Derivatives of hydroxamic and carboxylic acid having mmp inhibitory activity, and a pharmaceutical composition based on them

 

(57) Abstract:

Describes derivatives of hydroxamic and carboxylic acid having MMP inhibitory activity, represented by formula I, where m equals 0-1; X is SO2Y is HE or NHOH; R1is1-6alkyl or piperidinyl, optionally substituted; R2represents N or C1-6alkyl; or CR1R2is cycloalkyl, piperidinyl or tetrahydropyranyl, optionally substituted; each is the same or different and represents H, C1-6alkylated, C1-6alkylphenyl, C1-6alkyl, cycloalkyl, which is optionally condensed with benzene, C1-6alkylsilanes, phenyl, furanyl, thiophenyl, pyrrolyl, optionally condensed with benzene, C1-6alkylbenzenes, C1-6alkylbenzoates, C1-6acylinder where any of these groups is optionally substituted, or B-N-B is piperidinyl, substituted = NOR4; or, when R1or R2is not N, B-N-B is piperazinil, piperidinyl, pyrrolidinyl, optionally condensed with benzene and optionally substituted; R4represents H, C1-6alkyl, phenyl, C

This invention relates to derivatives of hydroxamic and carboxylic acids and to their use in medicine.

Metalloproteinases, including matrix metalloproteinases (MMPs), (human fibroblasts)collagenase, gelatinase and TNF to the Mac (TAS), and their modes of action, and their inhibitors, and their clinical effects are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the content of which is included here by reference. MMP inhibitors may also be useful in the inhibition of other metalloproteinases mammals, such as adamantinoma family (or ADAMs), whose members include the TNF Mac (TAS) and ADAM-10, which can cause the secretion of TNF from cells, and others, which are expressed by cells of the articular cartilage of human rights and is also involved in the destruction of maleinovogo basic protein, a phenomenon associated with multiple sclerosis.

Compounds that have the property ingibirovaniya and gelatinase, as shown, inhibit the secretion of TNF both in vitro and in vivo. Cm. Gearing et al (1994) Nature 370:555-557; McGeehan et al (1994) Nature 370:558-561; GB-A-2268934 and WO-A-9320047. All these inhibitors contain associated with the zinc group, hydroxamic acid, as well as contain and substituted imidazole compounds described in WO-A-9523790. Other compounds that inhibit MMP and/or TNF, are described in WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035714.

The invention includes compounds that are inhibitors of matrix metalloproteinases and/or TNF-mediated diseases, including degenerative diseases and certain cancers. These compounds represented by formula (I):

< / BR>
in which

m equals 0-2;

X represents S(O)1-2,

Y is HE or NHOH;

R1represents H or a group (optionally substituted by R7) selected from C1-6of alkyl, C2-6alkenyl, aryl, C1-6alkyl-aryl, heteroaryl, C1-6alkyl-heteroaryl, geterotsiklicheskie, C1-6alkyl-geterotsiklicheskie, cycloalkyl and C1-6alkylcyclohexane, and R2represents N or C1-6alkyl;

or CR1R2is cycloalkyl or geteroseksualnoe ring, optionally substituted by RLa, heteroaryl and C1-6alkyl-heteroaryl;

each is the same or different and represents H or a group selected from C1-6alkyl-aryl, C1-6of alkyl, cycloalkyl, C1-6alkyl-cycloalkyl, cycloalkenyl, geterotsiklicheskie, C1-6alkyl-heteroaryl, geterotsiklicheskie, C1-6alkyl-geterotsiklicheskie, aryl or heteroaryl, of which any group is optionally substituted by a Deputy selected from R3C1-6alkyl-R3WITH2-6alkenyl-R3, aryl (optionally substituted by R3), aryl-C1-6alkyl-R3C1-6alkyl-aryl (optionally substituted by R3), C1-6alkyl-heteroaryl (optional substituted R3), aryl-C2-6alkenyl-R5, heteroaryl (optional substituted R3), heteroaryl-C1-6alkyl-R3, cycloalkyl (optional substituted R3and geterotsiklicheskie (optional substituted R3), provided that NB2is not NH2,

or B-N-B is geteroseksualnoe ring, substituted by =O or = NOR4,

or, when none of the R1and R2is not N, B-N-B is geteroseksualnoe or geterotsyklicescoe ring, ner>, aryl (optionally substituted by R3), aryl-C1-6alkyl-R3C1-6alkyl-aryl (optionally substituted by R3), C1-6alkyl-heteroaryl (optional substituted R3), aryl-C2-6alkenyl-R5, heteroaryl (optional substituted R3), heteroaryl-C1-6alkyl-R3, cycloalkyl (optional substituted R3), and geterotsiklicheskie (optional substituted R3):

R3represents C1-6alkyl, C2-6alkenyl-R5, halogen, CN, NO2N(R4)2, OR4C(= NOR6R4, CON(R4)2, COR4, CO2R8, NR4R5, S(O)0-2R6or SO2N(R4)2; R4represents H or a group selected from C1-6of alkyl, aryl, C1-6alkyl-aryl, heteroaryl, C1-6alkyl-heteroaryl, cycloalkyl, C1-6alkyl-cycloalkyl, geterotsiklicheskie and C1-6alkyl-geterotsiklicheskie in which a specified group optionally substituted by R6, COR6, SO0-2R6, CO2R6, OR6, CONR8R6, NR8R6, halogen, CN, SO2NR8R6or NO2and for each example N(R4)2group R4are the same6, SO0-2R6, CO2R6, OR6, CONR8R6, NR8R6, halogen, CN, SO2NR8R6or NO2;

R5is COR4, CON(R4)2, CO2R6or SO2R6;

R6represents C1-6alkyl, aryl, C1-6alkyl-aryl, heteroaryl or C1-6alkyl-heteroaryl; and

R7is OR4, COR4, CO2R8, CON(R4)2, NR4R5, S(O)0-2R6, SO2N(R4)2, halogen, CN or cycloimide (optional substituted R8); and

R8represents N or C1-6alkyl;

and its salt, solvate, hydrates, N-oxides, protected amino, protected carboxy or protected hydroxamic acid derivatives.

The compounds of formula (I) are first described as having therapeutic applications. The compounds of formula (I) are new, except for those in which Y is HE, and CR1R2is CH2or NB2represents NH2N(Ph)H, N(Ph)CH3N(C6H11)CH3or N(4-methoxybenzoyl)2.

Combinations of substituents and/or variables are permissible only if such combinations result in the article who's any one or more of the following applies:

X is SO2;

In is not H;

In the optionally substituted C1-6the alkyl, cycloalkyl, heterocyclization, C1-6alkyl-aryl or C1-6alkyl-heteroaryl;

B-N-B is optionally substituted geteroseksualnoe ring,

B-N-B is geteroseksualnoe ring, substituted =NOR4;

R1represents optionally substituted C1-6alkyl, C1-6alkyl-heteroaryl, C1-6alkyl-aryl or C1-6alkyl-heteroseksualci;

CR1R2represents the specified optionally substituted cycloalkyl or geteroseksualnoe ring;

R3represents C1-6alkyl, C2-6alkenyl-R5, halogen, CN, NO2N(R4)2, OR4, COR4, NR4R5, S(O)0-2R6or SO2N(R4)2;

R7represents CON(R4)2; NR4R5, SO2N(R4)2or cycloimide.

It is necessary to consider that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms and sulfur. The presence of one or more of these asymmetric centers in the compound of formula (I) may create stereo enantiomers and diastereoisomers and mixtures including racemic mixtures.

The following should be considered that the compounds according to the invention can contain the oxime. This oxime can create geometric isomers, and in each case means that the invention includes all such isomers and mixtures thereof.

According to the description, the term "C1-6alkyl", alone or in combination, refers to an alkyl fragment with a linear or branched chain, having from one to six carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and similar.

The term "C2-6alkenyl" refers to the alkyl portion with a linear or branched chain, having from two to six carbon atoms and having optionally one double bond in the E or Z stereochemistry where applicable. This term necessarily includes, for example, vinyl, 1-propenyl, 1 - and 2-butenyl, 2-methyl-2-propenyl etc.

The term "cycloalkyl" refers to saturated alicyclic fragment having from three to six carbon atoms, and which is not necessarily connected with benzene in any available position. This term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, is the fragment, having three to six carbon atoms and one or more heteroatoms selected from N, O, S, and their oxidized modifications, and which is not necessarily connected with benzene in any available position. This term includes, for example, azetidine, pyrrolidine, tetrahydrofuranyl, piperidinyl, indolinyl and tetrahydroquinolines.

The term "cycloalkenyl" refers to an alicyclic fragment having from three to six carbon atoms and having in addition one double bond. The term includes, for example, cyclopentenyl and cyclohexenyl.

The term "geteroseksualen" refers to an alicyclic fragment having from three to six carbon atoms and one or more heteroatoms selected from N, O, S, and their oxidized modifications, and having in addition one double bond. This term includes, for example, dihydropyran.

The term "aryl" refers to aromatic isocyclischen to a radical, having a single ring or two condensed rings. The term includes, for example, phenyl or naphthyl.

The term "heteroaryl" refers to aromatic ring systems of five to ten atoms, one at least of the atom in which/P> The term "colloidal" refers to a saturated ring of from five to ten atoms, containing a sequence of atoms,- C(=O)NC(=O)-. The ring can be optionally connected to the benzene in any available position. Examples include Succinimidyl, phthalimido and hydantoinyl.

The term "coupled with benzene" refers to the attachment of the benzene nucleus, share a common connection with a particular ring system.

