KR20050016902A - Nitrooxyderivatives of cyclooxygenase-2 inhibitors - Google Patents

Abstract

Formula (I): COX-2 inhibitors with MTY _A- NO ₂ and new compounds for the treatment and / or prevention of inflammatory progression that release NO.

Description

Nitrooxyderivatives of cyclooxygenase-2 inhibitors

The present invention relates to cyclooxygenase-2 inhibitors (hereinafter referred to as COX-2 inhibitors), drug compositions and arthritis containing them, osteoarthritis, rheumatoid arthritis, dysmenorrhea, analgesic and fever, gastrointestinal and cardiovascular diseases, rheumatic diseases For the treatment and / or prevention of inflammation, such as neoplasia and Alzheimer's disease, for alleviating or eliminating known side effects of COX-2 inhibitors, and for treating diseases resulting from elevated levels of cyclooxygenase-2, and And / or use for prevention.

Cyclooxygenase is an enzyme that converts arachidonic acid to prostanoids. In addition, for the development of nonsteroidal anti-inflammatory agents (NSAIDs), it has become clear that these compounds have a precise and direct relationship between activity and toxicity. In fact, even if they interfere with the formation of pro-algogen / inflammatory prostanoids, which inhibits cyclooxygenase activity, on the one hand it leads to a decrease in protective prostanoids and damage to the gastrointestinal tract is a definite result. Further studies have demonstrated that there are two different forms of cyclooxygenase enzymes, two of which are the constitutive forms responsible for the production of protective prostanoids (COX-1) and pro-alogen / inflammatory prostanoids. Producing inducible forms (COX-2) (JR Vane et al., Ann. Rev. Pharmacol. Toxicol. 1998, 38: 97-120). Therefore, it was hypothesized that NSAIDs anti-inflammatory effects are modulated by COX-2 inhibition, while their side effects are due to inhibition of COX-1. However, COX-1 enzymes are known to be physiologically associated with the production of prostaglandins that have protective effects on platelet aggregation as well as gastric mucosal, kidney and gastrointestinal levels. Thus, anti-inflammatory agents that inhibit COX-2, especially without COX-1 inhibition, should be free of the side effects associated with traditional NSAIDs. Patients taking selective COX-2 inhibitors have been demonstrated that NSAIDs should be administered to demonstrate cardioprotective action, but this method will result in gastrointestinal discomfort. In the same way, switching from nonsteroidal anti-inflammatory agents to selective COX-2 inhibitors will result in better anti-arthritic properties and loss of cardioprotective activity. For this initiative, selective COX-2 inhibitors have developed a desired therapeutic analysis table of anti-inflammatory agents without the side effects commonly associated with inhibition of COX-1. However, all these compounds have not been proven to be free of side effects such as for example indigestion and gastropathy, gastrointestinal and cardiovascular risks (Mohammed et al., N. Engl. J. Med., 340 (25) 2005, 1999 ).

Despite the continued development of new COX-2 inhibitors all the time, the problem of these side effects is still not solved. Therefore, the potential risk of cardiovascular disease, acute colitis, gastrointestinal bleeding, allergic vasculitis, intestinal disease has been reported.

WO 01/45703 describes compositions containing nitrosified and nitrosylated cyclooxygenase-2 inhibitors and at least one such new inhibitors and optionally at least one compound that donates, transfers or releases nitride oxides. The application described that the inhibitors can reduce or prevent side effects of known COX-2 inhibitors if they contain at least one nitrous acid, nitric acid, nitrous sulfide or nitrous acid group. In particular, in this patent the preparation of compounds containing -O-NO ₂ groups (nitrosified cyclooxygenase-2 inhibitors) directly linked to a portion of the COX-2 inhibitor and -S-NO linked indirectly to the precursor drug Synthesis of COX-2 inhibitor derivatives containing groups (nitrosylated cyclooxygenase-2 inhibitors) is illustrated.

It is an object of the present invention to provide novel derivatives of cyclooxygenase-2 inhibitors which do not have the above mentioned disadvantages, which are converted in vivo to compounds with enhanced COX-2 inhibitory activity and modulate the bioavailability of nitrogen oxides. It is to release molecules that can reduce or resolve problems with cardiovascular and / or gastrointestinal levels and to achieve synergism between COX-2 molecules and nitrogen oxides.

Subjects of the present invention are compounds and their salts with improved pharmaceutical assays capable of releasing COX-2 inhibitors and NO (nitrogen oxides) under conditions according to the parameters set out in Experiment 1 described below, and the following general formula (I) Has,

MTY _A -NO ₂

(Ⅰ)

here

MT is the residue of a COX-2 selective inhibitor, where T = -SO ₂ NH-, -SO ₂ NR-,-(CO)-, -O-, -S-, -NH-, -N (SO ₂ R )-, R is alkyl with 1-10 carbon atoms and is preferably methyl, wherein the COX-2 selective inhibitor, M-TH or M-TOH must meet Experiment 2 described below;

Y _A =-(B) _b0- (C) _c0 -where:

b0 and C0 are integers that are 1 or 0, provided that b0 and C0 cannot be zero at the same time,

B = -T _B -X ₂ -T _BI , where:

T _B = CO or X, wherein X = O, S, NH, NR and R are as defined above and T is -SO ₂ NH, -SO ₂ NR-, -O-, -S-, -NH- , T _B is CO when -N (SO ₂ R)-and T _B is X when T is -CO-;

When X is as defined above, T _BI is CO or X,

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

a)

here:

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

b)

here:

n2 and R ³ are as defined above;

Y ¹ is —CH ₂ —CH ₂ — or —CH═CH— (CH ₂ ) _{n 2} where n ₂ ′ is an integer equal to 0 or 1;

c)

here:

n4 is an integer from 1 to 20 and n5 is an integer from 0 to 20 and R ⁴ and R ^{4 ′} R ⁵ and R ^{5 ′} are independently selected from H, CH ₃ , OH, NH ₂ , NHCOCH _3, COOH; When the bond is a double bond between C ^A and C ^B carbons, it is not between R ⁴ and R ⁵ or R ^{4 ′} and R ^{5 ′} ;

