Drugs for chronic pains

1. Nitrooxyderivative compounds or salts thereof having the following general formula (I):

A—(B) bo —(C) co —NO 2   (I)

wherein:

c0 is 1;

b0 is an integer and is 0 or 1;

A=R—T 1 —, wherein R is the radical of an analgesic drug having formula II:

wherein:

W is a carbon atom;

m is an integer from 0 to 2;

R 0 =H, —(CH2) n —NHR 1A , n being an integer equal to 0 or 1, wherein R 1A =H;

R 1 =H;

R 2 is chosen between the following groups:

3-4 di-hydroxy substituted benzyl;

the radical of formula (IIA), wherein optionally one unsaturation of ethylene type can be present between the carbon atoms in position 1 and 2:

wherein:

p and p 1 are integers, equal to or different from each other and are 0 or 1;

p 2 and p 3 are equal to 0;

R 4 is hydrogen;

R 5 is hydrogen or —CH 3;

R 6 and R 6A are H;

R 7 and R 8 equal to or different, are H, methyl; or free valence;

with the proviso that in the radical of formula (IIA) when one unsaturation of ethylene type between C 1 and C 2 is present, R 4 and R 5 are free valences such as to form the double bond between C 1 and C 2; when the unsaturation is between C 4 and C 5 , R 7 and

R 8 are free valences such as to form the double bond between C 4 and C 5;

Q is equal to H, —OH 3 , guanidine (H 2 NC(═NH)NH—), or thioguanidine (H 2 NC(═S)NH—); wherein in formula (II), R 2 with R 1 and with W=C taken together form a C 6 saturated ring;

T 1 =(CO) t or (X) t′ , wherein X=O, S, NR 1C , R 1C is H or a linear or branched alkyl, having from 1 to 5 carbon atoms, 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 =(GO) when t=0, T 8 = X when t′=0, X being as above;

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; and tx=0 when txx=1; X is as above;

X 2 , bivalent radical, is such that the corresponding precursor of B T B -X 2 -T BI -wherein the free valences of T 6 and of T BI are saturated each with OZ, with Z or with —N(Z′)(Z″), being:

Z=H, C 1 –C 10 , preferably C 1 –C 5 alkyl linear or branched when possible,

Z′, Z″equal to or different have the values of Z 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 compound of B as above defined being selected from the following classes of compounds:

aminoacids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or esters thereof, preferably ethyl or isopropyl ester;

hydroxyacids, selected from the following: gallic acid, ferulic acid, gentisic acid citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid;

C=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 defined;

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

when c0=0: tx=0, T BI =X=—O—;

Y has one of the following meanings;

Y 0 , selected from the following: R′O wherein R′is a linear or branched when possible C 1 –C 20 alkyl

or Y is selected from one of the following groups:

wherein nf′ is an integer from 1 to 6;

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

Y AR , selected from:

Y AR1 :

wherein n3 is an integer from 0 to 5 and n3′is an integer from 1 to 3; or

Y AR2 :

wherein n3 and n3′ have the above meaning.

2. Compounds according to claim 1 , wherein:

when in formula (II) W=C, m=1 and R 0 =—(CH 2 ) n —NH 2 with n=1, R 2 and R 1 with W as above defined form together the cyclohexane ring, in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as gabapentin;

when in formula (II) W=C, m=0 and R 0 =—(CH 2 ) n —NH 2 with n=0, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =1, p 2 =p 3 =0, R 4 =R 5 =R 6 =R 6A =H, Q =H, in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as norvaline;

when in formula (II) W=C, m=0 and R 0 =—(CH 2 ) n —NH 2 with n=0, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =1, p 2 =p 3 0, R 4 =R 5 =R 6 =R 6A =H, Q is the guanidine group, in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as arginine;

when in formula (II) W=C, m=0 and R 0 =—(CH 2 ) n —NH 2 with n =0, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =1, p 2 =p 3 =0, R 4 =R 5 =R 6 =R 6A =H, Q is the thioguanidine group, in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as thiocitrulline;

