ITMI20011744A1 - DRUGS FOR VASCULOPATHIES - Google Patents

Description

Description of the industrial invention in the name:

The present invention relates to the use of drugs in the prevention and / or treatment of vasculopathies.

The most severe cardiovascular diseases (including restenosis, atherosclerosis, myocardial infarction, peripheral and central vascular diseases, etc.) are characterized by a pathological activation of vascular cells (vascular smooth muscle cells, endothelial cells) and blood (platelets, leukocytes) , monocytes / macrophages, etc.).

Vasculopathies and associated diseases are pathological conditions accompanied by an altered blood chemistry and clinical picture, which manifests itself with hyperglycemia and / or hyperinsulinemia, hyperlipidemia and / or water-saline retention and / or hyperproliferation of vascular and / or tumor cells, and / or prothrombotic and procoagulant activity, etc. Vasculopathies can facilitate the onset of other pathologies such as obesity, diabetes and cardiovascular diseases such as myocardial, cerebral and / or peripheral ischemias, retinopathies, polyneuropathies, gastroenteropathies, nephropathies, etc., hypertension (general and regional at the pulmonary, coronary level , portal, renal, etc.), atherosclerosis, Alzheimer's disease, cancer.

Vasculopathies also include particular pathologies such as syndrome X (or insulin resistance) and drug-induced vasculopathy.

There is no single therapeutic approach that is able to prevent and / or reduce vascular disease.

The ideal approach is to intervene on the different cellular processes, that is to prevent the pathological activation of the aforementioned cells, which leads to the establishment and progress of the pathological process affecting the cardiovascular system.

Currently the drugs used for vasculopathies and the therapeutic approaches used inhibit a single cell population, therefore they act only on one phase of the process, with only partially satisfactory results.

Statins, rapamycin, and radiation treatment only affect smooth muscle but not other cell populations. The results obtained with these pharmacological treatments and with radiotherapy are only partially satisfactory and therefore it is necessary to increase the dosages with consequent even severe side effects.

The need was felt to have drugs that would allow an effective therapeutic treatment of vascular diseases, overcoming the drawbacks associated with the therapeutic and surgical treatments currently used, and that were effective in inhibiting the pathological activation of different cell populations of the cardiovascular system and in addition that they were not toxic, in particular at the gastric level, and moreover they could be used for prolonged treatments without side effects.

This technical problem has now been solved by the Applicant using a specific class of drugs. Surprisingly and unexpectedly, the Applicant has found that the nitroxy derivatives of flurbiprofen, naproxen and diclofenac are active in the treatment of vasculopathies, acting on the cellular processes involved. This result is surprising since other nitroxy derivatives, such as for example the derivatives of piroxicam and ketorolac, were not active at non-toxic doses.

Therefore, the object of the present invention is the use in vasculopathies of drugs, or their salts, having the following general formula (I):

in which:

cO is an integer and is 0 or 1;

bO is an integer and is 0 or 1, with the proviso that cO and bO cannot be equal to zero at the same time. R is the radical of formula (All)

m which:

RAI is CH3 or H;

Ri is phenyl, or a 2,6-dichlorofenylamino- group; R6 is hydrogen or a halogen atom, preferably fluorine;

or Ri and R6 together form the radical of formula (Ala);

the precursor compound of B being selected from the following:

amino acids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicylamine, N-acetylpenicylamine, cysteine, N-acetylcystene, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxy acids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic, p-coumaric acid, vanillic acid;

aromatic and heterocyclic polyalcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sulfuretin, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxyhydroquinone, hydroxyhydroquinone, propyl gallate, sucrose-3,5 -4-hydroxybenzylthio glycollate, p-coumaric alcohol, 4-hydroxyphenylethyl alcohol, coniferyl alcohol. allopurinol;

compounds containing at least one free acid function, selected from the following: 3,3'-thiodipropionic acid, fumaric acid, dihydroximalic acid, edetic acid;

