WO2003013499A2

WO2003013499A2 - Drugs for vasculopaties

Info

Publication number: WO2003013499A2
Application number: PCT/EP2002/008374
Authority: WO
Inventors: Piero Del Soldato
Original assignee: Nicox SA
Current assignee: Nicox SA
Priority date: 2001-08-09
Filing date: 2002-07-26
Publication date: 2003-02-20
Anticipated expiration: 2004-02-09
Also published as: ITMI20011744A1; WO2003013499A3; ITMI20011744A0; AU2002333276A1

Abstract

Use for the vasculopathy treatment of compounds or salts thereof, having the following general formula (I): wherein R is the radical of formula (AII), the radicals RAI, R1, and R6 of formula (AII), and the bivalent linking groups B and C of the general (I) being as defined in the invention.

Description

DRUGS FOR VASCULOPATHIES

- -λ- -k ^■*^• "k

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

The most serious cardiovascular pathologies (among which restenosis, atherosclerosis, miocardium infarct, peripheral and central vascular diseases etc.) are characterized by a pathological activation of vascular cells (cells of the vasal smooth musculature ceils, endothelial cells) and haematic cells (platelets, leucocytes, monocytes/macrophages, etc.).

Vasculopathies and diseases related thereto are pathological conditions associated to an altered haematochemical and clinical picture, which shows itself with hyperglycemia and/or hyperinsulinemia, hyperlipide ia and/or hydric-saline retention and/or hyperproliferation of vasal and/or tu oral cells, and/or prothrombotic and procoagulant activity, etc. Vasculopathies can facilitate the growth of other pathologies such obesity, diabetes and cardiovascular diseases such for example myocardial, cerebral and/or peripheral ischaemias, retinopathies, polyneuropathies, gastroenteropathies, ne- phropa-thies, etc., hypertension (general and local at pulmonary, coronary, portal, renal level, etc.) atherosclerosis, Alzheimer disease, cancer.

Also particular pathologies such as the X syndrome (or insulin resistance) and the vasculopathy from drugs are comprised in vasculopathies.

An unitary therapeutic approach able to prevent and/or reduce vasculopathies does not exist.

The ideal approach is to operate on the various cell processes, i.e. to prevent the pathological activation of the aforesaid cells, which causes the growth and the progress of the pathological process affecting the cardiovascular system.

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

Statines, rapamycin and the radiotherapeutic treatment are active only on the smooth musculature but not on the other cell populations. The results obtained with said pharmacological treatments and with the radiotherapy are only partially satisfactory and therefore it is necessary to increase dosages with consequent even serious side effects.

The need was felt to have available drugs allowing to carry out an effective therapeutic treatment of vasculopathies, overcoming the drawbacks associated to the therapeutic and surgical treatments at present used, and being effective in inhibiting the pathological activation of various cell populations of the cardiovascular system and besides not resulting toxic, in particular at gastric level, and furthermore being usable for prolonged treatments without side effects.

This technical problem has been solved by the Applicant using a specific class of drugs. Surprisingly and unexpectedly the Applicant has found that specific nitrooxyderivatives of defined compounds, e.g. flurbiprofen, naproxen and diclofenac are active in the vasculopathy treatment, acting on the involved cell processes. Said result is surprising since other nitrooxyderivatives, such as for example the piroxicam and ke- torolac derivatives, have not proved to be active at non toxic doses .

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

0

R-C-(B)_b-(C)^N0₂

(I) wherein: 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 contemporaneously equal to zero.

R is the radical of formula (All)

E CCHH3—

(All) wherein:

Ri is phenyl, or a 2, 6-dichlorophenylamino- group; R₆ is hydrogen or one halogen atom, preferably fluorine; or Ri and R₆ form together the radical of formula (Ala);

(Ala) -T_B-X₂-T_Bι- wherein T_B and T_Bi are equal or different;

