GB2141705A - Imidazoles - Google Patents

Abstract

Compounds of the general formula <IMAGE> wherein a) each of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C1-C6 alkyl; C1-C6 alkoxy; C2-C4 acylamino; -SR', <IMAGE> -CH2OR', -COR or -CH2-COR, wherein R is -OR' or <IMAGE> and each of R' and R'', being the same or different, is hydrogen or C1-C6 alkyl; or b) one of R1, R2, R3 and R4 is a 5-tetrazolyl group; <IMAGE> wherein each of Ra and Rb, being the same or different, is hydrogen or C1-C6 alkyl or Ra and Rb, taken together with the nitrogen atom to which they are linked, form an unsubstituted morpholine or piperidine ring; -COCH2OR', <IMAGE> in which X is -O-, -S- or -NH- and R, R' and R'' are as defined above, and the others are as defined above under a); <IMAGE> wherein Y completes a bond or is -O- or -CH2- and one of R5 and R6 is hydrogen and the other is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or a phenyl or pyridyl ring, wherein the phenyl or pyridyl ring is unsubstituted or substituted by one to three substituents chosen from hydroxy and C1-C4 alkoxy; and wherein, when 'Z' is as defined above under a'), the symbol @ is a double bond and at least one of R1, R2, R3 and R4 is other than hydrogen; or, when 'Z' is as defined above under b'), the symbol @ is a single or double bond; one of R1, R2, R3 and R4 is <IMAGE> wherein Ra and Rb are as defined above and the others of R1, R2, R3 and R4 are as defined above under a); and the pharmaceutically acceptable salts thereof; are useful as inhibitors of thromboxane A2 synthetase and in the prevention or treatment of dislipidaemias or atherosclerosis.

Description

SPECIFICATION N-imidazolyl derivatives of bicyclic compounds and process for their preparation The present invention relates to new N-imidazolyl derivatives of bicyclic compounds, in particular to N-imidazolyl derivatives of 3,4-dihydro-2H-1 -benzopyran; 2H-1-benzopyran; 1,2,3,4, tetrahydronaphthalene; 1 ,2-dihydronaphthalene; naphthalene; indan and inden, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds having the following general formula (1)

wherein a) each. of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C1-C6 alkyl; C1-C6 alkoxy; a C2-C4 acyl or C2-C4 acylamino group; -SR',

-CH2OR', -COR or -CH2-COR, wherein R is -OR' or

and each of R' and R", being the same or different, is hydrogen or C1-C6 alkyl; or b) one of R1, R2, R3 and R4 is a 5-tetrazolyl group;

wherein each of Ra and Rb, being the same or different is hydrogen or C1-C6 alkyl, or Ra and Rb, taken together with the nitrogen atom to which they are linked, form an unsubstituted morpholine or piperidine ring; -COCH2OR',

or

in which X is -O-, -S- or -NH- and R, R' and R" are as defined above, and the others are as defined above under a); z is aS)

or b')

wherein Y completes a bond or is -O- or -CH2- and one of R5 and R6 is hydrogen and the other is hydrogen, Ci-Cs alkyl, C3-C6 cycloalkyl, or a phenyl or pyridyl ring, wherein the phenyl or pyridyl ring is unsubstituted or substituted by one to three substituents chosen from hydroxy and C1-C4 alkoxy; and wherein, when kzJ is as defined above under a'), the symbol ~ ~ ~ ~ is a double bond and at least one of R1, R2, Ra and R4 is other than hydrogen; or, when 7 is as defined above under b'), the symbol -NH- is a single or double bond, one of R1, R2, R3 and R4 is

wherein Ra and Rb are as defined above and the others of R1, R2, R3 and R4 are as defined above ander a), and the pharmaceutically acceptable salts thereof.

The present invention includes all the possible isomers (e.g. cis and trans isomers and optical isomers) of the compounds of formula (1) and their mixtures, and the metabolites and the metabolic precursors of the compounds of formula (1).