C is a divalent radical -T _C -Y-, wherein:

T _C = CO, X where X is as defined above _or- (CH ₂ ) _n6 OC (O)-where n6 is an integer from 1 to 20, preferably n6 is 1;

Y is a divalent radical having the following meanings:

d) -R ¹ O-, wherein R ¹ is:

Eventually contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, one or more -O (CO)-, -NH (CO)-, -S (CO)-, and R ⁶ is straight or branched C ₁ Straight or branched C ₁ -C ₂₀ -alkylene substituted with one or more of the following groups —OH, —SH, —NH ₂ , —NHCOR ⁶ , —C ₁₀ -alkyl, preferably CH ₃ ;

Cycloalkylene containing 5 to 7 carbon atoms as a cycloalkylene ring, wherein one or more carbon atoms can be substituted from heteroatoms selected from nitrogen, oxygen or sulfur and the ring is defined as R ⁶ is And may be substituted with side chain R ⁶ ;

e)

f)

Wherein n7 is an integer from 0 to 20 and n7 'is an integer from 1 to 20;

g)

M is an integer of 1 to 6, preferably 1 to 4, and Rf is an oxygen atom or CH ₃ ;

h)

here:

nIX is an integer of 0 to 10, preferably 1 to 5;

nIIX is an integer of 1 to 10, preferably 1 to 5;

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, preferably R _TⅨ , R _{TⅨ ′} , R _TIIⅩ , R _{TIIⅩ '} ego;

Y ³ is a heterocyclic saturated, unsaturated or aromatic 5 or 6 urea ring containing nitrogen, oxygen, sulfur and one or more heteroatoms selected from

Assume the following:

when b0 = 0, c0 = 1 and T = -SO ₂ NH-, -SO ₂ NR-, -O-, -S-, -NH-, -N (SO ₂ R)-, where R is defined above Then Tc = (CO) _or- (CH ₂ ) _n6 O (CO)-;

when b0 = 0, c0 = 1 and T = CO, T _C = X and X is as defined above;

b0 = 1 and T = -SO ₂ NH-, -SO ₂ NR-, -O-, -S-, -NH-, -N (SO ₂ R)-where R is as defined above, T _B = CO;

T _b = X where _b 0 = 1 and T = CO where X is as defined above;

T _C = X where b 0 = 1, _c 0 = 1 and T _B1 = CO where X is as defined above;

b0 = 1, c0 = 1 and T _B1 = X, where X is as defined above, T _C = (CO);

When b0 = 1 and c0 = 0, T _B1 has only the meaning of -O-.

Preferred compounds of formula (I) are wherein b0 = 1, c0 = 1, T and T _C are as defined in claim 1 and Y is straight C ₁ -C ₆ alkylene or

Where n7 is 0 or 1, and n7 'is 1 or 2, or

Where m is 2 and Rf is hydrogen.

Particularly preferred compounds of formula (I) are b0 = 0, c0 = 1, T = -N (SO ₂ R)-, T _c = CO _or- (CH ₂ ) _n6 O (CO)-where n6 = 1 and R = CH ₃ , where b0 = 0, c0 = 1, T = -SO ₂ NH- and Tc = CO _or- (CH ₂ ) _n6 O (CO)-where n6 = 1.

Subjects of the present invention are also drug compositions containing nitrogen-derivatives of at least one cyclooxygenase-2 inhibitor in combination with pharmaceutically acceptable carriers, inflammatory and cardiovascular diseases, arthritis, rheumatoid arthritis, dysmenorrhea, analgesic, The present invention relates to the use of to treat and / or prevent diseases resulting from cyclooxygenase-2 elevated levels and to reduce or eliminate known side effects of COX-2 inhibitors in the treatment and / or prevention of fever.

Test 1

COX-1 and COX-2 Activity Assays for Compounds of the Invention

Under test on rat liver homogenates isolated from potassium chloride (1.15%) and phosphate buffer (0.1 M, pH 7.4), compounds were added to the homogenate at 0.5 mM final concentration (dissolved in 1% DMSO) and homogenates Was maintained at room temperature for 30 minutes and then centrifuged (2000 rpm, 5 minutes). The supernatant was measured for COX-2 and COX-1 activity and released NO according to the method described below.

1-1) Human Whole Blood Assays of COX-2 and COX-1 Activities

Experiments were performed according to the method described in D. Riendeau et al., Magazine of Pharmaceutical and Experimental Therapy 296: 558-566, 2001.

For assessing COX-2 activity, human blood was collected from volunteers, heparin added (19 U / ml) and several 500 μl samples were serially diluted in LPS (100 μg / ml) and three times the supernatant described above. Incubated for 24 hours at 37 ° C. with 2 μl or 2 μl carrier (DMSO) of solutions of compounds (DMSO 1%) under different concentrations using (1:10, 1: 100, 1: 1000, 1: 10000) . COX-2 activity in the samples was measured in plasma after deproteinization as PGE2 concentration by radioimmunoassay (Amersham, Oakville, Ontario, Canada).

For the COX-1 assay, a 500 μl sample of human blood was used as a solution of compounds (DMSO) at different concentrations using a series of dilutions (1:10, 1: 100, 1: 1000 and 1: 10000) of three times the supernatant described above. 1%) 2 μl or 2 μl carrier (DMSO) and blood was clot at 37 ° C. for 1 hour.

COX-1 activity in the samples was measured in serum after deproteinization as TXB2 level using enzyme immunoassay (Cayman Chemicals, Ann Aybor, MI).

1-2) Measurement of NO emission by chemiluminescence

The supernatant (100 μl) sample described above was injected into the reaction chamber of the analyzer containing a reducing solution consisting of glacial acetic acid and potassium iodide. Under these conditions, the nitrate / nitrite shown in the sample is converted to the NO observed after reaction with ozone. This reaction provides light, which records the signal detected by the photomultiplier and proportional to the amount of light emitted will quantify the nitrate / nitrite present in the sample. For quantitative determination of emitted NO, a control is made of the standard curve obtained with scalar nitrite concentration.

