Bicyclic tetrahydropyrimidine or their pharmaceutically acceptable salts, pharmaceutical composition, method of inhibiting phosphodiesterase, treatment

 

(57) Abstract:

Bicyclic tetrahydropyrimidine formula I

< / BR>
where R1- C1-3alkyl; X is oxygen or two hydrogen atoms; R2C1-4alkyl, indolyl,3-7cycloalkyl or a group of formula II

< / BR>
a = 1 or 2; b and C = 0 or 1 ; R4-H, C1-5alkyl, alkoxyl,3-6cycloalkyl, halogen, CF3, CO2R6, CONR6R7, NR6R7, R6, R7- N or C1-4alkyl; Z - SO; Y1-5alkylene; R3has the meanings given for R2and methylenecyclopropane, provided that R2and R3cannot simultaneously denote methyl, or their pharmaceutically acceptable salts and pharmaceutical compositions on the basis of them inhibit phosphodiesterase type IV and the production of tumor necrosis factor. 4 c. and 4 C.p. f-crystals, 2 tab.

This invention relates to a series of bicyclic tetrahydropyrimidines, which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (hereafter TNF), and as such is applicable for the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic ri what's with the elaboration of TNF.

This invention also relates to a method of using such compounds to treat the aforementioned diseases in mammals, especially humans, and to pharmaceutical compositions suitable for this purpose.

Since then, as it became known that cyclic AMP is an intracellular secondary messagenum (E. W. Sutherland and T. W. Rall, Pharmacol. Rev. , 1960, 12, 265) inhibition of phosphodiesterase became a target for modulation and, accordingly, therapeutic intervention in several pathogenic processes. Recently been identified separate classes PDE (J. A. Beavo and D. H. Reifnyder, TiPS, 1990, 11, 150) and their selective suppression has led to improved drug therapy (C. D. Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991, 12, 19). More specifically, it was found that inhibition of PDE type IV can lead to the suppression of the selection of mediators of inflammation (M. W. Verghese et al. , J. Mol. Cell Cardiol., 1989, 12 (Suppl. 11), S 61) and the relaxation of smooth muscles of respiratory ways (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have weak activity against other types of PDE, should inhibit the secretion of mediators of inflammation and relax the smooth muscles of the respiratory tract without providing woah development of many infectious and autoimmune diseases (W. Friers, FEBS Letters, 1991, 285, 199). In addition, it was shown that TNF is a major mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunophathology, 1992, 62, S 11).

Summary of invention

This invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts; where

R1is hydrogen, (C1-C7)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or methylene(C3-C5)cycloalkyl, in which each alkyl or Alchemilla group may be arbitrarily substituted up to two (C1-C2)alkyl or triptoreline groups or up to three Halogens;

X is oxygen or two hydrogen atoms;

R2and R3each independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C1-C14)alkoxyl, (C2-C7)alkenyl, (C4-C7)heterocyclic group containing oxygen, sulfur, SO2or NR5where R5is hydrogen or (C1-C4)alkyl or a group of the formula

< / BR>
where

a is an integer from 1 to 5;

b and c is 0 or 1;

R4P>)alkoxyl, (C3-C6)cycloalkyl, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, NO2or SO2NR6R7where R6and R7each independently are hydrogen or (C1-C4)alkyl;

where Z is oxygen, sulfur, SO2or BR8where R8is hydrogen or (C1-C4)alkyl; and

Y is (C1-C5)alkylene or (C2-C6)alkenyl optionally substituted, up to 2, (C1-C7)alkyl or (C3-C7)cycloalkyl groups: or a group of the formula

< / BR>
where

p is an integer from 1 to 3,

W is oxopropoxy or hydroxyl,

R9is (C1-C3)alkyl;

where each specified alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be arbitrarily substituted from one to fourteen, preferably five groups from the group consisting of (C1-C2)alkyl, trifloromethyl or halogen, provided that when R1is ethyl and R2is a 4-were, R3cannot be hydrogen, stands, phenyl, 4-florfenicol or 2-pyridium, and provided that km or n-propylene, and provided that when R1is ethyl, and R2is phenyl, R3may not be 4-chlorophenyl, 4-florfenicol or 4-were, and provided that when R1is ethyl and R2is 4-methoxyphenyl, R3may not be 4-florfenicol.

In one implementation the invention relates to a connection with formula I, where R1is (C1-C3)alkyl and R2and R3each independently selected from the group consisting of (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SO2or a group with formula

< / BR>
where

a is an integer from 1 to 5 and

R4is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxyl or halogen.

In another implementation of the invention relates to a connection with formula I, where R1is ethyl or isopropyl; R2is phenyl, 2-were, 3-were, 2-methoxyphenyl, 3-methoxyphenyl or 3-cryptomaterial and R3is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolane, 4-florfenicol or 3,4-dichlorophenyl.

This invention also relates to pharmaceutical preparations is holding a pharmaceutically effective amount of the compounds corresponding to the formula I and its pharmaceutically acceptable salts and pharmaceutically acceptable carrier.

This invention also relates to a method for inhibiting the phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), including introduction to the patient an effective amount of a compound according to formula I and its pharmaceutically acceptable salts.

This invention also relates to a method of treating a condition of inflammation in a mammal, which includes an introduction to the specified mammal an antiinflammatory amount of a compound with formula I and its pharmaceutically acceptable salts.

