CLAIMS
1. Compounds or their salts of general formulas (I):
A~B (I)
wherein:
A = R~T1-, wherein
R is the drug radical and
T1 = (CO)t or (X)t., wherein X = O,/S/ NR1C, R1C is H
or a linear or branched alkyl, having from 1 to 5
carbon atoms, or a free valence, t and t' are
integers and equal to zero or 1, with the proviso
that t = 1 when t' - 0; t = 0 when t' - 1;
-T B~X2 wherein
T B= (CO) when t = 0, T B = X when t' - 0, X being as
above defined:
X2, monovalent radical, is such that the
corresponding precursor of B meets test 5 and/or test
4; said precursor of formula -T B~X2, wherein the T B
free valence is saturated with -OZ or Z wherein Z =
H or R1a, being R1a C1-C10 = linear or when possible
branched,alkyl, preferably C1-C5,
or with -Z I-N-Z II, Z I and Z II being equal or
~
different and having the Z values, depending on
whether T B = CO or X, in connection with the t, t'
values;
with the proviso that:
the drug A - R~T1-, wherein the free valence is
saturated as hereinafter mentioned:
- when t' = O with:
- O-Z wherein Z = H or R1a, or with
- Z I-N-Z II,
~
- when t = 0 with X-Z, wherein X and Z as
above defined,
is such as to meet at least one of tests 1-3;
wherein test 1 (NEM) is a test in vivo carried
out on four groups of rats (each formed by 10 rats),
the controls (two groups) and the treated (two
groups) of which one group of the controls and one
group of the treated respectively are administered
with one dose of 25 mg/kg s.c. of N-ethylmaleimide
(NEM), the controls being treated with the carrier
and the treated groups with the carrier + the drug of
formula A = R-T1- wherein the free valence is
saturated as above indicated, administering the drug
at a dose equivalent to the maximum one tolerated by
the rats that did not receive NEM, i.e. the highest
dose administrable to the animal at which there is no
manifest toxicity, i.e. such as to be
symptomatologically observable; the drug complies
with test 1, i.e. the drug can be used to prepare the
compounds of general formula (I) and (II), when the
111
group of rats treated with NEM + carrier + drug shows
gastrointestinal damages, or in the group treated
with NEM + carrier + drug are observed gastrointesti-
nal 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;
- wherein 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. the drug can be used to prepare
the compounds of general formula (I) and (II), if a
statistically significant inhibition of the apoptosis
(cellular damage) induced by CIP is not obtained with
p < 0.01 with respect to the group treated with the
carrier and CIP;
wherein test 3 (L-NAME), 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,
112
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-.omega.-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; after the said 4
weeks, the water supply is stopped for 24 hours and
then sacrificed, 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. the drug can be
used to prepare the compounds of general formula (I)
and (II), when in the group of rats treated with L-
NAME + carrier + drug, greater hepatic damages
(determined as higher values of GPT) and/or gastric
and/or cardiovascular damages (determined as higher
113
values of blood-pressure) are found in comparison
respectively with the group treated with the carrier
alone, or with the group treated with the carrier +
drug, or with the group treated with the carrier +
L-NAME;
wherein test 4 is an analytical determination
carried out by adding portions of methanol solutions
of the precursor of B or B1 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 as a
percentage by means of the following formula:
(1 - A s/A c)X100
wherein A s and A c are respectively the absorbance
values of the solution containing the test compound
+ DPPH and that of the solution containing only DPPH;
test 4 is met by the compounds used as precursors of
B if the % inhibition as above defined is higher than
or equal to 50%;
114
wherein test 5 is an analytical determination
carried out by adding aliquots of 10 -4 M methanol
solutions of the precursors of B 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
FeII(NH4)2(SO4)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
0.5 M, heating is effected at 100°C for 15 minutes
and the absorbance of the tested solutions is then
read at 532 nm; the inhibition induced by the
precursors of B in the confront of radical production
by FeII is calculated as a percentage by means of
the following formula:
(1 - A S/A C)X100
wherein A S and A C are respectively the absorbance
values of the solution containing the tested compound
and the iron salt and that of the solution containing
only the iron salt; the compound meets test 5 when
the % inhibition as above defined of th precursor of
B is higher than or equal to 50%.