Compounds satisfy Experiment 1 when the ratio between COX-1 inhibitory activity and COX-2 inhibitory activity, expressed as IC _50, is at least 5 and the amount of NO release detected by the instrument is at least 0.1 μM.

Test 2

   COX-1 and COX-2 Activity Assay of Precursor Compounds According to HWBA Method (Human Whole Blood Assays)

Experiments were performed using the same method described in D. Riendeau et al., Magazine of Pharmaceutical and Experimental Therapy 296: 558-566, 2001. 2.1 For assessing COX-2 activity, human blood was collected from volunteers, heparin added (19 U / ml) and 500 μl samples were serially diluted in LPS (100 μg / ml) and 3 times the highly tested concentration. Different concentrations using (1:10, 1: 100, 1: 1000, 1: 10000) were incubated for 24 hours at 37 ° C. with 2 μl solution of precursor compounds (DMSO 1%) or 2 μl carrier (DMSO). COX-2 activity in the samples was measured in plasma after deproteination as PGE2 concentration by radioimmunoassay (Amersham, Oakville, Ontario, Canada).

2.2 For the assessment of COX-1 activity, a sample of 500 μl of human blood was used at different concentrations using a series of dilutions (1:10, 1: 100, 1: 1000 and 1: 10000) three times the concentration tested at elevated altitudes. 2 μl or 2 μl carrier (DMSO) of the solution of (DMSO 1%) were mixed and the blood coagulated at 37 ° C. for 1 hour.

COX-1 activity in the samples was measured in serum after deproteinization as TXB2 concentration using enzyme immunoassay (Cayman Chemicals, Ann Aybor, MI).

Experiment 2 is satisfied by precursor compounds having a ratio of at least 5 between COX-1 inhibitory activity and COX-2 inhibitory activity expressed as IC ₅₀ .

Precursors that can be used for the preparation of the subject compounds of the present invention have been described in the following patents or patent applications:

WO 91/19708, WO 94/13635, WO 94/15932, WO 94/20480, WO 94/26731, WO 94/27980, WO 95/00501, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 95/18799, WO 95/21817, WO 95/30652, WO 95/30656, WO 96/03392, WO 96/03385, WO 96/03387, WO 96/03388, WO 96/06840, WO 96/09293, WO 96/09304, WO 96/10021, WO 96/13483, WO 96/16934, WO 96/19462, WO 96/19463, WO 96/19469, WO 96/21667, WO 96/23786, WO 96/24584, WO 96/24585, WO 96/25405, WO 96/31509, WO 96/36617, WO 96/36623, WO 96/37467, WO 96/37468, WO 96/37469, WO 96/38418, WO 96/38442, WO 96/41626, WO 96/41645, WO 96/03953, WO 97/11704, WO 97/13755, WO 97/13767 WO 97/14691, WO 97/16435, WO 97/25045, WO 97/27181, WO 97/28120, WO 97/28121, WO 97/29776, WO 7/34882, WO 97/36863, WO 97/37984, WO 97/38986, WO 97/40012, WO 97/41100, WO 97/44027, WO 97/44028, WO 97/45420, WO 98/00416, WO 98/03484, WO 98/04527, WO 98/05639, WO 98/06708, WO 98/07714, WO 98/11080, WO 98/14205, WO 98/21195, WO 98/22442, WO 98/32732, WO 98/33769, WO 98/39330, WO 98/41511, WO 98/41516, WO 98/43966, WO 98/473649, WO 98/476594, WO 98/47509, WO 98/47871, WO 98/47890, WO 98/50033, WO 98/50075, WO 98/52937, WO 98/57924, WO 99/05104, WO 99/10331, WO 99/10332, WO 99/11605, WO 99/12930, WO 99/13799, WO 99/14194, WO 99/14195, WO 99/15205, WO 99/15503, WO 99/15513, WO 99/15505, WO 99/18960, WO 99/20110, WO 97/27181, WO 97/28120, WO 97/28121, WO 97/29776, WO 97/34882, WO 97/36863, WO 97/37984, WO 97/38986, WO 97/40012, WO 97/41100, WO 97/44027, WO 97/44028, WO 97/45420, WO 98/00416, WO 98/03484, WO 98/04527, WO 98/05639, WO 98/06708 WO 98/07714, WO 98/11080, WO 98/14205, WO 98/21195, WO 98/22442, WO 98/32732, WO 98/33769, WO 98/39330, WO 98/41511, WO 98/41516, WO 98/43966, WO 98/43649, WO 98/46594, WO 98/47509, WO 98/47871, WO 98/47890, WO 98/50033, WO 98/50075, WO 98/52937, WO 98/57924, WO 99/05104, WO 99/10331 WO 99/10332, WO 99/11605, WO 99/12930, WO 99/13799, WO 99 / 14194, WO 99/14195, WO 99/15205, WO 99/15503, WO 99/15513, WO 99/15505, WO 99/18960, WO 99/20110, WO 99/20589, WO 99/21585, WO 99/22720, WO 99/23087, WO 99/25695, WO 99/33796, WO 99/35130, WO 99/41224, WO 99/45913, WO 99/55830, WO 99/59634, WO 99/59635, WO 99/61016, WO 99/61436, WO 99/62884, WO 99/64415, WO 00/00200, WO 00/01380, WO 00/08024, WO 00/10993, WO 00/13685, WO 00/23433, WO 00/24719, WO 00/25779, WO 00/26216, WO 00/27382, WO 00/29022, WO 00/29023, WO 00/37107, WO 00/38730, WO 00/38786, WO 00/40087, WO 00/48583, WO 00/51685, WO 00/52008, WO 00/53149, WO 00/68215, WO 01/70704, WO 01/15138, WO 01/68633, EP 0087629, EP 0418845, EP 0554829, EP 0745596, EP 0788476, EP 0826676, EP 0863134, EP 0882016, EP 0927555, EP 093772, EP 1006114, US 3,840,597, US 5,134,142, US 5,344,991, US 5,380,738, US 5,393,790, US 5,399,357, US 5,434,178, US 5,409,944, US 5,436,265, US 5,466,823, US 5,474,995 US 5,475,021 US 4,486,534 US 5,504,215, US 5,508,426, US 5,510,368, US 5,510,4521, US, 5,510,4521,5,5,521,519 , US 5,552,422, US 5,563,165 , US 5,580,985, US 5,585,504, US 5,596,008, US 5,604,253, US 5,604,260, US 5,616,601, US 5,620,999, US 5,633,272, US 5,630,780, US 5,643,933, US 5,668,161, US 5,677,3128, US 5,686,460,537 , US 5,698,584, US 5,700,816, US 5,710,140, US 5,719,163, US 5,733,909, US 5,753,688, US 5,756,530, US 5,760,530, US 5,760,068, US 5,783,597, US 5,789,413, US 5,807,875, US 5,840,5,924,5,924 5,859,257, US 5,861,419, US 5,883,267, US 5,908,852, US 5,908,858, US 5,925,631, US 5,935,990, US 5,945,539, US 5,972,986, US 5,981,576, US 5,985,902, US 5,990,148, US 5,994,6,002,679,38,679 US 6,025,353, US 6,028,072, US 6,046,191, US 6,071,936, US 6,071,954, US 6,077,869, US 6,080,876, US 6,083,969, US 6,136,839, US 5,681,842, US 5,776,967, US 5,824,394,5,589,385 , US 5,994,381, US 6,004,948, US 2002/0058690 and JP 2001139575,