C is the divalent radical in which

m which:

nix is an integer between 0 and 3, preferably 1;

nlIX is an integer comprised between 1 and 3, preferably 1;

RTIX RTIX't RriIXf RTIIX '/ equal or different from each other are H or linear or branched alkyl Οχ-04 preferably they are H-Y3 is a heterocyclic ring containing one or two nitrogen atoms, saturated, unsaturated or aromatic, at 5 or 6 atoms,

or Y can be:

Yo, chosen from the following:

an alkyleneoxy group R'O wherein R 'is C 1-C2o linear or branched when possible, preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be replaced by heteroatoms, the ring can have R 'type side chains, R' being as defined above;

or one of the following groups:

wherein nf 'is an integer from 1 to 6 preferably from 1 to 4;

where Ref = H, CH3 and nf 'is an integer from 1 to 6; preferably 1 to 4;

or Y is YAR and is chosen from the following:

wherein n3 is an integer from 0 to 3 and n3 'is an integer from 1 to 3;

in which n3 and n3 'have the meaning indicated above.

When in formula (All) RAI is CH3, Ri is the phenyl group in position 4 of the ring, R6 = F in position 3, the radical so defined is that of the precursor drug Flurbiprofen;

when in formula (All) RAI is CH3, Ri and RÈ are in positions 4 and 5 of the ring and together form the radical of formula (Ala), the radical thus defined is that of the precursor drug Naproxen;

when in formula (All) RAI is H, Ri is the 2,6-dichlorof enylamino- group and is in position 2 of the ring, R6 = H, the radical thus defined is that of the precursor drug Diclofenac.

Preferably Y <3> is selected from the following:

Preferably Y <3> is a 6-atom aromatic ring, containing a nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.

The preferred of Y <3> is Y12 (pyridyl) substituted in position 2 and 6. The bonds can also be in non-symmetrical position, for example Y12 (pyridyl) can also be substituted in position 2 and 3; Yl (pyrazole) can be 3,5-disubstituted.

The precursors of Yp, in which the free valence of the oxygen is saturated with H and the free valence of the terminal carbon is saturated either with a carboxylic or hydroxy group, are products available on the market or can be obtained by methods known in the art. 'art.

The precursor compounds of B of the groups indicated above are prepared according to the methods known in the literature and described, for example, in "The Merck Index", 12th Ed. (1996), incorporated herein by reference.

The preferred compounds of formula (I) are the following:

2-Fluoro-α-methyl [1,1'-biphenyl] -4-acetic acid 4- (nitro oxy) butyl ester

Trans-3- [4- [2-fluoro-alpha-methyl (1,1'-biphenyl) -4-acetyl oxy] -3-methoxyphenyl] -2-propenoic acid 4- (nitroxy) butyl ester (VI)

2-Fluoro-alpha-methyl [1,1'-biphenyl] -4-acetic acid 3- (nitrooxy methyl) phenyl ester (VII)

(S) -N-acetyl-S- [2-fluoro-alpha-methyl (1,1'-biphenyl) -4-acetyl] cysteine 4- (nitroxy) butyl ester (VIII)

2-Fluoro-alpha-methyl [1,1'-biphenyl] -4-acetic acid 6- (nitroxy methyl) -2-methylpyridinyl ester (IX)

(S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid 4- (nitro oxy) butyl ester (X)

(S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid 3- (nitroxy methyl) phenyl ester (XI)

(S) -6-methoxy-alpha-rciethyl-2-naphthalenacetic acid 6- (nitro oxymethyl) -2-methylpyridinyl ester (XII)

Trans-3- [4- [6-methoxy-alpha-methyl-2-naphthalenacetyl oxy] -3-methoxyphenyl] -2-propenoic acid 4- (nitroxy) butyl ester (XIII)

(S, S) -N-acetyl-S- (6-methoxy-alpha-methyl-2-naphthaleneacetyl) cysteine 4- (nitroxy) butyl ester (XIV)

