PT99820A - PROCESS FOR THE PREPARATION OF PYRIDYL DERIVATIVES OF SUBSTITUTED BICYLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

FARMITALIA CARLO ERBA S.R.L. " PROCESS FOR THE PREPARATION OF PYRIPILIC DERIVATIVES OF REPLACED BICYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM " The present invention relates to a process for the preparation of novel pyridyl derivatives of bicyclic compounds, in particular pyridyl derivatives of 1,2-dihydro-naphthalene and 1,2,3,4-tetrahydro-naphthalene, of pharmaceutical compositions which the contain and their application as therapeutic agents.

Compounds which exhibit TXA2 synthase inhibitory activity have been proposed as described for example in U.S. Patent Nos. 4,777,257 and 4,510,149.

More precisely, the present invention provides novel compounds of the following formula

in which the symbol ------ represents a single or a double bond; m is an integer from 1 to 3; R 2 represents a hydrogen atom or a 2-

C 1 -C 6 -alkyl represents - (CH 2) p - OR 4 wherein n is zero or an integer from 1 to 3; R 3 represents -OR 4 or - (R 4 R 5) wherein each of R 4 and R 5 is independently hydrogen, C 1-6 alkyl, optionally substituted with phenyl or phenyl, and p is zero or an integer of 1 to 4, and R 2 represents a hydrogen atom or a C 1 -C 4 alkyl group, with the proviso that at least one of R 2 and R 2 does not represent a hydrogen atom while simultaneously - R 2 represents a group of the general formula - (CH 2) -COR 3 in which n is as defined above and R 2 represents a group of the formula wherein R 4 represents a hydrogen atom or a C 1-6 alkyl group The above-mentioned conditions excluding the general formula 1 are unsubstituted. described in U.S. Patents 4,777,257 and Eur. J. Med. Chem. 26, 423-433, (1991). The present invention also encompasses within its scope possible stereoisomeric isomers and mixtures thereof and the metabolites and metabolic or bio-precursor precursors of the compounds of the general formula.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts with inorganic acids such as, for example, nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric acids or with organic acids such as acetic acid, propionic, glycocholic, lactic, oxalic, malonic, maleic, maleic, tartaric, citric, tyzoic, cinnamic, mandelic and salicylic acid salts and salts with inorganic bases, for example of alkali metals, especially sodium or potassium or alkali metals - especially calcium and magnesium or with organic bases such as for example alkylamines with triethylamine being preferred.

The alkyl groups may be branched or straight chain groups. : The alkyl group -g is preferably an alkyl group, in particular methyl, ethyl, propyl and isopropyl, preferably methyl and ethyl. The C1-4 alkyl group is for example a methyl, ethyl, propyl or isopropyl group in particular methyl or ethyl.

A C1-6 alkyl group substituted by a phenyl group is for example a benzyl or phenethyl group, in particular benzyl.

When their m and n and / or p represent an integer greater than 1, the resulting alkylene chain may be a straight or branched alkylene chain of which -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - and CH (CH2) n -. -4-

The substituent represented by may be attached to any of the carbon atoms of the benzene group. The substituent represented by R 1 is preferably a group of the formula - wherein n is 0 or 1, in particular zero, R 2 is -OR 4 or -N (R 2 R 3) and R 2 and R 2 are each independently hydrogen or alkyl, or (CH 2) n -OR 4 in which n is 1 and R 4 represents a hydrogen atom or a C 1 -C 4 alkyl group the pyridyl group - (CH 2) - is preferably a 3-pyridyl- (CH 2) - group wherein m represents 1 or 2, in particular 1.

As mentioned above the present invention also includes in its scope the pharmaceutically acceptable bioresonants, also known as prodrugs, of the compounds of formula 1, i.e. compounds having a different formula of the general formula 1 cited above, but which, however, after administration to a human is converted directly or indirectly in vivo into the compound of formula 1.

Preferred compounds of the present invention are compounds of Formula 1 wherein the symbol ------ represents a linkage of the body; m is 1; R represents a C1 -C4 alkyl group; R.sup.1 represents a group of the formula -COR na wherein R representa is -OR ou or -N (RRR)) and wherein each -

R4 and R4 are independently hydrogen or C1 -C4 alkyl; 1 * 2 represents a hydrogen atom; and their pharmaceutically acceptable salts.

