Drugs for the arthritis treatment

1 . Use for the preparation of disease-modifying drugs drugs for the prevention and treatment of arthritis therapy of compounds or salts thereof having the following general formula:

A-(B) b0 —(C) c0 —N(O) S   (I)

wherein:

s is an integer and is equal to 1 or 2, preferably 2;

c0 is an integer and is equal to 0 or 1;

b0 is an integer and is 0 or 1; with the proviso that at least one between c0 and b0 is different from zero;

A=R-T 1 -, wherein

R— is the radical of a non steroidal antiinflammatory precursor drug excluding the compounds having 2-oxo-1H-indolic structure, or the radical of a non steroidal antiinflammatory/analgesic drug;

T 1 =(CO) t or (X) t′ , wherein X=—O—, —S—, —N(R 1C )—, R 1C is H or C 1 -C 5 linear or branched alkyl, t and t′ are integers and equal to zero or 1, with the proviso that t=1 when t′=0; t=0 when t′=1;

B=-T B -X 2 -T BI - wherein

T B and T BI are equal or different;

T B =(CO) when the reactive function in the precursor drug is —OH or —NH(R 1C ); T B =X, as above, when the reactive function in the precursor drug is —COOH;

T BI =(CO) tx or (X) txx , wherein tx and txx have the value of 0 or 1; with the proviso that tx=1 when txx=0, tx=0 when txx=1; X is as above;

X 2 is a bivalent linking group as defined below;

C is the bivalent radical -T C -Y— wherein

when b0=c0=1: T C =(CO) when tx=0, T C =X when txx=0, X being as above;

when b0=0: T C =(CO) when t=0, T C =X when t′=0, X being as above;

when c0=0: tx=0, T BI =X=—O—.

Y is:

Y p :

wherein:

nIX is an integer from 0 to 10, preferably from 1 to 3;

nIIX is an integer from 1 to 10, preferably from 1 to 3;

R TIX , R TIX′ , R TIIX , R TIIX′ , equal to or different from each other are H or C 1 -C 4 linear or branched alkyl; preferably R TIX , R TIX′ , R TIIX , R TIIX′ are H.

Y 3 is a saturated, unsaturated or aromatic heterocyclic ring containing one or two nitrogen atoms having 5 or 6 atoms,

or Y can be:

Y 0 , selected from the following:

a —R′O— alkylenoxy group wherein R′ is linear or branched when possible C 1 -C 20 , preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R′ type, R′ being as above; or one of the following groups:

wherein nf′ is an integer from 1 to 6 preferably from 1 to 4;

wherein R 1f =H, CH 3 and nf′ is an integer from 1 to 6;

preferably from 1 to 4;

or Y is Y Ar and is selected from the following:

wherein n3 is an integer from 0 to 3 and n3′ is an integer from 1 to 3;

wherein n3 and n3′ have the above meaning;

X 2 , bivalent radicalm is such that the corresponding precursor of B, -T B -X 2 -T BI - wherein the free valences of T B and of T BI are saturated each with OZ, with Z or with —N(Z I )(Z II ), wherein Z=H, C 1 -C 10 , preferably C 1 -C 5 linear or branched when possible alkyl, Z I , Z II equal or different have the Z values as above, depending on that T B and/or T BI =CO or X, in function of the values of t, t′, tx and txx;

the precursor of B is selected from the following:

aminoacids,

hydroxyacids,

aromatic and heterocyclic mono- and polyalchols,

compounds containing at least one free acid function.

2 . Use according to claim 1 , wherein the precursor of B is selected from the following:—aminoacids selected from the following: L-carnosine (formula CI), anserine (CII), selenocysteine (CIII), selenomethionine (CIV), penicillamine (CV), N-acetylpenicillamine (CVI), cysteine (CVII), N-acetylcysteine (CVIII), glutathione (CIX) or esters thereof, preferably ethyl or isopropyl ester:

hydroxyacids, selected from the following: gallic acid (formula DI), ferulic acid (DII), gentisic acid (DIII), citric acid (DIV), caffeic acid (DV), dihydrocaffeic acid (DVI), p-cumaric acid (DVII), vanillic acid (DVIII):

