MXPA00001750A - Benzenesulfonamide inhibitors of pde-iv and their therapeutic use - Google Patents

Abstract

The present invention provides compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of diseases whose treatment benefits from the inhibition of phosphodiesterase (PDE-IV) or Tumour Necrosis Factor (TNF) including asthma, allergic diseases, rheumatoid arthritis, osteoarthritis, septic shock. The compounds provided by this invention have formula (I) wherein R1, R2, R3, R4 are as defined herein.

Description

BENCENSULFONAMIDE INHIBITORS OF THE PDE-IV AND ITS THERAPEUTIC USE FIELD OF THE INVENTION The present invention relates to novel sulfonamide compounds and pharmaceutically acceptable salts thereof, to processes for their production, formulation and their use as pharmaceuticals in the treatment of asthma, allergic diseases, rheumatoid arthritis, osteoarthritis, septic shock and other diseases that can be treated by inhibiting phosphodiesterase-IV (PDE-IV) or Tumor Necrosis Factor ..

BACKGROUND OF THE INVENTION Phosphodiesterases regulate cyclic AMP concentrations. Phosphodiesterase IV has been shown to be the main regulator of cyclic AMP in non-striated respiratory muscle and in inflammatory cells (Trophy and Creslinski, Molecular Pharmacology 37: 206 (1990), Dent, et al., British Journal of Pharmacology, 90: 163 (1990)). PDE-IV inhibitors have been considered as prophylactic bronchodilator and asthma agents and as agents for inhibiting eosinophil accumulation and eosinophil function (eg, Giembycz and Dent, Clinical and Experimental Allergy, 22: 237 (1992)). ) and to treat other diseases and conditions characterized by, or having an etiology including, morbid eosinophilia. Inhibitors of phosphodiesterase-IV are also involved in the treatment of inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.

Excessive or irregular production of Tumor Necrosis Factor (TNF), a serum glycoprotein, has been implicated in the mediation or exacerbation of various diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.; sepsis, septic shock, anaphylactic shock, gram-negative sepsis, toxic shock syndrome, symptoms of respiratory distress in adults, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft reaction vs. host, allograft rejections, fever and myalgias due to infection, such as influenza, secondary cachexia due to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, tissue formation of scarring, Crohn's disease, ulcerative colitis or piresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosus.

TNF has played several roles in other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus and herpes virus.

TNF is also associated with yeast and fungal infections. Specifically, it has been shown that Candida albicans induces TNF production in vitro in human monocytes and natural killer cells [see Riipi, et al, Infection and Immunity, 58 (9): 2750-54 (1990) and Jafari, et al. ., Journal of Infectious Diseases. 162: 211-214 (1990)].

The Bencensulfonamide inhibitors of PDE-IV and TNF of the general formula: have been described in: International Patent Application WO 94/02465 describes inter alia compounds, of Formula I, wherein Ri represents an alkyl; R2 represents an alkyl or cycloalkyl; R3 represents H and R4 represents an aryl or a heteroaryl.

International Patent Application WO 95/35283 discloses compounds of Formula I, wherein R ^ represents H or even alkyl; R 2 represents an optionally substituted heterocycloaatic compound or an optionally substituted monocyclic or bicyclic aryl group; R3 is alkyl; R4 represents (Alk) t (X) nAr, where Alk is a long or branched chain alkyl, optionally substituted; optionally interrupted by an atom or a group X, where X is -O-, -S (O) m, or -N (Rb) -, (where Rb is a hydrogen atom or an optionally substituted alkyl group and m is zero or an integer of value 1 or 2 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from the oxygen, sulfur or nitrogen atoms.

International Patent Application WO 96/36611 discloses compounds of Formula I, wherein Ri represents a C 1-3 alkyl optionally substituted with halogen; R 2 represents an optionally substituted C 1-6 alkyl or optionally substituted cycloalkyl; R3 and R4, together with the hydrogen atom to which they are attached; they form a 6 or 7 membered heterocyclic ring, said ring is fused with an optionally substituted carboxylic, aryl, heteroaryl or heterocyclic ring.

