HUP0200747A2 - Pharmaceutical compounds and pharmaceutical compositions containing them - Google Patents

Description

P02 00 74 7

DANUBIA Patent and Trademark Office Ltd. p ^Buda P ^est PUBLICATION - ¹ COPY

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The invention relates to novel active compounds which can be administered systemically or non-systemically, and to compositions containing such compounds. The compounds and compositions of the invention are useful in the treatment of diseases caused by oxidative stress and/or endothelial disorders.

Oxidative stress is the formation of free radicals or radical compounds that damage both cells and surrounding tissues (Pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998, 48-54).

The term endothelial disorders refers to disorders of the vascular endothelium. Damage to the vascular endothelium is known to be one of the most important events that causes serious pathological changes in various organs and body parts, as previously described (Pathophysiology: The biological basis for disease in adults and children, McCance & Huether 1998, 1025).

Oxidative stress and/or endothelial dysfunction are known to be associated with various pathologies, as described below. Oxidative stress can be caused by the toxicity of a wide variety of drugs, significantly affecting the performance of the active ingredients.

95450-8077 OE/OEM

-2Such pathological events are chronic, debilitating, and very often characteristic of old age. As already mentioned, in such pathological conditions the active substance shows significantly reduced performance.

Pathological changes caused by oxidative stress and/or endothelial dysfunctions (disorders) or old age include, for example:

in the cardiovascular system: myocardial and vascular ischemia in general, hypertension, stroke, arteriosclerosis, etc.

in connective tissues: rheumatoid arthritis and related inflammatory diseases, etc.

in the pulmonary system, asthma and related inflammatory diseases, etc.

ulcerative and non-ulcerative digestive disorders in the gastrointestinal system, inflammatory bowel diseases, etc.

in the central nervous system: Alzheimer's disease, etc. in the urogenital system: impotence, incontinence, in the skin system: eczema, neurodermatitis, acne, infectious diseases in general (Schwarz - KB, Brady Oxidative stress during viral infection: A review Free radical Biol. Med. 21/5, 641-649 1996).

Furthermore, the aging process can also be considered a true pathological condition (Pathophysiology: the biological basis for disease in adults and children, 71-77).

If patients have a known predisposition to pathological changes associated with oxidative stress and/or endothelial dysfunction

-3- :.:.-:: ·· ··active substances are administered, they show lower activity and/or higher toxicity.

This happens, for example, in the case of the following active substances: anti-inflammatories, cardiovascular active substances, substances acting on the respiratory system, substances acting on the central nervous system, substances acting on the skeletal system, antibiotics, substances acting on the urogenital system, substances acting on the endocrine system, etc.

Research on active ingredients is aimed at developing new molecules with an increased therapeutic index (efficacy/toxicity ratio) or a lower risk/benefit ratio in the above-mentioned pathological cases, in which the therapeutic index has been reduced for a large number of active ingredients. In fact, in the above cases, triggered by oxidative stress and/or endothelial dysfunction, many active ingredients show reduced activity and/or higher toxicity.

Many anti-inflammatory agents, such as various NSAIDs and anti-colitic agents, such as 5-aminosalicylic acid and its derivatives, exhibit the above-mentioned disadvantages. In the case of NSAIDs, toxicity occurs in particular when the organ is weakened or is exposed to pathological effects attributable to oxidative stress. Such effects include, for example, the following: age, pre-existing ulcer, pre-existing gastric bleeding, debilitating chronic diseases, such as those affecting the cardiovascular, renal organs, blood components, etc. (Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal antiinflammatory drugs. A randomized, double blind, placebo-controlled trial. FE Silverstein et al., Ann. Intern. Med. 123/4, -241-9, 1995; Martindale 31a. ed. 1996, 73, Current Medical Diagnosis and Treatment 1998, 431 - 794).

The administration of the above anti-inflammatory agents for the treatment of the aforementioned pathological lesions can only be carried out at lower doses in order to avoid significant toxicity, thus the anti-inflammatory effect is weak.

Beta-blockers, which are used to treat angina, high blood pressure and cardiac arrhythmia, have side effects on the respiratory system (difficulty breathing, bronchial constriction) and can thus cause problems in patients with disorders of these organs (asthma, bronchitis). In this way, beta-blockers can even worsen respiratory diseases, such as asthma. Therefore, such active substances can only be administered to asthmatic patients in reduced doses so as not to further compromise the functioning of the respiratory organs. In this way, the effect of beta-blockers is significantly reduced.

Anti-thrombotic agents such as dipyridamole, aspirin, etc., which are used to prevent thrombotic events, have similar drawbacks. In patients with pathological changes caused by oxidative stress and/or endothelial dysfunction, the therapeutic effect or tolerability of these agents, for example aspirin, is greatly reduced.

Bronchodilators, such as salbutamol, etc., are used to treat asthma and bronchitis, while substances that act on the cholinergic system are used to treat, for example, urinary incontinence. These

-5- .: -:

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may cause side effects affecting the cardiovascular system and may cause problems in patients with heart disease and hypertension. Heart disease and hypertension are pathological changes associated with oxidative stress and/or endothelial dysfunction. These active ingredients also show the disadvantages mentioned above.

Expectorants and mucolytics, which are used to treat inflammatory conditions of the respiratory tract, also have disadvantages in patients with the diseases described above. In such cases, administration may cause heartburn and gastric irritation, especially in the elderly.

Bone resorption inhibitors, such as diphosphonates (e.g. alendronate, etc.), have high gastrointestinal toxicity. Thus, these drugs also have the same disadvantages as those mentioned above.

Phosphodiesterase inhibitors, such as sildenafil, zaprinast, which are used in cardiovascular and respiratory diseases, also show problems related to tolerability and/or efficacy in pathological conditions associated with oxidative stress and/or endothelial dysfunctions.

Antiallergic agents, such as cetirizine, montelukast, etc., show similar problems in the aforementioned pathological conditions, especially with regard to their efficacy.

-6- ·.'* ;** .5 '·*:

Anti-angiotensin-active substances, such as ACE inhibitors, such as enalapril, captopril, etc., and receptor inhibitors, such as losartan, etc., are also disadvantageous due to their side effects on the respiratory system (e.g. cough, etc.) when the above pathological conditions exist.

Antidiabetic drugs, both insulin-sensitizing and hypoglycemic, such as sulfonylureas, tolbutamide, glipizide, gliclazide, glyburide, nicotinamide, etc., are used to prevent diabetic complications. Side effects, such as gastric damage, may also occur during their administration. These phenomena become more intense under the pathological conditions described above.

Antibiotics (such as ampicillin, clarithromycin, etc.) and antiviral drugs (acyclovir, etc.) may cause tolerability problems, for example, they may cause gastrointestinal irritation.

Antitumor agents such as doxorubicin, daunorubicin, cisplatin, etc., are highly toxic to various organs, such as the stomach and intestines. This toxicity is further exacerbated in the pathological conditions associated with oxidative stress and/or endothelial dysfunction mentioned above.

Antidementia drugs, such as nicotine and cholinomimetics, are characterized by poor tolerability, especially in the above pathological cases.

In the case of active substances with a steroid structure, which are used, for example, in acute diseases (e.g. asthma) or chronic diseases (e.g. intestinal, liver, respiratory diseases,

-Ί - :./ ··/ female genitals, skin-related diseases) significant toxic effects occur in connection with various organs, especially in the above oxidative stress-induced diseases.

Steroid drugs (e.g. hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone-acetonide, fluocinolone-acetonide, beclomethasone, acetoxipregnelone, etc.) have significant pharmaco-toxicological effects on various organs and therefore both their clinical use and withdrawal cause serious side effects, some of which can be very serious (Goodman & Gilman, The pharmaceutical Basis of Therapeutics 9th ed., 1459-1465, 1996.)

Among the toxic effects mentioned, we can mention, for example, the effect on bone tissue, which can lead to altered cellular metabolism and the development of significant osteoporosis; they affect the cardiovascular system, inducing hypertension and affect the gastrointestinal system, causing gastric damage (Martindale The extrapharmacopoeia, 30th edition, 712-723, 1993).

Bile acids are a group of steroid drugs that are used in cases of liver damage and biliary colic. Ursodeoxycholic acid is also used in certain liver disorders (biliary cirrhosis, etc.). Their tolerability is greatly impaired in cases of gastrointestinal complications (chronic liver damage, acid ulcers, enteritis, etc.). Oxidative stress is also a significant factor in the case of bile acids.

-8- .: · significantly affects the performance of the active substance: both efficacy and tolerability are significantly impaired in the case of chenodeoxycholic acid and ursodeoxycholic acid. In particular, the undesirable effect on the liver is high. Among the steroid compounds, we can also mention, for example, estrogens, which can be used to treat dyslipidemia, hormonal dysfunctions, and tumors of the female organs. These steroids also show the above side effects, especially affecting the liver.

It is apparent from the prior art literature cited above that it is nearly impossible to separate the therapeutic effect from the side effects (see Goodman et al., supra, p. 1474).

There is a need for active ingredients that exhibit improved therapeutic effects, i.e., lower toxicity and/or greater efficacy, such that they can be administered to patients with adverse conditions caused by oxidative stress and/or endothelial dysfunction, without the disadvantages of the active ingredients known to date.

Surprisingly and unexpectedly, we have found that the above problems with the administration of active substances to patients suffering from diseases caused by oxidative stress and/or endothelial dysfunctions or old age can be solved with the new family of active substances described below.

Based on the above, our invention relates to compounds of general formula (I) and their salts - in the formula

A is R—T _r , where R is an active group and Ti is (CO) _t or (X) _t , where X=O, S, NR] _C , where R _lc is H or a straight or branched chain 1-5 carbon atom

-9-alkyl group or a valence bond, t and t' are 0 or 1, with the proviso that t=1, hat'=0; t=0 when t-1;

B is -T _B ~X2, where T _B is (CO) when t=0, T _B is X, when t'=0, X is as above;

X ₂ is a monovalent group and is such that the corresponding precursor B satisfies test 5 and/or test 4; said precursor -T _B —X, where T _B is a free valence, is saturated with an OZ or Z group, where Z=H or R _{1 a} , R] _a =C 1-10 straight or branched chain alkyl group, preferably C 1-5 alkyl group, or a

-ΖρΝ-Ζπ group, where Zj or Z _It is the same as or different from the value of Z, depending on whether T _B = CO or X, t, t' are associated with the values;

with the proviso that:

the A=R—Tj- group, where the free valence is saturated as follows:

- if t —0 with the following group:

- OZ, where Z=H or R _ia , which has the meaning above, or

with the group -Zj-N-Zn, where Zj and Z _B have the same meanings as above,

- if t=0, with group XZ, where X and Z have the same meanings as above,

- 10 such that it meets at least one of the following tests 1-3;

wherein test 1 (NEM) is an in vivo test performed on four groups of rats (each group containing 10 rats), two of which are control groups, two of which are treated groups, one of which is treated with 25 mg/kg sc N-ethylmaleimide (NEM), the controls are treated with vehicle and the treated groups are treated with vehicle + A=R-Ti- active compound, where the free valence is saturated as above, the dose of active compound is the maximum dose tolerated by rats not given NEM, i.e. the highest dose at which no toxicity occurs in the animals, i.e. no appreciable amount is observed; the active ingredient satisfies Test 1, i.e. the active ingredient can be used to prepare the compounds of formula (I) and (II) if the group of rats treated with the combination of NEM + vehicle + active ingredient shows gastrointestinal damage, or if the group treated with the combination of NEM + vehicle + active ingredient shows gastrointestinal damage that is greater than that observed in the group treated with the vehicle, or in the group treated with the combination of vehicle + active ingredient or in the group treated with the combination of vehicle + NEM;

where test 2 (CIP) is an in vitro test in which human endothelial cells are collected from the umbilical vein under standard conditions and then divided into two groups (each group containing five replicates), one of which is treated with a mixture containing 10' ⁴ M of active substance and culture medium, the other with vehicle only, and cumene hydroperoxide (CIP) is then added to both groups at a concentration of 5 mM in culture medium; the active substance satisfies test 2, i.e. the active substance can be used for the preparation of compounds of general formula (I) and (II) if the inhibition of apoptosis (cell damage) induced by CIP is not statistically significant at p <0.01 compared to the group treated with vehicle and CIP;

wherein test 3 (L-NAME) is an in vivo test conducted on four groups of rats (each containing ten rats) for four weeks, to which drinking water is administered, the control group (two groups) and the treatment group (two groups) constitute two groups, of which a control group and a treatment group are administered Ν-ω-nitro-L-arginine methyl ester (L-NAME) in the drinking water at a concentration of 400 mg/l for four weeks; the control group is administered a vehicle for 4 weeks, the treatment group is administered a vehicle + active ingredient combination for 4 weeks, the vehicle or vehicle + active ingredient combination is administered once a day, and the amount of active ingredient is the maximum dose tolerated by the group of rats that have not been pretreated with the L-NAME compound, i.e. the highest dose that can be administered without toxicity, i.e. without noticeable toxicity; after 4 weeks, water intake is stopped for 24 hours, then the rats are killed, blood pressure is determined 1 hour before killing, then after killing the rats, the plasma glutamine-pyruvate transaminase (GPT) amount is measured and the stomach tissue is examined; the active substance satisfies test 3, i.e. the active substance can be used for the preparation of compounds of general formula (I) and (II), if L-NAME +

- 12The group treated with the vehicle + active ingredient combination showed greater liver damage (higher GPT value) and/or stomach damage and/or cardiovascular damage (higher blood pressure value) compared to the group treated with vehicle alone or the group treated with the vehicle + active ingredient combination or the group treated with the vehicle + L-NAME combination;

where test 4 is an analytical test performed by adding a methanol solution containing 10' ⁴ M of precursor to a methanol solution of DPPH (2,2-diphenyl-l-picrylhydrazyl free radical); then the solution is kept at room temperature away from light for 30 minutes, then the absorbance of the test solution and the solution containing only DPPH is measured at 517 nm; then the inhibition of radical formation induced by the precursor by DPPH is calculated in percent based on the following relationship:

(1 - A _s /A _c )X100 where A _s and A _c are the absorbance of the solution containing the test compound + DPPH combination and the solution containing only DPPH, respectively; precursor compound B complies with test 4 if the percentage of inhibition is greater than or equal to 50%;

where test 5 is an analytical test performed by adding an aliquot of a methanolic solution of 10' ⁴ MB precursor, the free valence of which has been saturated as above, to a solution obtained by mixing an aqueous solution of 2 mmol of deoxyribose with 100 mmol of phosphate buffer and 1 mmol of Phen(NH ₄ ) ₂ (SO 4 ) 2 salt; then the solution is incubated at 37°C for 1 hour, and then 2.8% sodium hydroxide is added in this order

- 13 aliquots of aqueous trichloroacetic acid solution and 0.5 M thiobarbituric acid, then mix for 15 minutes at 100°C and measure the absorption of the test solutions at 532 nm; the percentage inhibitory effect of the B or B] or C=-T _c -YH precursors on the radical formation induced by Fen is calculated based on the following relationship:

(1 - A _s /A _c )X100 where A _s and A _c are the absorbances of the test compounds and iron salt, and of the solutions containing only iron salt, the compound satisfies Test 5 if the percentage inhibition value determined as above for precursor B is greater than or equal to 50%.