2. Compounds according to claim 1 wherein the precursor
compound of B that meets test 5 is selected from the
following. compounds
115
- Aminoacids: aspartic acid (PI), histidine (PII),
5-hydroxytryptophan (PIII), 4-thiazolidincarboxylic
acid (PIV), 2-oxo-4-thiazolidincarboxylic acid (PV)
<IMGS>
- mono and polyalcohols or thiols: 2-thiouracil (QI),
2-mercaptoethanol (QII), esperidine (QIII),
secalciferol (QIV), 1-.alpha.-OH vitamin D2 (QV),
flocalcitriol (QVI), 22-oxacalcitriol (QVII), the
116
vitamin D3 derivative esterified with the vitamin A
radical (QVIII), the formula (QIX) compound, 24,28-
methylene-1.alpha.-hydroxyvitamin D2 (QX) the compound
derived from 1a,25-dihydroxyvitamin D2 (QXI), 2-mer-
captoimidazol (QXII)
<IMGS>
117
<IMGS>
118
<IMGS>
119
<IMG>
wherein n°3, equal to or different from each other,
are an integer equal to zero or one; n3, equal to or
different from each other, are integers from zero to
three; W, equal to or different from each other, are
selected among the following: HX with X as above
defined, COOH, R' , OR' wherein R' is a linear or when
possible branched alkyl having from 1 to 20 carbon
atoms, preferably from 1 to 6 carbon atoms; Rf, ORf
wherein Rf is as R' but containing at least one
halogen atom instead of H, preferably F; at least one
of the W radicals is XH, when the drug reactive
function is a carboxyl; or COOH when the drug
reactive function is XH;
when n°3 - 0 if n3 is different from zero then the
free valence of the n3 group is saturated with one of
the following substituents : R', OR', Rf, ORf, H, when
n°3 - 0 and n3 - 0, the free valence is saturated
with H.
3. Compounds according to claim 1, wherein the precursor
compound of B which meets test 4 is selected from the
following classes of compounds:
120
Aminoacids, selected from the following: L-carnosine
(formula CI), anserine (CII), selenocysteine (CIII),
selenomethionine (CIV),
<IMGS>
121
- hydroxyacids, selected from the following: galiic
acid (formula DI), ferulic acid (DII), gentisic acid
(DIII), citric acid (DIV), caffeic acid (DV), hydro
caffeic acid (DVT), p-coumaric acid (DVTI), vainillic
acid (DV=II), chlorogenic acid (DIX), kynurenic acid
(DX), syringic acid (DXI):
<IMGS>
122
<IMGS>
Aromatic and heterocyclic mono- and polyalcohols,
selected from the following: nordihydroguaiaretic
acid (EI), quercetin (EII), catechin (EIII), ka-
empferol (EIV), sulphurethyne (EV), ascorbic acid (E-
VI), isoascorbic acid (EVII), hydroquinone (EVIII),
gossypol (EIX), reductic acid (EX), methoxy-
hydroquinone (EXI), hydroxyhydroquinone (EXII), pro-
123
pyl gallate (EXIII), saccharose (EXIV), vitamin E
(EXV), vitamin A (EXVI), 8-quinolol (EXVII), 3-
tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyflavo-
ne (EXIX), 3,5-tert-butyl-p-hydroxytoluene (EXX), p-
tert-butyl phenol (EXXI), timolol (EXXII), xibornol
(EXXIII), 3,5-di-tert-butyl-4-hydroxybenzyl-thio-
glycolate (EXXIV), 4'-hydroxybutyranilide (EXXV),
guaiacol (EXXVI), tocol (EXXVII), isoeugenol (EX-
XVIII), eugenol (EXXIX), piperonyl alcohol (EXXX),
allopurinol (EXXXI), conyferyl alcohol (EXXXII), 4-
hydroxyphenetyl alcohol (EXXXIII), p-coumaric alcohol
(EXXXIV), curcumin (EXXXV):
<IMGS>
124
124
<IMGS>
125
<IMGS>
126
<IMGS>
127
<IMGS>
- aromatic and heterocyclic amines, selected from the
following: N, N'-diphenyl-p-phenylenediamine (MI),
ethoxyquin (MII), thionine (MIII), hydroxyurea (M-
IV):
<IMGS>
128
- Compounds containing at least a free acid function,
selected from the following: 3,3'-thiodipropionic
acid (NI), fumaric acid (NII), dihydroxymaleic acid
(NIII), thioctic acid (NIV), edetic acid (NV),
bilirubin (NVI), 3,4-methylendioxycinnamic acid (NVI-
I), piperonylic acid (NVIII):
<IMGS>
129
<IMGS>
4. Compounds according to claims 2-3, wherein the precursor
compounds of B are those meeting test 4.