The invention additionally relates to pharmaceutical compositions for the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF, comprising pharmaceutically effective amount of a compound according to formula I and its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

This invention also relates to a method lessstructured diseases of the respiratory tract, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF, including the introduction to the patient an effective amount of a compound according to formula I and its pharmaceutically acceptable salts.

Specific preferred compounds of this invention are:

3-ethyl-1-(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1-(4-forfinal)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-were)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-triptoreline)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo-[3,4-c]pyridine;

3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo - 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,

3-ethyl-1-cyclopentyl-6-(2-were)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3-sulfophenyl)-6-(3-were)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3-sulfophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-were)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3-sulfophenyl)-6-(3-triptoreline)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-triptoreline)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(2-were)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine.

A detailed description of the invention

The term "halogen", which is used here, unless otherwise indicated, includes chlorine, bromine and fluorine.

Unless otherwise specified, alkyl, CNS and alkeneamine groups referred to herein may be straight chain, or if they contain three or more carbon atoms, can be straight chain, branched chain, cyclic, or a combination of cyclic and branched or straight chain parts.

"Inflammatory diseases", which can be treated according to this invention, include, but are not limited to, asthma, HRO is used here, unless otherwise noted, are what defined above, with reference to formula I.

The following schematic reactions illustrate, but are not limited to, obtaining the compounds of the present invention.

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< / BR>
In reaction 1 of scheme 1 2-pyrrolidinone compound of formula IV is converted to the corresponding N-(aryl)-2-pyrolidine connection V, where "aryl" is a group of formula II, by reacting IV with a clean helgaleena in the presence of a copper catalyst and potassium carbonate. Suitable aryl halides include 1-iodine - or 1-bromo-4-methoxybenzoyl, 3-methoxybenzoyl, 2-ethoxybenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-methylbenzoyl, 3-triptoreline, 2-triptoreline, 3,4-dimethoxybenzene or 3-cyclopentyloxy-4-methoxybenzoyl. The reaction temperature should generally be in the range of from about 110oC to about 170oC, preferably about 150oC, over a time period of from about 14 hours to about 22 hours, preferably about 18 hours, provided the reaction in an inert environment.

In reaction 2 of scheme 1, R1the halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated at stake is Arvale from about -15oC to approximately 15oC, preferably to about 0oC. is Then added N-(aryl)-2 - pyrrolidinone compound with the formula V, and the reaction mixture is heated to room temperature with stirring over a period of time from about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkylhalogenide include bromatan, bromatan or bromopropane. Suitable anhydrous aprotic solvent is anhydrous ether. After completion of the reaction, the desired intermediate compound may be isolated in the usual way, for example, first washing of mixed organic substances with water and brine, then dried with sodium sulfate, filtration and concentration under reduced pressure to get easily allocated to precipitate in the form of a white solid.

The above residue is converted into the corresponding 2,5,6-tetrahydropyridine compound of formula VI by dispersing the precipitate in a mixture of non-polar aprotic solvent and a base. After vigorous stirring is added ETHYLACETYLENE, and the reaction mixture is heated in a flask under reflux over a period of time from about 1.5 canotorilor is benzene, and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After heating in a flask under reflux over a period of time from about 1 hour to about 3 hours, preferably for about 1.5 hours, the mixture is concentrated under reduced pressure and acidified to pH 3 with hydrochloric acid.

In reaction 3 of scheme 1, the compound of formula VI is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound VII by heating in a flask with reflux of the reaction mixture of VI and 3-methyl-1-p-tolyltriazole in an aprotic solvent. Preferred aprotic solvent is 1,2-dichloroethane. The time period for the reaction is in the range from about 30 minutes to about 120 minutes, preferably approximately 45 minutes.

In reaction 1 of scheme 2 1,2,5,6-tetrahydropyridine compound of formula VIII, where R5is hydrogen or stands, turns into a corresponding 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-C]pyridine compound IX VIII by reaction with hydrazine with the formula, R3HNNH2. As the original mA is hypoxia sets of reaction conditions.

One of the combinations of reaction conditions 1,2,5,6 - tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX VIII by reaction with hydrazine hydrochloride and sodium alkoxide in anhydrous proton polar solvent. The preferred sodium alkoxide is sodium methoxide and the preferred anhydrous proton polar solvent is anhydrous ethanol. The reaction mixture is heated in a flask under reflux over a period of time equal to from about 9 hours to about 15 hours, preferably about 12 hours.

When the second combination of reaction conditions 1,2,5,6-tetrahydropyridine compound is converted into the corresponding compound of formula IX by reaction of VIII with hydrazinobenzene acid in anhydrous proton polar solvent, preferably ethanol. The reaction mixture is heated in a flask under reflux over a period of time from about 16 hours to about 24 hours, preferably for 20 hours. Connection IX, thus obtained, can further react with formation of the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine compounds by the reaction of IX with labels the RNO 15 minutes to about 45 minutes, preferably within 30 minutes. Polar proton solvent is removed under reduced pressure, the solid residue is suspended in non-polar aprotic solvent, preferably benzene, and then the polar solvent is removed under reduced pressure. The resulting dry solid suspendered in cold ether and treated with oxalylamino and N,N-dimethylformamide and left under stirring for a period from about 30 minutes to about 90 minutes, preferably 60 minutes. Then the solvent is removed and the crude residue is dissolved in dry tetrahydrofuran. The resulting solution added dropwise to mix the ammonium hydroxide at a temperature of from about -10oC to about 10oC, preferably at 0oC.

