,715 mmole) and stirring was continued for 30 minutes After cooling to room temperature, and concentration to a volume of 50 ml was added 3.0 ml of 1 M sodium hydroxide solution, the mixture was stirred over night at room temperature. The mixture was concentrated in vacuo and the residue was chromatographically on silica gel using a gradient of dichloromethane and methanol, obtaining, after recrystallization from a mixture of dichloromethane/hexane 1,035 g (2,31 mmole, 85%) of methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid, tPL287-288°C. MS (ES, m/z): 448 [+H] +.

Example 89

1-(3-Methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-hinzelin-6-yl)-1H-imidazole-4-carboxylic acid:

To a solution of methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid (150 mg, 0,335 mmole) in 10 ml of dimethylformamide was added 1.7 ml of 1 M aqueous sodium hydroxide solution and stirred at room temperature for 1 h and at 50°C for 2 hours After cooling to room temperature the solvent was evaporated in vacuo, the residue was taken into water, acidified with 5 ml of 1 M hydrochloric acid and was extracted three times in 15 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated, getting 126 mg (0,29 mmole, 87%) amorphous 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid, MS (ES, m/z): 434 [M+H]+.

Example 90

Dimethylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid:

A solution of 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid (120 mg, 0,277 mmole) in 10 ml of dimethylformamide was treated with dimethylamine hydrochloride (46 mg, 0,554 mmole) of the hydrochloride of N-3-dimethylaminopropyl-N'-ethylcarbodiimide (60 mg, 0,305 mmole), N-hydroxybenzotriazole (11 mg, 0.08 mmole) and triethylamine (0.1 ml, 0.72 mmole). The solution was heated at 100°C for 1 h, cooled to room temperature, evaporated in vacuo and the residue was chromatographically on silica gel, receiving 22 mg (0,048 mmole, 17%) dimethylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid, tPL284-286°C. MS (ES, m/z): 461 [M+H]+.

Example 91

Methylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid:

A solution of methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid (800 mg, to 1.79 mmole) and N-methylformamide (0,357 ml, 6 mmol) in 5 ml of dimethylformamide was heated to 120°C. and with stirring was added sodium methylate (100 mg, to 1.79 mmole). After 2 h at 120°C was added 100 mg of sodium methylate and stirring at 120°C was continued for an additional 2 hours After cooling to room temperature the solution was evaporated in vacuum and the residue was chromatographically, receiving 560 mg (1.25 mmole, 70%) methylamide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid, tPL292-295°C. MS (ES, m/z): 447 [M+H]+.

Example 92

Amide -(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-hinzelin-6-yl)-1H-imidazole-4-carboxylic acid:

A solution of methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid (50 mg, 0,112 mmole) and formamide (0.15 ml, 0,374 mmole) in 5 ml of dimethylformamide was heated to 120°C. and with stirring was added sodium methylate (6 mg, 0,112 mmole). After 2 h at 120°C. the solution was cooled to room temperature, evaporated in vacuo and the residue was chromatographically, receiving 30 mg (0,069 mmole, 62%) amorphous amide 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid, MS (ES, m/z): 433 [M+H]+.

Example 93

N-[6-(4-Hydroxymethylimidazole-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A solution of methyl ester 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid (300 mg, 0.67 mmole) in 5 ml of a mixture (1:1) dioxane and water was treated with sodium borohydride (40 mg, 1 mmol) and was stirred over night. After evaporation in vacuo the residue was purified preparative HPLC, receiving 20 mg (0,048 mmole, 7%) of N-[6-(4-hydroxymethylimidazole-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide, tPL225-230°C. MS (ES, m/z: 420 [M+H]+.

Example 94

N-[6-(4-Cyanomelana-1-yl)-2,4-dioxo-7-tripto the methyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

A solution of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid (3.2 g, 11,98 mmole), 1H-imidazole-4-carbonitrile (2,017 g, 14,37 mmole) and ethyldiethanolamine (8,4 ml, 47,9 mmole) in 10 ml of dioxane was heated at boiling for 24 hours the Solution was allowed to cool to room temperature and was evaporated. The residue was chromatographically on silica gel using a gradient of dichloromethane and methanol, getting 0.36 g (1.05 mmole, 8,8%) amorphous methyl ester 5-(4-cyanomelana-1-yl)-2-nitro-4-triftorperasin acid, MS (ES, m/z): 341 [M+H]+.

A solution of 350 mg (equivalent to 1.03 mmole) of the methyl ester 5-(4-cyanomelana-1-yl)-2-nitro-4-triftorperasin acid in 100 ml of methanol was treated with 22 mg of 10% palladium on coal and was first made at room temperature under hydrogen pressure of 1 bar for 16 hours After separation of the catalyst by filtration, the residue was chromatographically on silica gel using dichloromethane and increasing to 15% of methanol, receiving 35 mg (0,113 mmole, 11%) amorphous methyl ester 2-amino-5-(4-cyanomelana-1-yl)-4-triftorperasin acid, MS (ES, m/z): 311 [M+H]+.

A solution of methyl ester 2-amino-5-(4-cyanomelana-1-yl)-4-trifluoromethyl-benzoic acid (35 mg, 0,113 mmole) in dioxane (25 ml) was treated with ethyldiethanolamine is (0.5 ml, 2.86 mmole) and triphosgene (34 mg, 0,113 mmole) and the mixture was stirred at 80°C for 1 h was Added methysulfonylmethane (13 mg, 0,113 mmole) and stirring was continued for 1 h After cooling to room temperature the solution was concentrated in vacuo and the residue was chromatographically on silica gel, receiving 20 mg (0,048 mmole, 42%) of N-[6-(4-cyanomelana-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide, tPL143-145°C. MS (ES, m/z): 415 [M+H]+.

Example 95

N-[6-(4-Bromoimidazo-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

Just as in the previous example, a solution of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid (1 g, of 3.73 mmole), 4-bromoimidazo (0.68 g, 4.5 mmole) and N-ethyldiethanolamine (2,62 ml, 14.9 mmole) in 10 ml of dioxane was heated at boiling for 16 hours After appropriate processing procedures was obtained 1.4 g (3,55 mmole, 95%) methyl ester 5-(4-bromoimidazo-1-yl)-2-nitro-4-triftorperasin acid, tPL90°C. MS (ES, m/z): 395 [M+H]+.

Similarly a solution of methyl ester 5-(4-bromoimidazo-1-yl)-2-nitro-4-triftorperasin acid (300 mg, 0.8 mmole) in 50 ml of methanol was first made over 43 mg of 10% palladium on charcoal, to get after the usual procedure of 160 mg (0,466 mmole, 58%) methyl ester 2-amino-5-(4-br is imidazol-1-yl)-4-triftorperasin acid, tPL163-165°C. MS (ES, m/z): 365 [M+H]+.

Similarly a solution of methyl ester 2-amino-5-(4-bromoimidazo-1-yl)-4-triftorperasin acid (160 mg, 0,439 mmole) and ethyldiethanolamine (of 0.52 ml, 3 mmole) in 100 ml dioxane was treated first by triphosgene (132 mg, 0,439 mmole) and then methysulfonylmethane (49 mg, 0,439 mmole), after receiving conventional treatment 95 mg (0.2 mmole, 46%) of N-[6-(4-bromoimidazo-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide, tPL229-233°SMS (ES, m/z): 469 [M+H]+.