The term "optionally substituted" means optionally substituted by one or more specific groups in any available position or positions.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The terms "protected amino", "protected carboxy" and "protected hydroxamic acid" refers to amino, carboxy and hydroxamic acid group which may be protected by a method familiar to specialists in the field of technology. For example, the amino group can be protected by benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or similar group or may be in the form of phthalimido or similar group, the Carboxyl group can be protected in the form of ester, such as methyl ethyl, benzyl or t is to O-benzyl or O-tert-butyldimethylsilyl.

Salts of compounds of formula (I) include pharmaceutically acceptable salts, for example salts of accession acid produced from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluensulfonate, phosphates, sulfates, perchlorates, acetates, triptoreline, propionate, citrates, malonate, succinate, lactates, oxalates, tartratami and benzoate.

Salt can also be formed with bases. Such salts include the salts produced from inorganic or organic bases, for example alkali metal salt such as magnesium salt or calcium, salts of organic amines, such as salts of the research, piperidine, dimethylamine or diethylamine.

When the "protected carboxy" group in the compounds according to the invention represents an esterified carboxyl group, it may be a metabolically-labile ester of the formula CO2R9where R9can be ethyl, benzyl, fenetylline, phenylpropanol, or naftilos, 2,4-dimethylaniline, 4-tert-butylphenyl, 2,2,2-triptoreline, 1-(benzyloxy)benzyl, 1-(benzyloxy) ethyl, 2-methyl-1-propionoxypiperidine, 2,4,6-trimethylbenzenesulfonyl or pivaloyloxy group.

Must take into account that require a particular stereoisomer of formula (I) described herein synthetic methods can be used with the corresponding homochiral original substance and/or isomers that can be separated from mixtures using conventional methods of separation (e.g., HPLC).

Compounds according to the invention can be obtained in the following way. In the description, and the following formulas group, R1, R2, R3, R4, R5, R6, R7, R8, R9In, X and Y are as defined above, except specially marked cases. Must take into account that functional groups such as amino, hydroxyl or carboxyl groups present in various of the following compounds, and want to keep, may need to be in a protected form before any reaction begins. In such cases, the removal of the protective group may be the final stage in a particular reaction. Suitable protective groups for such functionality are obvious to experts in the given field of technology. For specific details, see Greene et al, "Protective Groups in Organic Synthesis", Wiley Interscience.

JV is the volume formula Z-X - (CH2)m-CR1R2-COY (III) in which Z represents a suitable leaving group (e.g. halogen, such as bromine, and Y is HE or NHOH, or a protected form. This reaction can be performed in an inert solvent, such as tetrahydrofuran, in the presence of organic or inorganic bases.

Alleluya agents of the formula (III), where X=SO2; can be obtained from R10S-(CH2)m-CR1R2-COY (IV), where R10represents H or a suitable labile group, such as acetyl, treatment with chlorine in an appropriate solvent such as water, at an appropriate temperature, such asoC. Alleluya agents of the formula (III), where X=SO, can also be obtained from compound (IV) the processing of SO2Cl2and acetic anhydride in an appropriate solvent, such as dichloromethane, at suitable temperatures, such as 0oC.

Sulfanilimide the compounds of formula (IV) are easily obtained by alkylation of compounds R10SH alkylating agent of the form ZA-(CH2)m-CR1R2-COY (V), where ZArepresents a leaving group (e.g. halogen, such as bromine, or an ester of alkylsulfonate, such as metilsulfate in the art by standard chemistry from commercially available substances.

The compounds of formula (V), where m=1, can be obtained from compounds of formula NON2CR1R2COY (VI). Thus, for example, the compound of formula (V), where ZArepresents methanesulfonate, can be obtained by treating compounds of formula (VI) methanesulfonanilide in the presence of organic bases such as triethylamine, in an inert solvent such as dichloromethane.

The compounds of formula (VI) can be obtained by reduction of compounds of formula R11O2CCR1R2COY (VII), where COOR11is suitable ester, such as ethyl ether. Suitable conditions for recovery include the use of diisobutylaluminium in toluene at -40oC.

The compounds of formula (VII) can be obtained by sequential alkylation, for example, diethyl ester of malonic acid alkylating agents of the formula R1-ZA(VIII) and R2-ZA(IX) in which ZAis the same as defined above, followed by hydrolysis under basic conditions. Many alkylating agents of the formula (VIII) or (IX) are commercially available or can be obtained from commercially available substances known to specialists in this action connection R10SH with acrylate type H2C=CR1CO2H (X). The compounds of formula (X) can be obtained by the reaction of manniche (i.e. with paraformaldehyde and piperidine in a suitable organic solvent, such as 1,4 dioxane) based on the dicarboxylic acid of General formula BUT2C-CHR1-CO2H (XI). This reaction involves an elimination phase decarboxylation, leading directly to the formation of ,-unsaturated carboxylic acids (i.e., where Y=OH).

Dicarboxylic acid of the formula (XI) can be obtained by alkylation, for example, diethyl ester of malonic acid alkylating agent of formula R1-ZA(VIII) in which ZAis the same as defined above, followed by hydrolysis under basic conditions.

Amines of the structure shown in formula (II) are commercially available or can be obtained by standard aromatic, heteroaromatic or other chemicals, known to experts in the art from commercially available substances.

The compounds of formula (I) can also be obtained by the mutual transformation of other compounds of formula (I). Thus, for example, the compound of formula (I) in which R1predstavliaiushchaia, such as alcohol, e.g. ethyl alcohol) compounds of formula (I) in which R1represents C2-6alkenylphenol group. Similarly, the compound of formula (I), where X= SO2; can be obtained from compounds of formula (I), where X=SO by oxidation, for example, periodate sodium trihydrate and ruthenium chloride in an appropriate solvent, for example azionitelecomitalia - water. Acids of General formula (I) (Y=OH) can be converted into a hydroxamic acid (Y=NHOH) when using methods known to experts in this field of technology.

Any mixture of end-products or derived intermediates can be separated on the basis of the physicochemical differences of the constituents in a known manner on a clean final products or intermediate compounds, such as chromatography, distillation, fractional crystallization or the formation of salt, if it is appropriate or possible under these circumstances.

Compounds according to the invention exhibit in vitro inhibitory activity against stromelysins, collagenases and gelatinases. Compounds according to the invention can also exhibit in vitro inhibition effects flushing membrane, which, as you know, op is rasiwasia IL-1 receptor, dropping CD23 and dropping L-selectin. The activity and selectivity of compounds can be determined using the appropriate test of inhibition of the enzyme, for example, as described in examples a-M WO 98/05635 or the next test for inhibition of dropping CD23.

The effectiveness of compounds of General formula (I) to act as inhibitors dropping CD23 is determined by applying the following procedure: a 100 μm solution of test compound or its dilutions cultivated at 37oC in an atmosphere of 5% CO2from RPMI 8866 cells, which shed CD23 spontaneously without stimulation. After 1 hour the cells are removed by centrifugation and the supernatant is tested for values of SCD23, when using commercially available ELISA kit. Activity in the presence of 0.1 mm inhibitor or dilutions compared to activity in a control sample, devoid of inhibitor and results reported as the concentration of inhibitor engaged in 50% inhibition of dropping CD23.

The invention also relates to a method of treatment for patients (including man and/or increasing livestock mammals animals in the dairy, meat, or fur industries manufactures the Sano, and, in particular, to a method of treatment, which consists in the introduction of inhibitors of formula (I) matrix metalloproteinases as active components.

Accordingly, the compounds of formula (I) can be used among others for the treatment of osteoarthritis and rheumatoid arthritis and diseases and indications caused by palexporussia these matrix metalloproteinases, such as found in some metastatic tumor cell lines.

As mentioned above, the compounds of formula (I) used in the treatment of human or veterinary medicine since they are active as inhibitors of TNF and MMPs. Accordingly, in another aspect, this invention relates:

method of treatment or prophylaxis of diseases or conditions mediated by TNF and/or MMPs in mammals, particularly in humans, the method consisting in the introduction to the mammal an effective amount of the compound of the above formula (I) or its pharmaceutically acceptable salts, and

the compounds of formula (I) for use in human medicine or veterinary medicine, in particular for the treatment or prevention of diseases or conditions mediated by TNF and/or MMPs; and

the use of the compounds of formula (I) for agent management (under which the task or condition, above include inflammatory diseases, cancer, autoimmune diseases, cardiovascular diseases, diseases involving tissue destruction, such as rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer's disease, stroke, vasculitis, Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis and diseases involving tissue destruction, such as bone loss, hemorrhage, coagulation, acute phase response, cachexia and anorexia, acute infectious disease, HIV infection, fever, shock, vaccine reactions owner, dermatological conditions, surgical wound healing, psoriasis, allergic dermatitis, congenital bullous bullosa, tumour growth, tissue regeneration and the introduction of secondary metastases, ophthalmological disease, retinopathy, corneal ulceration, reperfusion injury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endoskeleton and spiridonievsky antithrombus.

The compounds of formula (I) can also be used to treat inflammatory diseases of the pelvic (PID), age d is Oh, for example, selected from fibrous-cystic fibrosis, respiratory distress syndrome in adults (ARDS), emphysema, obliterating organized pneumonia (WOOR), idiopathic pulmonary fibrosis (PIF), diffuse alveolar destruction, pulmonary cell Wegener Langerhan, lymphangioma-myomatosis lungs (LAM) and chronic obstructive lung disease (COPD).

