WO1992011240A1

WO1992011240A1 - Pyridyl derivatives of substituted bicyclic compounds and process for their preparation

Info

Publication number: WO1992011240A1
Application number: PCT/EP1991/002104
Authority: WO
Inventors: Paolo Cozzi; Antonio Pillan; Leone Bertone; Patricia Salvati
Original assignee: Farmitalia Carlo Erba S.R.L.
Priority date: 1990-12-17
Filing date: 1991-11-07
Publication date: 1992-07-09
Also published as: AU8845991A; GB9027258D0; IL100301A0; IE914368A1; MX9102503A; PT99820A

Abstract

The present invention relates to new pyridyl derivatives of bicyclic compounds having general formula (I) wherein the symbol ------ represents a single or double bond; m is an integer of 1 to 3; R is hydrogen or a C1-C6 alkyl group; R1 is a -(CH2)n-COR3 group, wherein n is zero or an integer of 1 to 3 and R3 is an -OR4 or -N(R4R5) group in which each of R4 and R5 independently is hydrogen, C1-C6 alkyl optionally substituted by phenyl or phenyl; or a -(CH2)p-OR4 group wherein p is zero or an integer of 1 to 4 and R4 is as defined above; R2 is hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; and wherein, when at the same time the symbol ------ is a single bond and R1 is a -(CH2)n-COR3 group in which n is as defined above and R3 is an OR4 group wherein R4 is hydrogen or unsubstituted C1-C6 alkyl, then at least one of R and R2 is other than hydrogen, which are useful in the treatment of diseases related to an enhancement of TxA2 synthesis.

Description

PYRIDYL DERIVATIVES OF SUBSTITUTED BICYCLIC COMPOUNDS

AND PROCESS FOR THEIR PREPARATION

The present invention relates to new pyridyl derivatives of bicyclic compounds, in particular to pyridyl derivatives of 1,2-dihydro-naphthalene and 1,2,3,4-tetrahydro-naphthalene, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.

Compounds having TxA₂ synthase inhibition activity have been proposed as disclosed for instance in US-A-4,777,257 and US-A-4,510,149,

More exactly the present invention provides new compounds having the following general formula (I)

wherein

the symbol represents a single or double bond;

m is an integer of 1 to 3;

R is hydrogen or a C₁-C₆ alkyl group;

R₁ is a -(CH₂)_n-COR₃ group, wherein n is zero or an integer of 1 to 3 and R₃ is an -OR₄ or -N(R₄ R₅) group in which each of R₄ and R₅ independently is hydrogen , C₁-C₆ alkyl optionally substituted by phenyl , or phenyl ;

or a -(CH₂)_p-OR. group wherein p is zero or en integer of 1 to 4 and R₄ is as defined above; R₂ is hydrogen or C₁-C₄ alkyl; and the pharmaceutically acceptable salts thereof, and wherein, when at the same time the symbol - - - - - - is a single bond and R₁ is a

-(CH₂)_n-COR₃ group in which n is as defined above and R₃ is an OR₄ group wherein R₄ is hydrogen or unsubstituted C₁-C₆ alkyl, then at least one of R and R₂ is other than hydrogen.

The above proviso excludes from formula (I) the

compounds previously disclosed by US-A-4,777,257 and Eur. J.Med.Chem. (1991) 26, 423-433.

The invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I).

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with

inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propoinic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salycylic acids, and salts with inorganic e.g. alkaly metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases, or with organic bases, e.g. alkylamines, preferably triethyl-amine.

The alkyl groups may be branched or straight chain groups.

A C₁-C₆ alkyl group is preferably a C₁-C₄ alkyl group, in particular methyl, ethyl, propyl and isopropyl, more preferably methyl and ethyl. A C₁-C₆alkyl group is e.g. methyl, ethyl, propyl or isopropyl, in particular methyl or ethyl.

A C₁-C₆ alkyl group substituted by phenyl is e.g. benzyl or phenethyl, in particular benzyl.

When m,n and/or p is an integer higher than 1, the resulting alkylene chain may be a branched or straight alkylene chain, examples of such chain are -CH₂-CH₂-,

-CH₂-CH₂-CH₂- and -CH(CH₂)-.

The substituent R₁ can be linked to any of the carbon atoms of the benzene moiety.