Preferred examples in the compounds of Formula 1 are as follows: 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-pyridymethyl) -2-naphthalenecarboxylic acid; and their pharmaceutically acceptable salts.

The compounds of the present invention and their salts may be prepared from the process consisting of: a) subjecting a compound of general formula

2-

in which R 1, R 2, R 3 and R 2 have the meanings given above, and M represents a hydrogen atom or an acyl group, to a B-elimination reaction to give a compound of formula I in which the symbol - ---- represents a connection of pla; )

OR b) in subjecting a compound of general formula

in which one of R1 and R2 is a hydrogen atom or an alkyl group and the other is hydrogen; and R 2, R 2 and n are as defined above; to an isomerization reaction to give a compound of formula I wherein R1 is a C1-C6 alkyl group; or c) reducing a compound of formula -7-

(IV) in which > R 2, R 2, R 2 and R 2 have the meanings as defined above, to give a compound of formula I in which - ------ represents a single bond and optionally converting the resulting compound of formula I into a further compound of general formula I, and / or optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof, and / or optionally converting a salt into a free compound, and / or possibly a mixture of isomers of compounds of general formula I in their individual isomers.

When M in the compound of formula II represents an acyl group, i.e., for example, a C2 -C4 carboxylic acyl group, in particular acetyl or is a mesyl or tosyl group. The reduction in a compound of general formula II according to the process of a) described above may be carried out in the presence of a suitable organic solvent such as glacial acetic acid mixtures of acetic anhydride and pyridine, dimethylformamide or dimethyl sulfoxide or benzene in the presence of suitable amounts, even catalytic amounts

of a strong acid, for example concentrated sulfuric acid, hydrochloric acid or paratoluene sulfonic acid, at temperatures ranging from about 50 ° C to reflux temperatures. The same conversion can also be carried out at reflux in the compound of general formula and in concentrated acids, for example in hydrochloric acid, trifluoroacetic acid or hydrobromic acid. When in a compound of formula II R represents an acyl group, in particular acetyl, the reaction may 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 the process described in b), may be carried out by known methods, for example by heating a strong organic acid, for example example trifluoroacetic acid or paratoluenesulfonic acid in a mineral acid such as sulfuric acid or a Lewis acid for example aluminum trichloride.

The reaction may be carried out using the same acid as the solvent or an organic solvent chosen, for example, from benzene, toluene or acetic acid, at temperatures preferably in the range of about 60ø to 120øC. The reduction of the compounds of formula IV to give a compound of formula I according to the process described in c) may be carried out, for example, by catalytic hydrogenation, in the presence of a suitable catalyst such as palladium , platinum, platinum oxide, ruthenium or nickel of 9-

Raney in an appropriate organic solvent, preferably selected from the lower alkanols; for example, 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 temperatures ranging from room temperature to about 100 ° C.

The compounds of Formula I may be converted, if appropriate, to other compounds of Formula I.

These conversions may be carried out by conventional methods.

Compounds of formula I which contain a carboxy esterified group may be converted into a compound of formula I containing a free carboxy group by acid or alkaline hydrolysis at temperatures ranging from room temperature to 100 ° C about.

Compounds of formula I which contain a free carboxy group may be converted into compounds of formula I containing an esterified carboxy group by esterification through, for example, or corresponding to the acid buffer, for example chloride, by reacting with the excess of an appropriate alkyl alcohol -C g or by direct esterification by the application of acid catalysis, i.e. in the presence of hydrochloric acid or anhydrous sulfonyl chloride or bromo-etherate trifluoride.

The compounds of formula I contain a

May be converted into compounds of formula I containing a carboxy group by hydrolysis, preferably in acidic hydrolysis, in a suitable solvent such as water or by treatment with sodium nitrite, in a strongly aqueous medium for example with sulfuric acid at temperatures ranging from room temperature to 100 ° C.

Compounds of general formula I containing a free or esterified carboxy group may be converted into compounds of formula (I). or a general formula I containing a group -CON in which R 5 and R 8 are as defined above.

Accordingly, the conversion of an esterified carboxy group to the corresponding amide may be carried out by direct reaction with ammonia or with an appropriate amine in a suitable aprotic solvent, for example diethyl ether or benzene using an excess of amine with solvent, at temperatures which range from room temperature to reflux temperature. Conversion of a free carboxy group to the corresponding amides may be carried out via an intermediate reactive derivative which may optionally be isolated.