For the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and symptoms caused by palexporussia matrix metalloendopeptidases, such as found in some metastatic tumor cell lines or other diseases mediated matrix metalloendopeptidases or increased TNF production, the compounds of formula (I) can be administered orally, topically, parenterally, by inhalation spray or rectally in formulations dosage units containing a non-toxic pharmaceutically acceptable carriers, adjuvant and fillers. The term parenteral as applied to the description includes subcutaneous injections, intravenous, intramuscular, epigastric ways injection or infusion. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, soba is I, containing the active ingredient may be in a form suitable for oral administration, for example in the form of tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be obtained according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, to provide pharmaceutically elegant and acceptable forms. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable inert excipients, which are suitable for the manufacture of tablets. These inert fillers can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezinfeciruyuhimi agents such as corn starch or alginic acid; binding agents, ApriI or talc. Tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and, therefore, to provide a supported activity for a longer period. For example, there may be used a substance is the time delay, such as glycerylmonostearate or glycerylmonostearate. They may also be coated by the methods described in U.S. patent 4256108; 4166452 and 4265874 for education osmotic therapeutic tablets for controlled allocation.

Formulations for oral use may also be as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin oil or olive oil. Aqueous suspensions contain the active substance in a mixture with inert fillers, suitable for the manufacture of aqueous suspensions. Such inert fillers are suspendresume agents, such as sodium carboxymethyl cellulose, methylallyl; dispersing or wetting agents can be found in nature fosfatados, for example lecithin, or condensation products of accelerated with fatty acids, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters of polyhydric alcohol, produced from fatty acids and exit, such as polyoxyethylene with partial esters of polyhydric alcohol, produced from fatty acids, and anhydrides of exit, such as monooleate of polyoxyethylenesorbitan. Aqueous suspensions may also contain one or more preservatives, for example ethyl-, or n-propyl-p-hydroxy-benzoate, one or more coloring substances, one or more flavoring agents, and one or more sweetening agent such as sucrose or saccharin.

Oil suspensions can be prepared by suspendirovanie active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as vase is in or cetyl alcohol. Sweeteners, such as substances, as proposed above, and flavoring agents may be added to provide acceptable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for obtaining aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or wetting agents and suspendresume agents are illustrated, for example, sweetening, flavoring and coloring agents can also be present.

The pharmaceutical compositions according to the invention can also be in the form of emulsions of oil-in-water". The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example, vaseline oil, or mixtures thereof. Suitable emulsifying agents may be naturally occurring resins such as Arabian gum or tragacanth gum found in nature phosphatides, for example soy beans, lecitina of exit, for example monooleate sorbitan, and the condensation products mentioned partial esters of a polyhydric alcohol with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsions may also contain sweetening and flavouring substances.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a means of reducing the irritation, preservative, flavoring and coloring substances. The pharmaceutical compositions can be in the form of sterile injectively aqueous or oily suspensions. This suspension may be formulated according to known methods with the use of suitable dispersing or wetting agents and suspendida agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable fillers and solvents that can be used is water, ringer's solution and isotonic sodium chloride solution. Croatoa goals can be applied to any soft non-volatile oil, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in obtaining injectively solutions.

The compounds of formula (I) can also be administered in the form of suppositories for rectal administration of medicinal means. These compositions can be obtained by mixing the drug with a suitable non-irritating inert filler, which is solid at ordinary temperatures but liquid at rectal temperature and therefore, naturally, melt in the rectum, releasing the drug. Such substances are cocoa butter and polyethylene glycols.

For local use apply creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of formula (I). For the purposes of this description local applications include liquid for rinsing the mouth and throat.

Doses of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are used in the treatment of the indicated conditions (about 2.5 mg to about 7 g per patient per day). For example, inflammation may be effectively treated by the introduction of from about 0.01 to 50 mg of compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g carriers to produce a single dose, of course, varies depending on the patient and the particular route of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition. Dosage forms typically contain from about 1 mg to about 500 mg of the active component.

Naturally, the actual dose for any particular patient depends on a number of factors, including the specific activity of the applied compound, the age, body weight, General health, sex, time of administration, route of administration, rate of excretion, combination of drugs, and severity of the particular disease undergoing therapy.

The following examples illustrate the invention. In the examples the following abbreviations are used:

TNF-tumor necrosis factor

LPS LPS

ELISA enzyme-linked immunosorbent assay

EDC 1-Ethyl-2-dimethylaminopropylamine

RT room temperature.

The intermediate connection 1

3-Iodine-1-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-propane

Sodium hydride (2.2 g) was added to a solution of 3,4,4-trimethylhydantoin (7,1 g) in dimethylformamide (50 ml) at room temperature, and the mixture stir for 1 h is at (300 ml) and was extracted with diethyl ether; the ether layer was then dried (MgS4) and was evaporated, the residue was dissolved in acetone (100 ml) to which was added sodium iodide (10 g). The mixture was heated at flavobacteria for 18 h, then evaporated, and the residue was dissolved in diethyl ether and was washed with water, then dried (MgSO4) and evaporated, giving a connection header (11 g, 70%) as a brown oil.

Rf0,85 (diethyl ether).

Intermediate compound 2

Dimensiony ether (3-(3,4,4-trimethyl 2-5-dioxoimidazolidin-1-yl)propyl)malonic acid

The solution dibenzoylmethanato (5.7 g) in anhydrous tetrahydrofuran (200 ml) was treated at 0oWith sodium hydride (60% dispersion in mineral oil, 3.1 g). The mixture was allowed to warm to room temperature and stir it for 30 min in nitrogen atmosphere. The mixture was then treated with a solution of intermediate compound 1 (6.2 g) in tetrahydrofuran (100 ml) and was heated at flavobacteria within 12 hours the Reaction was then cooled, filtered, and the filtrate was evaporated in vacuum. The residue was separated between ethyl acetate (200 ml) and saturated aqueous ammonium chloride (150 ml). The organic layer was washed with water (100 ml), brine solution (100 ml), dry the on silica gel with elution with 20% ethyl acetate in hexane, making the connection header (7,1 g, 80%) as a colorless oil.

Rf0,53 (diethyl ether).

Intermediate compound 3

2-Methylene-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

A solution of intermediate compound 2 (10 g) in dioxane (200 ml) was treated with 10% palladium on activated carbon (1.7 g) and gidrirovaniya at atmospheric pressure until stopped absorption of hydrogen. The catalyst was removed by filtration through Celite, and the filtrate was treated with piperidine (3.2 g) at room temperature. After 30 min the reaction was treated with formaldehyde (37% solution in water; 15 ml), stir for two hours at room temperature and then was heated at 80oC for two hours. The mixture was cooled, the solvent was removed in vacuo, and the residue was separated between ethyl acetate (200 ml) and 10% aqueous citric acid (100 ml). The organic layer was washed with water (100 ml), brine solution (100 ml), dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuum. The residue was purified column chromatography on silica gel with elution with 40% ethyl acetate in hexane, developing the connection header (of 5.40 g, 95%) as a colorless oil acid

Morpholine (39,4 g) was added to a solution of isopropylmalonic acid (60.1 g) in water (300 ml) and acetic acid (47 ml). The mixture stir for 20 minutes, then was added a solution of aqueous formaldehyde (37% aqueous, 18,54 g). The mixture was stir at room temperature overnight, then heated at 80oC for 2 hours and again cooled to room temperature. The mixture was filtered, podslushivaet with sodium bicarbonate and washed with dichloromethane (100 ml). the pH was brought to 4 with diluted HCl, then the mixture was extracted with dichloromethane (3 200 ml), the organic extracts were combined and were washed with water and with brine, dried (MgSO4and then was evaporated, yielding compound of the title as colorless oil (32 g).

Rfto 0.45 (EtOAc).

The intermediate compound 5

2-methyl bromide-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

Intermediate compound 3 (5,4 g) was processed 45% hydrogen bromide in acetic acid (50 ml) at room temperature. After three hours the solution was poured into water (300 ml), and the product was extracted with ethyl acetate (3 x 100 ml). The organic extracts were combined, were washed with water (100 ml), brine solution (100 is the azeotrope with toluene (2 x 10 ml), making the connection header (4.0 g, 56%) as a viscous oil.

Rfof 0.35 (ethyl acetate).

Similarly turned out

The intermediate compound 6

2-methyl bromide-3-metallocarborane acid

Of intermediate compound 4 (32 g) as a colorless liquid (52,3 g).

Rfof 0.43 (EtOAc).

Intermediate compound 7

Methyl ester 2-methyl bromide-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

Acetylchloride (15 ml) was added to ice methanol (200 ml) dropwise over 20 min, then was added a solution of intermediate compound 5 (3.5 g) in methanol (20 ml) and the solution was stir at room temperature for 3 hours the Mixture was then evaporated in vacuo, and the residue was dissolved in dichloromethane (100 ml) and was washed with a saturated solution of sodium bicarbonate and saline. The solvent was dried and evaporated, giving a connection header (2,05 g) as a pale yellow oil.

Rf0,65 (ether).

Intermediate compound 8

tert-Butyl ester 2-methyl bromide-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

Isobutylene (100 ml) was added to a solution of intermediate compound 5 Xia, and the mixture was stir at room temperature for 24 h, then was cooled to -5oC, and the solution was removed and was washed with saturated sodium carbonate and water, then dried(MgSO4) and was evaporated, yielding compound of the title as colorless oil (35,9 g).

Rf0,73 (ether).

Similarly turned out

Intermediate compound 9

tert-Butyl ester 2-methyl bromide-3-metallocarboranes acid

From intermediate 6 (52,3 g) as a colorless liquid (64,0 g).