Examples of preferred COX-2 selective inhibitors of formula M-TH or M-TOH are as follows:

4- (5-methyl-3-phenylisoxazol-4-yl) benzinesulfonamide (valdecokship), 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazole -1-yl] benzenesulfon-amide (celecoxib), 4- (4-cyclohexyl-2-methylroxazol-5-yl) -2-fluoro-benzenesulfonamide (tilmacockship), N- [6 -[(2,4-difluorophenyl) thio] -2,3-dihydro-1-oxo-1H-inden-5-yl] -methanesulfonamide (L-745337), N- (4-nitro 2-phenoxyphenyl) methanesulfonanilide, N- (4-nitro-2-cycloexyloxy-phenyl) methanesulfonanilide, 2-[(2-fluoro-6-fluorophenyl) -amino]- 5-Methylbenzeneacetic acid (COX189), 2-[(2-chloro-6-fluorophenyl) -amino] -4-methylbenzeneacetic acid.

Preferred drugs of formula (I) according to the invention are:

N- (6- (2,4-difluorophenyl) thio-2,3-dihydro-1-oxo-1-iden-5-yl) -N- (4-, nitrooxy) butyroyloxy Methyl) methanesulfonamide, N- (6- (2,4-difluoro-phenyl) thio) -2,3-dihydro-1-oxo-1-eden-5-yl) -N- (3- Nitrooxymethyl) -benzoyloxymethyl) methanesulfonamide, (Z) -2- (4-methylsul-fonyl) phenyl) -3-phenyl-2-butane-1,4-diol-1-((4- Nitrooxymethyl) benzoate), N- (4- (5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenylsulfonyl) -4-nitrooxybutane Amide, N- (3-nitrooxymethyl) benzoyl-oxymethyl-N- (2-phenoxy-4-nitrophenyl) methanesulfonamide.

Since the small compounds of formula (I) possess one or more asymmetric carbon atoms, they are optically pure enantiomers, pure diastereomers, enantiomeric mixtures, diastereomeric mixtures, enantiomeric racemate mixtures, racemates Or as racemic mixtures. Also subject of the present invention are all stereoisomers and mixtures thereof. It is understood that the present invention includes all isomers and mixtures thereof, including the carbon-carbon double bonds that may exist as E or Z geometric isomers.

As mentioned above, the present invention is drug compositions containing at least one compound of the invention of formula (I) in combination with non-toxic adjuvant and / or carrier which are always used in the field of pharmacy.

The daily dosage of the active ingredient to be administered may be a single dose or may be an effective amount divided into several smaller dosages to be administered during the day. In general, the total daily dose is 1 to 2000 mg, preferably 1 to 1000 mg, especially 50 to 500 mg. Prescription dosages and frequency of treatment for treating such diseases with a compound of the present invention and / or a pharmaceutical composition of the present invention may be, for example, age, weight, patient's sex and medical condition and the severity of the disease, and consideration of pharmacological administration. Selection will be made in terms of a number of factors including the route and the therapeutics that ultimately accompany the other agents. In some cases, dosage levels above and / or below and / or more often in the above-mentioned range will be appropriate, which will inevitably be at the discretion of the physician and will depend on the disease state.

The compounds of the present invention may be formulated orally, parenterally, rectally or topically, by inhalation or by aerosols, and ultimately, ultimately, containing conventional non-toxic drug-soluble carriers, adjuvants and carriers. Can be. Topical administration may also involve the use of transdermal administration such as transdermal patches or ion transport devices. As used herein, the term "percutaneous" includes techniques of subcutaneous injection, intravenous, intramuscular, intrasternal or fluid.

Injectable treatments, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Among the acceptable carriers and solvents are water, Ringer's solution, and sodium chloride isotonic solution. In addition, sterile, fixed oils have traditionally been used as a solvent or suspending medium. For this purpose any hypoallergenic fixed oil may be employed including synthetic mono or diglycerides and fatty acids such as oleic acid may be used in the preparation of injectables.

Suppositories for rectal administration of a medicament may be prepared by mixing the active ingredient with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent such as sugar, lactose or starch. Such dosage forms may also contain, in normal practice, inert diluents and other additional substances, for example brighteners such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may contain a buffer. Tablets and pills may additionally be formulated with enteric coatings.