The substituent R₁ is preferably a -(CH₂)_n-COR₃ group wherein n is zero , 1 or 2 , in particular zero , R₃ is an -OR₄ or -N(R₄,R₅) group and each of R₄ and R₅ independently is hydrogen or C₁-C₄ alkyl; or -(CH₂)_n- -OR₄ group in which n is 1 and R₄ is hydrogen or C₁-C₄ alkyl.

The pyridyl -(CH₂)_m- group is preferably a 3-pyridyl-(CH₂)_m- group in which m is 1 or 2, in particular 1.

As stated above the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise) known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). Preferred compounds of the invention are the compounds of formula (I) wherein

the symbol - - - - - - is a double bond;

m is 1;

R is C₁-C₄ alkyl;

R₁ is a -COR group wherein R₃ is -OR₄ or -N(R₄R₅) in which each of R₄ and R₅ is independently hydrogen or C₁-C₄ alkyl;

R₂ is hydrogen; and the pharmaceutically acceptable salts thereof.

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

5,6-Dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

Ethyl 5,6-Dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylate;

5, 6-Dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxamide;

7, 8-Dihydro-5-methyl-6-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

5, 6-Dihydro-8-ethyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

and the pharmaceutically acceptable salts thereof.

The compounds of the invention and the salts thereof can be prepared by a process comprising: a) submitting to ß-elimination a compound of formula (II)

wherein

R, R₁, R₂ and m are as defined above and M represents hydrogen or an acyl group, thus obtaining a compound of formula ( I ) , wherein the symbol - - - - - - represents a double bond; or b) isomerizing a compound of formula (III)

wherein

one of R₆ and R₇ is hydrogen or C₁-C₅ alkyl and the other is hydrogen; and R₁, R₂ and m are as defined above, thus obtaining a compound of formula (I) wherein the symbol - - - - - - is double bond and R is C₁-C₆ alkyl; or c) reducing a compound of formula (IV)

wherein

R, R₁, R₂ and m are as defined above, thus obtaining a compound of formula ( I ) wherein the symbol - - - - - - represents a single bond, and if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof, and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers.

When M in a compound of formula (II) is an acyl group, it is, for example, a C₂-C₄ carboxylic acyl group, in particular acetyl, or it may be a mesyl or tosyl group, ß-elimination on a compound of formula (II), according to process a) reported above may be carried out in the presence of a suitable organic solvent, such as glacial acetic acid, mixtures of acetic anhydride-pyridine, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or benzene, in the presence of suitable amounts, even catalytic amounts, of a strong acid, e.g. concentrated H₂SO₄, HCl, or p-toluene-sulphonic acid, at

temperatures ranging from about 50°C to the reflux temperature.

The same conversion may also be performed by refluxing a compound of formula (II) in concentrated acids, e.g. hydrochloric, trifluoroacetic or hydrobromic acid. When in a compound of formula (II) M is an acyl group, in particular, acetyl, the reaction may also be carried out by pyrolysis, at temperatures ranging, preferably, from about 200°C to about 300°C.

Isomerization of a compound of formula (III) to obtain a compound of formula (I), according to process b), may be performed by known methods, for example by heating in a strong organic acid, for example trifluoroacetic acid or p. toluenesulfonic acid or in a mineral acid, e.g. sulfuric acid, or a Lewis acid, e.g. AlCl₃. The reaction may be performed by using the same acid as solvent or in an organic solvent chosen for example from benzene, toluene or acetic acid, at temperatures ranging preferably from about 60°C to 120°C.

Reduction of compounds of formula (IV) to obtain a compound of formula (I), according to process c), may be performed, for example, by catalytic hydrogenation in the presence of a suitable catalyst, e.g. palladium, platinum, PtO₂, ruthenium or Raney-nickel in a suitable organic solvent, preferably chosen from a lower alkanol; e.g. methanol or ethanol, hydrochloric acid, acetic acid, cyclohexane, n-hexane, ethyl acetate, benzene, toluene or mixtures thereof, operating at a pressure ranging from atmospheric pressure to about 30 atmospheres and at temperatures ranging from room temperature to about

100°C.

A compound of formula (I) may be converted, if desired, into another compound of formula (I).

These optional conversions may be carried out by methods known in themselves.

A compound of formula (I) containing an esterified carboxy group, may be converted into a compound of formula (I) containing a free carboxy group, by acidic or alkaline hydrolysis, operating at a temperature ranging from room temperature to about 100°C.