Preferably, precursor B, which satisfies test 5, is selected from the following compounds:

amino acids: aspartic acid (PI), histidine (PII), 5-hydroxytryptophan (PII), 4-thiazolidinecarboxylic acid (PIV), 2oxo-4-thiazolidinecarboxylic acid (PV);

mono- and polyalcohols and thiols: 2-thiouracil (QI) compound, 2-mercaptoethanol (QII) compound, hesperidin (QIII) compound, secalciferol (QIV) compound, 1-oc-OH vitamin D2 (QV) compound, flocalcitriol (QVI) compound, 22-oxacalcitriol (QVII) compound, vitamin D3 derivative esterified with vitamin A group compound (QVIII) compound, (QIX) compound, 24,28-methylene-la-hydroxyvitamin D2 (QX) compound, la,25-dihydroxyvitamin D2 derivative compound (QXI) compound, 2mercaptoimidazole (QXII) compound,

- 14-succinic acid compound (Rí), compound of general formula (RII), in which n°3 is identically or differently zero or 1, n3 is identically or differently a number from 0 to 3; W is identically or differently one of the following groups: HX, where X is as above, COOH, R', OR', where R' is a straight or branched alkyl group having 1-20 carbon atoms, preferably 1-6 carbon atoms; Rf, ORf, where Rf is identically or differently R', but contains at least one halogen atom instead of H, preferably F; at least one of the W groups is XH, the reactive group of the active ingredient is a carboxyl group; or COOH, if the reactive group of the active ingredient is XH; if n°=0, if n3 is different from O, then the free valence of the n3 group is saturated with one or more of the following groups: R', OR', Rf, ORf, H; if n°3=0 and n3=0, the free valence is saturated with H.

The precursor compound B that satisfies test 4 is preferably selected from the following compounds:

amino acids, which are the following: L-carnosine (Cl) compound, anserine (CII) compound, selenocysteine (CIII) compound, selenomethionine (CIV) compound, penicillamine (CV) compound, N-acetylpenicillamine (CVI) compound, cysteine (CVII) compound, N-acetylcysteine (CVIII) compound, glutathione (CIX) or esters thereof, preferably ethyl or isopropyl esters.

- 15 In the case of the compound of formula (CV), the compound of formula (CVI), the compound of formula (CVII) and the compound of formula (CVIII), where an SH group is present, the corresponding SN(O) _s compound can also be used, where s is 1 or 2;

hydroxy acids from the following: gallic acid (Dl), ferulic acid (DII), gentisic acid (Dili), citric acid (CIV), caffeic acid (DV), hydrocaffeic acid (DVI), p-coumaric acid (DVII), vanillic acid (DVIII), chlorogenic acid (DIX), kynurenic acid (DX), syringic acid (DXI), aromatic and heterocyclic mono- and polyalcohols from the following:

nordihydrogallate (EI) compound, quercetin (EH) compound, catechin (EIII) compound, kaempferol (EIV) compound, sulfuretin (EV) compound, ascorbic acid (ÉVI) compound, isoascorbic acid (ÉVII) compound, hydroquinone (EVIII) compound, gossypol (EIX) compound, reductic acid (EX) compound, methoxyhydroquinone (EXI) compound, hydroxyhydroquinone (EXII) compound, propylgallate (EXIII) compound, sucrose (EXIV) compound, vitamin E (EXV) compound, vitamin A (EXVI) compound, 8-quinolol (EXVII) compound, Compound of formula 3-tert-butyl-4-hydroxyanisole (EXVIII), compound of formula 3-hydroxyalicone (EXIX), compound of formula 3,5-tert-butyl-p-hydroxytoluene (EXX)

- compound 16, compound of formula p-tert-butylphenol (EXXI), compound of formula timolol (EXXII), compound of formula xibornol (EXXIII), compound of formula 3,5-di-tert-butyl-4-hydroxybenzylthioglycolate (EXXIV), compound of formula 4'-hydroxybutyranilide (EXXV), compound of formula guaiacol (EXXVI), compound of formula tocol (EXXVII), compound of formula isoeugenol (EXXVIII), compound of formula eugenol (EXXIX), compound of formula piperonyl alcohol (EXXX), compound of formula allopurinol (EXXXI), compound of formula coniferyl alcohol (EXXXII), compound of formula 4-hydroxyphenethyl alcohol (EXXXIII), compound of formula p-coumarin alcohol (EXXXIV), curcumin (EXXXV);

aromatic and heterocyclic amines from the following: N,N'-diphenyl-p-phenylenediamine (MI), ethoxyquin (MII), thionine (MII), hydroxyurea (MIV);

a compound containing at least one free acid group from the following: a compound of the formula 3,3'-thiodipropionic acid (NI), a compound of the formula fumaric acid (NII), a compound of the formula dihydroxymaleic acid (NIII), a compound of the formula thioctic acid (NIV), a compound of the formula edetic acid (NV), a compound of the formula bilirubin (NVI), a compound of the formula 3,4-methylenedioxycinnamic acid (NVII), a compound of the formula piperonyl acid (NVIII).

The active ingredient and the precursor compounds B are prepared according to methods known in the art, for example as described in The Merck Index, 12th edition, (1996).

- 17A retinoic acid derivative of vitamin D3 (formula QVIII) is

According to JP 93039261 (CA 119 117617), the compound of formula (QIX) according to EP 562497; 24,28-methylene-1α-hydroxyvitamin D2 (QX) according to EP 578494; and the dehydroxyvitamin D2 (QXI) derivative according to EP 549318.

Compounds B that satisfy Test 4 are preferred.

The tests for identifying the precursor of the active ingredient R in the compound of general formula (I) are detailed as follows:

Test 1 (NEM): evaluation of gastrointestinal damage caused by oxidative stress induced by free radicals following the administration of N-ethylmaleimide (NEM) (HG Utley, F. Bernheim, P. Hochstein Effects of sulphydril reagents on peroxidation in microsomes Archiv. Biochem. Biophys. 118, 29-32 1967).

The test animals (rats) are divided into the following groups (10 animals per group):

A) control group

Group 1: treatment: with vehicle only (1% w/v aqueous carboxymethylcellulose suspension, dose 5 ml/kg, if the active substance is administered orally or physiological saline solution, if the administration is carried out parenterally, e.g. subcutaneously, intraperitoneally, intravenously or intramuscularly),

Group 2: treatment: vehicle as above + NEM, groups treated with active substance B):

- Group 18I: treatment: vehicle + active substance,

Group II: treatment: vehicle + active substance + NO.

Administration is carried out according to known dosages for the active ingredient and may be oral or subcutaneous, intraperitoneal, intravenous or intramuscular.

The dose of NEM is 25 mg/kg in saline (subcutaneously) and the active substance is administered 1 hour later, suspended in the vehicle, at a dose corresponding to the maximum or highest dose that can be tolerated by the rats in the group that have not been pretreated with NEM, i.e. the highest dose that can be administered without toxicity, i.e. no clear symptoms of toxicity. The animals are sacrificed after 24 hours and then examined for damage to the gastrointestinal mucosa.

The active substance satisfies test 1, i.e. it can be used for the preparation of compounds (I) and (II), if gastrointestinal damage is detected in rats treated with the combination of NEM + vehicle + active substance, or the observed gastrointestinal damage is greater than that shown by the group treated with vehicle alone or with the combination of vehicle + active substance or with the combination of vehicle + NEM, even if the pharmacotherapeutic efficacy of the active substance is not significantly reduced when tested with specific tests.

Test 2 (CIP): endothelial cell protection parameters against oxidative stress induced by cumene hydroperoxide (CIP).

- 19 • ·« ·*· · ·

Umbilical vein endothelial cells are prepared in a known manner. Fresh umbilical veins are saturated with a 0.1% by weight collagenase solution and incubated at 37°C for 5 minutes.

The veins are then flushed with M 199 (GIBCO, Grand Island, NY) pH 7.4 medium, to which the substances described in the examples are added. The cells are then separated from the flushing fluid by centrifugation, transferred to T-75 culture medium and pretreated with human fibronectin. The cells are then collected in the same medium, 10 ng/ml of bovine hypothalamic growth factor is added. When in primary cell culture (i.e. obtained directly ex vivo) the cells form a single layer of confluent cells (approx.

000 000 cells/dish), the culture is stopped, the layers are washed and trypsinized. The suspensions are then transferred to the wells of a 24-well cell culture plate, half of the wells are added with the same culture medium containing ΙΟ' ⁴ M active substance and incubated at 37°C with constant humidity. Only cells from the first subculture are used for cumene hydroxyperoxide (CIP) experiments. The cells are identified as endothelial cells by morphological examination and their specific immunoreactivity to factor VIII; these cultures showed no contamination from myocytes or fibroblasts.

Before starting the test, the cell culture medium is removed from the cellular layers and washed carefully with physiological saline at 37°C. The wells of the culture plate are then incubated for 1 hour in the presence of 5 mM CIP. Cell damage (apoptosis) is assessed by determining the

-20«·« ♦ ·« · « • · * « · ·4· ·· ·4 · ·

Percentage change in DNA fragmentation compared to the control group (group treated with CIP compound only), determined by fluorescence change at 405-450 nm. The tests are performed on five parallel samples.

The active ingredient complies with the test, i.e. it can be used to produce compounds of general formula (I) and (II), if the inhibition of apoptosis (cell damage) induced by CIP compared to samples treated with CIP alone is not statistically significant at p < 0.01.

Test 3 (L-NAME): Evaluation of endothelial dysfunction induced by administration of L-NAME (N ^w -nitro-L-arginine methyl ester) (J. Clin. Investigation 90, 278-281, 1992).

Endothelial functions were examined and evaluated by determining gastrointestinal mucosal damage, liver damage, and hypertension induced by L-NAME administration.

The experimental rats were divided into the following groups: for L-NAME administration, the treatment was carried out for 4 weeks, the compound was administered in a quantity of 400 mg/l in drinking water. The following groups were formed (10 animals per group):

A) control groups

Group 1: only vehicle was administered (1% w/v aqueous suspension of carboxymethylcellulose, dose 5 ml/kg if the active substance was administered orally, physiological saline if the administration was parenterally),

2nd group: carrier + L-NAME,

B) drug-treated groups:

3° group: carrier + active ingredient,

-21 4° carrier + active ingredient + L-NAME.

Administration was carried out in a manner known for the active substance, orally, subcutaneously, intraperitoneally, intravenously or intramuscularly.

The drug was administered at the highest dose tolerated by animals not treated with L-NAME, i.e. the highest dose at which no apparent toxicity, i.e. no noticeable symptoms, occurred. The drug was administered once daily for 4 weeks.

After 4 weeks of treatment, drinking water was withdrawn and the animals were killed after 24 hours.

Blood pressure was determined 1 hour before sacrifice and the increase in blood pressure was considered as damage to the vascular endothelium. Gastric mucosal damage was performed as described in Test 1 (see Example F1). Liver damage was examined by determining glutamine-pyruvate transaminase (GPT increase) after sacrifice.

The active substance complies with test 3, i.e. it can be used for the preparation of compounds of general formula (I) and (II), if animals treated with the combination of L-NAME + active substance + vehicle showed greater liver damage (GPT) and/or greater stomach damage and/or greater cardiovascular damage (higher blood pressure) compared to the groups treated with vehicle alone or with the combination of vehicle + active substance or with the combination of vehicle + L-NAME; even if

-22 the pharmacotherapeutic efficacy of the active substance was not significantly reduced as determined by a specific test.

In in vivo tests 1 and 3 above, the therapeutic index of the active substance decreased because the usual dose at which the active substance could exert its effect was no longer tolerable.

Test 4 is a colorimetric assay to determine whether precursor B inhibits the formation of radicals induced by DPPH (2,2-diphenyl-1picrylhydrazyl) (MS Nenseter et al., Atheroscler. Thromb. 15, 1338-1344, 1995).

A 100 pmol methanol solution of the test substances is prepared and an aliquot of the solution is added to a 0.1 M methanol solution containing DPPH. The resulting solutions are stored at room temperature, protected from light, for 30 minutes, and then their absorbance is measured at 517 nm, simultaneously with the appropriate, similar concentration of DPPH solution. The increase in absorbance is determined in comparison to the DPPH solution of the same concentration. The effectiveness of the test compound in inhibiting DPPH-induced radical formation is calculated based on the following relationship:

(1 - A _s /A _c )X100 where A _s and A _c are the absorbance of the test compound and DPPH combination and the solution containing only DPPH, respectively.

A precursor compound satisfies Test 4 if the percentage inhibition of radical formation from DPPH, determined as above, is greater than or equal to 50%.

Test 5 is a colorimetric assay in which a 10' ⁴ M methanol solution of the compounds to be tested is added.

-23 is prepared and a 0.1 ml aliquot is added to a test tube containing 0.2 ml of a solution composed of the following: 2 ml of 2 M deoxyribose, 0.4 ml of phosphate buffer pH 7.4, 100 mM and 0.1 ml of 1 mM Fe _n (NH4) ₂ (SO4)2 salt in 2 mM HCl. The test tubes are incubated at 37°C for 1 hour, then the following are added to each in this order: 0.5 ml of 2.8% aqueous trifluoroacetic acid solution and 0.5 ml of 0.1 M aqueous thiobarbituric acid solution. The reference solution is obtained by adding 0.5 ml of methanol to the test tube containing only the aqueous solution as described above. The test tubes are closed and heated in an oil bath at 100°C for 15 minutes. A pink coloration develops, the intensity of which is proportional to the amount of deoxyribose undergoing radical oxidative degradation. The solutions are cooled to room temperature and the absorbance at 332 nm is measured relative to the blank. The inhibitory effect of precursor AB on Fen-induced radical formation is calculated using the following equation:

(1 - A _s /A _c )X100 where A _s and A _c are the absorbance of the test compound + iron salt combination and the iron salt only solution, respectively, the compound satisfies Test 5 if the percentage inhibition of radical formation is greater than or equal to 50%.

Surprisingly, we have found that the compounds of general formula (I) according to the invention show an increased therapeutic index among oxidative stress effects, compared to the precursor active ingredients.

By way of illustration, the following compounds are referred to in the tests described above (see tables).

Test 1: precursor drug: indomethacin

- Maximum dose for rats 2.5 mg/kg po. At higher doses, toxicity can be observed, characterized by enteropathy, tremors and sedation up to death (within 24 hours).

- Rats treated with the combination of NEM + indomethacin suffer gastrointestinal damage at the above dose.

Since indomethacin induces gastrointestinal damage in animals treated with NEM compound, this satisfies Test 1. Indomethacin can thus be used to prepare the compounds of formula (I) and (II) according to the invention.

Test 2: precursor active ingredients: indomethacin, paracetamol and mesalamine.

Indomethacin and paracetamol satisfy test 2, as the inhibition of cell damage (apoptosis) induced by the CIP compound does not differ significantly compared to the control.

Based on the above, these active ingredients can be used for the preparation of the compounds of the general formula (I) and (II) according to the invention.

In contrast, mesalamine does not satisfy Test 2, as it inhibits CIP-induced apoptosis. Therefore, mesalamine cannot be used as a precursor for the preparation of compounds of formula (I) and (II) according to the invention according to Test 2. However, we have found that mesalamine causes gastrointestinal damage according to Test 1.

-25Based on this, mesalamine can also be used as a precursor of the compounds of the invention of general formula (I) and (II).

Test 3 (L-NAME precursor drugs): paracetamol, simvastatin, omeprazole

Paracetamol and simvastatin satisfy test 3 because the gastric and hepatic damage caused is greater than the damage caused by the L-NAME + vehicle combination and the drug + vehicle combination.

In this way, these active ingredients can be used as precursors in the preparation of the compounds of general formula (I) and (II) according to the invention.

In contrast, we found that omeprazole neither causes gastric nor hepatic damage nor does it affect blood pressure. Based on test 3, omeprazole cannot be used as a precursor in the preparation of the compounds of general formula (I) and (II) according to the invention.

