JP2944048B2 - Bicyclic tetrahydropyrazolopyridine - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present invention is a selective inhibitor of the production of phosphodiesterase (PDE) type IV or tumor necrosis factor (hereinafter TNF), which is itself asthma, arthritis, bronchitis, chronic Obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock, and TNF
A series of bicyclic tetrahydropyrazolopyridines useful for the treatment of other diseases involving the production of.

The invention also relates to methods of using the compounds in treating the above diseases in mammals, especially humans, and pharmaceutical compositions useful for the use.

Cyclic AMP is the second mediator between cells (EWS
utherland and TWRall, Pharmacol.Rev., 1960,12,26
5) Since then, phosphodiesterase inhibition has been a target for the regulation of a range of disease processes and thus therapeutic intervention. More recently, a completely different type of PDE has been identified (JABeavo and DH Reifsnyder, TiPS, 1990,11,15).
0), its selective inhibition improves the efficacy of drug therapy (CDN
icholson, RAChalliss and M.Shahid, TiPS, 1991,12,1
9). In particular, inhibition of PDE type IV inhibits the release of inflammatory mediators (MW Verghese et al., J. Mol. Cell Cardiol., 1989, 12
(Suppl.II), S61), relax airway smooth muscle (TJTorphy,
Directions for New Anti-Asthma Drugs, SRO'Donne
ll and CGA Persson, eds., 1988, 37, Birkhauser-Verla
g) can be. That is, compounds that inhibit PDE type IV but have low activity on other types of PDEs inhibit the release of inflammatory mediators without inducing cardiovascular or antiplatelet activity, resulting in airway smooth muscle Will relax.

TNF has been identified as being involved in many infectious and autoimmune diseases (W. Friers, FEBS Letters, 19
91,285,199). Furthermore, TNF has been shown to be a major mediator of the inflammatory response seen in sepsis and septic shock (CESpooner et al., Clinical Immunology).
and Immunopathology, 1992, 62, S11).

SUMMARY OF THE INVENTION The present invention provides a compound of formula I: Wherein R ¹ is hydrogen, (C ¹ -C ⁷ ) alkyl, (C ² -C ³ ) alkenyl, (C ³ -C ⁵ ) cycloalkyl or methylene (C ³ -C ⁵ ) cycloalkyl (each alkyl Or the alkenyl group is optionally substituted with up to ² (C ¹ -C ² ) alkyl or trifluoromethyl groups or up to 3 halogens); X is oxygen or 2
R ² and R ³ are each independently hydrogen, (C ¹ -C ¹⁴ ) alkyl, (C ¹ -C ¹⁴ ) alkoxy,
(C ² -C ⁷⁾ alkenyl, or an oxygen, sulfur, SO ₂ or NR ^5, (R ⁵ is hydrogen or (C ¹ -C ⁴⁾ alkyl.)
A (C ⁴ -C ⁷ ) heterocyclic group comprising Wherein a is an integer from 1 to 5; b and c are 0 or 1; R ⁴ is hydrogen, hydroxy, (C ¹ -C ⁵ ) alkyl, (C ² -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, NO 2 or SO ₂ R ⁶ R ⁷ (R
⁶ and R ⁷ are each independently hydrogen or (C ¹ ~C ⁴⁾ alkyl. ); Z is oxygen, sulfur, SO ₂ or NR ⁸
(R ⁸ is hydrogen or (C ¹ -C ⁴ ) alkyl.); Y is optionally up to two (C ¹ -C ⁷ ) alkyl or (C ³ -C ⁷ ) cycloalkyl groups. Substituted (C ¹ ~
C ⁵⁾ alkylene or (C ² ~C ⁶⁾ alkenyl or formula: Wherein p is an integer from 1 to 3; W is oxo or hydroxy, and R ⁹ is (C ¹ -C ³ ) alkyl. ]. Wherein each alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group is optionally 1 to 14, preferably 1 to 5, (C ¹ -C ² ) alkyl, trifluoromethyl or halogen With the proviso that when R ¹ is ethyl and R ² is 4-methylphenyl, R ³ is hydrogen,
Methyl, phenyl, instead of 4-fluorophenyl and 2-pyridyl, R ² is 4-methylphenyl, R ³
If R is 4-fluorophenyl, R ¹ is not phenyl, methyl and n-propyl; if R ¹ is ethyl and R ² is phenyl, then R ³ is 4-chlorophenyl, 4-fluoro If R ¹ is ethyl and R ² is 4-methoxyphenyl, but not phenyl and 4-methylphenyl, then R ³ is not 4-fluorophenyl. And pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention provides a compound of formula I, wherein R ¹ is (C ^1-
C ³ ) alkyl, wherein R ² and R ³ are each independently
(C ³ ~C ⁷⁾ cycloalkyl, including SO ₂ (C ⁴ ~C ⁷⁾ heterocyclic group, or a group of the formula III,: Wherein a is an integer of 1 to 5, and R ⁴ is hydrogen, hydroxy, (C ¹ -C ⁵ ) alkyl, (C ¹ -C ⁵ ) alkoxy or halogen. ] The compound which is a group of this.

In another embodiment of the present invention, in formula I, R ¹ is ethyl or isopropyl and R ² is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl,
A compound wherein R ³ is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.

The present invention further relates to phosphodiesterase (PDE) type IV and tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition that inhibits production.

The present invention further provides for the production of phosphodiesterase (PDE) type IV and tumor necrosis factor (TNF) comprising administering to a patient a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable salt thereof. A method of inhibiting.

The present invention further relates to a method of treating inflammation in a mammal, comprising administering to the mammal an effective amount of a compound of Formula I and a pharmaceutically acceptable salt thereof as an anti-inflammatory agent.