In the third combination of reaction conditions 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX VIII by reaction with hydrazine hydrochloride in proton polar solvent, preferably methanol. The reaction mixture is heated to a temperature of from about 70oC to about 110oC, preferably to about 90oC with gentle passing nitrogen D. what about the 120oC to about 180oC, preferably to about 150oC, during the period of time from about 30 minutes to about 90 minutes, preferably for about 60 minutes.

Educated thus compounds with the formula IX can be converted into the corresponding 6-R2-4,5,6,7-tetrahydro-7-oxo - 1H-pyrazolo[3,4-C]pyridine compound, where R2is another group, not II, IX by reaction in solution in a polar aprotic solvent, preferably acetonitrile, solution ammoniuria (IV) nitrate in water at a temperature of from about -15oC to approximately 15oC, preferably at about 0oC, during the period of time from about 20 minutes to about 50 minutes, preferably for about 35 minutes. After completion of the reaction the mixture is diluted with water and extracted with ethyl acetate. Mixed organic matter is then washed with saturated sodium bicarbonate solution and then with sodium sulfide. Thus obtained compound in a polar aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride is heated in a flask under reflux with stirring over a period of time from about 30 minutes to about 60 is about 30oC, preferably to about 25oC, and add alkylhalogenide with the formula, R2where R2is what defined in the explanation to the formula I, and not a group of formula II. The reaction mixture was stirred and heated in a flask under reflux over a period of time from about 12 hours to about 20 hours, preferably for 16 hours.

In reaction 2 of scheme 2 2-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C] pyridine compound IX is converted to the corresponding compound of formula X by reaction of IX with regenerating means, preferably layalina hydride, in a polar aprotic solvent, preferably ether. The reaction mixture is stirred for a period of time from about 12 hours to about 20 hours, preferably 16 hours. Then water is added and the base, preferably sodium hydroxide, and the reaction mixture is stirred for a period of time from about 1.5 hours to about 2.5 hours, preferably within 2 hours, and filtered. The filtrate is concentrated to obtain a white solid.

The ability of these compounds or their pharmaceutically acceptable salts to inhibit the phosphodiesterase IV (PDE4) were in vitro studies.

BIOLOGICAL TEST

(Human lung PDEIV)

Thirty to forty grams of tissue of the human lung is placed in 50 ml of Tris/phenylmethylsulfonyl (PMSF) /sucrose buffer, pH 7.4 and homogenized using a Tekmar TissumizerR(Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate was centrifuged at 48000xg for 70 minutes at 4oC. the Supernatant was filtered twice through a 0.22 μm filter and applied to a Mono Q column for liquid Express chromatography of proteins (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equilibrated Tris/PMSF buffer pH 7.4. For application of the sample to the column using a flow rate of 1 ml/min with subsequent flow rate of 2 ml/min for the subsequent washing and elution. The sample elute using a gradually increasing gradient of NaCl in buffer Tris/PMSF pH 7.4. Collect fractions of 8 ml Fractions have specific PDEIVactivity, as defined by [3H]cyclic amp hydrolysis and on the ability of the known inhibitor of PDEIV(for example, rolipram) to suppress hydrolysis. The appropriate fractions are combined diluted with ethylene glycol (2 ml of ethylene glycol/5 ml of enzyme) and stored at -20oC before and is inane, 4% DMSO). Additional serial dilution is performed by 4% DMSO to achieve the desired concentrations. The final concentration of DMSO in the test tube is 1%. In a glass test tubes 12 x 75 mm in two replications added the following in order (all concentrations are given as the final concentration in the test tube):

I) 25 μl of compound or DMSO (1%, for control or blank samples);

II) 25 ál of Tris-buffer pH 7.5;

III) [3H]camp (1 μm);

IV) 25 ál of the enzyme PDEIV(for a blank sample, the enzyme is pre-incubated in boiling water for 5 minutes).

The reaction tubes are shaken and placed in a water bath (37oC) for 20 minutes, after this time the reaction is stopped by placing the tubes in a bath of boiling water for 4 minutes. In each tube in an ice bath, is added to the washing buffer (0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/0.1 M NaCl, pH 8.5). The contents of each tube is put on a column of Affi-Gel 601 (Biorad Laboratories P. O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (similarity (medium) boronates the gel layer volume 1 ml), pre-balanced detergent buffer. [3H] camp was washed with 2 x 6 ml proryvnym buffer and then [3H]-5 AMP elute 4 modheader vessel, stirred by rotation and calculate [3H].

< / BR>
IC50defined as the concentration of compound that inhibits 50% of specific hydrolysis of [3H]camp and [3H]5 AMP.

(TNF)

The ability of these compounds or their pharmaceutically acceptable salts to inhibit the production of TNF, therefore, to show efficacy in the treatment of diseases associated with the production of TNF, shown in the following in vitro tests.

