HUT77517A - Bicyclic tetrahydro pyrazolopyridines and their use as medicaments - Google Patents

Description

CONTAINING MEDICINAL PRODUCTS

EXTRACT

The present invention relates to novel bicyclic tetrahydropyrazolopyridine derivatives, to pharmaceutical compositions containing such compounds, and to compounds of formula IV. type II phosphodiesterase (PDE) or tumor necrosis factor (TNF), including selective inhibition of asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, hay fever, dermatitis and other inflammatory diseases, and in the manufacture of a medicament for the treatment of a disease involving TNF production. In the compounds of the invention, R ^{1 is} hydrogen, alkyl, alkenyl, cycloalkyl or cycloalkylmethylene, X is oxygen or two hydrogen, while R ² and R ^{3 are} different organic groups.

Representative:

DANUBIA Patent and Trademark Office Ltd. Budapest

BICYCLIC TETRAHYDRO-PYRAZOLO-PYRIDINE DERIVATIVES AND SUCH COMPOUNDS

CONTAINING MEDICINAL PRODUCTS

The present invention relates to novel bicyclic tetrahydropyrazolopyridine derivatives, to pharmaceutical compositions containing such compounds, and to compounds of formula IV. type II phosphodiesterase (PDE) or tumor necrosis factor (TNF), including selective inhibition of asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, hay fever, dermatitis and other inflammatory diseases, and in the manufacture of a medicament for the treatment of a disease involving TNF production.

Since it was discovered that cyclic AMP is an intracellular secondary messenger molecule (Sutherland, E.W. and Rali, T.W., Pharmacol. Rev., 12, 265 (1960)], inhibition of phosphodiesterases has been the subject of research and therapies have been attempted for a variety of diseases kia85446-4231 / MR-Ko.

-2 based on said mechanism. Recently, various types of PDE have been recognized (Beavo, JA and Reifsnyder, DH: TiPS, 11, 150, (1990)) and their selective inhibitory capacity has been found to be useful in therapy [Nicholson, CD, Challiss, RA and Shahid, M .: TiPS. 12, 19 (1991)]. In particular, it was recognized that IV. Inhibition of Type II PDE to Inhibit the Production of Inflammatory Mediators [Verghese, M.W., et al., J.Mol. Cell, Cardiol., 12 (Suppl. II), 61 (1989)] and leads to respiratory smooth muscle relaxation (see Torphy, TJ, page 37 of Directions for New Anti-Asthma Drugs, 1988). Published by Birkhauser-Verlag, and edited by O'Donnel, SR, and Persson, CGA], so that compounds which are the subject of IV. however, they have only a weak effect on other types of PDE, inhibit the production of mediators of inflammatory processes, and have a relaxing effect on the airway smooth muscle without exerting any cardiovascular or antiplatelet effect.

TNF is known to be involved in a number of infectious and autoimmune diseases (Friers, W., FEBS Letters, 285: 199 (1991)). It has also been reported that TNF is the primary mediator of inflammatory events in sepsis and septic shock (Spooner, C.E. et al., Clinical Immunology and Immunopathology, 62, 11, 1992).

It has now been found that the novel compounds of formula I and their pharmaceutically acceptable salts have valuable therapeutic properties. In formula I, R ¹ is hydrogen or alkyl of 1 to 3 carbon atoms, alkenyl of 2 or 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms.

A cycloalkylmethylene group of 3 or C 3 to 5 carbon atoms, said alkyl or alkenyl groups being optionally substituted with up to 3 halogens or up to 2 alkyl or trifluoromethyl groups having 1 or 2 carbon atoms;

X is oxygen or two hydrogen;

R ² and R ³ are each independently hydrogen; alkyl of 1 to 14 carbon atoms optionally substituted with halogen or cyano; alkylsulfonyl containing from 1 to 14 carbon atoms in the alkyl moiety; Alkoxy having 1 to 14 carbon atoms; naftalilesöpört; Alkenyl of 2 to 7 carbon atoms; Cycloalkyl having from 3 to 7 carbon atoms; C 1-4 alkyl-C 3-7 cycloalkyl; Cycloalkyl (C 3 -C 7) alkyl (C 1 -C 4); a heterocyclic group containing oxygen and 4 to 7 carbon atoms; S; sulfonyl; -NR ⁵ wherein R ⁵ is hydrogen or C 1-4 alkyl; Heterocycloalkyl (W) _d - (C 4 -C 7), wherein the heterocycloalkyl (C 4 -C 7) contains one or more oxygen or sulfur or sulfonyl or -NR ⁵ , wherein R ⁵ is hydrogen or alkyl of 1 to 4 carbon atoms, optionally substituted with halogen, d is 0 or 1 and W is alkyl, carbonyl or sulfonyl of 1 to 4 carbon atoms; -CONR ¹⁰ R ¹¹ wherein R ¹⁰ and R ^{11 are} •;

-4 independently of one another hydrogen or alkyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 5 carbon atoms, alkoxycarbonyl of 1 to 5 carbon atoms, alkyl of 1 to 5 carbon atoms of 1 to 5 carbon atoms ) alkyl means (C 1 -C 5) alkoxycarbonyl (C 1 -C 5) alkyl or (C 1 -C 5) alkoxy (C 1 -C 5) alkyl; -R ¹² R ^{13 is} N (C 1 -C 5) alkyl wherein R ¹² and R ¹³ are each independently hydrogen or C 1 -C 5 alkyl; or a group of the formula II wherein a is 0, 1, 2, 3, 4 or 5, b and c are 0 or 1, ^R4a is independently hydrogen or hydroxy, containing from 1 to 5 carbon atoms; Alkenyl of 2 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, halogen, trifluoromethyl, -CO ² R ⁶ , -CONR ⁶ R ⁷ , -NR ⁶ R ⁷ , - CONHOH, CN, -NO 2 or -SO R ⁶ and R ⁷ are independently hydrogen, 1 ₂ NR ⁶ R ⁷ and the latter group - represents an alkyl group having 4 carbon atoms, and Y represents a 1 - 4 carbon atoms, alkyl of 2 -C 5 alkylene or up to two C 17 alkyl or C 3-7 cycloalkyl substituted C 2-5 alkenyl, and Z is oxygen or sulfur or carbonyl, sulfonyl or -NR ⁸ , and in the latter R ⁸ is hydrogen or alkyl of 1 to 4 carbon atoms; or a group of the general formula (XI) wherein p is 1, 2 or 3, W is hydroxy and R ^{9 is} an alkyl group having 1 to 3 carbon atoms, and the alkyl, alkenyl, cycloalkyl, alkoxy mentioned above alkyl or heterocyclic groups may be optionally substituted with 1 to 14, preferably 1 to 5 halogen, or trifluoromethyl or 1 or 2 carbon atoms; or a group of the formula XII wherein m, n and p are 1 or 2; or a group of formula (XIII) wherein Q is hydroxy-substituted or XIV;

with the proviso that when R ¹ is ethyl and R ² is 4-methylphenyl, then R ³ is other than hydrogen or methyl, phenyl, 4-fluorophenyl or 2-pyridyl, and when R ² is 4-methylphenyl - and R ³ is 4-fluorophenyl, then R ¹ is other than phenyl, methyl or n-propyl, and if R ¹ is ethyl and R ² is phenyl then R ³ is 4-chlorophenyl, other than fluorophenyl or 4-methylphenyl; furthermore, when R ¹ is ethyl and R ² is 4-methoxyphenyl, then R ³ is other than 4-fluorophenyl; and when W is carbonyl or sulfonyl, d is 1;

with the further proviso that R ² and R ³ may not at the same time be hydrogen, C 1 -C 14 alkyl, C 1 -C 14 alkoxy, C 2 -C 7 alkenyl, or C 4 -C 7 heterocyclic which is oxygen. or having a sulfur atom or a sulfonyl or -NR ⁵ radical in which R ⁵ is hydrogen or C 1-4 alkyl or

A group of formula -6 in which a is 0,1,2,3,4 or 5, b and c are 0 or 1, ^R4a is independently hydrogen or hydroxy, C1-5 alkyl, 2-5 C 1 -C 5 alkenyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkoxy, halogen, trifluoromethyl, -CO ² R ⁶ , -CONR ⁶ R ⁷ , -NR ⁶ R ⁷ , -CONHOH, -CN , -NO ₂ or -SO ₂ NR ⁶ R ⁷ and in the latter groups R ⁶ and R ⁷ are independently hydrogen or C 1-4 alkyl, and Y is C 1-4 alkyl, C 2-5 alkylene or up to two C2-C5 alkenyl substituted with up to two C 1-7 alkyl or C 3-7 cycloalkyl groups, and Z is oxygen or sulfur or carbonyl, sulfonyl or -NR ⁸ , and in the latter R ⁸ is hydrogen or 1-4 or a group of the general formula (XI) wherein p is 1, 2 or 3, W is a hydroxy group and R ⁹ is an alkyl group of 1 to 3 carbon atoms, in addition to the above-mentioned alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups may be optionally substituted with 1 to 14, preferably 1 to 5 halogen, or trifluoromethyl or 1 or 2 carbon atoms.

