EP1192129A2 - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds

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Publication number
EP1192129A2
EP1192129A2 EP00917074A EP00917074A EP1192129A2 EP 1192129 A2 EP1192129 A2 EP 1192129A2 EP 00917074 A EP00917074 A EP 00917074A EP 00917074 A EP00917074 A EP 00917074A EP 1192129 A2 EP1192129 A2 EP 1192129A2
Authority
EP
European Patent Office
Prior art keywords
acid
drugs
drug
test
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00917074A
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German (de)
English (en)
French (fr)
Inventor
Piero Del Soldato
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Nicox SA
Original Assignee
Nicox SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel drugs for systemic use and non systemic use, and the compositions thereof, to be used in oxidative stress and/or endothelial dysfuntions cases.
  • oxidative stress it is meant the generation of free radicals or radicalic compounds , which causes injury both of the cell and that of the surrounding tissue (Pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998 pages 48-54).
  • endothelial dysfunctions those relating to the vasal endothelium.
  • the damage of the vasal endotheliu is known as one of those important events that can cause a series of pathological processes affecting various organs and body apparatuses, as described hereinafter (Pathophysiology: The biological basis for disease in adults and children, McCance & Huether 1998 page 1025).
  • the oxidative stress and/or the endothelial dysfunctions are associated to various pathologies as reported hereinafter.
  • the oxidative stress can also be caused by toxicity of a great variety of drugs, which significantly affects their performances .
  • Said pathological events are of a chronic, debilitating character and are very ofthen typical of the elderly.
  • the drugs used show a remarkably worsened performance.
  • pathological situations caused by the oxidative stress and/or by the endothelial dysfunctions, or present in elderly are the following:
  • cardiovascular system myocardial and vascular ischae ia in general, hypertension, stroke, arteriosclerosis, etc.
  • ulcerative and non ul- cerative dyspepsias ulcerative and non ul- cerative dyspepsias, intestinal inflammatory diseases, etc.
  • Drug research is directed to find new molecules having an improved therapeutic index ( efficacy/toxicity ratio) or a lower risk/benefit ratio, also for pathological conditions as those above mentioned, wherein the therapeutic index of a great number of drugs results lowered.
  • therapeutic index efficacy/toxicity ratio
  • a lower risk/benefit ratio also for pathological conditions as those above mentioned, wherein the therapeutic index of a great number of drugs results lowered.
  • many drugs show a lower activity and/or higher toxicity.
  • NSAIDs result toxic particularly when the organism is debilitated or affected by morbid conditions associated to oxidative stress. Said conditions are for example the following: age, pre-existing ulcer, pre-existing gastric bleeding, debilitating chronic diseases such as in particular those affecting cardiovascular, renal apparatuses, the haematic crasis, etc.
  • Mcisoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. A randomized, double blind, placebo-controlled trial.”
  • Beta-blockers used for the angina, hypertension and cardiac arrhythmia treatment, show side effects towards the respiratory apparatus (dyspnoea, bronchoconstriction) , and therefore they can cause problems in patients affected by pathologies to said organs (asthma, bronchitis). Therefore beta-blockers can even worsen respiratory diseases such as asthma. Therefore in asthmatic patients reduced doses of said drugs must be used in order not to jeopardize even more the respiratory functionality. Thus the efficacy of the beta- blockers results very reduced.
  • Antithrombotics such as for example dipyridamole, aspirin, etc., used for the prophylaxis of thrombotic phenomena, have the same drawbacks.
  • the therapeutic action or the tolerability of these drugs, as in the case of aspirin is greatly reduced.
  • Bronchodilators for example salbutamol , etc . are used in the asthma and bronchitis treatment and drugs active on the cholinergic system are used in pathologies such as urinary incontinence. Their administration can produce similar side effects affecting the cardiovascular apparatus, causing problems both to cardiopathic and to hypertensive patients. Cardiopathies and hypertension are pathologies associated, as above said, to the oxidative stress and/or endothelial dysfunctions. Also these drugs show the same drawbacks as those above mentioned.
  • Expectorant and mucolytic drugs which are used in the therapy of inflammatory states of the respiratory organs, show drawbacks in patients affected by the above described conditions. Their administration can give rise to heartburn and gastric irritability, particularly in the elderly.
  • Bone resorption inhibitors such as diphosphonates (for example alendronate, etc.) are drugs showing high gastrointestinal toxicity. Therefore also these drugs can show the same drawbacks as those above mentioned.
  • Phosphodiesterase inhibitors such as for example sildenafil, zaprinast, used in the cardiovascular and respiratory system diseases, are charaterized by similar problems as to tolerability and/or efficacy in the mentioned pathological conditions of oxidative stress and/or endothelial dysfunctions .
  • Antiallergic drugs for example cetirizine, montelukast, etc. show similar problems in the mentioned pathological conditions, particularly for that it concerns their efficacy.
  • Anti-angiotensin drugs f .i. ACE-inhibitors, for example enalapril, captopril, etc., and receptor inhibitors, for example losartan, etc. , are used in the cardiovascular disease treatment.
  • Their drawback is to give side effects to the respiratory apparatus (i.e. cough, etc. ) in the above mentioned pathological conditions .