T_B = X, wherein X = 0, S, NRι_C, Ric is H or a linear or branched alkyl having from 1 to 5 carbon atoms ; TBI = (CO)tx or (X)txχr wherein tx and txx have the value of 0 or 1; with the proviso that tx = 1 when txx = 0, tx = 0 when txx = 1; X is as above; X₂, bivalent radical, is such that the corresponding precursor of B, -TB-X≥-TB_I- wherein the free valence of T_B is saturated with Z, and that of T_Bι with OZ, Z or with -N(Z^I) (Z¹¹), wherein Z = H, C₁-C10, preferably C_3.-C₅ alkyl linear or branched when possible, Z¹, Z¹¹ equal or different have the values of Z as above, depending on that T_B and/or T_BI = CO or X, in function of the values of tx and txx; the precursor compound of B being selected from the following: aminoacids, selected from the following: L- carnosirie, anserine, selenocysteine, selenome- thionine, penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxyacids, selected from the following: gallic acid, ferulic acaid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; aromatic and hetrocyclic polyalcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sulphurethyne, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxyhydroquinone, hydroxyhydroquinone, propyl gallate, saccharose, 3, 5-di-tertbutyl-4-hydroxybenzyl-thio glycolate, p-cumaric alcohol, 4-hydroxy- phenylethylalcohol, coniferyl alcohol, allopu- rinol; compounds containing at least one free acid function, selected from the following: 3,3'- thiodipropionic acid, fumaric acid, dihydroxy- maleic acid, edetic acid; C is the bivalent radical -T_c-Y- wherein when bO = cO = 1: T_c = (CO) when tx = 0, T_c = X when txx = 0, X being as above defined, when bO = 0 : Tc = X, X being as above defi- ned, when cO = 0 tx = 0 , T_BI = X = -0-;

Y is :

( III ) wherein : nIX is an integer comprised between 0 and 3, preferably 1; nllX is an integer comprised between 1 and 3, preferably 1;

R_TIX, RTIX', T_IIXΛ R _II '/ equal to or different from each other are H or linear or branched Cι-C₄ alkyl; preferably R_TIX, R_Tιx_', R_Tnx, RTIIX' are H. Y³ is a saturated, unsaturated or aromatic heterocy- clic ring containing one or two nitrogen atoms, having 5 or 6 atoms, or Y can be: Yo, selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible Cι-C₂₀, preferably having from 2 to 6 carbon atoms, or a cycloal- kylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R' type, R' being as above; or one of the following groups: -(CH₂- CH₂ O)'nf

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

( O)_nf-

wherein R_if = H, CH₃ and nf is an integer from 1 to

6; preferably from 1 to 4; or Y is Y_AR and is selected from the following:

YftRi :

-

wherein n3 is an integer from 0 to 3 and n3 ' is an integer from 1 to 3; YAR2 :

wherein n3 and n3 ' have the above meaning.

When in formula (All) R_AI is CH₃, Ri is the phenyl group in position 4 of the ring, R₆ = F in position 3, the so defined radical is that of the precursor drug Flurbiprofen; when in formula (All) R_Aι is CH₃, Ri and R₆ are in position 4 and 5 of the ring and form together the radical of formula (Ala) , the so defined radical is that of the precursor drug Naproxen; when in formula (All) R_Aι is H, Ri is the 2,6- dichlorophenylamino group and is in position 2 of the ring, R₆ = H, the so defined radical is that of the precursor drug Diclofenac.

Preferably Y³ is selected from the following:

(YD (Y2; (Y3! ( Y4 ) ( Y5 ) ( Y6 )

(Y7) IY8 ( Y9 ) ( Y10 ) ( Yl l )

(Y12) (Y13) (Y14) (Y15)

Preferably Y³ is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.

The preferred of Y³ is Y12 (pyridyl) substituted in position 2 and 6. The bonds can also be in an asymmetric position, for example Y12 (pyridyl) can be substituted also in position 2 and 3; Yl (pyrazol) can be 3, 5-disubstituted.

The precursors of Y_p, wherein the oxygen free valence is saturated with H and the free valence of the end carbon is saturated either with a carboxylic or an hydroxyl group, are compounds available on the market or can be obtained by meth^¬ ods known in the prior art .

The functional linking groups between, respectively, R and X₂, between X₂ and Y, or between R and Y, can be ester, am- ideor thioester. The precursor compounds of B of the above groups are pre- pard according to the methods known in the prior art and described for example in "The Merck Index", 12th Ed. (1996), herein incorporated by reference.