A compound of formula (I) containing a free carboxy group, may be converted into a compound of formula (I) containing an esterified carboxy group by esterification, e.g. via the corresponding acid halide, e.g. chloride, reacting with an excess of a suitable C₁-C₆ alkyl alkohol, or by direct esterification by means of acidic catalysis i.e. in the presence of dry HCl or SOCl₂ or BF₃-etherate.

A compound of formula (I) containing a carbamoyl group may be converted into a compound of formula (I)

containing a free carboxy group by hydrolysis,

preferably by acid hydrolysis, in a suitable solvent, such as water, or by treatment with NaNO₂

and an aqueous strong inorganic acid, i.e. H₂SO₄, operating at temperatures ranging between room temperature and 100°C.

A compound of formula (I) containing a free or

esterified carboxy group may be converted into a compound of formula (I) containing a group,

wherein R₄ and R₅ are as defined above.

Accordingly, the conversion of an esterified carboxy group into the corresponding amide may be performed by direct reaction with ammonia or an appropriate amine in a suitable aprotic solvent, e.g., ether or benzene or using an excess of the amine as solvent, at temperatures ranging from room temperature to reflux.

The conversion of free carboxy group into the

corresponding amides may be carried out via an intermediate reactive derivative which may be isolated or not. Intermediate reactive derivatives may be active esters e.g. NO₂ -phenyl esters, or N-hydroxysuccinimide ester acid halides, preferably chloride, mixed anhydrides e.g. ethoxycarbonyl or tert-butylcarbonyl anhydrides, or the reactive intermediates obtained in situ by reaction of the acid with dicyclohexylcarbodimide or carbonyldiimidazole. The reactive intermediates obtained following conventional ways, as those usually employed in the synthesis of peptides, are reacted with ammonia or an appropriate amine in a suitable solvent or with an excess of the amine itself at temperatures ranging from about -10°C to about 50°C.

A compound of formula (I) wherein R₁ is a -(CH₂)_n-COR group in which the COR₃ group is a free or esterified carboxy group, in particular a lower alkoxycarboxyl group, may be converted into a compound of formula (I) wherein R₁ is a -(CH₂)_n+1 OH group by reduction in conventional ways, preferably with LiAlH₄ in a suitable solvent, e.g. ethylether or THF.

The optional salification or a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by

conventional methods.

For example the separation of a mixture of geometric isomers, e.g. cis- and trans-isomers, may be carried out by fractional crystallization from a suitable solvent or by chromatography, either column chromatography or high pressure liquid chromatography.

A compound of formula (II), wherein M and R are

hydrogen, may be obtained by reducing a compound of formula (V)

wherein R₁, R₂ and n are as defined above, according to well known procedures, for example , by treatment with an alkali metal borohydride , e . g. NaBH₄ , in a suitable solvent , e . g. methanol or ethanol or a mixture of water and ethanol, or by treatment with LiAlH in an anhydrous solvent, e.g. diethyl ether or tetrahydrofuran, at a temperature ranging, in both cases, preferably between 0°C and the reflux temperature, for reaction times varying approximately from 1 to 5 hours.

A compound of formula (II), wherein M represents hydrogen and R is C₁-C₆ alkyl, may be obtained by reacting a compound of formula (V), as defined above, with a compound of formula R -Mg-X, wherein R is C₁-C₆ alkyl and X is halogen atom, in particular chlorine or bromine.

The reaction can be performed according to well known procedures for the Grignard reaction, e.g. by operating at temperatures ranging from about -78°C to the reflux temperature, preferably from about -10°C to about 30°C, in a suitable anhydrous solvent, e.g.

diethyl ether or tetrahydrofuran, for reaction times ranging approximately from 1 to 6 hours.

A compound of formula (II), wherein M represents an acyl group, as defined above, may be obtained according to known methods, e.g. by reacting a compound of formula (II) wherein M is hydrogen, with the suitable acyl or sulfonyl halide, preferably chloride, for example, with acetyl chloride or with tosyl or mesyl chloride operating e.g. in anhydrous pyridine or in an inert solvent, e.g. anhydrous benzene, if desired in the presence of an equimolar amount of a base such as triethylamine, at temperatures ranging from room temperature to about 60°C. A compound of formula (III) may be obtained by

alkylenation, i.e. olefination, of a compound of formula (V), as defined above by following known methods, e.g. by Wittig reaction or Horner-Emmons reaction. For example a compound od formula (V) may be reacted with a phosphonjum salt of formula (VI)

wherein

R₆ and R₇ are as defined above; Q is an aryl group, in particular a phenyl group; and Hal is halogen,

preferably iodine or bromine.