International Patent Application WO 96/36595 discloses compounds of Formula I, wherein R 1 represents a C 1-3 alkyl optionally substituted with halogen; R 2 represents an optionally substituted C 1-6 alkyl or an optionally substituted cycloalkyl; R 3 represents an arylalkyl, a heteroarylalkyl, a heterocycloalkyl, COR 5, S (O) mR 5 or an optionally substituted C 1 - β alkyl (where R 5 represents an optionally substituted aryl, a heteroaryl, a heterocycle or an alkyl C ? _6 and m is zero, 1 or 2 and R4 represents an arylalkyl, a heteroarylalkyl or heterocycloalkyl.

International Patent Application WO 96/36596 discloses compounds of Formula I, wherein R 1 represents a C 1-3 alkyl optionally substituted with halogen; R 2 represents an optionally substituted C 1-6 alkyl or an optionally substituted cycloalkyl; R3 represents H, an arylalkyl, a heteroarylalkyl, a heterocycloalkyl, COR5, S (O) mR5 or an optionally substituted C1-6 alkyl (wherein R5 represents an optionally substituted aryl, a heteroaryl, a heterocycle or a Ci-β alkyl and m is zero, 1 0 2 and R 4 represents an optionally substituted 5 or 6-membered carbocyclic or a heterocyclic ring, said ring is fused with an optionally substituted aryl, a heteroaryl, a carbocyclic or a heterocyclic ring .

Despite the progress made, there is still a need for compounds that are useful for the treatment and intermediation of TNF and PDE-IV in mammals suffering from the diseases produced by them. This need is greater in terms of compounds that are relatively simple structurally speaking and, therefore, are easier to synthesize and, consequently, less expensive in their manufacture.

SUMMARY OF THE INVENTION The present invention comprises compounds of Formula I which are useful for treating diseases associated with proteins involved in cellular activity, for example, for inhibiting TNF and / or inhibiting PDE-IV. The present invention provides compounds that are simpler and relatively easier to produce than previously described compounds that inhibit PDE-IV or TNF. According to the invention, the compounds are of Formula I: wherein: R-i and R2 represent a lower alkyl or a cycloalkyl; R3 and R4 independently represent a C1-C4 alkyl, a cycloalkyl, C2-C4 alkenes having double bond, to C2-C4 alkenes having a triple bond, to (CH2) nCO (CH2) mCH3, to (CH2) ) PCN, al (CH2) pC0 Me or taken together with the nitrogen atom to which they are attached, form a ring of 3 to 10 members and pharmaceutically acceptable salts thereof; N and m are independently 0 to 3 and P is 1 to 3.

The invention also comprises pharmaceutical compositions and methods of using the compounds for the inhibition of PDE-IV and TNF, in vitro and in vivo.

The foregoing only summarizes certain aspects of the present invention and is not intended to limit the invention in any way. All patents or other publications referred to herein are incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION The present invention comprises inhibitors of PDE-IV and TNF of Formula I which are useful in vitro and in vivo. In vitro, these compounds are useful as research tools to inhibit TNF and PDE-IV for the study of the effects of such inhibition on systemic and cellular biological processes. In vivo, these compounds are useful for the treatment of diseases associated with TNF and PDE-IV. The present invention provides compounds that are simpler and relatively easier to produce than previously described compounds that inhibit PDE-IV or TNF. According to the invention, the compounds are of Formula I: wherein: R-i and R2 represent a lower alkyl or a cycloalkyl; R3 and R4 independently represent a C1-4 alkyl, a cycloalkyl, a C2- alkylene, a C2-4 alkyne, (CH2) nCO (CH2) mCH3, al (CH2) pCN, (CH2) PC? 2Me or taken together with the nitrogen atom to which they are attached, they form a ring of 3 to 10 members; n and m are 0 to 3; p is 1 to 3; and the pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include those in which Ri and R2 are ethyl, R3 is a C1.4 alkyl and R4 is a C2-4 alkene with a double bond.