Test 4 (test for precursor compounds B)

N-acetylcysteine inhibits the formation of DPPH-induced radicals by 100% in the aforementioned test. Since this percentage is higher than the 50% limit, this active ingredient cannot be used as precursor B in the solution according to the invention.

4-Thiazolidinecarboxylic acid does not inhibit DPPH-induced radical formation to any extent (Table 5), so this active ingredient does not meet the requirements of Test 4 and can be used as precursor B if it meets the requirements of Test 5.

Test 5 (test for precursor B)

-26From Table III for this test, it is apparent that 4-thiazolidinecarboxylic acid satisfies the requirements of Test 5, since the inhibition value is 100%. Thus, this compound can be used as precursor B.

In the compounds of general formula (I) according to the invention, preferably group B contains free reactive functional groups, which are preferably one or more of the following groups: XZ or

-Z _r NZ _n where X, Z, Zi and Z _n are as above or COOH, =NH.

If the group B contains a free reactive group, it can be suitably reacted with compounds of general formula (III), where the free valence is saturated with reactive groups and thus capable of reacting with the reactive group of B, in general formula (III) the value of n1X is a number from 0 to 3, preferably 1,

Rtix, R-tix', identically or differently, represent a hydrogen atom or a straight or branched chain alkyl group having 1-4 carbon atoms, preferably Rtix, Rtix· represents a hydrogen atom.

Y ³ represents a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom, preferably one or two nitrogen atoms, which ring has 5 or 6 atoms, the Y ring may optionally be substituted, the substituent may be, for example, a CH ₂ OH group.

-27 In general formula (III), Y ³ preferably represents a nitrogen-containing group of the formula (Y1)-(Y15), π

Particularly preferably, Y is a pyridyl group (Y12).

The salts of the compounds of formula (I) are prepared by reacting them with an equimolar amount of an appropriate organic or inorganic acid in an organic solvent, for example acetonitrile or tetrahydrofuran.

Examples of organic acids include: oxalic acid, tartaric acid, maleic acid, succinic acid, citric acid.

Examples of inorganic acids include: nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.

The compounds of the invention can be used to provide the desired benefits in the therapeutic indications of the precursor drugs, some of which are listed below:

Anti-inflammatory NSAID agents: the compounds of the invention are well tolerated and effective even when the body is weakened and exposed to oxidative stress. These agents can also be used in pathological conditions where inflammation plays a significant pathogenic role, such as, but not limited to, cancer, asthma, myocardial infarction.

Adrenergic blockers, α- or β-blocking type: the spectrum of action of the compounds of general formula (I) is broader than that of the starting active ingredients: the direct effect on smooth muscles is accompanied by the inhibition of β-adrenergic neural signals controlling the contraction of the hepatic ducts. Side effects affecting the respiratory system (cough, tracheal contraction) are less.

-28 Anti-thrombotic agents: the effect on platelet aggregation is increased and in the case of aspirin derivatives, gastric tolerability is better.

Bronchodilators and agents acting on the cholinergic system: side effects affecting the cardiovascular system (tachycardia, high blood pressure) are less.

Expectorants and mucolytic agents: gastrointestinal tolerability is better.

Diphosphonates, the toxic effect on the gastrointestinal tract is drastically reduced.

Phosphodiesterase (PDE) inhibitors (bronchodilators): the therapeutic effect is increased at the same dose; this makes it possible to administer the active ingredients of the invention at lower doses and thus reduce side effects.

Anti-leukotriene agents: better efficacy.

ACE inhibitors: better therapeutic efficacy, fewer side effects on the respiratory system (cough, shortness of breath).

Anti-diabetic agents (insulin sensitizing and hypoglycemic), antibiotic, antiviral, anti-tumor, anti-colitic agents and agents used in the treatment of dementia: improved efficacy and/or better tolerability.

Active substances that can be used as precursors for the compounds of the invention include all active substances that satisfy at least one of the above tests 1, 2, 3. For example, the following are examples of such precursor active substances:

-29y.:

anti-inflammatory agents: aceclofenac, acemetacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, alclofenac, alminoprofen, amfenac, bendazac, bermoprofen, oc-bisabolol, bromfenac, bromosaligenin, bucloxylic acid, butibufen, carprofen, cinemtacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazol, enfenamic acid, etodolac, etofenamate, felbinac, fenbufen, fenclosic acid, fendosal, fenoprofen, fentiazac, fepradinol, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, glucamethacin, glycol salicylate, ibuprofen, ibuproxam, indomethacin, indoprofen, isofezolac, isoxepac, isoxicam, ketoprofen, ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mesalamine, methiazic acid, mofezolac, naproxen, niflumic acid, oxaceprol, oxaprozin, oxyphenbutazone, parsalmide, perisoxal, phenylacetylsalicylate, olsalazine, pyrazolac, piroxicam, pirprofen, pranoprofen, protisic acid, salacetamide, salicylamide O-acetic acid, salicylic acid, salsalate, sulindac, suprofen, suxibuzone, tenoxicam, tiaprofenic acid, tiaramide, tinoridine, tolfenamic acid, tolmetin, tropesin, xenbucin, ximoprofen, zaltoprofen, zomepirac, tomoxiprole;

analgesic active ingredients: acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicylic-2-amino-4-picolinic acid, acetylsalicylicsalicylic acid, anileridine, benoxaprofen benzylmorphine, 5-bromosalicylic-acetic acid, bucetin, buprenorphine, butorphanol, capsaicine, cinchofen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, etilmorphine, eugenol,

-30-*· ·* ··· ·· floctafenine, fosfosai, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactofenetide, levorphanol, meptazinol, metazocine, metopone, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oximorphone, pentazocine, phenazocine, fenocoll, fenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarite;

from substances acting on the respiratory and urinary systems (bronchodilators and substances acting on the cholinergic system, expectorants/mucolytics, anti-asthma/anti-allergic antihistamines):

bronchodilators and substances acting on the cholinergic system: acephylline, albuterol, bambuterol, bamifylline-, bevonium methyl sulphate, bitolterol, carbuterol, clenbuterol, chlorprenaline, dioxethedrine, diphylline, ephedrine, epinephrine, eprozinol, etafredine, etilnorepinephrine, etophylline, fenoterol, flutoprium bromide, hexoprenaline, ipratropium bromide, isoetharine, isoprotenerol, mabuterol, metaproterenol, oxybutynin, oxitropium bromide, pirbuterol, procaterol, protokylol, proxiphylline, reproterol, ricniterol, salmeterol, soterenol, terbutaline, 1-theobromineacetic acid, tiotropium bromide, tretocruinol, tulobuterol, zaprinast, cyclodrine, NS-21, 2-hydroxy-2,2-diphenyl-N-( 1,2,3,6-tetrahydropyridin-4-ylmethylacetamide;

expectorants/mucolytic agents: ambroxol, bromexine, domiodol, erdosteine, guaiacol, guaifenesin, iodinated glycerin, letosteine, mesna, sobrerol, stepronin, terpin, tiopronin;

-31 ·”· ^; *> j. · anti-asthma/anti-allergy antihistamines: acrivastine, alloclamide, amlexanox, cetirizine, clobenzapem, chromoglycate, chromolyn, epinastine, fexofenadine, formoterol, histamine, hydroxyzine, levocabastine, lodoxamide, mabuterol, matron s, montelukast, nedocromil, repirinast, seratrodast, suplatast tosylate, terfenadine, tiaramide, urushiol, bromhexine;

cardiovascular agents (ACE inhibitors, beta-blockers, antithrombotic and vasodilator agents, antidiabetic and hypoglycemic agents):

ACE inhibitors: alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, losartan, moveltipril, naphthopidil, perindopril, guinapril, ramipril, spirapril, temoicapril, trandolapril, urapidil;

beta-blockers: acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, dilevalol, epanolol, esmolol, indenolol, labetalol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nifenolol, nipridalol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, xibenolol;

anti-thrombotic and vasoactive agents: acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodilhemisuccinate, benziodarone, betahistine, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamole, droprenilamine, enoxaparin, fendiline,

-32J.

·· · ·· ifenprodil, iloprost, indobufen, isbogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin sodium salt, ridogrel, suloctidil, tinofedrine, tinzaparin, triflusal, xanthinol niacinate;

anti-diabetics: acarbose, carbutamide, glibornuride glybutiazol(e), miglitol, repaglinide, troglitazone, 1-butyl-3-methanylurea, tolrestat, nicotinamide;

antitumor drugs: ancitabine, anthramycin, azacitidine, azaserine, 6-azauridine, bicalutamide, carubicin, carzinophilin, chlorambucil, chlorzotocin, cytarabine, daunorubicin, defosfamide, demecolcine, denopterin, 6-diazo-5-oxo-L-norleucine, docetaxel, doxifluridine, doxorubicin, droloxifene, edatrexate, eflornithine, enocitabine, epirubicin, epithiostanol, etanidazole, etoposide, fenretinide, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubicin, lonidamine, mannomustine, melphalan, menogaril, 6-mercaptopurine, methotrexate, mitobronitol, mitolactol, mitomycins, mitoxantrone, mopidamol, mycophenolic acid, ninopterin, nogalamycin, paclitaxel, pentostatin, rubicin, pyritrexim, plicamycin, podophyllic acid, porfimer sodium, porphyrornycin, propagermanium, puromycin, ranimustine, retinoic acid, roquinimex, streptonigrin, streptozocin, teniposide, tenuazonic acid, thiamiprine, thioguanine, tomudex, topotecan, trimetrexate, tubercidin, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin;

antiulcer agents: ε-acetamidocaproic acid, arbaprostil, cetraxate, cimetidine, ecabet, enprostil, esaprazole, irsogladine, misoprostol, omeprazole, omoprostil, pantoprazole, plaunotol, rioprostil, rosaprostol, rotraxate, sofalcone, trimoprostil;

hyperlipidemic agents (statins): atorvastatin, cilastatin, dermostatin, fluvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, privastatin sodium, simvastatin;

antibiotics/antivirals: antibiotics: amdinocillin, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, azidamphenicol, azidocillin, azlocillin, aztreonam, benzoylpas, benzylpenicillinic acid, biapenem,! bicozamycin, capreomycin, carbenicillin, carindacillin, carumonam, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefclidine, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin C, cephalothin, cephapyrin sodium, cephradine, chloramphenicol, chlortetracycline, cinoxacin, clavulanic acid, clometocillin, cloxacillin, cyclacillin, cycloserine, demeclocycline, dicloxacillin, epicillin, fenbecillin, flomoxef, floxacillin, hetacillie, imipenem, lenampicillin, loracarbef, lymecycline, mafenide, meclocycline, meropenem, metampicillin, methacycline, methicillin sodium, mezlocillin, minocycline, moxalactam, mupirocin, myxin, negamycin, novobiocin, oxacillin, panipenem, penicillin G potassium salt, penicillin N, penicillin O, penicillin V, fenethicillin potassium salt, pipacycline, piperacillin, pirlimycin, porfiromycin, propycillin, quinacillin, ritipenem, rolitetracycline, sancycline, sedecamycin, spectinomycin, sulbactam, sulbenicillin, temocillin, tetracycline, ticarcillin, tigemonam, tubercidin, azithromycin, clarithromycin, dirithromycin, enviomycin, erythromycin, josamycin, midecamycin, myocamycin, oleandomycin, rifabutin, rifamide, rifamycin, rifaximin, rokitamycin, spiramycin, troleandromycin, viomycin, virginiamycin;

amikacin, apramycin, arbekacin, dibekacin, dihydrostreptomycin, fortimycin, gentamicin, micronomicin, neomycin, netilmicin, paromomycin, ribostarnycin, sisomycin, spectinomycin, streptomycin, tobramycin, trospectomycin; bacampicillin, cefcapene pivoxil, cefpodoxime proxetil, panipenem, pivampicillin, pivcephalexin, sultamicillin, talampicillin;

carbomycin, clindamycin, lincomycin, mikanrycin, rosaramycin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pazufloxacin, pefloxacin, pipemidic acid, pyromidic acid, rufloxacin, sparfloxacin, tosufloxacin, trovafloxacin, clomocycline, guamecycline, oxytetracycline, nifurpirinol, nifurprazine; p-aminosalicylic acid, p-aminosalicylic acid hydrazide, clofazimine, deoxydihydrostreptomycin,

ethambutol, glyconiazide, isoniazid, opinazide, phenylaminosalicylate, rifampin, rifapentine, salinazid, 4-4'-sulfinyldianiline, acediasulfone, dapsone, succisulfone, p-sulfanylylbenzylamine, thiazolsulfone, acetylsulfamethoxypyrazine, mafenide, 4'-(methylsulfamoyl)sulfanilanilide, salazosulfadimidine, sulfabenzamide, sulfacetamide, sulfachlorpyridasine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfamerazine, sulfameter,sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfamethylthiazole, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, 2-p-sulfanyllanilinoethanol, N ⁴ -sulfanilylsulfanilamide, sulfanilylurea, N-sulfanilyl3,4-xylamide, sulfaperine, sulfafenazole, sulfaproxiline, sulfapyrazine, sulfapiridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfisomidine, sulfisoxazole, 4-sulfanilamidosalicylic acid; negamycin, carumonan, cloxiguin, nitroxoline, arginine, metronidazole;

antiviral agents: acyclovir, amantadine, cidofovir, cytarabine, didanosine, dideoxyadenosine, edoxidine, famciclovir, floxuridine, ganciclovir, idoxuridine, indanavir, kethoxal, lamivudine, MADU, penciclovir, podophyllotoxin, ribavirin, rimantadine, sacjuinavir, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xenazoic acid, zalcitabine, zidovudine;

-36- j, substances that inhibit bone resorption (diphosphonates): alendronic acid, butedronic acid, etidronic acid, oxidronic acid, pamidronic acid, risedronic acid;

anti-dementia drugs: amiridine, lazabemide, mofegiline, salbeluzol, oxiracetam, ipidacrine, nebracetam, tacrine, velnacrine.

The following materials are preferred:

anti-inflammatory drugs: acetylsalicylic acid, 5-aminoacetylsalicylic acid, carprofen, diclofenac sodium, diflunisal, etodolac, flufenamic acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mesalamine, naproxen, niflumic acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, tolfenamic acid, tolmetin, zomepirac, tomoxiprole;

from analgesics: acetaminophen, acetylsalicylic acid, benoxaprofen, buprenorphine, butorphanol, capsaicin, diacereine, dihydrocodeine, ethylmorphine, eugenol, phenylbutazone, meptazinol, morphine, nalbuphine, pentazocine, tiorphan, tramadol, actarit;

from substances acting on the respiratory and urogenital systems: (bronchodilators, active substances acting on the cholinergic system, expectorants/mucolytics, anti-asthma/anti-allergic antihistamines):

bronchodilators and substances acting on the cholinergic system: albuterol, carbuterol, clenbuterol, diphylline, etophylline, fenoterol, ipratropium bromide, metaproterenol, oxybutynin, pirbuterol, salmeterol, terbutaline, tiotropium bromide,

-37zaprinast, cyclodrine, NS-21, 2-hydroxy-2,2-diphenyl-N-(1,2,3,6-tetrahydropyridin-4-ylmethyl)acetamide;

expectorants/mucolytics: ambroxol, bromexine, guaiacol, sobrerol;

anti-asthma/anti-allergy antihistamine active ingredients: cetirizine, chromoglycate, histamine, levocabastine, lodoxamide, montelukast, terfenadine, bromexine.

