Benzenesulfon amide-compound treatment of a pathological condition linked to an excessive effect of TNF

1. A method for inactivating TNF-alpha to treat a non-cancer pathology linked to an excessive effect of TNF-alpha, comprising administering to a patient in need thereof:

(i) a sulphonated compound of formula I

in which

• R1 represents

Φ a —CHR4-CO—R3 group, in which

R4 represents a hydrogen atom or a C1-C5 alkyl and

R3 represents an organic group, said organic group comprising 11 or more than H and containing from 6 to 30 carbon atoms including one or more rings or heterocycles, saturated or unsaturated, fused or not, unsubstituted or substituted by one or more substituents chosen from the C1-C5 alkyl, C1-C5 alkenyl, halo, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulphonyl, acyl, hydroxy, NH2, nitro, C1-C5 alkylamino, di(C1-C5 alkyl)amino, acylamino radicals, said organic group not being linked to the carboxyl by a —NH—CH2— group or by a —NH—CH-alk-group where alk represent an alkyl radical with 1 to 5 carbon atoms, said organic group not comprising a

 group in which m represents 0, 1 or 2, a, b and c represent CR, where each R represents independently a hydrogen or a C1-C4 alkyl,

R1 represents a C1-C4 alkyl or a C3-C7 cycloalkyl, said organic group not comprising a —CO—NHOH group, said organic group not representing a

 group in which n=1 or 2 and R1 represents H, halogen, CN, lower alkyl or alkoxy, optionally substituted by a halogen,

Φ a benzofuran group, unsubstituted or substituted by one or more substituents chosen from the C1-C5 alkyl, C1-C5 alkenyl, halo, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulphonyl, acyl, hydroxy, NH2, nitro, C1-C6 alkylamino, di(C1-C6 alkyl)amino, acylamino radicals,

Φ a hydrogen atom,

Φ a group chosen from

• R2 represents

Φ a phenyl or C4-C7 cycloalkyl group unsubstituted or substituted by one or more substituents chosen from the C1-C5 alkyl, C1-C5 alkenyl, halo, C3-C8 cycloalkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylsulphonyl, acyl radicals except for —CO NHOH, hydroxy, NH2, nitro, C1-C6 alkylamino, di(C1-C6 alkyl)amino radicals; two substituents in meta position relative to one another being able to form a ring, said group being directly linked to the nitrogen, or linked by a —(CH 2 ) n — group where n=1, 2 or 3,

Φ a hydrogen atom,

it being understood that R1 and R2 cannot at the same time represent hydrogen,

• X represents a hydrogen atom or one or more substituents chosen from the C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkenyl, halo, C3-C8 cycloalkyl, C1-C5 alkylthio, C1-C5 alkylsulphonyl, acyl, hydroxy, NH2, nitro, C1-C6 alkylamino, di(C1-C6 alkyl)amino, acylamino radicals, it being understood that X is not a 3,4-dialkoxy or a 3,4-dialkylthio,

with the proviso that the sulphonated compound of formula I is not N—[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]—N—(3,4-dimethylphenyl)-4-methylbenzenesulphonamide;

(ii) a compound of formula I below for which R2=H:

the compound for which

the compound for which

the compound for which

the compound for which

the compound for which

or

(iii) 3-(3-phenoxyphenyl)-2-(phenylsulphonyl)—N—(3-pyridinylmethyl) acrylamide,

or an addition salt of (i), (ii) or (iii) with pharmaceutically acceptable acid it being understood that

if R1=H and X is a 3-nitro,4-chloro, R2 is not a benzyl radical,

if R1=H, R2 is not a 3,4-dimethoxy phenethyl,

if R1=H and X=H or alkyl optionally substituted at position 4, R2 is not an optionally substituted phenyl radical.