As used herein, the terms "alkyl" and "lower alkyl", used alone or as part of another group, mean long or branched chain hydrocarbons having from 1 to 4 carbon atoms The term alkene means an alkyl group which contains at least one double bond The term "alkyne" means an alkyl group that "contains at least one triple bond. The cycloalkyl includes a non-aromatic cyclic or a multicyclic ring system of 3 to 10 carbon atoms.

The term "Intermediation of TNF in diseases" means any and all disease in which TNF plays a role, either in the production of TNF by itself or by TNF, causing another cytosine to be released, such as, but not limited to, IL-1 or IL-6. A disease in which IL-1, for example, is a major component and whose production or action is exacerbated or secreted in response to TNF, would be considered a disease caused by it. Since TNF-β (also known as lymphotoxin) has a structural homology similar to TNF-a (also known as cachectin) and since each induces similar biological responses and binds to the same cellular receptor, both TNF-a and TNF-β are inhibited by the compounds of the present invention and collectively referred to herein as "TNF" unless otherwise specified.

The viruses contemplated for the treatment referred to herein are those that produce TNF as a result of an infection or those that are sensitive to inhibition, by replication decreased, directly or indirectly, by the TNF inhibitors of Formula I. Such viruses include, but are not are limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and Herpes virus group, such as, but not limited to, Herpes zoster and Herpes simplex This application relates more specifically to a method for treating a mammal affected by the human immunodeficiency virus (HIV), which comprises administering to said mammal an effective amount of a compound of the Formula I or a pharmaceutically acceptable salt thereof, to inhibit TNF.

The compounds of this invention can also be used in association with a veterinary treatment, when there is a need to inhibit the production of TNF. Diseases caused by TNF in animals, in a therapeutic or prophylactic manner, include the aforementioned diseases, but in particular, viral infections. Examples of such viruses include, but are not limited to, feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anemia caused by viruses, caprine arthritis virus, visna virus, maedi virus and others. lentivirus.

The compounds of this invention are also useful in the treatment of infections by parasites, yeast and fungi, wherein such yeast and fungi are sensitive to high regulation by TNF or will produce TNF in vivo. A preferred disease for the treatment referred to herein is fungal meningitis.

This invention also comprises a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE-IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administration to said mammal of an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to inhibit PDE-IV or TNF.

PDE-IV inhibitors are useful in the treatment of a wide variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, inflammation of the eyes, allergic responses in the eyes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis, Crohn's disease, respiratory distress in adults, diabetes insipidus, keratosis, atopic dermatitis, atopic eczema, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, fulminant attack and intermittent claudication. Additionally, PDE-IV inhibitors can be used as gastroprotectors.

A preferred embodiment of the therapeutic methods of the present invention is the treatment of asthma.

The compounds of Formula I are preferably in a pharmaceutically acceptable form. By pharmaceutically acceptable form is understood, inter alia, a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives, such as diluents and carriers and without including any material considered toxic at normal dose levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and even more preferably 95% A process for the preparation of a compound of Formula I comprises the reaction of an appropriate sulfonyl chloride of Formula II with a suitable amine of Formula III.

(II) (the) wherein R1a represents Ri as defined in relation to Formula I or a group convertible to Ri and R2a-R4a represent similarly R2-R4 or groups convertible to R2-R4 respectively and therefore, if required, convert any group R a to R 1 and / or R 2a to R 2 and / or R 3a to R 3 and / or R 4a to R 4.

The reaction of a sulfonyl chloride of the Formula II with a compound of the Formula III can be carried out under any of the appropriate conditions known to those skilled in the art. When the compound (iii) is an amine, the reaction is favorably carried out in the presence of a suitable base, for example, an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.

Alternatively, the substituents R3a and R4a can be added sequentially in a two-step process. This alternative process for preparing a compound of Formula la, comprises the reaction of a suitable sulfonyl chloride of Formula II with a suitable primary amine of Formula VI and the reaction of the resulting sulfonamide VII with a compound of Formula VIII ( for example, an alkyl halide, wherein X is a residual group such as chlorine or bromine) and a base such as sodium hydride.