when in formula (II) W=C, m=1 and R 0 =—(CH 2 ) n —NH 2 with n=1, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =p 2 =p 3 =0, R 4 =H, R 5 =Q CH 3 , in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as pregabalin;

when in formula (II) W=C, and has configuration (S), m=1 and R 0 =—(CH 2 ) n —NH 2 with n=1, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =p 2 =p 3 =0, R 4 =H, R 5 =Q=CH 3 , in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as (S) 3-isobutylGABA;

when in formula (II) W=C, m=1 and R 0 =R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =1, p 2 =p 3 =0, R 4 =R 5 =R 6 =R 6A =H, Q is the guanidine group, in the radical A of formula (I) T 1 =NH and the free valence of A is saturated with H, the precursor drug of R is known as agmatine;

when in formula (II) W=C, m=2 and R 0 =—(CH 2 ) n —NH 2 with n=0, R 1 =H, R 2 is the radical of formula (IIA) wherein p=p 1 =p 2 =p 3 =0, R 4 and R 5 are free valences and between C 1 and C 2 there is one ethylene unsaturation, Q=H, in the radical A of formula (I) T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as vigabatrin;

when in formula (II) W=C, m=0 and R 0 =—(CH 2 ) n —NH 2 with n=0, R 1 =H, R 2 is the radical 3-4 di-hydroxy substituted benzyl, T 1 =CO and the free valence of A is saturated with OH, the precursor drug of R is known as 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (dopa).

3. Compounds according to claim 1 , wherein when in formula (I) b0=0, Y in the bivalent linking group C is Y AR as above defined.

4. Compounds according to claim 1 , wherein in formula (I) the precursors of B are the following: ferulic acid, N-acetylcysteine, cysteine, caffeic acid, hydro-caffeic and gentisic acid.

5. Compounds according to claim 1 , selected from the following:

1-(aminomethyl)cyclohexan acetic acid 2-methoxy-4-[(1E)-3[4-(nitrooxy) butyoxy]-3-oxy-1-propoxy]phenyl hydrochloride ester (XV)

1-(aminomethyl)cyclohexan acetic acid 3-(nitrooxymethyt) phenyl hydrochloride ester (XVI)

2-aminopentanoic acid 3-(nitrooxymethyl) phenyl hydrochloride ester (XVII)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester, 2-amino hydrochloride pentanoate (XVIII)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester, 1-(aminomethyl) cyclohexanacetate hydrochloride (XIX)

alpha-amino-delta-thioureidopentanoic acid, 3-(ni-trooxy methyl)phenyl hydrochloride ester (XXI)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester, alpha-amino, delta-thioureidopentanoate hydrochloride (XXII)

alpha-amino-delta-thioureidopentanoic acid, 2-me-thoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenyl hydrochloride ester (XXIII)

2-amino-5-guanidinopentanoic acid, 3-(nitrooxy methyl)phenyl hydrochloride ester (XXIV)

2-amino-5-guanidinopentanoic acid-, 2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenyl hydrochloride ester (XXV)

(S)-N-acetylcysteine-4-(nitrooxy)butyl ester, 2-amino-5-guanidinopentanoate hydrochloride (XXVI)

4-(guanidine)butyl-3-nitrooxymethylbenzamide (XXVII)

4-(guanidine)butyl-3-[4-(4′-nitrooxybutyryloxy)-3-(methoxy)]phenyl-2-propenamide chloride (XXVIII)

1-(aminomethyl)cyclohexan acetic acid 4-(nitroxy)butyl hydrochloride ester (XXIX)

6. Compounds according to claim 1 , as nitrate salts.

7. Pharmaceutical compositions for parenteral, oral and topical use, comprising the compounds according to claim 1 .

8. A method of treating chronic pain, comprising administering to a subject a compound according to claim 1 .

9. The method of claim 8 , wherein the chronic pain is neuropathic pain.