Example 96

N-[6-(4-Cryptomaterial-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

Similarly a solution of methyl ester of 5-fluoro-2-nitro-4-cryptomerioides acid (1.5 g, 5,62 mmole), 4-cryptomaterial (0,945 g, 6,74 mmole) and ethyldiethanolamine (3,94 ml, 22.5 mmole) in 10 ml of dioxane was heated at boiling for 48 hours After the procedure was obtained 1.4 g (3.65 mmole, 65%) amorphous methyl ester 5-(4-cryptomaterial-1-yl)-2-nitro-4-triftorperasin acid, MS (ES, m/z): 384 [M+H]+.

Similarly a solution of methyl ester 5-(4-cryptomaterial-1-yl)-2-nitro-4-triftorperasin acid (1.0 g, 2.6 mmole) in 100 ml of methanol was first made over 55 mg of 10% palladium on charcoal, to get after the usual procedure clicks the processing 840 mg (2,38 mmole, 91%) of amorphous methyl ester 2-amino-5-(4-cryptomaterial-1-yl)-4-triftorperasin acid, MS (ES, m/z): 354 [M+H]+.

Similarly a solution of methyl ester 2-amino-5-(4-trifluoromethyl-imidazol-1-yl)-4-triftorperasin acid (840 mg, of 2.38 mmole) and ethyldiethanolamine (4 ml mmole) in 100 ml dioxane was treated first by triphosgene (706 mg, of 2.38 mmole) and then methysulfonylmethane (262 mg, of 2.38 mmole), after receiving the usual treatment of 470 mg (equivalent to 1.03 mmole, 43%) of N-[6-(4-cryptomaterial-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide, tPL144-147°SMS (ES, m/z): 458 [M+H]+.

Example 97

N-(2,4-Dioxo-6-pyrrol-1-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide:

A solution of 80 mg (0,236 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and 0,092 ml (0,709 mmole) of 2,5-dimethoxyethane-hydrofuran in 1.5 ml of acetic acid was heated at boiling for 2 hours After evaporation of the solvent on the rotary evaporator, the residue was purified by chromatography on reversed phase (C18) with a gradient of acetonitrile-water and the product liofilizirovanny, receiving 54 mg (59%) of N-(2,4-dioxo-6-pyrrol-1-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in a solid brown color. MS (ES, m/e): 389 [M+H]+.

Example 98

N-[6-(3-Formyl rol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a solution of 100 mg (0,296 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in 2 ml of acetic acid was added a solution of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde in 1 ml of acetic acid and the mixture was heated at boiling for 3 hours the Solvent was removed by evaporation on a rotary evaporator and the brown oil was purified by chromatography on reversed phase (C18) with a gradient of acetonitrile-water, receiving 80 mg (65%) of N-[6-(3-formylphenol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in a solid black color. MS (ES, m/e):

417 [M+H]+.

Example 99

N-[6-(2-Hydroxy-1-phenylethylamine)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a solution 0,101 ml (0,887 mmole) of styrene oxide in 1 ml of acetonitrile was added 242 mg (or 1.77 mmole) of zinc chloride and the mixture was stirred for 15 minutes To the resulting white suspension was added 50 mg (0,148 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and the mixture was stirred at 70°C for 90 min was Added addition of 0.017 ml (0,147 mmole) of styrene oxide and the mixture was stirred for further 30 minutes at 70°C. the Solvent was evaporated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed with water, R is the target of potassium carbonate (1 M) and an aqueous solution of citric acid (10%). The crude product was purified by chromatography on reversed phase (C18)using a gradient of acetonitrile-water. When lyophilization received 12 mg of N-[6-(2-hydroxy-1-phenylethylamine)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide in a solid yellow color. MS (ES, m/e): 459 [M+H]+.

Example 100

1-(3-Benzosulfimide-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-hinzelin-6-yl)-1H-imidazole-4-carboxylic acid:

Suspended 200 mg (of 0.58 mmole) of methyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-imidazole-4-carboxylic acid in 3 ml of tetrahydrofuran was added 209 mg (of 0.71 mmole) of triphosgene. Ten minutes later was added to the suspension 0,112 ml diisopropylethylamine. A clear solution was stirred for additional 2 h at room temperature and half of the solvent was evaporated. Then through a syringe was added a solution of 121 mg (0,705 mmole) benzosulphochloride in anhydrous tetrahydrofuran. The resulting suspension was stirred for 20 min at 60°C, then was treated with 2 ml of 1 M aqueous sodium hydroxide solution and was stirred for 6 h at room temperature to complete the saponification of ester. After evaporation of the solvents the residue was dissolved in ethyl acetate, the solvent extract was dried, Phil is trevali and evaporated, getting 1-(3-benzosulfimide-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid.1H-NMR (DMSO-d6, 400 MHz, ppm): 8,15 (s, 1H, imidazole); 8,10 (s, 1H, imidazole); to 7.99 (s, 1H, aromatics); 7,71 (s, 1H, aromatics); LC-MS: 494 [M-N]-; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

The original connection, methyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-imidazole-4-carboxylic acid, was prepared as follows:

To a solution of 8.00 g (29,95 mmole) of methyl ester of 5-fluoro-2-nitro-4-triftorperasin acid in 40 ml of anhydrous tetrahydrofuran was added to 5.40 g (42,00 mmole) methyl ester 1H-imidazole-4-carboxylic acid. The reaction mixture was stirred at 70°C for 48 h (after 16 h the addition of 0.3 equivalent methyl ester 1H-imidazole-4-carboxylic acid). Then the solvent was evaporated and the residue is a light brown color was extracted with dichloromethane. The combined organic extracts were dried, the solvent was evaporated, obtaining crystals of pale purple. The crude product was purified flash chromatography (dichloromethane/methanol (100:90/0:10)to give methyl ester 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-imidazol-4-carbon is howling acid. 1H-NMR (DMSO-d6, 400 MHz, ppm): 8,71 (s, 1H, aromatics); 8,31 (s, 1H, aromatics); of 8.27 (s, 1H, imidazole); of 8.09 (s, 1H, imidazole); to 3.92 (s, 3H, Ar-SOON3); of 3.80 (s, 3H, SOON3); LC-MS: 374 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

A solution of 4.4 g (to 11.79 mmole) of methyl ester 1-(5-methoxycarbonyl-4-nitro-2-triptoreline)-1H-imidazole-4-carboxylic acid in 400 ml of methanol was treated with 400 mg of 10% palladium on coal and was first made at room temperature under hydrogen pressure of 60 pounds/inch2within 2 hours After separation of the catalyst by filtration through a layer of Hyflo SuperCel® and evaporation of the solvent was obtained pure methyl ester 1-(4-amino-5-methoxycarbonyl-2-triptoreline)-1H-imidazole-4-carboxylic acid in the form of a solid white color.1H-NMR (DMSO-d6, 400 MHz, ppm): 8,03 (s, 1H, aromatics); 7,87 (s, 1H, aromatics); for 7.78 (s, 1H, imidazole); to 7.35 (s, 1H, imidazole); is 3.82 (s, 3H, Ar-SOON3); of 3.77 (s, 3H, SOON3); LC-MS: 344 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 101