Peripheral blood (100 mls) was collected from human volunteers in ethylenediaminetetraacetic acid (EDTU). Monocytes secrete using Ficoll/Hypaque and three times washed in an incomplete balanced salt solution Hanks (SRH). Cells are re-suspended to a final concentration of 1 to 106cells / ml in pre-warmed RPMI (containing 5% fetal calf serum, glutamine, pen/step and nystatin). Monocytes were sown in suspension 1 106cells in 1.0 ml in 24-cell Board. Cells are incubated at 37oC (5% carbon dioxide) and allowed to attach to cards within 2 hours, after this time neprecejusies cells are removed by careful laundering. Then add the subjects matter in 3 - 4 concentrations each to their night (18 hours) at 37oC. At the end of the incubation period were analyzed for TNF using a sandwich ELISA (set R&D Quantikine). Determine the IC50made for each connection based on linear regression analysis.

Pharmaceutically acceptable salts of this invention include, but are not limited to, those formed with HCl, HBr, HNO3H2SO4H2PO4CH3SO3H, p-CH3C6H4SO3H, CH3CO2H, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically acceptable cationic salts of the compounds of this invention with formula I, where R4is the CO2R6and R6is hydrogen, include, but are not limited to, those formed with sodium, potassium, calcium, magnesium, ammonium, N,N,-dibenziletilendiaminom, N-methylglucamine (meglumine), ethanolamine and diethanolamine.

To introduce people in the treatment and prevention of inflammatory diseases of the dose of the compounds of formula 1 and their pharmaceutically acceptable salts (hereafter also referred to as the active compounds of this invention for oral administration are mostly in the range of from 0.1 to 100 mg per day for the average wiat from 0.1 to 50 mg of active compound in a suitable pharmaceutically acceptable carrier or excipient. Doses for intravenous administration are typically in the range from 0.1 to 10 mg in a single dose when necessary. For intranasal or inhalation dosage form is usually created in the form of 0.1-1% solution (weight/volume). In practice, the physician will determine the actual dosage which will be most appropriate for a particular patient and will vary depending on age, weight and response of the particular patient. The above dosages are exemplary of the average case, but may, of course, be instances when you require a higher or lower dosage levels, and such doses are covered by the scope of this invention.

When used by people to suppress TNF can use a variety of conventional routes of administration including oral, parenteral and topical application. Mainly active compound will be administered orally or parenterally in doses of from about 0.1 to 25 mg/kg of body weight of a subject in need of treatment per day, preferably from 0.3 to 5 mg/kg But will meet some modification of dosage as necessary depending on the condition of the subject in need of treatment. The person responsible for polizovanii for people active compounds of this invention can be administered in pure form, but mostly will be used in a mixture with a pharmaceutical diluent or carrier, depending on the intended route of administration and standards of pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or pills, or in pure form or in a mixture with excipients, or in the form of elixirs or suspensions containing improves the taste or tint tools. They can be entered in the form of a parenteral injection; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose to make the solution isotonic.

Thus, in an additional aspect this invention is a pharmaceutical composition containing the compound with the formula I and their pharmaceutically acceptable salts together with a pharmaceutically acceptable diluent and a carrier.

The invention is illustrated by the following examples, but is not limited to their details.

Example 1

3-Ethyl-1-(4-methoxyphenyl)-6-phenyl-what Regina (1.0 g, 4.1 mmole), 4-methoxyphenylhydrazine hydrochloride (0.8 g, 4.6 mmole) and sodium methoxide (0.11 g, 2 mmole) in 35 ml of anhydrous ethanol (distilled from Mg) was heated in a flask with reflux condenser. After 12 hours the solvent was removed by distillation on a rotary evaporator under reduced pressure and the crude residue was chromatographically on a column of silica 4 x 20 cm, using ether/hexane 1:1 as eluent to obtain 345 mg of the substance named in the title, in the form of a red oil, which crystallized upon standing at room temperature. The desired 1-(4-methoxyphenyl)-regioisomer less polar than 2-(4-methoxyphenyl)- by-product.

So pl. 43-45oC.

IR (chloroform) lactam C=O, 1665 cm-1;

1H NMR (300 MHz, CDCl3) d 1.32 (t, J = 7.6 Hz, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.10 (t, J = 6.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 7.22-7.39 (m, 5H), 7.45 (d, J = 9.0 Hz, 2H);

The calculated analysis for C21H21N3O2:

C, 72.60; H, 6.09; N, 12.09 .

Found: C, 72.48; H, 6.08; N, 11.66;

MC m/z [M+] 347.

Examples 2-15, see the end of the description.

Example 16

3-Ethyl-1-(4-phenylcarbamoyl acid)-6-phenyl-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine

A mixture of 3-hydroxy-2-oxo-1-Bednogo ethanol was heated in a flask with reflux condenser. After 20 hours the mixture was concentrated in a rotary evaporator under reduced pressure and the solid residue suspended in a mixture of ethyl acetate (500 ml) and buffer pH (200 ml). The organic layer was separated (leaving the greater part of 2-(4-phenylcarbinol acid) is a by - product), washed with saline, dried with sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from methanol gives 0.64 gram of the connection specified in the header, in the form of an orange solid.

So pl. 261-263oC.