The preferred compounds of formula (I) are the following: 2-Fluoro-α-methyl [1, 1' -biphenyl] -4-acetic acid 4- (nitrooxy) butyl ester (V)

(V) Trans-3- [ 4- [2-f luoro-alpha-methyl ( 1 , 1 ' -biphenyl ) -4-acetyl oxy] -3-methoxyphenyl] -2-propenoic acid 4- (nitrooxy) butyl ester (VI )

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

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

(VIII) 2-fluoro-alpha-methyl [1, 1' -biphenyl] -4-acetic acid 6- (nitrooxy methyl) -2-methylpyridinyl ester (IX)

(IX) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid nitrooxy) butyl ester (X)

(X)

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

(XI) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid (nitrooxy ethyl) -2-methylpyridinyl ester (XII)

rieo

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

(XIII) (S, S) -N-acetyl-S- ( 6-methoxy-alpha-methyl-2-naphthalena- cetyl) cysteine 4- (nitrooxy) butyl ester (XIV)

ileO

(XIV)

2- [ (2, 6-dichlorophenyl) aminojbenzenacetic acid [nitrooxy) butyl ester (XV)

(XV) 2- [ (2, 6-dichlorophenyl) aminojbenzenacetic acid 4- (nitro oxymethyl) phenyl ester (XVI)

2- [ ( 2 , 6-dichlorophenyl ) a ino] benzenacetic acid 6- (nitro oxymethyl ) -2-methylpyridinyl hydrochloride ester (XVII )

(XVII)

The compounds of formula (I) are generally obtained by methods known in the prior art, see for example 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 centres, they can be in a race ic form or as mixtures of diastereoisomers, as single en- antiomers or single diastereoisomers; when they show a geometric asymmetry, the compounds in the cis or trans form can be used.

When in the molecule of the compounds of formula (I) a salifiable functional group is present, for example an aminic or heterocyclic nitrogen, it is possible to use the corresponding salts of the above compounds, obtainable by reaction in organic solvent such as for example acetonitrile, tetrahy- drofuran, with an equimolar amount of the corresponding organic or inorganic acid. Examples of usable organic acids are the following: ox^¬ alic, tartaric, maleic, succinic, citric acids.

Examples of usable inorganic acids are the following: nitric, hydrochloric, sulphuric, phosphoric acids. Nitric and hydrochloric acids are preferred.

By using the products of the invention the vasculopathy is significantly reduced and in particular the restenosis process which can grow in people subjected to angioplasty and in particular_, in those more at risk such as old people, diabetic, hyperlipidemic people.

The therapeutic use of the products described in the present invention results advantageous, as said, since these compounds are able to act both on the duct (endothelial and vasal smooth musculature cells) and on haematic cells (platelets, leucocytes) and ha-ematic 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 prior art, together with the usual excipi- ents; see for example the volume "Remington's Pharmaceutical Sciences 15th Ed.".

The amount on a molar basis of the active principle in said formulations is equal to or lower than the maximum posol- ogy indicated for the precursor drugs. Also higher doses can be used considering their very good tolerability. The daily doses of the precursor drugs can be found in the publications of the prior art, such as for example in "Physician's Desk reference".

The following Examples illustrate the invention but are not limitative of the scope of the same. EXAMPLE FI

Efficacy of Flurbiprofen and of 2-fluoro-alpha-methyl-4- diphenylacetic acid (4-nitrooxy) butyl ester in an experimental model of restenosis induced in rats

2-fluoro-alpha-methyl-4-diphenylacetic acid (4- nitrooxy) butyl ester (NO-Flurbiprofen) was synthesized as described in Example 1 of patent application WO 95/30641.

Wistar male rats of 300-350 g weight were anaesthetized by intraperitoneal injection of ketamine (100 g/kg) and xylazine (5 mg/kg) and subjected to angioplasty according to the procedure described by Indolfi et Al . , Circulation 1995 92 1230-1235, by using a little balloon catheter. The balloon was first introduced in the aortic arch through the right carotid, then swollen and passed three times forth and back in the duct lumen.

After the vascular damage the animals were divided in the two groups indicated below and subjected for 14 days to the pharmacological treatment as described ereunder: one group was treated by os by means of a gastric cannula with NO-Flurbiprofen at the dose of 10 mg/kg dissolved in polyethylene glycol (PEG 400), and the other group (control) received only the carrier (PEG 400, 0.2 ml/rat).