Among the cardiovascular active ingredients:

ACE inhibitors: captopril, enalapril, lisinopril, losartan, ramipril;

beta blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, timolol;

anti-thrombotic and vasoactive agents: acetylsalicylic acid, acetorphan, argatroban, clopidogrel, dalteparin, dipyridamole, enoxaparin, heparin, iloprost, midodrine, ozagrel, phenylpropanolamine trifusal;

antidiabetics: tolrestat, nicotinamide;

antitumor agents: anthramycin, daunorubicin, doxorubicin, epirubicin, fluorouracil, methotrexate, vinblastine;

anti-ulcer drugs: cimetidine, omeprazole, pantoprazole;

anti-hyperlipidemic agents: lovastatin, pravastatin sodium, simvastatin;

of antibiotic/antiviral agents: antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenecillin, cefaclor, cefadroxil, cefamandole, cefatrizine, cefoxitin, clavulanic acid, dicloxacillin, imipenem, meclocycline, methacycline, moxalactam, panipenem, sulbactam, azithromycin, erythromycin, josamycin, myokamycin, rifabutin, rifamide, rifamycin, gentamicin, paromomycin, sisomycin, bacampicillin, carbomycin, clindamycin, ciprofloxacin, clinafloxacin, difloxacin, enrofloxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pipemidic acid, apicycline, clomocycline, oxytetracycline, nifurpirinol, nifurprazine, isoniazid, rifampin, rifapentine, dapsone, thiazolsulfone, sulfamethoxazole, sulfamoxole, metronidazole, arginine;

antiviral drugs: acyclovir, famciclovir, ganciclovir, penciclovir, ribavirin, vidarabine, zidovudine;

substances that inhibit bone resorption: alendronic acid, etidronic acid, pamidronic acid;

anti-dementia drugs: oxiracetam, tacrine, velnacrine.

The above-mentioned materials, precursors R, can be prepared by methods known in the art, for example as described in The Merck Index, 12th edition (1996). If available, the corresponding isomers, such as optical isomers, can be used.

Tomoxiprole can be prepared, for example, as described in EP 12,866.

Steroid compounds in which A = R— are described by the formula S, where the following substituents may be present in place of the hydrogen atoms of the CH groups or in place of the two hydrogen atoms of the CH ₂ groups:

at position 1-2: double bond;

-39a in position 2-3: group corresponding to SI formula:

at the 2-position: Cl, Br;

at the 3-position: CO, -O-CH ₂ -CH ₂ -Cl, OH;

at position 3-4: double bond;

at position 4-5: double bond;

at position 5-6: double bond;

at positions 5-10: double bond;

at the 6-position: Cl, F, CH ₃ , -CHO;

at the 7-position: Cl, OH;

at the 9-position: Cl, F;

at the 11-position: OH, CO, Cl, CH ₃ ;

at the 16-position: CH ₃ , OH, =CH ₂ ;

at the 17-position: OH, CH ₃ , OCO(O) _ua (CH ₂ ) _va CH ₃ , a group of formula C^CH or S2, ua is 0 or 1, va is a number from 0 to 4;

a group of formula S3, S4 or S5 in the 16-17-position,

R and R' can be the same or different and can be a hydrogen atom or a straight or branched chain alkyl group having 1-4 carbon atoms, preferably R=R-CH ₃ ,

R is -(CO-L) _t -(L) _t2 -(X ₀ i) _t i where t, ti and t2 are the same or different and can be 0 or 1, with the proviso that if t=0, t2=1 and if t=1, t2=0, and that t and ti or t2 and ti cannot be 0 at the same time, if A does not contain OH groups, the divalent bridging group L is (CR4R5)na(O) _n b(CR4R5) _n ' _a (CO) _n 'b(O) _n b(CO) _n 'b(CR4R5) _{n a} where na, n'a, na are the same or different and are a number from 0 to 6, preferably 1-3; nb, n'b and nb and n' are

-40 are the same or different and have a value of 0 or 1; R ₄ , R ₅ are the same or different and have a value of H, a straight or branched chain alkyl group having 1-5 carbon atoms, preferably 1-3 carbon atoms;

Xoi is as above or X ₂₁ , where X ₂ i is OH, CH ₃ , Cl, N(-CH ₂ -CH ₃ ) ₂ , SCH ₂ F, SH, or a group of formula S6,

R is preferably -CO- _CH2OH , -CH( _CH3 ) _-CH2 - _CH2 -COOH.

Preferred precursor steroids are those in which the hydroxyl group is in the 3- and/or 11-position and/or the hydroxyl or carboxylic acid group in the R value is in the terminal position.

The precursor steroids A, and the preferred ones mentioned below, can be prepared by methods known in the art.

Among the precursors and the corresponding processes, mention is made of those described in the following literature: The Merck Index, 12th edition, 1996. The precursors (according to Merck nomenclature) are, for example, the following, in which H ₂ , H, R, R', R have the meanings mentioned above: Budesonide, Hydrocortisone, Alclomethasone, Algestone, Beclomethasone, Betamethasone, Chlorprednisone, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Cortisone, Corticosterone, Deflazacort, Despnide, Desoximethasone, Dexamethasone, Diflorasone Diflucortolone, Difluprednate, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortyn Butyl, Fluocortolone, Fluormetholone, Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide,

-41 Formocortal, Halcinonide, Halobetasol Propionate, Halomethasone, Halopredone Acetate, Hidrocortamate, Loteprednol Etabonate, Medrysone, Meprednisone, Methylprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25-Diethylaminoacetate, Prednisolone Sodium Phosphate, Prednisone, Prednival, Prednylidene, Rimexolone, Triamcinolone, Triamcinolone Acetonide, 21-Acetoxypregnenolone, Cortivazole, Amcinonide, Fluticasone Propionate, Mazipredone, Tixocortol, Triamcinolone Hexacetonide, Ursodeoxycholic Acid, Chenodeoxycholic Acid, Mitatrienediol, Moxestrol, Ethynylestradiol, Estradiol, Mestranol.

Compounds of formula (I) can be prepared as described below.

If the reactive group (e.g. -COOH, -OH) in the active ingredient is covalently bonded, for example an ester, amide, ether type group, these groups can be restored by methods known in the art.

The reactions used to prepare the compounds of general formula (I), for example to form ester, amide, thioester type bonds, are known in the art.

If other COOH and/or HX functional groups are present in the two reaction components, they must be protected, as is known in the art; for example, as described in the following literature: Th. W. Greene: Protective groups in organic synthesis, Harvard University Press, 1980.

-42 If there is a second reactive group in group B, such as XZ or

-Z _r NZ _n where X, Z, Z] and Ζ _π have the same meanings as above, or a COOH, =NH group, it is possible to attach a group of general formula (III) to group B, where a reactive group is attached to the free valence which can be coupled with the second reactive group of group B. In this case too, we can proceed according to methods known in the art.

The resulting compound is reacted with the drug precursor.

The compounds of the invention may be formulated into pharmaceutical compositions for parenteral, oral or topical administration, using conventional excipients known in the art, see, for example, Remington's Pharmaceutical Sciences 15a.

The amount of active ingredient in such compositions is the same as or lower than the amount used for the corresponding prodrug.

The daily dose is the same as or lower than the dose used for the precursor. The daily dose is generally found in publications standard in the art, such as various physician's desk references.

The following examples illustrate the invention in more detail without limiting it.

example

-43 (S,S)-N-Acetyl-S-(6-methoxy-α-methyl-2-naphthaleneacetyl)cysteine (compound of formula (1))

The precursor A is naproxen (compound of formula VI) and the precursor B is N-acetylcysteine (compound of formula CVIII).

a) (S,S)-N-Acetyl-S-(6-methoxy-α-methyl-2-naphthaleneacetyl)cysteine g (43.4 mmol) of 6-methoxy-α-methyl-2-naphthaleneacetic acid is dissolved in 100 ml of chloroform and 6 ml of Ν,Ν-dimethylformamide, 7.04 g (43.4 mmol) of 1,1'-carbonyldiimidazole are added, after 15 minutes 7.08 g (43.4 mmol) of (S)-N-acetylcysteine are added to the resulting solution and left to stand at room temperature for 12 hours. The mixture is then washed with 5% hydrochloric acid, then water, and finally brine, the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate) to give 11.6 g of the desired product as a white solid, mp 122°-126°C.

'H-NMR (CDCl3): 7.71-7.65 (3H, m), 7.34 (1H, dd), 7.167.09 (2H, m), 6.36 (1H, d), 4.67 (1H, m), 4.00 (1H, q), 3.90 (3H, s) 3.32 (2H, t), 1.84 (3H, s), 1.59 (3H, d) .example (S)-N-Acetyl-S-{a-methyl[4-(2-methylpropyl)benzene]acetyl}cysteine) ((compound of formula 2))

Precursor A is ibuprofen of formula (VII), precursor B is N-acetylcysteine of formula (CVIII).

a) (S)-N-Acetyl-S-{α-methyl[4-(2-methylpropyl)benzene]acetylcysteine g (48.48 mmol) of α-methyl[4-(2-methylpropyl)benzene]acetic acid is dissolved in 100 ml of chloroform, 6 ml of N,N-dimethylformamide and 7.86 g (48.48 mmol) of 1,1'-carbonyldiimidazole are added. After 1 hour, 7.91 g (48.47 mmol) of (S)-N-acetylcysteine are added to the resulting solution and the mixture is left to stand at room temperature for 24 hours. The resulting mixture is washed with 5% hydrochloric acid, then water, then brine, the organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate) to give 13.3 g of the desired product as an oil.

1H-NMR (CDCl ₃ ): 10.17 (1H, s) 7.13 (2H, d) 6.54 (1H, d), 4.76 (1H, m), 3.93 (1H, q), 3.42-3.30 (2H, m), 2.49 (2H, d), 1.85-1.83 (4H, m), 1.55 (3H, d), 0.93 (6H, d)

Example 3 (S)-N-Acetyl-S-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetyl]cysteine (compound of formula (3))

Precursor A is indomethacin of formula (VIII), and precursor B is N-acetylcysteine of formula (CVIII).

a) (S)-N-Acetyl-S-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-

-1H-indole-3-acetyl]cysteine g (28.00 mmol) l-(4-chlorobenzoyl)-5-methoxy-2-methyl-1Hindole-3-acetic acid was dissolved in 100 ml of chloroform, 2 ml of Ν,Ν-dimethylformamide and 4.53 g (28.00 mmol) of Ι,Γcarbonyldiimidazole were added. After 1 hour, 4.56 g of

-45 (28.00 mmol) of (S)-N-acetylcysteine were added and the mixture was left to stand at room temperature for 24 hours. The mixture was then washed with 20% hydrochloric acid, water, and brine, the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel (ethyl acetate) to give 7.79 g of the desired product as a yellow solid, mp 129°C.

1H-NMR (DMSO-d ₆ ): 12.90 (1H, s), 8.21 (1H, d), 7.697.64 (4H, m), 7.06 (1H, d), 6.96 (1H, d), 6.73 (1H, dd), 4.33 (1H, m), 4.02 (2H, s), 3.77 (3H, s), 3.33-2.96 (2H, m), 2.22 (3H, s), 1.78 (3H, s)

Example 4 (S)-N-Acetyl-[2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetyl]cysteine (compound of formula (4))

Precursor A is flurbiprofen of formula (IX), precursor B is N-acetylcysteine of formula (CVIII).

The compound was prepared as described in Example 1, the obtained material was an oil, yield 70%.

1H-NMR (CDCl ₃ ): 8.38 (1H, d), 7.67-7.50 (6H, m), 7.497.53 (2H, m), 4.52-4.41 (1H, m), 4.22 (1H, g), 3.50-3.10 (2H, m), 1.92 (3H, s), 1.58 (3H, d)

Example 5 trans-3-[4-[oc-Methyl-[4-(-2-methylpropyl)benzene]acetyloxy]-3-methoxyphenyl]-2-propanoic acid (compound of formula (5))

Precursor A is ibuprofen with formula (VII), precursor B is ferulic acid with formula (DII).

-46a) trans-3-[4-[cc-Methyl-[4-(-2-methylpropyl)benzene]acetyloxy]-3-methoxyphenyl]-2-propenoic acid

5.03 g (24.4 mmol) of α-methyl-[4-(2-methylpropyl)benzene]acetic acid were dissolved in 100 ml of tetrahydrofuran, 5 ml of N,N-dimethylformamide and 4.25 g (24.8 mmol) of 1,1-carbonyldiimidazole were added. After 1 hour, 4.90 g (25 mmol) of ferulic acid and 89 mg of sodium ethylate were added to the resulting solution, and the mixture was stirred at room temperature for 12 hours. The mixture was then washed with 5% hydrochloric acid, water and brine, the organic phase was dried over sodium sulfate and concentrated under reduced pressure.

The residue was chromatographed on silica gel (ethyl acetate/n-hexane=7/3) to give 5.1 g of trans-3-[4-[α-methyl-[4-(-2-methylpropyl)benzene]acetyl]-3-methoxyphenyl]-2-propenoic acid as a white solid, mp: 131°-137°C.

1H-NMR (CDCl 3 ): 7.72 (1H, d), 7.32 (2H, dd), 7.26 (1H, m), 7.16-7.07 (4H, m), 6.98 (1H, d), 6.37 (1H, d), 3.99 (1H, q), 3.73 (3H, s), 2.47 (2H, d), 1.88 (1H, m), 1.63 (3H, d), 0.92 (6H, d)

Example 6 trans-3-[4-[2-Fluoro-α-methyl-(1,1'-biphenyl)-4-acetyloxy]-3-methoxyphenyl]-2-propenoic acid (compound of formula (6))

The precursor A is flurbiprofen of formula (IX), and the precursor B is ferulic acid of formula (DII).

The title compound was prepared as described in Example 5, the overall yield was 60%, the compound was an amorphous solid.

*H-NMR (CDCl ₃ ): 7.75 (1H, d), 7.52 (2H, m), 7.46-7.26 (4H, m) 7.26 (3H, m), 7.05 (2H, m), 7.00 (1H, d), 6.37 (1H, d), 4.03 (1H, q), 3-77 (3H, s), 1.65 (3H, d)

Example 7 (N-Acetyl-S-[(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetyl]-(S)-cysteine (compound of formula (7))

Clopidogrel of the precursor formula (XI) and N-acetic cysteine of the precursor formula (CVIII) are present.

The title compound was prepared as described in Example 1, yield 51%.