1H NMR (300 MHz, DMSO-d6) 1.23 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.6 Hz, 2H), 2.94 (t, J = 6.5 Hz, 2H), 4.05 (t, J = 6.5 Hz, 2H), 7.20-7.41 (m, 5H), 7.65 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 13.05 (s, 1H);

MC m/z [M+] 362.

Example 17

1-(4-Benzamide)-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine

To a stirred solution of methoxy sodium in methanol (obtained from 6.6 mg Na) add 3-ethyl-6-(4-methoxyphenyl)-1- (4-phenylcarbamoyl acid)-7-oxo-4,5,6,7-tetrahydro-1H - pyrazolo[3,4-c] pyridine (96 mg, 0.25 mmole). After 30 minutes, the methanol was removed under reduced pressure, the solid residue suspended in benzene, and the benzene was removed under reduced pressure. The resulting dry solid activities N N-dimethylformamide (1 drop). After stirring for 1 hour the volatiles were removed under reduced pressure, and the crude residue was dissolved in anhydrous tetrahydrofuran. The resulting solution was added dropwise to intensively mix the ammonium hydroxide at 0oC. After warming to room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure until, until he started to precipitate a yellow solid. At this time, the mixture was diluted with water to about 100 ml and filtered, the precipitate washed with water to obtain 81 mg of the substance named in the title.

Decomposition temperature 243-245oC.

1H NMR (DMSO-d6) 1.24 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.6 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 3.75 (s, 3H), 3.99 (t, J = 6.5 Hz, 2H), 6.94 (d, J = 9.1 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.43 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 8.04 (s, 1H);

Analysis calculated C22H22N4O3:

C, 67.68; H, 5.68; N, 14.35.

Found: C, 67.19; H, 5.31; N, 13.55.

HRMS calculated for C22H22N4O3[M+] 391.1770.

Found: 391.1781.

The original 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarbamoyl acid)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-(3,4-dichlorophenyl)-3-ethyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine

Stir a mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4 - propionyl 1,2,5,6-tetrahydropyridine (0.49 g, 1.7 mmole), 3,4-dichloropyridazine hydrochloride (0.40 g, 1.87 mmole) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated in a flask with reflux condenser. After 16 hours the mixture was concentrated under reduced pressure and was chromatographically on silikagelevye column using ethyl acetate/hexane 1:4 as eluent to obtain white solids. Recrystallization from ether gave 0.46 grams of white needle-shaped crystals.

So pl. 97-99oC.

1H NMR (250 MHz, CDCl3) 1.31 (t, J = 7.5 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.09 (t, J = 6.6 Hz, 2H), 6.78-6.91 (m, 3H), 7.29-7.49 (m, 3H), 7.73 (d, J = 1.8 Hz, 1H);

MS m/z [M+] 416.

Examples 19 - 42

The reaction of the corresponding hydrazinecarboxamide with the desired 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, similarly to the procedure of example 18 gives the following compounds. (see end of description).

Example 43

1-Cyclohexyl-3-ethyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[3,4-c]pyridine

A solution of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl 1,2,5,6-pyridine (0.80 g, 2.8 mmole) and cyclohexyldimethylamine (0.54 g, 3.6 mm is seeking. Undiluted mixture was then heated to approximately 150oC in nitrogen atmosphere for 1 hour. After cooling to room temperature the mixture was dissolved in ether and washed with 1N hydrochloric acid followed by washing with saline, dried with sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate/hexane 1:1 as eluent gives 0.47 gram of the connection specified in the header, in the form of a yellow oil.

1H NMR (250 MHz, CDCl3) 1.20-1.52 (m, 6H, including t at 1.23, J = 7.6 Hz, 3H), 1.64-1.74 (m, 1H), 1.80-2.06 (m, 6H), 2.67 (q, J = 7.6 Hz, 2H), 2.87 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 5.13 (tt, J = 4.3 and 11.3 Hz, 1H), 6.79-6.93 (m, 3H), 7.31 (t, J = 8.1 Hz, 1H);

HRMS calculated for C21H27N3O2[M+]: 353.2103.

Found: 353.2094.

Examples 44 - 57

The reaction of the corresponding hydrazinecarboxamide with the desired 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, similar to the procedure of example 43, gives the following compounds (see below).

Example 58

3-Ethyl-6-(4-forfinal)-1-(4-methoxyphenyl)-4,5,6,7-tetrahydro - 1H-pyrazolo[3,4-c]pyridine

To a stirred solution of 3-ethyl-6-(4-forfinal)-1-(4-methoxyphenyl)- 7-O. 86 mmole). After stirring for 16 hours was added water (0.5 ml) and then N sodium hydroxide (1 ml). After stirring for 2 hours the white precipitate was filtered through brownmillerite and the filtrate was concentrated under reduced pressure. Chromatography on silikagelevye column using ethyl acetate/hexane 1:3 gives 0.12 gram of the connection specified in the header, in the form of a pale yellow paste.

1H NMR (250 MHz, CDCl3) 1.28 (t, J = 7.6 Hz, 3H), 2.66 (q, J = 7.6 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.84 (s, 3H), 4.23 (s, 2H), 6.84-6.99 (m, 6H), 7.36 (d, J = 9.0 Hz, 2H);

MS m/z [M+] 352.