The intermediate reactive derivatives may be active esters, for example N-2-phenyl esters or N-hydroxysuccinimide esters, acid halides, preferably chlorides, anhydride mixtures for example, ethoxycarbonyl or tert-butylcarbonyl anhydride or reactive intermediates thereof in situ by reaction of the acid with dicyclohexylcarbomide or carbonyl-diimidazole.

X

Reactive intermediates obtained by conventional procedures such as those used in peptide synthesis 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 and about 50 ° C.

Compounds of formula I in which R 2 represents a group - (CH 2) n-COR 3, in which the COR 3 group represents a free or esterified carboxy group, in particular a lower alkoxy carboxyl group may be converted in a compound of the general formula in which - (ΟΗ 2) η + ΟΗ is by reduction of conventional processes, preferably with lithium aluminum hydride, in a suitable solvent such as diethylether or tetrahydrofuran, dihydro-furan. The possible salification of a compound of formula I, as well as the conversion of a salt into the free compound and separation of a mixture of isomers into the isolated isomers, may be carried out by conventional methods.

For example the separation of a mixture of geometric isomers, for example cis and trans isomers may be carried out by fractional crystallization with an appropriate solvent either by chromatography, column chromatography or high performance liquid chromatography.

Compounds of formula II in which M and R are hydrogen may be obtained by reduction of a compound of formula V

or

in which the meanings given above are in accordance with known methods, for example by treatment with an alkali metal borohydride such as sodium borohydride, in a suitable solvent such as methanol or ethanol or a mixture of water and ethanol or by treatment with lithium aluminum hydride in an anhydrous solvent, for example diethyl ether or tetrahydrofuran at a temperature varying in any case preferably from 0 ° C to reflux temperature for reaction times which range from approximately 1 to 6 hours.

Compounds of formula II in which M is hydrogen and R um is C -C-C alquilo alkyl may be obtained by reacting a compound of formula V as defined above with the compound of formula R -Mg-X, in which R represents a C1-6 alkyl group and X represents a halogen atom, in particular chlorine or bromine. The reaction may be carried out according to methods known for the Grignard reaction, for example operating at temperatures ranging from -78 ° C to reflux temperature, preferably from about -10 ° C to 30 ° C in an appropriate anhydrous solvent such as diethyl ether or tetrahydrofuran for reaction times ranging from about 1 to about 6 hours.

The compounds of formula II in which M represents an acyl group as defined above may be obtained according to conventional methods, for example by reacting a compound of formula II in which M represents a hydrogen atom , with an appropriate acyl or sulphonyl halide, preferably chloride, for example with acetyl chloride or mesyl chloride, or tosyl chloride in anhydrous pyridine or in an inert solvent such as anhydrous benzene, the presence of an equimolar amount of a base such as triethylamine, at temperatures ranging from room temperature to about 60 ° C.

The compounds of formula III can be obtained by alkylation ie olefination of a compound of formula V as defined above by the application of conventional methods for example a Wittig reaction or a Horner-Emmons reaction. For example, a compound of formula V may be reacted with a phosphane salt of the general formula VI (VI) wherein Q

R 2 and R 2 are as defined above; Q represents an aryl group, in particular a phenyl group and Hal represents a halogen atom, preferably iodo or bromo. The reaction of the compound of formula V with a compound of formula VI may be carried out in the presence of a strong basic agent, for example a C1-6 alkyl lithium, preferably lithium butyl, lithium phenyl, or a sodium alkoxy or potassium alkoxy, preferably potassium tert-butylate, a sodium amide or sodium hydride. The reaction may be carried out in a suitable organic solvent, for example tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν, Ν-dimethylformamide, benzene, or one to the lower isol; at temperatures which preferably range from about -60 ° C to about 90 ° C.

Compounds of general formula IV are compounds of general formula I according to the present invention in which ---- represents a double bond and can be obtained by the process described above under a); therefore due to the reduction of a compound of formula IV, according to the process described in c) above, can be considered as an example of a possible conversion of a compound of formula I into another compound of formula I.

Compounds of formula V can be obtained by processes known in the organic chemistry, see for example the method recited in Example 1. When groups in the compounds of the present invention and groups of the intermediates are present which need protection during the reactions described previously, these groups can be protected in a convenient manner

The reaction was then carried out and the groups were finally deprotected according to known methods.