The invention further comprises a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis. And pharmaceutical compositions for treating allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock, and other diseases involving the production of TNF.

The invention further comprises administering to the patient an effective amount of a compound of Formula I and a pharmaceutically acceptable salt thereof.
Asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases,
The present invention relates to a method for treating or preventing a condition selected from the group consisting of AIDS, septic shock, and other diseases involving the production of TNF.

 Preferred specific compounds of the present invention are as follows.

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-fluorophenyl) -6- (2
-Methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (3-methylphenyl) -7 -Oxo-4,5,6,7-tetrahydro-1H-
Pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (3-trifluoromethylphenyl) -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-4,5,
6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (2-methylphenyl) -7-oxo-4,5,6,7-tetrahydro- 1H−
Pyrazolo- [3,4-c] pyridine; 3-ethyl-1- (3-sulfolanyl) -6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1- (3-sulfolanyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3 , 4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine 3-ethyl-1- (3-sulfolanyl) -6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-
Tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H- Pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (2-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4 -C] pyridine Detailed description of the invention "Halogen" as used herein, unless otherwise indicated, includes chloro, fluoro and bromo.

Unless otherwise specified, alkyl, alkoxy and alkenyl groups used herein are straight-chain, or, when containing three or more carbons, straight-chain, branched, cyclic or cyclic and straight-chain. It may be a combination of chain or branched chain portions.

"Inflammatory diseases" which can be treated according to the present invention
Include, but are not limited to, asthma, chronic obstructive airway disease, bronchitis and arthritis.

As used herein, R ¹ , R ² and R ³ are as defined above for Formula I, unless otherwise specified.

The production of the compound of the present invention is illustrated by the following reaction scheme, but is not limited thereto.

In reaction 1 of Scheme 1, 2-pyrrolidinone compound of formula IV, when properly reacted with an aryl halide in the presence of copper powder and potassium carbonate, the corresponding N-
(Aryl) -2-pyrrolidone compound V (aryl has the formula
Group II. ). Suitable aryl halides include 1-iodo- or 1-brominated 4-methoxybenzene, 3-methoxybenzene,
-Methoxybenzene, 3-methylbenzene, 4-methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-
Dimethoxybenzene or 3-cyclopentoxy-4-
Methoxybenzene is mentioned. The reaction temperature is generally
About 110 ° C. to about 170 ° C., preferably about 150 ° C .;
Under inert reaction conditions, about 14 hours to about 22 hours, preferably about
Incubate for 18 hours.

In reaction 2 of Reaction Scheme 1, R ¹ halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed, and then cooled to a temperature of about -15C to about 15C, preferably about 0C. The N- (aryl) -2- of formula V is then
Add the pyrrolidone compound and allow the reaction mixture to
Warm to room temperature with stirring for about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or bromopropane. Preferably, the anhydrous aprotic solvent is an anhydrous ether. After completion of the reaction, the desired intermediate is prepared in a conventional manner, for example, first, the organic substances are combined, washed with water and brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a precipitate that can be easily recovered. It can be isolated by obtaining as a white solid.

The precipitate corresponds to Formula VI by dispersing the precipitate in a mixture of a non-polar aprotic solvent and a base.
Converted to 1,2,5,6-tetrahydropyridine compound.
With vigorous stirring, ethyl oxalyl chloride is added and the reaction mixture is heated to reflux for about 1.5 hours to about 4.5 hours, preferably for about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvent is removed and the residue obtained is treated with a solution of sodium alkoxide in ethanol. After heating at reflux for about 1 hour to about 3 hours, preferably about 1.5 hours, the mixture is concentrated under reduced pressure and acidified with hydrochloric acid to pH = 3.

In reaction 3 of Reaction Scheme 1, the reaction mixture of the compound of Formula VI and 3-methyl-1-p-tolyltriazene is heated to reflux in an aprotic solvent to convert the compound of Formula VI to the corresponding 3- Converted to methoxy-1,2,5,6-tetrahydropyridine compound VII. The preferred aprotic solvent is 1,2-dichloroethane. The reaction time is from about 30 minutes to about 120 minutes, preferably about 45 minutes.

In reaction 1 of Scheme 2, by reacting 1,2,5,6-tetrahydropyridine compound of formula VIII with (R ⁵ is hydrogen or methyl.) With a hydrazine of the formula R ³ HNNH _2, corresponding 4 , 5,6,7-Tetrahydro-7-oxo-1H
-Conversion to pyrazolo [3,4-c] pyridine compound IX.
Both derivatives of the compound of formula VIII (3-hydroxy and 3-methoxy) can be used as starting materials in the following three reactions.

Under the first reaction conditions, the compound of formula VIII is converted to a compound of formula IX by reacting the 1,2,5,6-tetrahydropyridine compound of formula VIII with hydrazine hydrochloride and sodium alkoxide in an anhydrous polar protic solvent. Converted to the corresponding compound. A preferred sodium alkoxide is sodium methoxide, and a preferred anhydrous polar protic solvent is absolute ethanol. The reaction mixture is about 9 to about
Heat to reflux for 15 hours, preferably about 12 hours.