2- [(2,6-dichlorophenyl) amino] benzene acetic acid 4- (nitro oxy) butyl ester (XV)

2- [(2,6-dichlorophenyl) amino] benzenacetic acid 4- (nitro oxymethyl) phenyl ester (XVI)

2- [(2,6-dichlorophenyl) amino] benzene acetic acid 6- (nitro oxymethyl) -2-methylpyridinyl ester hydrochloride (XVII)

The compounds of formula (I) are generally obtainable with methods known in the art, see for example the patent applications WO 00/61537, WO 00/51988, WO 95/30641, in the name of the Applicant.

When the compounds of formula (I) usable in the present invention have one or more chiral centers, they can be in racemic form or as mixtures of diastereoisomers, as single enantiomers or single diastereomers; if they show geometric asymmetry, compounds in the cis or trans form can be used.

When a salifiable functional group is present in the molecule of the compounds of formula (I), for example an amino or heterocyclic nitrogen, it is possible to use the corresponding salts of the aforementioned compounds, obtainable by reaction in an organic solvent such as for example acetonitrile, tetrahydrofuran, with a equimolecular quantity of the corresponding acid, organic or inorganic.

Examples of usable organic acids are the following: oxalic, tartaric, maleic, succinic, citric acid.

Examples of usable inorganic acids are the following: nitric, hydrochloric, sulfuric, phosphoric acid. Preferred are nitric and hydrochloric acid.

Using the products of the invention, vasculopathy is markedly reduced and in particular the restenosis process that can occur in subjects undergoing angioplasty, and in particular in those most at risk such as the elderly, diabetics, hyperlipidemics.

The therapeutic use of the products described in the present invention is advantageous, as mentioned, since these compounds are able to act both on the vessel (endothelial cells and vascular smooth muscle) and on blood cells (platelets, leukocytes) and blood factors.

The compounds of formula (I) or the corresponding salts are formulated in the corresponding pharmaceutical compositions for parenteral, oral use according to the techniques well known in the art, together with the usual excipients; see for example the volume "Remington's Pharmaceutical Sciences 15th Ed.".

The quantity on a molar basis of the active principle in these formulations is equal to or lower than the maximum dosage indicated for the precursor drugs. Higher doses can also be used due to their excellent tolerability. The daily doses of precursor drugs can be found in the publications of the branch, such as in the "Physician's Desk reference".

The following examples illustrate the invention and are not limitative of its scope.

EXAMPLE F1

Efficacy of Flurbiprofen and 2-fluoro-alf a-methyl-4-diphenylacetic acid (4-nitroxy) butyl ester in an experimental model of induced restenosis in the rat

The 2-fluoro-alpha-methyl-4-diphenylacetic acid (4-nitroxy) butyl ester (NO-Flurbiprofen) was synthesized as described in example 1 of WO 95/30641.

males weighing 300-350 g were anesthetized by intraperitoneal injection with ketamine (100 mg / kg) and xylazine (5 mg / kg) and subjected to angioplasty according to the procedure described by Indolii et Al., Circulation 1995 92 1230-1235, using a balloon catheter that was first introduced into the aortic arch through the right carotid, then inflated and then passed back and forth three times into the vessel lumen.

The animals were divided into the two groups indicated below and subjected to pharmacological treatment as described below for the 14 days following the vascular damage: one group was treated orally, by gastric tube, with NO-Flurbiprofen at doses of 10 mg / kg dissolved. in polyethylene glycol (PEG 400), and the other (control) received only the vehicle (PEG 400, 0.2 ml / rat).

The animals were sacrificed and the carotids removed. Six 6 µm thick sections were isolated for each artery. The stomachs were removed and analyzed to assess damage to the gastric mucosa by detecting any lesions, determining the respective areas of the lesions, bleeding or not.