The reaction of a compound of formula (V) with a compound od formula (VI) can be carried out in the presence of a strong basic agent, such as a C₁-C₆ alkyllithium, preferably butyllithium; phenyllithium; a sodium or potassium alkoxide, preferably potassium tert. butylate; sodium amide or sodium hydride. The reaction may be performed in a suitable organic solvent, e.g. tetrahydrofuran, dioxane, dimethyl sulfoxide,

N,N-dimethylformamide, benzene or a lower alkanol; at temperatures preferably ranging from about -60°C to about 90°C.

The compounds of formula (IV) are compounds of formula

(I) according to the present invention, in which the symbol represents a double bond and can be

obtained by process a) described above. Thence the reduction of a compound of formula (IV), according to process c) described above, may be regarded as an example of the optional conversion of a compound of formula (I) into another compound of formula (I).

The compounds of formula (V) may be obtained by known procedures in organic chemistry; see, e.g., the method reported in example 1. When in the compounds of the invention and in the intermediate products thereof groups are present which need to be protected during the reactions reported above, the groups can be protected in a conventional way before the reaction takes place and then deprotected after its end, according to weel known methods.

PHARMACOLOGY

We have found that the compounds of formula (I), and the pharmaceutically acceptable salts thereof, are selective inhibitors of thromboxane A (TxA₂) synthesis and are therefore useful in the treatment of diseases related in particular to an enhancement of TxA₂

synthesis in mammals, including humans.

The compounds of formula (I) were for example tested for their ability to inhibit TxA₂ synthase activity (as reflected by TxB generated in whole blood during clotting) in vitro in the rat. Method

The effect of a representative compound according to the present invention on TxB₂ synthesis was evaluated in comparison with known products in whole blood of normal

Sprague Dawley rats (Charles River Italy). Blood was withdrawn from the abdominal aorta of the animals under light ether anesthesia. The blood was immediately divided in portions of 0.5 ml and distributed in glass tub«»s each containing a concentration of the test compound, or of the reference compounds.

Samples were then allowed to clot for 1 hour at 37ºC, centrifuged at 3000 rpm for 10 min, serum collected and stored at -20°C until assayed. TxB₂ levels were determined by RIA according to previously described orocedures (Thromb. Res. 17, 3/4, 317, 1980) using highly sensitive antibody. Table 1 herebelow shows that the compounds according to the present invention markedly inhibit TxA₂ synthesis in whole blood.

Internal code FCE 26949 means

5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

Internal code FCE 22178 means

5,6-dihydro-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid, which is known from US-A-4,510,149 and is a

thromboxane synthase inhibitor;

Acetyl salicylic acid (ASA) is a cyclooxygenase inhibitor.

The compounds of the invention, being able to inhibit selectively the formation of TxA₂, can be used as vasodilatory and antiaggregant agents, for example in all the cases of thrombosis, peripheral vasculopathies and coronary artery disease. In fact inhibition of TxA₂ production reduces the probability of thrombi formation and of vasoconstriction with consequent ischemic events and leaving unaltered (or increasing) PGI₂ production, improves vasodilation, tissue blood supplies and protects the vessel wall. Another use of the compounds of the invention is for the treatment of migraine. As is known, for example, in the case of migraine it has been demonstrated a diffused vasoconstriction induced by platelet TxA₂ overproduction (J.

Clin. Pathol. (1971), 24, 250; J. Headache (1977) 17, 101). A platelet overproduction of TxA₂ and MDA (malondialdehyde) in diabetes mellitus has been demonstrated and correlated with microcirculatory defects in the illness (Metabolism (1979) 28, 394; Eu. J. Clin. Invest. (1979) 9, 223; Thrombosis Haemost. (1979), 42, 983; J. Lab. Clin. Med.

(1981) 97, 87). Therefore, the compounds of the invention can be used in the treatment of diabetes, in particular, diabetic microangiopathy.