The animals were sacrificed and the carotids removed. For each artery no. 6 sections having a thickness of 6 μm were obtained. Stomachs were also removed and inspected to evaluate damages to the gastric mucosa. Areas of both bleeding lesions and non bleeding lesions were determined.

3 out of the 6 sections of each artery were stained with hematoxylin and eosin to evidence the different types of cells, the remaining 3 sections were stained first with aldehyde fuchsin and then with the Gieson solution to evidence the internal elastic lamina. The sections were photographed and the imagines were analyzed by an image analysis system (Qwin Lite, Leica, Milan) .

The thicknesses, respectively, of the middle and neoin- tima tunica, and of the duct wall were measured. The results reported in Table 1 are expressed as percentage of restenosis and have been calculated as a ratio between the thickness of the neointima tunica to that of the middle tunica (M/N) measured in the sections of the various groups, assuming equal to 100 the N/M ratio of the control group.

The results are reported in Table 1. EXAMPLE F2

Example FI is repeated but using NO-Flurbiprofen at the dose of 30 mg/Kg. The results are reported in Table 1. EXAMPLE F3 Comparative

Example FI is repeated but using Flurbiprofen at the dose of 7 mg/Kg. The results are reported in Table 1. EXAMPLE F4 Comparative

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

In this Example the 5-benzoyl-2, 3-dihydro-lH-pyrrolidin- 1-carboxylic acid (4-nitrooxy) butyl ester (NO-ketorolac) is used, sinthesized as described in Example IF of patent application WO 95/30641.

Example FI is repeated but using NO-Ketorolac at the dose of 10 mg/Kg. Comments on Table 1

The results reported in Table 1 show that the restenosis induced by the lesion with the little balloon catheter is significantly reduced by administering low doses of NO- Flurbiprofen. Flurbiprofen is not very effective in reducing restenosis even at the dose of 20 mg/Kg. The number of gastric lesions following administration of Flurbiprofen is very high in the confront of NO-Flurbiprofen.

NO-Ketorolac appears not very effective with respect to NO-Flurbiprofen and at effective doses it produces gastric lesions .

Table 1

Claims

Use for the preparation of drugs for the vasculopathy treatment, of compounds, or salts thereof, having the following general formula (I) :

0 R-C-(B)So-(C)Hb- 0₂

R is the radical of formula (All)

(All) wherein: R_AI is CH₃ or H;

Ri is phenyl, or a 2, 6-dichlorophenylamino- group; Re is hydrogen or one halogen atom, preferably fluo^¬ rine; or Ri and Re form together the radical of formula (Ala) ;

(Ala)

B = -T_B-X₂-T_Bi- wherein T_B and T_BI are equal or different;

T_B = X, wherein X = 0, S, NRχ_c, Ric is H or a linear or banched alkyl having from 1 to 5 carbon atoms; TBI = (CO)tx or (X) _tχx, wherein tx and txx have the value of 0 or 1; with the proviso that tx = 1 when txx = 0, tx = 0 when txx = 1; X is as above; X₂, bivalent radical, is such that the corresponding precursor of B, -T_B-X₂-T_BI- wherein the free valence of T_B is saturated with Z, and that of T_BI with OZ, Z or with -N(Z^I) (Z¹¹) , wherein Z = H, Ci-Cio, preferably C1-C₅ alkyl linear or branched when possible, Z¹, Z¹¹ equal or different have the values of Z as above, depending on that T_B and/or T_Bι = CO or X, in function of the values of tx and txx; the precursor compound of B being selected from the following: aminoacids, selected from the following: L- carnosine, anserine, selenocysteine, selenome- thionine, penicillamine, N-acetylpenicillamine, cysteine, N-acetilcysteine, glutathione or its esters, preferably ethyl or isopropyl ester; hydroxyacids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; - aromatic and heterocyclic polyalcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sul- phurethyne, ascorbic acid, isoascorbic acid, hydroquinone, gossypol, reductic acid, methoxy- hydroquinone, hydroxyhydroquinone, propyl gal- late, saccharose, 3, 5-di-tertbutyl-4- hydroxybenzyl-thio glycolate, p-cumaric alcohol, 4-hydroxy-phenylethylalcohol, coniferyl alcohol, allopurinol; compounds containing at least one free acid function, selected from the following: 3,3'- thiodipropionic acid, fumaric acid, dihydroxy- maleic acid, edetic acid; C being the bivalent radical -T_c-Y- wherein