Methyl ether (3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroxy the Zolin-6-yl)carbamino acid:

To a solution of 40 mg (0.12 mmole) of N-(2,5-diamino-4-trifloromethyl)-methanesulfonamide in 1 ml of tetrahydrofuran and 0.04 ml of ethyldiethanolamine was added to 0.11 ml of 0.20 mmole) solution of phosgene in toluene (0,94 g/ml). The reaction mixture was stirred at 110°C. in a microwave reactor for 10 minutes the Mixture was cooled to room temperature and was poured into methanol, the solvent was evaporated giving a solid yellow color. The crude product was extracted with ethyl acetate and water. The organic fractions were combined, dried and evaporated, obtaining methyl ether (3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbamino acid, tPL232,4-240,2°C.1H-NMR (DMSO-d6, 400 MHz, ppm): to 7.95 (s, 1H, aromatics); 7,51 (s, 1H, aromatics); to 3.64 (s, 3H, SOON3); 3.15 in (s, 3H, SO2CH3). LC-MS: 397 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

The original compound, N-(2,5-diamino-4-trifloromethyl)meanswhen-hydrazide was obtained as follows.

To a solution of 490 mg (of 1.85 mmole) methyl ester 2-amino-5-nitro-4-triftorperasin acid in 5 ml of methanol was added to 4.7 ml (9,27 mmole) of 2 M sodium hydroxide solution. VC is the first solution was stirred at 60°C for 12 hours Then was added hydrochloric acid (1 M)to bring the pH value to 2. The volume of solvent was reduced by evaporation and the residue was extracted with ethyl acetate. The organic layers were combined, dried and the solvent was evaporated, obtaining 2-amino-5-nitro-4-triftorperasin acid.1H-NMR (DMSO-d6, 400 MHz, ppm): 8,58 (s, 1H, aromatics); 8,10 (s (ush.), 2H, NH2); 7,35 ('s. 1H, aromatics).; LC-MS: 249 [M-N]-; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, 4,6h50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

To a solution of 400 mg (1,60 mmole) of 2-amino-5-nitro-4-triftorperasin acid in 1 ml of dimethylformamide was added 363 mg (1,76 mmole) N,N'-dicyclohexylcarbodiimide and 0.21 ml (1,92 mmole) N-methylmorpholine and the solution was left to mix at room temperature for 10 minutes and Then was added 73 mg (0.48 mmole) of the monohydrate of 1-hydroxybenzotriazole and 705 mg (6,40 mmole) methanesulfonanilide and the reaction mixture was stirred at 40°C for 12 h the Solvent was evaporated and the yellow residue was extracted with ethyl acetate and the solution 1 M hydrochloric acid. The organic fractions were combined, dried, evaporated and purified flash chromatography (gradient 0-40% cyclohexane/ethyl acetate)to give N-(2-amino-5-nitro-4-trifloromethyl)-meta is sulfohydrazide, tPL221,2-226,8°C;1H-NMR (DMSO-d6, 400 MHz, ppm): 8,54 (s, 1H, aromatics); 7,89 (s (ush.), 2H, NH2); 7,33 (s, 1H, aromatics); to 3.02 (s, 3H, SO2-CH3). LC-MS: 341 [M-H]-; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

To a solution of 80 mg (0,23 mmole) of N-(2-amino-5-nitro-4-trifloromethyl)-methanesulfonamide 1.5 ml of concentrated hydrochloric acid was added 270 mg (1,17 mmole) chloride dihydrate tin(II) and the mixture was stirred at room temperature for 20 minutes the Mixture was neutralized at 0°C with an aqueous solution of ammonia. The product was extracted with ethyl acetate. The combined organic fractions were dried, evaporated and purified flash chromatography (gradient 0-70% cyclohexane/ethyl acetate)to give N-(2,5-diamino-4-trifloromethyl)-methanesulfonamide in the form of cleaners containing hydrochloride salt, tPL220,8-225,5°C;1H-NMR (DMSO-d6, 400 MHz, ppm): 6,98 (s, 1H, aromatics); to 6.88 (s, 1H, aromatics); 2,98 (s, 3H, SO2-CH3). LC-MS: 313 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 102

N-[6-(2-Methylpyrrole-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin--yl]methanesulfonamide:

To a solution of 200 mg (0,59 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in 10 ml of acetic acid was added 87 mg (0.60 mmole) of 2-methyl-2,5-dimethoxytetrahydrofuran and the reaction mixture was stirred at boiling for 5 hours Then the solvent was evaporated and the residue was dried for 1 day at 60°C and high vacuum, obtaining N-[6-(2-methylpyrrole-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide.1H-NMR (DMSO-d6, 400 MHz, ppm): of 7.69 (s, 1H, aromatics); rate of 7.54 (s, 1H, aromatics); and 6.6 (s, 1H, N-CH=SN in the pyrrole); 5,97 (t, 1H, CH=CH=SN in the pyrrole); of 5.83 (m, 1H, CH=CH- (CH3)-N-pyrrole); 3,05 (s, 3H, SO2-CH3); is 1.82 (s, 3H, pyrrole-1-CH3). LC-MS: 403 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 103

Methyl ester 1-(3-benzosulfimide-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid:

A solution of 20 mg (0.04 mmole) of 1-(3-benzosulfimide-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid in 50 ml of 6 M hydrochloric acid in methanol was stirred at 70°C for 2 days. Every half-day priba the Lyali additional 50 ml of 6 M hydrochloric acid in methanol. Then the solvent and hydrochloric acid was evaporated, obtaining methyl ester 1-(3-benzosulfimide-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-imidazole-4-carboxylic acid;1H-NMR (DMSO-d6, 400 MHz, ppm): 8,16 (s, 1H, imidazole); 8,10 (s, 1H, aromatics); 7,98 (s, 1H, imidazole); of 7.70 (s, 1H, aromatics); 3,79 (s, 3H, SOON3). LC-MS: 510 [M+H]+; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; positive ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 104

1-(3-Methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-pyrrol-3-ymetray ether acetic acid:

To a solution of 130 mg (0,39 mmole) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in 5 ml of acetic acid was added a solution of 95 mg (0,39 mmole) of 2-(2,5-dimethoxytetrahydrofuran-3-ylethoxy)tetrahydro-Piran (obtained according to Frydman, Benjamin; Ojea, Maria I. 1,4-Diaminobutanes from furans: a new synthetic approach to substituted putrescines. Tetrahedron Letters (1998), 39(27), SS-4768) and the reaction mixture was stirred at boiling for 3 hours the Solvent was evaporated in high vacuum, obtaining 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-pyrrol-3-ymetray ether acetic acid.1H-NMR (DMSO-d6, 400 MHz, ppm): a 7.85 (s, 1H, aromatics); 762 (s, 1H, aromatics); 7,03 (s, 1H, N-CH=C(CH2) pyrrole); 6,91 (m, 1H, N-CH=CH pyrrole); 6,27 (m, 1H, CH=CH- (CH2)-N-pyrrole); 4,96 (s, 2H,CH2OSON3); and 3.16 (s, 3H, SO2-CH3); 2,03 (s, 3H, CH2-OCOCH3); LC-MS: 459 [M-H]-; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 105