aromatic and heterocyclic mono- and polyalcohols, selected from the following: nordihydroguaiaretic acid (EI), quercetin (EII), catekin (EIII), kaempferol (EIV), sulphurethyne (EV), hydroquinone (EVIII), gossypol (EIX), reductic acid (EX), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), propyl gallate (EXIII), 3,5-di-ter-butyl-4-hydroxybenzyl-thioglycolate (EXXIV), allopurinol (EXXXI); saccharose (EC), ascorbic (ECI) and isoascorbic acid (ECII), p-cumaric alcohol (ECIII), 4-hydroxy-phenylethylalcohol (ECIV), coniferyl alcohol (ECV):

compounds containing at least one free acid function, selected from the following: 3,3′-thiodipropionic acid (NI), fumaric acid (NII), dihydroxymaleic acid (NIII), edetic acid (NV):

3 . Use according to claim 1 , wherein in the compounds of formula (I) when b0=c0=1, the bonds between the drug radical and X 2 and between X 2 and Y are, independently the one from the other, of ester, thioester, amide type;

when b0=0 and c0=1 the bond between the drug radical and Y is of ester, thioester, amide type.

4 . Use according to claim 1 , wherein the R radical is selected from the following groups:

wherein:

R 1 is H or —OCOR 3 ; wherein R 3 is methyl, ethyl or C 3 -C 5 linear or branched alkyl, or the residue of an heterocycle with only one ring having 5 or 6 atoms partially or totally hydrogenated, or aromatic, containing one or more heteroatoms independently selected from O, N and S;

R 2 is hydrogen, hydroxy, halogen, C 1 -C 4 linear or branched alkyl, C 1 -C 4 linear or branched alkoxyl; a C 1 -C 4 linear or branched perluoroalkyl, for example trifluoromethyl; nitro, amino, mono- or di-(C 1-4 )alkylamino;

with the proviso that in formula Ia) R 1 and R 2 are not contemporaneously H;

preferably when R 1 =H R 2 =OH;

preferably in the compounds of formula Ia) T 1 =—CO— and:

R 1 =acetoxy, preferably in ortho position with respect to —CO—, R 2 is hydrogen; in this case the formula Ia) represents the acetylsalicylic acid residue;

R 1 =H R 2 =OH, preferably in ortho position with respect to —CO—, in this case the formula Ia) represents the salicyilic acid residue;

in formula Ib) nI is an integer 0 or 1;

preferably in the compounds of formula Ib) R 3 =CH 3 , nI=0, T 1 =—CO—; in this case Ib) is the acetylsalicylsalicylic acid residue;

wherein:

R II5 is H, C 1 -C 3 linear or branched when possible alkyl;

R II6 has the same meaning as R II5 , or when R II5 is H it is benzyl;

R II1 , R II2 and R II3 are independently hydrogen, C 1 -C 6 linear or branched alkyl, or C 1 -C 6 linear or branched alkoxy, or Cl, F, Br;

R II4 is R II1 or bromine;

the compounds are preferred wherein R II1 , R II4 are hydrogen and R II2 and R II3 are chlorine in ortho position with respect to NH; R II5 and R II6 are H, T 1 =—CO—, when the free valence is saturated with OH the precursor compound is known as diclofenac.

IIb) is the residue of the 2-[(2-methyl-3-(trifluoro methyl)phenyl]amino]-3-pyridincarboxylic] acid when T 1 =—CO— and the free valence is saturated with OH the compound is known as flunixin;

wherein:

R 2a and R 3a are H, C 1 -C 12 linear or branched, substituted or not, alkyl or allyl, with the proviso that when one of the two is allyl the other is H;

preferably R 2a and R 3a , equal or different, are H, C 1 -C 4 alkyl;

R 1a is selected from:

IIID) R 1a corresponds to the following formulas:

wherein the meanings are the following:

when R 1a is as defined in formula (IV), Ketoprofen residue:

R II1 is H, SR III3 wherein R III3 is C 1 -C 4 linear or branched alkyl;

R III2 is H, hydroxy;

the compounds wherein R III1 and R III2 are H, R 3a is H, and R 2a is methyl, T 1 =—CO— are preferred;

when R 1a is as defined in formula (XXI), carprofen residue:

R xxio is H, alkyl from 1 to 6 C atoms linear or branched, C 1 -C 6 alkoxycarbonyl linked to a C 1 -C 6 alkyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl;

R xxi is H, halogen, hydroxy, CN, C 1 -C 6 alkyl containing or not containing OH groups, C 1 -C 6 alkoxy, acetyl, benzyloxy, SR xxi2 wherein R xxi2 is C 1 -C 6 alkyl; C 1 -C 3 perfluoroalkyl; C 1 -C 6 carboxyalkyl containing or not containing OH groups, NO 2 , amino; sulphamoyl, dialkyl sulphamoyl with C 1 -C 6 alkyl, or difluoroalkylsulphonyl with C 1 -C 3 alkyl;

R xxi1 is halogen, CN, C 1 -C 6 alkyl containing one or more OH groups, C 1 -C 6 alkoxy, acetyl, acetamido, benzyloxy, SR III3 being R III3 as above, C 1 -C 3 perfluoroalkyl, hydroxy, C 1 -C 6 carboxyalkyl, NO 2 , amino, C 1 -C 6 mono- or di-alkyl-amino; sulphamoyl, C 1 -C 6 di-alkylsulphamoyl, or di-fluoroalkylsulphamoyl as above; or R xxi together with R xxi1 is a C 1 -C 6 alkylen-dioxy;

the compounds are preferred wherein R xxio is H, the linking group is in position 2, R xxi1 is H, R xxi1 is chlorine and is in para position with respect to the nitrogen;

R 3a is H, R 2a is methyl and T 1 =—CO—;

when R 1a is as defined in formula (XXXV) tiaprofenic acid residue:

Ar is phenyl, hydroxyphenyl optionally mono- or polysubstituted with halogen, alkanoyl and C 1 -C 6 alkoxy, C 1 -C 6 trialkyl, preferably C 1 -C 3 , cyclopentyl, cyclohexyl, cycloheptyl, heteroaryl, preferably thienyl, furyl containing or not containing OH, pyridyl;

the preferred compounds of (XXXV) are those wherein Ar is phenyl, R 3a is H, R 2a is methyl and T 1 =—CO—;

when R 1a is as defined in formula (II), suprofen residue, R 3a is H, R 2a is methyl and T 1 =—CO—;

when R 1a is as defined in formula (VI), R is the residue of indoprofen when T 1 =—CO—, R 2a =H and R 3a =CH 3 ; of indobufen when R 2a is equal to H and R 3a =C 2 H 5 ; T 1 =—CO—;

when R 1a is as defined in formula (VIII), R is the etodolac residue when R 2a =R 3a =H and T 1 =—CO—;

when R 1a is as defined in formula (VII), R is the fenoprofen residue when R 3a =H, R 2a =CH 3 and T 1 =—CO—;

when R 1a is as defined in formula (III), R is the fenbufen residue when R 2a =R 3a =H and T 1 =—CO—;

when R 1a is as defined in formula (IX), R is the flurbiprofen residue when R 3a =H, R 2a =CH 3 , T 1 =—CO—;

when R 1a is as defined in formula (X) R is the tolmetin residue when R 2a =R 3a =H, T 1 =—CO—.

In group IIID) R 1a corresponds to the following formulas:

IIIa), when R 2a =H and R 3a =CH 3 the pranoprofen residue is obtained: α-methyl-5H-[1]benzopyran-[2,3-b]pyridin-7-acetic acid; in the preferred compound R 2a =H, R 3a =CH 3 , T 1 =—CO— and in the precursor the free valence is saturated with OH;

(XXX), when R 2a =H and R 3a =CH 3 the bermoprofen residue is obtained: dibenz[b,f]oxepin-2-acetic acid; in the preferred compound R 2a =H, R 3a =CH 3 , T 1 =—CO—;

(XXXI), when R 2a =H and R 3a =CH 3 , R is the radical of the compound CS-670: 2-[4-(2-oxo-1-cyclohexyliden methyl)phenyl]propionic acid; the preferred compound has R 2a =H, R 3a =CH 3 , T 1 =—CO—;