Liquid dosage forms for oral administration may contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. In addition, such compositions may contain adjuvant such as wetting agents, emulsifying and suspensions and sweetening agents, flavoring agents and the like.

Methods of synthesizing precursor drugs are reported in the publications mentioned above. The precursor compounds of B described above are easy to purchase compounds or can be obtained according to methods known in the art described for examples in the "Merck Index" 13th edition 2001. Precursors of Y having the formula (IA) are wherein the free atoms of oxygen are saturated with H and the free atoms of carbon are saturated with carboxyl, hydroxy or amine groups, which are readily available materials or are well known in the art. Can be prepared accordingly.

In general, the nitrooxyderivatives of the present invention are known in the technical literature or by methods described in the following patents or patent applications EP 722434, EP 759899, WO 00/51988, WO 00/61537, WO 00/61541 in the name of the applicant Can be synthesized using.

A) Compounds of formula (I) as defined above wherein T is -N (SO ₂ R), b 0 = 0, _c 0 = 1, T _C =-(CH ₂ ) _{n 6} O (CO)-, wherein R, Y is as defined above and n6 = 1 and can be obtained by reacting the compound of formula (II).

Wherein M. R is as defined above and Y has one of the above-mentioned meanings, wherein there is no oxygen terminal atom and is substituted by halogen atom Hal ₁ in formula (II), Hal ₁ having AgNO ₃ Halogen atom, preferably Br or Cl.

The reaction is carried out at a temperature of 0 ° C. to 80 ° C. in a suitable organic solvent, such as acetonitrile or THF.

Compounds of formula (II) as defined above can be obtained by reacting compounds of formula (III).

M-NSO ₂ R-Na ⁺

(Ⅲ)

Where M and R are as defined above as compounds of formula (IV)

Hal-CH ₂ OC (O) -Y-Hal ₁

(Ⅳ)

Wherein Hal is a halogen atom, Hal and Hal ₁ may have the same or different meanings and Y has one of the aforementioned meanings, wherein there is no oxygen terminal atom and is substituted by halogen atom Hal ₁ in formula (IV) do.

The reaction is carried out at a temperature of 0 ° to 80 ° in a suitable solvent such as dry THF.

Compounds of formula (III) are either commercially available compounds or can be obtained by chlorinating the corresponding secondary sulfonamide groups by well known reactions or by the well known reactions described in the above patents or patent applications.

The compounds of formula (IV) are either commercially available compounds or can be obtained from known compounds by well known reactions.

B) Compounds of formula (I) as defined above include T = -SO ₂ NH, b0 = 0, c0 = 1, T _C = CO, wherein M, Y as defined above are compounds of formula (V) It can be obtained by reacting.

M-SO ₂ NH-C (O) -Y-Hal ₁

(Ⅴ)

Wherein M is as defined above, Y has one of the meanings defined above and there is no oxygen terminal atom and is substituted by halogen atom Hal ₁ in formula (V) and Hal ₁ is halogen atom with AgNO ₃ , Preferably Br or Cl.

The reaction is carried out at a temperature of 0 ° to 80 ° in a suitable organic solvent such as acetonitrile or THF.

Compounds of formula (V) as defined above may be obtained by reacting compounds of formula (VI).

M-SO ₂ NH ₂ (Ⅵ)

Wherein M is a compound of formula (VIII) as defined above or a corresponding anhydride of formula (VIII)

Hal-C (O) -Y-Hal ₁ (Ⅶ) or (Hal ₁ -Y-CO) ₂ (Ⅷ)

Wherein Hal ₁ is as defined above, Hal is a halogen atom, Hal and Hal ₁ may have the same or different meanings, Y has one of the above-mentioned meanings and there is no oxygen terminal atom and no formula ( In VI) and (iii) by the halogen atom Hal ₁ .

  The reaction is carried out at a temperature of 0 ° to 80 ° in a suitable solvent, for example THF or DMF.

Compounds of formula (IV) are either commercially available compounds or can be obtained by the well known reactions described in the patent or patent application.

Compounds of formulas (iii) and (iii) are either commercially available compounds or can be obtained from known compounds by well known reactions.

The invention will be described in more detail by reference examples for the following non-limiting examples.

Example 1

N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-eden-5-yl] -N- [4- (nitrooxy) butyroyloxymethyl ] -Methanesulfonamide

1.A) N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [4- (chloro) Butyroyloxymethyl] -methanesulfonamide (1A)

A solution of chloromethyl (4-chloro) butyrate (1 g, 5.40 mmol) in anhydrous tetrahydrofuran (5 ml) was added N- [6- (2,4-difluorophenyl) in anhydrous tetrahydrofuran (25 ml). To the suspension of) thio) -2,3-dihydro-1-oxo-eden-5-yl] methanesulfonamide sodium salt (2.04 g, 5.40 mmol) was slowly added dropwise. The reaction was left overnight at room temperature with stirring. The solvent was evaporated in vacuo and the remainder was treated with methylene chloride (40 ml) and the resulting solution was washed with 5% sodium bicarbonate solution and then with water. The organic phase was dried over sodium sulfate. The crude product was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 1.12 g of the desired product.

1.B) N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [4- (nitrooxy Butyroyloxymethyl] -methanesulfonamide

A solution of product 1A (1 g, 1.98 mmol) in acetonitrile (20 ml) was added as silver nitrate (0.67 g, 3.96 mmol). The solution was heated at 80 ° C. for 15 hours without light. Silver salts were filtered off and the solvent evaporated in vacuo. The crude product was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 503 mg of the title product.