Moreover, the compounds of the invention can be used as anti-inflammatory agents. As is known, for example, fluid obtained from carrageenin-induced granuloma converts

arachidonic acid into TxA₂ in vitro and TxA levels are increased in the synovial fluid of rheumatoid arthritis patients and in the fluid of carrageenin-induced inflammation in rats (Prostaglands (1977), 13, 17; Scand. J. Rheum. (1977), 6, 151). Recently it has been also demonstrated

that an overproduction of TxA₂ is involved in the pathogenesis of hypertension and that a specific inhibitor of TxA₂ production may be employed in hypertension (Eu. J. Pharmacol. (1981), 70, 247). In fact the compounds of the invention can be used as hypotensive agents.

For example an increased TxA₂ synthesis and decreased prostacyclin synthesis are reported in pregnancy-induced hypertension (Am. J. Obstet:Gynecol. (1987), 157, 325; Hypertension (1988), 11, 550). Treatment with thromboxane synthase inhibitors is therefore useful in this pathology.

Furthermore it has been shown a role of TxA₂ in the pathogenesis of ulcerative disorders of the stomach in accordance with its powerful gastric vasoconstrictory activity, so that also in this field a TxA₂ inhibitor is useful (Nature (1981), 202, 472). In fact the compounds of the invention are indicated for the treatment of peptic ulcers.

The compounds of the invention can be also antltumoral agents. It is known, for example, that a selective inhibition of

TxA₂ synthesis has been demonstrated to reduce the number of lung metastases and to slow down tumor growth (Nature (1982), 295, 188).

In view of the correlation between TxA₂ synthesis and calcium transport, recently showed by some authors, specific TxA₂ synthetase inhibitors, such as the compounds of the invention, can also find use in the treatment of osteoporosis, e.g.

poεt-menopausal osteoporosis (Prostaglandins (1981), 21, 401). Moreover the compounds of the invention are indicated for the treatment of angine pectoris and heart failure. In this

respect, it is known, for example, that high levels of TxB₂ have been found in patients with Prinzmetal's angina

(Prostaglandins and Med. (1979), 2, 243) and in patients with recurrent angina attacks (Sixth Intern. Congress on

Thrombosis, Monte Carlo October, 1980 Abs Nº 140).

The platelet antiaggregatory activity of the compounds of the invention was evaluated in vitro and in vivo, for example, according to the modified methods of Born (Born G.V.R.,

Nature 194, 927 (1962)) and Silver (Silver M.J., Science

183, 1085 (1974)). The compounds of this invention were found in vitro to have inhibitory activity on platelet aggregation induced by collagen or ADP ( adenosine-5'-diphosphate) in platelet rich plasma of guinea pig (Dunkin Hantley Iva: PDH (SPF) Ivanovas GmbH, Germany).

Therefore the compounds of the invention may be useful in preventing of reducing platelet loss during extracorporeal circulation; for example during coronary artery bypass and graft procedures or during kidney dialysis. It has been moreover shown that circulatory shock, for example endotoxic and haemorhagic shock, is associated with increased TxA₂ synthesis so that the compounds of the invention can be useful in these pathologies. Moreover, the compounds of the present invention can also be useful for the treatment of bronchial hyperreactivity in the therapy of asthma.

A role for TxA₂ in asthma can be inferred on thebasis of its bronchoconstrictory activity in experimental animal models (Br. J. Pharmacol. (1984), 82 (3) 565). An inhibitory activity of bronchospasm induced by Platelet Activating Factor (PAF) in rats is also reported, e.g. for the TxA₂ synthetase inhibitors described in GB-B-2205494.

The compounds of the present invention can also find use in the treatment of nephropathies, alone or in association with an ACE inhibitor e.g. forms of glomerulonephritis, diabetic nephropathy or nephropathies secondary to systemic lupus erithematous (SLE), and in the prevention and/or treatment of Cyclosporin A-induced nephrosis. Accordingly the compounds of this invention can also be used for preventing and/or treating toxemia durinq pregnancy, typically preeclampsia, eclampsia and preeclamptic (eclamptic,

eclamptogenic) toxemia.

Recently a positive correlation between enhanced intrarenal synthesis of TxA₂ and the progression of chronic glomerular disease has been demonstrated in different animal models of immune and non-immune renal damage and in humans (J. Clin. Invest. (1985), 75, 94, J. Clin. Invest. (1985), 76 101 H.