The foregoing limitations serve to delimit the subject matter of the present application in PCT Application No. PCT / IB / 94/00156.

• «· ·

-7 Preferably, in the formula (I), R ¹ is an alkyl group containing from 1 to 3 carbon atoms, R ³ is a cycloalkyl group containing from 3 to 7 carbon atoms, a heterocyclic group containing from 4 to 7 carbon atoms or a sulfonyl group; R 1 is 1, 2, 3, 4 or 5, while R ^{4 is} independently selected from the group consisting of hydrogen, halogen, C 1-5 alkyl, and C 1-5 alkoxy.

Further preferred are compounds of formula I wherein R ¹ is ethyl or isopropyl; R ² is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, hydroxyphenyl, cyclopropylmethyl, benzyl, isobutyl, isobutenyl, 2-ethylphenyl, naphthalenyl, 2-chlorophenyl, 3-methylbutyl, dimethylcarbamyl, 1-methyl- benzyl, isopropyl, 1-picolyl, 2-picolyl, 3-picolyl, 2-methyl-5-chlorophenyl, 2-chlorothiophen-5-ylmethyl, 2-hydroxy-5-methyl -phenyl, 3,5-dimethyl-isoxazol-4-ylmethyl, 3-chlorobenzyl, thiophen-2-ylmethyl, 2-hydroxy-5-chlorophenyl, thiophene-2- carbonyl, tetrahydrofurfuryl, 3cyanobenzyl, morpholine-4-carbonylisopropylsulfonyl, 4-methoxyphenylsulfonyl or 3- (trifluoromethyl) phenyl, and R ³ is cyclobutyl, cyclopentyl, , cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.

The present invention also relates to pharmaceutical compositions which are particularly useful as compounds of formula IV. type phosphodiesterase (PDE) and tumor necrosis factor (TNF), such as asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, hay fever, dermatitis and other inflammatory diseases, and AIDS and septic shock, Suitable for the treatment of occupational diseases. THE " ·

The pharmaceutical compositions of the present invention contain, as active ingredient, a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in association with carriers and / or other excipients commonly used in the manufacture of pharmaceuticals.

The invention also relates to the use of compounds of formula I and pharmaceutically acceptable salts thereof IV. type II phosphodiesterase (PDE) and tumor necrosis factor (TNF).

The compounds or pharmaceutical compositions of the present invention can be used to treat inflammatory conditions in a mammal by administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Similarly, the compounds of the present invention may be used for the treatment or prevention of asthma, arthritis, bronchitis, chronic obstructive airways diseases, psoriasis, hay fever, dermatitis and other inflammatory diseases, and AIDS and septic shock and diseases involving the formation of TNF.

Referring to the substituents of formula I, the term halogen, unless otherwise indicated, means chlorine, fluorine and bromine. Unless otherwise indicated, the alkyl, alkoxy, and alkenyl groups mentioned above refer to straight or branched or combinations of three or more carbon atoms, or cyclic or cyclic, and branched or straight chain groups.

The term inflammatory disease includes asthma, chronic obstructive pulmonary disease, bronchitis and arthritis.

«·

The following describes some methods for preparing the compounds of the invention. Unless otherwise indicated, R ¹ , R ² and R ³ are as defined in formula (I).

The preparation of compounds of formula (X) is illustrated in Schemes 1 and 2.

In Scheme 1, Step 1, the 2-pyrrolidinone of formula (IV) is converted to the corresponding N- (aryl) -2-pyrrolidinone derivative of formula (V) wherein aryl corresponds to the group of formula (II): reacting the compound of formula (IV) with an aryl halide in the absence of a solvent in the presence of copper powder and potassium carbonate. Suitable aryl halides include, for example, 1-iodo or 1-bromo-4-methoxybenzene, -3-methoxybenzene, -2-methoxybenzene, -3-methylbenzene, -4-methylbenzene, methyl benzene, -3-trifluoromethylbenzene, -2-trifluoromethylbenzene, -3,4-dimethoxybenzene or -3-cyclopentoxy-4-methoxybenzene. The reaction temperature is generally 110 ° C to 170 ° C, preferably about 150 ° C, and the reaction time may be 14 hours to 22 hours, preferably 18 hours, under inert conditions.

In Scheme 1, Step 2, a suspension of R ^{1 in} anhydrous aprotic solvent is added to a suspension of R ¹ and the resulting reaction mixture is refluxed until all the magnesium is consumed. The reaction mixture is then cooled to -15 ° C to 15 ° C, preferably to about 0 ° C, and then an N- (aryl) -2-pyrrolidone derivative of formula (V) is added. The resulting reaction mixture is warmed to room temperature while stirring for 1.5 hours to 2.5 hours, preferably about 2 hours. As the al-10 alkyl halide, for example, bromomethane, bromoethane or bromopropane can be used. A preferred anhydrous aprotic solvent is anhydrous diethyl ether. After completion of the reaction, the desired intermediate can be isolated from the reaction mixture by conventional means, for example, washing the reaction mixture with water followed by saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering, and evaporating the filtrate under reduced pressure. This gives a white solid which is easily separable.

The resulting precipitate is then converted to the corresponding 1,2,5,6-tetrahydropyridine derivative of formula (VI) by dispersing the precipitate in a mixture of an apolar aprotic solvent and a base and then, with vigorous stirring, the resulting dispersion. oxalyl chloride is added. The resulting reaction mixture is then heated under reflux for a period of from 1.5 hours to 4.5 hours, preferably about 3 hours. The preferred apolar aprotic solvent is benzene and the preferred base is sodium hydroxide. After completion of the reaction, the solvents were removed and a solution of sodium alcoholate in ethanol was added to the resulting residue. Subsequently, refluxing is carried out for 1 hour to 3 hours, preferably about 1.5 hours, and the reaction mixture is concentrated under reduced pressure and the residue is acidified to pH 3 with hydrochloric acid.

In Scheme 1, Step 3, a compound of formula (VI) is converted to a corresponding 3-methoxy-1,2,5,6-tetrahydropyridine derivative of formula (VII) so that the compound of formula (VI) and a mixture of 3-methyl-1- (p-tolyl) triazine in an aprotic solvent is heated to reflux. A preferred aprotic solvent is 1,2-dichloroethane. The reaction

11 is generally complete within a time period of between 30 minutes and 120 minutes, preferably about 45 minutes.

In Scheme 2, Step 1, a 1,2,5,6-tetrahydropyridine derivative of Formula VIII wherein R ⁵ is hydrogen or methyl is prepared according to the corresponding 4,5,6,7 of Formula IX. -tetrahydro-7-oxo-1H-pyrazolo [3,4-c] pyridine by reacting a compound of formula VIII with a hydrazine derivative of formula R ³ HNNH ₂ . Both of the two compounds of formula (VIII), i.e. the 3-hydroxy and the 3-methoxy derivatives, can be used as starting materials for any one of the three reaction conditions described below.