In another reaction condition, the compound of formula VIII is converted to a compound of formula IX by reacting the 1,2,5,6-tetrahydropyridine compound of formula VIII with hydrazinobenzoic acid in an anhydrous polar protic solvent, preferably in ethanol. Converted to the corresponding compound. The reaction mixture is left for about 16 to about 24 hours, preferably about
Heat to reflux for 20 hours. The resulting compound of formula IX is prepared in a polar protic solvent, preferably in methanol.
Further reaction with sodium methoxide for about 15 minutes to about 45 minutes, preferably 30 minutes, gives the corresponding 1- (4-
Benzamide) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine compound. After removing the polar protic solvent under reduced pressure and suspending the solid residue in a non-polar aprotic solvent, preferably benzene, the non-polar solvent is removed under reduced pressure. The resulting dry solid is suspended in cold ether, treated with oxalyl chloride and N, N-dimethylformamide and stirred for about 30 minutes to about 90 minutes, preferably 60 minutes. Then the solvent is removed and the crude residue is dissolved in dehydrated tetrahydrofuran. The resulting solution is added dropwise to the stirred ammonium hydroxide at a temperature of about -10C to about 10C, preferably 0C.

In a third reaction condition, the compound of formula VIII is converted to a compound of formula IX by reacting the 1,2,5,6-tetrahydropyridine compound of formula VIII with hydrazine hydrochloride in a polar protic solvent, preferably methanol. Converted to the corresponding compound. The reaction mixture is heated to a temperature of about 70C to about 110C, preferably about 90C, under a gentle stream of nitrogen until all solvent is removed. Then, leave the mixture as it is for about 30 minutes to about
Heat to a temperature of about 120C to about 180C, preferably about 150C, for 90 minutes, preferably 60 minutes.

The resulting compound of formula IX is prepared by dissolving a compound of formula IX in a polar aprotic solvent, preferably acetonitrile, at about -15.
About 20 minutes to about 50 ° C at a temperature of about 0 ° C to about 15 ° C, preferably about 0 ° C.
Reaction with an aqueous solution of cerium (IV) ammonium nitrite for about 35 minutes, preferably about 35 minutes, to give the corresponding 6-R ²
4,5,6,7-tetrahydro-7-oxo -1H- pyrazolo [3,4-c] pyridine compounds (R ² is other than a group of formula II.) Can be converted into. After completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are then washed with saturated sodium bicarbonate and then with sodium sulfite. Treat the compound formed in a polar aprotic solvent, preferably tetrahydrofuran, with sodium hydride and heat to reflux for about 30 minutes to about 60 minutes, preferably
Stir for 45 minutes. The reaction mixture was about 20 ° C. ~ about 30 ° C., preferably cooled to a temperature of about 25 ° C., wherein: R ² halide (R
² is a group other than the group of formula II as defined for formula I. ) Is added. The reaction mixture is stirred and heated to reflux for about 12 hours to about 20 hours, preferably 16 hours.

In reaction 2 of Scheme 2, 2-oxo-4,5,6,7-tetrahydro -1H- pyrazolo [3,4-c] pyridine Compound I
Compound IX is converted to the corresponding compound of formula X by reacting X with a reducing agent, preferably lithium aluminum hydride, in a non-polar aprotic solvent, preferably ether. The reaction is stirred for about 12 hours to about 20 hours, preferably 16 hours. Then water and a base, preferably sodium hydroxide, are added and the reaction mixture is left
Stir and filter for 2.5 hours, preferably 2 hours. Concentration of the filtrate gives a white solid.

The ability of the compounds of the present invention or pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDE ₄ ) and be effective in treating inflammatory diseases is demonstrated by the following in vitro assays.

Biological Assay (PDE _IV of Human Lung) 30-40 g of human lung tissue was treated with 50 ml of Tris / phenylmethylsulfonyl fluoride (PMSF) / sucrose buffer (pH 7.
4), and add Tekmar Tissumizer (Tekmar Co., 7143 Kemp
er Road, Cincinnati, Ohio 45249) for 30 seconds,
Homogenize at maximum speed. 4 homogenates
Centrifuge at 48,000 xg for 70 minutes. The supernatant was filtered twice through a 0.22 μm filter and Mono-Q FPLC column (Pharmacia LKB) pre-equilibrated with Tris / PMSF buffer pH 7.4.
Biotechnology, 800 Centennial Avenue, Piscataway, New
Jersey 08854). After passing the sample through the column at a flow rate of 1 ml / min, washing and elution are performed at a flow rate of 2 ml / min. Elution of the sample is performed using a stepwise increasing NaCl gradient in Tris / PMSF buffer at pH 7.4. Collect 8 ml fractions. ^[3 H] is measured by comparison with the ability of cAMP hydrolysis and the known PDE _IV inhibitors which inhibit the hydrolysis (e.g. rolipram), specific PD of the fraction
Measure _EIV activity. The appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol / 5 ml enzyme sample) and stored at -20 ° C until use.

Compounds are dissolved in DMSO at a concentration of 10 mM and diluted 1:25 with water (400 μM compound, 4% DMSO). 4% more D
Make serial dilutions with MSO to achieve the desired concentration. The final DMSO concentration in the assay tube is 1%. Add the following components to a 12 x 75 mm glass tube in this order:
Make up (all concentrations are final concentrations in assay tubes).

i) 25 μl compound or DMSO (1%; for control and blank) ii) 25 μl Tris buffer (pH 7.5) ii) [ ³ H] cAMP (1 μM) iv) 25 μl PDE _IV enzyme (for blank; enzyme) Pre-incubate in boiling water for 5 minutes.) Shake the reaction tube, place in a water bath (37 ° C.) for 20 minutes, and stop the reaction by placing the tube in a boiling water bath for 4 minutes. Wash buffer (0.5 ml; 0.1 M 4- (2
-Hydroxyethyl) -1-piperazine-ethanesulfonic acid (HEPES) /0.1 M NaCl; pH 8.5) is added to each tube on an ice bath. Fill the contents of each tube with an Affi-Gel 601 column (Biorad Laboratories,
POBox 1229,85A Marcus Drive, Melville, New York 11
747) (boronate affinity gel, 1 ml bed volume). [ ³ H] cAMP is washed with 2 × 6 ml of wash buffer, then [ ³ H] 5 ′ AMP is eluted with 4 ml of 0.25 M acetic acid. After shaking, add 1 ml of eluent to 3 ml of scintillation fluid in a suitable vial, shake and count [ ³ H].