Accordingly, the TxA₂ synthase inhibitors recently described e.g. in GB-B-2205240 were found to be active in reducing proteinuria and creatinine serum levels in the doxorubicin induced nephrosis in rats and in reducing proteinuria and increasing the glomerular filtration rate (GFR) in the

spontaneous focal glomerulosclerosis in the Milan Normotensive Strain (MNS) rats.

The compounds of the invention may be also used to inhibit the renal and cardiac transplant rejection. In fact after transplantation increased urinary TxB₂ excretion or whole blood TxA₂ synthesis have been reported both in man and rats (Lancet (1981), ii, 431; Transplantation (1987), 43, 346).

Another use of the compounds of the present invention is in the treatment of hyperlipidaemia, namely hypercholesterolaemia and hypertriglyceridaemia secondary to nephrotic syndrome. Hyperlipidaemia is a common feature of nephrotic syndrome in man (New Engl. J. Med. (1983) 312 (24) 1544) and in

addition elevated triglycex ides and cholesterol levels are reported in animal models such as doxorubicin induced

nephrotic syndrome (Expt. Mol. Pathology (1983), 39, 282);

elevated urinary albumin excretion has been suggested as the pathogenetic mechanisms (Kidney International (1987), 32,

813). Also TxA synthase inhibitors recently described in

GB-B-2205240, e.g. proved to be active in reducing cholesterol and triglycerides in aged Milan Normotenisve Strain rats and in reducing triglycerides in doxorubicin treated rats.

It has also been shown that in cholesterol fed rabbit, an animal model of diet induced atherosclerosis, arachidonic acid metabolism is an important factor in early lesion

development. In particular a shift in metabolism from TxA₂ to PGE may suppress lesion development (i.e. atheromatous plaque) in hypercholesterolemia.

The compounds of invention can be therefore used in this

pathology.

The compounds of the invention can also be used in association with thrombolytic agents (e.g. tPA, Streptokinase, pro-Urokinase) in order to reduce the dose of the latter required in thrombolytic therapy, and to lower the incidence of reocclusion and possibly haemorrhage.

A rurther application of the compounds of the invention is the prevention and/or treatment of restenosis after percutaneous transluminal angioplasty. The toxicity of the compounds of the invention is negligible, therefore they cam be safely used in therapy. Mice and rats which had been deprived of food for nine hours were treated orally with single administrations of increasing doses of compounds of the invention, then housed and normally fed.

In view of their high therapeutic index the compounds of the invention can be safely used in medicine. The therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology, taking into account, as usual, also the route of administration, the form in which the compound is administered and the age, weight and conditions of the subject irvnived. The oral route is employed, in general, for all conditions requiring such compounds. Preference is given to intravenous injection or infusion for the treatment of acute pathological states.

For maintenance regimens the oral or parenteral, e.g.

intramuscular, route is preferred.

The dosage level suitable for oral administration to adult humans of the compounds of the invention e.g. 5, 6-dihydro-8¬-methyl-7-(3-pyridylmethyl)-2-naphthalene-carboxylic acid, may range from about 50 mg to about 500 mg per dose 1 to 3 times a day.

Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.

The nature of the pharmaceutical compositions containing the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will of course, depend upon the desired route of administration.

The compositions may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions , or suspensions, tablets , pills , gelatine capsules , syrups, drops or suppositories.

Thus, for oral administration, the pharmaceutical composition containing the compounds of this invention are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starcnes,gelatine, methylcellulose, carboxymethylcellulose,gum-arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as starches, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and in general, non-toxic and pharmacologically inactive

substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugarcoating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

The suppositories may contain together with the active compound a pharmaceutically acceptable carrier e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the present invention.

Example 1

To a suspension of anhydrous magnesium (0.14 g) and a small crystal of iodine in anhydrous diethyl ether (3 ml) a

solution of methyl iodine (0.77 g) in anhydrous diethyl

ether (6 ml) is added dropwise. The mixture is refluxed

for 1 hour then cooled to room temperature. To this mixture a solution of tert-butyl 8-oxo-7-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate (0.46 g) in anhydrous tetrahydrofuran (25 ml) is added dropwise. The reaction mixture, after stirring at room temneratυre for 2 hours, is nnured into water, neutralized with diluted hydrochloric acid and extracted with methylene chloride. The organic layer is

dried over sodium sulfate and evaporated to dryness. The

residue is taken up with trifluoroacetic acid and refluxed for 45 minutes. The resulting solution is evaporated under reduced pressure and the residue is taken up with water.