In one such set of reaction conditions, a 1,2,5,6-tetrahydropyridine derivative of formula (VIII) is converted to the corresponding compound of formula (IX) by reacting a compound of formula (VIII) with a hydrazine hydrochloride and reaction with a sodium alkylate in anhydrous polar protic solvent. Preferred sodium alcoholate is sodium methylate and the preferred anhydrous polar protic solvent is anhydrous ethanol. The reaction mixture is refluxed for 9 hours to 15 hours, preferably for about 12 hours.

According to a second set of reaction conditions, the 1,2,5,6-tetrahydropyridine derivative of formula (VIII) is converted to the corresponding compound of formula (IX) by reacting the compound of formula (VIII) with hydrazinobenzoic acid in anhydrous polar in a protic solvent, preferably ethanol. The reaction mixture is refluxed for 16 hours to 24 hours, preferably for about 20 hours. The compound of formula (IX) thus obtained can then be further reacted with the corresponding 1- (4-benzamido) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine. by reacting a compound of formula (IX) with sodium methylate in a polar protic solvent, preferably methanol, for 15 minutes to 45 minutes, preferably 30 minutes. The polar protic solvent is then removed under reduced pressure, and the solid residue is suspended in an apolar aprotic solvent, preferably benzene, followed by removal of the apolar solvent under reduced pressure. The resulting dry solid was slurried in cold diethyl ether and oxalyl chloride and N, N-dimethylformamide were added to the slurry. The resulting mixture is then stirred for 30 minutes to 90 minutes, preferably 60 minutes, then the solvent is removed and the crude residue is dissolved in anhydrous tetrahydrofuran. The resulting solution is added dropwise to an aqueous solution of ammonium hydroxide at -10 ° C to 10 ° C, preferably at about 0 ° C.

According to a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine derivatives of formula (VIII) are converted to the corresponding compounds of formula (IX) by reacting the compound of formula (VIII) with a hydrazine hydrochloride in a polar protic solvent, preferably methanol. The reaction mixture is heated at a temperature between 70 ° C and 110 ° C, preferably around 90 ° C, under a gentle stream of nitrogen gas until all the solvent is removed. The residue is then heated at a temperature of 120 ° C to 180 ° C, preferably about 150 ° C for 30 minutes to 90 minutes, preferably 60 minutes.

• ·

13 The compounds of formula IX thus prepared are then converted to the corresponding 6-R ² -4,5,6,7-tetrahydro-7-oxo-1 H -pyrazolo [3,4-c] pyridine derivatives wherein R ² other than a compound of formula (II) may be formed by reacting a solution of a compound of formula (IX) with an aqueous solution of ammonium cerium (IV) nitrate in a polar aprotic solvent, preferably acetonitrile, at a temperature from -15 ° C to 15 ° C, preferably at about 0 ° C for 20 minutes to 50 minutes, preferably about 35 minutes. After completion of the reaction, the reaction mixture was diluted with water and extracted several times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution and then with aqueous sodium sulfite solution. Sodium hydride is added to a solution of the compound thus obtained in a polar aprotic solvent, preferably tetrahydrofuran, and the resulting reaction mixture is refluxed for 30 minutes to 60 minutes, preferably 45 minutes. After cooling to a temperature between 20 ° C and 30 ° C, temperature in the region C, preferably 25 ° C, and an R ² halide to alkyl halide of the formula: - wherein R ² is as defined in formula (I), but (II) other than the general formula (I). The reaction mixture is refluxed for 12 hours to 20 hours, preferably 16 hours.

In Scheme 2, Step 2, the 2-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine derivatives of formula IX are converted to the corresponding derivatives of formula X A compound of formula IX is reacted with a reducing agent, preferably lithium aluminum hydride, in an apolar aprotic solvent, preferably diethyl ether. The reaction is stirring

In the meantime, the reaction time is 12 hours to 20 hours, preferably 16 hours. Water and a base, preferably sodium hydroxide, are then added to the reaction mixture, and the resulting aqueous mixture is stirred and filtered for 1.5 hours to 2.5 hours, preferably 2 hours. The filtrate was evaporated to give a white solid.

The compounds of the present invention and their pharmaceutically acceptable salts are IV. Its ability to inhibit type II phosphodiesterase (PDEiv) and thus its efficacy in the treatment of inflammatory diseases will be demonstrated in the following in vitro study.

Biological examination (human lung PDE, _V )

30 to 40 g of human lung tissue are added to 50 ml of Tris / phenylmethylsulfonyl fluoride (PMSF) / sucrose buffer pH 7.4 and then at 30% speed with a Tekmar Tissumizer homogenizer (manufactured by Tekmar Co). ., 7143 Kemper Road, Cincinnati, Ohio 45249, United States of America). Subsequently, the homogenate is centrifuged at 48000 g for 70 minutes at 4 ° C and the supernatant is filtered twice through a 0.22 µm sieve. The twice-filtered material was then loaded onto a Mono-Q-FPLC column pre-equilibrated with Tris / PMSF pH 7.4 (supplied by Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854, USA). A sample flow rate of 1 ml / min was applied to the column, followed by a wash and elution flow rate of 2 ml / min. Elution was performed with a stepwise gradient of sodium chloride in Tris / PMSF pH 7.4. Fractions of 8 ml were collected. Fractions were assayed for specific PDEiv activity by hydrolysis of [ ³ H] cAMP and assayed for known PDE? _V inhibitors such as rolipram in this hydrolysis. The appropriate fractions were pooled and diluted with ethylene glycol (using 2 mL of ethylene glycol to 5 mL of enzyme preparation) and then stored at -20 ° C until use.

The test compounds were dissolved in dimethyl sulfoxide at a concentration of 10 mmol and then diluted with water (1: 25 by volume) to give 400 pmol solutions containing 4% dimethyl sulfoxide. Subsequently, serial dilutions were made with 4% dimethyl sulfoxide to ensure appropriate concentrations. The final concentration of dimethylsulfoxide in the test tube is 1%. In a duplicate series of experiments, weigh the following into a 12.75 mm glass tube (the final concentrations indicated in this tube are in the order indicated):

i) 25 µl of test compound or dimethylsulfoxide (1%, for control and blank);

ii) 25 µl Tris buffer, pH 7.5;

iii) [ ³ H] cAMP (1 pmol);

iv) 25 µl of PDEiv enzyme (in the blank sample, the enzyme is preincubated in boiling water for 5 minutes).

The reaction tubes were shaken in a 37 ° C water bath for 20 minutes and then quenched by boiling in a boiling water bath for 4 minutes. Then, in each ice tube, weigh into 0.5 ml of 4- (2-hydroxyethyl) -1-piperazinethane sulfonic acid in an ice bath.

0.1 M for H16 (HEPES) and 8.5 M for sodium chloride. The contents of each tube are then loaded onto an Affi-Gel 601 column equilibrated with buffer of the above composition (containing 1 ml of boronate affinity gel and supplied by Biorad Laboratories, PO Box 1229, 85A Marcus Drive, Melville, New York). United States). [ ³ H] cAMP is washed twice with 6 ml of the above-mentioned buffer, and [ ³ H] 5'AMP is then eluted with 4 ml of 0.25 M acetic acid. After treatment in a Vortex apparatus, 1 mL of eluate is added to a 3 mL scintillation fluid in a suitable test tube, the Vortex apparatus is treated again and the [ ³ H] content is then measured.

average stroke per minute (test compound) - average stroke per minute (blank)% inhibition = 1-average stroke per minute (control) - average stroke per minute (blank)

IC ₅ o value of the test compound is the concentration causing 50% inhibition of ^[3 H] cAMP hydrolysis and specific ^[3 H] -5'-AMP.

Inhibition of TNF Formation

The ability of the compounds of the present invention, or their pharmaceutically acceptable salts, to inhibit TNF production and hence their efficacy in treating diseases associated with TNF production will be demonstrated in the following in vitro experiment.