5. Compounds according to claims 1-4 wherein B contains free
reactive functions selected from one or more of the
following groups: XZ and <IMG> wherein X, Z, Z1
and Z II are as above defined, or COOH, =NH.
6. Compounds according to claim 5 wherein B is let react with
the compounds of formula (III) having the free valence
saturated with a reactive group such as to be capable to
react with the free reactive function of B:
<IMGS>
wherein:
nIX is an integer between 0 and 3, preferably 1;
R TIX, R TIX', equal to or different from each other are H or
a linear or branched C1-C4 alkyl; preferably R TIX, R TIX',
are H.
130
Y3 is a saturated, unsaturated or aromatic heterocyclic
ring containing at least one nitrogen atom, said ring
having 5 or 6 atoms.
7. Compounds according to claim 6 wherein
Y3 in formula (III) is selected from the following:
<IMGS>
8. Compounds according to claim 7 wherein Y3 is Y12
(pyridyl).
9. Compounds according to claims 1-8, wherein the precursor
drugs of the formula (I) compounds are selected from the
following: anti-inflammatory, analgesic drugs,
bronchodilators and drugs active on the cholinergic
system, expectorant-mucolytic drugs, antiasthmatic-
antiallergic, antihistaminic drugs, ACE-inhibitors, beta-
blockers, antithrombotic drugs, vasodilators,
antidiabetic, antitumoral, antiulcer, antihyperlipidemic,
antibiotic, antiviral drugs, bone reabsorption inhibitors,
antidementia drugs.
10. Compounds according to claim 9, wherein the precursor
drugs are selected from the following:
131
anti-inflammatory drugs: aceclofenac, acemetacin, acetyl-
salicylic acid, 5-aminoacetylsalicylic acid, alclofenac,
alminoprofen, amfenac, bendazac, bermoprofen, .alpha.-bisabolol,
bromfenac, bromosaligenin, bucloxic acid, butibufen,
carprofen, cinmetacin, clidanac, clopirac, sodium diclofe-
nac, diflunisal, ditazol, enfenamic acid, etodolac, eto-
fenamate, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentiazac, fepradinol, flufenamic acid, fluni-
xin, flunoxaprofen, flurbiprofen, glucametacin, glycol
salicylate, ibuprofen, ibuproxam, indomethacin,
indoprofen, isofezolac, isoxepac, isoxicam, ketoprofen,
ketorolac, lornoxicam, loxoprofen, meclofenamic acid,
mefenamic acid, meloxicam, mesalamine, metiazinic acid,
mofezolac, naproxen, niflumic acid, olsalazine, oxaceprol,
oxaprozin, oxypheributazone, parsalmide, perisoxal, phenyl
acetylsalicylate, pyrazolac, piroxicam, pirprofen, prano-
profen, protizinic acid, salacetamide, salicilamide O-
acetic acid, salicylsulphuric acid, salsalate, sulindac,
suprofen, suxibuzone, tenoxicam, tiaprofenic acid, tia-
ramide, tinoridine, tolfenamic acid, tolmetin, tropesin,
xenbucin, ximoprofen, zaltoprofen, zomepirac, tomoxiprol;
analgesic drugs: acetaminophen, acetaminosalol,
aminochlorthenoxazin, acetylsalicylic 2-amino-4-picoline
acid, acetylsalicylsalicylic acid, anileridine,
benoxaprofen benzylmorphine, 5-bromosalicylic acetate
132
acid, bucetin, buprenorphine, butorphanol, capsaicine,
cinchophen, ciramadol, clometacin, clonixin, codeine,
desomorphine, dezocine, dihydrocodeine, dihydromorphine,
dimepheptanol, dipyrocetyl, eptazocine, ethoxazene,
ethylmorphine, eugenol, floctafenine, fosfosal, glafenine,
hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-
lactophenetide, levorphanol, meptazinol, metazocine,
metopon, morphine, nalbuphine, nicomorphine,
norlevorphanol, normorphine, oxycodone, oxymorphone, pen-
tazocine, phenazocine, phenocoll, phenoperidine, phe-
nylbutazone, phenylsalicylate, phenylramidol, salicin, sa-
licylamide, tiorphan, tramadol, diacerein, actarit;
bronchodilators and drugs active on the cholinergic
system: acefylline, albuterol, bambuterol, bamifylline,
bevonium methyl sulphate, bitolterol, carbuterol,
clenbuterol, chlorprenaline, dioxethedrine, diphylline,