PHARMACOLOGY

The compounds of formula I and their pharmaceutically acceptable salts have been found to be selective inhibitors of the synthesis of thromboxane A2 (TxA2) and are therefore useful for the treatment of diseases related in particular to increased synthesis of A2 thromboxane in mammals, including humans.

Compounds of formula I were tested, for example, on their ability to inhibit TxA2 synthase activity, as reflected by the production of thromboxane B2 in whole blood during in vitro coagulation in the rat. Method

The effect of a representative compound of the present invention on the synthesis of TxB2 compared to known products in whole blood of a normal Sprague Dawley mouse (in Italy Charles River) was evaluated. Blood was drawn from the abdominal aorta of the animals under mild anesthesia with diethyl ether. Immediately the blood is distributed through 0.5 ml portions into glass tubes each containing a concentration of the test compound or reference compounds. The samples remained: coagulated for 1 hour at 37øC, centrifuged at 3000 rpm for 10 minutes, the serum collected and stored at -20øC until analysis . The TxB2 levels were determined by the RIA assay according to procedures described above (Thromb.Res.17, 3/4, 317, 1989) using very sensitive anti-bodies. Table 1 below demonstrates that the compounds according to the present invention markedly inhibit the synthesis of TxA2 in whole blood.

Table 1 - In vitro effect under TXB2 synthesis in normal mice.

The data are expressed by IC 50 (M) FCE 26949 5.15X 10-8 M (3.45-7.35 X 10.88) FCE 22178 1.0 x 10-6 M (0.56-1.6 X δ δ) ASA 3.1 The internal code FCE 26949 represents 5,6-dihydro-8-methyl-7- (3-pyridymethyl) -2-naphthalenecarboxylic acid; Internal code FCE 22178 represents 5,6-dihydro-7- (1H-imidazol-1-yl) -2-naphthalenecarboxylic acid which is known from U.S. Patent No. 4,510,149 constituting an inhibitor thromboxane synthase; Acetyl salicylic acid (ASA) is an inhibitor of cyclo-17- κ% Λ. oxigenase. The compounds of the present invention are capable of selectively inhibiting the formation of A2 thromboxane, and may be used as a vasodilator of anti-aggregation agents, for example in all cases of thrombosis, peripheral vasculipathy and coronary artery disease. In fact, inhibition of TxA2 production reduces the likelihood of thrombus formation and vasoconstriction with consequent ischemic events, and the production of PGI2 remains unchanged or increased, vasodilatation, blood supply to tissues and protection of the vessel wall .

Another application of the compounds of this invention is in the treatment of migraine, as is known, for example, in the case of migraine diffuse vasoconstriction induced by overproduction of platelet TxA2 (J. Clin. Pathol. (1971), 24, 250 ; J. Headache (1977) V7, 101).

Overproduction has been demonstrated in platelets of TxA2 and malondialdehyde in diabetes mellitus and diseases related to microcirculatory insufficiencies (Metabolism, 28, 394 (1979)), J. Clin Invest 9, 223 (1997), Thrombosis Haemost. The compounds of the present invention can therefore be used for the treatment of diabetes, in particular in diabetic microangiopathy.

In addition, the compounds of the present invention may be used as anti-inflammatory agents. As is known, for example, the liquid obtained in carrageenan-induced granuloma converts arachidonic acid to TxA2 in vitro and TxA2 / -18- increases in the synovial fluid of patients with rheumatoid arthritis and in the fluid of inflammation induced by carrageenin in the rat (Prostaglands, 13, 17 (1997), Scand. J. Rheum, 6, 151 (1977). Recently it has also been shown that overproduction of TxA2 is related to the pathogenesis of hypertension and that an inhibitor specific composition of the production of TxA2 can be used in hypertension (J.J. Pharmacol., TQ, 247 (1981)) In fact, the compounds of the present invention can be used as potentiating agents.

For example, increased synthesis of TxA2 and the decrease in prostacyclin synthesis in pregnancy-induced hypertension is reported (Am. J. Obstet: Gynecol 157, 325 (1987): Hypertension 11, 550 (1984)). inhibitors of thromboxane synthase is therefore useful in this pathology.