  • Antidiabetic drugs both of the insulin-sensitizing and of hypoglycaemizing type, such as for example sulphonylureas , tolbutamide, glypiride, glyclazide, glyburide, nicotinamide etc., are ineffective in the prophylaxis of diabetic complications. Their administration can give rise to side effects, such as for example gastric lesions. These phenomena become more intense in the pathological conditions above mentioned.
  • Antibiotics for example ' ampicillin, clarihtromycin, etc., and antiviral drugs, acyclovir, etc., show problems as regards their tolerability, for example they cause gastro-intestinal irritability.
  • Antitumoral drugs for example doxorubicin, daunorubicin, cisplatinum, etc., have high toxicity, towards different organs, among which are stomach and intestine. Said toxicity is further worsened in the above mentioned pathologies of oxidative stress and/or endothelial dysfunctions.
  • Antidementia drugs for example nicotine and colino- mimetics, are characterized by a poor tolerability especially in the above mentioned pathologies .
  • Drugs having a steroidal structure which are used in the therapy of acute (asthma, etc.) or chronic diseases (intestinal, hepatic, respiratory diseases , female reproductive apparatus diseases, cutaneous diseases, etc.) are characterized by marked toxic effects affecting various organs, particularly in the above mentioned oxidative stress conditions.
  • the class of steroidal drugs among which hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, desoxi- corticosterone, methylprednisolone, triamcinolone, para- methasone, betamethasone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, beclomethasone, acetoxy- pregnelone, etc., has remarkable farmaco-toxicological effects .on various organs , and for this reason both their clinical use and its interruption cause a series of side effects, some of which very serious. See for example Goodman & Gilman, "The pharmaceutical Basis of Therapeutics" 9°ed. , pag. 1459-1465, 1996.
  • biliary acids that have been used in the therapy of hepatic dysfunctions and in biliary colics.
  • Ursodesoxycholic acid is also used in some hepatic dysfunctions (hepatic cirrhosis of biliary origin, etc.). Their tolerability is strongly worsened in the presence of gastrointestinal complications (chronic hepatic damage, peptic ulcer, intestinal inflammation, etc.).
  • biliary acids the oxidative stress remarkably affects drug performance: both the efficacy and the tolerability of chenodeoxycholic and ursodesoxycholic acids are significantly reduced. In particular the unwanted effects on liver are found exalted.
  • estrogens for the treatment of dislipidaemias, hormonal dysfunctions, female apparatus tumours treatment can be mentioned.
  • said steroids show side effects as above mentioned, in particular at the hepatic level.
  • An object of the invention are compounds or their salts having the following general formula (I):
  • R is the drug radical
  • R la , R la C--C-J ⁇ linear or when possible branched alkyl, preferably C ⁇ C ⁇ or with -Z I -N-Z 11 , Z 1 and Z 11 being equal or I
  • NEM N-ethylmaleimide
  • the drug can be used to prepare the compounds of general formula (I) and (II), when the group of rats treated with NEM + carrier + drug shows gastrointestinal damages, or in the group treated with NEM + carrier + drug are observed gastrointestinal damages greater than those of the group treated with the carrier, or of the group treated with the carrier + drug, or of the group treated with the carrier + NEM;
  • test 2 CIP is a test in vitro wherein human endothelial cells from the umbilical vein are harvested under standard conditions, then divided into two groups (each group replicated five times), of which one is treated with a mixture of the drug 10 "4 M concentration in the culture medium, the other group with the carrier; then cumene hydroperoxide (CIP_) having a 5 mM concentration in the culture medium is added to each of the two groups; the drug meets test 2, i.e.
  • test 3 is a test in vivo carried out on four groups of rats (each group formed by 10 rats) for 4 weeks and receiving drinking water, the controls (two groups) and the treated (two groups), of which one group of the controls and of the treated respectively receives in the above 4 weeks drinking water added of N- ⁇ -nitro-L-arginine methyl ester (L-NAME) at a concentration of 400 mg/litre, the controls in the 4 weeks being administered with the carrier and the treated in the 4 weeks with the carrier + the drug, administering the carrier or the drug + carrier once a day, the drug being administered at the maximum dose tolerated by the group of rats not pretreated with L-NAME, i.e.
  • the highest dose administrable to animals at which no manifest toxicity appears i.e. such as to be symptomatologically observable
  • the water supply is stopped for 24 hours and then sacrified, determining the blood pressure 1 hour before sacrifice, and after sacrifice of the rats determining the plasma glutamic -pyruvic transaminase (GPT) after sacrifice, and examining the gastric tissue; the drug meets test 3, i.e.
  • test 4 is an analytical determination carried out by adding portions of methanol solutions of the precursor of B at a 10 "4 M concentration, to a methanol solution of DPPH (2,2- diphenyl-1-picryl hydrazyl - free radical); after having maintained the solution at room temperature away from light for 30 minutes, it is read the absorbance at the wave length of 517 nm of the test solution and of a solution containing only DPPH in the same amount as in the test solution; and then the inhibition induced by the precursor towards the radical production by DPPH is calculated
  • test 4 is met by B precursor compounds if the inhibition percentage as above defined is higher than or equal to 50%; wherein test 5 is the following: it is an analytical determination carried out by adding aliquots of 10 "4 M methanol solutions of the precursor of B having the free valence saturated as above indicated, to a solution formed by admixing a 2 mM solution of desoxyribose in water with 100 mM of phosphate buffer and 1 mM of the salt Fe I: ⁇ : (NH 4 ) 2 (S0 4 ) 2 ; after having thermostatted the solution at 37°C for one hour, are added, in the order, aliquots of aqueous solutions of trichloroacetic acid 2.8% and of thiobarbituric acid
  • the compound meets test 5 when the inhibition percentage as above defined of the precursor of B is higher than or equal to 50%.