Volunteers receive peripheral blood in 100-100 mL volumes of ethylenediaminetetraacetic acid (EDTA). Mononuclear cells were isolated using Ficol / Hypaque and washed three times with incomplete HBSS. The cells are then resuspended 1. 10 ⁶ cells / ml in final concentration in preheated RPMI containing 5% FCS, glutamine, pen / step and nystatin. In 24-well plates in a volume of 1 ml. 10 ⁶ cells in proportion to monocytes

-17 wells were incubated and incubated at 37 ° C in 5% carbon dioxide for 2 hours to adhere to the plates. The non-adherent cells are then removed by gentle washing. The test compounds are added to the cells in a volume of 10 µl in triplicate and incubated for 1 hour. 10 μΙ LPS was then added to the appropriate wells. The plates are then incubated for 18 hours at 37 ° C, and the TNF is analyzed for TNF at the end of the incubation period. sandwich ELISA (R&D Quantikine Kit). IC _{50 for} each test compound is determined by linear regression analysis.

Pharmaceutically acceptable acid addition salts of the compounds of the invention include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, gluconic acid, tartaric acid and maleic acid. Examples of pharmaceutically acceptable cationic salts of the compounds of formula (I) wherein R ⁴ is -CO ₂ R ⁶ and R ⁶ is hydrogen include the corresponding sodium, potassium, calcium, magnesium, ammonia, Ν, Ν ' salts of dibenzylethylenediamine, N-methylglucamine, ethanolamine and diethanolamine.

For the treatment or prophylaxis of inflammatory diseases in humans, the oral dosage of the compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as the active ingredient of the present invention) is generally in the range of 0.1 mg to 100 mg daily.

-18 adult patients (70 kg). Thus, for such a typical adult patient, each tablet or capsule will contain from 0.1 to 50 mg of the active ingredient in combination with excipients and / or other excipients commonly used in the pharmaceutical field. In the case of intravenous administration, the dose is typically 0.1 mg to 10 mg in a single administration. For intranasal or inhalation administration, a pharmaceutical composition is prepared containing the active ingredient in a concentration of 0.1% to 1% by volume. In practice, the physician will determine the dose to be used in the particular case, which will be appropriate to the condition of the patient and will depend, among other things, on the patient's age, weight and response to the active ingredient. The above-mentioned dose values are average values, so that, in certain cases, lower or higher doses may be employed.

To prevent TNF formation in humans, various routes of administration, such as oral, parenteral or topical administration, may be employed. In general, the active ingredient is administered orally or parenterally at doses of 0.1 mg / kg to 25 mg / kg, preferably 0.3 mg / kg to 5 mg / kg / day. However, these values may vary with the condition of the individual patient. However, the person skilled in the art will always be able to determine the most suitable dose for a particular individual.

For human use, the compounds of the present invention may be administered alone, but will generally be administered with carriers and / or other excipients customary in the pharmaceutical art, and depending upon the intended mode of administration and customary pharmaceutical practice.

-19 is happening together. For example, for oral administration, tablets containing starch or lactose are used. In the case of capsules or ovules, the active ingredient may be present alone or in a suitable mixture, whereas, for example, elixirs or suspensions may contain flavoring or coloring agents. The active compounds of the present invention may be administered by parenteral injection, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the most preferred form of administration is a sterile aqueous solution which may contain additional additives, for example, salt or glucose, to make the solution isotonic.

The present invention thus encompasses such pharmaceutical compositions containing an active compound of formula (I) or a pharmaceutically acceptable salt thereof which contain, in addition to the active ingredient, carriers and / or other excipients commonly used in the manufacture of pharmaceuticals.

The following examples are intended to illustrate the invention.

Example 1

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

In a gentle stream of nitrogen, 0.80 g (2.8 mmol) of 3-methoxy-1- (3-methoxyphenyl) -2-oxo-4-propionyl-1,2,5,6-pyridine and 0.54 g A solution of cyclohexyl hydrazine hydrochloride (3.6 mmol) in methanol (15 mL) was heated at 90 ° C until all solvent was removed. The resulting residue was then heated under nitrogen atmosphere at about 150 ° C for 1 hour, then cooled to room temperature and dissolved in diethyl ether. The resulting solution was washed with 1N hydrochloric acid, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1: 1). 0.47 g of the title compound is obtained as a yellow oil.

¹ H NMR (250 MHz, CDCl ₃ ): 1.20 - 1.52 (m, 6H, including a triplet 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)

High Resolution Mass Spectrum (HRMS): Calcd. For C ₂₁ H ₂₇ N ₃ O ₂ [M ⁺ ]: 353.2103 Found: 353.2094.

2nd-16th Examples

In analogy to the method described in Example 1, the following compounds of formula IX can be prepared by reaction of a suitable hydrazine hydrochloride with a 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine. :

The serial number of the example R ¹ R ² R ³ Mp (° C) Mass spectrum or analysis (calculated as C%, H%, N%) Mass spectrum or analysis results (found C%, H%, N%) Second ethyl 2-methoxy phenyl cyclobutyl 123-4 70.13; 7.12; 12.91 69.93; 7.09; 12.81 Third ethyl 2-methyl- phenyl 3-methyl cyclopentane til oil [M +] 337.46 MS (m / z) 338 4th ethyl 2-ethylphenyl cyclobutyl oil [M +] 323.44 MS (m / z) 324 5th ethyl 2-ethylphenyl cyclopentyl til 106-7 [M +] 337.46 MS (m / z) 337 6th ethyl 1-naphthalene cyclopentyl til 188-90 [M +] 359.47 MS (m / z) 360 7th ethyl 1-naphthalene cyclohexyl 199-201 [M +] 373.5 MS (m / z) 372 8th ethyl 2-chloro-Fe nil cyclopentyl til 100-3 66.37; 6.45; 12.22 66.65; 6.61; 11.92 9th ethyl 2-chloro-Fe nil cyclohexyl oil [M +] 357.88 MS (m / z) 358 10th ethyl 2-methyl- phenyl bicyclo- [2.2.1] - hept-2-yl 141-2 75.61; 7.79; 12.02 75.74; 7.84; 11.85 11th ethyl 2-methoxy -5-methyl- phenyl cyclopentyl til 94-6 71.36; 7.70; 11.89 71.88; 7.71; 11.43 12th ethyl 5-chloro-2- -methyl- phenyl cyclopentyl til 109-11 67.12; 6.76; 11.74 67.30; 7.02; 11,21 13th ethyl 5-chloro-2- -methyl- phenyl 4-fluoro- phenyl 90-2 [M +] 383.85 MS (m / z) 384 14th ethyl 5-chloro-2- -methyl- phenyl cyclobutyl 135-7 66.37; 6.45; 12.22 67.17; 6.81; 11.78 15th ethyl 5-chloro-2- Methoxy- phenyl 4-fluoro- phenyl 129-30 63.08; 4.79; 10.51 63.08; 4.86; 10.41 16th ethyl 2-chloro-Fe nil 4-tetra- hidropira- nil oil [M +] 359.85 MS (m / z 360)

Recrystallization solvent: ^from ethyl acetate / pentane; ^b diethyl ether / pentane; ^c diisopropyl ether / pentane; ^d from ethyl acetate / petroleum ether; ^such as ethyl acetate; ^f ethyl acetate / hexane.

-2 217. EXAMPLE

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

While stirring, 0.3 g (0.82 mmol) of 3-ethyl-6- (4-fluorophenyl) -1- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-pyrazole To a solution of [3,4-c] pyridine in 50 mL of diethyl ether was added 33 mg (0.86 mmol) of lithium aluminum hydride and stirring was continued for 16 hours. The reaction mixture was then treated with water (0.5 mL) followed by 1 N sodium hydroxide (1 mL) and stirred for 2 hours. The white precipitate was removed by filtration with Celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate / hexane (1: 3 v / v) as the eluent. 0.12 g of the title compound is obtained in the form of a pale yellow paste.