ephedrine, epinephrine, eprozinol, etafredine, ethyl
norepinephrine, etofylline, fenoterol, flutoprium bromide,
hexoprenaline, ipratropium bromide, isoetharine,
isoprotenerol, mabuterol, metaproterenol, oxybutinyn, oxi-
tropium bromide, pirbuterol, procaterol, protokylol,
proxyphylline, reproterol, rimiterol, salmeterol,
soterenol, terbutaline, 1-teobromineacetic acid, tiotro-
pium bromide, tretoquinol, tulobuterol, zaprinast,
cyclodrine, NS-21, 2-hydroxy-2,2-diphenyl-N-(1,2,3,6-
133
tetrahydro-pyridin-4-ylmethyl)acetamide ;
expectorant/mucolytic drugs: ambroxol, bromhexine,
domiodol, erdosteine, guaiacol, guaifenesin, iodinated
glycerol, letosteine, mesna, sobrerol, stepronin, terpin,
tiopronin;
antiasmatic/antiallergic antihistaminic drugs:
acrivastine, alloclamide, amlexanox, cetirizine, cloben-
zepam, chromoglycate, chromolyn, epinastine,
fexofenadine, formoterol, histamine, hydroxyzine,
levocabastine, lodoxamide, mabuterol, metron s, montelu-
kast, nedocromil, repirinast, seratrodast, suplatast
tosylate, terfenadine, tiaramide, urushiol, bromhexine;
ACE-inhibitors: alacepril, benazepril, captopril,
ceronapril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, imidapril, lisinopril, losartan,
moveltipril, naphthopidil, perindopril, quinapril,
ramipril, spirapril, temocapril, 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, me-
pindolol, metipranolol, metoprolol, moprolol, nadolol,
nadoxolol, nebivolol, nifenalol, nipridalol, oxprenolol,
penbutolol, pindolol, practolol, pronethalol, propranolol,
134
sotalol, sulfinalol, talinolol, tertatolol, tilisolol,
timolol, toliprolol, xibenolol;
antithrombotic and vasoactive drugs: acetorphan, acetylsa-
licylic acid, argatroban, bamethan, benfurodil
hemisuccinate, benziodarone, betahistine, brovincamine,
bufeniode, citicoline, clobenfurol, clopidogrel,
cyclandelate, dalteparin, dipyridamole, droprenilamine,
enoxaparin, fendiline, ifenprodil, iloprost, indobufen,
isbogrel, isoxsuprine, heparin, lamifiban, midodrine,
nadroparin, nicotinyl alcohol, nylidrin, ozagrel,
perhexiline, phenylpropanolamine, prenylamine, papa-
veroline, reviparin sodium salt, ridogrel, suloctidil,
tinofedrine, tinzaparin, triflusal, xanthinol niacina-
te;
antidiabetic drugs: acarbose, carbutamide,
glibornuride glybuthiazol(e), miglitol, repaglinide,
troglitazone, 1-butyl-3-metanyl-urea, tolrestat,
nicotinamide;
antitumoral drugs: ancitabine, anthramycin,
azacitidine, azaserine, 6-azauridine, bicalutamide,
carubicin, carzinophilin, chlorambucil, chlorozotocin,
cytarabine, daunorubicin, defosfamide, demecolcine,
denopterin, 6-diazo-5-oxo-L-norleucine, docetaxel,
doxifluridine, doxorubicin, droloxifene, edatrexate,
eflornithine, enocitabine, epirubicin, epitiostanol,
135
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, pira-
rubicin, piritrexim, plicamycin, podophyllic acid,
porfimer sodium, porfiromycin, propagermanium, puromycin,
ranimustine, retinoic acid, roquinimex, streptonigrin,
streptozocin, teniposide, tenuazonic acid, thiamiprine,
thioguanine, tomudex, topotecan, trimetrexate, tubercidin,
ubenimex, vinblastine, vincristine, vindesine,
vinorelbine, zorubicin;
antiulcer drugs: .epsilon.-acetamidocaproic acid,
arbaprostil, cetraxate, cimetidine, ecabet, enprostil,
esaprazole, irsogladine, misoprostol, omeprazole,
ornoprostil, pantoprazole, plaunotol, rioprostil,
rosaprostol, rotraxate, sofalcone, trimoprostil;
anti-hyperlipidemic drugs: atorvastatin, cilastatin,
dermostatin, fluvastatin, lovastatin, mevastatin,
nystatin, pentostatin, pepstatin, sodium privastatin,
simvastatin;
antibiotics: amdinocillin, amoxicillin, ampicillin,
apalcillin, apicycline, aspoxicillin, azidamfenicol,
azidocillin, azlocillin, aztreonam, benzoylpas, benzyl pe-
136
nicillinic acid, biapenem, bicozamycin, capreomycin,