N-[6-(3-Hydroxymethylfurfural-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a solution of 100 mg (0.22 mmole) of 1-(3-methanesulfonamido-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-6-yl)-1H-pyrrol-3-Eletropaulo ester of acetic acid in 0.5 ml of methanol was added of 36.4 mg (0,26 mmole) of potassium carbonate and the reaction mixture was stirred at 55°C for 8 hours the Mixture was cooled to room temperature and stirred for another 12 hours Then the reaction mixture for neutralization was added a solution of phosphate buffer, pH 7, and the solvent was carefully evaporated (danger of degradation). The crude residue was purified preparative thin-layer chromatography (dichloromethane/methanol (8:2))to give N-[6-(3-hydroxymethylfurfural-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide.1H-NMR (DMSO-d6, 400 MHz, ppm): of 7.82 (s, 1H, aromatics); to 7.64 (s, 1H, aromatics); 6,86 (m, 1, N-CH=CH pyrrole); at 6.84 (s, 1H, N-CH=C(CH2) pyrrole); 6,21 (m, 1H, CH=CH- (CH2)-N-pyrrole); 4,37 (d, 2H, CH2-HE); and 3.16 (s, 3H, SO3-CH3); LC-MS: 417 [M-N]-; the instrument Agilent LC/MSD series 1100; LC-MS: column SunFireC18, 4,6h50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Example 106

N-[6-(4-Methyl-2-oxo-2,3-dihydropyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide:

To a solution of 60 mg of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide in 5 ml of acetic acid was added 26 mg (of 0.18 mmole) of 2,5-dimethoxy-3-methyltetrahydrofuran (obtained according to Markwell, Roger Edward; Hadley, Michael Stewart; Blaney, Frank Edward. Azabicycloalkane derivatives and medicaments containing them. Eur. Pat. Appl. (1983) EP 95262 A1). The reaction mixture was stirred at boiling for 10 hours Then the solvent was evaporated and the crude product was purified flash chromatography (cyclohexane/ethyl acetate from 100:0 to 20:80)to give N-[6-(4-methyl-2-oxo-2,3-dihydropyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl]methanesulfonamide.1H-NMR (DMSO-d6, 400 MHz, ppm): of 8.06 (s, 1H, aromatics); of 7.60 (s, 1H, aromatics); 7,13 (m, 1H, H-CH=C(CH3)); 4,24 (s, 2H,-CH2- (CH3)); and 3.16 (s, 3H, SO2-CH3); of 1.84 (d, 3H, CH3); LC-MS: 417 [M-N]-; the instrument Agilent LC/MSD series 1100; LC-M is: column SunFireC18, a 4.6×50 mm, particle size 3.5 µm; negative ions; water/acetonitrile (95:5 to 5:95 in 5 min, flow rate 1.5 ml/min

Biological assays

The binding of AMPA receptor

This may be demonstrated in standard tests, for example in the test binding of [3N]-6-cyano-7-nitrogenation-2,3-dione ([3H]-CNQX) (nré and others, Biochem. Pharmacol. 1989, 38: SS-3212). This test is carried out as follows.

The membranes of the brain. Animals decapitate, brains were removed and homogenized in 10 volumes of ice 10% sucrose in a glass/Teflon homogenizer in positions 5 within 30 seconds Membrane centrifuged at 1000 g for 10 min and the supernatant centrifuged at 20000 g for 15 minutes the resulting precipitate is again suspended in 10 volumes of cold water with a tissue homogenizer (Brinkman, transmitter station) in position 5 in 15 seconds and the suspension is centrifuged at 8000 g for 10 min. the Supernatant, including the yellow layer, centrifuged at 40,000 g for 20 min, the precipitate suspended again 5 volumes of water and the suspension is frozen (20-30 min in a mixture of dry ice/methanol) and thaw (water bath at 37°C) twice. The suspension is centrifuged at 40,000 g for 20 min, the precipitate is again suspended in 50 mm HEPES/KOH, pH 7.5, and centrifuged at 40,000 g for 10 minutes the resulting sludge is again suspended with a glass/Teflon homogenizer in 5 of the volume of the buffer HEPES/KOH; aliquots of 2 ml of cryopreserved and stored in liquid nitrogen.

Pre-treatment of the membranes. Membranes are thawed at 35°C and once washed with 50 mm HEPES/KOH by centrifugation at 39000 g for 10 min Final precipitate again suspended with a glass/Teflon homogenizer in the same buffer.

Analysis of the binding of radioligand. It is carried out using 96-well titration microplate in a volume containing 0.3 ml of 50 mm HEPES/KOH, rn,2, 100 μg of membrane protein, 5 nm [3H]-CNQX (NEN) and the connection that should be investigated. Incubation was performed at 4°C for 40 min and the reaction is stopped by centrifugation (Sigma 4K10) at 3700 g for 30 minutes the Precipitate is washed once with cold buffer, and then dissolved in 0.02 ml of tissue solubilizer Soluene for 20 minutes Add two hundred μl of scintillation fluid Microscint 20 (Packard) and the radioactivity counted in a scintillation counter Packard Topcount efficiency of 40-45%. Nonspecific binding is determined using 10 μm CNQX. The analyses are carried out three times. For example, in this analysis the compound of example 4 had a value IC500.29 micrometers.

Functional test for AMPA-receptor activity

To determine the functional agonism or antagonism against AMPA receptor were carried out experiments on Xenopus oocytes, as previously the center described (Urwyler and others, Mol. Pharmacol. 2001, 60, cs-971). Briefly, data logging two-electrode voltage-clamp carried out from Xenopus laevis oocytes expressing the receptor GluR3 AMPA. The plasmids for rat GluR3 subunit-(flop) (Hollmann and others, Science 1991, 252, SS-853) linearized and are transcribed in kupirovaniu crnc using a set of RNA synthesis in vitro (Ambion, Texas) with T7 polymerase. The starting solutions containing 70% ethanol. Before using crnc is deposited and again suspendered in water, treated with diethylpyrocarbonate (DEPC). The oocytes injected with RNA encoding the rat receptor GluR3-(flop) AMPA. For registration, the oocytes are placed in a perfusion chamber with a continuous gravity frog ringer's solution. For data recording from oocytes expressing receptors rGluR3-(flop), is used frog ringer's solution containing Mg2+(81 mm NaCl; 2.5 mm KCl; 1 mm CaCl2; 1 mm MgCl2, 2.5 mm NaHCO3, 5 mm HEPES, pH 7,4). The compounds are washed with gravity. For example, in this analysis the compound from example 4 is an antagonist against receptor rGluR3 AMPA with the value of the IC50the 2.3 ám.