2. The method of claim 1 , wherein the non-cancer pathology linked to an excessive effect of TNF-alpha is selected from the group consisting of an inflammatory disease of the intestine, inflammation, chronic inflammatory diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, arthrosis, refractory rheumatoid arthritis, non-rheumatoid chronic arthritis, bone resorption/osteoporosis, Crohn's disease, haemorrhagic rectocolitis, septic shock, endotoxin shock, atherosclerosis, ischaemia-reperfusion lesions, coronary heart disease, vasculitis, amydoloidosis, multiple sclerosis, septicaemia, chronic recurrent uveitis, hepatitis C virus, malaria, ulcerative colitis, cachexia, psoriasis, endometriosis, Behçet's disease, Wegener's granulomatosis, meningitis, AIDS, HIV infections, auto-immune diseases, immunodeficiency, common variable immunodeficiency (CVID), chronic graft-versus-host diseases, trauma and graft rejections, respiratory distress syndrome, pulmonary fibrosis, diabetes, juvenile diabetes, ankylosing spondylitis, and skin disorders due to delayed-type hypersensitivity reactions, Alzheimer's disease, disseminated lupus erythematosus, and allergic asthma, and an inflammatory diseases for which the anti-TNF biotherapies (monoclonal antibodies, soluble receptors) are effective.

3. The method of claim 1 , wherein, in the sulphonated compound,

R1 represents a —CHR4-CO—R3 group, in which

R4 represents a hydrogen atom or a C1-C5 alkyl and

R3 has the meanings already indicated in claims 1 and

R 2 and X have the meaning already indicated in claim 1 ,

or one of its addition salts with pharmaceutically acceptable acids.

4. The method of claim 1 , wherein, in the sulphonated compound,

R1 represents a —CHR4-CO—R3 group, in which R3 and R4 have the meaning already indicated,

R2 represents an optionally substituted phenyl group, said phenyl group being directly linked to the nitrogen, or linked by a —(CH 2 )— group, and

X has the meaning already indicated,

or one of its addition salts with pharmaceutically acceptable acids.

5. The method of claim 1 , wherein, in the sulphonated compound,

R1 represents a —CHR4-CO—R3 group, in which

R4 represents a hydrogen atom or a C1-C5 alkyl and

R3 represents a

 group in which m has the value 0, 1 or 2, Z has the meaning N or CH, and Ar represents an optionally substituted aryl radical,

R2 represents an optionally substituted phenyl group, said phenyl group being directly linked to the nitrogen, or linked by a —(CH 2 )— group, and

X has the meaning already indicated,

or one of its addition salts with pharmaceutically acceptable acids.

6. The method of claim 1 , wherein, in the sulphonated compound,

R1 represents a —CHR4-CO—R3 group in which

R4 represents a hydrogen atom or a C1-C5 alkyl and

R3 represents a

 group in which m has the value 0, 1 or 2, Z has the meaning N or CH, and Ar represents an optionally substituted aryl radical, and

R2 and X have the meaning already indicated,

or one of its addition salts with pharmaceutically acceptable acids.

7. The method of claim 1 , wherein, in the sulphonated compound,

R1 represents an optionally substituted benzofuran or naphthofuran group

R2=H and

X has the meaning already indicated,

or one of its addition salts with pharmaceutically acceptable acids.

8. The method of claim 1 , wherein the compound administered is selected from the sulphonated compounds consisting of:

1—N-(3-acetyl-2-methylnaphthho[1,2-b]furan-5-yl)-4-ethoxybenzene sulphonamide;

2—N-(3-acetyl-2,6-dimethyl-1-benzofuran-5-yl)-4-methoxybenzene sulphonamide;

3—N-benzyl-4-methoxy-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}-3-methylbenzenesulphonamide;

4—methyl 1-(2-fluorophenyl)-2-methyl-5-oxo-4-[(5-{[(phenylsulphonyl)amino]methyl}-2-furyl)methylene]-4,5-dihydro-1H-pyrrole-3-carboxylate;

5—methyl 5-{[(4-methoxyphenyl)sulphonyl]amino}-2-methyl-1-benzofuran-3-carboxylate;

6—N-(1′,2-dihydroxy-1.2′-binaphthhalen-4′-yl)-4-methoxybenzene-sulphonamide;