(VII) (VIII) (IA) The sulfonyl chlorides of Formula II are commercially available and can also be prepared using standard procedures known to those skilled in the art. For example, a sulfonyl chloride is conveniently prepared from the appropriate sulfonic acid (IV) by reaction with a suitable chlorinating agent such as thionyl chloride or oxalyl chloride. A suitable sulfonic acid can be prepared from a compound of Formula (V) by sulfonation, using a suitable sulfonating agent, for example, chlorosulfonic acid. Alternatively, a sulfonyl chloride of Formula II can be prepared directly from a compound of Formula V, by using it in excess of chlorosulfonic acid.

The compounds of Formula V are commercially available or can be prepared by standard procedures known to those skilled in the art.

In some cases, the compounds of Formula III are amides (due to the inclusion of a carbonyl group in R3, R4, R3a or R4a) and in them, their reaction with a sulfonyl chloride requires a stronger base, such as sodium hydride and a polar solvent, favorably, N, N-dimethylformamide.

(") The present invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable dissolving agent thereof and a pharmaceutically acceptable carrier.

The active compound can be formulated for administration by any suitable route, the preferred route depending on the disorder for which the treatment is required and is preferably in the form of a unit dose or in a form such that a human patient can administer it in a single dose. . As an advantage, the composition is suitable for oral, rectal, topical or parenteral administration, or through the respiratory tract. The preparations can be designed to provide a slow and controlled release of the active ingredient.

The term "parenteral" used in this document includes subcutaneous, intravenous, intramuscular, intransternal injections or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc .; The compounds of the invention are also effective in the treatment of humans.

The compositions of the invention may be in the form of tablets, capsules, sachets, ampules, powders, granules, lozenges, suppositories, reconstituting powders or liquid preparations such as parenteral, oral or sterile solutions or suspensions. Topical formulations can also be used where appropriate, for example, in transdermal patch systems, lotions and creams.

In order to obtain consistency in administration, it is preferred that a composition of the invention be in unit dosage form.

The unit dosage forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example, acacia, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone. Fillers may be used, for example, microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine. Lubricants can be used for the formation of the tablets, for example, magnesium stearate, as well as disintegrants, for example, starch, polyvinylpyrrolidone, sodium glycolate starch or microcrystalline cellulose and pharmaceutically acceptable wetting agents such as lauryl. sodium sulfate.

Oral solid compositions can be prepared by conventional mixing, filling and tabletting methods or the like.

Repetitive mixing operations can be used to distribute the active agent in all those compositions that employ large amounts of fillers.

Such operations are, of course, conventional in the art. The tablets can be coated in accordance with methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The liquid oral preparations may be in the form of, for example, emulsions, syrups or elixirs or may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, edible hydrogenated fats, emulsifying agents, for example, lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oleaginous esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives, for example propyl or methyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents.

The compositions may also be prepared for administration in the respiratory tract, for example, as a powder or aerosol or solution for a nebulizer or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the active compound have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example, from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns . When appropriate, small amounts of other antiasthmatics and bronchodilators, for example sympathomimetic amines, such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine or corticosteroids such as prednisolone and adrenal stimulants such as ACTH, may be included For parenteral administration, fluid unit dose forms are prepared using a compound of Formula I and a sterile vehicle and, depending on the concentration used, can be suspended or dissolved in the vehicle. In preparing the solutions, the active compound can be dissolved in water for injection and filtered sterilized before filling for administration by any appropriate route or ampule and finally sealed.

As an advantage, they can dissolve in the vehicle; a local anesthetic, a preservative and stabilizing agents. To improve the stability, the composition can be frozen for later filling in the selected way and the water can be removed under vacuum. Parenteral suspensions are prepared substantially in the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization can not be carried out by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in a sterile vehicle. Another advantage resides in the fact that, a surfactant or wetting agent is included in the composition to facilitate the uniform distribution of the compound.