(XXXII), when R 2a =R 3a =H, the pemedolac residue is obtained;

when R 2a =R 3a =H T 1 =—CO—;

(XXXIII), when R 2a =R 3a =H, the pirazolac residue is obtained: 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazol acid derivatives;

the preferred compounds have R 2a =R 3a =H, T 1 =—CO—;

(XXXVI), when R 2a =H, R 3a =CH 3 the zaltoprofen residue is obtained; when the residue is saturated with an hydroxyl or aminic group, or with the carboxylic function the compounds are known as dibenzotiepin derivatives; in the preferred compounds R 2a =H, R 3a =CH 3 , T 1 =—CO—;

(XXXVII), when R 2a =R 3a =H the mofezolac residue is obtained: 3,4-di(p-methoxyphenyl)isoxazol-5-acetic acid when the residue is CH 2 —COOH; in the preferred compounds R 2a =R 3a =H, T 1 =—CO—;

(XII), when R 2a =R 3a =H the bromfenac residue is obtained: 2-amino-3-(4-bromobenzoyl)benzeneacetic acid; the preferred compounds have T 1 =—CO—, R 2a =R 3a =H;

(XXXX) when R 2a =R 3a =H the sulindac residue is obtained: (Z)-5-fluoro-2-methyl-1-[[4-(methyl sulphinyl)-phenyl]methylene]-1H-inden-3-acetic aid; the preferred compounds have T 1 =—CO—, R 2a =R 3a =H;

in Group IV) R is

wherein:

R IVd and R IVd1 are at least one H and the other an alkyl from C 1 to C 6 linear or branched, preferably C 1 -C 2 , or difluoroalkyl with C 1 -C 6 alkyl, C 1 preferred, or R IVd and R IVd1 form together a methylene group;

R IV has the following meaning;

wherein the compounds of group IV) have the following meanings:

in formula (IIB):

R IV-ii is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 7 alkoxymethyl, C 1 -C 3 trifluoroalkyl, vinyl, ethynyl, halogen, C 1 -C 6 alkoxy, difluoroalkoxy with C 1 -C 7 alkyl, C 1 -C 7 alkoxymethyloxy, alkylthiomethyloxy with C 1 -C 7 alkyl, alkyl methylthio with C 1 -C 7 alkyl, cyano, difluoromethylthio, phenyl- or phenylalkyl substituted with the C 1 -C 8 alkyl; preferably R iV-ii is CH 3 O—, R IVd is H and R IVd1 is CH 3 , and is known as naproxene residue; T 1 =—CO—;

in formula (XB), of which the loxoprofen residue has been indicated, the compounds wherein R IVd is H and R IVd1 is CH 3 , T 1 =—CO— are preferred;

in formula (IIIB):

R iV-iii is a C 2 -C 5 branched or not branched alkyl, C 2 and C 3 alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl from 5 to 7 C atoms, optionally substituted in position 1 by a C 1 -C 2 alkyl;

the compound is preferred wherein R iV-iii is

and R IVd =H, R IVd1 is CH 3 , compound known as ibuprofen residue, T 1 =—CO—;

In group V), the compounds have the following meanings:

when R is the formula (IIC),

R Vii is H or a C 1 -C 4 linear or branched alkyl;

R Vii-1 is R Vii , or C 1 -C 4 linear or branched alkoxy; Cl, F, Br; the position of R Vii-1 being ortho, or meta, or para;

the Ketorolac residue is preferred, wherein R Vii and R Vii-1 are H, and T 1 =—CO—;

when R is the formula (VIIC),

of which the tenoxicam residue has been indicated, T 1 =—O—;

when R is the formula (IXC), wherein T 1 =—O—, the piroxicam residue has been indicated;

when R is the formula (IIIC),

wherein T 1 =—CO—, of which the nabumetone residue has been indicated;

when R is the formula (IVC),

wherein T 1 =—CO—, of which the indomethacin residue has been indicated;

when R is the formula (XC), the residue X is known as meloxicam;

the preferred compounds are those in which T 1 =—CO—;

when R is the formula (XI) the residue is known as ampiroxicam when the termination is —CH(CH 3 )OCOC 2 H 5 ; the preferred compounds have T 1 =—CO—;

when R is the formula (XIII) and the valence is saturated with H, the residue derives from lornoxicam; the preferred compounds have T 1 =—O—;

when R is the formula (XXXXV), T 1 =—O— and the valence is saturated with H, the compound known as paracetamol is obtained.