7—N-2-(3-chlorobenzyl)-N-1-(2,4-dimethoxyphenyl)-N-2-[(4-methylphenyl)sulphonyl]glycinamide;

8—3-(4-fluorophenyl)-4-oxo-4H-chromen-7-yl N-[(4-methylphenyl)sulphonyl]-beta-alaninate;

9—methyl 2-methyl-5-{[(4-methylphenyl)sulphonyl]amino}-1-benzofuran-3-carboxylate;

10—5-[4-(benzylamino)-1-phthalazinyl]-2-methyl-N-(tetrahydro-2-furanylmethyl)benzenesulphonamide;

11—N-(1,2-dihydro-5-acenaphthhylenyl)-2.4,6-trimethylbenzenesulphonamide;

12—N-1-(3-acetylphenyl)-N-2-(2,5-dimethoxyphenyl)-N-2-[(4-methylphenyl)sulphonyl]glycinamide; and

an addition salt thereof with pharmaceutically acceptable acid.

9. The method of claim 1 , wherein the compound administered is a benzene sulphonamide selected from the consisting of:

13—N-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-N-(3-chlorophenyl)-4-methyl benzenesulphonamide;

14—N-benzyl-4-chloro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulphonamide;

15—N-benzyl-4-bromo-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulphonamide;

16—N-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-N-(4-chlorophenyl)-4-methyl benzenesulphonamide;

17—N-benzyl-4-methoxy-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}-3-methylbenzenesulphonamide;

18—N-benzyl-4-methyl-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulphonamide;

19—N-{2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-N-(4-methylbenzyl) benzenesulphonamide;

20—4-chloro-N-(4-fluorobenzyl)-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulphonamide;

22—N-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-N-(3-chloro-2-methylphenyl)benzenesulphonamide;

23—4-chloro-N-(3,4-dichlorobenzyl)-N-[2-(4-methyl-1-piperidinyl)-2-oxoethyl]benzenesulphonamide;

24—N-benzyl-4-fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl}benzenesulphonamide;

25—N-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-N-(3,5-dimethylphenyl)-4-methylbenzenesulphonamide;

26—N-benzyl-N-{2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-4-methoxybenzenesulphonamide;

27—N-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethyl]-N-(3,5-dimethylphenyl)-3,4-dimethoxybenzenesulphonamide;

28—3,4-dimethoxy-N-(4-methylphenyl)-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulphonamide;

29—N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-N-(4-methylbenzyl)benzenesulphonamide;

30—N-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-N-(4-fluorophenyl)-4-methylbenzenesulphonamide;

31—N-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-methyl-N-(2-methylphenyl)benzenesulphonamide;

32—N-benzyl-N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-4-methylbenzenesulphonamide;

33—N-(3-chlorophenyl)-4-methyl-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulphonamide;

34—N-benzyl-N-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-3,4-dimethoxybenzenesulphonamide;

35—N-{2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethyl}-N,4-dimethyl benzenesulphonamide

36—N-(3-nitrophenyl)-N-[2-oxo-2-(4-phenyl-1-piperazinyl)ethyl]benzenesulphonamide: and

an addition salt thereof with pharmaceutically acceptable acid.

10. The method of claim 8 , wherein th sulphonated compound administered is a benzene sulphonamide compound bearing the number 1 or 2, or one of its additional salts with pharmaceutically acceptable acids.

11. The method of claim 1 , wherein the compound, or an addition salt thereof with a pharmaceutically acceptable acid, administered is an active ingredient in a pharmaceutical composition which further comprises a compound having anti-TNF-alpha properties of a different kind, or an addition salt thereof with a pharmaceutically acceptable acid, and one or more pharmaceutically acceptable excipients.

12. The method of claim 9 , wherein the sulphonated compound administered is a benzene suplhonamide compound bearing the number 13, 14, 15, 16, 18, 19 or 22, or one of its addition salts with pharmaceutically acceptable acids.

13. The method of claim 12 , wherein the benzene supohonamide compound is bearing the number 13, 14 and 16, or one of its addition salts with pharmaceutically acceptable acids.