The compositions may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration.

The compounds of Formula I or if appropriate, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable dissolving agent thereof, can also be administered as a topical formulation in combination with conventional topical excipients.

Topical formulations may be presented as, for example, ointments, creams or lotions, impregnated bandages, gels, stick gels, sprays and aerosols and may contain appropriate conventional additives such as preservatives, solvents to aid in the penetration of the drug and emollients in Ointments and creams. The formulations may contain conventional compatible carriers, such as bases for creams or ointments and ethanol or oleyl alcohol for lotions.

Suitable formulations of creams, lotions, gels, stick gels, ointments, sprays and aerosols that can be used for the compounds of Formula I (or, if appropriate, a pharmaceutically acceptable salt or pharmaceutically acceptable dilution agent thereof) are formulations conventional ones well known in the art, for example, as described in standard textbooks such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences and the British and American Pharmacopoeias.

The compound of Formula I, or if appropriate, a pharmaceutically acceptable salt or diluting agent thereof, will mean from about 0.5% to about 80% by weight of the formulation, typically from about 1% to about 50% and ideally from about 5% to about 20%.

The dose of the compound used in the treatment of the invention will vary in the usual way with respect to the type of disorder in question, the weight of the sufferer and the relative efficacy of the compound. However, in the form of a general guide; an appropriate unit dose may be from 0.1 to 500 mg, for example, 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example; 0.5.1, 2, 3, 4 or 5 mg and such dose units can be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day , so that the total daily dose for a 70 kg adult is within the range of 0.1 to approximately 10.0 mg / kg / day, such as 0.1 to 8.0 mg / kg / day, for example 1 or 2 mg / kg / day and such therapy can be extended to several weeks or months.

As used herein, the term "pharmaceutically acceptable" encompasses materials suitable for both veterinary and human uses.

The following examples are provided for illustrative purposes only and are not intended in any way to limit the invention. Those skilled in the art will appreciate that various modifications and variations thereof may be made, without departing from the spirit or scope of the present invention and appended claims.

EXAMPLE 1 N-.2-Propynyl) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 104-105 ° C 3,4-Dimethoxybenzene sulfonyl chloride (11.8 g) in tetrahydrofuran (100 ml) was added slowly with stirring to a mixture of N-methylpropargylamine (3.5 g), triethylamine (5.05 g) and tetrathydrofuran (100 ml). The resulting mixture was refluxed 1 hour, cooled, filtered and evaporated to dryness. The residue was treated with water, filtered, washed with water and dried. Recrystallization from ethanol gave 8.7 g of the product mentioned in the title of this example.