Examples 59 - 63

The reaction of the corresponding 7-oxo-2,5,6,7-tetrahydro-1H - pyrazolo[3,4-c] pyridine with lithium-aluminum hydride, similar to the procedure in example 58 gives the following connections (see the end of the description).

Example 64

1-Cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine

Mix a solution of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl)- 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] pyridine (2.58 g, 7.60 mmole) in acetonitrile (90 ml) at 0oC is treated with a solution of cerium-ammonium nitrate (12.5 g, 22.8 mmole) in water (110 ml). After stirring for 35 minutes, the mixture was diluted with water (550 ml) and was extracted with utilizati then a 10% solution of sodium sulfite until until the wash water layer becomes pale yellow. Then the organic layer was further washed with a saturated solution of sodium bicarbonate and with brine and treated cleaning staining coal. After stirring for 30 minutes, the mixture was dried with sodium sulfate, filtered through brownmillerite and concentrated under reduced pressure. The brown residue was recrystallized from ether to obtain 0.814 grams of a yellowish-brown solid.

So pl. 143-145oC;

MS (m/h) 234;

1H NMR (250 MHz, CDCl3)) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1H), 5.61 (pentec, J = 7.7 Hz, 1H).

Example 65

1-cyclopentyl-3-ethyl-6-cyclopropylmethyl-7-oxo-4,5,6,7 - tetrahydro-1H-pyrazolo[4,4-c]pyridine

A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H - pyrazolo[3,4-c]pyridine (0.21 g, 0.92 mmole) in THF (5 ml) is treated with 60% solution of sodium hydride in mineral oil (40 mg, 1.01 mmole). After stirring under heating in a flask under reflux for 45 minutes, the reaction mixture was cooled to 25oC was added (methyl bromide)cyclopropane (0.31 g, 2.29 mmole). The mixture is stirred while heating in a flask with a return to the cold of matography on silica gel with elution by ethyl acetate/hexane gives 0.19 g of compound, named in the title, in the form of a colorless oil.

MC m/z [M+] 288;

1H NMR (300 MHz, CDCl3) 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.06 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H), 1.62-2.08 (m, 8H), 2.61 (g, J = 7.6 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 3.39 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 5.67 (pentec, J = 7.8 Hz, 1H).

The drug 1

4-Isobutyryl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine

Mix a solution of freshly Diisopropylamine (0.16 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0oC and was treated with 2.5 M n-butyllithium (0.85 ml, 2.11 mmole). After 15 minutes the mixture was cooled to -78oC and added dropwise via cannula was added pre-cooled solution of 4-propionyl 3-methoxy-1-phenyl-2 - oxo-1,2,5,6-tetrahydropyridine (0.52 g, 2.0 mmole) in tetrahydrofuran (4 ml). After about 20 minutes, was added methyliodide (0.20 ml, 3.0 mmole) to bright orange-red solution, and the mixture was allowed to take room temperature for 2.5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the organic layer was washed with salt solution, dried with sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silikagelevye column using ethyl acetate/hexane 1:4 as the starting material.

1H NMR (250 MHz, CDCl3) 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (septet, 1H), 3.82 (t, 2H), 3.97 (s, 3H), 7.21-7.45 (m, 5H);

MC m/z [M+] 274.

Preparations 2 to 3

The reaction of the corresponding 3-methoxy-2-oxo-4-propionyl 1,2,5,6 - tetrahydropyridine with lifedisabilities and methyliodide, similar to the procedure of preparation 1, gives the following compounds of formula VII (see end of description)

The drug 4

3-Methoxy-1-(4-were)-2-oxo-4-propionyl 1,2,5,6-tetrahydropyridine

A solution of 3-hydroxy-1-(4-were)-2-oxo-4-propionyl 1,2,5,6-tetrahydropyridine (5.9 g, 23 mmole and 3-methyl-1-p - tolyltriazole (5.1 g, 34 mmole) in 1,2-dichloroethane was heated in a flask under reflux for 45 minutes. The mixture was allowed to cool to room temperature and poured into water and acidified using 6N hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride and the combined organic extracts washed with 1N hydrochloric acid, then with water and brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting quantifiable brown oil was pure by thin-layer chromatography and1H NMR and was used without purification.


MC [M+] 273.

Drugs 5 - 14

The reaction of the corresponding 3-hydroxy-1-aryl-2-oxo-4-alkanoyl - 1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazole, similar to the procedure for the preparation 4, gives the following compounds of formula VI (see end of description).

Preparation 15

3-Hydroxy-1-(3-were)-2-oxo-4-propionyl 1,2,5,6-tetrahydropyridine

To a stirred suspension of magnesium turnings (1.9 g, 79 mmole) in 30 ml of anhydrous ether was added dropwise bromatan (5.9 ml, 79 mmole). Low boil in a flask with reflux condenser was started after adding about 1 ml, After all the magnesium was consumed, the reaction mixture was cooled to 0oC and was added N-(3-were-2-pyrrolidone (8.7 g, 50 mmol). After heating to room temperature and stirring for 2 hours the reaction mixture was poured into ice and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried sodium sulfate, filtered and concentrated under reduced pressure to obtain 8.8 grams of a white solid.

The above solid was dispersively in a mixture of 40 ml of benzene and 86 ml of 1N sodium hydroxide and firm the AI in the flask under reflux for 1.5 hours, the layers are separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure to obtain an amber oil.