Rf0,72 (EtOAc).

Intermediate compound 10

Methyl ester 2-acetylsalicylate-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

Thioacetate potassium (1.2 g) was added to a solution of intermediate compound 7 (1.5 g) in dimethylformamide (20 ml) at room temperature, and the mixture then was heated at 100oC for 3 hours the Mixture was added to water and extracted with ether (3 50 ml). The solvent was washed with sodium hydrogen carbonate solution, water and saline, dried (MgSO4) and evaporated giving a brown oil. It was purified silikagelevye column chromatography with elution with ether, giving a connection header (1.2 g) kakenya 11

tert-Butyl ester 2-acetyl-sulfanilyl-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

From intermediate 8 (35,9 g) as a yellow oil (34,5 g).

Rf0,66 (ether).

Intermediate compound 12

tert-Butyl ester 2-acetyl-sulfanilyl-3-metallocarboranes acid

From intermediate 9 (64 g) as a colorless oil (55.7 g).

Rfof 0.68(EtOAc).

Intermediate compound 13

Methyl ester of 2-(chlorosulfonylphenyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

The chlorine gas was barotiwala through a suspension of intermediate 10 (1.2 g) in 5% aqueous acetic acid (50 ml) at 0oC for 20 minutes Suspension stir for 20 min, then placed in a vacuum to remove excess chlorine for 5 min the Suspension was then extracted with dichloromethane (2 50 ml), and the solvent was washed with water and saline solution. The organic layer was dried over magnesium sulfate and evaporated, giving a connection header (1.10 g) as a pale yellow oil, which slowly crystallized upon standing.

Rf0,45 (ether).

Likewise happened:

InterMedia is PENTACARBONYL acid

From the intermediate compound (11) (1.04 g) as a viscous pale yellow oil (0,86 g).

Rf0,48 (ether).

Intermediate compound 15

tert-Butyl ester 2-chlorosulfonyl-3-metallocarboranes acid

Of intermediate compound 12 (50 g) as a pale yellow oil (to 49.9 g).

Rfof 0.54 (EtOAc).

The intermediate connection 16

N-Methyl-2-phenoxyethylamine

This compound was obtained according to the method described

Grieco and Bahsas (J. Org. Chem., 1987, 52, 5747-5749) of 2-phenoxyethylamine (1,00 g) as an almost colourless oil (0.88 g, 81%).

Rf0,32 (94:5:1 dichloromethane/methanol/ ammonium hydroxide)

Intermediate compound 17

2-Hydroxymethylbenzene

To stir the solution benzofuran-2-carboxylic acid (2.50 g) in tetrahydrofuran (50 ml) at 0oC in an atmosphere of nitrogen was added a solution of socialogical (1.0 M, and 7.7 ml) in tetrahydrofuran. Stirring continued for 2 h, allowing the temperature to rise to RT. The mixture was diluted with diethyl ether (50 ml) and quenched with water (30 ml). The aqueous layer was separated and was extracted with diethyl ether (2 x 25 ml). The combined extracts were washed with water (30 ml), a solution of sodium hydroxide (1M; 30 ml), the low pressure had developed a connection header (1,11 g, 49%) as a colorless oil.

Rfto 0.29 (2:1 hexane/etelaat).

Intermediate compound 18

2-Chlorodibenzofuran

To stir a solution of intermediate 17 (1.10 g) in dichloromethane (50 ml) at RT was added pyridine (646 mg) and 4-toluensulfonate (1.56 g). Stirring is continued for 72 h at RT and further 24 h at flavobacteria. The cooled solution was diluted with dichloromethane (50 ml) and was washed with diluted hydrochloric acid (1M; 25 ml), water (2 25 ml), brine solution (25 ml) and dried (MgSO4). Filtration and evaporation of the solvents under reduced pressure and purification of the residue silikagelevye column chromatography with elution with 5:1 hexane/ethyl acetate produced connection header (337 mg, 27%) as a colorless oil.

Rf0,49 (2:1 hexane/ethyl acetate).

Intermediate compound 19

N-methyl-benzofuran-2-yl-methylamine

This compound was obtained according to the method Butera et al (J. Med. Chem., 1991, 34, 3212-3228) of the intermediate compound 18 (330 mg) as a nearly colorless oil (883 mg, 8%).

Rfof 0.30 (9:1 dichloromethane/methanol)

Intermediate compound 20

Diethyl ether tetrahydropyran-4,4-dicarboxylic acid
4) and was evaporated. The residue was then purified thin-layer column chromatography on silica gel with elution with 4:1 hexane/ether, giving a connection header (28,0 g) as colorless liquid.

Rfof 0.33 (4:1 hexane/ether).

The intermediate connection 21

Ethyl ester of 4-hydroxyethylacrylate-4-carboxylic acid

The solution diisobutylaluminium in toluene (82 mmole) was added to a solution of intermediate 20 (9.5 g) in toluene at -40oC for 30 minutes the Mixture stir for 1 h, then was added dropwise ethyl alcohol (100 ml) for 30 minutes Then added detribalized (2.0 g) in small portions over 20 min, and the mixture stir for 1 h and Then was added dropwise a saturated sodium sulfate (100 ml) followed by ethyl acetate (200 ml). The mixture vigorously stir for 1 h, then.

Rfof 0.60 (EtOAc).

Intermediate compound 22

Ethyl ester of 4-(methanesulfonate)methyltetrahydrofuran-4-carboxylic acid

To a solution of intermediate 21 (11,0 g) at 0oWith in dichloromethane (30 ml) was added methanesulfonamide (4.6 ml), followed by triethylamine (8.0 ml). The mixture stir for 1 h, then was washed with citric acid (5% aqueous, 30 ml), saturated sodium bicarbonate and saline. The organic layer was separated, and then dried (MgSO4), and was evaporated, yielding compound of the title as colorless oil (15.2 g).

Rf0,65 (ether).

Intermediate compound 23

Ethyl ester of 4-(acetylsalicyloyl) tetrahydropyran-4-carboxylic acid

A solution of intermediate 22 (16.0 g), sodium iodide (0.2 g) and potassium thioacetate (12.0 g) in dimethylformamide (100 ml) was heated at 80oWith over 6 hours of the Final black viscous mixture was then added to aqueous bicarbonate (300 ml) and was extracted with ether. The ether layer was washed with water and with brine, then dried (MgSO4) and was evaporated. The residue was purified thin-layer column chromatography on silica gel with elution with 1: 1 ether/hexing">

Intermediate compound 24

Ethyl ester of 4-(chlorosulfonyl) methyltetrahydrofuran-4-carboxylic acid

The chlorine gas was barotiwala through a suspension of intermediate 23 (3.2 g) in water (100 ml) and acetic acid (5 ml) at 0oC for 30 minutes the Yellow suspension was stir at the same temperature for 30 min, then was partially evaporated under vacuum and the aqueous residue was extracted with dichloromethane (100 ml). The combined organic extracts were washed with cooled with ice water and with brine, then dried (MgSO4) and evaporated, giving a connection header (3.3 grams) as a colorless solid.

Rf0,45 (ether).

Intermediate compound 25

2-(4-Chlorphenoxy)-2,2-dimethylpropionic

To stir a solution of 2-(4-chlorphenoxy)-2,2-dimethylpropionic acid (5,00 g) in dichloromethane (100 ml) and dimethylformamide (2 drops) atoC in an atmosphere of nitrogen was added the acid chloride oxalic acid (14.8 g). The mixture was stir during the night, with the temperature rising up to RT. The mixture was evaporated under reduced pressure to dryness, producing the connection header (5,26 g, 97%) as brown liquid.

Rf0,65 (5:karbonovoi acid

To stir a 40% aqueous solution of methylamine (20 ml) at 0oWith added intermediate compound 25 (1,00 g). The mixture stir for 30 min, and then the resulting precipitate was collected by filtration and dried under vacuum, producing a connection header (576 mg, 59%) as a white solid.

Rf0,47 (2:1 ethyl acetate/hexane).

Intermediate compound 27

N-[2-(4-chlorphenoxy)-2,2-dimethylpropyl]-N-methylamine

To stir a solution of intermediate 26 (300 mg) in tetrahydrofuran (10 ml) at 0oC in an atmosphere of nitrogen was added a solution of brandibelle in tetrahydrofuran (2M, 1 ml). The mixture was heated at flavobacteria for 4 h, then cooled and diluted with water (30 ml). The mixture was extracted with dichloromethane (3 20 ml) and the combined extracts were washed with water (2 20 ml), with brine (20 ml) and dried (MgSO4). Filtration and evaporation of the solvent under vacuum produced a colorless oil. To stir a solution of the oil in methanol (20 ml) at RT was added concentrated hydrochloric acid (3 ml). The mixture stir for 2.5 h, then was diluted with water (80 ml) and was washed with hexane (2 20 ml). The aqueous mixture was podslushivaet (2 is), salt solution (20 ml) and dried (MgSO4). Filtration and evaporation of the solvent under vacuum produced connection header (146 mg, 58%) as a colorless oil.

Rf0,32 (94:5:1 dichloromethane/methanol/ammonium hydroxide).

The intermediate connection 28

N-(tert-butyloxycarbonyl)-4-piperidinol

Was obtained according to method K. M. Wells et al (Tetrahedron Lett., 1996, 37(36), 6439-6442) as a pale yellow solid (46,5 g, 99%).

Rfof 0.67 (EtOAc).