IC ₅₀ is defined as the concentration of compound that inhibits the specific hydrolysis of [ ³ H] cAMP to [ ³ H] 5′AMP by 50%.

(TNF) The compound of the present invention or a pharmaceutically acceptable salt thereof is TN
The ability to inhibit the production of F, and thus show efficacy for the treatment of diseases involving the production of TNF, is described in vitro below.
o Shown by assay.

Human peripheral blood (100 ml) is collected from volunteers in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells to Ficoll / H
Isolate by ypaque and wash three times with incomplete HBSS. Pre-warmed cells with RPMI (5% FCS, glutamine, pen / step
And nystatin) at a final concentration of 1 × 10 ⁶ cells / ml. 1 x 10 mononuclear cells in a 24-well plate
Plate as ⁶ cells / 1.0 ml. Cells at 37 ° C
(5% carbon dioxide) and add 2
After allowing to adhere for a time, non-adherent cells are removed by gentle washing. Then, test compound (10 μl) was added to each of 3
Add to cells at ４4-fold concentration and incubate for 1 hour. LPS (10 μl) is added to the appropriate well. Incubate the plate at 37 ° C. overnight (18 hours). At the end of the incubation period, TNF is placed in a sandwich ELISA (R
& D Quantikine kit). IC ₅₀ measurements for each compound are made based on linear regression analysis.

Pharmaceutically acceptable acid addition salts of the compounds of the present invention include, but are not limited to, HCl, HBr, HNO ₃ , H ₂ S
_{O 4, H 3 PO 4,} CH 3 SO 3 include _{H, p-CH 3 C 6} H 4 SO 3 H, CH 3 CO 2 H, gluconic acid, tartaric acid, acid addition salts formed by maleic acid and succinic acid Can be Pharmaceutically acceptable cationic salts of the compounds of the present invention wherein R ⁴ is COR ⁶ and R ⁶ is hydrogen in Formula I include, but are not limited to,
Sodium, potassium, calcium, magnesium, ammonium, N, N'-dibenzylethylenediamine, N
-Salts of methylglucamine (meglumine), ethanolamine and diethanolamine.

When administered to humans for the treatment or prevention of inflammatory diseases, the oral dosage of a compound of Formula I and pharmaceutically acceptable salts thereof (hereinafter, referred to as the active compound of the present invention) will generally be lower than that of adults. Range from 0.1 to 100 mg daily for targeted patients (70 kg). That is, for a typical adult patient, the individual tablets or capsules may contain from 0.1 to 5 tablets in a suitable pharmaceutically acceptable vehicle or carrier.
Contains 0 mg of active compound. The dose for intravenous administration is
Typically, the range is 0.1 to 10 mg as needed per single dose. For intranasal or inhaled administration, generally
Prepare as a 0.1-1% (w / v) solution. In practice, the physician will determine the actual dose that will be most suitable for an individual patient,
It depends on the age, weight and response of the particular patient. The above doses are examples of the average case, and of course there may be individual cases where higher or lower dose ranges are advantageous, and all such doses are within the scope of the invention.

When administered to humans for the inhibition of TNF, various usual administration methods such as oral, parenteral and topical administration can be used. Generally, the active compounds will be administered orally or parenterally at a dose of about 0.1 to 25 mg, preferably about 0.3 to 5 mg per kg of body weight of the patient being treated. However, some variation in dosage will necessarily occur depending on the condition of the patient being treated. Regardless, the person responsible for administration will determine the appropriate dose for the individual patient.

For use in humans, the active compounds of the present invention can be administered alone, but generally will be administered in a mixture with a pharmaceutical diluent or carrier selected with regard to the dosage regimen used and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or capsules or ovales alone or mixed with excipients, or elixirs or suspensions containing flavoring or coloring agents. It can also be injected parenterally, 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 yet another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

The present invention will be described with reference to the following examples, but the present invention is not limited to the details.

Example 1 3-ethyl-1- (4-methoxyphenyl) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine 35 ml of absolute ethanol ( 3-Hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydropyridine (1.0 g, 4.1 mmol), 4-methoxyphenylhydrazine hydrochloride (0.8 g,
A mixture of 4.6 mmol) and sodium methoxide (0.11 g, 2 mmol) was heated to reflux. After 12 hours, the solvent is removed on a rotary evaporator under reduced pressure and the crude residue is chromatographed (4 × 20 cm silica column;
(1: 1 ether / hexanes as eluent) gave 345 mg of the title compound as a red oil which crystallized on standing at room temperature. Desired 1-
The (4-methoxyphenyl) regioisomer is less polar than the 2- (4-methoxyphenyl) by-product. Melting point: 43-45
° C; IR (chloroform) lactam C = O, 1665 cm ^-1 ; ¹ HNMR
(300MHz, CDCl ₃ ) δ: 1.32 (t, J = 7.6Hz, 3H), 2.74 (q, J
= 7.6Hz, 2H), 2.96 (t, J = 6.6Hz, 2H), 3.79 (s, 3H), 4.
10 (t, J = 6.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 7.22 to 7.
39 (m, 5H), 7.45 (d, J = 9.0 Hz, 2H); Elemental analysis: Calculated (as C ₂₁ H ₂₁ N ₃ O ₂ ): C, 72.60; H, 6.09; N, 12.09; : C, 72.48; H, 6.08; N, 11, 66; MSm / z (M ⁺ ) 347. Examples 2-15 The appropriate hydrazine hydrochloride was prepared in the same manner as in Example 1 to give the required 4-alkanoyl- When reacted with 3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine, the following compound is obtained.