The numbering used to identify the positions in the compounds of formula (1) is the conventional one, as is depicted in the following examples:

Pharmaceutically acceptable salts of the compounds of formula (1) include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases, or with organic bases, e.g. alkylamines, preferably triethylamine.

The alkyl, alkoxy and alkylthio groups may be branched or straight chain groups.

A halogen atom is, for example, fluorine, chlorine or bromine, preferably chlorine or bromine.

A C1-C6 alkyl group is preferably a C1 -C4 alkyl group.

A C1-C6 alkoxy group is preferably a C,-C4 alkoxy group, in particular methoxy, ethoxy or isopropoxy.

The term acyl in C2-C4 acyl and C2-C4 acylamino groups refers to acyl groups deriving from both saturated and unsaturated carboxylic acids, preferably alkanoic acids, e.g. acetyl, propionyl and butyryl.

A C1-C6 cycloalkyl ring is preferably cyclopropyl or cyclohexyl, in particular cyclopropyl.

When one or more of R1, R2, R3 and R4 is halogen, it is preferably chlorine or bromine.

When one or more of R1, R2, R3 and R4 is C1-C6 alkyl, it is preferably methyl, ethyl, isopropyl or tert.butyl.

When one or more of R1, R2, R3 and R4 is C2-C4 acyl, it is preferably acetyl or propionyl.

When one or more of R1, R2, R3 and R4 is C2-C4 acylamino, it is preferably acetylamino or propionylamino.

When Ra and/or Rb and/or R' and/or R" is C1-C6 alkyl, it is preferably C1-C4 alkyl, in particular methyl or ethyl. When one of R,, R2, R3 and R4 is

it is preferably a radical chosen from -COOCH2CH2NH2, -COOCH2CH2NH(C,-C4)alkyl, -COOCH 2-CH2N(C,-C4)di-alkyl, -COOCH2CH2-morpholino, and COOCH2-CH2-piperidino. When one of R1, R2, R3 and R4 is -COCH2OR', it is preferably -COCH2OH or -COCH2O(C1-C4)alkyl, in particular -COCH2OCH3 or -COCH2OC2H5.

When one or more of R1, R2, R3 and R4 is -SR', it is -SH or -S(C1-C4)alkyl, in particular methylthio, ethylthio or isopropylthio.

When one or more of R1, R2, R3 and R4 is

it is preferably -N H2, -NHCH3, -NHC2Hs, -N(CH3)2 or -N(C2Hs)2. When one or more of R1, R2, R3 and R4 is -CH2OR', it is preferably -CH2OH, -CH2OCH3 or -CH2OC2H5.

When one or more of R1, R2, R3 and R4 is -COR, it is preferably carboxy or C,-C4 alkoxycarbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl, or it is amino-carbonyl or di(C,-C4 alkyl)amino-carbonyl, in particular dimethylamino-carbonyl or diethylamino-carbonyl.

When one or more of R,, R2, R3 and R4 is -CH2COR, it is preferably carboxymethyl or C1-C4 alkoxy-carbonylmethyl, in particular methoxy-carbonylmethyl or ethoxycarbonylmethyl or it is aminocarbonylmethyl or di(C1 -C4)alkylaminocarbonylmethyl, in particular dimethylamino-carbonylmethyl or diethylaminocarbonylmethyl.

When one of R1, R2, R3 and R4 is

it is preferably

wherein R' and R", being the same or different are hydrogen, methyl or ethyl and R is hydroxy.

C1-C4 alkoxy, preferably methoxy or ethoxy, or R is amino or C1-C4 alkylamino, in particular, methylamino or ethylamino, or it is di(C1-C4) alkyl amino, in particular dimethylamino or diethylamino.

When one of R1, R2, R3 and R4 is

R' is preferably hydrogen, methyl or ethyl and R is preferably hydroxy, methoxy, ethoxy, amino.

methylamino, ethylamino, dimethylamino or diethylamino.

When R5 or R6 is C1-C6 alkyl, it is preferably C1-C4 alkyl, in particular methyl or ethyl.