Intermediate compound 29

bis(Triptorelin)-4-(piperidine-4-yloxy)pyridine

Sodium hydride (1.8 g) was added to a solution of intermediate 28 (3.4 g) in dimethylformamide (15 ml), cooled in ice and kept in a nitrogen atmosphere. The slurry is then stir at room temperature for 1 h, were treated with hydrochloride 4-chloropyridine (2.7 g) and was heated to 100oC for further 2 hours After cooling, the mixture was divided between diethyl ether (100 ml) and water (100 ml). The organic phase was collected, rinsed with water (20 ml), saturated salt solution (20 ml), dried (Na2SO4) and was evaporated to dryness in vacuum. Beige solid residue was precrystallizer of diethyl ether, prevennia solid was then dissolved in dichloromethane (80 ml), processed triperoxonane acid (20 ml) and stir at room temperature for 16 hours the Mixture was then concentrated under reduced pressure and evaporated together with 50% dichloromethane/hexane (20 ml), providing the connection header as a beige solid (4.8 g, 70%).

Rf0,11 (8% methanol/dichloromethane to trace the triethylamine).

Likewise happened:

The intermediate connection 30

Triptorelin 4-(4-cyanovinylene)piperidine

From intermediate 28 (3.0 g) and 4-perbenzoate (1/95 g) as a colorless solid (1,34 g, 28%).

Rf0,1 (50% hexane and 0.1% Asón in EtOAc).

The intermediate connection 31

The hydrochloride of 4-(4-chlorophenoxy) piperidine

Sodium hydride as a 60% dispersion in mineral oil (2,11 g) was added to a solution of intermediate 28 (10.0 g) in anhydrous dimethyl sulfoxide (200 ml). After stirring for 30 min at RT under nitrogen atmosphere was added benzodioxolyl potassium (8,46 g), followed after 20 min 1-chloro-4-florasulam (6,90 g). The mixture was heated at 60oC for 2 h, then cooled to RT and was diluted with water (600 ml) and the pH was brought to 5. The solution was rinsed with hexane (100 ml), paddel the saturated aqueous saline solution (50 ml), were dried over sodium sulfate and evaporated and then the residue is crystallized from hexane. The resulting crystalline solid was dissolved in a mixture of ethanol and dioxane (1:1, 150 ml) and saturated with hydrogen chloride gas. After 2 h at RT the solution was purged with nitrogen gas and then concentrated under reduced pressure. The residue was dissolved in minimum quantity of methanol, and then was diluted with ether. The precipitate was collected by filtration and dried giving the product header (are 5.36 g, 41%) as a colorless solid.

Rf0,35 (8% Meon/dichloromethane).

The intermediate connection 32

N-(tert-Butoxycarbonyl)-4-piperidone

This compound was obtained according to the method of I. M. Labouta et al, Eur. J. Med. Chem. Chim, Ther., 1982, 17, 531-535, as a colourless solid (9,72 g, 98%).

The intermediate connection 33

tert-Butyl ether 4-hydroxylaminopurine-1-carboxylic acid

Hydroxylamine hydrochloride (2,95 g), sodium acetate (3.80 g) and intermediate compound 32 (of 7.70 g) were combined in ethanol (40 ml) and stir at room temperature for 72 hours, water was Added (100 ml) and the mixture was extracted with diethyl ether (2 50 ml). The combined organization is the target (30 ml), were dried (MgSO4) and was concentrated in vacuo, providing the connection header (7,94 g, 96%) as a pale yellow solid.

Rf0,30 (2% methanol/dichloromethane to trace the triethylamine).

The intermediate connection 34

tert-Butyl ester 4-(4-cyanobenzene)piperidine-1-carboxylic acid

Sodium hydride as a 60% dispersion in mineral oil (0,103 g) was added to a solution of intermediate 33 (0.50 g) in anhydrous tetrahydrofuran (30 ml) and the mixture was stir under nitrogen atmosphere at room temperature. After 30 minutes 4-perbenzoate was added as a solution in dry tetrahydrofuran (3 ml) and the mixture stir for a further 24 h at room temperature. The solvents were then removed in vacuo, the residue was azeotropically twice with toluene before cleaning silikagelevye column chromatography with 2% methanol/dichloromethane as the solvent for elution, providing a connection header (0,57 g, 78%) as a pale yellow solid.

Rf0,63 (2% methanol/dichloromethane to trace the triethylamine).

Likewise happened:

The intermediate connection 35

tert-Butyl ester 4-(4 chlorobenzylamino)piperidine-1-kesto (0.54 g, 43%) after purification silikagelevye column chromatography with 7% diethyl ether/dichloromethane as the solvent for elution.

Rfof 0.50 (7% diethyl ether/dichloromethane).

Intermediate compound 36

Trifurcata salt of 4-(4-cyanobenzene)piperidine

Triperoxonane acid (1 ml) was added to a solution of intermediate 34 (0.56 g) in dichloromethane (9 ml). After stirring for 6 h at room temperature the solvents were removed in vacuum. The residue was dissolved in dichloromethane (1 ml) and was diluted in diethyl ether to induce crystallization. The mixture was cooled, filtered and washed with diethyl ether, giving the connection header (0.56 g, 96%) as not quite white solid.

Rf0,28 (8% methanol/dichloromethane to trace the triethylamine).

Likewise happened:

The intermediate connection 37

Trifurcata salt of 4-(4-chloro-benzylamino)piperidine

From intermediate 35 (0.54 g) as a white solid (0,49 g, 87%).

Rf0,15 (3% methanol/dichloromethane to trace the triethylamine).

Example 1 Methyl ester of 2-((2-Phenoxyethanol)methyl)-5-(3,4,4-trimethyl-2,5-dioxo is) in dichloromethane (25 ml) at 0oWith added 2-phenoxyethylamine (186 mg) and triethylamine (137 mg). Stirring is continued for 18 h, with the temperature rising up to RT. The reaction mixture was diluted with dichloromethane (50 ml) and was washed with water (2 20 ml), hydrochloric acid (1M; 20 ml), water (20 ml), with brine (20 ml) and then dried (MgSO4). Filtration and evaporation of the solvent under vacuum produced connection header (581 mg, 91%) as a colorless oil.

Rf0,31 (3:1 ethyl acetate/hexane).

MS 467 (M+).

Likewise happened:

Example 2 Methyl ether 2-((N-methyl-(2-phenoxyethyl)sulfamoyl) methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

From intermediate 16 (328 mg) and intermediate 13 (800 mg) as a colorless oil (874 mg, 83%).

Rf0,27 (3:1 ethyl acetate/hexane).

MS 484 (M+)

Example 3 Methyl ether 2- ((N-methyl-(2-(4-chlorophenoxy)ethyl)-sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

From 2-(4-chlorophenoxy)-N-methylethylamine (416 mg) and intermediate 13 (827 mg) as a colorless oil (955 mg, 82%).

Rf0,35 (3:1 ethyl acetate/hexane).

MS 518(M+)

the one-1-yl)PENTACARBONYL acid

From intermediate 19 (180 mg) and intermediate 14 (459 mg) as a colorless oil (589 mg, 98%).

Rf0,44 (2:1 ethyl acetate/hexane).

MS 536 (M+).

Example 5 Ethyl ester of 4-(4-(4-chlorophenyl)piperazine-1-yl) sulfanilyl)tetrahydropyran-4-carboxylic acid

The dihydrochloride of 4-chlorophenylpiperazine (7,3 g) and triethylamine (12 ml) stir in dichloromethane for 10 min, then the mixture was cooled in ice and a solution of intermediate 24 (6.9 g) in dichloromethane was added dropwise over 10 minutes and the Mixture was stir at 0oC for 3 h were washed with 2% aqueous citric acid, saturated sodium bicarbonate and with brine, dried (MgSO4) and was evaporated, the residue was purified by chromatography (EtOAc), giving the compound of the title (at 8.60 g) as a beige solid.

Rf0,29 (ether).

MS 430 (M+).

Likewise happened:

Example 6 Ethyl ester of 4-(4-pyridylacetate-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid

From the intermediate compound 24 (1.0 g) and intermediate compound 29 (1.6 g) as a colorless solid (1.45 g).

Rf0,37 (6% Meon/dichloromethane 1% NH4the Il tetrahydropyran-4-carboxylic acid

From the intermediate compound 24 (1.0 g) and intermediate 30 (1.24 g) as a beige solid (1.20 g).

Rf0,32 (ether).

MS 436 (M+).

Example 8 Ethyl ester of 4-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)tetrahydropyran-4-carboxylic acid

From intermediate 24 (685 mg) and N-(2-(4-chlorophenoxy) ethyl)-N-methylamine (500 mg) as a colorless oil (944 mg, 84%).

Rfof 0.50(2:1 ethyl acetate/hexane).

M+420.

Example 9 Ethyl ester of 4-(4-(4-chlorophenoxy)piperidine-1 yl) sulfonylureatolerant-4-carboxylic acid

From intermediate 24 (3.28 g) and intermediate 31 (3,01 g) as a brown solid (4,47 g, 83%).

Rf0,40 (ether).

Example 10 tert-Butyl ester 2-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-3-metallocarboranes acid

N-2-(4-chlorophenoxy)ethyl-N-methylamine (300 mg) was added to a solution of intermediate 15 (438 mg) and triethylamine (1.2 ml) in dichloromethane (50 ml) at 0oC. the Solution stir for 2 h, then was filtered aqueous citric acid (5%, 50 ml), saturated bicarbonate solution (50 ml) and with brine, dried (MgSO4and Wyatt).

MS 420 (M+).