¹ H NMR (250 MHz, CDCl ₃ ): 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.

EXAMPLE 18

In a manner analogous to that described in Example 17, the following compound of formula IX can be prepared from a 7-oxo-2,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine derivative using lithium aluminum hydride live:

The serial number of the example R ¹ R ² R ³ Mp (° C) molecular Weight Mass spectrum [M ⁺ ] (found) 18th ethyl isobutyl cyclopentyl til oil 275.44 MS (m / z) 276

EXAMPLE 19

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

0.12 g (0.51 mmol) of 1-cyclopentyl-3-ethyl-6-benzyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine in 5 ml A solution of 32 mg (0.77 mmol) of 60% sodium hydride in mineral oil was added to a solution of dimethylformamide, followed by stirring at room temperature for 1 hour, followed by addition of 0.22 g (1.29 mmol) of benzyl bromide. After 4 hours, the reaction mixture was diluted with water (50 mL) and extracted several times with ethyl acetate. The combined organic extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1: 4 v / v). 0.13 g of the title compound is obtained as a colorless oil. Mass Spectrum (MS): m / z [M ⁺ ] 324.

20 - 68 EXAMPLES

In a manner analogous to that described in Example 19, 1-cyclopentyl-3-ethyl-7-OXO-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine is reacted with sodium hydride in dimethylformamide. followed by addition of a suitable electrophile. thus be the following groups, ^R1 is ethyl and the compound of formula ³ wherein A is a cyclopentyl (IX): R is obtained:

The serial number of the example electrophilic R ² Mp (° C) Mass spectrum or analysis (calculated as C%, H%, N%) Mass spectrum or analysis results (found C%, H%, N%) 20th cyclopropyl bromomethane cyclopropylbenzamide propyl-methyl oil [M ⁺ ] 287.41 MS (m / z) 288 21st cyclopentyl bromide cyclopentyl til oil [M ⁺ ] 301.43 MS (m / z) 302 22nd isobutyl-bro- mid isobutyl oil [M ⁺ ] 289.42 MS (m / z): 290 23rd methallylaniline bro- mid methallylaniline oil [M ⁺ ] 287.41 MS (m / z) 288 24th isoamyl bro- mid 3-methyl butyl oil [M ⁺ ] 303.45 MS (m / z) 304 25th ethyl-2-bromo- butyrate 1-ethoxy- carbonyl propyl oil [M ⁺ ] 347.46 MS (m / z) 348 26th dimethyl-carba mil dimethyl -karbamil oil [M ⁺ ] 304.39 MS (m / z) 305 27th neo bromide neopentyl oil [M ⁺ ] 303.45 MS (m / z) 304 28th Ethyl 4-bromo- butyrate 3-ethoxy carbonyl propyl oil [M ⁺ ] 347.46 MS (m / z) 348 29th 1-bromo-2-Fe- nil ethane 2-phenylethyl oil [M ⁺ ] 337.41 MS (m / z) 338 30th 1-bromo-1-Fe- nil ethane 1-phenylethyl 70-1 74.74; 8.06; 12.45 74.66; 8.22; 12.47 31st N, N-dimethyl- methylene-am- ammonium chlorides anhydride Ν, Ν-di- methyl-amino aminomethyl oil [M ⁺ ] 290.41 MS (m / z) 291 32nd isopropyl bro- mid isopropyl oil [M ⁺ ] 275.40 MS (m / z) 276 33rd acetyl chloride acetyl oil [M ⁺ ] 275.35 MS (m / z) 276 34th 2-bromomethyl -1,3-dioxolane 1,3-di- oxolan-2- -ylmethyl 52-3 [M *] 319.41 MS (m / z) 320 35th 3-picolyl chloride 3-picolyl oil [M ⁺ ] 324.43 MS (m / z) 325 36th 2-picolyl chloride 2-picolyl oil [M ⁺ ] 324.43 MS (m / z) 325 37th 4-picolyl chloride 4-picolyl oil [M ⁺ ] 324.43 MS (m / z) 325 38th benzene sulfonate sulfonylchloride benzene- sulfonyl oil [M ⁺ ] 373.48 MS (m / z) 374 39th isopropyl-sulfonic sulfonylchloride isopropyl sulfonyl 117-9 56.61; 7.42; 12.38 56.78; 7.43; 12.33 40th 2-chloro-5- (chloro- methyl) thiophene 2-thio thiophene-5-yl- -methyl oil [M ⁺ ] 363.91 MS (m / z) 364

• · • · · ·

41st 3-chloromethyl- anisole 3-methoxy benzyl oil [M ⁺ ] 353.47 MS (m / z) 354 42nd 4-methyl- -3,5-dimethyl- isoxazole 3,5-dimethoate methyl-isoxazolin zol-4-yl -methyl 98-9 66.64; 7.65; 16.36 66.46; 7.79; 16.33 43rd 3-chlorobenzyl bromide 3-Cl benzyl oil [M ⁺ ] 357.89 MS (m / z) 358 44th 2-chlorobenzyl bromide 2-Cl benzyl 68-9 67.12; 6.76; 11.74 67.13; 7.03; 11.90 45th thiophene-2-sulfonic sulfonylchloride thiophene-2- sulfonyl oil [M ⁺ ] 379.50 MS (m / z) 380 46th 4-chloro-benzene sulfonyl -chloride 4-chloro- -benzene- sulfonyl oil [M ⁺ ] 407.92 MS (m / z) 408 47th methane-sulfo nil chloride methane- sulfonyl 55-60 [M ⁺ ] 311.40 MS (m / z) 312 48th 4-methoxy- benzene-sulfonic sulfonylchloride 4-me- toxicity petrol benzene-sulfonic sulfonyl 118-126 [M ⁺ j] 403.50 MS (m / z) 404 49th 3-chloro-benzene sulfonyl chlorides anhydride 3-Cl -benzene- sulfonyl 89-94 [M ⁺ j] 407.92 MS (m / z) 408 50th 2-chloromethyl- thiophene thiophene-2- -ylmethyl oil [M ⁺ j] 329.47 MS (m / z): 330 51st 2,5-dichloro- benzene-sulfonic sulfonylchloride 2,5-di- chloro-benzenesulfonic benzene-sulfonic sulfonyl oil [M ⁺ ] 442.37 MS (m / z) 442 52nd thiophene-2-carboxylic carbonyl chloride thiophene-2- carbonyl 77-8 62.95; 6.16; 12.23 62.87; 6.25; 12.35 53rd isobutyryl chlorides anhydride isobutyryl oil [M ⁺ ] 303.40 MS (m / z) 303 54th tetrahidrofur- furyl chloride tetrahydroisoquinolyl ro-furfuryl oil [M ⁺ j] 317.43 MS (m / z) 318 55th chloride benzoyl 72-4 [M ⁺ j] 337.42 MS (m / z) 338 56th isonicotinic tinoil- -chloride izoniko- -tinoil oil [M ⁺ j] 338.41 MS (m / z) 339 57th nicotinoyl chlorides anhydride nicotinoyl 103-5 [M ⁺ ] 338.41 MS (m / z) 339 58th 2-bromoethyl methyl ether 2-methoxy -ethyl oil [M ⁺ ] 291.39 MS (m / z) 292 59th 3- (bromo-me- methyl) benzonitrile 3-cyano benzyl oil 72.39; 6.94; 16.08 72.19; 6.98; 15.75 60th methyl chloro- form from methoxy carbonyl oil 61.84; 7.26; 14.42 61.34; 7.47; 14,23 61st 2- (bromomethyl me- methyl) benzonitrile 2-cyano- benzyl oil 72.3; 6.9; 16.1 72.5; 7.2; 15.3 62nd 4- (bromo-me- methyl) benzonitrile 4-cyano -ethyl oil 72.3; 6.9; 16.1 70.6; 6.9; 15.5