When R5 or R6 is C3-C6 cycloalkyl, it is preferably cyclopropyl.

When R5 or R6 is a phenyl or a pyridyl ring, said ring is preferably unsubstituted, or when substituted, it is preferably substituted by one or two substituents chosen from hydroxy and C1 -C3 alkoxy, in particular methoxy.

Preferred compounds of the invention are the compounds of formula (1) wherein a") each of R1, R2, R2 and R4 is independently hydrogen, hydroxy, halogen, hydroxymethyl, C1 -C4 alkyl, C1-C4 alkoxy, or a group -COORC or

wherein each of Rc and Rd is independently hydrogen, or C1-C4 alkyl; or one of R1, R2, R3 and R4 is a substituent chosen from b") C2-C4 alkanoyl, -CH2COORC,

wherein Rc and Rd are as defined above, and the others are as defined above under a"); as as defined above under a'); the symbol ~ ~~~ is a double bond, and at least one of R,, R2, R3 and R4 is other than hydrogen, and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula (1), wherein one of R1, R2, R3 and R4 is

-CH2COORd or -COR9, wherein R9 is -ORC or -NH2 and R & and Rd are as defined above, and the others are hydrogen; as Z/i; as defined above under a'); and the symbol -- - - is a double bond; and the pharmaceutically acceptable salts thereof.

Among the more preferred compounds of the invention, particularly preferred are the compounds of formula (1), wherein one of R1, R2, R3 and R4 is

wherein Rc, Rd and R g are as defined above, and the others are hydrogen; 'Z'is as defined above under a'); the symbol - - - - is a double bond; and the pharmaceutically acceptable salts thereof.

Examples of preferred compounds of the invention are: 2-( 1 -imidazolyl)-7-(2-ethoxy-carbonyl-isopropoxy)-naphthalene; 2-(1 -imidazolyl)-7-carboxy-naphthalene; 2-(1 -imidazolyl)-6-carboxy-naphthalene; 1 ,2-dihydro-3-(1 -imidazolyl)-6-(2-dimethylamino-ethoxycarbonyl)-naphthalene, the pharmaceutically acceptable salts thereof and, when appropriate, the C,-C4 alkyl esters thereof.The compounds of the invention can be prepared by a process comprising: A) converting a compound of formula (II)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined above and M is hydrogen or an acyl group, into a compound of formula (1), wherein R1, R2, R3 and R4 are as defined above, Z is as defined above under b') and the symbol -- - - represents a double bond; or B) reducing a compound of formula (II), as defined above, thus obtaining a compound of formula (I), wherein R1, R2, R3 and R4 are as defined above,Z is as defined above under b') and the symbol - - - - represents a single bond; or C) reducing a compound of formula (III)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined above, thus obtaining a compound of formula (I), wherein R1, R2, R3 and R4 are as defined above, xZo is as defined above under b') and the symbol ---- represents a single bond; or D) reducing a compound of formula (IV)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined above, thus obtaining a compound of formula (I) wherein R1, R2, R3 and R4 are as defined above,'Z' is as defined above under b') and the symbol = represents a single bond; or E) oxidizing a compound of formula (V)

wherein R1, R2, R3 and R4 are as defined above, thus obtaining a compound of formula (I), wherein R1, R2, R3 and R4 are as defined above,'Z > is as defined above under a') and the symbol - - - - is a double bond; and, if desired, converting a compound of formula (I) into another compound of formula (1), and/or, if desired, converting a compound of formula (1) 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 formula (1) 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 to tosyl group.