  • the compound precursor of B which meets test 5 is selected from the following compounds:
  • Aminoacids aspartic acid (PI), histidine (PII), — 5-hydroxytryptophan (PHI), 4-thiazolidincarboxylic acid (PIV), 2-oxo-4-thiazolidincarboxylic acid (PV)
  • PV polyalcohols or thiols
  • Aminoacids selected from the following: L-carnosine (formula CI), anserine (CII), selenocysteine (CHI), se- lenomethionine (CIV), penicillamine (CV) , N-acetyl- penicillamine (CVI), cysteine (CVII), N-acetylcysteine (CVIII), glutathione (CIX) or its esters, preferably ethyl or isopropyl ester:
  • the corresponding compound SN(0) s can also be used instead of SH; hydroxyacids, selected from the following: gallic acid (formula DI), ferulic acid (DII), gentisic acid (Dili), citric acid (DIV), 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 selected from the following: nordihydroguaiaretic acid (El), quercetin (EH), catechin (EIII), kae pferol (EIV), sulphurethyne (EV), ascorbic acid (EVI), isoascorbic acid
  • EXII hydroquinone
  • EXIX gossypol
  • reductic acid EX
  • methoxyhydroquinone EXI
  • hydroxyhydroquinone EXII
  • propyl gallate EXIII
  • saccharose EXIV
  • vitamin E EXV
  • vitamin A EXVI
  • 8-quinolol EXVII
  • 3- tert-butyl-4-hydroxyanisole EXVIII
  • 3-hydroxyflavone EXIX
  • 3,5-tert-butyl-p-hydroxytoluene EXX
  • p-tert- butyl phenol EXXI
  • timolol EXXII
  • xibornol EXXIII
  • 3,5-di-ter-butyl-4-hydroxybenzyl-thioglycolate EXXIV
  • 4' -hydroxybutyranilide EXXV
  • guaiacol EXVI
  • EXXXV aromatic and heterocyclic amines , selected from the following: N, N' -diphenyl-p-phenylenediamine (MI), ethoxyquin (Mil), thionine (Mill), hydroxyurea (MIV) :
  • the drug and B precursor compounds are prepared according to the known methods in the prior art and described, for example, in "The Merck Index, 12a Ed. (1996), herein incorporated by reference.
  • the vitamin D3 derivative with retinoic acid (QVIII) is prepared as described in JP 93039261 (ref. C.A. 119 117617); the formula (QIX) compound according to EP 562497; 24,28- methylene-lor-hydroxyvitamin D2 (QX) according to EP 578494; the derivative compound of dehydroxyvitamin D2 (QXI) according to EP 549318.
  • the preferred B compounds are those meeting test 4.
  • Test 1 evaluation of the gastrointestinal damage from oxidative stress induced by free radicals formed following administration of N-ethylmaleimide (NEM) (H.G. Utley, F. Bernheim, P. Hochstein "Effects of sulphydril reagents on pe- roxidation in microsomes" Archiv. Biochem. Biophys. 118, 29-32 1967 ) .
  • the animals are distributed in the following groups (no. 10 animals for group) :
  • treatment only carrier (aqueous suspension 1% w/v of carboxymethylcellulose, dose: 5 ml/Kg when the drug is administered by os, or a physiologic solution when parenterally administered, i.e. by subcutaneous , intraperitoneal , intravenous or intermuscular route) ,
  • the administration routes are those known for the drug, and can be the oral or subcutaneous , intraperitoneal , intravenous or intramuscular route.
  • the NEM dose is of 25 mg/kg in physiologic solution (sub cutaneous route) and the drug is administered one hour later, in suspension in the carrier, as a single dose which corresponds to the maximum one, or the highest still tolerated by the animals of the group of rats not pretreated with NEM, i.e. the highest administrable dose to said group at which there is no manifest toxicity in the animals, defined as a toxicity that is clearly recognizable for its symptoms .
  • the animals are sacrificed after 24 hours and then one proceeds to the evaluation of the damage to the gastrointestinal mucosa.
  • the drug meets test 1, i.e. it can be used to prepare the compounds of general formula ( I ) and ( II ) , when the group of rats treated with NEM + carrier + drug shows gastrointestinal damages, or in said group the gastrointestinal damages noticed are greater than those shown by the group treated with the carrier alone, or the group treated with carrier + drug, or the group treated with carrier + NEM, even though the drug pharmacotherapeutic efficacy, assayed by using specific tests, is not significantly reduced.
  • CIP Protection parameter of endothelial cell against the oxidative stress induced by cumene hydroperoxide
  • Human endothelial cells of the umbilical vein are prepared according to an usual standard procedure. Fresh umbilical veins are filled with a 0.1% by weight collagenase solution and incubated at 37°C for 5 minutes.
  • the veins are perfused with medium M 199 (GIBCO, Grand Island, NY) pH 7.4 further added of other substances, as described in the examples.
  • the cells are collected from the perfusate by centrifugation and harvested in culture flasks T-75, pretreated with human fibronectin. The cells are then harvested in the same medium, further added with 10 ng/ml of bovine hypothalamic growth factor.