In addition, the performance of TxA2 in the pathogenesis of stomach ulcer diseases has been demonstrated, in accordance with its great potential for gastric vasoconstricting activity, and (hence also useful or inhibitory of TxA2 in this regard (Nature 202, 472 (1981)). In fact the compounds of this invention are indicated for the treatment of peptic ulcers.

The compounds of the present invention may also be used as antitumor agents. It is known, for example, that selective inhibition of TxA2 synthesis has been shown to reduce a number of lung metastases and to slow the development of tumors (Nature 295, 188 (1982).

In view of the correlation between TxA2 synthesis and calcium transport, some authors have recently demonstrated that specific TXA2 synthase inhibitors, such as the compounds of the present invention, may also find application in the treatment of osteoporosis, for example osteoperose (Prostaglandins 21, 401 (1981).) Also, the compounds of the present invention are indicated for the treatment of angina pectoris and cardiac failure. In this respect, it is known, for example, that high levels of B2 thromboxane have been detected in patients with Prinzmetal's angina (Prostaglandins and Med 2, 243 (1979) and in patients with recurrent angina attacks (Sixth International Congress on Thrombosis, Monte Carlo October, Abs Ne 140 1980) .

The anti-platelet aggregation activity of the compounds of this invention was evaluated in vitro and in vivo, for example, according to the modified Born methods (Born GVR., Nature 944, 927 (1962)) and Silver MJ Sciense 183, 1085 (1974)).

The compounds of the present invention have been found in vitro to have platelet aggregation inhibitory activity induced by calagen or adenosine 5'-diphosphate in guinea pig platelet-rich plasma (Dunkin Hantley Iva: PDH (SPF) Ivanovas Gra311, Germany ).

Therefore the compounds of this invention may be useful for preventing platelet loss during extra-corporeal circulation; for example during " bypass " of the coronary artery and grafting processes or during renal dialysis. It has further been shown that circulatory shock, for example endotoxic shock

H

or hemorrhagic syndrome is associated with increased h2-thromboxane synthesis, therefore, the compounds of this invention may be useful in this type of disorder. In addition, the compounds of the present invention may further be useful for the treatment of bronchial hyperreactivity in of asthmatics. The performance of A2 thromboxane in asthma may be deduced based on its bronchoconstriction activity or animal experience (Br. J. Pharmacol. 82 (3) 565 (1984)). A platelet activating factor (PAF) -induced bronchospasm inhibitory activity in rats is also disclosed the inhibitors of TxA2 synthetase in GB-B-2205494.

The compounds of this invention may furthermore find application in the treatment of nephropathies, alone or in combination with ACE inhibitors, for example in forms of glomerulonephritis, diabetic nephropathy or secondary systemic lupus erythematosus (SLE) nephropathy and in the prevention and / or treatment of cyclosporin-induced nephrosis. Thus, the compounds of this invention may further be applied for the prevention and treatment of toxemia during pregnancy, typical preeclampsia, eclampsia toxin or preeclamptic (eclamptic, aclamphogenic).

Recently the relationship between the synthesis of enhanced intrarenal TxA2 and the progression of chronic glomerular disease in different animal species of immune and non-immune damage and in humans has been demonstrated (J. Clin. Invest., 75, 94 (1985), J. Clin .

Invest. 76 1011 (1985)).

Thus, the synthase inhibitors, recently described, for example in GB-B-2205240, have been found to have activity to reduce proteinuria and serum creatinine levels in doxorubicin-induced nephrosis in the rat and to reduce proteinuria and increase the rate of glomerular filtration (GFR) in focal spontaneous glomerulosclerosis in the Milan, Normotensive strain.

The compounds of this invention may also be used to inhibit rejection of cardiac and renal transplants. In fact, both the human urine and the rat have been reported to increase urinary TxBβ synthesis or to TxAâ,, synthesis in whole blood after transplantation (Lancet ii, 431 (1981), Transplantation 43, 346 (1987)). .

Another application of the compounds of the present invention is in the treatment of hyperlipidaemia, in particular in hypercholesterolemic and secondary hypertriglyceridaemia of the nephrotic syndrome. Hyperlipidemia is a common aspect of nephrotic syndrome in man (New Engl. J. Med. 312 (24) 1544 (1983)) and elevated levels of triglycerides and cholesterol are reported in animal experiments such as nephrotic syndrome induced by doxor bicine (Expt Mol. Pathology 30, 282 (1983)); it has been suggested that elevated urine albumin excretion as the pathogenic mechanism (Kidney International 32, 81, (1998)). Recently, as described in GB-B-2205240, TXA2 synthase inhibitors, for example, have been shown to have cholesterol-lowering and triglyceride activity in Normotensive Milan rats and adults and to reduce triglycerides in rats treated with doxorubicin.