Example 16 3-Ethyl-1- (4-phenylcarboxylic acid) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine 3-hydroxy- 2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydropyridine (1.0 g, 4.
08 mmol), 4-hydrazinobenzoic acid (0.68 g, 4.49 mmol) and 30 ml of absolute ethanol were heated to reflux. After 20 hours, the mixture was concentrated under reduced pressure on a rotary evaporator, and the solid residue was concentrated in ethyl acetate (50%).
0 ml) and a buffer of pH 4 (200 ml). The organic layer was separated (most of the 2- (4-phenylcarboxylic acid) by-product remains behind), washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Recrystallization from methanol gives 0.64 g of the title compound as an orange solid. ^{Mp: 261~263 ℃; 1 HNMR (300MHz} , DM
SO−d ⁶ ) δ: 1.23 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.6 Hz,
2H), 2.94 (t, J = 6.5Hz, 2H), 4.05 (t, J = 6.5Hz, 2H),
7.20 to 7.41 (m, 5H), 7.65 (d, J = 8.6 Hz, 2H), 7.96 (d, J
= 8.6 Hz, 2H); 13.05 (s, 1H); MSm / z (M ⁺ ) 362 Example 17 1- (4-Benzamido) -3-ethyl-6- (4-methoxyphenyl) -7-oxo- A stirred solution of 4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine sodium methoxide in methanol (6.6 mg
Of 3-ethyl-6- (4-methoxyphenyl) -1- (4-phenylcarboxylic acid) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3, 4-c]
Pyridine (96 mg, 0.25 mmol) is added. After 30 minutes,
The methanol was removed under reduced pressure, the solid residue was suspended in benzene, and the benzene was removed under reduced pressure. The obtained dry solid was suspended in cold ether (ice bath) and oxalyl chloride (31 μl, 0.35
Mmol) and anhydrous N, N-dimethylformamide (1
Drops). After stirring for 1 hour, volatiles were removed under reduced pressure and the crude residue was dissolved in dehydrated tetrahydrofuran. The resulting solution was added dropwise at 0 ° C. to vigorously stirred ammonium hydroxide. After warming to room temperature over 2 hours, the reaction mixture was concentrated in vacuo until a yellow solid began to precipitate. At this time, the mixture was diluted to about 100 ml with water, filtered, and the precipitate was washed with water to obtain 81 mg of the title compound. Decomposition temperature: 243-245 ° C .; ¹ H NMR (DMSO-d ₆ ) δ: 1.24 (t, J = 7.6 H
z, 3H), 2.68 (q, J = 7.6Hz, 2H), 2.93 (t, J = 6.5Hz, 2
H), 3.75 (s, 3H), 3.99 (t, J = 6.5 Hz, 2H), 6.94 (d, J =
9.1Hz, 2H), 7.27 (d, J = 9.0Hz, 2H), 7.43 (s, 1H), 7.59
(D, J = 8.5Hz, 2H), 7.90 (d, J = 8.6Hz, 2H), 8.04 (s, 1
H); Elemental analysis: Calculated (as _{C 22 H 22 N 4 O 3} ): C, 67.68;
H, 5.68; N, 14.35; Found: C, 67.19; H, 5.31; N, 13.55; HRMS:
Calculated (as _{C 22 H 22 N 4 O 3} ) [M ^+]: 391.1770; Found: 3
91.1781 Starting material 3-ethyl-6- (4-methoxyphenyl) -1- (4-phenylcarboxylic acid) -7-oxo-
4,5,6,7-Tetrahydro-1H-pyrazolo [3,4-c] pyridine was synthesized according to the method of Example 16 using appropriate reagents.

Example 18 1- (3,4-dichlorophenyl) -3-ethyl-6
(3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine 3-methoxy-1- (3-methoxyphenyl) -2-
Of oxo-4-propionyl-1,2,5,6-tetrahydropyridine (0.49 g, 1.7 mmol), 3,4-dichlorophenylhydrazine hydrochloride (0.40 g, 1.87 mmol) and sodium methoxide (46 mg, 0.85 mmol) The mixture in absolute ethanol was stirred and heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed (silica gel column; 1: 4 ethyl acetate / hexane as eluent) to give a white solid. Recrystallization from ether yielded 0.46 g of white needles. Melting point:
97-99 ° C .; ¹ H NMR (250 MHz, CDCl ₃ ) δ: 1.31 (t, J = 7.5 Hz,
3H), 2.73 (q, J = 7.6Hz, 2H), 2.96 (t, J = 6.6Hz, 2H),
3.79 (s, 3H), 4.09 (t, J = 6.6 Hz, 2H), 6.78 to 6.91 (m, 3
H), 7.29-7.49 (m, 3H), 7.73 (d, J = 1.8 Hz, 1H); MSm / z
[M +]: 416. Examples 19-42 The appropriate hydrazine hydrochloride was prepared in the same manner as in Example 18 by requisite 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydro When reacted with pyridine, the following compound is obtained.