GHS [M+] 305.

The above intermediate compound was dissolved in 20 ml of anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared by careful addition of sodium (1.0 g) in 10 ml of anhydrous methanol). After stirring under heating in a flask under reflux for 1.5 mixture was concentrated under reduced pressure and added 100 ml of water. The mixture was acidified to pH 6 6N hydrochloric acid, and dull yellow precipitate was filtered and washed with water. Recrystallization from 75 ml of isopropyl ether gave 6.8 g of pale yellow crystals.

So pl. 115-116oC;

1H NMR (300 MHz, CDCl3) 1.6 (t, J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.74-2.82 (m, 4H), 3.85 (t, J = 6.8 Hz, 2H), 7.08-7.14 (m, 3H), 7.30 (t, J 7.7 Hz, 1H);

MC m/z [M+] 259.

Drugs 16 - 29

The reaction of the corresponding 2-pyrrolidinone with the right alkalinisation with subsequent processing ethoxysilane and grounds similar to those soo 30

N-(2-Methoxyphenyl)-2-pyrrolidone

A mixture of 2-pyrrolidone (15.0 g, 176 mmol), 2-yoganidra (7.6 ml, 59 mmol), copper powder (7.5 g, 117 mmol) and potassium carbonate (8.1 g, 59 mmol) was stirred in nitrogen atmosphere at 150oC. After 18 hours the reaction mixture was filtered through a bed of silica gel, elwira with ethyl acetate/hexane to obtain pale yellow oil. Unreacted reagents were removed by vacuum distillation (0.6 mm, 80-100oC) leaving 9.2 grams of the connection specified in the header, in the form of methodologi oil.

1H NMR (300 MHz, CDCl3) 2.20 (pentec, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.93-7.02 (m, 2H), 7.25-7.30 (m, 2H);

MC m/z [M+] 191.

Drugs 31 - 39

The reaction of the corresponding iodine - or bromine benzol with 2 pyrrolidinone, similar to the one reported in section Preparation 30, gives the following compounds of formula V (see the end of the description).

By the applicant of the compounds of the present invention (compound No. 1 - 18) and compare the connection (connection N 19 - 22) the above links were tested in vitro using the method of analysis of PDE4in light of the person who is recognized at the present level of technology as a standard to determine Yunosti for the treatment of inflammatory diseases (see table Conn. 1-22 at the end of the description).

Method of analysis of PDE4in light of man, as it was mentioned in the specifications on page 10, is the following.

From thirty to forty grams of lung tissues were placed in 50 ml of buffer Tris /phenylmethylsulfonyl (PMSF)/ sucrose with pH 7.4 and was gomogenizirovannogo using a Tekmar TissumizerR(Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate was centrifugals at 48000 g for 70 minutes at 4oC. the Supernatant was filtered twice through 0.22 μm filter and applied to a column of Mono - Q FPLC (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854), previously brought into equilibrium with buffer Tris/PMSF with a pH of 7.4. To make the sample column was used with flow rate 1 ml/min, after which he established a flow rate of 2 ml/min for the subsequent washing and elution. The sample was elyuirovaniya using increasing stepwise gradient of NaCl in buffer Tris/PMSF with a pH of 7.4. Collected fractions eight ml. Fractions were analyzed for specific activity of PDE4defined by the hydrolysis of [3H] cAMP and on the ability of the known inhibitor of PDE4(for example, rolipram) to inhibit the hydrolysis. Straylize at -20oC until use.

Compounds were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mm and diluted 1:25 in water (400 μm compound, 4% DMSO). Further serial dilutions were carried out in 4% dimethyl sulfoxide to achieve the required concentrations. The final concentration of DMSO in the test tube was 1%. In duplicate, the following reagents, in order, were added to glass test tubes 12 x 75 mm (all concentrations are given for the final concentrations in the test tube).

i) 25 μl of compound or DMSO (1% for the control and blank sample).

ii) 25 ál of Tris buffer with pH 7.5.

iii) [3H] cAMP (1 μm).

iv) 25 ml of the enzyme PDE4(for a blank sample of the enzyme was pre-aged in boiling water for 5 minutes).

Tubes for the reaction was shaken for mixing and placed in a water bath (37oC) for 20 minutes, after this time the reaction was stopped by placing the tubes in boiling water bath for 4 min. In an ice bath in each tube was added to the washing buffer (0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazine-econsultancy acid (HEPES)/0.1 M NaCl, pH 8.5). The contents of each paragraph the volume of the substrate 1 ml), pre-reduced in the balance of the washing buffer. [3H] cAMP was filtered washing buffer 2 x 6 ml, and after that, [3H] 5'AMP was elyuirovaniya 4 ml of 0.25 molar acetic acid. After intensive mixing 1 ml of the eluate was added to 3 ml scintillation fluid in the corresponding tube, carried out an intensive mixing and counting [3H].

% inhibition = 1 - (mean cpm (cpm. in the tested sample) - mean cpm (blank sample)/(mean cpm (control sample) is the average cpm (blank sample)

IC50is defined as the concentration of compound that inhibits 50% of specific hydrolysis of [3H] cAMP with the formation of [3H] 5'AMP.