63rd 3-bromo-pro- then coupling 2-cyano- -ethyl oil 67.09; 7.74; 19.56 66.82; 7.55; 18.92 64th 3-bromo-2-Bu doctrine 2-butane -3-onyl 59-61 67.3; 8.31; 13.85 67.1; 8.21; 13.50 65th morpholin-4- carbonyl chlorides anhydride morpholino -4-carboxylic carbonyl 153-4 [M ⁺ ] 346.43 MS (m / z) 347 66th Ethyl chloro-for formate ethoxy-carboxylic carbonyl oil [M ⁺ ] 306.38 MS (m / z) 306 67th 2- (2-bromo- ethyl) -1,3-di- dioxolane 2- (1,3-di- oxolan-2- -yl) ethyl oil [M ⁺ ] 333.43 MS (m / z) 334 68th 2- (chloromethyl) - -tetrahydro rán tetrahydroisoquinolyl oxethane, tetrahydropyrane -2-ylmethyl oil [M ⁺ ] 331.46 MS (m / z) 332

EXAMPLE 69

6- (2-Chloro-thiophen-5-ylmethyl) -3-ethyl-1- (4-fluoro-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3 , 4-c] pyridine

In a manner analogous to that described in Example 19, 3-ethyl-1- (4-fluorophenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine is obtained in a reaction with chloro-5- (chloromethyl) thiophene to give the title compound. MS (m / z) 390.

Example 70

3-Ethyl-1- (4-fluorophenyl) -7-oxo-6- (thiophen-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

In a manner analogous to that described in Example 19, 3-ethyl-1- (4-fluorophenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine is obtained in a reaction with chloromethylthiophene to give the title compound. Mp 106-107 ° C; MS (m / z) 356.

• · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · total · total

-2 771. EXAMPLE

1-Cyclopentyl-3-ethyl-6- (2-hydroxy-5-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

1-Cyclopentyl-3-ethyl-6- (2-methoxy-5-methyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-piazole (0.32 g, 0.91 mmol) [ A solution of 3,4-c] pyridine in 10 ml of 30% hydrobromic acid in acetic acid was stirred at 95 ° C for 24 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed first with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized from diisopropyl ether to give the title compound (0.15 g), mp 181-182 ° C.

MS (m / z) 340.

Analysis results for C20H25N3O2:

Found: C, 70.77; H, 7.42; N, 12.38. Found: C, 71.03; H, 7.49; N, 12.60.

72 - 78. Examples

In a manner analogous to that described in Example 71, a appropriately selected methoxyphenyl-substituted 4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine was reacted with 30% hydrogen bromide in glacial acetic acid. to yield the following compounds of formula IX.

[

The serial number of the example R ¹ R ² R ³ Mp (° C) Mass spectrum or analysis (calculated as C%, H%, N%) Mass spectrum or analysis results (found C%, H%, N%) 72nd ethyl 2-hydroxy- phenyl cyclopentyl til 164-5 [M ⁺ ] 325.41 MS (m / z) 326 73rd ethyl 3-hydroxy- phenyl cyclohexyl 178-9 [M +] 339.44 MS (m / z) 340 74th ethyl 4-hydroxy- phenyl cyclopentyl til 228-9 70.13; 7.12; 12.91 69.02; 7.05; 12.79 75th ethyl 5-chloro-2- hydroxy phenyl cyclopentyl til 124-5 63.41; 6.16; 11.68 63.60; 6.24; 11.56 76th ethyl 5-chloro-2- hydroxy phenyl 4-fluoro- phenyl 173-4 62.26; 4.44; 10.89 62.41; 4.61; 10.86 77th ethyl 3-hydroxy- phenyl cyclopentyl til 161-2 70.13; 7.12; 12.91 70.18; 7.25; 12.86 78th ethyl 3-hydroxy- benzyl cyclopentyl til 134-9 [M ⁺ ] 339.44 MS (m / z) 340

EXAMPLE 79

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

0.12 g (0.41 mmol) of 6-acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine in 25 mL To a solution of dioxane in water (60 ml) was added potassium carbonate (0.035 g), followed by 33 ml of a solution of NalO ₄ (2.1 g) and KMnO ₄ (0.026 g) in water (100 ml). After 1 hour, the reaction mixture was extracted several times with diethyl ether, and the combined extracts were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using ethyl acetate / hexane (1: 3 v / v) as the eluent. 0.042 g of the title compound is obtained as a colorless oil. MS (m / z): 290.

-2 980. EXAMPLE

1-Cyclopentyl-3-ethyl-6- (2-hydroxypropyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine at 30 [deg.] C. , 10 mmol) 1-cyclopentyl-3-ethyl-6- (2-hydroxypropyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine 2 ml anhydrous 38 mg of sodium borohydride are added to the solution of methanol, and after 15 minutes, a saturated aqueous solution of ammonium chloride is added and the reaction mixture is extracted several times with diethyl ether. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 2). 20 mg of the title compound are obtained as a colorless oil. MS (m / z) 292.

EXAMPLE 81

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

A solution of 0.15 g of 6-acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine in 5 ml of anhydrous pyridine at room temperature 0.040 g. Hydroxylamine hydrochloride (g) was added and after 20 hours the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The slurry was washed with water followed by saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound (0.10 g), m.p. ·

147 DEG-149 DEG C. as a white solid.

MS (m / z) 305.

Analysis results for C16H24N4O2:

H, 7.94; N, 18.41 Found: C, 62.80; H, 8.20; N, 18.55.

EXAMPLE 82

6- (O-Aminocarbonyl-oxime-acetonyl) -1-cyclopentH-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine ° C -on 0.10 g of 6- (oxime-acetonyl) -1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine in 5 ml Chlorosulfonyl isocyanate (70 mg) was added to a solution of tetrahydrofuran, followed by stirring at 25 ° C for 1 h, and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water, then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using ethyl acetate / hexane (1: 3 v / v) as the eluent. The title compound was obtained as a pale yellow oil. MS (m / z) 348.

83 to 86

In a manner analogous to that described in Example 19, 1-cyclopentyl-3-ethyl-4,5,5,7,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine is reacted with sodium hydride in dimethylformamide and a suitable electrophile is added. The compounds of formula (X), wherein R ¹ is ethyl and R ³ is cyclopentyl, are listed below:

The serial number of the example electrophilic R ² Mp (° C) Mass spectrum or analysis (calculated as C%, H%, N%) Mass spectrum or analysis results (found C%, H%, N%) 83rd isopropyl-sulfonic sulfonylchloride isopropyl sulfonyl 108-113 59.05; 8.37; 112.91 58.79; 8.38; 12.51 84th thiophene-2-carboxylic carbonyl chloride thiophene-2- carbonyl oil 65.62; 7.04; 12.75 62.60; 6.74; 11.84 85th dimethyl-carba mils chloride dimethyl -damage- urea oil [M ⁺ ] 290.41 MS (m / z) 291 86th 2-chloro-5- (chloro- methyl) thiophene 2-thio thiophene-5-yl- -methyl oil [M ⁺ ] 349.93 MS (m / z): 350

1. Reference Example

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

While stirring, a solution of freshly distilled diisopropylamine (0.16 mL, 2.21 mmol) in anhydrous tetrahydrofuran (4 mL) was cooled to 0 ° C and 2.5 M n-butyl (0.85 mL, 2.11 mmol) was added. lithium solution. After 15 minutes, the reaction mixture was cooled to -78 ° C and 0.52 g (2.0 mmol) of 4-propionyl-3-methoxy-1-phenyl-2-oxo-1,2,5 was added dropwise via cannula. 6-Tetrahydropyridine, pre-cooled in 4 mL of tetrahydrofuran. After about 20 minutes, methyl iodide (0.20 mL, 3.0 mmol) was added to the bright orange-red solution, and the reaction mixture was allowed to warm to room temperature over 2.5 h. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the organic phase was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane 1: 4 (v / v).

··· · ··· · · · using the hockey. 0.12 g of the title compound are obtained as a yellow oil and 0.1 g of unchanged starting material is isolated.