The processes above listed as A), B), C) and D) and the processes for obtaining the compounds of formula (if), (III) and (IV) have been already described in detail in the co-pending British Patent Application No. 8219412. The oxidation of a compound of formula (V) may be carried out according to known methods, for example, such aromatization may be obtained by one of the following procedures: 1) by heating at a temperature ranging from about 120"C to about 300"C, for several hours, e.g. from about 10 hours to about 40 hours, in the presence of a suitable amount of sulfur varying from the equimolar one to a ten-fold excess; either without any solvent or in the presence of a high-boiling solvent, e.g., naphthalene, quinoline or dimethylformamide; or 2) by heating at a temperature ranging from about 220"C to about 350"C for several hours, in the presence of an excess of powdered selenium; or 3) by heating at a temperature ranging from about 200"C to about 350"C for several hours, in the presence of a metal catalyst, e.g. a metal of the platinum periodic group, preferably palladium or platinum, supported on charcoal, asbestos, barium sulfate or aluminium oxide, and if desired in an appropriate solvent, e.g., benzene, acetone, quinoline, naphthalene or xylene; or 4) by treatment, at a temperature ranging from about 25"C to about 200"C, with equimolar amount, or with an excess, of a suitable quinone, e.g., chloranil or DDQ, i.e., 2,3-dichloro-5,6 dicyano-1 ,4-quinone, in a suitable solvent, e.g., benzene, xylene or chloroform; or 5) by heating at a temperature ranging from about room temperature to about 100"C with an excess of concentrated sulfuric acid.

A compound of formula (I) may be converted, if desired, into another compound of formula (l) These optional conversions may be carried out by methods known per se.

Thus, for example, a compound of formula (I), wherein one or more of R1, R2, R3 and R4 is hydrogen, may be converted into a compound of formula (I) wherein one or more of R1, R2, R3 and R4 is a halogen atom, e.g. chlorine or bromine, by reaction with chlorine or bromine in the presence of a Friedel-Crafts catalyst, preferably AICI3, operating in a suitable solvent, e.g.

CH2CI2 A compound of formula (I), wherein one or more of R1, R2, R3 and R4 is hydrogen, may be converted into a compound of formula (I), where one or more of R1, R2, R3 and R4 is C,-C6 alkyl, by alkylation through a Friedel-Crafts reaction, e.g. by reaction with a) a C1 -C6 alkylhalide, preferably chloride, bromide or iodide, or with b) a C,-C6 aliphatic alcohol in a suitable solvent, e.g. nitrobenzene or CH2CI2, or CS2.The reaction is performed in both the cases a) and b) in the presence of appropriate amount of a Friedel-Crafts catalyst, such as AICI3, ZnCI2, or SF3, or when a C,-C6 aliphatic alcohol is used also in the presence of a strong mineral acid as HF, HClO4 or, if desired, in concentrated H2SO4 or in concentrated H3PO4 without additional solvent, at temperatures ranging from the room temperature to 100"C.

A compound of formula (I), wherein one or more of R1, R2, R3 and R4 is a C,-C6 alkoxy group, may be converted into a compound of formula (I), wherein one or more of R1, R2, R3 and R4 is a hydroxy group, by following conventional procedures well known in organic chemistry, for example by treatment with a strong mineral acid, i.e. HCI, HBr, HI, preferably HBr, at temperature ranging from 30"C to the reflux temperature, preferably at reflux temperaure, or by treatment with a Lewis acid, for example AICI3 or SF3, in a suitable solvent, e.g. CH2CI2 or nitrobenzene, at temperature ranging from the room temperature to 80"C.

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 temperature ranging from the room temperature to about 1 00'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, by reaction with an excess of a suitable C,-C6 alkyl alcohol, or by direct esterification by means of acidic catalysis i.e. in the presence of dry HCI or SOCI2 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 the Bouveault procedure, that is by treatment with NaNO2 and an aqueous strong inorganic acid, e.g. H2SO4, operating at temperatures ranging from the room temperature and 100"C.

A compound of formula (I) containing a free or esterified carboxy group may be converted in a compound of formula (I) containing a

group, wherein R' and R" 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 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 Nhydroxysuccinimide esters, acid halides, preferably chlorides, mixed anhydrides, e.g. ethoxycarbonyl or tert-butylcarbonyl anhydrides, or the reactive intermediates obtained in situ by reaction of the acid with dicyclohexylcarbodiimide or carbonyldiimidazole.