carbenicillin, carindacillin, carumonam, cefaclor,
cefadroxil, cefamandole, cefatrizine, cefazedone,
cefazolin, cefbuperazone, cefclidin, 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, cephapirin sodium, cephradine,
chloramphenicol, chlortetracycline, cinoxacin, clavulanic
acid, clometocillin, cloxacillin, cyclacillin,
cycloserine, demeclocycline, dicloxacillin, epicillin,
fenbecillin, flomoxef , floxacillin, hetacillin, imipenem,
lenampicillin, loracarbef, lymecycline, mafenide, me
clocycline, meropenem, metampicillin, methacycline, methi
cillin sodium, mezlocillin, minocycline, moxalactam, mupi
rocin, myxin, negamycin, novobiocin, oxacillin, pamipenem,
penicillin G potassium salt, penicillin N, penicillin O,
penicillin V, phenethicillin potassium salt, pipacycline,
piperacillin, pirlimycin, porfiromycin, propycillin,
quinacillin, ritipenem, rolitetracycline, sancycline,
137
sedecamycin, spectinomycin, sulbactam, sulbenicillin,
temocillin, tetracycline, ticarcillin, tigemonam,
tubercidin, azithromycin, clarithromycin, dirithromycin,
enviomycin, erythromycin, josamycin, midecamycin,
miokamycin, oleandomycin, rifabutin, rifamide, rifamycin,
rifaximin, rokitamycin, spiramycin, troleandromycin,
viomycin, virginiamycin;
amikacin, apramycin, arbekacin, dibekacin,
dihydrostreptomycin, fortimicins, gentamicin,
micronomicin, neomycin, netilmicin, paromomycin,
ribostamycin, sisomicin, spectinomycin, streptomicin,
tobramycin, trospectomycin, bacampicillin, cefcapene
pivoxil, cefpodoxime proxetil, panipenem, pivampicillin,
pivcefalexin, sultamicillin, talampicillin;
carbomycin, clindamycin, lincomycin, mikamycin,
rosaramicin, ciprofloxacin, clinaf loxacin, difloxacin,
enoxacin, enrofloxacin, fleroxacin, flumequine,
grepafloxacin, lomefloxacin, nadifloxacin, nalidixic acid,
norfloxacin, ofloxacin, pazufloxacin, pefloxacin,
pipemidic acid, piromidic acid, rufloxacin, sparfloxacin,
tosufloxacin, trovafloxacin, clomocycline, guamecycline,
oxytetracycline, nifurpirinol, nifurprazine;
p-aminosalicylic acid, p-aminosalicylic acid hydrazide,
clofazimine, deoxydihydrostreptomycin, ethambutol,
glyconiazide, isoniazid, opiniazide, phenyl
138
aminosalicylate, rifampin, rifapentine, salinazid, 4-4'-
sulfynyldianiline,
acediasulfone, dapsone, succisulfone, p-sulfanilylbenzyl
amine, thiazolsulfone, acetyl sulfamethoxypyrazine,
mafenide, 4'-(methylsulfamoyl)sulfanilanilide,
salazosulfadimidine, sulfabenzamide, sulfacetamide,
sulfachlorpyridazine, sulfachrysoidine, sulfacytine,
sulfadiazine, sulfadicramide, sulfadimethoxine,
sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole,
sulfalene, sulfamerazine, sulfameter, sulfamethazine,
sulfamethizole, sulfamethomidine, sulfamethoxazole,
sulfamethoxypyridazine, sulfamethylthiazole, sulfametrole,
sulfamidochrysoidine, sulfamoxole, sulfanilamide, 2-p-
sulfanilylanilinoethanol, N4-sulfanilylsulfanilamide,
sulfanilylurea, N-sulfanilyl-3,4-xylamide, sulfaperine,
sulfaphenazole, sulfaproxyline, sulfapyrazine,
sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole,
sulfathiourea, sulfisomidine, sulfisoxazole, 4-
sulfanilamido salicylic acid; negamycin, carumonan,
cloxyquin, nitroxoline, arginine, metronidazole;
antiviral drugs: aciclovir, amantadine, cidofovir,
cytarabine, didanosine, dideoxyadenosine, edoxudine,
famciclovir, floxuridine, ganciclovir, idoxuridine,
indanavir, kethoxal, lamivudine, MADU, penciclovir,
podophyllotoxin, ribavirin, rimantadine, saquinavir,
139
sorivudine, stavudine, trifluridine, valacyclovir,
vidarabine, xenazoic acid, zalcitabine, zidovudine;
bone resorption inhibitors: alendronic acid, butedro-
nic acid, etidronic acid, oxydronic acid, pamidronic acid,
risedronic acid;
antidementia drugs: amiridine, lazabemide,
mofegiline, salbeluzol, oxiracetam, ipidacrine,
nebracetam, tacrine, velnacrine.