Example 43 1-Cyclohexyl-3-ethyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H
-Pyrazolo [3,4-c] pyridine 3-methoxy-1- (3-methoxyphenyl) -2-
Oxo-4-propionyl-1,2,5,6-pyridine (0.80
g, 2.8 mmol) and cyclohexylhydrazine hydrochloride (0.54 g, 3.6 mmol) in methanol (15 ml) were warmed to 90 ° C. under a gentle stream of nitrogen to remove all solvent. The mixture was then heated to about 150 ° C. under nitrogen for 1 hour. After cooling to room temperature, the mixture was dissolved in ether, washed with 1N hydrochloric acid, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (using 1: 1 ethyl acetate / hexane as eluent) gave 0.47 g of the title compound as a yellow oil. ¹ H NMR (250 MHz, CDCl ₃ ) δ: 1.20 to 1.52
(M, 6H, 1.23 include t, J = 7.6 Hz, 3H), 1.64 to 1.74 (m, 1
H), 1.80-2.06 (m, 6H), 2.67 (q, J = 7.6Hz, 2H), 2.87
(T, J = 6.7Hz, 2H), 3.82 (s, 3H), 3.97 (t, J = 6.7Hz, 2
H), 5.13 (tt, J = 4.3 and 11.3Hz, 1H), 6.79-6.93
(M, 3H), 7.31 (t, J = 8.1 Hz, 1H); HRMS: Calculated (C ₂₁ H ₂₇
As N ₃ O ₂₎ [M ^+]: 352.2103; Found: 353.2094 Example 44 to 57 the appropriate hydrazine hydrochloride in the same manner as in Example 43, required 4-alkanoyl-3-methoxy-2 When reacted with -oxo-1,2,5,6-tetrahydropyridine, the following compound is obtained.

Example 58 3-ethyl-6- (4-fluorophenyl) -1- (4
-Methoxyphenyl) -4,5,6,7-tetrahydro-1H-
Pyrazolo [3,4-c] pyridine 3-ethyl-6- (4-fluorophenyl) -1-
(4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine (0.3 g,
To a stirred solution of 0.82 mmol) in 50 ml of ether was added lithium aluminum hydride (33 mg, 0.86 mmol). After stirring for 16 hours, water (0.5 ml) was added followed by 3N sodium hydroxide (1 ml). After stirring for 2 hours, the white precipitate is filtered through celite and the filtrate is concentrated under reduced pressure. When subjected to silica gel column chromatography (1: 3 ethyl acetate / hexane as eluent),
0.12 g of the title compound was obtained as a pale yellow paste. ¹
HNMR (250 MHz, CDCl ₃ ) δ: 1.28 (t, J = 7.6 Hz, 3H), 2.66
(Q, J = 7.6Hz, 2H), 2.71 (t, J = 5.7Hz, 2H), 3.49 (t, J
= 5.7Hz, 2H), 3.84 (s, 3H), 4.23 (s, 2H), 6.84 ~ 6.99
(M, 6H), 7.36 (d, J = 9.0 Hz, 2H); MSm / z [M ⁺ ]: 352 Examples 59-63 Suitable 7-oxo-4,5,6,7-tetrahydro-1H- When pyrazolo [3,4-c] pyridine is reacted with lithium aluminum hydride in the same manner as in Example 58,
The following compound is obtained.

Example 64 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,
7-tetrahydro-1H-pyrazolo [3,4-c] pyridine 1-cyclopentyl-3-ethyl-6- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1
A solution of H-pyrazolo [3,4-c] pyridine (2.58 g, 7.60 mmol) in acetonitrile (90 ml) was stirred at 0 ° C. and this was treated with cerium ammonium nitrite (12.5 g, 22.8 mmol) in water (110 ml). Treat with solution. After stirring for 35 minutes, the mixture is diluted with water (550 ml) and extracted with ethyl acetate (4 × 100 ml). Combine organics, 50%
Wash with saturated sodium bicarbonate (250 ml) and then with 10% sodium sulfite until the aqueous wash is pale yellow. The organic layer is then further washed with saturated bicarbonate and brine and treated with decolorizing carbon. After stirring for 30 minutes, the mixture is dried over sodium sulfate, filtered through celite and concentrated in vacuo. The brown residue was recrystallized from ether to give .814g
A tan solid is obtained. Melting point: 143-145 ° C; MS (m / z) 2
34; ¹ H NMR (250 MHz, CDCl ₃ ) δ: 1.21 (t, J = 7.6 Hz, 3 H),
1.62 to 2.13 (m, 8H), 2.62 (q, J = 7.6Hz, 2H), 2.73 (t, J
= 6.8Hz, 2H), 3.51 (dt, J = 2.7 and 6.8Hz, 2H), 5.47
(S, 1H), 5.61 (quintet, J = 7.7 Hz, 1H) Example 65 1-Cyclopentyl-3-ethyl-6-cyclopropylmethyl-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo [3,4-c] pyridine 1-cyclopentyl-3-ethyl-7-oxo-4,5,
A solution of 6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine (0.21 g, 0.92 mmol) in THF (5 ml) is treated with 60% sodium hydride / mineral oil (40 mg, 1.01 mmol). After stirring at reflux for 45 minutes, the reaction mixture was brought to 25 ° C.
And cooled to (bromomethyl) cyclopropane (0.31 g, 2.
29 mmol) are added. The mixture is stirred at reflux for 16 hours, then cooled to 25 ° C. and concentrated under reduced pressure. Chromatography on silica gel (eluting with 1: 1 ethyl acetate / hexanes) gives 0.19 g of the title compound as a colorless oil. MSm / z [M ⁺ ]: 288; ¹ HNMR (300 MHz, CDCl ₃ )
δ: 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.0
6 (m, 1H), 1.20 (t, J = 7.6Hz, 3H), 1.62 ~ 2.08 (m, 8
H), 2.61 (q, J = 7.6 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 3.
39 (d, J = 6.9Hz, 2H), 3.63 (t, J = 6.8Hz, 2H), 5.67 (5
Doublet, J = 7.8Hz, 1H) Production Example 1 4-isobutyryl-3-methoxy-1-phenyl-2-
Oxo-1,2,5,6-tetrahydropyridine Freshly distilled diisopropylamine (0.16 ml, 2.21
(Mmol) in anhydrous tetrahydrofuran (4 ml) was cooled to 0 <0> C and treated with 2.5 M n-butylthylium (0.85 ml, 2.11 mmol). After 15 minutes, the mixture was cooled to -78 ° C and the pre-cooled 4-propionyl-3
A solution of -methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine (0.52 g, 2.0 mmol) in tetrahydrofuran (4 ml) was added dropwise via cannula.
After about 20 minutes, methyl iodide (0.20 ml, 3.0 mmol) was added to the bright red-orange solution and the mixture was allowed to come to room temperature over 2.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography (silica gel column; eluted with 1: 4 ethyl acetate / hexane) provided 0.12 g of the title compound as a yellow oil and 0.1 g of starting material was recovered. ¹ HNMR (250 MHz, CDCl
₃ ) δ: 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (7-fold, 1H),
3.82 (t, 2H), 3.97 (s, 3H), 7.21 to 7.45 (m, 5H); MSm / z
[M ⁺ ] 274 Preparation Examples 2-3 The appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine was prepared in the same manner as in Preparation Example 1 by adding lithium diisopropylamine and When reacted with methyl iodide, the following compound of formula VII is obtained.