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

MS (m / z) [M ⁺ ] 274.

Reference Examples 2 - 3Ac

In analogy to the method described in Reference Example 1, a suitable 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine is reacted with lithium diisopropylamine and methyl iodide to give the following compound of formula VII: compounds can be prepared:

Reference number of the reference example R ² Mp (° C) molecular Weight Mass Spectrum [M ⁺ ] Second 4-methoxyphenyl oil 303.36 304 Third 3-methoxyphenyl oil 303.36 304

4. Reference Example

3-Methoxy-1- (4-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine 5.9 g (23 mmol) of 3-methoxy-1- (4- methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine and 5.1 g (34 mmol) of 3-methyl-1- (p-tolyl) triazine 1,2- dichloroethane solution was refluxed for 45 minutes, then allowed to cool to room temperature and poured into water. The resulting aqueous mixture was acidified with 6N hydrochloric acid and extracted three times with methylene chloride. The combined extracts were washed with 1 N hydrochloric acid, water, and finally saturated aqueous sodium ·· * · · · · · ·

It is washed with a solution of -33-chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The brown oil obtained in quantitative yield is pure by TLC and ¹ H NMR and can be used without further purification.

¹ H NMR (300 MHz, CDCl ₃ ) 1.12 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 2.71 (t, J = 6.7 Hz, 2H) , 2.93 (q, J = 7.2 Hz, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.94 (s, 3H), 7.20 (s, 4H)

MS [M ⁺ ] 273.

5th-14th PREPARATION

In Reference Example 4, the reaction of an appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1- (p-tolyl) triazine is analogous to The following compounds of formula VI can be prepared:

Reference number of the reference example R ¹ R ² Mp (° C) molecular Weight Mass Spectrum [M ⁺ ] 5th ethyl phenyl oil 259.31 26 6th methyl 4-methoxy- phenyl oil 275.30 275 7th ethyl 4-methoxy- phenyl 81-82 289.33 289 8th n-propyl 4-methoxy- phenyl oil 303.36 303 9th ethyl 3-methoxy phenyl 59-60 289.33 289; 290 10th ethyl 2-methoxy phenyl oil 289.33 289 11th ethyl 3,4-dimethoate methoxyphenyl oil 319.26 319 12th ethyl 3-cyclopent- oxy-4-me- methoxyphenyl oil 373.45 373 13th ethyl 3-methylphenyl oil 273.33 273 14th ethyl 3-trifluoromethyl methylphenyl oil 327.30 327

15. Reference Example

3-Hydroxy-1- (3-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine 1.9 g (79 mmol) of magnesium turnings in 30 ml of anhydrous diethyl Bromoethane (5.9 mL, 79 mmol) was added dropwise to a suspension of ether. After the addition of nearly 1 mL of the latter compound, the reaction mixture begins to boil more slowly. After all the magnesium had been consumed, the reaction mixture was cooled to 0 ° C and 8.7 g (50 mmol) of N- (3-methylphenyl) -2-pyrrolidone was added in one portion. The reaction mixture was warmed to room temperature, stirred for 2 hours, and then poured onto ice. The ice mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and then with a saturated aqueous sodium chloride solution.

It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 8.8 g of a white solid are obtained.

This solid was dispersed in a mixture of benzene (40 mL) and 1N aqueous sodium hydroxide (86 mL) and ethyl oxalyl chloride (7.2 mL, 64 mmol) was added to the dispersion with vigorous mechanical stirring. The reaction mixture was refluxed for 1.5 hours with stirring, then the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. This gives an amber oil. GCMS [M ⁺ ] 305.

The intermediate thus obtained is dissolved in 20 ml of anhydrous ethanol, and to the resulting solution is added carefully a solution of 1.0 g of sodium methoxide in metal sodium and 10 ml of anhydrous methanol. The reaction mixture was refluxed for 1.5 hours with stirring and then concentrated under reduced pressure. Water (100 mL) was added to the residue, and the resulting aqueous mixture was adjusted to pH 3 with 6N hydrochloric acid. A yellow precipitate is formed which is filtered off, washed with water and finally recrystallized from 75 ml of diisopropyl ether. Yield: 6.8 g of the title compound as pale yellow crystals, m.p. 115-116 ° C.

¹ H NMR (300 MHz, CDCl ₃ ) 1.16 (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)

MS (m / z) [M ⁺ ] 259.

*** »• * 4 ·» • · · · ··· · ··

-3 616. -29. PREPARATION

In a manner analogous to that described in Reference Example 15, the appropriate 2-pyrrolidinone is reacted with the appropriate alkyl magnesium bromide and then treated with ethyl oxalyl chloride and a base to give the following compounds of formula VI:

Reference number of the reference example R ¹ R ² Mp (° C) molecular Weight Mass Spectrum [M ⁺ ] 16th methyl phenyl oil 231.25 231 17th ethyl phenyl 140-142 245.28 245 18th ethyl 4-fluorophenyl 133-135 263.27 263 19th methyl 4-methoxy- phenyl oil 261.28 262 20th ethyl 4-methoxy- phenyl 121-122 275.30 276 21st n-propyl 4-methoxy- phenyl 125-126 289.33 289 22nd ethyl 3-methoxy phenyl 129-130 275.30 275 23rd ethyl 2-methoxy phenyl 119-120 275.30 275 24th ethyl 4-methylphenyl 110-112 259.30 260 25th ethyl 2-methylphenyl oil 259.30 259 26th ethyl 3-trifluoromethyl methylphenyl 117-118 313.28 313 27th ethyl 2-trifluoro- methylphenyl oil 313.28 313 28th ethyl 3,4-dimethoate methoxyphenyl 179-180 305.33 306 29th ethyl 3-cyclopent- oxy-4-me- methoxyphenyl 133-134 359.42 360

30. Reference Example

N- (2-methoxyphenyl) -2-pyrrolidone

Under a nitrogen atmosphere, 15.0 g (176 mmol) of 2-pyrrolidone, 7.6 mL (59 mmol) of 2-iodoanisole, 7.5 g (117 mmol) of copper powder and 8.1 g (59 mmol) of potassium carbonate were added. The mixture was stirred at 150 ° C for 18 hours and then stirred at room temperature for 6 hours. It was filtered through a 15 cm silica gel pad, eluting with a 1: 1 mixture of ethyl acetate and hexane. This gave a pale yellow oil, from which the unreacted reagents were removed by vacuum distillation at 80-100 ° C at 0.6 mm Hg. 9.2 g of the title compound are obtained as a honey-like oil.

¹ H NMR (300 MHz, CDCl ₃ ) 2.20 (pentet, 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)

MS (m / z) [M ⁺ ] 191.

31-39 Reference Examples

Reaction of iodine or bromobenzene with 2-pyrrolidone in a manner analogous to that described in Reference Example 30 gives the following compounds of formula (V):

Reference number of the reference example R molecular Weight Mass spectrum [M ⁺ ] 31st 4-methoxyphenyl 191.22 191 32nd 3-methoxyphenyl 191.22 191 33rd 3-methylphenyl 175.23 175 34th 4-methylphenyl 175.23 175 35th 2-methylphenyl 175.23 175 36th 3- (trifluoromethyl) phenyl 229.20 229 37th 2- (trifluoromethyl) phenyl 229.20 229 38th 3,4-dimethoxyphenyl 221.26 221 39th 3-cyclopentoxy-4-methoxyphenyl 275.35 275

