Nitrooxyderivatives of cyclooxygenase-2 inhibitors

1. A compound of formula (I) or a salt thereof

M-T-Y A —NO 2   (I)

wherein:

M-T is the residue of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, wherein T=—SO 2 NH—, and

Y A =—(B) b0 -(T C -Y) c0 — wherein:

b0 and c0 are the integers 1 or 0, with the proviso that b0 and c0 cannot be simultaneously 0,

B=-T B -X 2 -T BI -, in which:

T B =CO;

T BI =CO or X, in which X is O, S, NH, or NR, wherein R is an alkyl with 1-10 carbon atoms;

X 2 is a divalent radical and is selected from the following compounds:

wherein:

n1 and n2 are integers 0 or 1; R 2 and R 3 are independently selected from H or CH 3 ;

wherein:

n2 and R 2 are as above defined;

Y 1 is —CH 2 —CH 2 — or —CH═CH—(CH 2 ) n2′ — wherein n2′ is an integer 0 or 1;

wherein:

n4 is an integer from 1 to 20 and n5 is an integer from 0 to 20; R 4 , R 4′ , R 5 and R 5′ are independently selected from the group consisting of H, CH 3 , OH, NH 2 , NHCOCH 3 , and COOH; when the bond between the C A and C B carbons is a double bond, then R 4 and R 5 or R 4′ and R 5′ are absent;

T C =CO, X wherein X is as defined above, or —(CH 2 ) n6 OC(O)— wherein n6 is an integer from 1 to 20;

Y is a bivalent radical having the following meanings:

d) —R 1 O—, in which R 1 is:

straight or branched C 1 -C 20 -alkylene optionally containing one or more heteroatoms selected from oxygen, nitrogen, sulphur, or one or more groups —O(CO)—, —NH(CO)—, —S(CO)—, optionally substituted with one or more of the following groups —OH, —SH, —NH 2 , —NHCOR 6 , in which R 6 is straight or branched C 1 -C 10 -alkyl;

cycloalkylene containing from 5 to 7 carbon atoms into cycloalkylene ring, wherein one or more carbon atoms can be replaced by heteroatoms selected from nitrogen, oxygen or sulphur, and the ring can be substituted with side chains R 6 , R 6 being as defined above;

wherein n7 is an integer from 0 to 20, and n7′ is an integer from 1 to 20;

wherein m is an integer from 1 to 6, Rf is a hydrogen atom or CH 3 ;

wherein:

nIX is an integer from 0 to 10;

nIIX is an integer from 1 to 10;

R TIX , R TIX′ , R TIIX , R TIIX′ , are the same or different, and are H or straight or branched C 1 -C 4 -alkyl;

Y 3 is selected from the group consisting of:

with the proviso that:

when b0=0, and c0=1, then T C =(CO) or —(CH 2 ) n6 O(CO)—;

when b0=1, then T B =CO;

when b0=1, c0=1 and T B1 =CO then T C =X wherein X is as above defined;

when b0=1, c0=1 and T B1 =X, wherein X is as above defined, then T C =(CO);

when b0=1, c0=0 the T B1 has only the meaning of —O—.

2. A compound of formula (I) according to claim 1 wherein b0=0, c0=1, T and T C are as defined in claim 1 , Y is a straight C 1 -C 6 alkylene or

wherein n7 is 0 or 1, and n7′ is 1 or 2, or

wherein m is 2, Rf is hydrogen.

3. A compound of formula (I) according to claim 2 wherein b0=0, c0=1, T=-SO 2 NH— and T c =CO or (CH 2 ) n6 O(CO)— wherein n6=1.

4. A compound according to claim 3 , that is N-[4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenylsulfonyl]-4-nitrooxybutanamide.

5. A compound of formula (I) or a salt thereof according to claim 1 , wherein said compound is a therapeutic agent.

6. A method of treatment of pain, fever and inflammatory disorders selected from the group consisting of: arthritis, rheumatoid arthritis, osteoarthritis, dysmenhorrea, allergic rhinitis, sinusitis, chronic obstructive pulmonary diseases, dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, vasculitis and organ transplant rejection, comprising administering to a subject a compound of formula (I) or a salt thereof according to claim 1 .

7. A method of treatment of cardiovascular diseases selected from the group consisting of: atherosclerosis, restenosis, coronary artery disease, angina, diabetes mellitus, diabetic nephropathy, diabetic retinopathy, stroke and myocardic infarct, comprising administering to a subject a compound of formula (I) or a salt thereof according to claim 1 .

8. A method of treatment of gastrointestinal disorders selected from the group consisting of: inflammatory intestinal disorders, Crohn's disease, gastritis, ulcerative colitis, peptic ulcer, haemorrhagic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison's syndrome, bacterial infections, hypersecretory states associated with systemic mastocytosis or basophilic leukaemia and hyperhystaminemia, comprising administering to a subject a compound of formula (I) or a salt thereof according to claim 1 .

9. A method of treatment of Alzheimer's disease, comprising administering to a subject a compound of formula (I) or a salt thereof according to claim 1 .

10. A method of treating disorders resulting from elevated levels of COX-2 selected from the group consisting of: angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, neoplasia, ophthalmic diseases, pulmonary inflammations, central nervous system disorders, allergic rhinitis, atherosclerosis, endothelial disorders, organs and tissues preservation, and inhibition or prevention of platelet aggregation, comprising administering to a subject a compound of formula (I) or a salt thereof according to claim 1 .

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) or a salt thereof according to claim 1 .

12. A composition according to claim 11 in a suitable form for the oral, parenteral, rectal, topic and transdermic administration, by inhalation spray or aerosol or iontophoresis devices.

13. A liquid or solid pharmaceutical composition for oral, parenteral, rectal, topic and transdermic administration or inhalation in the form of tablets, capsules and pills optionally with enteric coating, powders, granules, gels, emulsions, solutions, suspensions, syrups, elixir, injectable forms, suppositories, in transdermal patches or liposomes, containing a compound of formula (I) according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.