3 of the 6 sections of each artery were stained with hematoxylin and eosin to highlight the different types of cells, the remaining 3 sections were stained first with aldehyde fuchsin and then with Gieson's solution to highlight the internal elastic lamina (IEL). The sections were photographed and the images were analyzed through an image analysis System (Qwin Lite, Leica, Milan)

The thicknesses of the middle and neointima tunic and, respectively, of the vessel wall were then measured. The results reported in Table 1 are expressed as a percentage of restenosis and were calculated as the ratio between the thickness of the neointima tunic and that of the average tunic (M / N) measured in the sections of the various groups and setting the N / M ratio equal to 100. of the control group.

The results are reported in Table 1.

EXAMPLE F2

Example FI is repeated but using NO-Flurbiprof en at the dose of 30 mg / Kg. The results are reported in Table 1.

EXAMPLE F3 Comparison

Example FI is repeated but using Flurbiprofen at a dose of 7 mg / Kg. The results are reported in Table 1.

EXAMPLE F4 Comparison

Example FI is repeated but using Flurbiprofen at a dose of 21 mg / Kg. The results are reported in Table 1. EXAMPLE F5 Comparison

In this example, 5-benzoyl-2, 3-dihydro-1H-pyrrolidin-1-carboxylic acid (4-nitroxy) butyl ester (NO-ketorolac) is used, synthesized as described in example 1F of WO 95 / 30641.

Example FI is repeated but using NO-Ketorolac at a dose of 10 mg / Kg.

Comments to Table 1

The results reported in Table 1 show that the restenosis induced by the lesion with the balloon catheter is significantly reduced already by administering low doses of NO-Flurbiprof en. Flurbiprofen is not very active in reducing restenosis even at a dose of 20 mg / kg, however it causes considerable gastric lesions compared to the NOFlurbiprofen of the invention.

NO-Ketorolac (comparison) proves to be ineffective compared to NO-flurbiprofen and induces gastric lesions at effective doses.

Claims (7)