The aqueous solution is alkalinized with diluted NaOH, then filtered and acidified with acetic acid.

The solid precipitated is filtered, washed with water and dried to give 0.25 g of 5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid,

m.p. 203-205°C

N.M.R. (DMSO-d₆) ppm: 2.15(5H,m,CH₃,Ph-CH₂-CH₂);

2.70(2H,m,CH₂-Ph); 3.65( 2H,s,CH₂-Py); 7.2-7.85(5H,m,phenyl, N-CH-CH-CH); 8.45(2H,m,CH-N-CH). By proceeding analogously, the following compounds can be prepared:

7,8-Dihydro-5-methyl-6-(3-pyridylmethyl)-2-naphthalenecarboxylic-acid and

5,6-Dihydro-8-ethyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid.

The tert-butyl 8-oxo-7-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate used above is prepared as follows: a mixture of tert-butyl 8-oxo-7-(3-pyridylmethylene)-5,6,7,8¬-tetrahydro-2-naphthalenecarboxylate (2.75 g), ethanol (200 ml) and 10% palladium on activated charcoal (0.4 g) is hydrogenated for 5 hours at room temperature in a Parr Burgess apparatus at an initial pressure of 50 psi. The catalyst is filtered off, the solution is evaporated and the residue gives 2.65 g of tert-butyl 8-oxo-7-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2¬-naphthalenecarboxylate.

The tert-butyl 8-oxo-7-(3-pyridylmethylene)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate used above is prepared as follows:

A mixture of tert-butyl 8-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate (6.15 g), pyridin-3-carboxaldehyde (2.5 g), acetic acid (10 ml) and piperidine (6 ml) is heated at 100°C for

6 hours. After cooling the volatile material is evaporated and the residue is dissolved in ethyl acetate. The solution is extracted with diluted HCl, the aqueous solution is washed with methylene chloride then is made alkaline with dilute sodium hydroxide solution.

The solid is filtered off, washed with water and dried to give 5.5 g of tert-butyl 8-oxo-7-(3-pyridylmethylene)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate.

Example 2

To a solution of hydrogen chloride in absolute ethanol (50 ml), 5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid hydrochloride (0.5 g) was added.

The reaction mixture was heated at 60°C for 3 hours and then evaporated under reduced pressure to dryness.

The residue, taken up with ethylether and filtered to give ethyl 5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylate hydrochloride (0.45 g).

Example 3

To a suspension in dry benzene (25 ml) of 5,6-dihydro-8-methyl¬-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid (0.5 g), oxahyl chloride (0.40 ml) was added dropwise under cooling in an ice bath. The reaction mixture was stirred 2 hours at 8-10°C and then evaporated to dryness under reduced pressure.

The residue was dissolved in anhydrous DMF (15 ml) and

gaseous NH₃ was passed through the solution with stirring and cooling in an ice bath for 5 hours.

The reaction mixture was evaporated to dryness under reduced pressure. 1 ^NNaOH was added to the residue and extracted with ethyl acetate.

The organic phase, dried on Na₂SO₄ and filtered was evaporated to dryness and the residue taken up with ethylether and filtered to give 5,6-dihydro-8-methyl-7-(3-pyridylmethy])-2-naphthalenecarboxamide (0.24).

Example 4

Tablets, each weighing 150 mg and containing 50 mg of the active substance can be manufactured as follows:

Composition (for 10,000 tablets)

5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid 500 g

Lactose 710 g

Corn starch 237.5 g

Talc powder 37.5 g

Magnesium stearate 15 g

5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid, lactose and a half of the corn starch are mixed: the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 mg) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium are added carefully mixed, and processed into tablets using punches of 8 mm diameter.

Example 5

A mixture of 5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid (1.5 g), 10% palladium on activated carbon (0.65 g), ethanol 95% (100 ml), glacial acetic acid (30 ml) and concentrated hydrochloric acid (10 ml) is hydrogenated for 8 hours at room temperature in a Parr-Burgess low pressure apparatus at an initial pressure of 50 psi.

At the end of this time the theoretical amount of hydrogen has been absorbed.