The following compounds were prepared by the same method from the 3,4-dimethoxybenzene sulfonyl chloride and the corresponding amine: EXAMPLE 2 N, N-Dimethyl-3,4-dimethoxybenzenesulfonamide: melting point 114-115 ° C EXAMPLE 3 N, N-Diethyl-3,4-dimethoxybenzenesulfonamide: melting point 96-98 ° C EXAMPLE 4 N, N-Dipropyl-3,4-dimethoxybenzenesulfonamide: melting point 46-47 ° C EXAMPLE 5 N, N-Di- (2-propenyl) -3,4-dimethoxybenzenesulfonamide: melting point 68-69 ° C EXAMPLE 6 N, N-D-methyl-3,4-diethoxy-benzenesulfonamide: melting point 100-102 ° C EXAMPLE 7 N- (3,4-Dimethoxybenzenesulfonyl) piperidine: melting point 99-100 ° C EXAMPLE 8 N- (3,4-dim? Toxibennesulfonyl) pyrrolidine: melting point 129-130 ° C EXAMPLE 9 N- (3,4-dimethoxybenzenesulfonyl) cyclohexylamine: melting point 99-100 ° C EXAMPLE 10 N- (2-Propinyl) -N-methyl-3,4-diethoxybenzenesulfonamide: melting point 69-70 ° C EXAMPLE 11 N-Ethyl-N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 71-72 ° C Sodium hydride (2.1 g) was added with stirring to a solution of 3,4-dimethoxybenzene-sulfonamide (11.55 g) in dimethylformamide (100 g). ml). The mixture is cooled to 15 ° C and ethyl iodide (7.8 g) is added with stirring. The solution is stirred at room temperature for 5 hours, heated in a steam bath for 30 minutes and concentrated in vacuo. The residue is triturated with water, filtered, washed with water and dried to give 7.52 g of the title product of this example. The following compounds are prepared by the same method from 3,4-dimethoxybenzene-methyl-sulfonamide or from 3,4-diethoxybenzene-sulfonamide and the corresponding halide XR4a: EXAMPLE 12 N-Propyl-N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 84-85 ° C EXAMPLE 13 N-Butyl-N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 79-80 ° C EXAMPLE 14 N- (2-Methylethyl) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 93-94 ° C EXAMPLE 15 N- (2-Propenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 44-46 ° C EXAMPLE 16 N- (2-Butenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 93-94 ° C EXAMPLE 17 N- (2-Propenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 61-62 ° C EXAMPLE 18 N- (3-Propylnitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 90-92 ° C EXAMPLE 19 N-.4-Butylnitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 50-52 ° C EXAMPLE 20 N-Met l-N- (2-Oxopropyl) -3,4-dimethoxybenzenesulfonamide: mp 95-96 ° C EXAMPLE 21 N-Methyl-N- (3-Oxopentyl) -3,4-dimethoxybenzenesulfonamide: melting point 94-96 ° C EXAMPLE 22 Ethyl-N- (carboxymethylene) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 94-96 ° C EXAMPLE 23 N- (methylene-nitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide: melting point 101-103 ° C.

EXAMPLE 24 N- (methylene-nitrile.-N-methyl-3,4-diethoxy-benzenesulfonamide: melting point 95-97 ° C. Procedure for the PDE-IV test.

The representative compounds to be tested were diluted in 96 crucibles. The compounds were received either as a 10 mM solution in DMSO or as a solid that was resuspended at a concentration of 10 mM in DMSO. The compounds were initially tested at 10, 3, 1, 0.3 and 0.1 μM to calculate an IC50. In some cases, the crucibles containing diluted compounds were frozen before being tested. In such cases, the compounds were melted for 15 minutes at 37 ° C and agitated before proceeding.

Two microliters of the compounds diluted in Rolipram were marked in a test crucible. Ninety-eight microliters of the reaction mixture containing the PDE-IV enzyme were added to each of the crucibles. Subsequently, the crucible was stirred for 2 minutes at a settling of 3.5 in a vortex and incubated for 1 hour at 37 ° C. The reaction was terminated with 50 μL of 0.5X SPA beads and the reaction tray was incubated at room temperature for 20 minutes before the radioactivity was measured using standard instrumentation.

The reaction mixture contained 35.2 mM Tris, pH 8.0, 9.4 mM MgCl 2, 4 mM β-mercaptoethanol, 200 nM cAMP, 8 nM 3 H-cAMP, 2% DMSO, 1% U937 lysate (from ABS). The reaction mixture was prepared by adding 87 Ml of H2O to 10 mL of 10 X Test Stabilizer, 40 μL 1 μCi / μL3H-cAMP, 20 μL of IMAM cAMP (new cAMP solution, prepared each time it was to be used) and 1 mL of U937 cellular lysate. The 10X test stabilizer was prepared by mixing 400 mM Tris Base with 400 mM Tris HCl at a pH of 8.0, adding 100 mL of this stabilizing solution Tris, 1.017g of MgC, 319 μL of β-mercaptoethanol, the 0.5X SPA beads were prepared by adding 500 mg of beads to 56 mL of H2O for a final concentration of 8.9 mg / mL of beads and 9 mM of zinc sulfate.