Audiogone model fits

Compounds according to the invention have, for example, pronounced anticonvulsive properties that define in vivo, for example, in mice, with reference to their pronounced protective effect against convulsions caused by the sound, electric shock or metrazole. Caused by sound seizures are seen in mice of the DBA/2 (R.L.Collins in: Experimental models of epilepsy, as amended Pupura, Penry Tower, Walter Woodbury; Raven Press, New York, 1972). For the study of 20-day-old animals are placed in a chamber with poor sound. After a period of habituation 60 with animals excite, using narrow-band noise (14-20 kHz, the sound pressure level (SPL) 118 dB), continued at most 60 C. Mouse DBA/2 respond to acoustic stimuli sequence uncontrolled running, clonic seizures, tonic seizures and stopped breathing. For data analysis measured the presence and duration of different behavioral phases. Calculated values of the ED50for different behavioral phases. The values of the ED50after systemic use of drugs (intraperitoneal, subcutaneous, oral) are in the range between 0.5 and 100 mg/kg

In addition, the compounds according to the invention show a pronounced effect on the well-developed murine models of electric shock or murine model convulsions caused by metrazol, according to Schmutz and others, Naunyn-Schmiedeberg''s Arch. Pharmacol. 1990, 342, SS-66. The values of the ED50are in the range between 1 and 200 mg/kg

Antihistaminics activity of the compounds according to the invention can be demonstrated, for example, in the test of hyperlocomotion, call the Anna amphetamine. Blockade of hyperlocomotion caused by amphetamine, well known as a kind of screening antihistaminics activity.

In addition, the compounds of formula (I) (also referred to as antagonists of the AMPA receptor) can be combined with other active ingredients ("combined preparation").

The structure of other active ingredients identified by code numbers, generic or trade names may be taken from the latest edition of the standard reference edition "The Merck Index" or from databases, e.g., international patent (e.g. IMS World Publications). Appropriate their contents are hereby incorporated by citation. Any specialist in this field are quite able to identify the active ingredients and on the basis of these references can also get them to explore the pharmaceutical indications and properties in standard test models both in vitro and in vivo.

The term "a combined preparation", as used in the context determines mainly a "kit of parts" in the sense that the first and second active ingredients as defined above can be dosed independently or by use of different predetermined combinations with distinguished amounts of the ingredients, i.e. simultaneously or at different time points. Parts set of parts can then, e.g. the, to be introduced simultaneously or chronologically differentiated, i.e. at different time points and with equal or different time intervals for any part of the kit parts. Rather it is preferable to choose the time intervals so that the effect on the treated disease in the combined use of the parts was greater than the impact that could be obtained using only one of the active ingredients. The ratio of total amounts of the active ingredient 1 to the active ingredient 2, which must be entered in the combined preparation may vary, for example, in order to satisfy the needs of a subpopulation of patients undergoing treatment, or one patient, whose requests can vary due to age, sex, body weight, etc. Preferably has at least one beneficial effect, for example the joint impact of the first and second active ingredients, in particular a synergism, e.g. a more than additive effect, additional beneficial effects, less side effects, a combined therapeutical effect in ineffective dose of one or both of the first and second active ingredients, and is particularly strong synergistic action of the first and second active ingredients.

When discussing ways to be on the up, that links to the active ingredients also mean the inclusion of pharmaceutically acceptable salts. If the data of the active ingredients are, for example, at least one basic center, they can form acid additive salt. The corresponding acid additive salts may also be formed having optionally present basically the center. Active ingredients having an acid group (for example COOH)can also form salts with bases. The active ingredient or its pharmaceutically acceptable salt can also be applied in the form of a hydrate or may include other solvents used for crystallization.

Such a combination of drugs have favorable pharmaceutical effects, for example, such drugs are synergistic action. A combination of drugs can be used according to the indications listed in this description. The invention provides a method of application of the combined drugs to prevent, treat, delay of progression of disorders and diseases mentioned in this description.

Below are the combination and application of special significance.

Thus, in a further aspect the invention relates to a combination that includes at least one compound of formula (I) ("the antagonist is eceptor AMR") and at least one nootrop. In such combinations of active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally present at least one pharmaceutically acceptable carrier; the combination is intended for simultaneous, separate or sequential use.

The term "memory"as it is used in a context that includes, but without limitation, nootropic plant extracts, calcium antagonists, cholinesterase inhibitors, dihydroergotoxine, nicergoline, piracetam, a derivative of purine, pyritinol, vincamine and Vinpocetine. In a preferred variant embodiment of the invention component combination is a cholinesterase inhibitor.

The term "nootropic plant extracts", as it is used in a context that includes, but without limitation, the extracts from the leaves of Ginkgo. The term "calcium antagonists"as used in the context, includes, but without limitation, Cinnarizine and nimodipine. The term "cholinesterase inhibitors", as used in the context, includes, but without limitation, hydrochloride donepezil, rivastigmine and galantamine hydrobromide. The term "purine derivatives"as it is used in a context that includes, but without limitation, peniillin.

Extracts from the leaves of Ginkgo can be introduced, for example, in a form that implements narince, for example, under the trademark of ginatilan™, according to the information provided in the package insert. Cinnarizine can be entered, for example, in a form that is sold on the market, e.g. under the trademark Cinnarizine Forte-Ratiopharm™. Nimodipine may be entered, for example, in a form that is sold on the market, for example, under the trade name nimotop™. Hydrochloride donepezil can be entered, for example, in a form that is sold on the market, for example, under the trade name aricept™. Rivastigmine can be obtained, as disclosed in patent US 5602176. It can be entered, for example, in a form that is sold on the market, for example, under the trade name Exelon™. The galantamine hydrobromide can be entered, for example, in a form that is sold on the market, for example, under the trade name reminyl™. Dihydroergotoxine can be entered, for example, in a form that is sold on the market, for example, under the trademark of hydergine™. Nicergoline can be entered, for example, in a form that is sold on the market, for example, under the brand name of the pharmacological™. Piracetam can be entered, for example, in a form that is sold on the market, for example, under the brand name of cerebriform™. Peniillin can be entered, for example, in a form that is sold on the market, e.g. under the trademark coalton™. Pyritinol can be put in place is Yong, for example, in a form that is sold on the market, e.g. under the trademark engjefabol™. Vinpocetine can be entered, for example, in a form that is sold on the market, e.g. under the trademark Cavinton™.

The structure of the active ingredients identified by code numbers, generic or trade names mentioned in the context, can be taken from the latest edition of the standard reference edition "The Merck Index" or from databases, e.g., international patent (e.g. IMS World Publications). Appropriate their contents are hereby incorporated by citation. Any specialist in this field are quite able to identify the active ingredients and on the basis of these references can also get to explore the pharmaceutical indications and properties in standard test models both in vitro and in vivo.

When discussing the ways it will be understood that references to the active ingredients also mean the inclusion of pharmaceutically acceptable salts. If the data of the active ingredients are, for example, at least one basic center, they can form acid additive salt. The corresponding acid additive salts may also be formed having optionally present basically the center. Active ingredients having an acid group (for example COOH), can that is the same to form salts with bases. The active ingredient or its pharmaceutically acceptable salt can also be applied in the form of a hydrate or may include other solvents used for crystallization.