Elemental analysis

Calculated: C 48.64%; H 4.27%; F 7.32%; S 12.37%

Found: C 48.57%; H 4.03%; F 7.31%; S 12.33%

Example 2

N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [3- (nitrooxymethyl) benzoyloxy Methyl] methanesulfonamide

2.A) N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [3- (chloromethyl ) Benzoyloxymethyl] methanesulfonamide (2A)

A solution of chloromethyl (3-chloromethyl) benzoate (1.5 g, 6.80 mmol) in anhydrous tetrahydrofuran (7 ml) was added N- [6- (2,4-difluoro) in anhydrous tetrahydrofuran (45 ml). To the suspension of rophenyl) thio) -2,3-dihydro-1-oxo-eden-5-yl] -methanesulfonamide sodium salt (2.57 g, 6.80 mmol) was slowly added dropwise. The reaction was left overnight at room temperature with stirring. The solvent was evaporated in vacuo and the remainder was treated with methylene chloride (60 ml) and the resulting solution was washed with 5% sodium bicarbonate solution followed by water. The organic phase was dried over sodium sulfate. The crude product was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 1.31 g of the desired product.

2.B) N- [6- (2,4-difluorophenyl) thio) -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [3- (nitrooxy Methyl) benzoyloxymethyl] -methanesulfonamide

A solution of product 2A (1 g, 1.86 mmol) in acetonitrile (20 ml) was added as silver nitrate (0.47 g, 2.78 mmol). The solution was heated at 80 ° C. for 15 hours without light. Silver salts were filtered off and the solvent evaporated in vacuo. The crude product obtained was purified by chromatography on a silica gel column with n-hexane / ethyl acetate as eluent 8/2 to give 623 mg of the title compound.

Elemental analysis

Calculated: C 53.19%; H 3.56% F 6.73%; S 11.60%

Found: C 53.27%; H 3.43%; F 6.79%; S 11.5%

Example 3

(Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol-1-[(4-nitrooxymethyl) benzoate]

3.A) (Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol

A solution of 1M DIBAL in toluene (185 ml) was 3- [phenyl-4- (4-methylsuponyl) phenyl] -2- (5H) -furan (18.1 g, 57.1 mmol) in tetrahydrofuran (750 ml). Was slowly added into the solution.

The solution was placed under stirring at 0 ° C. for 90 minutes and then left at room temperature overnight. A 1M solution of sodium tartrate was added dropwise to the reaction mixture cooled at 0 ° C. The solution was extracted with ethyl acetate and the organic phase was washed with water and dried over sodium sulfate to give 15 g of the desired compound.

3.B) (Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol-1-[(4-chloromethyl) benzoate] (3B)

(Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol (15 g, 46.7 mmol) in a methylene chloride (30 ml) cooled to 0 ° C., tri Ethyleneamine (13.3 ml, 95.7 mmol) and 4-dimethylaminopyridine (0.76 g, 6.26 mmol) were added slowly in a solution of 4-chloromethyl benzoyl chloride (8.8 g, 46.7 mmol) in methylene chloride (30 ml). The reaction mixture was placed under stirring for 30 minutes and then oxidized with 1N HCl (100 ml). The separated organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product obtained was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 4.3 g of the titled compound.

3.C) (Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol-1-[(4-nitrooxymethyl) benzoate]

Silver nitrate (1.07 g, 6.38 mmol) was added to a solution of product 3B (3 g, 6.38 mmol) in acetonitrile (60 ml). The solution was heated at 50 ° C. for 8 hours without light. Silver salts were filtered off and the solvent evaporated in vacuo. The crude product obtained was purified by chromatography on silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 1.3 g of the titled compound.

Elemental analysis

Calculated: C 60.36%; H 4.65%; S 6.43%

Found: C 60.40%; H 4.63%; S 6.33%

Example 4

Synthesis of N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] -4-nitrooxy-butanamide

4A) N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] -4-chlorobutanamide (4A)

N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] benzenesulfonamide in pyridine (50 ml) cooled at 0 ° C. For (1 g, 2.262 mmol) solution, 4-chlorobutyrylchloride was added dropwise (0.294 ml), the solution was kept under stirring at 0 ° C. for 10 minutes, then the temperature was raised to room temperature and the solution was 2 hours Was kept under stirring. HCl was then added (50 ml, 0.1 N) and the mixture was extracted with CH ₂ Cl ₂ . The combined organic phases were washed with water, dried and the solvent was evaporated at reduced pressure. The crude compound was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 0.400 mg of product 4A.

4B) N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] -4-nitrooxybutanamide.

Silver nitrate (0.265 g, 1.56 mmol) was added to a solution of product 4A (0.380 g, 0.78 mmol) in acetonitrile (5 ml) and the solution was heated at 50 ° C. for 8 hours without light. Silver salts were filtered off and the solvent evaporated under reduced pressure. The crude product obtained was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 8/2 as eluent to give 0.4 g of the title compound.

Elemental analysis

Calculated: C 49.22%; H 3.74%; S 6.26%; F 11.12%

Found: C 49.26%; H 3.77%; S 6.28%; F 11.09%

Example 5

Synthesis of N-[(3-nitrooxymethyl) benzoyloxymethyl] -N- (2-phenoxy-4-nitrophenyl) methanesulfonamide

5.A) N-[(3-chloromethyl) benzoyloxymethyl] -N- (2-phenoxy-4-nitrophenyl) methanesulfonamide (5A)

A solution of chloromethyl 3-chloromethylbenzoate (1.5 g, 6.80 mmol) in anhydrous tetrahydrofuran (7 ml) was added N- (2-phenoxy-4-nitrophenyl) methane in anhydrous tetrahydrofuran (45 ml). To the suspension of sulfonamide sodium salt (2.25 g, 6.80 mmol) was slowly added dropwise. The reaction was left overnight at room temperature with stirring. The solvent was evaporated under reduced pressure and the rest was dissolved in methylene chloride (60 ml) and the resulting solution was washed with 5% sodium bicarbonate solution and then with water. The organic phase was dried over sodium sulfate. The crude product obtained was purified by chromatography on a silica gel column with n-hexane / ethyl acetate 7/3 as eluent to give 0.830 g of product 5A.