The catalyst is filtered off, washed with 95% ethanol, and the solution is evaporated under reduced pressure to give 1.4 g of 5,6,7,8-tetrahydro-8-methyl-7-(3-pyridylmethyl)-2¬-naphthalenecarboxylic acid hydrochloride,

Elemental Analysis:

Found: C 67.90; H 6.29; Cl 11.13; N 4.44

Calculated for C ₁₈H₂₀Cl N O₂ : C 68.03; H 6.34;

Cl 11.16; N 4.41

T.L.C.: Eluant CH₂Cl₂ : CH₃OH (90:10)

Rf = 0.3.

By proceeding analogously, the following compounds can be prepared:

5,6,7,3-tetrahydro-8-ethyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid hydrochloride;

5,6,7,8-tetrahydro-5-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid hydrochloride. Example 6

After treatment of a compound, prepared according to Example

5, with a stoichiometric amount of sodium bicarbonate the following compound can be for instance prepared:

5,6,7,8-tetrahydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid.

Claims

1. A compound of formula (I)

wherein

the symbol - - - - - - represents a single or double bond ;

m is an integer of 1 to 3;

R is hydrogen or a C₁-C₆ alkyl group;

R₁ is a - ( CH ₂) _n -COR₃ group , wherein n is zero or an intege of 1 to 3 and R₃ i s an -OR₄ or -N( R₄ R ₅) group in which each of R₄ and R ₅ independently is hydrogen , C ₁-C₆ alkyl optionally substituted by phenyl or phenyl ;

or a -(CH₂)_p -OR group wherein p is zero or an integer of 1 to 4 and R₄ is as defined above;

R₂ is hydrogen or C₁-C₄ alkyl; or a pharmaceutically acceptable salt thereof; and wherein, when at the same

time the symbol is a single bond and R₁ is a

-(CH₂)_n-COR group in which n is asdefined above and R₃ is an OR₄ group wherein R₄ is hydrogen or unsubstituted C₁-C₆ alkyl, then at least one of R and R₂ is other than hydrogen.

2. A compound of formula (I), according to claim, wherein: the symbol - - - - - - is a double bond;

m is 1;

R is C₁-C₄ alkyl;

R₁ is a -COR group wherein R₃ is -OR₄ or -N(R₄R₅) in which each of R, and R_c is independently hydrogen or C₁-C₄ alkyl R₂ is hydrogen; or a pharmaceutically aceptable salt

thereof.

3. A compound selected from: 5,6-Dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

Ethyl 5,6-dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalene¬carboxylate;

5, 6-Dihydro-8-methyl-7-(3-pyridylmethyl)-2-naphthalenecarboxamide 7,8-Dihydro-5-methyl-6-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

5,6-Dihydro-8-ethyl-7-(3-pyridylmethyl)-2-naphthalenecarboxylic acid;

and the pharmaceutically acceptable salts thereof.

4. A process for the preparation of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, the process comprising: a) submitting to ß-elimination a compound of formula (II)

wherein

R, R₁, R₂ and m are as defined in claim land M represents hydrogen or an acyl group, thus obtaining a compound of formula (I), wherein the symbol - - - - - - represents a double bond ; or b) isomerizing a compound of formula (III)

wherei

n

one of R₆ and R₇ is hydrogen or C₁-C₅ alkyl and the other is hydrogen; and R₁ , R₂ and m are as defined above, thus obtaining a compound of formula ( I ) wherein the symbol - - - - - - is a double bond and R is C₁-C₆ alkyl; or c) reducing a compound of formula (IV)

wherein

R, R₁, R₂ and m are as defined above, thus obtaining a compound of formula (I ) wherein the symbol - - - - - - represents a single bond, and if desired, converting a compound of formula (I) into another compound of formula (I), and/or, il desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof, and/or, if

desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers.

5. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

6. A compound of formula (I) or salt thereof, according to claim 1, for use in the treatment of a disease related to an enhancement of thromboxane A₂ synthesis.

7. A compound of formula (I) or a salt thereof, according to claim 1, for use in the treatment of nephropathies.

8. A compound of formula (I) or a salt thereof, according to claim 1, for use in the prevention and/or treatment of cyclosporin A-induced nephrosis.

9. A compound of formula (I) or a salt thereof, according to claim 1, for use in the treatment of hyperlipidaemia secondary to nephrotic syndrome.

10. An agent for use in treating a disease related to an anhancement of thromboxane A₂ synthesis comprising a compound of formula (I), according to claim 1, or a pharmaceutically acceptable carrier.