5 . Use according to claim 1 , wherein in the compounds of formula (I) Y 3 of formula (III P ) of C is selected from the following bivalent radicals:

6 . Use according to claim 5 , wherein Y 3 is selected from the following: (Y12) with the two free valences in the ortho positions with respect to the nitrogen atom; (Y16) with the two valences linked to the two heteroatoms, Y1 (pyrazol) 3,5-disubstituted; Y16 is particularly preferred.

7 . Use according to claim 1 , wherein the following compounds are used:

2-acetyloxybenzoic acid 3-nitrooxymethyl phenyl ester (I C );

2-fluoro-alpha-methyl[1,1′-biphenyl]-4-acetic acid 4-ni-trooxy butylester (II C );

2-[(2,6-dichlorophenyl)amino]benzenacetic acid 4-ni-trooxy butyl ester (III C );

(S)-N-acetyl-[alpha-methyl-4-(2-methylpropyl)benzen-acetyl]cysteine 4-nitrooxybutylester having formula:

4-nitrooxybutanoic acid 4-acetylaminophenylester (V C );

trans-3-[4-[2-fluoro-alpha-methyl(1,1′-biphenyl)-4-acetyloxy]-3-methoxyphenyl]-2-propenoic acid 4-(nitrooxy)butyl ester, having formula:

2-Fluoro-alpha-methyl[1,1′-biphenyl]-4-acetic acid 3-(ni-trooxymethyl)phenyl ester having formula:

(S)-N-acetyl-[2-fluoro-alpha-methyl(1,1′-biphenyl)-4-acetyl]cysteine 4-(nitrooxy)butyl ester having formula:

2-Fluoro-alpha-methyl[1,1′-biphenyl]-4-acetic acid 6-(nitrooxy methyl)-2-methylpyridyl ester having formula

(S)-6-methoxy-alpha-methyl-2-naphthalenacetic acid 4-(nitrooxy)butyl ester having formula:

(S)-6-methoxy-alpha-methyl-2-naphthalenacetic acid 3-(nitrooxymethyl)phenyl ester having formula:

(S)-6-methoxy-alpha-methyl-2-naphthalenacetic acid 6-(nitrooxymethyl)-2-methylpyridyl ester having formula:

trans-3-[4-[6-methoxy-alpha-methyl-2-naphthalenacetyl oxy]-3-methoxyphenyl]-2-propenoic acid 4-(nitrooxy)butyl ester having formula:

(S,S)-N-acetyl-S-(6-methoxy-alpha-methyl-2-naphthaleneacetyl)cysteine 4-(nitrooxy)butyl ester having formula:

2-[(2,6-dichlorophenyl)amino]benzenacetic acid 4-(nitrooxy methyl)phenylmethyl ester having formula:

2-[(2,6-dichlorophenyl)amino]benzenacetic acid 6-(nitrooxymethyl)-2-methylpyridyl hydrochloride ester having formula:

(S)-3-benzoyl-alpha-methyl-benzenacetic acid 4-(nitro oxybutyl)ester having formula:

(S)-3-benzoyl-alpha-methyl-benzenacetic acid 3-(nitro oxypropyl)ester having formula:

(S)-3-benzoyl-alpha-methyl-benzenacetic 4-(nitro oxymethyl)phenylmethyl ester having formula:

5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 4-(nitrooxy)butyl ester having formula:

2-[(2,6-dichlorophenyl)amino]benzenacetic acid 5 (nitro oxy)ethyloxyethyl ester having formula:

1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 3-(nitrooxymethyl)phenyl ester (XXI C )

8 . Use according to claim 1 , wherein the compounds of formula (I) are administered in pharmaceutical formulations by oral, parenteral and topical administration.

9 . Use according to claim 1 for the prevention of arthritis relapses.