When part of the combination used in combination according to the invention, applied in the form in which they are marketed as individual drugs, their dosage and the type of injection can be carried out according to the information provided on the sheet appropriate boxes sold in the market of the drug in order to result in a favorable effect described in the context of, if not stated otherwise. In particular, Cinnarizine can be administered to the patient in a total daily dose of between about 75 mg to about 150 mg of Nimodipine may be administered to the patient in a total daily dose of between about 60 mg to about 120 mg of donepezil Hydrochloride can be administered to the patient in a total daily dose of between about 5 mg and 10 mg of Rivastigmine can be administered to the patient in a total daily dose of between about 6 mg to about 12 mg Galantamine can be administered to the patient in a total daily dose of between about 12 mg and 24 mg, for example, 12 mg twice a day. Dihydroergotoxine can be introduced in the form of his methansulfonate the patient in a total daily dose of between about 4 mg and 10 mg, for example about 8 mg. Nicergoline to be introduced in the form of tartrate intramuscular injection to a patient in a total daily dose of between about 4 mg and 8 mg Piracetam can be administered to the patient in a total daily dose of between about 1200 mg and 5000 mg, such as 4800 mg/day. Peniillin can be administered to the patient in a total daily dose of between about 400 mg and 800 mg of Pyritinol can be introduced in the form of its hydrochloride to a patient in a total daily dose of about 600 mg of Vinpocetine can be administered to the patient in a total daily dose of between about 10 mg and 15 mg

In a further aspect the invention provides a combination that includes at least one AMPA receptor antagonist and at least one compound selected from the group consisting of (a) anti-epileptic drug, selected from barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, suktinimidov, valproic acid and other derivatives of fatty acids and other anti-epileptic drugs, and/or (b) conventional antipsychotic agents, and/or (C) atypical antipsychotic agents, the effect of which in combined drug more than additive. Furthermore, the combination disclosed in the context, can be applied for the treatment of schizophrenia, which is resistant to monotherapy using only one of the components of the combination.

The term "barbiturates and derivatives thereof," as it is used in a context that includes, but without limitation, phenobarbital, pentobarbital, mephobarbital and amidon. The term "benzodiazepines", as it is used in a context that includes, but without limitation, clonazepam, diazepam and lorazepam. The term "carboxamide"as it is used in a context that includes, but is not limited to, carbamazepine, oxcarbazepine, 10-hydroxy-10,11-dihydrocarbamazepine and the compounds of formula (II)

where R1' is (C1-C3)alkylsulphonyl. The term "hydantoins", as it is used in a context that includes, but without limitation, phenytoin. The term "suktinimida"as it is used in a context that includes, but without limitation, ethosuximide, phensuximide and mesuximide. The term "volpaia acid and other derivatives of fatty acids," as it is used in a context that includes, but without limitation, the sodium salt of valproic acid, monohydrate hydrochloride of tiagabine and vigabatrin. The term "other anti-epileptic drugs"as it is used in a context that includes, but without limitation, levetiracetam, lamotrigine, gabapentin, Altium, felbamate, 1,2,3-1H-triazole disclosed in the European patent EP 114347, and 2-aryl-8-oxidiser-purines disclosed in the international application WO 99/28320.

The term "conventional antipsychotic drugs," as it is used in a context that includes, but not limited to haloperidol, fluphenazine, thiothixene and flupentixol.

The term "atypical, antipsychotic the ski drugs", as it is used in context, refers to clozaril, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole.

The structure of the active ingredients identified by code numbers, generic or trade names, and obtaining them can be taken from the latest edition of the standard reference edition "The Merck Index" (for example, M.J.O'Nell and others, as amended, "The Merck Index", 13-e edition, Merck Research Laboratories, 2001) or from databases, e.g. international patents (e.g. IMS World Publications). Appropriate their contents are hereby incorporated by citation. Any specialist in this field are quite able to identify the active ingredients and on the basis of these references can also get them to explore the pharmaceutical indications and properties in standard test models both in vitro and in vivo.

In a further aspect the invention provides a combination that includes at least one AMPA receptor antagonist and at least one compound selected from the group consisting of drugs, preventing anxiety, antidepressants, antihistamines, anticonvulsants, vasodilating agents, zinc salts and anesthetics, the effect of which in combined preparations more than additive. Furthermore, the combination disclosed in the context, can be used for the treatment of tinnitus, which ostoich is in to monotherapy, using only one of the components of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of drugs, preventing anxiety, antidepressants, antihistamines, anticonvulsants, vasodilating agents, zinc salts and anesthetics, in which the active ingredients are in each case present in free form or in the form of pharmaceutically acceptable salts, and includes the optional at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential administration.

The term "AMPA receptor antagonists"as used in the context, includes the compounds of formula (I).

The term "drug, preventing anxiety"as it is used in a context that includes, but without limitation, alprazolam.

The term "antidepressant"as it is used in a context that includes, but without limitation, nortriptyline (N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ilidene)Propylamine).

The term "anticonvulsants"as it is used in a context that includes, but without limitation, oxcarbazepine.

The term "anesthesia"as it is used in a context that includes,but without limitation, lidocaine.

The term "vasodilator drugs"as it is used in a context that includes, but without limitation, pentoxifylline.

The term "zinc salts", as used in the context, include, but are not limited to, zinc sulfate.

Topiramate may be entered, for example, in the form in which it is sold, for example, under the brand name topamax™. The compounds of formula (I), as well as methods for their preparation and their compositions are known, for example, international application WO 98/17672. Alprazolam may be entered, for example, in the form in which it is sold, for example, under the brand name xanax™. Nortriptyline can be entered, for example, in the form in which it is sold, for example, under the trade name trileptal™. Oxcarbazepine may be entered, for example, in the form in which it is sold, for example, under the trade name trileptal™. Lidocaine can be injected in the form of its hydrochloride, for example in the form in which it is sold on the market as injection solution, for example, under the trade name hevener™, zinc sulfate may be entered, for example, in the form in which it is sold, for example, under the trade name zinc Sandoz™. Pentoxifylline may be entered, for example, in the form in which it is sold, for example, under the brand name trental™.

Structure the RA of the active ingredients, identified by code numbers, generic or trade names may be taken from the latest edition of the standard reference edition "The Merck Index" or from databases, e.g. international patents (e.g. IMS World Publications). Appropriate their contents are hereby incorporated by citation. Any specialist in this field are quite able to identify the active ingredients and on the basis of these references can also get them to explore the pharmaceutical indications and properties in standard test models both in vitro and in vivo.

In a further aspect the invention provides a combination that includes a compound of formula (I) and anti-epileptic drug, selected from the list consisting of barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, suktinimidov, valproic acid and other derivatives of fatty acids and other anti-epileptic drugs. therapeutic effect of this combination is higher than the additive effect of each individual drug. Furthermore, the combination disclosed in the context, can be applied for the treatment of epilepsy that is resistant to monotherapy using only one of the components of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which which includes two anti-epileptic agent, selected from the list consisting of barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, suktinimidov, valproic acid and other derivatives of fatty acids, AMPA antagonists and other anti-epileptic drugs in which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "barbiturates and derivatives thereof," as it is used in a context that includes, but without limitation, phenobarbital, pentobarbital, mephobarbital and primidone. The term "benzodiazepines", as it is used in a context that includes, but without limitation, clonazepam, diazepam and lorazepam. The term "carboxamide"as it is used in a context that includes, but is not limited to, carbamazepine, oxcarbazepine, 10-hydroxy-10,11-dihydrocarbamazepine and the compounds of formula (II).