The reactive intermediates obtained following conventional ways, as those usually employed in the synthesis of a 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 - 1 0,C to about 50'C.

A compound of formula (I), wherein one of R1, R2, R3 and R4 is a free or esterified carboxy group, in particular a lower alkoxycarboxyl group, may be converted into a compound of formula (I) wherein one of R1, R2, R3, R4 is a CH2OH group by reduction in conventional ways, preferably with LiAIH4 in a suitable solvent, e.g. ethylether or THF.

A compound of formula (I), wherein one of Rt, R2, R3, R4 is a free or esterified carboxy group, in particular a lower alkoxycarbonyl group, may be converted into a compound of formula (I), wherein one of R,, R2, R3 R4 is, for example, a

group, wherein Rc and R' are as defined above, by reducing first the free or esterified carboxy group to a formyl group, then condensing the obtained aldehyde with the desired phosphoraneacetate or phosphonate-acetate following a Wittig or a Horner-Emmons procedure, or in addition, when the desired Rc is hydrogen, condensing the above aldehyde with diethylmalonate, following a malonic synthesis procedure, heating then the obtained malonate with strong mineral acids to hydrolyse and decarboxilate it.

The above mentioned reduction to aldehyde may be performed: a) starting from an esterified carboxy group by using diisobutylaluminium hydride (DIBAH), or with diaminoaluminium hydrides b) starting from a free carboxy group by using bis-(4-methylpiperazinyl)aluminium hydride in THF, or diisobutylaluminium hydride, or diaminoaluminium hydrides c) starting from a free carboxy group previously converted into the acid chloride in conventional ways e.g. by SOCI2, by reducing the chloride with lithium-tri-t-butoxy-aluminium hydride or by a conventional Rosenmund hydrogenation procedure using poisoned platinum catalyst, or by using tri-butyltin hydride.

The above mentioned Wittig condensation can be carried out e.g. with

wherein Q is phenyl or lower alkyl, Rc is as above defined and R', being as defined above, is preferably, methyl or ethyl, in a suitable solvent, preferably in dimethoxyethane or THF or DMSO at temperatures ranging from room temperature to about 60"C. The analogous Horner Wittig procedure may be carried out, e.g., with

wherein Rc is as above defined and R' is, preferably, methyl or ethyl in the same solvent mentioned above for the Wittig procedure in the presence of a strong base, such as, sodium hydride, butyl lithium, or sodium amide.

The above described malonic synthesis may be performed using as condensing agent an alkali metal alkoxide e.g. potassium tert-butoxide in tert-butanol; the subsequent hydrolysis and decarboxylation may be performed by boiling in a suitable acid, e.g. conc. HCI.

A compound of formula (I), wherein one of R1, R2, R3 and R4 is a free or esterified carboxy group or a carbamoyl group, may be converted into a compound of formula (I) wherein one of R1, R2, R3 and R4 is a 5-tetrazolyl group by transforming, first, the carboxy or carbamoyl group into a CN group, and then reacting the obtained nitrile with NaN3 in DMF or a mixture CH3COOH-tert-BuOH thus getting a 5-tetrazolyl derivative of formula (I). The above mentioned nitrile may be obtained, e.g., a') directly from the free carboxy group, by reaction with chlorosulfonylisocyanate and subsequent decomposition by heating in DMF the corresponding chlorosulfonylamide.

b') directly from the carbamoyl group by dehydration with chlorosulfonylisocyanate or POCI3 or dicyclohexylcarbodiimide (DOC); or c') from free or esterified carboxy group, previously transformed in a formyl group, by one of the reductive methods above mentioned.

The obtained aldehyde is then converted into the corresponding oxime, which, either isolated or not, is transformed into nitrile by dehydrating agents e.g. at DCC.

A compound of formula (I) wherein one or R1, R3, R3 and R4 is an -OH or -SH group may be converted into a compound of formula (I) wherein one of R1, R2, R3 and R4 is for example

wherein Rc, Rd, R' and R" are as above defined, by reaction with compound of formula

wherein A is an halogen atom, preferably chlorine or bromine or a reactive ester group, preferably a tosylate group, in the presence of a suitable base in a suitable solvent e.g. with tert BuOH, or with anhydrous K2CO3 in acetone or with sodium hydride in DMF at temperatures ranging from room temperature to reflux.