Elemental analysis:

calculated: C: 53.03% H: 4.67% N: 6.18% S: 14.16% Cl: 17.82% measured: C: 53.00% H: 4.63% N: 6.15% S: 14.10% Cl:

17.87%

Example 8 [3-Methoxy-4-hydroxyphenyl]-2-trans-propenoyl-4-[(2-amino-3,5-dibromophenyl]methylamino]cyclohexanol ester (compound of formula (8))

Ambroxol with the formula (XII) of precursor A and ferulic acid with the formula (DII) of precursor B:

a) 4-[(2-tert-Butoxycarbonylamino-3,5-dibromophenyl)methylamino] trans-cyclohexanol g (13.22 mmol) [4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexanol is mixed with 35 ml of dioxane, 50 ml of water and 3.31 ml (23.7 mmol) of triethylamine and 3.46 g (15.86 mmol) of di-tert-butyldicarbonate are added while stirring. After 24 hours, the solution is concentrated in vacuo, then adjusted to neutral pH with 1% hydrochloric acid, pH=7, and the organic phase is extracted with ethyl acetate. The organic phase was then dried over sodium sulfate and concentrated in vacuo to give 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanol, which was used without further purification.

b) (3-Methoxy-4-hydroxyphenyl)-2-trans-propenoyl-4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl]methylamino]cyclohexanol ester g (20.5 mmol) ferulic acid is dissolved in 40 ml tetrahydrofuran, cooled to 0°C and 3.34 g (20.5 mmol) Ι,Γ-carbonyldiimidazole is added. After 10 minutes, 9.8 g (20.5 mmol) 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanol is added to the solution and left to stand at room temperature for 4 hours. The mixture is then concentrated in vacuo, treated with methylene chloride, washed with 1% hydrochloric acid and then with water, the organic phase is dried over sodium sulfate and concentrated in vacuo. The resulting material Chromatography on silica gel (n-hexane/ethyl acetate=1/1) gave the title compound (3-methoxy-4-hydroxyphenyl)-2-trans-propenoyl-4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino].

c) [3-Methoxy-4-hydroxy)phenyl]-2-trans-propenoyl-4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexanol ester g (3.06 mmol) of (3-methoxy-4-hydroxyphenyl)-2-trans-propenoyl-4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl)methylamino]cyclohexanol ester was dissolved in 50 ml of ethyl acetate, cooled to 0°C and 3.17 ml of 5N HCl/ethyl acetate solution were added while stirring. The precipitate formed was then filtered, the crude product obtained was treated with ethyl acetate to which 5% sodium bicarbonate solution was added. The resulting mixture was shaken and the bicarbonate solution was replaced with an equal volume of water. The resulting mixture was shaken again, the organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure to give the title [3-methoxy-4-hydroxyphenyl]-2-trans-propenoyl-4-[(2amino-3,5-dibromophenyl)methylamino]cyclohexanol ester, yield: 41%.

Elemental analysis:

calculated: C: 50.90% H: 4.62% N: 4.94% Br: 28.22% found: C: 50.81% H: 4.63% N: 4.89% Br: 28.18%

Example 9

S-[[2-[4-(4-Chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]acetyl]penicillamine (compound of formula (9))

The precursor (XIV) is cetirizine and the precursor B is penicillamine:

a) S-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetyl]-N-tert-butoxycarbonylpenicillamine

The compound was prepared as described in Example 1, using N-tert-butoxycarbonylpenicillamine instead of N-acetylcysteine.

b) S-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetyl]-penicillamine

- 504. '

The title compound was prepared starting from the above according to Example 8, point c), to remove the N-tert-butoxycarbonyl protecting group and restore the amine function. Yield: 29%.

Elemental analysis:

calculated: C: 58.96% H: 6.59% N: 7.63% S: 5.83%

Cl: 16.44% measured: C: 58.89% H: 6.50% N: 7.58% S: 5.79%

Cl: 16.40%

Example 10

N-Acetyl-S-[(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline]cysteine (compound of formula (10))

Precursor (XV) is enalapril, precursor B is N-acetylcysteine (CVIII):

The compound is prepared as described in Example 1, yield: 35%

Elemental analysis:

calculated: C: 58.30% H: 6.96% N: 7.84% S: 5.98% found: C: 58.25% H: 6.94% N: 7.88% S: 5.87%

Example 11

N-nicotinyl-P-alanyl(L)-histidine (compound of formula (11))

Precursor A is nicotinamide with formula (XXIII) and precursor B is carnosine with formula (Cl).

a) N-nicotinyl-3-alanyl(L)-histidine

2.5 g (20.5 mmol) of nicotinic acid are dissolved in 40 ml of tetrahydrofuran, cooled to 0°C and 3.34 g (20.5 mmol) are added.

- 51 ··< * *·♦* ·Ι· · l,l'-carbonyldiimidazole while stirring. After 10 minutes, 4.6 g (20.5 mmol) of L-carnosine solution is added, followed by stirring at room temperature for 4 hours. The mixture is then concentrated in vacuo, methylene chloride is added, washed with 1% hydrochloric acid and then with water, the organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate) to give N-nicotinyl-3-alanyl-(L)-histidine. Yield: 45%.

Elemental analysis:

calculated: C: 54.49% H; 4.88% N: 21.27% found: C: 54.30% H: 5.00% N: 21.30%

Example 12

7-[2-Hydroxy-3-[3-methoxy-5-hydroxybenzoyl]trans-2-propenoyl]theophylline (compound of formula (12))

The precursor A is diphylline with formula (XXVI) and the precursor B is ferulic acid with formula (DII).

The active ingredient is prepared as described in Example 8, yield: 28%.

Elemental analysis:

calculated: C: 57.66% H: 5.32% N: 10.13% found: C: 57.70% H: 5.37% N: 10.11%

Example 13

N-Acetyl-S-(2-acetylbenzoyl)cysteine (compound of formula (13))

Precursor A is acetylsalicylic acid of formula (XXVII) and precursor B is N-acetylcysteine of formula (CVIII).

-52»·«* *··* « *

The compound was prepared as described in Example 1, yield 63%.

Elemental analysis:

calculated: C: 51.69% H: 4.65% N: 4.31% S: 9.86% found: C: 51.64% H: 4.68% N: 4.33% S: 9.89%

Example 14

4-[3-[3-Methoxy-5-hydroxyphenyl]-2-propenoyloxy]-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (compound of formula (14))

Precursor A is piroxicam with formula (XXVIII) and precursor B is ferulic acid with formula (DII).

The compound was prepared as described in Example 8, yield 25%.

Elemental analysis:

calculated: C: 59.14% H: 4.17% N: 8.31% S: 6.31% found: C: 59.01% H: 4.09% N: 8.20% S: 6.21%

Example 15

S-[2-[(2,6-Dichlorophenyl)amino]benzeneacetyloxy]penicillamine (compound of formula (15))

Precursor A is diclofenac with formula (XXIX) and precursor B is penicillamine with formula (CV).

The compound was prepared as described in Example 9, yield 53%.

Elemental analysis calculated: C: 49.88% H: 3.66% N: 7.30% S: 8.32%

Cl: 18.40%

-53 measured: C: 49.90% H: 3.64% N: 7.29% S: 8.25%

Cl: 18.35%

Example 16

3-[2-Fluoro-a-methyl-(1,1'-biphenyl)-4-acetyl]thiazolidine-4-carboxylic acid (compound of formula (16))

The precursor is flurbiprofen of formula (IX) and the precursor B is (L)-4-thiazolidinecarboxylic acid of formula (PIV).

a) 3-[2-Fluoro-α-methyl-(1,1'-biphenyl)-4-acetyl]thiazolidine-4-carboxylic acid g (41 mmol) of 2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid is dissolved in 100 ml of toluene, 10 ml of N,N-dimethylformamide is added, cooled to 0°C and 3.52 ml (82 mmol) of oxalyl chloride are added. The reaction is carried out for 2 hours at room temperature, then the solution is concentrated under reduced pressure, the residue is dissolved in 50 ml of acetone and the resulting solution is added to 5.44 g (41 mmol) of 4-thiazolidinecarboxylic acid dissolved in 50 ml of acetone and 14.9 ml (106 mmol) of triethylamine, which is cooled to 0°C. After 2 hours, the mixture was acidified with 4N hydrochloric acid, concentrated in vacuo, the residue was treated with ethyl acetate, the organic phase was washed first with 2N hydrochloric acid and then with water, the organic phase was dried over sodium sulfate, concentrated under reduced pressure. The residue was recrystallized from ethyl acetate in N-hexane to give 9.4 ml of the desired compound as a white solid, mp: 142°-147°C.

-54'H-NMR (CDCl3): 7.74-7.62 (4H, m), 7.35 (2H, t), 7.187.13 (2H, m), 5.06 (1H, m), 4.63 (1H, d), 4.42 (1H, d), 4.14 (1H, q), 3.13 (2H, m), 1.53 (3H, d)

Example 17

3-(6-Methoxy-α-methyl-2-naphthaleneacetyl)thiazolidine-4-carboxylic acid (compound of formula (17))

The starting material is naproxen of formula (VI), precursor B (PIV) is (L)-4-thiazolidinecarboxylic acid.

a) 3-(6-Methoxy-α-methyl-2-naphthaleneacetyl)thiazolidine-4-carboxylic acid

4.02 g (17.5 mmol) of 6-methoxy-α-methyl-2-naphthaleneacetic acid were dissolved in 30 ml of toluene, 0.3 ml of N,N-dimethylformamide were added, cooled to 0°C and 2.92 ml (34.06 mmol) of oxalyl chloride were added. The reaction was carried out for 2 hours at room temperature, then the solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of acetone and the solution was added to 2.33 g (17.5 mmol) of 4-thiazolidinecarboxylic acid and 6.34 ml (45.5 mmol) of triethylamine dissolved in 50 ml of acetone, which solution was cooled to 0°C. After 2 hours, the solution was acidified with 4N hydrochloric acid, concentrated in vacuo, the residue was treated with ethyl acetate, the organic phase was washed with 2N hydrochloric acid and then with water, the organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 4.43 g of the desired product as a white solid, mp: 165°-168°C.

-55' H-NMR (CDCI ₃ ): 7.75-7.66 (3H, m), 7.34 (1H, d), 7.14-7.11 (2H, m), 5.14 (1H, m), 4.80-4.61 (2H, m), 4.07 (1H, q), 3-91 (3H, s), 3.30-3.23 (2H, m), 1.53 (3H, d)

Example 18

3-(6-Methoxy-α-methyl-2-naphthaleneacetyl)-(R)-2-oxothiazolidine-4-carboxylic acid (compound of formula (18))

The starting material is naproxen of formula (VI), and the precursor B is (L)-2-oxo-4-thiazolidinecarboxylic acid of formula (PV).

a) 3-(6-Methoxy-α-methyl-2-naphthaleneacetyl)-(R)-2-oxothiazolidine-4-carboxylic acid

7.0 g (30.4 mmol) of 6-methoxy-α-methyl-2-naphthaleneacetic acid were dissolved in 100 ml of toluene, 10 ml of N,N-dimethylformamide were added, then cooled to 0°C and 5.23 ml (61 mmol) of oxalyl chloride were added. The reaction was carried out for 2 hours at room temperature, then the mixture was concentrated under reduced pressure, the residue was dissolved in 50 ml of tetrahydrofuran and a mixture of 4.07 g (27.6 mmol) of 2-oxothiazolidine-4-carboxylic acid, 0.84 g (6.9 mmol) of 4-dimethylaminopyridine, 7.69 ml (55.2 mmol) of triethylamine and 50 ml of tetrahydrofuran was added, which was cooled to -10°C. The reaction was carried out at room temperature for 24 hours, then washed with 5% hydrochloric acid and then with water, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (methylene chloride/methanol^95/5) to give 6.79 g of the desired product as an amorphous solid.

Elemental analysis:

-56calculated: C; 60.16% H: 4.76% N: 3.89% S: 8.92% found: C: 60.22% H: 4.80% N: 3.83% S: 8.91%

Example 19

[2-[(2,6-Dichlorophenyl)amino]benzeneacetyloxy]-(L)-histidine (compound of formula (19))

The precursor active ingredient is diclofenac with formula (XXIX), and precursor B is (L)-histidine with formula (PH).

a) [2-[(2,6-Dichlorophenyl)amino]benzeneacetyloxy]-L-histidine g (10.13 mmol) of diclofenac is dissolved in 50 ml of tetrahydrofuran, cooled to 0°C and 1.69 g (10.13 mmol) of 1,1'-carbonyldiimidazole are added with stirring. After 10 minutes, 1.57 g (10.13 mmol) of L-histidine are added to the solution and the mixture is stirred at room temperature for 4 hours. The mixture is then concentrated in vacuo, treated with methylene chloride, then washed with 1% hydrochloric acid and then with water. The organic phase is dried over sodium sulfate, concentrated in vacuo, and the residue is chromatographed on silica gel (ethyl acetate) to give [2-[(2,6-dichlorophenyl)amino]benzeneacetyloxy]-L-histidine. Yield 61%.

Elemental analysis:

calculated: C: 55.45% H: 4.18% N: 12.92% Cl 16.36% found: C: 55.48% H: 4.23% N: 12.88% Cl 16.25%

Pharmacological studies

Examples

Acute toxicity

Acute toxicity was tested by administering a single dose of the drug to groups of 10 rats weighing 20 g.

-57 test compound in the form of a 2% w/w aqueous carboxymethylcellulose suspension via cannula.

The animals were observed for 14 days. No toxic symptoms were observed in any animal, even at a dose of 100 mg/kg.

Example FI

Test 1: experimental in vivo model with N-ethylmaleimide (NEM): gastric tolerability of some active ingredients used as precursors for the compounds of the invention.

The animals (rats weighing approximately 200 g) were divided into the following groups (10 animals per group):

A) control group:

Group 1: treatment: vehicle only (1% w/v aqueous carboxymethylcellulose suspension, dose: 5 ml/kg, for oral administration and for parenteral administration of physiological saline,

2nd group: treatment: vehicle + NO

Group B: all treated with active substance

Group I: treatment: vehicle + active substance

Group II: treatment: vehicle + active substance + NO.

In this experiment, the following active ingredients were tested (Table I): indomethacin, ambroxol, mesalamine, sodium alendronate, tacrine, omeprazole, misoprostol.

Indomethacin, ambroxol and alendronate were administered orally, mesalamine intracolonically (rectally), and tacrine, omeprazole and misoprostol subcutaneously.

The maximum tolerated dose for each substance administered as above to animals not treated with NEM is summarized in Table I.

At doses higher than those given in Table -58, enteropathy, diarrhea, depression, tremors, and sedation occurred in animals.

In this experiment, the animals were first treated with NEM by subcutaneous injection at a dose of 25 mg/kg in saline. The active substance was administered 1 hour later, suspended in the vehicle. The animals were sacrificed after 24 hours and the damage to the gastrointestinal mucosa was evaluated by counting the number of rats in each group that had visual gastric damage. The number of such rats was then divided by the total number of rats and multiplied by 100, and the percentages thus obtained are summarized in Table L. It is evident from the table that no gastric damage was detected in the rats treated with the said active substance without NEM.

In rats belonging to group Π (treated with NEM compound) gastric damage was observed after administration of the following active ingredients: indomethacin, ambroxol, mesalamine, sodium alendronate, tacrine. The active ingredients can thus be used for the preparation of the compounds of the invention.

Omeprazole and misoprostol cannot be used for the preparation of the compounds of the invention based on the results shown in Test 1.

Example F2

Test 2 (in vitro): apoptosis (DNA fragmentation) induced by CIP inhibition in endothelial cells, some findings

-59in the presence of active ingredients that can be used as precursors in the compound according to the invention.

The following precursor drugs were examined (Table II): indomethacin, paracetamol, clopidogrel, salbutamol, ambroxol, sodium alendronate, diphylline, cetirizine, enalapril, nicotinamide, ampicillin, aciclovir, mesalamine, tacrine, simvastine, omeprazole.

Human endothelial cells from umbilical vein are prepared in a known manner. Fresh umbilical veins are saturated with 0.1% by weight collagenase solution and incubated at 37°C for 5 minutes.

The veins were then flushed with M 199 medium (GIBCO, Grand Island, NY) pH 7.4 containing 0.1% v/v collagenase, 10 mcg/ml 10% fetal bovine serum, 50 mcg/ml sodium heparin, 2.4 mcg/ml thymidine, 2.30 mcg/ml glutamine, 100 IU/ml pencillin, 100 mcg/ml streptomycin, and 0.125 mcg/ml streptomycin-B. The cells were separated from the flushing medium by centrifugation (800 rpm) and transferred to T-75 culture dishes pretreated with human fibronectin. The cells were then separated in the same medium supplemented with 100 ng/ml bovine hypothalamic growth factor. When the cells of the primary cell culture (cells that were directly removed from the ex vivo dissolved vein) form a confluent monolayer (8,000,000 cells/dish), the culture is stopped and the layers are washed and trypsinized. The cell suspensions are then transferred to the wells of a culture plate, where half of the 24 wells are added with the same culture medium, containing 10' ⁴ M.