In a further aspect the invention provides a combination that includes at least one compound of formula (I) ("AMPA receptor antagonist") and at least one compound selected from the group consisting of lithium, sodium salt valproic acid, conventional antipsychotic agents, atypical antipsychotic Agay is tov, levels of lamotrigine, methylphenidate, antidepressants and anti-epileptic agents, and which is stronger than the additive effect of the combined drugs.

Moreover, such combinations may be used to treat emotional disorders and disorders of attention, which is resistant to monotherapy using only one of the components of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, sodium salt valproic acid, conventional antipsychotic agents, atypical antipsychotic agents, levels of lamotrigine, methylphenidate, antidepressants and anti-epileptic agents, in which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "emotional disturbance, impaired attention," as it is used in a context that includes, but without limitation, bipolar violation, such as manic-depressive psychosis, mania with psychotic features or without impaired attention and hyperactivity (ADHD) and other violations of attention, for example autism, as well as those behavioral States that are characterized by social isolation, such as negative symptoms.

The term "lithium"as it is used in a context that includes, but without limitation, lithium acetate, lithium carbonate, lithium chloride, lithium citrate, and lithium sulfate. The term "conventional antipsychotic agent", as used in the context, include, but are not limited to, haloperidol and fluphenazine. The term "atypical antipsychotic agent," as it is used in a context that includes, but without limitation, olanzapine, heapin and risperidone. The term "antidepressant"as it is used in a context that includes, but without limitation, tricyclic antidepressants, selective inhibitors of reuptake of serotonin (SSRI's) or selective inhibitors of reuptake of serotonin and norepinephrine (SNRI's). A tricyclic antidepressant, is suitable for the present invention, chosen mainly from amitriptyline, butriptyline, clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline, trimipramine, maprotiline, mianserin and mirtazapine. Suitable for the present invention, a selective inhibitor of the reuptake of serotonin choose mainly from fluoxetine, fluvoxamine, sertraline, paroxetine, citalop the AMA and ESCITALOPRAM, and selective inhibitor of the reuptake of serotonin and norepinephrine choose from venlafaxine and DULOXETINE.

The term "anti-epileptic drugs"as it is used in a context that includes, but without limitation, barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, suktinimida, valproate acid and other derivatives of fatty acids, AMPA antagonists and other anti-epileptic drugs in which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "barbiturates and derivatives thereof," as it is used in a context that includes, but without limitation, phenobarbital, pentobarbital, mephobarbital and primidone. The term "benzodiazepines", as it is used in a context that includes, but without limitation, clonazepam, diazepam and lorazepam. The term "carboxamide"as it is used in a context that includes, but is not limited to, carbamazepine, oxcarbazepine, 10-hydroxy-10,11-dihydrocarbamazepine and the compounds of formula (II).

where R1' is (C1-C3)alkylsulphonyl. The term "hydantoins", as it is used in a context that includes, but free is ing, phenytoin. The term "suktinimida"as it is used in a context that includes, but without limitation, ethosuximide, phensuximide and mesuximide. The term "volpaia acid and other derivatives of fatty acids," as it is used in a context that includes, but without limitation, the sodium salt of valproic acid, monohydrate hydrochloride of tiagabine and vigabatrin. The term "other anti-epileptic drugs"as it is used in a context that includes, but without limitation, levetiracetam, lamotrigine, gabapentin, Altium, felbamate, 1,2,3-1H-triazole disclosed in the European patent EP 114347, especially rufinamide, amide [1-(2,6-diferensial)-1H-[1,2,3]triazole-4-carboxylic acid, and 2-aryl-8-oxopiperidine disclosed in the international application WO 99/28320.

In a further aspect the invention provides a combination that includes at least one compound of formula (I) ("AMPA receptor antagonist") and at least one compound selected from the group consisting of benzodiazepines, selective inhibitors of reuptake of serotonin (SSRIs), selective inhibitors of reuptake of serotonin and norepinephrine (SNRIs), buspirone and pregabalin that is stronger than the additive effect of combination drugs. Furthermore, the combination disclosed in the context, can be used to treat anxiety disorders or other psychia the historic disorders with underlying anxiety symptoms, which are resistant to monotherapy using only one component of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of benzodiazepines, selective inhibitors of reuptake of serotonin (SSRIs), selective inhibitors of reuptake of serotonin and norepinephrine (SNRIs), buspirone and pregabalin, in which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "anxiety or other psychiatric disorders with underlying anxiety symptoms"as it is used in a context that includes, but without limitation, anxiety disorders such as General anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, panic and anxiety that occur after discontinuation of psychostimulants, or receiving other psychotropic drugs with nepoverennogopribora.

Selective inhibitor of reuptake of serotonin (SSRI), suitable for the present invention, chosen mainly from fluoxetine, uvoxamine, sertraline, paroxetine, citalopram and ESCITALOPRAM.

Selective inhibitor of the reuptake of serotonin and norepinephrine (SNRI), is suitable for the present invention, chosen mainly from venlafaxine and DULOXETINE.

The term "benzodiazepines", as it is used in a context that includes, but without limitation, clonazepam, diazepam and lorazepam.

In a further aspect the invention provides a combination that includes at least one compound of formula (I) ("AMPA receptor antagonist") and at least one compound selected from the group consisting of pirenzepine, telenzepine, ortho-methoxycyclohexanone, γ-aminobutyric acid (GABA) and GABA agonists, a combination that is stronger than the additive effect of the combined drugs. Furthermore, the combination disclosed in the context, can be applied for the treatment of myopia, which is resistant to monotherapy using only one of the components of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one connection is out, selected from the group consisting of pirenzepine, telenzepine, ortho-methoxysilyl-hexocyclium, γ-aminobutyric acid (GABA) and GABA agonists, in which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

Topiramate may be entered, for example, in the form in which it is sold, for example, under the brand name topamax™. The compounds of formula (I), and the method of their production and their pharmaceutical compositions are known, for example, international application WO 98/17672.

Pirenzepine, telenzepine and ortho-methoxycyclohexyl can be applied, as described in patent US 5122522.

The term "γ-aminobutyric acid (GABA) and GABA agonists"as used in the context, includes, but without limitation, the compounds disclosed in international application WO 03/032975.

In a further aspect the invention provides a combination that includes at least one AMPA receptor antagonist and at least one component of the combination selected from the group consisting of cyclo-oxygenase inhibitors, antagonists vanilloideae receptor, opioids, tricyclic antidepressants, anticonvulsants, inhibit the s cathepsin S and agonists of the receptor SAVA Inthat is stronger than the additive effect of the combined drugs. Furthermore, the combination disclosed in the context, can be applied for treatment of pain that is resistant to monotherapy using only one of the components of the combination.

Consequently, the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one component of the combination selected from the group consisting of cyclo-oxygenase inhibitors, antagonists vanilloideae receptor, opioids, tricyclic antidepressants, anticonvulsants, inhibitors of cathepsin S and receptor agonists GABABin which the active ingredients are in each case present in free form or in the form of a pharmaceutically acceptable salt, and optionally includes at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "pain" refers mainly, but without limitation, to newnational pain.