The results are shown in the following table: Table of Inhibition of PDE-IV Example PDE-IV Example PDE-IV (ICsoμM) (ICsoμM) 4 0.46 11 0.7 5 0.45 12 0.47 6 0.28 15 0.66 7 3.6 16 1.56 8 3.2 17 0.02 9 2.2 23 1.76 10 0.17

Claims (1)

CLAIMS 1. A method for inhibiting PDE-IV or TNF comprising the contact * of a cell with a compound of the general formula: where: Ri and R2 represent a C1-C4 alkyl or a C3-C10 cycloalkyl; R3 and R4 independently represent a C1-4 alkyl, a cycloalkyl, C2-C4 alkenes having a double bond, C2-C4 alkynes having a triple bond, to (CH2) nCO (CH2) mCH3, al ( CH2) pCN, to (CH2) PCO2Me, or taken together with the nitrogen atom to which they are attached, form a ring of 3 to 10 members; n and m are 0 to 3; p is 1 to 3 and the pharmaceutically acceptable salts thereof. A method according to claim 1, wherein R-i and R2 are independently a C1-C4 alkyl. A method according to claim 1, wherein R1 and R2 are ethyl. A method according to claim 1, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. A method according to claim 2, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. A method according to claim 3, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. A method according to claim 1, selected from the group consisting of: N- (2-Propinyl) -N-methyl-3,4-dimethoxybenzenesulfonamide, N, N-Dimethyl-3,4-dimethoxybenzenesulfonamide, N, N- Diethyl-3,4-dimethoxybenzenesulfonamide, N, N-Dipropyl-3,4-dimethoxybenzenesulfonamide, N, ND- (2-Propenyl) -3,4-dimethoxybenzenesulfonamide, N, N-Dimethyl-3,4-diethoxybenzenesulphonamide, N- (3,4-dimethoxybenzenesulfonyl) piperidine, N- (3,4-dimethoxybenzenesulfonyl) pyrrolidine, N- (3,4-dimethoxybenz-Tnsulfonyl) cyclohexylamine, N - (2-Propinyl) -N-methyl-3,4-diethoxybenzenesulfonamide, N-Ethyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N-Propyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N-Butyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-Methylethyl) ) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-Propenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-Butenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-Propenyl) -N-methyl-3,4-diethoxybenzenesulfonamide, N- (3-Propylnitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (4-Butylnitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide, N-MTethyl-N- (2-Oxopropyl) -3,4-dimethoxybenzenesulfonamide, N-Methyl-N- (3-Oxopentyl) -3,4-dimethoxybenzenesulfonamide, Ethyl N- (carboxymethylene) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (methylene-nitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide and N- (methylene-nitrile) -N-methyl-3,4-diethoxybenzenesulfonamide. 8. A pharmaceutical composition comprising a compound of the general formula: wherein: Ri and R represent a lower alkyl or a cycloalkyl; R3 and R4 independently represent a C1-4 alkyl, a cycloalkyl, C2-C4 alkenes having a double bond, C2-C4 alkynes having a triple bond, to (CH2) nCO (CH2) mCH3, al ( CH2) pCN, to (CH2) pCO2Me, or taken together with the nitrogen atom to which they are attached, form a ring of 3 to 10 members; n and m are 0 to 3; p is 1 to 3 and the pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition according to claim 8, wherein R-i and R2 are independently a C1-C4 alkyl. 10. A pharmaceutical composition according to claim 8, wherein Ri and R2 are ethyl. 11. A pharmaceutical composition according to claim 8, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. 12. A pharmaceutical composition according to claim 9, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. 13. A pharmaceutical composition according to claim 10, wherein R3 and R4 independently represent a C1-C4 alkyl, C2-C4 alkenes having a double bond or C2-C4 alkynes having a triple bond. 14. A pharmaceutical composition according to claim 8, comprising a compound selected from the group consisting of: N- (2-Propinyl) -N-methyl-3,4-dimethoxybenzenesulfonamide, N, N-Dimethyl-3,4-dimethoxybenzenesulfonamide , N, N-Diethyl-3,4-dimethoxybenzenesulfonamide, N, N-Dipropyl-3,4-dimethoxybenzenesulfonamide, N, N-Di- (2-Propenyl) -3,4-dimethoxybenzenesulfonamide, N, N-Dimethyl-3 , 