- 60% of the active substance and incubated at 37°C at constant humidity (90%), _CO2 =5%. If the active substance is insoluble in the culture medium, it is dissolved in a small amount of dimethyl sulfoxide beforehand. The maximum amount of dimethyl sulfoxide that can be added to the culture medium is 0.5%. Only cells from this first subculture are used in the cumene hydrogen peroxide (CIP) experiment. The cells are identified as endothelial cells by morphological examination and by their specific immunological reaction with factor VIII; these cultures never show contamination with myocytes or fibroblasts.

Before starting the test, the cell culture medium is removed, the cell layers are gently washed with standard physiological saline adjusted to pH 7.0 with 0.1 M phosphate buffer at 37°C. The contents of each culture well are then incubated for 1 hour with a CIP suspension, the concentration of which in the culture medium is 5 mM. The evaluation of cell damage (apoptosis) is then carried out by determining the percentage change in DNA fragmentation in the culture medium containing the active substance and CIP compound, compared to the controls treated with CIP compound alone. This percentage change in DNA fragmentation is evaluated by fluorescence change, performed using a BX60 Olympus microscope (Olympus Co., Rome) at a wavelength of 405-450 nm, the fluorescence value of the test samples being compared to the optical density of the controls. Fluorescence was measured in five replicates for each sample. Statistical evaluation was performed using Student's t test (p < 0.01).

-61 The results obtained are summarized in Table II., which show that indomethacin, paracetamol, clopidogrel, salbutamol, sodium alendronate, diphylline, cetirizine, enalapril, nicotinamide, ampicillin, aciclovir, tacrine, omeprazole do not significantly inhibit apoptosis, and these active ingredients can thus be used to prepare the compounds of the invention.

In contrast, ambroxol, mesalamine and simvastatin inhibit apoptosis. Thus, based on the results of test 2, these compounds are not suitable for the preparation of the compounds of the invention.

Example F3

Test 3: experimental in vivo model using N ^w -nitro-L-argininemethyl ester (L-NAME): to determine the gastric tolerability (occurrence of gastrointestinal damage), hepatic tolerability (GPT, glutamine-pyruvate transaminase dose) and cardiovascular (blood pressure) tolerability of a compound used as a precursor for the preparation of some compounds of the invention.

The experiment was performed as described in the following literature: J. Clin. Investigation 90, 278-281, 1992.

To evaluate endothelial dysfunction, we determined the damage induced by L-NAME administration on the gastrointestinal mucosa, liver damage (GPT increase), and vascular endothelium or cardiovascular damage with the development of hypertension.

-62The animals (rats, average weight 200 g) were grouped as follows. The groups were treated with L-NAME for 4 weeks, the compound was administered in a concentration of 400 mg/l dissolved in the drinking water. The following groups (10 animals per group) were formed:

A) control groups:

Group 1: treatment: vehicle only (1% w/v aqueous suspension of carboxymethylcellulose, dose 5 ml/kg for oral administration and physiological saline for parenteral administration.

2nd group: treatment: vehicle + L-NAME,

B) drug-treated groups:

3° group: treatment: vehicle + active ingredient

Group 4: treatment: vehicle + active substance + L-NAME.

The tested drugs were: paracetamol, doxorubicin, simvastatin, omeprazole and misoprostol. The drugs were administered once daily for 4 weeks.

The maximum tolerable dose was determined by administering increasing amounts of the drug in separate doses to untreated animals and examining the appearance of symptoms, such as enteropathy, diarrhea, depression, tremors, and sedation.

After 4 weeks of treatment, water was withdrawn and the animals were killed after 24 hours.

Blood pressure was determined 1 hour before sacrifice and the increase in blood pressure was used to indicate the damage induced on the vascular endothelium.

The study of damage to the gastric mucosa was carried out according to the aforementioned test 1 (Example F1).

-63To determine liver damage, the amount of glutamine-pyruvate aminotransferase (GPT increase) was determined after the animals were killed.

Test 3 is satisfied by the active ingredients and thus suitable for the production of the compounds of the invention if rats treated with the combination of L-NAME + active ingredient + carrier have greater liver damage (higher GPT values) and/or greater stomach damage and/or greater cardiovascular damage (higher blood pressure) than those treated with vehicle alone or with the combination of vehicle + active ingredient or with the combination of vehicle + L-NAME.

The results obtained are summarized in Table IV. The percentage of gastric damage was determined according to test 1. The percentage GPT and percentage blood pressure values are related to the values measured in the first group of animals of the control groups. The average blood pressure value in this group was 105±8 mm Hg.

According to the results obtained, paracetamol, doxorubicin and simvastatin cause liver damage and gastroenteropathy (GPT values and percentage gastric damage are higher than in animals treated with the corresponding active ingredient without L-NAME, and in control animals treated with the L-NAME compound).

In this way, these active ingredients can be used to prepare the compounds of the invention.

Omeprazole and misoprostol cannot be used to produce the products of the invention based on this test.

Example -64F4

Test 4: Inhibition of DPPH-induced radical formation in the case of some substances used as B precursors.

The assay method is based on a colorimetric test using DPPH (2,2-diphenyl-1-picrylhydrazyl) as a radical generator (MS Nenseter et al., Atheroscler. Thromb. 15, 1338-1344, 1995).

Methanol solutions of the test substances were prepared at a concentration of 100 μΜ. 0.1 ml of this solution was then added to 1 ml of 0.1 M DPPH methanol solution and the final volume was adjusted to 1.5 ml. The solutions were then stored at room temperature, protected from light, for 30 minutes, and the absorbance was measured at 517 nm. The decrease in absorbance was determined relative to a solution containing the same concentration of DPPH.

The inhibitory efficacy of the tested compounds on radical formation is determined based on the following relationship:

(1 - A _s /A _c )X100 where A _s and A _t are the absorbance of the solution containing the test compound + DPPH concentration and the solution containing only DPPH, respectively.

Compounds useful according to the invention satisfy the requirements of Test 4 if the inhibition of radical formation, as determined above, is 50% or greater.

Table V summarizes the results obtained with the following substances: N-acetylcysteine, cysteine, ferulic acid, (L)-carnosine, gentisic acid, 4-thiazolidinecarboxylic acid and 2-oxo-4-thiazolidinecarboxylic acid.

-65Table V shows that N-acetylcysteine, cysteine, ferulic acid, (L)-carnosine and gentisic acid satisfy the requirements of test 4, as they inhibit DPPH-induced radical formation by more than 50%.

4-Thiazolidinecarboxylic acid and 2-oxo-4-thiazolidinecarboxylic acid are ineffective as they do not inhibit DPPH-induced radical formation. Thus, these compounds can be used as precursors in the preparation of the compounds of the invention if they meet the requirements of Test 5.

Example F5

Test 5: Inhibition of Fe _n -induced radical formation by compounds used as precursor B

A ⁴ M methanolic solution of 4-thiazolidinecarboxylic acid and 2-oxo-4-thiazolidinecarboxylic acid is prepared and 0.1 ml of such solutions is added to test tubes to which 0.2 ml of 2 mM deoxyribose, 0.4 ml of phosphate buffer pH 7.4, 100 mM and 0.1 ml of 1 mM Fe _! (NH ₄ ) 2 (SO ₄ ) 2 in 2 mM HCl have been added. The test tubes are then incubated at 37°C for 1 hour, and then 0.5 ml of 2.8% aqueous trichloroacetic acid and 0.5 ml of 0.1 M aqueous thiobarbituric acid are added to each in this order. Blank 0.1 ml of methanol instead of 0.1 ml of the test compound in methanol. The test tubes were then sealed, heated in an oil bath for 15 minutes, and the intensity of the pink color formed was measured, which is proportional to the amount of deoxyribose that had undergone radical oxidative degradation. The solutions were cooled to room temperature, and the absorbance values were measured at 532 nm against the blank.

- 66 The magnitude of the inhibition induced by the precursors AB or Bi or C=-T _c -YH (where the free valence is bound as above) relative to the radical formation induced by Fen is determined as a percentage based on the following relationship: (1 - A _s /A _c )X100 where A _s and A _c are the absorbance of the test compound + iron salt combination and the solutions containing only iron salt, respectively.

The results obtained are summarized in the following table, which shows that both acids inhibit the radical formation from iron ions. Thus, these compounds can be used as precursor B in the preparation of the compounds of the invention.

Example F6

Gastric tolerability of the compounds of the invention compared to the corresponding precursor drugs in the case of endothelial disorders induced by L-NAME (N ^w -nitro-L-arginine methyl ester).

The gastric tolerability was evaluated as described in Example F3 for the following prodrugs and the corresponding derivatives according to the invention:

- diclofenac and the corresponding derivative according to Example 15,

- piroxicam and the corresponding derivative according to Example 14.

- aspirin and the corresponding derivative according to Example 13.

The results obtained are summarized in Table VI, which show that the compounds, i.e. the compound of the invention and the corresponding precursor drug, administered at the same dose significantly reduced the incidence of gastropathy.

- 67 is reduced or disappears in the groups treated with the compounds of the invention.

Example 20

3-(3-Methoxy-4-hydroxyphenyl)-2-trans-propenoic acid 1-[(1-methylethyl)amino]-3-(1-naphthalenoxy)-2-propyl ester (compound with formula (CCI))

The title compound is prepared from propranolol of formula (XXIV) and ferulic acid of formula (DII) as precursor B.

The preparation is carried out as described in Example 8, yield 30%.

Elemental analysis:

calculated: C: 71.71 H: 6.71 N: 3.22 found: C: 71.79 H: 6.75 N: 3.17

Example 21

N-acetyl-S-[1-(5-(2,5-dihydro-5-oxo-3-furanyl)-3-methyl-2-benzofuranyl]ethyloxy-4-oxo-butanoyl]-cysteine (compound of formula (CCII))

The compound is prepared from benfurodil hemisuccinate corresponding to the formula (XXXI) and N-acetylcysteine as precursor B (CVIII). The preparation is carried out as described in Example 1, yield: 13%.

Elemental analysis:

calculated: C: 57.25 H: 5.00 N: 2.78 S: 6.37 found: C: 57.30 H: 5.02 N: 2.72 S: 6.35

Example 22

-685-Methoxy-2-[[[(3-methoxy-4-hydroxyphenyl)-2-trans-propenoyloxy]-3,5-dimethyl-2-pyridinyl]methyl]sulfinyl-3-1H-benzimidazole (compound of formula (CCIII))

The compound is obtained from 4-hydroxyomeprazole of formula (XXII) and ferulic acid of formula (DII).

The preparation is carried out as described in Example 8, yield: 43%

Elemental analysis:

calculated: : C : 61.65 H : 4.78 N : 8.30 S : 6.33 found: : C : 61.71 H : 4.85 N : 8.25 S : 6.35

Example 23

[1S-[1a,3a,73,8p,(2S*,4S*)]]-2,2-Dimethylbutanoic acid-1,2,3,7,8,8-hexahydro-3,7-dimethyl-8-[2-[tetrahydro-4-[(3-methoxy-4-hydroxyphenyl)-2-trans-propenoyloxy]-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester (compound of formula (CCIV))

The compound is obtained from samvastatin of formula (XXI) and ferulic acid of formula (DII). The preparation is carried out as described in Example 8, yield: 21%.

Elemental analysis:

calculated: C: 70.68 H: 7.80, found: C: 70.70 H: 7.82

Example 24

S-[4-Da-aminobenzylpenicillaminoyl]penicillamine (compound with formula (CCV))

-69A is obtained from ampicillin (XVI) and penicillamine (CV). The preparation is carried out as described in Example 9, yield: 13%.

Elemental analysis:

calculated: C: 52.48 H: 5.87 N: 11.66 S: 13.34 found: C: 52.51 H: 5.90 N: 11.61 S: 13.30

Example 25

9-[[2-[(S)-α-Amino-1H-imidazole-4-propanoyloxy]ethoxy]methyl]guanine (compound of formula (CCVI))

The compound is obtained from acyclovir of formula (XVII) and histidine of formula (PII). The preparation is carried out as described in Example 19, yield: 17%.

Elemental analysis:

calculated: C: 50.14 H: 4.77 N: 27.29 found: C: 50.17 H: 4.75 N: 27.22

Example 26

[4-amino-[(3-Methoxy-4-hydroxyphenyl)-2-trans-propenoyl]-1-hydroxybutylidene]bisphosphonic acid (compound of formula (CCVII))

The compound is obtained from alendronic acid of formula (XXXVI) and ferulic acid of formula (DII). The preparation is carried out as described in Example 8, yield: 10%.

Elemental analysis:

calculated: : C : 39.54 H : 4.98 N : 3.29 P : 14.57 found: : C : 39.57 H : 5.01 N : 3.24 P : 14.56

Example 27

- 705[[(S)-a-Amino-1H-imidazole-4-propanoyl]amino]-2-1,2,3,4-tetrahydroacridine (compound of formula (CCVIII))

The compound is obtained from tactrine of formula (XXXV) and histidine of formula (PH). The preparation is carried out as described in Example 19, yield 15%.

Elemental analysis:

calculated: C: 68.04 H: 6.31 N: 20.88 found: C: 68.08 H: 6.37 N: 20.84

Example 28 (8S-cis)-10[(3-Amino-2,3,6-trideoxy-aL-ixo-exo-pyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-[[[(3-methoxy-4-hydroxyphenyl)-2-trans-propenoyloxy]methyl-oxo]-1-methoxy-5,12-naphthacenedione (compound of formula (CCIX))

The compound is obtained from doxorubicin of formula (XXXII) and ferulic acid of formula (DII). The preparation is carried out as described in Example 8, yield: 10%.

Elemental analysis:

calculated: C: 61.75 H: 5.18 N: 1.95 found: C: 61.81 H: 5.22 N: 1.90

Example F7

Proceeding as described in Example FI, three test groups are formed (each consisting of 10 animals), each of which is administered NEM orally as follows: a. control group: vehicle, which is a 1% w/w aqueous carboxymethylcellulose suspension,

b. one group (group b - comparison), simultaneously administered 100 mg/kg (0.45 mmol/kg) ibuprofen + 79 mg/kg (0.48 mmol/kg) N-acetylcysteine in the same vehicle,

c. One group (group c) was administered 170.4 mg/kg (0.48 mmol/kg) of an ester derived from indomethacin and N-acetylcysteine (reference example 2) in the above vehicle.

The results obtained are summarized in Table VII, which show that the mixture administered to group b (comparison) is less effective than the compound of the invention administered to group c in reducing gastric damage.

Table I

Test 1: Examination of the gastric tolerability of the compounds of the invention in untreated and NEM compound-treated animals (oxidative stress effect). To determine the percentage incidence, the number of animals showing gastric damage was compared to all groups. Compound dose (mg/kg)/ route of administration Gastroenteropathy (% incidence) Without NO NOT with dosing carrier 0 0 Indomethacin 7.5/month 0 100 Ambroxol 25/Mon 0 80 Mesalamine 750/ic 0 60 Alendronate 15/Mon 0 90 Tacrine 1/sc 0 100 Omeprazole 30/sc 0 0 Misoprostol 0.5/sc 0 0

po = orally; ic = intracolonically;

sc = subcutaneous

-ΊΊTable II.