Production Example 4 3-Methoxy-1- (4-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine 3-hydroxy-1- (4-methylphenyl) -2-
Oxo-4-propionyl-1,2,5,6-tetrahydropyridine (5.9 g, 23 mmol) and 3-methyl-1-p
A solution of tolyltriazine (5.1 g, 34 mmol) in 1,2-dichloroethane was heated at reflux for 45 minutes. The mixture was cooled to room temperature, poured into water and acidified with 6N hydrochloric acid. The aqueous layer was extracted three times with methylene chloride, and the combined organic layers were washed with 1H hydrochloric acid, then with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The quantitatively obtained brown oil was analyzed by thin-layer chromatography and ¹ H NMR and was free of impurities and used without purification. ¹ HNM
R (300 MHz, CDCl ₃ ) δ: 1.12 (t, J = 7.2 Hz, 3H), 2.34 (s,
3H), 2.71 (t, J = 6.7Hz, 2H), 2.93 (q, J = 7.2Hz, 2H),
3.77 (t, J = 6.8Hz, 2H), 3.94 (s, 3H), 7.20 (s, 4H); MS
[M ⁺ ] 273 Preparation Examples 5 to 14 Suitable 3-hydroxy-1-aryl-2-oxo-
4-Alkanoyl-1,2,5,6-tetrahydropyridine was converted to 3-methyl-1-p in the same manner as in Production Example 4.
When reacted with tolyltriazine, the following compound of formula VI is obtained.

Production Example 15 3-Hydroxy-1- (3-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine Magnesium turnings (1.9 g, 79 mmol) in anhydrous ether (30 ml) The bromoethane (5.9 ml, 79
Mmol) was added dropwise. After about 1 ml was added, mild reflux was started. After all the magnesium was consumed, the reaction mixture was cooled to 0 ° C. and N- (3-methylphenyl) -2-pyrrolidone (8.7 g, 50 mmol) was added in one portion. After warming to room temperature and stirring for 2 hours, the reaction mixture was poured onto ice and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 8.8 g of a white solid.

The solid was dispersed in a mixture of 40 ml of benzene and 86 ml of 1N sodium hydroxide and ethyl oxalyl chloride (7.2 ml, 64 mmol) was added with vigorous mechanical stirring. After stirring at reflux for 1.5 hours, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give an amber oil. GCMS
[M ⁺ ] 305 The above intermediate was dissolved in 20 ml of absolute ethanol, and a methanol solution of sodium methoxide (sodium (1.0 g)
(Prepared by careful addition to 10 ml of anhydrous methanol). After stirring at reflux for 1.5 hours, the mixture was concentrated under reduced pressure and 100 ml of water was added. 6N mixture
Acidified to pH 3 with hydrochloric acid and the cloudy yellow precipitate was filtered and washed with water. Recrystallization from 75 ml of isopropyl ether gives 6.8 g of pale yellow crystals. Mp: 115-116 °; ¹ H
NMR (300 MHz, CDCl ₃ ) δ: 1.16 (t, J = 7.2 Hz, 3H), 2.37
(S, 3H), 2.74 ~ 2.82 (m, 4H), 3.85 (t, J = 6.8Hz, 2H),
7.08 ~ 7.14 (m, 3H), 7.30 (t, J = 7.7Hz, 1H); MSm / z
[M ⁺ ] 259 Preparations 16-29 The appropriate 2-pyrrolidinone was reacted with the required alkylmagnesium bromide in a similar manner to Preparation 15, followed by treatment with ethyl oxalyl chloride and a base to give the formula
The following compound of VI is obtained.