CLAIMS 1. Use for the preparation of drugs for the treatment of vasculopathies, of compounds, or their salts, having the following general formula (I): m which: cO is an integer and is 0 or 1; bO is an integer and is 0 or 1, with the proviso that cO and bO cannot be equal to zero at the same time. R is the radical of formula (All) in which: RAI is CH3 or H; Ri is phenyl, or a 2,6-dichlorophenylamino- group; R6 is hydrogen or a halogen atom, preferably fluorine; or Ri and R6 together form the radical of formula (Ala); ΤΒ and TEI are the same or different; TB = X, where X = 0, S, NRic, Rie is H or a linear or branched alkyl, having from 1 to 5 carbon atoms; TBi = (CO) tx or (X) txx, where tx and txx have the value of 0 or 1; with the condition that tx = 1 when txx = 0, tx = 0 when txx = 1; X is as defined above; X2, divalent radical, is such that the corresponding precursor of B, in which the free valences of TB is saturated with Z, and that of ΤΒΪ with OZ, Z or with, in which Z = H, Ci-Cio, preferably C1- C5 linear or branched alkyl when possible, Z <1>, Z <11> equal or different have the values of Z as defined above, depending on whether TB and / or TBI = CO or X, depending on the values of tx and txx ; the precursor compound of B being selected from the following: amino acids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicylamine, N-acetylpenicylamine, cysteine, N-acetylcystene, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxy acids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic, p-coumaric acid, vanillic acid; aromatic and heterocyclic polyalcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sulfuretin, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxyhydroquinone, hydroxyhydroquinone, propyl gallate, sucrose-3,5 -4-hydroxybenzylthio glycollate, p-coumaric alcohol, 4-hydroxy-phenylethyl alcohol, coniferyl alcohol, allopurinol; compounds containing at least one free acid function, selected from the following: 3,3'-thiodipropionic acid, fumaric acid, dihydroximalic acid, edetic acid; in which: nix is an integer between 0 and 3, preferably 1; nlIX is an integer comprised between 1 and 3, preferably 1; RTIX / RTIX'1 RTIIX, R-TIIX'r equal or different from each other are H or linear or branched C1-C4 alkyl; preferably R-nx, RTIX1 / RTIIX / RTIIX1 are H. Y3 is a heterocyclic ring containing one or two nitrogen atoms, saturated, unsaturated or aromatic, with 5 or 6 atoms, or Y can be: Yo, chosen from the following: an alkyleneoxy group R'O in which R 'is C1-C20 linear or branched when possible, preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more atoms carbon can be replaced by heteroatoms, the ring can have side chains of the R 'type, R' being as defined above; or one of the following groups: wherein nf 'is an integer from 1 to 6 preferably from 1 to 4; where Ref = H, CH3 and nf 'is an integer from 1 to 6; preferably from 1 to 4; or Y is YAR and is chosen from the following: wherein n3 is an integer from 0 to 3 and n3 'is an integer from 1 to 3; in which η3 and η3 'have the meaning indicated above. 2. Use according to claim 1 wherein: when in formula (All) RAI is CH3, Rx is the phenyl group in position 4 of the ring, R6 = F in position 3, the radical thus defined is that of the precursor drug Flurbiprofen; when in formula (All) RM is CH3, Ri and R6 are in position 4 and 5 of the ring and together form the radical of formula (Ala), the radical thus defined is that of the precursor drug Naproxen; when in formula (All) R3⁄4i is H, Ri is the 2,6-dichlorophenylamino- group and is in position 2 of the ring, R6 = H, the radical thus defined is that of the precursor drug Diclofenac. Use according to claims 1-2 wherein Y <3> is selected from the following: 4. Use according to claim 3 wherein Y3 is a 6-atom aromatic ring, containing a nitrogen atom, having the two free valences in position 2 and 6. 5. Use according to claims 3-4 wherein Y3 is Y12 (pyridyl). 6. Use according to claims 1-5 wherein the compounds of formula (I) The preferred compounds of formula (I) are the following: 2-Fluoro-a-methyl [1,1'-biphenyl] -4-acetic acid 4- (nitro oxy) butyl ester (V) Trans-3- [4- [2-fluoro-alf a-methyl (1,1'-biphenyl) -4-acetyl oxy] -3-methoxyphenyl] -2-propenoic acid 4- (nitroxy) butyl ester (VI ) 2-Fluoro-alpha-methyl [1,1'-biphenyl] -4-acetic acid 3- (nitrooxy methyl) phenyl ester (VII) (S) -N-acetyl-S- [2-fluor-alpha-methyl (1,1 '-biphenyl) -4 acetyl] cysteine 4- (nitroxy) butyl ester (VIII) 2-Fluoro-alpha-methyl [1,1-1-biphenyl] -4-acetic acid 6- (nitroxy methyl) -2-methylpyridinyl ester (IX) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid 4- (nitro oxy) butyl ester (X) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid 3- (nitroxy methyl) phenyl ester (XI) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid 6- (nitro oxymethyl) -2-methylpyridinyl ester (XII) trans-3- [4- [6-methoxy-alpha-methyl-2-naphthalen acetyloxy] -3-methoxyphenyl] -2-propenoic 4- (nitroxy) butyl ester (XIII) () (S, S) -N-acetyl-S- (6-methoxy-alpha-methyl-2 -naphthalene acetyl) cysteine 4- (nitroxy) butyl ester (XIV) 2- [(2,6-dichlorophenyl) amino] benzene acetic acid 4- (nitrooxy) butyl ester (XV) 2- [(2,6-dichlorophenyl) amino] benzenacetic acid 4- (nitroxymethyl) phenyl ester (XVI) 2- [(2,6-dichlorophenyl) amino] benzene acetic acid 6- (nitroxymethyl) -2-methylpyridinyl ester hydrochloride (XVII) Use according to claims 1-6 wherein the compounds of formula (I) or the corresponding salts are formulated in the corresponding pharmaceutical compositions for parenteral, oral use.