Likewise happened:

Example 11 tert-Butyl ester 2-[N-Methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)sulfamoyl]methyl-3-metallocarboranes acid

From intermediate 27 (366 mg) and intermediate 15 (464 mg) as a colorless oil (464 mg, 61%).

Rf0,66 (2:1 hexane/ethyl acetate).

MS 448 (M+).

Example 12 tert-Butyl ester 2-(4-(4-cyanobenzene) piperidine-1-sulfonylated)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

The triethylamine (0,30 ml) was added via syringe to an ice-cold solution of intermediate 14 (0,437 g) and intermediate 36 (0,350 g) in anhydrous dichloromethane (20 ml) and the mixture was stir under nitrogen atmosphere for 3 days at RT. After evaporation of the mixture under reduced pressure, the residue was dissolved in diethyl ether (40 ml) and was washed with 2.5% aqueous citric acid (2 10 ml), water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), saturated salt solution (10 ml), dried (MgSO4) and was concentrated under vacuum, producing a connection header (0,434 g, 69%) as a white solid.

Rf0,34 (diethyl ether).

Likewise happened:

From intermediate 36 (0,193 g) and intermediate 15 (0,181 g) as a colourless resin (0,087 g, 34%).

Rf0,40 (2% diethyl ether/dichloromethane).

Example 14 tert-Butyl ester 2-(4-(4-chlorobenzylamino) piperidine-1-ylsulphonyl)-3-metallocarboranes acid

From intermediate 37 (0,48 g) and intermediate 15 (0.39 g) as resin color straw (0,60 g, 92%).

Rf0,40 (2% diethyl ether/dichloromethane).

MS 473 (MN+).

Example 15 2-((2-Phenoxyethanol)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

To stir the solution of example 1 (555 mg) in dioxane (25 ml) in an ice-salt bath was added a solution of lithium hydroxide (149 mg) in water (10 ml). The stirring continued for 5 h, then the mixture was diluted with water (50 ml) and was extracted with diethyl ether (2 25 ml). The aqueous mixture was padillas citric acid to pH 4 and then was extracted with ethyl acetate (5 to 30 ml). United an ethyl acetate extracts were washed with water (2 20 ml), with brine (20 ml) and dried (MgSO4). Filtration and evaporation of the solvent under vacuum produced connection header (443 mg, 82%) as white foam.

Example 16 2-((N-Methyl-N-(2-phenoxyethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

Example 2 (850 mg) as a colorless oil (642 mg, 78%).

Rf(2:1 ethyl acetate/hexane).

MS 470 (M+).

Example 17 2-((N-Methyl-N-(2-(4-chlorophenoxy)ethyl)sulfamoyl) methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

Example 3 (947 mg) as a colorless oil (772 mg, 84%).

Rf0,26 (3:1 ethyl acetate/hexane).

MS 504 (M+).

Example 18 2-((N-Methyl-(benzofuran-2-yl)methylsulfanyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

To stir the solution of example 4 (575 mg) in dichloromethane (18 ml) at 0oWith added triperoxonane acid (2 ml). The mixture stir for 16 h, with the temperature rising up to RT. The solvent was removed in vacuo, and the residue was azeotropically with toluene (2 50 ml), generating the connection header (515 mg, 100%) as a colorless oil.

Rf0,17 (2:1 ethyl acetate/hexane).

MS 480 (M+).

Example 19 4-(4-(4-Chlorophenyl)piperazine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid

The lithium hydroxide (6 g) was added to p is. mesh was cooled to RT, evaporated to half volume under reduced pressure, and then the solution was washed with ether. The aqueous phase was padillas citric acid to pH 5 and extracted with dichloromethane (4 100 ml). The solvent was washed with brine, dried (MgSO4) and was evaporated, yielding compound of the title (the ceiling of 5.60 g, 70%) as a beige solid.

Rfof 0.20 (EtOAc).

MS 402 (M+).

Likewise happened:

Example 20 4-(4-Pyridylacetate-1-yl)sulfonylated)-tetrahydropyran-4 carboxylic acid

Example 6 (1.45 g) as a beige solid (0.20 g).

Rf0,20 (10% Meon/dichloromethane 1% Asón)

MS 384 (M+).

Example 21 4-(4-(4-Cianfrocca)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid

Example 7 (1.20 g) as a colorless solid (0.25 g).

RfOf 0.54 (EtOAc + 1% Asón).

MS 408 (M+).

Example 22 4-(N-(2-(4-Parfenov)ethyl)-N-methylcarbamoylmethyl)tetrahydropyran-4-carboxylic acid

Example 8 (930 mg) as a colorless solid (688 mg, 79%).

Rf0,30 (2:1 ethyl acetate/hexane).

MS 392 (M+).

Example 23 4-(4-(4-Chlorophenoxy)piperidine-vo (2.6 g, 90%).

Rf0,40 (ether).

MS 416 (M-1).

Example 24 2-(N-(2-(4-Chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-3-metallocarborane acid

The solution of example 10 (465 mg) was dissolved in 30% triperoxonane acid in dichloromethane (50 ml) and the solution stir for 2 hours the Solution was then evaporated under reduced pressure and the residue was azeotropically to dryness with dichloromethane/hexane (3 100 ml). The residue was dissolved in saturated sodium bicarbonate (50 ml) and washed with ether. The aqueous layer was sekilala citric acid and was extracted by EtOAc (2 100 ml), the solvent was dried (MgSO4) and evaporated, giving a connection header (403 mg, 100%) as a colorless oil.

Rf0,55 (2:1 ethyl acetate/hexane).

MS 363 (M+).

Likewise happened:

Example 25 2-(N-Methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)-sulfamoyl)-3-metallocarborane acid

Example 11 (450 mg) as a colorless oil (379 mg, 97%).

Rf0,68 (2:1 ethyl acetate/hexane).

MS 392 (M+).

Example 26 2-(4-(4-Cyanobenzene)piperidine-1-ylsulphonyl-methyl)-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)PENTACARBONYL acid

Triperoxonane acid (2 ml) is. After 18 h the reaction mixture was evaporated under bonigen pressure, and the residue was azeotropically twice with toluene. The resulting oil was purified silikagelevye column chromatography with elution with 4% methanol/dichloromethane, gave the result of the connection header (0,232 59%) as a pale yellow resin.

Rf0,22 (4% methanol/dichloromethane),

MS 534 (MN+).

Likewise happened:

Example 27 2-(4-(4-Cyanobenzene)piperidine-1-ylsulphonyl-methyl)-3-metallocarborane acid

Example 13 (0,087 g) as a colorless solid (of 0.085 g, 100%).

Rf0,49 (3% methanol/dichloromethane).

MS 394 (MN+).

Example 28 2-(4-(4-Chlorobenzylamino)piperidine-1-ylsulphonyl-methyl)-3-metallocarborane acid

Example 14 (0,60 g) as a white solid (0,42 g, 80%).

Rfof 0.50 (5% methanol/dichloromethane).

MS 417 (MN+).

Example 29 N-hydroxyamide 2-((2-Phenoxyethanol)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

To stir a solution of example 15 (440 mg) in dichloromethane (20 ml) at 0oWith added EDC (189 mg) and O-tert-butyldimethylchlorosilane (141 mg). Stirring is continued for the water (3 20 ml), salt solution (20 ml) and dried (MgSO4). Filtration and evaporation of the solvents under reduced pressure gave a colorless oil, which was dissolved in dichloromethane (15 ml) and was treated with a solution of hydrogen chloride in diethyl ether (1M; 3.0 ml). The mixture stir for 1 h before the solvents were removed in vacuo, and the residue was purified silikagelevye column chromatography with elution 3:1 ethyl acetate/hexane, gave the result of the connection header (264 mg, 57%) as a white solid.

Rf0,32 (3:1 ethyl acetate/hexane).

MS 471 (M+).

Likewise happened:

Example 30 N-Hydroxyamide 2-((N-methyl-(2-phenoxyethyl)sulfamoyl) methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

Example 16 (500 mg) as a white solid (175 mg, 34%).

Rfof 0.16 (ethyl acetate).

MS 485 (M+).

Example 31 N-Hydroxyamide 2-((N-methyl-(2-(4-chlorophenoxy)ethyl) sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

Example 7 (750 mg) as a white solid (332 mg, 43%).

Rfof 0.18 (ethyl acetate).

MS 519 (M+).

Example 32 N-Hydroxyamide 2-((N-methyl-(b is From example 18 (250 mg) as a white solid (98 mg, 38%).

Rf0,10 (9:1 ethyl acetate/methanol).

MS 495 (M+).

Example 33 N-Hydroxyamide 2-(N-methyl-N-(2-(4-chlorophenoxy)ethyl) sulfamoyl)-3-metallocarboranes acid

Example 24 (400 mg) as a white foam (386 mg, 96%).

Rf0,46 (3:1 ethyl acetate/hexane).

M+379.

Example 34 N-hydroxyamide 2-(N-methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)sulfamoyl)-3-metallocarboranes acid

Example 25 (370 mg) as a white solid (141 mg, 37%).

Rf0,32 (3:1 ethyl acetate/hexane).

M+407.