5. The results of the above test the following:

Connection number - HUPDE*4IC50μm

1. - 0.0299

2. - 0.0119

3. - 0.0062

4. - 0.0136

5. - 0.0036

6. - 0.0170

7. - 0.0123

8. - 0.0306

9. - 0.0015

10. - 0.0006

11. - 0.031

12. - 0.0019

13. - 0.13

14. - 0.22

15. - 0.17

16. - 0.21

17. - 0.15

18. - 0.26

19. - 0.44

20. - 3.84

21. - 9.30

22. - 1.66

*Method of analysis of PDE4in light of the man.

6. From my side of the connection of the present invention (compounds N 1 N is crosa tumors (hereinafter referred to as TNF), recognized as state of the art as a standard to determine inhibit whether the connection receiving TNF, and, consequently, demonstrate their effectiveness for treating diseases in which is formed of TNF (see connection table 2 at the end of the description).

< / BR>
Analysis method THF is as follows.

Peripheral blood (100 ml) from volunteers was collected in ethylenediaminetetraacetic acid (EDTA). Menagerie cells were isolated using Ficoll/Hipaque and were washed three times in incomplete HBSS. Cells were suspendibility again with a final concentration of 1 to 104cells / ml in pre-warmed RPMI containing 5% FCS, glutamine, pen/step and nystatin). Monocytes were applied in the form of 1 to 106cells in 1.0 ml per plate with 24 cells. Cells were maintained at 37oC (5% carbon dioxide) and left to adhere to the plates for 2 hours, after this time, unattached cells were removed with the help of careful washing. After this was added the test compound (10 μl) to the cells at 3 - 4 concentrations each, and were holding for 1 hour. LPS (10 ál) was added to the corresponding cell. Plates were kept in SA (R&D Quantikine Kit). Determine the IC50were conducted for each connection based on linear regression analysis.

7. The results of the above test the following:

Connection number - TNF - HM*THE IC50**μm

1. - 0.025

2. - 0.008

3. - 0.043

4. - 0.035

5. - 0.024

6. - 0.011

7. - 0.087

8. - 0.060

9. - 0.014

10. - 0.033

11. - 0.41

*The method of analysis of human monocytes TNF.

**IC50based on linear regression analysis.

8. The above data demonstrate that the compounds of the claimed invention in the above application have unexpected properties, for example, the best inhibition of phosphodiesterase IV and receiving tumor necrosis factor when compared with the compounds of the prior art.

Dated: March 7, 1994. Allen J. Duplantier

1. Bicyclic tetrahydropyrimidine formula I

< / BR>
or their pharmaceutically acceptable salt,

where R1is (C1-C3) alkyl;

X is oxygen or two hydrogen atoms;

R2selected from the group consisting of (C1-C4) alkyl; indlela, (C3-C7) cycloalkyl or group is gorodom, (C1-C5) alkyl, (C1-C5) alkoxyl, (C1-C6) cycloalkyl, halogen, trifluoromethyl, CO2R6, NR6R7, NR6R7where R6and R7are hydrogen or (C1-C4) alkyl;

where Z is the SO2;

Y is a (C1-C5) alkylene;

R3has the meanings given for R2and methylenecyclopropane, provided that R2and R3cannot simultaneously denote methyl.

2. Connection on p. 1, where R1is (C1-C3) alkyl and R2and R3each independently selected from the group consisting of (C1-C7) cycloalkyl or groups of the formula I

< / BR>
where a is an integer from 1 to 2;

R4is hydrogen, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxyl and halogen.

3. Connection on p. 1, where R1is ethyl or isopropyl; R2is phenyl, 2-were, 3-were, 2-methoxyphenyl, 3-methoxyphenyl or 3-cryptomaterial and R3is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolane, 4-florfenicol or 3,4-dichlorophenyl.

4. The connection is[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(4-forfinal)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-were)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(3-triptoreline)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclopentyl-6-(2-were)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3-sulfophenyl)-6-(3-were)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-(3-sulfophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-were)-7-oxo-4,5,6,7-tetrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(3-triptoreline)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;

3-ethyl-1-cyclobutyl-6-(2-were)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine.

5. The pharmaceutical composition inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), containing the active ingredient and pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains an effective amount of the compounds under item 1.

6. Method of inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), characterized in that it is administered to the patient an effective amount of the compounds under item 1.

7. The pharmaceutical composition according to p. 5, containing the active ingredient and a pharmaceutically acceptable carrier and intended for the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF, characterized in that it contains as active ingredient pharmaceutically effective amount of a compound of Pete, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF, characterized in that it is administered to the patient an effective amount of the compounds on p. 1.

 

Same patents:

The invention relates to biologically active compounds, namely cyclohexylamino chinoline[2,1-b]hinzelin-12-he-5-carboxylic acid formula

< / BR>
with antireverse activity, suggesting the possibility of its use in medicine as a drug for the treatment of tick-borne encephalitis

The invention relates to an improved process for the preparation of pyrazole and its derivatives of the formula I

< / BR>
in which the radicals R1-R4have the meanings specified below,

from,- unsaturated carbonyl compounds of the formula II

< / BR>
and hydrazine or hydrazine derivatives of formula III

H2N-OTHER4

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to therapeutically active derivatives of hydroxamic acids, processes for their preparation, pharmaceutical compositions containing them and to the use of such compounds in medicine

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions
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