Production Example 30 N- (2-methoxyphenyl) -2-pyrrolidone 2-pyrrolidone (15.0 g, 176 mmol), 2-iodoanisole (7.6 ml, 59 mmol), copper powder (7.5 g, 117 mmol) and potassium carbonate (8.1 g, 59 mmol) is stirred at 150 ° C. under nitrogen. After 18 hours, the reaction mixture was filtered through a 6 × 15 cm pad of silica gel, eluting with 1: 1 ethyl acetate / hexane to give a pale yellow oil. The unreacted reagent is removed by vacuum distillation (0.6 mm, 80-100 ° C.), leaving behind 9.2 g of the title compound as a honey-like oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ: 2.20 (quintuple, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.9
3-7.02 (m, 2H), 7.25-7.30 (m, 2H); MSm / z [M ⁺ ] 191 Preparations 31-39 The appropriate iodo or bromobenzene was prepared in a similar manner to Preparation 30 to give 2 When reacted with -pyrrolidinone, the following compound of formula V is obtained.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 471/04 A61K 31/435 WPIL (DERWENT)

Claims (6)

(57) [Claims] (1) The following formula I: Wherein R ¹ is hydrogen, (C ¹ -C ³ ) alkyl, (C ² -C ³ ) alkenyl, (C ³ -C ⁵ ) cycloalkyl or methylene (C ³ -C ⁵ ) cycloalkyl (each alkyl Or the alkenyl group is optionally substituted with up to ² (C ¹ -C ² ) alkyl or trifluoromethyl groups or up to 3 halogens); X is oxygen or 2
R ² and R ³ are each independently hydrogen, (C ¹ -C ¹⁴ ) alkyl, (C ¹ -C ¹⁴ ) alkoxy,
(C ² -C ⁷⁾ alkenyl, or an oxygen, sulfur, SO ₂ or NR ^5, (R ⁵ is hydrogen or (C ¹ -C ⁴⁾ alkyl.)
A (C ⁴ -C ⁷ ) heterocyclic group comprising Wherein a is an integer from 1 to 5; b and c are 0 or 1; R ⁴ is hydrogen, hydroxy, (C ¹ -C ⁵ ) alkyl, (C ² -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, NO 2 or SO ₂ R ⁶ R ⁷ (R
⁶ and R ⁷ are each independently hydrogen or (C ¹ ~C ⁴⁾ alkyl. ); Z is oxygen, sulfur, SO ₂ or NR ⁸
(R ⁸ is hydrogen or (C ¹ -C ⁴ ) alkyl.); Y is optionally up to two (C ¹ -C ⁷ ) alkyl or (C ³ -C ⁷ ) cycloalkyl groups. Substituted (C ¹ ~
C ⁵⁾ alkylene or (C ² ~C ⁶⁾ alkenyl or formula: Wherein p is an integer from 1 to 3; W is oxo or hydroxy, and R ⁹ is (C ¹ -C ³ ) alkyl. ]. Wherein each alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group is optionally 1 to 14, preferably 1 to 5, (C ¹ -C ² ) alkyl, trifluoromethyl or halogen With the proviso that when R ¹ is ethyl and R ² is 4-methylphenyl, R ³ is hydrogen,
When R ² is 4-methylphenyl and R ³ is 4-fluorophenyl instead of methyl, phenyl, 4-fluorophenyl and 2-pyridyl, R ¹ is phenyl,
When R ¹ is ethyl and R ² is phenyl, but not methyl and n-propyl, R ³ is not 4-chlorophenyl, 4-fluorophenyl and 4-methylphenyl, and R ¹ is ethyl; When R ² is 4-methoxyphenyl, R ³ is not 4-fluorophenyl, and further in formula I either R ² or R ³ is H, (C ^1-
C ³⁾ alkyl, (C ¹ ~C ³⁾ alkenyl, (C ⁵ ~C ⁶⁾ cycloalkyl, (C ⁵ ~C ⁶⁾ cycloalkyl (C ¹ ~C ³⁾ alkyl, pyridyl, (C ¹ -C ³ ) Alkylpyridyl and Formula II: Wherein (Y) _b- (Z) _c -is (C ¹ -C ³ ) alkyl, or b and C are 0, a is 0 or 1, and R ⁴ is (C ¹ -C ³⁾ alkyl, (C ¹ ~C ³⁾ alkoxy, ^{_{halo, CF 3, (C 1 ~C}} 3) alkyl -S- or di (C ¹ -C
³ ) is a substituent at the para position selected from alkylamino, or a is 2 and R ⁴ is 3,4-dichloro]
Not the base of And a pharmaceutically acceptable salt thereof. 2. A method according to claim 1, wherein R ¹ is (C ¹ -C ³ ) alkyl, R ² and
R ³ is each independently a (C ³ -C ⁷ ) cycloalkyl, SO ₂
A (C ⁴ -C ⁷ ) heterocyclic group comprising Wherein a is an integer of 1 to 5, and R ⁴ is hydrogen, hydroxy, (C ¹ -C ⁵ ) alkyl, (C ¹ -C ⁵ ) alkoxy or halogen. The compound according to claim 1, which is a group represented by the formula: Wherein R ¹ is ethyl or isopropyl, R ²
Is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl, and R ³ is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or The compound according to claim 1, which is 3,4-dichlorophenyl. 4. 3-Ethyl-1- (4-methoxyphenyl) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; -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-fluorophenyl) -6- (2
-Methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (3-methylphenyl) -7 -Oxo-4,5,6,7-tetrahydro-1H-
Pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (3-trifluoromethylphenyl) -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-4,5,
6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (2-methylphenyl) -7-oxo-4,5,6,7-tetrahydro- 1H−
Pyrazolo- [3,4-c] pyridine; 3-ethyl-1- (3-sulfolanyl) -6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1- (3-sulfolanyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3 , 4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4-c] pyridine 3-ethyl-1- (3-sulfolanyl) -6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-
Tetrahydro-1H-pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H- Pyrazolo- [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (2-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4 The compound according to claim 1, wherein the compound is selected from the group consisting of: -c] pyridine. 5. A disease caused by the production of phosphodiesterase (PDE) type IV and tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating. 6. Asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, skin comprising a pharmaceutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical compositions for treating inflammation and other inflammatory diseases, AIDS, septic shock, and other diseases involving TNF production.