Test 2: Inhibition of CIP-induced apoptosis (DNA fragmentation) in endothelial cells in the presence of some representatives of the active ingredient groups presented according to the invention Compound Apoptosis % compared to groups treated with CIP only Indomethacin 95 Paracetamol 120 Clopidogrel 110 Salbutamol 90 Ambroxol 70 Alendronate 160 Diphylline 95 Cetirizine 115 Enalapril 80 Nicotinamide 98 Ampicillin 94 Acyclovir 95 Mesalamine 74 Tacrine 90 Simvastatin 72 Omeprazole 90

Table III

Test 5: Efficacy of the given compounds in inhibiting radical formation induced by Fe _n ions Compound name % inhibition of Fe _n induced radical formation Blind test 0 2-oxo-4-thiazolidine carboxylic acid 100 4-thiazolidinecarboxylic acid 100 histidine 90

Table -74V

Test 4: Efficacy of the listed compounds in inhibiting radical formation from DPPH Compound name % inhibition of DPPH-derived radical formation Solvent 0 N-acetylcysteine 100 Cysteine 100 Ferulic acid 100 (L)-carnosine 80 Gentisic acid 80 4-thiazolidinecarboxylic acid 0 2-oxo-4-thiazolidinecarboxylic acid 0 histidine 0

Table VI

Gastric tolerability of the derivatives of the invention compared to the corresponding precursor drug Treatment dose mg/kg Gastropathya % incidence Carrier - 30 diclofenac 10 100 diclofenac derivative (Example 15) 10 10 piroxicam 10 100 piroxicam derivative (Example 14) 10 0 aspirin 50 100 aspirin derivative (Example 13) 50 0

-75Table VII.

Study of gastric tolerability after oral administration of NEM compound (Example F7 Groups dose mg/kg p.o. % incidence of gastropathy Control groups - - group b - comparative ibuprofen (A) + N-acetylcysteine (B) mixture 100(A) + 79(B) 60 group c - comparative ibuprofen/N-acetylcysteine ester 170.4 10

Claims (18)