It has also been shown that rabbits fed with cholesterol, in an animal experiment of atherosclerosis-inducing diet, the metabolism of arachidonic acid is an important factor in the development of early lesions. In particular the variation in the metabolism1 of TxA2 to PGE2 may suppress the development of the lesion, i.e. the atheromatous plaque, in hypercholesterolemia.

The compounds of this invention may therefore be used in these conditions.

The compounds of the present invention may further be used in combination with thrombolytic agents, for example with TPA, Streptokinase, pro-Urokinase, in order to reduce the dose of subsequent required therapy with thrombolytic agents and to decrease the incidence of reocclusion and possible hemorrhage.

Another application of the compounds of this invention is in the prevention and treatment of restenosis following percutaneous trans luminal angioplasty. The toxicity of the compounds of this invention is negligible, so they can be safely used therapeutically. Deprived mice and rats were treated for 9 hours orally with single administrations of increased doses of compounds of this invention, and then were conditioned and fed normally. In view of their high therapeutic index the compounds of this invention can be safely used in medicine. The therapeutic regimen of the different clinical syndromes should be adapted to the type of disorder taking into account, as usually, also the route of administration, the form under which the compound is administered the age and mass and conditions of the related patient. The oral route is generally used in all situations requiring these compounds. Preferably they are injected intravenously or infused when treating acute pathological conditions.

For maintenance regimens, the oral or pa-rheteric route is preferred, for example by the intramuscular route. The appropriate dose value for oral administration in human adults of the compounds of this invention, for example 5,6-dihydro-8-methyl-7- (3-pyridymethyl) -2-naphthalenecarboxylic acid, may be varied between about 50 mg and 500 mg approximately for each dose applied between one and three times daily.

Of course, these dosages may be adjusted to provide an optimal therapeutic response. The nature of the pharmaceutical compositions containing the compounds of this invention in combination with acceptable pharmaceutical carriers or diluents will, of course, be dependent on the intended route of administration.

The compositions may be formulated in a conventional manner with usual components. For example, the compounds of this invention may be administered in the form of aqueous or oily solutions, or aqueous or oily suspensions,

capsules, syrups, drops, or suppositories.

Thus, for oral administration, the pharmaceutical compositions containing compounds of this invention are preferably among tablets, pills or gelatin capsules which contain the active substance together with solvents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose ; luting agents such as for example silica, talc, stearic acid, calcium or magnesium stearate and / or polyethylene glycols; or may further contain binders such as starches, gelatin, methylcellulose, carboxymethylcellulose, gum arabic, gum tragacanth, polyvinylpyrrolidone; disintegrating agents such as starches, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; dyes; flavoring agents; wetting agents such as lecithin, polysorbate, and lauryl sulfates; and, in general, non-toxic pharmacologically inactive substances used in the pharmaceutical compositions. The above-mentioned pharmaceutical preparations may be prepared in a conventional manner, for example by means of a sugar coated pressure granulation mixture and film coating processes. Liquid dispersions for oral administration may be for example syrups, emulsions or suspensions.

The syrups may contain as carrier, for example, sucrose or sucrose with glycerine and / or mannitol and / or sorbitol. The suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, etc. carboxylmethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain together with the active component a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol.e, if appropriate amount of hydrochloride of lidocaine.

Solutions for intravenous or infusion application may contain as carrier, for example, sterile water or may preferably be in the form of sterile isotonic aqueous sodium chloride solutions.

The suppositories may contain together with the active component a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, an ester of a polyoxyethylene sorbitan fatty acid as surfactant or lecithin.