Claims (6)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I) and pharmaceutically acceptable salts thereof ^R1 is hydrogen or a C1-3 alkyl, alkenyl containing 2 or 3 carbon atoms, cycloalkyl containing 3-5 carbon atoms, cycloalkyl-CH (C 3-5 alkyl), each of said alkyl or alkenyl may be optionally substituted with up to 3 halogen or up to two alkyl or trifluoromethyl groups containing 1 or 2 carbon atoms; X is oxygen or two hydrogen; R ² and R ³ are each independently hydrogen; alkyl of 1 to 14 carbon atoms optionally substituted with halogen or cyano; alkylsulfonyl containing from 1 to 14 carbon atoms in the alkyl moiety; Alkoxy having 1 to 14 carbon atoms; naphthalic sweep; Alkenyl containing from 2 to 7 carbon atoms; Cycloalkyl having from 3 to 7 carbon atoms; C 1-4 alkyl-C 3-7 cycloalkyl; Cycloalkyl (C 1-7) alkyl (C 1-4); a heterocyclic group containing oxygen and 4 to 7 carbon atoms; S; sulfonyl; -NR ⁵ where R ⁵ is hydrogen or C 1-4 alkyl; (4 - containing 7 carbon atoms), heterocycloalkyl (W) _d - radical, wherein the 4 - 7 carbon atoms, heterocycloalkyl containing one or more oxygen atoms or sulfur atoms or sulphonyl or ^NR5 general • • · · · · · · · · • R ⁵ is hydrogen or an optionally substituted C 1 -C 4 alkyl group, d is 0 or 1 and W is C 1 -C 4 alkyl, carbonyl or C 1 -C 4 alkyl group; sulfonyl; -CONR ¹⁰ R ¹¹ wherein R ¹⁰ and R ¹¹ are each independently hydrogen or C 1-4 alkyl, C 1-5 alkylcarbonyl, C 1-5 alkoxycarbonyl, ( C 1-5 alkylcarbonyl (C 1-5) alkyl, C 1-5 alkoxycarbonyl (C 1-5) alkyl, or (C 1-5) alkoxy; Alkyl having 1 to 5 carbon atoms; -R ¹² R ^{13 is} N (C 1 -C 5) alkyl wherein R ¹² and R ¹³ are each independently hydrogen or C 1 -C 5 alkyl; or a group of the formula II wherein a is 0, 1, 2, 3, 4 or 5, b and c are 0 or 1, ^R4a is independently hydrogen or hydroxy, containing from 1 to 5 carbon atoms; Alkenyl of 2 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, halogen, trifluoromethyl, -CO ² R ⁶ , -CONR ⁶ R ⁷ , -NR ^S R ⁷ , -CONHOH , -CN, -NO ₂ or -SO ₂ NR ⁶ R ⁷ and in the latter groups R ⁶ and R ⁷ are each independently hydrogen or C 1-4 alkyl, and Y is C 1-4 alkyl, 2- C 5 -alkylene or up to two C 1-7 -alkyl or C 3-7 -cyclo-41-C 2 -C 5 -alkenyl, and Z; is oxygen or sulfur or carbonyl or sulfonyl y is -NR ⁸ and in the latter R ⁸ is hydrogen or C 1-4 alkyl; or a group of the general formula (XI) wherein p is 1, 2 or 3, W is hydroxy and R ⁹ is an alkyl group having 1 to 3 carbon atoms, and the aforementioned alkyl, alkenyl, cycloalkyl, alkoxyalkyl, or the heterocyclic groups may be optionally substituted with 1 to 14, preferably 1 to 5, halogen or trifluoromethyl or alkyl having 1 or 2 carbon atoms; or a group of the formula XII wherein m, n and p are 1 or 2; or a group of formula (XIII) wherein Q is hydroxy or a group of formula (XIV); with the proviso that when R ¹ is ethyl and R ² is 4-methylphenyl, then R ³ is other than hydrogen or methyl, phenyl, 4-fluorophenyl or 2-pyridyl, and when R ² is 4-methylphenyl - and R ³ is 4-fluorophenyl, then R ¹ is other than phenyl, methyl or n-propyl, and if R ¹ is ethyl and R ² is phenyl then R ³ is 4-chlorophenyl, other than fluorophenyl or 4-methylphenyl; furthermore, when R ¹ is ethyl and R ² is 4-methoxyphenyl, R ³ is other than 4-fluorophenyl; and when W is carbonyl or sulfonyl, d is 1; with the proviso that R ² and R ³ may not at the same time be hydrogen, C 1-14 alkyl, C 1-14 » An alkoxy group of -42, a alkenyl group of 2 to 7 carbon atoms, or a heterocyclic group of 4 to 7 carbon atoms containing oxygen or sulfur, or a sulfonyl or -NR ⁵ group in which R ⁵ is hydrogen or 1 - An alkyl group containing 4 carbon atoms or a group of the formula II in which a is 0, 1, 2, 3, 4 or 5, b and c are 0 or 1, R ^4a independently of one another is hydrogen or hydroxy; C 5 -alkyl, C 2 -C 5 -alkenyl, C 1 -C 5 -alkoxy, C 3 -C 6 -cycloalkoxy, halo, trifluoromethyl, -CO ² R ⁶ , -CONR ⁶ R ⁷ , - NR ⁶ R ⁷ , -CONHOH, -CN, -NO ₂ or -SO ₂ NR ⁶ R ⁷ and in the latter groups R ⁶ and R ⁷ independently of one another are hydrogen or C 1-4 alkyl, and Y is 1 to 4 carbon alkyl, C2-C5 alkylene, or up to two cycloalkyl groups containing 1 to 7 carbon atoms or C2-C7 alkenyl substituted with 2 to 5 carbon atoms, and Z is oxygen or sulfur or carbonyl, sulfonyl or -NR ⁸ group, and in the latter R ⁸ is hydrogen or C 1 - alkyl group having 4 carbon atoms - or (XI) a group of formula - in the latter, wherein: p is 1, 2 or 3, and W is OH and R ⁹ is from 1 to 3 carbon atoms wherein the alkyl, alkenyl, cycloalkyl, alkoxyalkyl, or heterocyclic groups mentioned above are optionally substituted bt · b · · · · · · · · · · · · · · · · · · · ·· « -43 may have from 1 to 14, preferably from 1 to 5 halogen or trifluoromethyl or alkyl having 1 or 2 carbon atoms. Compounds according to claim 1, wherein R ¹ is C 1 -C 3 alkyl, R ³ is C 3 -C 7 cycloalkyl, a sulfonyl C 4 -C 7 heterocyclic group or a group of formula III, and the latter wherein a is 1, 2, 3, 4 or 5 and R ^{4 is} independently selected from hydrogen, halogen, C 1-5 alkyl or C 1-5 alkoxy. Compounds according to claim 1, wherein R ¹ is ethyl or isopropyl; ^R2 is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl 3-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxy -phenyl, cyclopropylmethylbenzyl, isobutyl, isobutenyl, 2-ethylphenyl, naphthalenyl, 2-chlorophenyl, 3-methylbutyl, dimethylcarbamyl, 1-methylbenzyl, , isopropyl, 1-picolyl, 2-picolyl, 3-picolyl, 2-methyl-5-chlorophenyl, 2-chlorothiophen-5-ylmethyl, 2-hydroxy-5-methyl -phenyl, 3,5-dimethyl-isoxazol-4-ylmethyl, 3-chlorobenzyl, thiophen-2-ylmethyl, 2-hydroxy-5-chlorophenyl, thiophene-2- carbonyl, tetrahydrofurfuryl, 3-cyanobenzyl, morpholine-4-carbonyl, isopropylsulfonyl, 4-methoxyphenylsulfonyl or 3- (trifluoromethyl) phenyl, and R ³ is cyclobutyl-; cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl. 4. Pharmaceutical preparation, in particular IV. type phosphodiesterase (PDE) and tumor necrosis factor (TNF), such as asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, hay fever, dermatitis and other inflammatory diseases, ··· For the treatment of AIDS and septic shock and / or TNF disease, comprising an effective amount of a compound according to claim 1 in association with carriers and / or other excipients commonly used in the pharmaceutical field. . Use of compounds according to claim 1 IV. type II phosphodiesterase (PDE) and tumor necrosis factor (TNF). Use of compounds according to claim 1, such as asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, hay fever, dermatitis and other inflammatory diseases, and AIDS and septic shock and TNF-producing diseases.