  • the cells of the primary cell culture i.e. that directly obtained from ex-vivo
  • the culture is stopped and the layers washed and trypsinized.
  • the cellular suspensions are transferred into the wells of a cell culture plate having 24 wells, half of which is then additioned with the same culture medium containing the drug at a 10 * M concentration, and harvested in a thermostat at 37°C at a constant moisture. Only the cells coming from said first sub-cultures are used for the experiments with cumene hydroperoxide (CIP).
  • CIP cumene hydroperoxide
  • the cells are identified as endothelial cells by morphological examination and by their specific immunological reaction towards factor VIII; said cultures did not show any contaminations from myocytes or fibroblasts.
  • the cellular culture medium is removed and the cellular layers are carefully washed with a physiologic solution at a temperature of 37°C.
  • the wells of the culture plate are then incubated for one hour with CIP at a 5 mM concentration in the culture medium.
  • the evaluation of cellular damage is carried out by determining the per cent variation of the DNA fragmentation with respect to the control group (treated with CIP alone), evaluating the fluorescence variation at the wave length of 405-450 nm. 5 replicates for each sample are carried out.
  • the drug meets the test, i.e. it can be used for preparing the compounds of general formula (I) and (II), when a statistically significant inhibition of apoptosis (cellular damage) induced by CIP with respect to the group treated with CIP alone is not obtained at p ⁇ 0.01.
  • Test 3 evaluation of the endothelial dysfunction induced by administration of L-NAME (N -nitro-L-arginine-methyl ester) J. Clin. Investigation 90, 278-281,1992.
  • the endothelial dysfunction is evaluated by determining the damage to the gastrointestinal mucosa, the hepatic damage and blood hypertension induced by administration of L-NAME.
  • the animals are divided in groups as herein below shown.
  • the group receiving L-NAME is treated for 4 weeks with said compound dissolved at a concentration of 400 mg/litre in drinking water.
  • the following groups are constituted (No. 10 animals for group) :
  • 1° group only carrier aqueous suspension 1% w/v of carboxy- methylcellulose, dose: 5 ml/Kg when the drug is administered by os, phisiologic solution when administered parenterally
  • the administration routes are those known for the drug, and can be the oral or subcutaneous , intraperiteneal , intravenous or intramuscular route.
  • the drug is administered at that dose which results the highest still tolerated by the animals of the group of rats not pretreated with L-NAME, i.e. the highest administrable dose at which there is no evident toxicity in the animals, i.e a toxicity recognizable for its symptoms.
  • the drug is administered once a day for 4 weeks.
  • a blood pressure increase is taken as an evaluation of the damage to vascular endothelium.
  • the damage to the gastric mucosa is evaluated as illustrated in test 1 ( see example Fl).
  • the hepatic damage is determined by evaluation of the glutamic-pyruvic transaminase (GPT increase) after sacrifice.
  • the drug meets test 3, i.e. it can be used for preparing the compounds of general formula ( I ) and ( II ) , when in the group of rats treated with L-NAME + drug + carrier it is found an higher hepatic damage (GPT) and/or an higher gastric damage and/or an higher cardiovascular (blood-pressure) damage in comparison to that of the group treated with the carrier alone, or of the group treated with carrier + drug, or of the group treated with carrier + L-NAME; even if the drug pharmaco- therapeutic efficacy, assayed by specific tests, is not significantly reduced.
  • GPT hepatic damage
  • gastric damage and/or an higher cardiovascular (blood-pressure) damage
  • Test 4 is a colorimetric test which affords to establish whether the precursor of B inhibits the production of radicals from DPPH ( 2 , 2-diphenyl-l-picryl-hydrazyl) (M.S. Nenseter et Al., Atheroscler. Thromb. 15, 1338-1344, 1995).
  • 100 ⁇ M solutions in methanol of the tested substances are prepared, and an aliquot of each of said solutions is added to a DPPH solution in methanol 0.1 M. After having stored the solutions at room temperature away from light for 30 minutes, their absorbances are read at the wave length of 517 n , together with that of the corresponding DPPH solution at the same concentration. The absorbance decrease with respect to that of the solution of DPPH at the same concentration of the test solutions is determined.
  • the effectiveness of the tested compound in inhibiting formation of radicals by DPPH is expressed by the following formula:
  • the compound precursor of B meets test 4 when the inhibition percentage of radical production from DPPH, expressed as a percentage according to the above equation, is higher than or equal to 50%.
  • Test 5 is a colorimetric test wherein 0.1 ml aliquots of 10 "4 M methanolic solutions of the tested products are added to test tubes containing a solution formed by 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 11 (NH 4 ) 2 (S0 4 ) 2 in 2mM HCl. The test tubes are then maintained at 37°C for one hour. Then in each test tube are added, in the order, 0.5 ml of a 2.8% solution in tri- chloroacetic acid water and 0.5 ml of an aqueous 0.1 M solution of thiobarbituric acid.
  • a reference blank is formed by adding to a test tube containing only the above described aqueous solution of reactants 0.1 ml of methanol .
  • the test tubes are closed and heated in an oil bath at 100°C for 15 minutes.
  • a pink coloration is developed the intensity of which is proportional to the quantity of deoxyribose undergone to radical oxidative degradation.