Compounds according to claims 9-10, wherein the precursor
drugs are selected from the following:
anti-inflammatory drugs: acetylsalicylic acid, 5-
aminoacetylsalicylic acid, carprofen, diclofenac sodium,
diflunisal, etodolac, flufenamic acid, flunixin, flur-
biprofen, ibuprofen, indomethacin, indoprofen, ketoprofen,
ketorolac, lornoxicam, loxoprofen, meclofenamic acid,
mefenamic acid, meloxicam, mesalamine, naproxen, niflumic
acid, olsalazine, piroxicam, salsalate, sulindac, supro-
fen, tenoxicam, tiaprofenic acid, tolfenamic acid, tolme-
tin, zomepirac, tomoxiprol;
analgesic drugs: acetaminophen, acetylsalicylsalicylic
acid, benoxaprofen, buprenorphine, butorphanol, capsaicin,
diacereine, dihydrocodeine, ethylmorphine, eugenol,
phenylbutazone, meptazinol, morphine, nalbuphine, penta-
zocine, thiorphan, tramadol, actarit;
bronchodilators and drugs active on the cholinergic
140
system: albuterol, carbuterol, clenbuterol, difhylline,
etofylline, fenoterol, ipratropium bromide, metaprotere-
nol, oxybutynin, pirbuterol, salmeterol, terbutaline,
tiotropium bromide, zaprinast, cyclodrine, NS-21, 2-
hydroxy-2,2-diphenyl-N-(1,2,3,6-tetrahydro-pyridin-4-
ylmethyl) acetamide;
expectorant/mucolytic drugs: ambroxol, bromexine, guaia-
col, sobrerol;
antiasthmatic/antiallergic antihistaminic drugs:
cetirizine, chromoglycate, histamine, levocabastine,
lodoxamide, montelukast, terfenadine, bromexine;
ACE-inhibitors: captopril, enalapril, lisinopril, losar-
tan, ramipril;
beta blockers: alprenolol, atenolol, bupranolol, labe-
talol, metipranolol, metoprolol, pindolol, propranolol,
timolol;
antithrombotic and vasoactive drugs: acetylsalicylic
acid, acetorphan, argatroban, clopidogrel, dalteparin,
dipyridamole, enoxaparin, heparin, iloprost, midodrine,
ozagrel, phenylpropanolamine, trifusal;
antidiabetic drugs: tolrestat, nicotinamide;
antitumoraldrugs: anthramycin, daunorubicin, doxorubicin,
epirubicin, fluorouracyl, methotrexate, vinblastine;
antiulcer drugs: cimetidine, omeprazole, pantoprazole;
antihyperlipidemic drugs: lovastatin, pravastatin sodium,
141
simvastatin;
antibiotics: amoxicillin, ampicillin, aztreonam, biapenem,
carbenecillin, cefaclor, cefadroxil, cefamandole, cefa-
trizine, cefoxitin, clavulanic acid, dicloxacillin, imi-
penem, meclocycline, methacycline, moxalactam, panipenem,
sulbactam, azithromycin, erythromycin, josamycin,
miokamycin, rifabutine, rifamide, rifamycin, gentamicin,
paromomycin, sisomicin, 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, pen-
ciclovir, ribavirin, vidarabine, zidovudine;
bone resorption inhibitors: alendronic acid, etidronic
acid, pamidronic acid.