Example 35 the Hydrochloride of N-hydroxyamide 4-(4-(4-chlorophenyl) piperazine-1-yl) sulfanilyl) tetrahydropyran-4-carboxylic acid

To a suspension of example 19 (5.6 g) in dichloromethane (100 ml) atoWith added acid chloride oxalic acid (4 ml), followed by dimethylformamide (1 drop). The mixture stir for 1 h, then evaporated in vacuo, and the residue was azeotropically with dichloromethane/hexane (3 100 ml). The crude product was dissolved in dichloromethane (50 ml), was added triethylamine (5,80 ml) and O-DMS (2.24 g). The mixture stir for 3 h, then was washed with water, aqueous sodium bicarbonate and hydrochloric who (1M, 50 ml) was added dropwise. The mixture vigorously stir for 30 min, then the product was collected by filtration and rinsed with ether (2 100 ml), giving a connection header (5.0 g) as a colorless powder.

Rfof 0.53 (10% Meon/dichloromethane 1% NH4OH).

MS 418 (M+).

Likewise happened:

Example 36 Hydrochloride N-hydroxyamide 4-(4-(4-pyridyloxy) piperidine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid

Example 20 (0,19 g) as a white solid (0.12 g).

Rf0,25 (7% Meon/dichloromethane 1% NH4OH).

MS 400 (M+).

Example 37 N-Hydroxyamide 4-(4-(4-cianfrocca)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid

Example 21 (0.25 g) as a white solid (5.5 mg).

Rf0,32 (5% Meon/dichloromethane).

MS 423 (M+).

Example 38 N-Hydroxyamide 4-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)tetrahydropyran-4-carboxylic acid

Example 22 (650 mg) as a colorless solid (412 mg, 74%).

Rfof 0.24 (ethyl acetate).

M+407.

Example 39 N-Hydroxyamide 4-(4-(4-chlorophenoxy)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic sour is n).

MS 431(M-1)

Example 40 N-hydroxyamide 2-[4-(4-cyanobenzene)piperidine-1-ylsulphonyl] -5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

EDC (is 0.102 g) was added to a suspension Of tert-butyldimethylchlorosilane (of 0.066 g) and example 26 (0,218 g) in dichloromethane (20 ml) and the mixture was stir at room temperature for 18 hours the Solvent was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and was washed with water (2 10 ml), saturated sodium bicarbonate (20 ml), water (10 ml), saturated salt solution (10 ml), and dried (MgSO4). The organic phase was then evaporated in vacuo, the residue was dissolved in tetrahydrofuran (5 ml) was cooled in an ice bath and was treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 0.45 ml). After 10 min the reaction was extinguished acetic acid (0.5 ml) and was separated between water (30 ml) and hexane (20 ml). Hexane was decontrols, and the aqueous phase was re-usbutils with hexane (20 ml). The aqueous phase was then extracted with ethyl acetate (2 20 ml) and the combined organic extracts were washed with 1: 1: 1 mixture of water, saturated sodium bicarbonate and saturated brine (15 ml). The organic layer is then Pomerantseva connection header (0,185 g, 82%) as a white solid.

Rf0,16 (5% methanol/dichloromethane).

MS 549 (MN+).

Likewise happened:

Example 41 N-Hydroxyamide 2-(4-(4-cyanobenzene)piperidine-1-ylsulphonyl)-3-metallocarboranes acid

Example 27 (of 0.085 g) as a white solid (0,017 g, 22%).

Rf0,13 (3% methanol/dichloromethane).

MS 409 (MN+).

Example 42 N-Hydroxyamide 2-(4-(4-chlorobenzylamino)piperidine-1-ylsulphonyl)-3-metallocarboranes acid

EDC (0,251 g) was added to a solution Of tert-butyldimethylchlorosilane (0,148 g) and example 28 (0,42 g) in dichloromethane (40 ml) and the mixture was stir at room temperature for 4 hours the Solvent was then evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (60 ml) and was washed with 1% citric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20 ml), water (10 ml), saturated salt solution (15 ml) and dried (MgSO4). The organic phase was then evaporated in vacuo, and the residue was purified silikagelevye column chromatography with 4% methanol/dichloromethane with predarwinian columns 4% methanol/5% triethylamine/dichloromethane, giving a white solid Vashem in the form of a 1.0 M solution in diethyl ether (3.0 ml). After 20 min at room temperature the solvents were removed and the residue was pulverized in a mixture of dichloromethane and diethyl ether, affording the compound of the title (0,294 g, 67%) as a colorless solid.

Rf0,14 (5% methanol/dichloromethane).

MS 432(MN+).

HPLC-MS conditions

In the following descriptions of experiments HPLC-MS was performed on a Hewlet Packard 1100 LC when using a Phenomenex Luna Cl8, 50 2.1 mm column at 35oWith probegaya gradient of solvent A: solvent of 95:5 to 35:65 for 4,70 min to 0:100 over 1,50 min at a flow rate of 0.90 ml/min Solvent a and the solvent is present In 95% water: 5% acetonitrile with 0.1% formic acid and 5% water: 95% acetonitrile with 0.1% formic acid, respectively. MS spectra were acquired with 1 cone voltage (30 V), on a Micromass Quattro (triple quadrupole) device.

Example 43 N-Hydroxyamide 2-((N-ethyl-n-(2-methoxyethyl)-sulfamoyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

(2-Methoxyethyl)ethylamine (0.1 mmole) was added to a solution of intermediate 15 (0.1 mmole) and N-methylmorpholine (1.1 equivalent) in dichloromethane (1 ml) at 0oIn scintillation vials, and the solutions were stir overnight at which Alice to dryness. The crude product was dissolved in 50% triperoxonane acid/dichloromethane (1 ml) and stir overnight at room temperature, then was evaporated to dryness and azeotropically with toluene. The crude acid was then taken in dichloromethane and then treated with one equivalent of each of the EDC, hydroxylamine hydrochloride and N-methylmorpholine for 18 hours the Solution was then rinsed with water and aqueous sodium bicarbonate and evaporated. The crude product was purified preparative HPLC, giving the compound of the title as colorless foam (10,8 mg).

HPLC Rt5,32 minutes

MS 436 (M+).

Likewise happened:

Example 44 N-Hydroxyamide 2-(3,3-diphenylpropylamines)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and 3.3-diphenylpropylamine as a white solid (14.3 mg).

HPLC Rt6,70 minutes

MS 544 (M+).

Example 45 N-Hydroxyamide 2-(cyclohexanesulfonyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and cyclohexylethylamine as a beige solid (5.5 mg).

HPLC Rt5,58 minutes

MS 446 (M
From intermediate 15 and 1-methyl-3-phenylpropylamine as a white solid (24,7 mg).

HPLC Rt5,88 minutes

MS 482 (M+).

Example 47 N-Hydroxyamide 2-((3-phenylpropyl)sulfamoyl-methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) pentane-carboxylic acid

From intermediate 15 and 3-phenylpropylamine as a beige solid (34,1 mg).

HPLC Rt5,61 minutes

MS 468 (M+).

Example 48 N-Hydroxyamide 2-((N-methyl-N-articulator)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and octylacrylamide as a colorless solid (19.1 mg).

HPLC Rt7,42 minutes

MS 476 (M+)

Example 49 N-Hydroxyamide 2-(N-(2-cyanoethyl)-N-octyl-sulfamoyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and (2-cyanoethyl)octylamine as a beige solid (3.1 mg).

HPLC Rtof 7.23 minutes

MS 515 (M+).

Example 50 N-Hydroxyamide 2-(N-(2-(4-chlorophenoxy)-1-methyl-ethyl)-N-methylcarbamoylmethyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

Of the sub is P> HPLC Rt6,46 minutes

MS 532 (M+).

Example 51 N-hydroxyamide 2-(N-methyl-N-genetically-methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and N-(phenethyl)methylamine as a white solid (13.2 mg).

HPLC Rt5,22 minutes

MS 468 (M+).

Example 52 N-hydroxyamide 2-(N-(2-(2-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-PENTACARBONYL acid

From intermediate 15 and N-(2-(2-chlorophenoxy)ethyl)methylamine as a brown solid (5.5 mg).

HPLC Rtof 5.68 min

MS 518 (M+).

Example 53 N-hydroxyamide 2-(N-ethyl-N-phenylsulfonyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid

From intermediate 15 and N-ethylaniline as a colorless solid (9.0 mg).

HPLC Rtof 5.89 min

MS 454 (M+).

Example 54 N-hydroxyamide 2-(N-(4-chlorophenyl)-N-methylcarbamoylmethyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) PENTACARBONYL acid

From intermediate 15 and N-(4-chlorophenyl)methylamine as a white solid (3.2 mg).

HPLC Rt the inhibitory activity, represented by the formula I

< / BR>
in which m = 0-1;

X is SO2;

Y is HE or NHOH;

R1is1-6alkyl or piperidinyl, optionally substituted R7;

R2represents N or C1-6alkyl;

or CR1R2is cycloalkyl, piperidinyl or tetrahydropyranyl, optionally substituted R7;

each is the same or different and represents H, C1-6alkylated, C1-6alkylphenyl, C1-6alkyl, cycloalkyl, which is optionally condensed with benzene, C1-6alkylsilanes, phenyl, furanyl, thiophenyl, pyrrolyl, optionally condensed with benzene, C1-6alkylbenzenes, C1-6alkylbenzoates, C1-6acylinder where any of these groups is optionally substituted by a Deputy selected from R3, phenyl, C1-6alkyl-R3where R3is C1-6by alkyl, halogen, CN, NO2, OR4, COR4, NR4R5, CO2R8, SO2R6, CON(R4)2provided that NB2is not NH2,

or B-N-B is piperidinyl, substituted = NOR4; or, when R1or R2is not Astelin substituted Deputy selected from R3WITH1-6alkyl-R3, phenyl, optionally substituted by R3C1-6alkylphenyl, optionally substituted R3, phenyl-C1-6alkyl-R3WITH1-6alkylthiophene, pyridyl-C1-6alkyl-R3, pyrimidinyl, pyridinyl, optionally substituted R3, oxazole, thiazole, isoxazol, optionally condensed with benzene, and R3represents C1-6alkyl, halogen, CN, NO2, OR4, COR4, CO2R8, NR4R5, SO2R6or CON(R4)2; R4represents H, C1-6alkyl, phenyl, C1-6alkylphenyl, pyridyl, pyrazinyl, optionally substituted R6, OR6, halogen, CN, NO2where R6represents C1-6alkyl and phenyl; R5is hydrogen; R7is CO2R2hydantoinyl, optionally substituted R8, COR4; R8represents N or C1-6alkyl,

and its salt, solvate, hydrate, protected amino, carboxy or protected derivatives of hydroxamic acids.