  • the solutions are cooled at room temperature and their absorbances are read at 532 nm against the blank.
  • the inhibition induced by the precursor of B in the confront of radical productionby Fe 11 is determined by means of the following formula:
  • a g and A c are respectively the absorbance values of the solution containing the tested compound + the iron salt and that of the solution containing only the iron salt, the compound satisfies test 5 when the inhibition percentage of radical production as above defined from the precursor of B is higher than or equal to 50%.
  • Test 1 precursor drug: indomethacin
  • the group of rats treated with NEM + indomethacin at the above mentioned dose shows gastrointestinal damages .
  • Indomethacin can therefore be used as a drug for preparing the compounds (I) and (II) of the present invention.
  • Test 2 precursor drugs: indomethacin, paracetamol and esala- mine
  • Indomethacin and paracetamol meet test 2 since the cellular damage (apoptosis) inhibition induced by CIP is not significantly different with respect to that of the controls.
  • mesalamine can be used as a precursor for preparing the compounds (I) and (II) of the present invention.
  • Test 3 (L-NAME) precurosr drugs: paracetamol, simvastatin, omeprazole
  • Paracetamol and simvastatin meet test 3 since they cause gastric and hepatic damages greater than those induced both by L-NAME + carrier and by the drug + carrier.
  • N-acetylcysteine in said test inhibits of 100% the production of radicals induced by DPPH. Since said percentage is higher than the limit of 50%, said drug cannot be used in the present invention as precursor of B. 4-Thiazolidin-carboxylic acid does not inhibit at any extent the production of radicals induced by DPPH (Table V) . Thus the drug does not meet test 4 as requested by the instant invention and it could be used as a precursor of B if it meets test 5.
  • Test 5 (test for the compound precursor of B)
  • Table III relating to this test shows that the 4- thiazolidincarboxylic acid meets test 5 since the % inhibition is of 100%. Therefore the compound can be used as precursor of B.
  • B contains free reactive functions, preferably selected from one or more of the following groups: XZ and Z j -N-Z IX wherein
  • B contains free reactive functions it can suitably be reacted with the compounds having formula (HI) wherein the free valence is saturated with a reactive group such as to be able to react with the free reactive function of B:
  • nIX is an integer between 0 and 3, preferably 1;
  • Ripjx, RTI X ' equal to or different from each other are H or a linear or branched C ⁇ -C 4 alkyl; preferably R ⁇ R IX ' are H.
  • Y 3 is a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom, preferably one or two nitrogen atoms , said ring having 5 or 6 atoms .
  • the Y 3 ring can optionally have substituents, for example CH 2 OH.
  • Y 3 in formula (III) is preferably selected from the following:
  • Y 3 The most preferred of Y 3 is Y12 (pyridyl).
  • the formula (I) compound salts are obtainable by reaction in organic solvent such as acetonitrile, tetrahydrofuran with an equimolecular amount of the corresponding organic or inorganic acid.
  • organic acids examples include oxalic, tartaric, maleic, succinic, citric acids.
  • the derivatives according to the invention can be used in the therapeutic -indications of the precursor drug, allowing to obtain the advantages exemplified hereinafter for some groups of these drugs :
  • Anti-inflammatory drugs NSAIDs the invention compounds result very well tolerated and effective, even when the organism is debilitated and finds under conditions of oxidative stress. Said drugs can be used also in those pathologies wherein inflammation plays a significant pathogenetic role, such as for instance, but not limited to, in cancer, asthma, miocardic infarction.
  • Adrenergic blockers of a- or /3-blocker type: the action spectrum of the formula (I) compounds results wider than that of the starting drugs : to a direct action on the smooth musculature the inhibition of the nervous beta- adrenergic signals governing the contraction of the hematic ducts is associated. The side effects (dyspnoea, bronchoconstriction) affecting the respiratory apparatus are lower.
  • Antithrombotic drugs the antiplatelet activity is potentiated and in the case of the aspirin derivatives the gastric tolerability is improved.
  • Bronchodilators and drugs active on the cholinergic system the side effects affecting the cardio-vascular apparatus (tachycardia, hypertension) result lowered.
  • Expectorants and mucolytic drugs the gastrointestinal tolerability results improved.
  • Diphosphonates the toxicity relating to the gastrointestinal tract is drastically lowered.
  • Phosphodiesterase (PDE) inhibitors bronchodilators: the therapeutic efficacy is improved, the dosage being equal; it is therefore possible, using the compounds of the invention to administer a lower dose of the drug and reduce the side effects.
  • Anti leukotrienic drugs better efficacy.
  • ACE inhibitors better therapeutic efficacy and lower side effects (dyspnoea, cough) affecting the respiratory apparatus .
  • Antidiabetic drugs insulin- sensitizing and hypoglycaemizing
  • antibiotic, antiviral, antitumoral, anticolitic drugs, drugs for the dementia therapy better efficacy and/or tolerability.
  • the drugs which can be used as precursors in the general formula of the compounds of the invention are all those meeting at least one of the above mentioned tests 1, 2, 3.