12. Compounds according to claims 1-8 wherein the precursor
drugs are steroidal compounds wherein A = R-, having the
following structure:
<IMG>
142
wherein in substitution of the hydrogens of the CH groups
or of the two hydrogens of the CH2 groups mentioned in the
general formula, there may be the following substituents;
in position 1-2: there may be a double bond;;
in position 2-3: there may be the following substituent:
<IMG>
in position 2: there may be Cl, Br:
in position 3: there may be CO, -O-CH2-CH2-C1, OH;
in position 3-4: there may be a double bond;
in position 4-5: there may be a double bond;
in position 5-6: there may be a double bond;
in position 5-10: there may be a double bond;
in position 6: there may be Cl, F, CH3, -CHO;
in position 7: there may be Cl, OH;
in position 9: there may be Cl, F;
in position 11: there may be OH, CO, Cl, CH3;
in position 16: there may be CH3, OH, =CH2;
in position 17: there may be OH, CH3, OCO(O)ua(CH2)va CH3,
C=CH or
<IMG>
143
wherein 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:
<IMG>
R and R', equal to or different from each other, can
be hydrogen or linear or branched alkyls from 1 to 4
carbon atoms, preferably R = R' = CH3;
R" is -(CO-L)t-(L)t2-(X OI)t1-
wherein t, t1 and t2 are integers equal to or
different from each other equal to 0 or 1, with the
proviso that when t = 0 t2 = 1 and when t = 1 t2 = 0, and
that t and t1, or t2 and t1, cannot contemporaneously be
equal to 0 when A does not contain -OH groups;
the bivalent bridging group L is selected from:
(CR4R5)na(O)nb(CR4R5)n'a(CO)n'b(O)n"b(CO)n",b(CR4R5)n"a
wherein 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; R4, R5, 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;
144
X0I is X as above defined, or equal to X2I wherein X2I
is equal to OH, CH3, Cl, N(-CH2-CH3)2, SCH2F, SH, or
<IMG>
13. Compounds according to claim 12 wherein R" = -CO-CH2OH, -
CH(CH3)-CH2-CH2-COOH.
14. Compounds according to claims 12-13 wherein the precursor
steroids are selected from those having the hydroxyl
function in position 3 and/or in position 11, and/or
having in R" an hydroxyl or carboxylic function in
terminal position.
15. Compounds according to claims 12-14 wherein the precursor
steroids are selected from the following: Budesonide,
Hydrocortisone, Alclomethasone, Algestone,
Beclomethasone, Betamethasone, Chloroprednisone, Clobeta-
sol, Clobetasone, Clocortolone, Cloprednol, Cortisone,
Corticosterone, Deflazacort, Desonide, Desoximethasone,
Dexamethasone , Diflorasone Diflucortolone , Difluprednate,
Fluazacort, Flucloronide, Flumethasone, Flunisolide,
Fluocinolone Acetonide, Fluocinonide, Fluocortyn Butyl,
Fluocortolone, Fluorometholone, Fluperolone Acetate, Flu-
prednidene Acetate, Fluprednisolone, Flurandrenolide, For-
mocortal, Halcinonide, Halobetasol Propionate,
Halomethasone, Halopredone Acetate, Hydrocortamate,
145
Loteprednol Etabonate, Medrysone, Meprednisone, Methylpre-
dnisolone, Momethasone Furoate, Paramethasone, Prednicar-
bate, Prednisolone, Prednisolone 25-Diethylaminoacetate,
Prednisolone Sodium Phosphate, Prednisone, Prednival,
Prednylidene, Rimexolone, Triamcinolone, Triamcinolone
Acetonide,21-Acetoxypregnenolone,Cortivazol,Amcinonide,
Fluticasone Propionate, Mazipredone, Tixocortol,
Triamcinolone Hexacetonide, Ursodesoxycholic acid,
Chenodeoxycholic acid, Mitatrienediol, Moxestrol,
Ethynylestradiol, Estradiol, Mestranol.
16. Compounds or salts, or their compositions according to
claims 1-15 for use as a medicament.
17. Use of the compounds or salts, or their compositions
according to claims 1-15 for the preparation of drugs for
the therapeutic oxidative stress application.
18. Pharmaceutical formulations containing as active principle
the compounds or their salts of claims 1-15.
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