5.B) N- [6- (2,4-difluorophenyl) thio] -2,3-dihydro-1-oxo-1-iden-5-yl] -N- [3- (nitrooxy Methyl) benzoyloxymethyl] methanesulfonamide

Silver nitrate (0.55 g, 0.32 mmol) was added to a solution of product 5A (0.8 g, 1.63 mmol) in acetonitrile (20 ml). The solution was heated at 80 ° C. for 15 hours without light. Silver salts were filtered off and the solvent evaporated under reduced vacuum. The crude product obtained was purified by chromatography on silica gel column with n-hexane / diethyl ether 8/2 to give 0.330 g of the desired compound.

¹ H NMR (CDCl ₃ ) ppm: 3,26 (3H, s); 5,98 (2H, s); 5,5 (2H, s); 6,98-8,01 (17H, m)

Example F1

Comparison of Gastric Tolerance and Blood Pressure Effects of Compounds of the Present Invention versus Precursor Compounds

Experiments are described in M.N. Muscara 'et al. Br. J. Pharmacol. Groups of 10 mice were performed following the method described by 133, 1314, 2001 and weighing 200-250 g each.

The compounds, suspended in 1% carboxymethylcellulose, were administered orally for 2 weeks at a daily dose of 10 mg / kg body weight.

Hypertension was induced by the addition of L-NAME (N-omega-nitro-L-arginine methylester) to the beverage at a concentration of 400 mg / liter. At the end of the treatment, blood pressure was measured 16 hours after the last dose by intubation into the femoral artery and measurement of the polygraphic transducer. The animal was then sacrificed and eventually gastrointestinal damage appeared.

Example 4, described in N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] -4-nitrooxybutanamide It has been shown that the subject product of the invention is resistant to increased blood pressure. In contrast, the control COX-2 inhibitor celecoxib causes up to 80% of treated animals with gastrointestinal damage and an increase in blood pressure with an average of 15 mmHg.

Claims (23)