2. The compound of formula I under item 1, in which Y is HE, B-N-B is optionally substituted by piperidinyl and/or CR1R2is optional Zan.

4. The compound according to any one of the preceding paragraphs, in which R3represents C1-6alkyl, halogen, CN, NR2, OR4, COR4, NR4R5, SO2R6.

5. The compound according to any one of paragraphs. 1-4, in which R7is hydantoinyl.

6. The compound according to any one of paragraphs. 1-5, in which R1is1-6alkyl, optionally substituted R7.

7. The compound according to any one of paragraphs. 1-6, in which each independently represents optionally substituted C1-6alkyl, cycloalkyl, C1-6alkylated, C1-6alkylphenyl or C1-6alkylbenzenes, C1-6acylinder or C1-6alkylbenzoates.

8. The compound according to any one of paragraphs. 1-3, selected from

methyl ester of 2-((2-Phenoxyethanol)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

methyl ester of 2-((N-methyl-(2-phenoxyethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pentacosanoic acid,

methyl ester of 2-((N-methyl-(2-(4-chlorophenoxy)ethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

tert-butyl ester 2-((N-methyl-(benzofuran-2-yl)methylsulfanyl)methyl)-5-(-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

2-((N-methyl-(2-phenoxyethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

2-((N-methyl-(2-(4-chlorophenoxy)ethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

2-((N-methyl-(benzofuran-2-yl)methylsulfanyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

N-hydroxyamide 2-((2-Phenoxyethanol)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

N-hydroxyamide 2-((N-methyl-(2-phenoxyethyl)sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

N-hydroxyamide 2-((N-methyl-(2-(4-chlorophenoxy)ethyl)-sulfamoyl)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid,

N-hydroxyamide 2-((N-methyl-(benzofuran-2-yl)methylsulfanyl) methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)PENTACARBONYL acid.

9. The compound according to any one of paragraphs. 1-5, selected from

ethyl 4-(4-(4-chlorophenyl)piperazine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylate,

ethyl 4-(4-pyridylacetate-1-yl)sulfanilyl-tetrahydropyran-4-carboxylate,

ethyl 4-(4-(4-cianfrocca)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carbox is 4-(4-(4-chlorophenoxy)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylate,

tert-butyl 2-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-3-methyl-butanoate,

tert-butyl 2-[N-methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)sulfamoyl] -methyl-3-methylbutanoate,

tert-butyl 2-(4-(4-cyanobenzene)piperidine-1-sulfonylated)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pentanoate,

tert-butyl 2-(4-(4-cyanobenzene)piperidine-1-ylsulphonyl)-3-methylbutanoic acid,

tert-butyl 2-(4-(4-chlorobenzylamino)piperidine-1-ylsulphonyl)-3-methylbutanoate,

4-(4-(4-chlorophenyl)piperazine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid,

4-(4-pyridylacetate-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid,

4-(4-(4-cianfrocca)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid,

4-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)tetrahydropyran-4-carboxylic acid,

4-(4-(4-chlorophenoxy)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid,

2-(N-(2-(4-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-3-methylbutanoic acid,

2-(N-methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)-sulfamoyl)-3-methylbutanoic acid,

2-(4-(4-cyanobenzene)piperidine-1-yl)sulfonylated)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin,

2-(4-(4-chlorobenzylamino)piperidine-1-yl)sulfonylated)-3-methylbutanoic acid,

N-hydroxyamide 2-(N-methyl-N-(2-(4-chlorophenoxy)ethyl)-sulfamoyl)-3-methylbutanoic acid,

N-hydroxyamide 2-(N-methyl-N-(2-(4-chlorphenoxy)-2,2-dimethylethyl)-sulfamoyl)-3-methylbutanoic acid,

N-hydroxyamide hydrochloride 4-(4-(4-chlorophenyl)piperazine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid,

N-hydroxyamide hydrochloride 4-(4-(4-pyridyloxy)piperidine-1-yl)sulfonylated)-tetrahydropyran-4-carboxylic acid,

N-hydroxyamide 4-(4-(4-cianfrocca)piperidine-1-yl)sulfanilyl-tetrahydropyran-4-carboxylic acid,

N-hydroxyamide 4-(N-(2-(4-chlorophenoxy)ethyl)-N-methyl-sulfamoyl)tetrahydropyran-4-carboxylic acid,

N-hydroxyamide 4-(4-(4-chlorophenoxy)piperidine-1-yl)-sulfanilyl-tetrahydropyran-4-carboxylic acid,

N-hydroxyamide 2-[4-(4-cyanobenzene)piperidine-1-yl)-sulfanilyl] -5- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pentanol acid,

N-hydroxyamide 2-(4-(4-cyanobenzene)piperidine-1-yl)-sulfonylated)-3-methylbutanoic acid,

N-hydroxyamide 2-(4-(4-chlorobenzylamino)piperidine-1-yl)-sulfonylated)-3-methylbutanoic acid,

The N,

N-hydroxyamide 2-(3,3-diphenylpropylamines)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(cyclohexanesulfonyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(1-methyl-3-phenylpropylamine)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pentanol acid,

N-hydroxyamide 2-((3-phenylpropyl)sulfamoyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-((N-methyl-N-articulator)methyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(N-(2-cyanoethyl)-N-articulatory)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(N-(2-(4-chlorophenoxy)-1-methylethyl)-N-methylcarbamoylmethyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(N-methyl-N-penicillamine)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(N-(2-(2-chlorophenoxy)ethyl)-N-methylcarbamoylmethyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol acid,

N-hydroxyamide 2-(N-ethyl-N-phenylsulfonyl)-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanol sour Lanovoy acid.

10. The compound according to any one of paragraphs. 1-9 in the form of an individual enantiomer or diastereoisomer.

11. The compound according to any one of paragraphs. 1-10 designed to produce tools for the treatment or prevention of a condition associated with the activity of matrix metalloproteinases.

12. Connection on p. 11, in which the specified condition is a rheumatoid arthritis or osteoarthritis.

13. The pharmaceutical composition inhibiting the activity of matrix metalloproteinase, comprising the compound according to any one of the preceding paragraphs and a pharmaceutically acceptable diluent or carrier.

Priorities for items:

12.11.1997 on p. 8;

06.02.1998 on PP. 1-7;

26.06.1998 on p. 9;

12.11.1998 on PP. 10-14.

 

Same patents:

The invention relates to the field of organic chemistry and relates to compounds of formula (I) and their pharmaceutically acceptable salts and difficult ether derivatives

< / BR>
where Ar represents a phenyl group which may be optionally substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and triptorelin groups having antifungal activity

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to an improved process for the preparation of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione used as antifibrillatory and antiarrhythmic agent, the General formula

< / BR>
incorporating the following stages: a) interaction 1- [[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-2,4-imidazolidinedione formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and their mixtures, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione 4-methylpiperazine education 1-[[[5-(4-chlorophenyl)-2-furanyl] the methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichloro is tons of potash, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to new Amida acids of the formula I

< / BR>
where R1- C1-C6alkanoyl,1-C6alkoxycarbonyl, benzoyl, benzoyl substituted halogen (C1-C6)-alkoxy, C1-C6alkylsulfonyl, phenylsulfonyl, phenylsulfonyl, substituted with halogen, or cyclo (C3-C6) alkylsulphonyl, R2- phenyl, phenyloxy or phenylamino, where each phenyl may be substituted with halogen; pyridyl or pyridylamino, a represents a single bond, E is ethylene, X represents CH, Y is-NR5where R5is hydrogen, Q is-C(O)- or-SO2-, R3and R4together form ethylene, or their pharmaceutically acceptable salts

The invention relates to new indole derivative of the formula I

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where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new cyclic diamine compounds of the formula I, where

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represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to a form of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent

The invention relates to N-oxides of heterocyclic compounds of the formula (I), where R1is CH3CH2F, CHF2, CF3; R2is CH3, CF3; R3represents F, Cl, Br, CH3; R4represents H, F, Cl, Br, CH3

The invention relates to the use of 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic to modulate the activity of metabotropic glutamate receptors (mGluR) and to the treatment of mGluR5 mediated diseases, to pharmaceutical compositions intended for use in such therapy, as well as to new 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic

The invention relates to substituted 3-cyanohydrins formula (1), where R1, R2, R3, R4, Y and X are such as defined in the claims

The invention relates to a vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, how you can get it by heating the crystalline modification a or a mixture of crystalline modification a and crystalline modification of hydrate 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic]-N-methylamino] -2,6-dichloraniline] -2-methylinosine at a temperature below its melting point and then cooled

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

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where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

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is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to a new method of producing compounds of the formula I

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where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases
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