T_c = (CO) when tx = 0, T_c = X when txx = 0, X being as above defined;

Y is :

Yr

R -TIX R ^■TIIX

^■[C] nIX Y³— [Cl_πt x-O

R ^^•TTI R ⁱ TTIIX

( I I I ) wherein : nIX is an integer comprised between 0 and 3, preferably 1; nllX is an integer comprised between 1 and 3, preferably 1;

R_Tx, RTIX¹, RTI_IXΛ R_TI_IX'Λ equal to or different from each other are H or linear or branched Cι~C alkyl; preferably Rιx, RTIX- , RTIIX, RTIX- are H. Y³ is a saturated, unsaturated or aromatic hetero- cyclic ring containing one or two nitrogen atoms, having 5 or 6 atoms, or Y can be: Yo, selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible Cι-C₂₀, 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 substituted by het- eroatoms, the ring can have side chains of R' type,

R' being as above; or one of the following groups:

(CH₂- CH₂-O) 'nf-

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

( 0)nf

wherein R_if = H, CH₃ and nf is an integer from 1 to

6 ; preferably from 1 to 4 ; or Y is Y_AR and is selected from the following :

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

wherein n3 and n3 ' have the above meaning. 2. Use according to claim 1, wherein: when in formula (All) R_AI is CH₃, R_x is the phenyl group in position 4 of the ring, R₅ = F in position 3, the so defined radical is that of the precursor drug Flurbiprofen; when in formula (All) R_AΣ is CH₃, Ri and R₆ are in po^¬ sition 4 and 5 of the ring and form together the radical of formula (Ala) , the so defined radical is that of the precursor drug Naproxen; when in formula (All) R_AΪ is H, Ri is the 2,6- dichlorophenylamino- group and is in position 2 of the ring, R₆ = H, the so defined radical is that of the precursor drug Diclof'enac.

Use according to claims 1-2, wherein Y³ is selected from the following:

[YD : Y2 ' (Y3) (Y4) (Y5) (Y6J

(Y12 ;γi3; (Y14) (Yi5;

Use according to claim 3, wherein Y³ is an aromatic ring having 6 atoms, containing one 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 preferred com^¬ pounds of formula (I) are the following:

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

(V)

Trans-3- [4- [2-fluoro-alpha-methyl (1, 1' -biphenyl) -4- acetyloxy] -3-methojcyphenyl] -2-propenoic acid 4- (nitrooxy) butyl ester (VI)

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

(VII) (S) -N-acetyl-S- [2-f luoro-alpha-methyl (1,1'- biphenyl) -4-acetyl] cysteine 4- (nitrooxy) butyl ester

(VIII)

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

(IX) (S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid - (nitrooxy) butyl ester (X)

(X)

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

(S) -6-methoxy-alpha-methyl-2-naphthalenacetic acid - (nitrooxymethyl) -2-methylpyridinyl ester (XII) H

(xii)

Trans-3-^'[4- [6-methoxy-alpha-methyl-2-naphthalen ace- tyloxy] -3-methoxyphenyl] -2-propenoic acid 4- (nitrooxy) butyl ester (XIII)

(XIII) (S, S) -N-acetyl-S- ( 6-methoxy-alpha-methyl-2- naphthalene acetyl) cysteine 4- (nitrooxy) butyl ester (XIV)

(XIV) 2- [ (2, 6-dichlorophenyl) amino] benzenacetic acid [nitrooxy) butyl ester (XV)

(XV) 2- [ (2, 6-dichlorophenyl) amino] benzenacetic acid (nitrooxymethyl) phenyl ester (XVI)

2- [ (2 , 6-dichlorophenyl ) amino] benzenacetic acid 6- (nitrooxymethyl ) -2-methylpyridinyl hydrochloride ester (XVII )

(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 paren- teral, oral use.