Has the following general formula (Ⅰ), MTY _A -NO ₂ (Ⅰ) here MT is the residue of a COX-2 selective inhibitor, where T = -SO ₂ NH-, -SO ₂ NR-,-(CO)-, -O-, -S-, -NH-, -N (SO ₂ R )-, R is alkyl with 1-10 carbon atoms and is preferably methyl, wherein the COX-2 selective inhibitor, M-TH or M-TOH must meet Experiment 2 described below; Y _A =-(B) _b0- (C) _c0 -where: b0 and C0 are integers that are 1 or 0, provided that b0 and C0 cannot be zero at the same time, B = -T _B -X ₂ -T _BI , where: T _B = CO or X, wherein X = O, S, NH, NR and R are as defined above and T is -SO ₂ NH, -SO ₂ NR-, -O-, -S-, -NH- , T _B is CO when -N (SO ₂ R)-and T _B is X when T is -CO-; When X is as defined above, T _BI is CO or X, X ₂ is a divalent radical and is selected from the following compounds: a) here: n1 and n2 are integers that are 0 or 1; R ² and R ³ are independently selected from H or CH ₃ ; b) here: n2 and R ³ are as defined above; Y ¹ is —CH ₂ —CH ₂ — or —CH═CH— (CH ₂ ) _{n 2} where n ₂ ′ is an integer equal to 0 or 1; c) here: n4 is an integer from 1 to 20 and n5 is an integer from 0 to 20 and R ⁴ and R ^{4 ′} R ⁵ and R ^{5 ′} are independently selected from H, CH ₃ , OH, NH ₂ , NHCOCH _3, COOH; When the bond is a double bond between C ^A and C ^B carbons, it is not between R ⁴ and R ⁵ or R ^{4 ′} and R ^{5 ′} ; C is a divalent radical -T _C -Y-, wherein: T _C = CO, X where X is as defined above _or- (CH ₂ ) _n6 OC (O)-where n6 is an integer from 1 to 20, preferably n6 is 1; Y is a divalent radical having the following meanings: d) -R ¹ O-, wherein R ¹ is: Eventually contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, one or more -O (CO)-, -NH (CO)-, -S (CO)-, and R ⁶ is straight or branched C ₁ Straight or branched C ₁ -C ₂₀ -alkylene substituted with one or more of the following groups —OH, —SH, —NH ₂ , —NHCOR ⁶ , —C ₁₀ -alkyl, preferably CH ₃ ; Cycloalkylene containing 5 to 7 carbon atoms as a cycloalkylene ring, wherein one or more carbon atoms can be substituted from heteroatoms selected from nitrogen, oxygen or sulfur and the ring is defined as R ⁶ is And may be substituted with side chain R ⁶ ; e) f) Wherein n7 is an integer from 0 to 20 and n7 'is an integer from 1 to 20; g) M is an integer of 1 to 6, preferably 1 to 4, and Rf is an oxygen atom or CH ₃ ; h) here: nIX is an integer of 0 to 10, preferably 1 to 5; nIIX is an integer of 1 to 10, preferably 1 to 5; 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, preferably R _TⅨ , R _{TⅨ ′} , R _TIIⅩ , R _{TIIⅩ '} ego; Y ³ is a heterocyclic saturated, unsaturated or aromatic 5 or 6 urea ring containing nitrogen, oxygen, sulfur and one or more heteroatoms selected from Assume the following: when b0 = 0, c0 = 1 and T = -SO ₂ NH-, -SO ₂ NR-, -O-, -S-, -NH-, -N (SO ₂ R)-, where R is defined above Then Tc = (CO) _or- (CH ₂ ) _n6 O (CO)-; when b0 = 0, c0 = 1 and T = CO, T _C = X and X is as defined above; b0 = 1 and T = -SO ₂ NH-, -SO ₂ NR-, -O-, -S-, -NH-, -N (SO ₂ R)-where R is as defined above, T _B = CO; T _b = X where _b 0 = 1 and T = CO where X is as defined above; T _C = X where b 0 = 1, _c 0 = 1 and T _B1 = CO where X is as defined above; b0 = 1, c0 = 1 and T _B1 = X, where X is as defined above, T _C = (CO); When b0 = 1 and c0 = 0, T _B1 can release COX-2 inhibitors and NO (nitrogen oxides) under conditions according to the parameters set in Test 1 mentioned in the detailed description of the invention, which only has the meaning of -O-. Compounds of formula (I) or salts thereof. The compound of claim 1, wherein b0 = 1, c0 = 1, T and T _C are as defined in claim 1, and Y is straight C ₁ -C ₆ alkylene or Where n7 is 0 or 1, and n7 'is 1 or 2, or Wherein m is 2 and Rf is hydrogen. The compound of claim 2, wherein b0 = 0, c0 = 1, T = -N (SO ₂ R)-, T _c = CO _or- (CH ₂ ) _n6 O (CO)-where n6 = 1 and R = CH ₃ sign Compound of Formula (I). The compound of formula (I) according to claim 2, wherein b0 = 0, c0 = 1, T = -SO ₂ NH- and Tc = CO _or- (CH ₂ ) _n6 O (CO)-wherein n6 = 1. 5. The MT according to claim 1, wherein MT is 4- (5-methyl-3-phenyllyxazol-4-yl) benzinesulfonamide (valdecokship), 4- [5- (4- Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfon-amide (celecoxib), 4- (4-cyclohexyl-2-methylroxazol-5-yl) -2 -Fluoro-benzenesulfonamide (tilmacocksip), N- [6-[(2,4-difluorophenyl) thio] -2,3-dihydro-1-oxo-1H-inden-5-yl] Methanesulfonamide (L-745337), N- (4-nitro-2-phenoxyphenyl) methanesulfonanilide, N- (4-nitro-2-cycloexyloxy-phenyl) methanesulfonanilide, 2- [ Consist of (2-fluoro-6-fluorophenyl) -amino] -5-methylbenzeneacetic acid (COX189), 2-[(2-chloro-6-fluorophenyl) -amino] -4-methylbenzeneacetic acid A compound of formula (I) or a salt thereof, wherein the compound is a residue of a COX-2 selective inhibitor of formula M-TH or M-TOH. 4. A compound according to claim 3, wherein N- (6- (2,4-difluorophenyl) thio-2,3-dihydro-1-oxo-1-eden-5-yl) -N- (4-, nitro Oxy) butyroyloxymethyl) methanesulfonamide. 4. A compound according to claim 3, wherein N- (6- (2,4-difluoro-phenyl) thio) -2,3-dihydro-1-oxo-1-eden-5-yl) -N- (3- Nitrooxymethyl) -benzoyloxymethyl) methanesulfonamide. The compound according to claim 3, which is (Z) -2- (4-methylsulfonylphenyl) -3-phenyl-2-butane-1,4-diol-1-[(4-nitrooxymethyl) benzoate] . The compound according to claim 4, which is N- [4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenylsulfonyl] -4-nitrooxybutanamide compound. 4. The compound of claim 3, which is N- (3-nitrooxymethyl) benzoyl-oxymethyl-N- (2-phenoxy-4-nitrophenyl) methane-sulfonamide.  The compound of formula (I) or a salt thereof according to any one of claims 1 to 10 as a therapeutic agent.  Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament which can be used in the treatment or prevention of inflammatory diseases, pain and the invention.  13. The method of claim 12, including but not limited to arthritis, rheumatoid arthritis, osteoarthritis, dysmenorrhea, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease, dermatitis, psoriasis, cystic fibrosis, multiple sclerosis, vasculitis, and organ transplant rejection Use of a compound of formula (I) or salts thereof characterized by an inflammatory disease selected from Use of a compound of formula (I) or salts thereof according to any one of claims 1 to 10 for the manufacture of a medicament which can be used in the treatment or prevention of cardiovascular diseases. The method of claim 14, wherein the cardiovascular diseases are selected from the group consisting of, but not limited to, arteriosclerosis, restenosis, coronary artery disease, angina pectoris, diabetes, diabetic nephropathy, diabetic retinopathy, encephalopathy, and myocardial infarction. Use of a compound of formula (I) or a salt thereof characterized by the above-mentioned. Use of a compound of formula (I) or a salt thereof for the preparation of a medicament for use in the treatment or prevention of gastrointestinal diseases. 17. The method of claim 16, wherein the gastrointestinal diseases are inflammatory bowel disease, Crohn's disease, gastritis, ulcerative colitis, peptic ulcer, hemorrhagic ulcer, gastric acidosis, indigestion, gastric palsy, Solinger-Elison syndrome, bacterial infection, systemic mastocytosis or Use of a compound of formula (I) or a salt thereof, wherein said compound is selected from the group consisting of but not limited to hypersecretory conditions associated with basophilic leukemia and hyperhystaminemia. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament that can be used in the treatment or prevention of tumors and Alzheimer's disease. Use of a compound of formula (I) or a salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament that can be used in the treatment or prevention of diseases resulting from elevated COX-2 levels. The method of claim 19, wherein the disease resulting from elevated COX-2 levels is angiogenesis, arthritis, asthma, bronchitis, dysmenorrhea, tendinitis, bursitis, neoplasm, ophthalmic disease, pulmonary inflammation, central nervous system disease, allergic rhinitis, Use of a compound of formula (I) or a salt thereof, which is selected from the group consisting of, but not limited to, atherosclerosis, endothelial disease, organ and tissue preservation, inhibition and / or prevention of platelet aggregation. The pharmaceutical composition according to any one of claims 1 to 10, comprising a pharmaceutically effective amount of the compound of formula (I) or salts thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 21 in suitable oral, parenteral, rectal or topical form and in a percutaneous suitable form by inhalation spray or aerosol or ion transport device. The tablets, capsules and eventually enterically coated pills, powders, according to any one of claims 1 to 10, which contain the compound of formula (I) or salts thereof and pharmaceutically acceptable carriers. Liquid or solid pharmaceutical compositions for oral, parenteral, rectal or topical administration and inhalation in granules, gels, emulsions, solutions, suspensions, syrups, elixirs, injectable forms, suppositories, transdermal patches or liposomes.