  • Examples of precursor drugs which can be used are the following:
  • anti-inflammatory drugs aceclofenac, acemetacin, acetylsali- cylic acid, 5-amino-acetylsalicylic acid, alclofenac, almi- noprofen, amfenac, bendazac, bermoprofen, or-bisabolol, bromfe- nac, bromosaligenin, bucloxic acid, butibufen, carprofen, cinmetacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazol, enfenamic acid, etodolac , etofenamate, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentiazac, fepradinol, flufenamic acid, flu
  • ACE-inhibitors alacepril, benazepril, captopril, cero- napril, cilazapril, delapril, enalapril, enalaprilat, fo- sinopril, imidapril, lisinopril, losartan, moveltipril, na- phthopidil, perindopril, quinapril, ra ipril, spirapril, temo- capril, trandolapril , urapidil; beta-blockers: acebutolol, alprenolol, amosulalol, aroti- nolol, atenolol, betaxolol, bevantolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilol, cara
  • the preferred substances are the following: among anti-inflammatories: 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, tomoxi- prol ; among analgesic drugs: acetaminophen, acetyls
  • ACE-inhibitors captopril, enalapril, lisinopril, losar- tan, ramipril; beta blockers: alprenolol, atenolol, bupranolol, labe- talol, metipranolol, metoprolol, pindolol, propranolol, ti o- lol; antithrombotic and vasoactive drugs: acetylsalicylic acid, acetorphan, argatroban, clopidogrel, dalteparin, dipyri- damole, enoxaparin, heparin, iloprost, midodrine, ozagrel, phenylpropanolamine trifusal ; antidiabetic drugs: tolrestat, nicotinamide; among antitumoral drugs: anthramycin, daunorubicin, doxo- ruber
  • R precursors are prepared according to the methods known in the prior art . See for example in "The Merck Index, 12a Ed. (1996), herein incorporated by reference. When available, the corresponding isomers, comprising optical isomers, can be used.
  • ua is an integer equal to 0 or 1
  • va is an integer from 0 to 4 ; in position 16-17: there may be the following groups:
  • the bivalent bridging group L is selected from:
  • na, n'a, and n''a, equal to or different from each other are integers from 0 to 6, preferably 1-3; nb, n'b, n' 'b and n' ' 'b, equal to or different from each other, are integers equal to 0 or 1; R 4 , R 5 , equal to or different from each other, are selected from H, linear or branched alkyl from 1 to 5 carbon atoms, preferably from 1 to 3; Q 1 is X as above defined, or equal to X 2 1 wherein X 2 X is equal to OH, CH 3 , Cl, N( -CH 2 -CH 3 ) 2 , SCH 2 F, SH,
  • R" -CO-CH 2 OH, -CH(CH 3 ) -CH 2 -CH 2 -COOH.
  • the precursor steroids of A which can be mentioned and which are preferred, are those listed hereinunder, obtainable according to the processes known in the art.
  • H 2 , H, R, R' , R' ' have the meaning mentioned in the compounds listed herein: Budesonide, Hydrocortisone, Alclome- thasone, Algestone, Beclomethasone, Betamethasone, Chloro- prednisone, Clobetasol, Clobetasone, Clocortolone, Cloprednol, Cortisone, Corticosterone, Deflazacort, Desonide, Desoxi- methasone, Dexamethasone , Diflorasone Diflucortolone, Diflu- prednate, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocort
  • the reactive function of the drug for example -COOH, - OH
  • a covalent bond for example of ester, amide, ether type
  • the reactions used for obtaining the formula (I) compounds are reactions leading to the formation of bonds for example of ester, amide, thioester type well known to the skilled in the f ield .
  • the obtained compound is reacted with the drug precursor.
  • the compounds object of the present invention are formulated in the corresponding pharmaceutical compositions for parenteral , oral and topic use according to the well known methods of the prior art, along with the usual excipients; see for example the paper "Remington's Pharmaceutical Sciences 15a Ed.”.
  • the amount on a molar basis of the active principle in these formulations is the same, or lower, compared with that used of the corresponding precursor drug.
  • the daily administrable doses are those of the precursor drugs, or in case lower.
  • the daily doses can be found in the publications of the field, such as for example in "Physician's Desk reference".
  • the precursor is naproxene (Formula VI)
  • the precursor of B is N-acetylcysteine of formula (CVIII)
  • the precursor is ibuprofen of formula VII, the precursor of B is N-acetylcysteine of formula (CVIII)
  • the precursor is indomethacin of formula (VIII)
  • the pre' cursor of B is N-acetylcysteine of formula (CVIII)
  • the precursor is flurbiprofen of formula (IX)
  • the precursor of B is N-acetylcysteine of formula (CVIII)
  • the precursor is ibuprofen of formula (VII), the precursor of B is ferulic acid of formula (DII):
  • the precursor is flurbiprofen of formula (IX), the precursor of B is ferulic acid of formula (DII)
  • the precursor is the diphylline of formula (XXVI) and the precursor of B is the ferulic acid (formula DII):
  • precursor drug of the invention compound is diclofenac of formula (XXIX) and the precursor compound of B is (L) -histidine of formula (PII):
  • Acute toxicity has been evaluated by administering to a group of 10 rats weighing 20 g a single dose of each of the tested compounds, by cannula, by os in an aqueous suspension of carboxymethylcellulose 2% w/v. The animals are kept under observation for 14 days. In no animal of the group toxic symptoms have appeared, even after administration of a 100 g/Kg dose.
  • Test 1 experimental model in vivo with N-ethylmaleimide (NEM) : study of the gastric tolerability of some drugs screened as precursors of the compounds of the invention.