4-diethoxybenzenesulfonamide, N- (3,4-dimethoxybenzenesulfonyl) piperidine, N- (3,4-dimethoxybenzenesulfonyl) pyrrolidine, N- (3,4-dimethoxybenzenesulfonyl) cyclohexylamine, N- (2-propynyl) -N- methyl-3,4-diethoxybenzenesulfonamide, N-Ethyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N-Propyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N-Butyl-N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-MethylThyl) -N-methyl-3,4-dimethoxybenthenesulfonamide, N- (2-Propenyl) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (2-Butenyl) -N-methyl- 3,4-dimethoxybenzenesulfonamide, N- (2-Propenyl) -N-methyl-3,4-diethoxybenzenesulfonamide, N- (3-Propyltromethyl) -Nm ethyl-3,4-dimethoxybenzenesulfonamide, N- (4-Butylnitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide, N-Methyl-N- (2-Oxopropyl) -3,4-dimethoxybenzenesulfonamide, N-Methyl-N- (3-Oxopentyl) -3,4-dimethoxybenzenesulfonamide, Ethyl-N- (carboxymethylene) -N-methyl-3,4-dimethoxybenzenesulfonamide, N- (methylene-nitrile) -N-methyl-3,4-dimethoxybenzenesulfonamide and N- (methylene-nitrile) -N-methyl-3,4-diethoxybenzenesulfonamide. 15. A method for treating a disease associated with a function of PDE-IV, eosinophilic accumulation or an eosinophil function, comprising administering to a patient suffering from such a disease, an effective amount of a pharmaceutical composition in accordance with claim 8 16. A method for treating a disease associated with a function of PDE-IV, eosinophilic accumulation or an eosinophil function, comprising administering to a patient suffering from such disease, an effective amount of a pharmaceutical composition in accordance with claim 11. 17. A method for treating a disease associated with a function of PDE-IV, eosinophilic accumulation or an eosinophil function, comprising administering to a patient suffering from such a disease, an effective amount of a pharmaceutical composition in accordance with claim 14 18. The method according to claim 15, wherein the disease is a pathological condition capable of being modified by the inhibition of PDE-IV. The method according to claim 15, wherein the pathological condition is selected from asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, inflammation of the eyes, allergic responses of the eyes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis, Crohn's disease, respiratory distress in adults, diabetes insipidus, keratosis, eczema atopic, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, fulminant attack and intermittent claudication. The method according to claim 15, wherein the pathological condition is asthma. A method for treating a disease capable of being modified by inhibiting TNF, comprising administering to a patient suffering from such a disease, an effective amount of a pharmaceutical composition according to claim 8. A method for treating a disease capable of being modified by inhibiting TNF, comprising administering to a patient suffering from such a disease, an effective amount of a pharmaceutical composition according to claim 11. 23. A method for treating a disease capable of being modified by inhibiting TNF, comprising administering to a patient suffering from such a disease, an effective amount of a pharmaceutical composition according to claim 14. 24. The method according to claim 21, wherein the disease is an inflammatory disease or an autoimmune disease. 25. The method of claim 21, wherein the disease is selected from: inflammation of the joints, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, asthma, bone resorptive diseases, reperfusion injury, graft vs. host reaction, graft rejection, fever and myalgia due to infection, such as influenza, malignant myalgias, HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis , systemic lupus erimatoso, multiple sclerosis, type 1 diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purple nephritis, chronic glomerulonephritis, inflammatory bowel disease and leukemia. 26. The method according to claim 21, wherein the disease is inflammation of the joints. 27. The method according to claim 15 or claim 21, wherein the disease is tardive dyskinesia. 28. The method of claim 21, wherein the disease is a yeast or fungal infection. 29. A method for gastroprotection, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 8. 30. A method for gastroprotection, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 11.

1. A method for gastroprotection, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 14. \