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

Example 1 To a suspension of 0.14 g of anhydrous magnesium and a small crystal of iodine in 3 ml of anhydrous diethyl ether is added dropwise a solution of 0.77 g of methyl iodide in 6 ml of anhydrous diethyl ether . The mixture was refluxed for one hour and then cooled to room temperature. To this mixture was added dropwise a solution of 0.46 g

of tert-butyl δ-δχο-7- (3-pyridylmethyl) -5,6,7,8-tetrahydro-2-naphthalenecarboxylate in 25 ml of anhydrous tetrahydrofuran. This reaction mixture was poured after 2 hours of stirring at room temperature into water, neutralized with dilute hydrochloric acid and extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was taken up in trifluoroacetic acid and refluxed for 45 minutes. The resulting solution was evaporated under reduced pressure and the residue was taken up in water. The aqueous solution was basified with dilute sodium hydroxide and then filtered and acidified with acetic acid.

A solid precipitated which was filtered, washed with water and dried to give 0.25 g of 5,6-dihydro-8-methyl-7- (3-pyridylmethyl) -2-phthalenecarboxylic acid.

203-205 ° C R.M.N. (DMSO-d 6) ppm: 2.15 (5H, m, CH 3, Ph-CH 2 -CH 2); 2.70 (2H, m, CH 2 -Ph); 3.65 (2H, s, CH 2 -Ph); 7.2-7.85 (5H, m, phenyl, N-CH-CH-CH); 8.45 (2H, m, CH-N-CH).

By analogous procedure, 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-pyridymethyl) -5,6,7,8-tetrahydro-2-naphthalenecarboxylate, used above, was prepared as follows: A mixture of 2.75 g of tert-butyl 8-oxo-7- (3-pyridimethylene) -5,6,7,8-tetrahydro-2-naphthalenecarboxylate, 200 ml of ethanol and 0.4 g of 10% palladium on activated carbon is hydrogenated for 5 hours at room temperature in a Parr Burgess apparatus with an initial pressure of 50 psi. The catalyst is removed by filtration and the solution is evaporated to give a residue of 2.65 g of 8-oxo-7- (3-pyridylmethyl) -5,6,7,8-tetrahydro-2 tert-butyl naphthalenecarboxylate. The tert-butyl 8-oxo-7- (3-pyridylmethylene) -5-, 6,7,8-tetrahydro-2-naphthalenecarboxylate, described above, was prepared as follows: a mixture of 6 , 15 g of tert-butyl 8-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate, 2.5 g of pyridine-3-carboxaldehyde, 10 ml of acetic acid and 6 ml of piperidine was heated at 100 ° C for 6 hours. After cooling the volatile material was evaporated and the residue was dissolved in ethyl acetate. The solution was extracted with dilute hydrochloric acid, and the aqueous solution was washed with methylene chloride and then basified with dilute sodium hydroxide solution.

The solid was collected by filtration, washed with water and dried to give 5.5 g of 8-oxo-7- (3-pyridylmethylene) -5,6,7,8-tetrahydro-2- naphthalenecarboxylate.

Example 2 To a solution of hydrogen chloride in 50 ml of ethanol-

In absolute ethanol, 0.5 g of 5,6-dihydro-8-methyl-7- (3-pyridymethyl) -2-naphthalenecarboxylic acid hydrochloride was added.

The reaction mixture was heated at 60 ° C for 3 hours and then evaporated under reduced pressure to dryness. The residue was partitioned between diethyl ether and filtered to give 0.45 g of ethyl 5,6-dihydro-8-methyl-7- (3-pyridylmethyl) -2-naphthalenecarboxylate as hydrochloride .

Example 3 To a suspension of 25 ml of anhydrous benzene with 0.5 g of 5,6-dihydro-8-methyl-7- (3-pyridymethyl) -2-naphthalenecarboxylic acid, there was added, dropwise, , 40 ml of oxalyl chloride under ice-bath cooling.

The reaction mixture was stirred for 2 hours at a temperature between 8 and 10 ° C and then evaporated to dryness under reduced pressure.

The residue was dissolved in 15 ml of anhydrous dimethylformamide and a stream of gaseous ammonia was passed through the solution under stirring and ice cooling for 5 hours.

The reaction mixture was evaporated to dryness under reduced pressure, and normal sodium hydroxide was added to the residue and extracted with ethyl acetate.

The organic layer was dried over sodium sulfate and filtered, then evaporated to dryness, and the residue was taken up in diethyl ether, then filtered to give 0.24 g

of 5,6-dihydro-8-methyl-7- (3-pyridymethyl) -2-naphthalenecarboxamide.