  • the animals (rats, weight about 200 g) are distributed in the following groups (No. 10 animals for group):
  • treatment only carrier (aqueous suspension 1% w/v of carboxymethylcellulose, dose: 5 ml/Kg when the drug is administered by os, physiologic solution when by parenteral route) ,
  • Groups administered with each drug group I : treatment : carrier + drug, group II: treatment: carrier + drug + NEM.
  • the drugs assayed in this experiment are the following (Table I): indomethacin, ambroxol, mesalamine, sodic alendro- nate, tacrine, omeprazol, misoprostol.
  • Indomethacin, ambroxol and alendronate are administered by os, mesalamine by intracolonic (rectal) route and tacrine, omeprazol, misoprostol by subcutaneous route.
  • the maximum tolerated dose determined by administering each substance by the above said routes to the animals not treated with NEM, is reported in Table I. With higher doses than those reported in the Table, enteropathy, diarrhoea, depression, tremor and sedation have appeared in the animals.
  • mice are at first treated with NEM by subcutaneous injection at a dose of 25 mg/kg in physiologic solution.
  • the drug is administered one hour later, in suspension in the carrier.
  • Animals are sacrificed after 24 hours and evaluation of the damage to the gastrointestinal mucosa is made by counting the number of rats, inside each group, with lesions to the stomach at a visual inspection. The total number of said rats is then divided by the total number of rats of the group and multiplied by 100. The thus obtained percentages are reported in Table I.
  • the Table shows that in the groups of rats treated with said drugs without NEM, no gastric lesions were detectable.
  • EXAMPLE F2 Test 2 in vitro: inhibition of apoptosis (DNA fragmentation) induced in the endothelial cells by CIP in the presence of some drugs screened as precursors of the compounds of the invention.
  • Human endothelial cells of the umbilical vein are prepared according to a standard method. Fresh umbilical veins are filled with a collagenase solution 0.1% by weight and incubated at 37°C for 5 minutes.
  • the veins are perfused with the medium M 199 (GIBCO, Grand Island, NY) pH 7.4 with 0.1% (weight/volume) of collagenase, added with 10% of bovine fetus serum (10 mcg/ml), sodium heparin (50 mcg/ml), thimidine (2.4 mcg/ml), glutamine (230 mcg/ml), penicillin (100 Ul/ml), streptomycin (100 mcg/ml) and streptomycin B (0.125 mcg/ml).
  • bovine fetus serum 10 mcg/ml
  • sodium heparin 50 mcg/ml
  • thimidine 2.4 mcg/ml
  • glutamine 230 mcg/ml
  • penicillin 100 Ul/ml
  • streptomycin 100 mcg/ml
  • streptomycin B (0.125 mcg/ml
  • Cells are then harvested in the same medium, added with bovine hypothalamic growth factor (100 ng/ml).
  • bovine hypothalamic growth factor 100 ng/ml.
  • the cells of the primary cell culture the cells directly removed from ex-vivo umbilical vein
  • the layers are washed and trypsinized.
  • the cellular culture medium is removed and the cellular layers are carefully washed with a standard physiologic solution buffered with phosphate 0.1 M pH 7.0, at the temperature of 37°C. The content of each well is then incubated for one hour with a CIP suspension in the culture medium at a 5 mM concentration. Evaluation of the cellular damage (apoptosis) is carried out by determining the per cent variation of the DNA fragmentation in the cultures containing the drug + CIP with respect to the controls treated with CIP only. Said % variation of DNA fragmentation is determined by evaluating the fluorescence variation by a BX60 Olympus microscope (Olympus Co.
  • Results are given in Table II and show that indomethacin, paracetamol, clopidogrel, salbutamol, sodic alendronate, diphylline, . cetirizine, enalapril, nicotinamide, ampicilline, aciclovir, tacrine, omeprazol do not significantly inhibit apoptosis; these drugs can therefore be used for preparing the products of the invention.
  • Test 3 experimental in vivo model with N -nitro-L-arginine- methyl ester (L-NAME) : gastric tolerability (gastrointestinal damage incidence), hepatic (GPT dosage, glutamic-pyruvic transaminase) and cardiovascular (blood pressure) tolerability of some drugs screened as precursors of the compounds of the invention.
  • L-NAME N -nitro-L-arginine- methyl ester
  • the experimental model adopted is according to J. Clin. Investigation 90, 278-281,1992.
  • the endothelial dysfunction is evaluated by determining the damage induced by L-NAME administration to the gastrointestinal mucosa, the hepatic damage (GPT increase), and the vascular endothelium or cardiovascular damage as blood hypertension.
  • the animals (rats, average weight 200 g) are divided in groups as herein below described.
  • the group receiving L-NAME is treated for 4 weeks with said compound dissolved at the concentration of 400 mg/litre in drinking water.
  • the following groups (No. 10 animals for group) are constituted:
  • treatment only carrier (aqueous suspension 1% w/v of carboxymethylcellulose, dose: 5 ml/Kg when the drug is administered by os, physiologic solution when by parenteral route) ,
  • the drugs used in the test are paracetamol, doxorubicin, simvastatine, omeprazol and misoprostol. Each drug is administered once a day for 4 weeks.
  • the maximum tolerated dose of the drug being administered to the animals is determined by evaluating, in a separate dose scaling up experiment on untreated animals, the appearance in the animals of symptoms such as enteropathy, diarrhoea, depression, tremor, sedation.