- 76Patent claims 1. Compounds of general formula (I) and their salts - in the formula A is R—T _r , where R is an active ingredient group and T] is (CO) _t or (X) _t , where X=O, NR _lc , where R _]c is H or a straight or branched chain alkyl group of 1-5 carbon atoms or a valence bond, t and t' are 0 or 1, with the proviso that t=1, hat'=0; t=0 if t'=1; B is -T _B —X ₂ , where T _B is (CO) when t=0, T _B is X when t-0, X is as above; X ₂ is a monovalent group and is such that the corresponding precursor B satisfies test 5 and/or test 4; said precursor -T _B —X, where T _B is a free valence, is saturated with a group OZ or Z, where Z=H or R 1a, R j _a ⁼ a straight or branched chain alkyl group of 1-10 carbon atoms, preferably an alkyl group of 1-5 carbon atoms, or a -Zj-N-Zn group, where Z _r or Zn is the same as or different from the value of Z, depending on whether T _B = CO or X, t, t' in relation to the values; with the proviso that: the A=R—Ti- group, where the free valence is saturated as follows: - if t'=0 with the following group: -ΊΊ - - 0-Ζ, where Ζ=Η or Rj _a , which has the same meaning as above, or -Z _r NZ _n with group I, where Zj and Z _n have the same meanings as above, - if t=0, with a group X-Z, where X and Z have the same meanings as above, such that it satisfies at least one of the following tests 1-3; wherein test 1 (NEM) is an in vivo test performed on four groups of rats (each group containing 10 rats), two of which are control groups, two of which are treated groups, one of which is treated with 25 mg/kg sc N-ethylmaleimide (NEM), the controls are treated with vehicle and the treated groups are treated with vehicle + A=RT ₁ - active substance, where the free valence is saturated as above, the dose of active substance is the same as the maximum dose tolerated by rats not given NEM, i.e. the highest dose at which no toxicity occurs in the animals, i.e. no appreciable amount is observed; the active ingredient satisfies test 1, i.e. the active ingredient can be used to prepare compounds of general formula (I) and (II), if the group of rats treated with the combination of NEM + vehicle + active ingredient shows gastrointestinal damage, or if the group treated with the combination of NEM + vehicle + active ingredient shows gastrointestinal damage that is greater than that of the group treated with the vehicle, or if the combination of vehicle + active ingredient - 78 • ♦ · · · ·<· ·· ·♦· * observed in the group treated with nation or the vehicle + NEM combination; wherein test 2 (CIP) is an in vitro test in which human endothelial cells are collected from the umbilical vein under standard conditions and then divided into two groups (each group containing five replicates), one of which is treated with a mixture containing 10' ⁴ M of active substance and culture medium, the other with vehicle only, and cumene hydroperoxide (CIP) is then added to both groups at a concentration of 5 mM in culture medium; the active substance satisfies test 2, i.e. the active substance can be used for the preparation of compounds of general formula (I) and (II) if the inhibition of apoptosis (cell damage) induced by CIP is not statistically significant at p <0.01 compared to the group treated with vehicle and CIP; where test 3 (L-NAME) is an in vivo test conducted on four groups of rats (each containing ten rats) for four weeks, to which drinking water is administered, the control group (two groups) and the treatment group (two groups) constitute two groups, of which one control group and one treatment group are administered Ν-ω-nitro-L-arginine methyl ester (L-NAME) in the drinking water at a concentration of 400 mg/l for four weeks; the control group is administered vehicle for 4 weeks, the treatment group is administered vehicle + active ingredient combination for 4 weeks, the vehicle or vehicle + active ingredient combination is administered once a day, and the amount of active ingredient is the maximum dose tolerated by the group of rats that were not pretreated with the L-NAME compound, i.e. the highest dose that can be administered without toxicity, i.e. - 79without any toxicity; after 4 weeks, water is withheld for 24 hours, then the rats are killed, blood pressure is determined 1 hour before killing, then after killing, the plasma glutamine-pyruvate transaminase (GPT) amount is measured in the rats and the stomach tissue is examined; the active substance satisfies test 3, i.e. the active substance can be used for the preparation of compounds of general formula (I) and (II), if the group treated with the L-NAME + vehicle + active substance combination shows greater liver damage (higher GPT value) and/or stomach damage and/or cardiovascular damage (higher blood pressure value) compared to the group treated with vehicle only or the group treated with the vehicle + active substance combination or the group treated with the vehicle + L-NAME combination; where test 4 is an analytical test performed by adding a methanol solution containing 10' ⁴ M of precursor to a methanol solution of DPPH (2,2-diphenyl-l-picrylhydrazyl free radical); then the solution is kept at room temperature away from light for 30 minutes, then the absorbance of the test solution and the solution containing only DPPH is measured at 517 nm; then the inhibition of radical formation induced by the precursor by DPPH is calculated in percent based on the following relationship: (1 - A _s /A _c )X100 where A _s and A _c are the absorbance of the solution containing the test compound + DPPH combination and the solution containing only DPPH, respectively; precursor compound B complies with test 4 if the percentage of inhibition is greater than or equal to 50%; - 80wherein test 5 is an analytical test carried out by adding an aliquot of a methanolic solution of 10' ⁴ MB of precursor, the free valence of which has been saturated as above, to a solution obtained by mixing an aqueous solution of 2 mmol of deoxyribose with 100 mmol of phosphate buffer and 1 mmol of Phen(NH ₄ ) ₂ (SO ₄ ) ₂ salt; then the solution is incubated at 37°C for 1 hour, then an aliquot of 2.8% aqueous trichloroacetic acid solution and 0.5 M thiobarbituric acid are added in this order, then the mixture is stirred for 15 minutes at 100°C and the absorbance of the test solutions at 532 nm is measured; The percentage inhibition effect of the precursors B or Bi or C=-T _c -YH on the radical formation induced by Fe _n is calculated based on the following relationship: (1 - A _s /A _c )X100 where A _s and A _c are the absorbances of the compounds to be tested and the iron salt, and of the solutions containing only the iron salt, the compound satisfies test 5 if the percentage inhibition value determined as above for the precursor B is greater than or equal to 50%. 2. Compounds according to claim 1, wherein the precursor B satisfying the requirements of test 5 is one of the following compounds: amino acids: aspartic acid (PI), histidine (PII), 5-hydroxytryptophan (PII), 4-thiazolidinecarboxylic acid (PIV), 2-oxo-4thiazolidinecarboxylic acid (PV); mono- and polyalcohols and thiols: compound with formula 2-thiouracil (QI), compound with formula 2-mercaptoethanol (QII), compound with formula hesperidin (QIII), secalciferol (QIV) compound of formula, l-α-ΟΗ vitamin D2 compound of formula (QV), flocalcitriol compound of formula (QVI), 22oxacalcitriol compound of formula (QVII), vitamin D3 derivative esterified with vitamin A group compound of formula (QVIII), compound of formula (QIX), 24,28-methylene-1α-hydroxyvitamin D2 compound of formula (QX), compound derived from 1α,25dihydroxyvitamin D2 compound of formula (QXI), 2-mercaptoimidazole compound of formula (QXII), succinic acid compound of formula (Rí), compound of general formula (RII), in which n°3 is identically or differently zero or 1, n3 is identically or differently a number from 0 to 3; W is identically or differently one of the following groups: HX, where X is as above, COOH, R', OR ¹ , where R' is a straight or branched alkyl group having 1-20 carbon atoms, preferably 1-6 carbon atoms; Rf, ORf, where Rf is the same as that given for R', but contains at least one halogen atom instead of H, which is preferably F; at least one of the W groups is XH, the reactive group of the active ingredient is a carboxyl group; or COOH, if the reactive group of the active ingredient is XH; if n°=0, if n3 is different from O, then the free valence of the n3 group is saturated with one or more of the following groups: R', OR', Rf, ORf, H; if n°=0 and n3=0, the free valence is saturated with H. 3. Compounds according to claim 1, wherein the precursor B satisfying the requirements of test 4 is a compound belonging to one of the following compound groups: amino acids, which are: L-carnosine (Cl), anserine (CII), selenocysteine (CIII), selenomethionine (CIV); a compound of formula (CV), a compound of formula (CVI), hydroxy acids from the following: gallic acid (Dl), ferulic acid (DII), gentisic acid (Dili), citric acid (CIV), caffeic acid (DV), hydrocaffeic acid (DVI), p-coumaric acid (DVII), vanillic acid (DVIII), chlorogenic acid (DIX), kynurenic acid (DX), syringic acid (DXI), aromatic and heterocyclic mono- and polyalcohols from the following: nordihydrogallate (EI) compound, quercetin (EH) compound, catechin (EIII) compound, kaempferol (EIV) compound, sulfuretin (EV) compound, ascorbic acid (ÉVI) compound, isoascorbic acid (ÉVII) compound, hydroquinone (EVIII) compound, gossypol (EIX) compound, reductic acid (EX) compound, methoxyhydroquinone (EXI) compound, hydroxyhydroquinone (EXII) compound, propylgallate (EXIII) compound, sucrose (EXIV) compound, vitamin E (EXV) compound, vitamin A (EXVI) compound, 8-quinolol (EXVII) compound, 3-tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyflavone (EXIX), 3,5-tert-butyl-p-hydroxytoluene (EXX), p-tert-butylphenol (EXXI), timolol (EXXII), xibornol (EXXIII), 3,5-di-tert-butyl-4-hydroxybenzylthioglycolate (EXXIV), 4'-hydroxybutyranilide (EXXV), guaiacol (EXXVI), tocol (EXXVII), isoeugenol (EXXVIII), eugenol (EXXIX), piperonyl alcohol (EXXX), allopurinol (EXXXI), coniferyl alcohol (EXXΧΧΠ) compound of formula, 4-hydroxyphenethyl alcohol (EXXXIII), compound of formula p-coumarin alcohol (EXXXIV), curcumin (EXXXV); aromatic and heterocyclic amines from the following: Ν,Ν'-diphenylenediamine (MI) compound, ethoxyquin (MII) compound, thionine (MII) compound, hydroxyurea (MIV); a compound containing at least one free acid group from the following: a compound of the formula 3,3'-thiodipropionic acid (NI), a compound of the formula fumaric acid (NII), a compound of the formula dihydroxymaleic acid (NIII), a compound of the formula thioctic acid (NIV), a compound of the formula edetic acid (NV), a compound of the formula bilirubin (NVI), a compound of the formula 3,4-methylenedioxycinnamic acid (NVII), a compound of the formula piperonyl acid (NYIII). 4. Compounds according to claim 2 or 3, wherein the precursor compound B is a compound meeting the requirements of test 4. 5. A compound according to any one of claims 1-4, wherein precursor B contains as a free reactive group one or more of the following groups: XZ, or A group of the general formula -Z _r NZ _n , where X, Z, Z! and Z _n are as above, or COOH, =NH. 6. Compounds according to claim 5, wherein B is reacted with a compound of general formula (III) which contains a free valence saturated with a reactive group so that it is capable of reacting with the free, reactive group of group B - in which general formula (III) nlX represents a number from 0 to 3, preferably 1, T _T ix, Rtix· may be the same or different and represent H or a straight or branched C 1-4 alkyl group, preferably R _T i _X and R _TIX 'represent H, Y ³ represents a saturated, unsaturated or aromatic heterocyclic group containing at least one nitrogen atom and which ring is 5- or 6-membered. 7. A compound according to claim 6, wherein in formula (III) Y represents a group of formulae (Y1) to (Y-15). 8. Compounds according to claim 7, in which ^Y3 represents a pyridyl group (Y12 group). - 85 • · · · · ··· ···*· · 9. Compounds according to any one of claims 1-8, wherein the precursor active ingredient in the general formula (I) is one of the following active ingredients: anti-inflammatory agent, analgesic, vasodilator or cholinergic agent, expectorant-mucolytic agent, anti-asthma-antiallergic agent, antihistamine agent, ACE inhibitor, beta-blocker, antithrombotic agent, vasodilator, antidiabetic, antitumor agent, antiulcer agent, antihyperlipidemic agent, antibiotic, antiviral agent, bone resorption inhibitor, antidementia agent. 10. Compounds according to claim 9, wherein the prodrug is one of the following drugs: anti-inflammatory agents: aceclofenac, acemetacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, alclofenac, alminoprofen, amfenac, bendazac, bermoprofen, a-bisabolol, bromfenac, bromosaligenin, bucloxylic acid, butibufen, carprofen, cinemtacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazol, enfenamic acid, etodolac, etofenamate, felbinac, fenbufen, fenclosic acid, fendosal, fenoprofen, fentiazac, fepradinol, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, glucamethacin, glycol salicylate, ibuprofen, ibuproxam, indomethacin, indoprofen, isofezolac, isoxepac, isoxicam, ketoprofen, ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mesalamine, methiazic acid, mofezolac, naproxen, niflumic acid, oxaceprol, oxaprozin, oxyphenbutazone, parsalmide, perisoxal, phenylacetylsalicylate, olsalazine, pyrazolac, piroxicam, pirprofen, pranoprofen, protisic acid, salacetamide, salicylamide O-acetic acid, -86• · · · · · · · · · · · · · salicylic acid, salsalate, sulindac, suprofen, suxibuzone, tenoxicam, tiaprofenic acid, tiaramide, tinoridine, tolfenamic acid, tolmetin, tropesin, xenbucin, ximoprofen, zaltoprofen, zomepirac, tomoxiprole; analgesic active ingredients: acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicylic-2-amino-4-picolinic acid, acetylsalicylicsalicylic acid, anileridine, benoxaprofen benzylmorphine, 5-bromosalicylic-acetic acid, bucetin, buprenorphine, butorphanol, capsaicine, cinchofen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, etilmorphine, eugenol, floctafenine, phosphosai, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oximorphone, pentazocine, phenazocine, fenocoll, fenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarite; from substances acting on the respiratory and urinary systems (bronchodilators and substances acting on the cholinergic system, expectorants/mucolytics, anti-asthma/anti-allergic antihistamines): bronchodilators and substances acting on the cholinergic system: acephylline, albuterol, bambuterol, bamifylline-, bevonium methyl sulphate, bitolterol, carbuterol, clenbuterol, chlorprenaline, dioxethedrine, diphylline, ephedrine, epinephrine, eprozinol, etafredine, etilnorepinephrine, etofylline, fenoterol, flutoprium- 87• · · · · · · · · · · · * -bromide, hexoprenaline, ipratropium bromide, isoetharine, isoprotenerol, mabuterol, metaproterenol, oxybutynin, oxitropium bromide, pirbuterol, procaterol, protokylol, proxiphylline, reproterol, ricniterol, salmeterol, soterenol, terbutaline, 1-theobromoacetic acid, tiotropium bromide, tretocruinol, tulobuterol, zaprinast, cyclodrine, NS-21, 2-hydroxy-2,2-diphenyl-N-(1,2,3,6-tetrahydropyridin-4-ylmethyl)acetamide; expectorants/mucolytic agents: ambroxol, bromexine, domiodol, erdosteine, guaiacol, guaifenesin, iodinated glycerin, letosteine, mesna, sobrerol, stepronin, terpin, tiopronin; anti-asthma/anti-allergy antihistamines: acrivastine, alloclamide, amlexanox, cetirizine, clobenzapem, chromoglycate, chromolyn, epinastine, fexofenadine, formoterol, histamine, hydroxyzine, levocabastine, lodoxamide, mabuterol, matron s, montelukast, nedocromil, repirinast, seratrodast, suplatast tosylate, terfenadine, tiaramide, urushiol, bromhexine; cardiovascular agents (ACE inhibitors, beta-blockers, antithrombotic and vasodilator agents, antidiabetic and hypoglycemic agents): ACE inhibitors: alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, losartan, moveltipril, naphthopidil, perindopril, guinapril, ramipril, spirapril, temoicapril, trandolapril, urapidil; beta-blockers: acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilolol, carazolol, carteolol, -88♦ · · f * ·«· ♦· ··· * carvedilol, celiprolol, cetamolol, dilevalol, epanolol, esmolol, indenolol, labetalol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nifenalol, nipridalol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfmalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, xibenolol; anti-thrombotic and vasoactive agents: acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodilhemisuccinate, benziodarone, betahistine, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamole, droprenilamine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isbogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin sodium salt, ridogrel, suloctidil, tinofedrine, tinzaparin, triflusal, xanthinol niacinate; anti-diabetics: acarbose, carbutamide, glibornuride glybutiazol(e), miglitol, repaglinide, troglitazone, 1-butyl-3-methanylurea, tolrestat, nicotinamide; antitumor drugs: ancitabine, anthramycin, azacitidine, azaserine, 6-azauridine, bicalutamide, carubicin, carzinophilin, chlorambucil, chlorzotocin, cytarabine, daunorubicin, defosfamide, demecolcine, denopterin, 6-diazo-5-oxo-L-norleucine, docetaxel, doxifluridine, doxorubicin, droloxifene, edatrexate, eflornithine, enocitabine, epirubicin, epithiostanol, etanidazole, etoposide, fenretinide, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubicin, lonidamine, mannomustine, melphalan, menogaril, 6-mercaptopurine, methotrexate, -89...· ·..· .í. mitobronitol, mitolactol, mitomycins, mitoxantrone, mopidamol, mycophenolic acid, ninopterin, nogalamycin, paclitaxel, pentostatin, rubicin, piritrexim, plicamycin, podophyllic acid, porfimer sodium, porphyrornycin, propagermanium, puromycin, ranimustine, retinoic acid, roquinimex, streptonigrin, streptozocin, teniposide, tenuazonic acid, thiamiprine, thioguanine, tomudex, topotecan, trimetrexate, tubercidin, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin; antiulcer agents: ε-acetamidocaproic acid, arbaprostil, cetraxate, cimetidine, ecabet, enprostil, esaprazole, irsogladine, misoprostol, omeprazole, omoprostil, pantoprazole, plaunotol, rioprostil, rosaprostol, rotraxate, sofalcone, trimoprostil; hyperlipidemic agents (statins): atorvastatin, cilastatin, dermostatin, fluvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, privastatin sodium, simvastatin; antibiotics/antivirals: antibiotics: amdinocillin, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, azidamphenicol, azidocillin, azlocillin, aztreonam, benzoylpas, benzylpenicillinic acid, biapenem,! bicozamycin, capreomycin, carbenicillin, carindacillin, carumonam, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefclidine, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin C, cephalothin, cephapyrin sodium, cephradine, chloramphenicol, chlortetracycline, cinoxacin, clavulanic acid, clometocillin, cloxacillin, cyclacillin, cycloserine, demeclocycline, dicloxacillin, epicillin, fenbecillin, flomoxef, floxacillin, hetacillie, imipenem, lenampicillin, loracarbef, lymecycline, mafenide, meclocycline, meropenem, metampicillin, methacycline, methicillin sodium, mezlocillin, minocycline, moxalactam, mupirocin, myxin, negamycin, novobiocin, oxacillin, panipenem, penicillin G potassium salt, penicillin N, penicillin O, penicillin V, fenethicillin potassium salt, pipacycline, piperacillin, pirlimycin, porfiromycin, propycillin, quinacillin, ritipenem, rolitetracycline, sancycline, sedecamycin, spectinomycin, sulbactam, sulbenicillin, temocillin, tetracycline, ticarcillin, tigemonam, tubercidin, azithromycin, clarithromycin, dirithromycin, enviomycin, erythromycin, josamycin, midecamycin, myocamycin, oleandomycin, rifabutin, rifamide, rifamycin, rifaximin, rokitamycin, spiramycin, troleandromycin, viomycin, virginiamycin; amikacin, apramycin, arbekacin, dibekacin, dihydrostreptomycin, fortimycin, gentamicin, micronomicin, neomycin, netilmicin, paromomycin, ribostarnycin, sisomycin, spectinomycin, streptomycin, tobramycin, trospectomycin; bacampicillin, cefcapene pivoxil, cefpodoxime proxetil, -91 panipenem, pivampicillin, pivcephalexin, sultamicillin, talampicillin; carbomycin, clindamycin, lincomycin, mikanrycin, rosaramycin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pazufloxacin, pefloxacin, pipemidic acid, pyromidic acid, rufloxacin, sparfloxacin, tosufloxacin, trovafloxacin, clomocycline, guamecycline, oxytetracycline, nifurpirinol, nifurprazine; p-aminosalicylic acid, p-aminosalicylic acid hydrazide, clofazimine, deoxydihydrostreptomycin, ethambutol, glyconiazide, isoniazid, opinazide, phenylaminosalicylate, rifampin, rifapentine, salinazid, 4-4'-sulfyldianiline, acediasulfone, dapsone, succisulfone, p-sulfanylylbenzylamine, thiazolesulfone, acetylsulfamethoxypyrazine, mafenide, 4'-(methylsulfamoyl)sulfanilanilide, salazosulf adimidine, sulfabenzamide, sulfacetamide, sulfachlorpyridasine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfamethylthiazole, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, 2-p-sulfanyllanilinoethanol, N ⁴ -sulfanylsulfanilamide, sulfanylcarbamide, N-sulfanylyl3,4-xylamide, sulfaperine, sulfaphenazole, sulfaproxiline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfisomidine, sulfisoxazole, 4-92- -sulfanilamidosalicylic acid; negamycin, carumonan, cloxiguin, nitroxoline, arginine, metronidazole; antiviral agents: acyclovir, amantadine, cidofovir, cytarabine, didanosine, dideoxyadenosine, edoxidine, famciclovir, floxuridine, ganciclovir, idoxuridine, indanavir, kethoxal, lamivudine, MADU, penciclovir, podophyllotoxin, ribavirin, rimantadine, sacjuinavir, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xenazoic acid, zalcitabine, zidovudine; bone resorption inhibitors (diphosphonates): alendronic acid, butedronic acid, etidronic acid, oxidronic acid, pamidronic acid, risedronic acid; anti-dementia drugs: amiridine, lazabemide, mofegiline, salbeluzol, oxiracetam, ipidacrine, nebracetam, tacrine, velnacrine. 11. Compounds according to claims 9 or 10, wherein the prodrug is one of the following: anti-inflammatory drugs: acetylsalicylic acid, 5-aminoacetylsalicylic acid, carprofen, diclofenac sodium, diflunisal, etodolac, flufenamic acid, flunixin, flurbiprofen, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mesalamine, naproxen, niflumic acid, olsalazine, piroxicam, salsalate, sulindac, suprofen, tenoxicam, tiaprofenic acid, tolfenamic acid, tolmetin, zomepirac, tomoxiprole; from analgesics: acetaminophen, acetylsalicylic acid, benoxaprofen, buprenorphine, butorphanol, capsaicin, diacereine, dihydrocodeine, - 93 ethylmorphine, eugenol, phenylbutazone, meptazinol, morphine, nalbuphine, pentazocine, thiorphan, tramadol, actarit; bronchodilators and substances acting on the cholinergic system: albuterol, carbuterol, clenbuterol, diphylline, etophylline, fenoterol, ipratropium bromide, metaproterenol, oxybutynin, pirbuterol, salmeterol, terbutaline, tiotropium bromide, zaprinast, cyclodrine, NS-21, 2-hydroxy-2,2-diphenyl-N-(1,2,3,6-tetrahydropyridin-4-ylmethyl)acetamide; expectorants/mucolytics: ambroxol, bromexine, guaiacol, sobrerol; anti-asthma/anti-allergy antihistamine active ingredients: cetirizine, chromoglycate, histamine, levocabastine, lodoxamide, montelukast, terfenadine, bromexine; ACE inhibitors: captopril, enalapril, lisinopril, losartan, ramipril; beta blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindolol, propranolol, timolol; anti-thrombotic and vasoactive agents: acetylsalicylic acid, acetorphan, argatroban, clopidogrel, dalteparin, dipyridamole, enoxaparin, heparin, iloprost, midodrine, ozagrel, phenylpropanolamine trifusal; antidiabetics: tolrestat, nicotinamide; antitumor agents: anthramycin, daunorubicin, doxorubicin, epirubicin, fluorouracil, methotrexate, vinblastine; anti-ulcer drugs: cimetidine, omeprazole, pantoprazole; anti-hyperlipidemic agents: lovastatin, pravastatin sodium, simvastatin; -94 antibiotics: amoxicillin, ampicillin, aztreonam, biapenem, carbenecillin, cefaclor, cefadroxil, cefamandole, cefatrizine, cefoxitin, clavulanic acid, dicloxacillin, imipenem, meclocycline, methacycline, moxalactam, panipenem, sulbactam, azithromycin, erythromycin, josamycin, myokamycin, rifabutine, rifamide, rifamycin, gentamicin, paromomycin, sisomicin, bacampicillin, carbomycin, clindamycin, ciprofloxacin, clinafloxacin, difloxacin, enrofloxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pipemidine, apicycline, clomocycline, oxytetracycline, nifurpirinol, nifurprazine, isoniazid, rifampin, rifapentine, dapsone, thiazolsulfone, sulfamethoxazole, sulfamoxole, metronidazole, arginine; antiviral drugs: acyclovir, famciclovir, ganciclovir, penciclovir, ribavirin, vidarabine, zidovudine; Bone resorption inhibitors: alendronic acid, etidronic acid, pamidronic acid. 12. A compound according to any one of claims 1-8, wherein the prodrug is a steroid compound in which A=R- and which is represented by the general formula (S) - in which the following substituents may be present in place of the hydrogen atoms of the CH groups or in place of the two hydrogen atoms of the CH ₂ groups: at position 1-2: double bond; in position 2-3: group corresponding to the formula SÍ: at the 2-position: Cl, Br; at the 3-position: CO, -O-CH ₂ -CH ₂ -Cl, OH; at position 3-4: double bond; - 95 at position 4-5: double bond; at position 5-6: double bond; at positions 5-10: double bond; at the 6-position: Cl, F, CH ₃ , -CHO; at the 7-position: Cl, OH; at the 9-position: Cl, F; at the 11-position: OH, CO, Cl, CH ₃ ; at the 16-position: CH ₃ , OH, =CH ₂ ; at the 17-position: OH, CH ₃ , OCO(O) _ua (CH ₂ ) _va CH ₃ , OCH or S2, where ua is 0 or 1 and va is a number from 0 to 4; a group of formula S3, S4 or S5 in the 16-17-position, R and R' can be the same or different and can be a hydrogen atom or a straight or branched chain alkyl group having 1-4 carbon atoms, preferably R=R'=CH ₃ , R is -(CO-L) _t -(L) _t2 -(X ₀ i)ti where t, ti and t2 are the same or different and can be 0 or 1, with the proviso that if t=0, t2=1 and if t=1, t2=0, and that t and ti or t2 and ti cannot be 0 at the same time, if A does not contain an OH group, the bivalent bridging group L is (CR4R5)na(O)nb(CR4R5) _n ' _a (CO) _n 'b(O) _{n b} (CO) _n ' _b (CR4R5) _{n a} where na, n'a, na are the same or different and have a value from 0 to 6, preferably 1-3; nb, n'b and nb and n' are the same or different and have a value of 0 or 1; R ₄ , R ₅ are the same or different and are H, a straight or branched chain alkyl group having 1-5 carbon atoms, preferably 1-3 carbon atoms; -96Xoi is as above or X ₂₁ , where X ₂₁ is OH, CH ₃ , Cl, N(-CH ₂ -CH ₃ ) ₂ , SCH ₂ F, SH, or a group of formula S6. 13. Compounds according to claim 12, wherein R=-CO- _CH2OH -CH( _CH3 )-CH2- _{CH2 -} COOH. 14. Compounds according to any one of claims 12-13, wherein the precursor steroid is a compound containing a hydroxyl group in the 3- and/or 11-position and/or a hydroxyl or carboxyl group in the R group in the terminal position. 15. The 12-14. Compounds according to any one of claims 1 to 11, wherein the precursor steroid is one of the following active ingredients: Budesonide, Hydrocortisone, Alclomethasone, Algestone, Beclomethasone, Betamethasone, Chlorprednisone, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Cortisone, Corticosterone, Deflazacort, Despnide, Desoximethasone, Dexamethasone, Diflorasone Diflucortolone, Difluprednate, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortyn Butyl, Fluocortolone, Fluormetholone, Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide, Halobetasol Propionate, Halomethasone, Halopredone Acetate, Hidrocortamate, Loteprednol Etabonate, Medrysone, Meprednisone, Methylprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25-diethylaminoacetate, Prednisolone sodium phosphate, Prednisone, Prednival, Prednylidene, Rimexolone, Triamcinolone, Triamcinolone Acetonide, 21-Acetoxypregnenolone, Cortivazole, Amcinonide, 9 4-. · ♦ 4 » _t 4 . · > -* · < Fluticasone Propionate, Mazipredone, Tixocortol, Triamcinolone Hexacetonide, Ursodeoxycholic Acid, Chenodeoxycholic Acid, Mitatrienediol, Moxestrol, Ethynylestradiol, Estradiol, Mestranol. 16. Compounds according to any one of claims 1-15 or salts thereof for use as a medicament. 17. Use of a compound or its salts according to any one of claims 1-15 or compositions containing them for the preparation of medicaments suitable for combating oxidative stress. 18. Pharmaceutical compositions comprising as active ingredient a compound or salt thereof according to any of claims 1-15. The authorized person: ZGdctí DANUBIA '' Patent and Trademark Office Ltd. Gézáhé Olchváry, patent attorney