Example 4

Tablets weighing 150 mg each and containing 50 mg of active substance were prepared as follows:

Composition for 10 000 tablets. 5,6-dihydro-8-methyl-7- (3-pyridylmethyl) -2-naphthalenecarboxylic acid 500 g Lactose 71.0 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 half of the corn starch were mixed together, then the mixture was passed through a network of The granules were dried, dried over anhydrous magnesium sulfate, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness, 4 mm, and then the remaining amounts of starch, talc and magnesium were added and mixed thoroughly and tablets were punched with 8 mm diameter punches.

Example 5

A mixture of 1.5 g of 5,6-dihydro-8-methyl-7- (1-pyridylmethyl) -2-naphthalenecarboxylic acid, 0.65 g of 10% palladium on activated carbon, 100 ml of ethanol 95%, 30 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid was hydrogenated for a period of 8 hours at room temperature in a Parr Burgess apparatus at low pressure and at an initial pressure of 50 psi.

After that period the theoretical amount of hydrogen was absorbed.

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

Elemental Analysis:

Found: C 67.90; H, 6.29; Cl 11.13; N, 4.44 Calculated: C 68.03; H 6.34;

Cl 11.16; N 4.41 C.C.F. : Eluent CH 2 Cl 2: CH 3 OH (90:10)

Rf = 0.3.

By analogous procedure, the following compounds can be prepared:

5,6,7,8-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

J

After treatment of a compound prepared according to the method described in Example 5, with a stoichiometric amount of sodium hydrogen carbonate the following compound could be prepared: 5,6,7,8-tetrahydro- 8-methyl-7- (3-pyridylmethyl) -2-naphthalenecarboxylic acid.

Claims (3)

A process for the preparation of compounds of general Formula R in which either the symbol ----- represents a single double bond; m is an integer from 1 to 3; Â € ‡ â € ‡ â € ‡ Râ, ... represents a hydrogen atom or a 1-6â € ² alkanoyl group, â € ‡ â € ‡ â € ‡ â € ‡ Râ, R 2 represents -OR 3 or -N (R 2 R 3) wherein each of R 4 and R 5 is independently hydrogen, alkyl optionally substituted with phenyl , or a phenyl group; and p is zero or an integer from 1 to 4; and R 2 represents a hydrogen atom or a C 1-4 alkyl group; with the proviso that at least one of R 2 and R 2 is not hydrogen when both the symbol ----- represents a single bond and R 2 represents a group of the formula - wherein n has the meanings defined above and represents a group of the formula wherein R1 represents a hydrogen atom or an unsubstituted C1-6 alkyl group; or a pharmaceutically acceptable salt thereof, characterized in that: (a) subjecting a compound of general formula in which R 1, R 2, and m are as defined above; and M represents a hydrogen atom or an acyl group; to a β-elimination reaction to give a compound of formula I wherein ---- is a β-alkenyl; or (b) subjecting a compound of formula in which one of Rg and Ry is -O- hydrogen or a C 1-5 alkyl group and the other is hydrogen; and R 2, R 2 and m are as defined above; to an isomerization reaction to obtain a compound of general formula I in which R1 is a double bond and R3 is C1-6 alkyl; or (c) reducing a compound of formula in which R 1, R 2 and m are as defined above; to give a compound of formula I in which the symbol ----- represents a single bond and optionally converting the resulting compound of formula I into a further compound of general formula I and / or optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof, and / or optionally converting a salt into a free compound, and / or optionally , a mixture of isomers of compounds of general formula I in their individual isomers. I = -36- 2. A process as claimed in claim 1, for the preparation of compounds of general formula I in which the symbol ----- represents a double bond; m represents the integer 1; R 2 represents a C 1-4 alkyl group; R 2 represents a group of the formula -COR 2 in which R 2 represents a group of the formula -QR d or -N (R 4 R 5) wherein each of R 1 and R 2 is independently a hydrogen atom or a C1-4 alkyl group; and R 2 represents a hydrogen atom, or pharmaceutically acceptable salts thereof, characterized in that correspondingly substituted starting compounds are used. 3. A process for the preparation of pharmaceutical compositions suitable for the treatment of diseases related to the enhancement of the synthesis of thromboxane A2 (χ2) characterized in that an effective amount of from about 50 and 500 mg of a compound of formula I, prepared by the process according to claim 1, and having an inhibited action of the synthesis of thromboxane or a salt thereof with a carrier and / or diluent acceptable under point view. Lisbon, December 16, 1991