  • One hour before the sacrifice blood pressure is determined and a blood pressure increase is taken as an indication of a damage being occurred to vascular endothelium.
  • the damage to the gastric mucosa is evaluated as previously mentioned in test 1 (ex. Fl).
  • the hepatic damage is determined by evaluation after the sacrifice of the glutamic- pyruvic transaminase (GPT increase) .
  • the drug meets test 3 and it can therefore be used for preparing the compounds of the invention, when in the group of rats treated with L-NAME + drug + carrier, an higher hepatic damage (higher GPT values) and/or higher gastric damage and/or higher cardiovascular damage (higher blood pessure) are found in comparison with the group treated with the carrier only, or the group treated with carrier + drug, or the group treated with carrier + L-NAME.
  • the test results are reported in Table IV.
  • the % gastric lesions have been determined as in Test 1.
  • the % GPT and % blood pressure values are referred to the corresponding value found in the animals of the 1st group of the control groups.
  • the average value of the blood pressure in this group was of 105 ⁇ 8 mmHg.
  • the results obtained show that paracetamol , doxorubicin and simvastatine cause hepatic damage and gastroenteropathy (GPT values and the gastric lesions are % higher compared both with the corresponding groups treated with the drug, in the absence of L-NAME, and with the controls treated with L-NAME).
  • Test 4 inhibition of the radical production from DPPH of some substances used as precursors of B.
  • the method is based on a colorimetric test in which DPPH (2, 2-diphenyl-l-picryl-hydrazyl) is used as the compound- forming radicals (M.S. Nenseter et Al., Atheroscler. Thromb. 15, 1338-1344, 1995).
  • Solutions in methanol of the tested substances at a final concentration 100 ⁇ M are initially prepared. 0.1 ml of each of these solutions are added to aliquots of 1 ml of a methanol solution 0.1 M of DPPH and then the final volume is brought to 1.5 ml. After having stored the solutions at room temperature away from light for 30 minutes, the absorbance at the wave length of 517 nm is read. It is determined the absorbance decrease with respect to the absorbance of a solution containing the same concentration of DPPH.
  • the compound to be used according to the present invention meets test 4 if radical production inhibition, as above defined, is equal to or higher than 50%.
  • N-acetylcysteine, cysteine, ferulic acid, (L) -carnosine, gentisic acid meet test 4 since they inhibit the production of radicals induced by DPPH to an extent higher than 50%.
  • Test 5 inhibition of the radical production from Fe 11 from compounds used as precursors of B
  • test tubes containing an aqueous solution formed by mixing 0.2 ml of 2 mM deoxyribose, 0.4 ml of buffer phosphate pH 7.4 100 mM and 0.1 ml of 1 mM Fe II (NH 4 ) 2 (S0 4 ) 2 in 2mM HCl.
  • the test tubes are then kept at a temperature of 37°C for one hour.
  • test tube 0.5 ml of a 2.8% solution in trichloroacetic acid in water and 0.5 ml of an aqueous solution 0.1 M thio barbituric acid.
  • a reference blank is constituted by substituting the above 0.1 ml aliquots of the test compound methanolic solutions with 0.1 ml of methanol.
  • 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 quantity of deoxyribose undergone to radical oxidative degradation.
  • the solutions are cooled at room temperature and their absorbances at 532 nm are read against the blank.
  • Example F3 was repeated and it was evaluated gastric tolerability both of the following precursor drugs and of the corresponding derivatives according to the present invention:
  • Example Fl was repeated with three groups of rats (each group of of ten animals), all of them receiving NEM, and orally administered as it follows : a. control group : the vehicle formed of an aqueous suspension 1% w/v of carboxymethylcellulose, b. one group (group b - comparative ) administered at the same time with 100 mg/Kg (0.48 mmoles/Kg) of ibuprofen + 79 mg/Kg (0.48 mmoles/Kg) of N-acetylcysteine in the same above vehicle, c.
  • group c one group administered with 170.4 mg/Kg (0.48 mmoles/Kg) of the ester between indomethacin and N-acetyl cisteine (ref. ex. 2), in the above same vehicle.
  • group b one group administered with 170.4 mg/Kg (0.48 mmoles/Kg) of the ester between indomethacin and N-acetyl cisteine (ref. ex. 2), in the above same vehicle.
  • Table VII show that the mixture administered to group b (comparative) is less effective than the compound of the invention administered to group c in reducing gastric lesions.
  • Test 1 Gastric tolerability of drugs representative of the drug classes illustrated in the present invention in animals not treated or treated with NEM (oxidative stress conditions ) .
  • the % incidence is calculated from the ratio between the number of animals found with gastric lesions and that total of the group.
  • Test 3 Gastric tolerability (gastrointestinal damage incidence), hepatic (GPT, glutamic- pyruvic transaminase dosage), and cardiovascular (blood pressure) of some compounds representative of the drug classes illustrated in the present invention under conditions of endothelial trouble induced by L-NAME.
  • the results relating to the blood pressure and GPT are expressed as % values compared with those found in animals treated with the only carrier, without L-NAME.

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NO20014926L (no) 2001-12-13
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IL145632A0 (en) 2002-06-30
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IT1311921B1 (it) 2002-03-20
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ITMI990750A1 (it) 2000-10-13
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