The term "Cox inhibitors", as used in the context, includes, but without limitation, specific inhibitors of cyclooxygenase-2 (MOR-2), such as celecoxib and rofecoksib, and nonsteroidal anti-inflammatory drugs (NSAID), for example acetylsalicylic acid and propionic acid derivatives.

The term "tricyclic antidepressants"as it is used in a context that includes, but without limitation, anafranil®, Asendin®, aventyl®, elavil®, endep®, normani®, Norpramin®, pamelor®, sinequan®, surmontil®, cipramil®, Tofranil®, vivactil® and Tofranil-PM®.

The term "anticonvulsants"as it is used in a context that includes, but without limitation, oxcarbazepine and gabapentin. The term "inhibitors of cathepsin S," as it is used in a context that includes, but without limitation, the compounds disclosed in international application WO 03/020287. The term "receptor agonists OABAB"as it is used in a context that includes, but without limitation, L-baclofen.

The term "opioid"as it is used in the context, applies to all drugs, both natural and synthetic, with morphine-like effect. Opioid suitable for the present invention, chosen mainly from the group comprising Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclorphan, desomorphine, dextromoramide, dezocine, diampromide, Dihydrocodeine, dihydromorphine, eptazocine, Ethylmorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, levophenacylmorphan, Levorphanol, lofentanil, methylmorphine, morphine, neko is orpin, Normethadone, normorphine, opium, oxycodone, Oxymorphone, Pholcodine, profadol and Sufentanil.

Biological data

Analysis

The binding of AMPA-receptor compounds of the present invention (examples 69 and 73) was assessed as described on p.109-111 description of this application.

The results:

Connection[3H]CNQX IC50, [nm]
Example 6946
Example 7342

Biological tests in vivo

Analysis

Compounds of the present invention (examples 69 and 73) have been tested in animal models of epilepsy, the so-called analysis of the maximal electroshock test (MES as described on str (lines 24-28) the description of this application).

Briefly, the compounds of the present invention were tested on mice OF1 using test maximal electroshock test (MES), as described in detail Schmutz et al., Naunyn-Schmiedeberg's Arch Pharmacol, 1990, t, p.61-66. Induced clonic convulsions hind limbs induced by passing an electric current through temporal electrodes (%0 Hz, 18 A, 0.2 s). Mice treated with media, showed the average duration of attacks 12-14 C. as a positive control line is arranged for 30 mg/kg carbamazepine; mice were considered secure connection, if the duration of the attack was only 3 or less. For each of the treatment conditions used in 5 mice, and in the quality of the data being read was accepted percentage of protected mice (i.e., the connection could give 0%, 20%, 40%, 60%, 80% or 100% protection).

The results:

Connection example 69 was given at a dose of 50 mg/kg, orally, 1 hour before inducing seizures. It gave 20% protection.

Connection example 73 gave metered, oral, 0.25 hour before inducing convulsions, the values of ED50 (ED effective dose) was calculated using GraphPad Prism, v was 4.02. The ED50 value amounted to 10.7 mg/kg

1. 1H-hinzelin-2,4-dione selected from the group consisting of
N-(6-Imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(6-Morpholine-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(7-Nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide,
N-(7-Nitro-2,4-dioxo-6-[1,2,4]triazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(7-Nitro-2,4-dioxo-6-pyrazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(7-Nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(6-Azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide,
N-(7-Nitro-2,4-dioxo-6-[1,2,3]triazole-1-yl-1,4-dihydro-2H-hinzelin-3-yl)-means is lonarid,
N-(6-Morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide,
N-(2,4-Dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide,
(2,4-Dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)amide econsultancy acid,
N-(6-Imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide,
N-(2,4-Dioxo-6-thiomorpholine-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide.
N-(6-[1,4]Oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide and
N-(6-Azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide
and their physiologically acceptable salts.

2. 1H-hinzelin-2,4-dione according to claim 1, which is N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide.

3. 1H-hinzelin-2,4-dione according to claim 1, which is N-(6-morpholine-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide.

4. 1H-hinzelin-2,4-dione according to claim 1, which is N-(2,4-dioxo-6-[1,2,4]triazole-4-yl-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)-methanesulfonamide.

5. 1H-hinzelin-2,4-dione according to claim 1, which is N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide.

6. 1H-hinzelin-2,4-dione according to claim 1, which represent the possessing a N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-hinzelin-3-yl)methanesulfonamide.

7. Pharmaceutical composition having antagonistic activity against AMPA receptor, comprising a compound according to any one of claims 1 to 6 in therapeutically effective amounts.

8. The use of compounds according to any one of claims 1 to 6 to obtain a medicine for the prevention, treatment or delay of progression of a condition mediated by the AMPA receptor.

9. The use of compounds according to any one of claims 1 to 6 to obtain a medicine for the prevention, treatment or delay of progression of epilepsy or schizophrenia.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula I and to their pharmaceutically acceptable salts. In formula I p is integer, equal to 0-1; L2 is selected from group including -XOX-, -XSX- and -XSXO-; where X is independently selected from group, including bond and C1-C4alkylene; R13 is selected from group, including halogen, C1-C6alkyl, C1-C6alkoxygroup, -C(O) C1-C6alkyl; R14 is selected from group, including -XOXC(O)OR17 and -C1-C4alkylene-C(O)OR17; where X represents bond or C1-C4alkylene; and R17 is selected from group, including hydrogen and C1-C6alkyl; R15 and R16 are independently selected from group, including -R18 and -YR18; where Y represents C2-C6alkenylene, and R18 is selected from group, including C6-C10aryl, benzo[1,3]dioxolyl, pyridinyl, pyrimidinyl, quinolyl, phenoxatiinyl, benzofuranyl, dibenzofuranyl, benzoxasolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzooxasolyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, where any C6-C10aryl, pyridinyl, benzoxasolyl, indolyl in R18 is optionally substituted by 1-2 radicals, independently selected from group, including halogen, nitrogroup, cyanogroup, C1-C6alkyl, C1-C6alkoxygroup, C1-C6alkylthiogroup, hydroxy-C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, XS(O)0-2R17, -XNR17R17, -XNR17S(O)2R17, -XNR17C(O)R17, -XC(O)NR17R17, -XC(O)NR17R19, -XC(O)R17, -XC(O)R19 and -XOXR19, where X represents bond; R17 is selected from group, including hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, and R19 is selected from group, including C3-C12cycloalkyl, phenyl, piperidinyl, morpholinyl.

EFFECT: ensuring application of invention compounds for production of medication, modulating activity of activated receptors of peroxisome proliferators δ (ARPPδ), to pharmaceutical composition, possessing properties of ARPPδ activity modulator, including therapeutically efficient quantity of invention compound and to application of pharmaceutical composition for medication manufacturing.

8 cl, 1 tbl, 301 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula (IIa)

and its salt, involving use of protective groups which can be easily incorporated into the compound, have large mass, are stable in the presence of organometallic reagents and be easily, and with high output, removed from in an acidic medium, as well as to novel intermediate compounds used during steps of this method, having general formula (IVe)

, where R5 and R'5 independently denote C1-C7-alkyl, R6 and R8 denote hydrogen, R7 and R9 together form C2-C5-alkylene.

EFFECT: easy production of angiotensin receptor blocker.

8 cl, 11 ex

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