The optional salification of 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 may be employed. The compounds of formula (V) may be obtained, for example, according to process A), described both in the above mentioned British co-pending application and in the present one.

When in the compounds having the formulae (I), (if), (III), (IV) and (V) groups are present which need to be protected during the reactions reported above, e.g. amino, hydroxy, further carboxy groups, etc., such groups can be protected in a conventional way before the reaction takes place.

Examples of protecting groups are those usually employed in the synthesis of peptides, for example, to protect amino groups, acetyl benzoyl, tert-butoxy-carbonyl, pmethoxy-benzyloxycarbonyl, o-nitro-phenyl sulphonyl, dichloroacetyl protective groups may be employed.

To protect hydroxy groups acetyl, benzoyl, benzyloxy, tetrahydropyranyl, ssmethoxethoxyme- thyl (MEM) or a tri-alkylsilyl as tert-butyldimethylsilyl groups may be, for instance, employed. To protect the carboxy groups, tert-butyl, benzhydryl and p-methoxy-benzyl groups may be employed.

The protecting groups are then removed, at the end of the reaction, in a known manner, e.g.

by mild acid hydrolysis or by mild catalytic reduction, for example with Pd/C as catalyst at atmospheric pressure.

The amino, carboxy and hydroxy protecting groups are then removed at the end of the reaction, usually in a known manner. For example, when the amino protecting group is the monochloroacetyl group, it may be removed by treatment with potassium carbonate in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid.

The carboxy protecting groups, for example, may be removed by mild acid hydrolysis or by catalytic hydrogenation, e.g. with Pd/C at room pressure.

The hydroxy protecting groups, for instance, may be removed by mild reaction conditions, e.g. acid hydrolysis. The compounds of this invention are selective inhibitors of Thromboxane A2 (TxA2) synthetase and therefore increase the ratio between Prostacyclin (PG 12) and TxA2 levels.

The activity on TxA2 and PGl2 synthetase has been evaluated in vivo. For example, rats were treated with a single oral dose of compound and killed 2 hours later.

TxB2 and 6-keto-PGF1,, concentrations, the stable metabolites of TxA2 and PGl2 respectively, were determined on serum and plasma respectively.

For example, the compound 2-(1 -imidazolyl)-7-carboxynaphthalene reduces significatively serum TxB2 concentration.

In most tissues the main products of arachidonic acid metabolism are PGl2 and TxA2 and their ratio plays a paramount role in vascular haemostasis. PGl2 has antiaggregatory and vasodilatory activity while TxA2 is a proaggregatory (or aggregatory) and vasoconstrictory compound. The enzyme PGl2 synthetase is located mainly in the endothelial cell and produces PIG 12, which avoid adhesion of platelets to the arterial wall with production of thrombi and has a vasodilatory activity.

The enzyme TxA2 synthetase in turn is mainly located in platelets and produces TxA2 which blocks haemorrhage via the formation of platelet aggregates and vasoconstriction.

Balancing the opposite activities, vascular haemostasis is regulated.

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, periferal vasculopaties and coronary artery diseases. In fact inhibition of TxA2 production reduces the probability of thrombi formation and of vasoconstriction with consequent ischemic events and, leaving unaltered (or increasing) PGl2 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, i.e., 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, e.g., in the treatment of 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 TxA2 levels are increased in the synovial fluid of rheumatoid arthritis patients and in the fluid of carrageenin-induced inflammation in rats [Prostaglandins (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 the elimination of such a factor in hypertension [Eu. J. Pharmacol. (1981), 70, 247]. In fact the compounds of the invention can be used as hypotensive agents.

Furthermore it has been shown a role of TxA3 in the phatogenesis 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), 292, 472]. In fact the compounds of the invention are indicated for the treatment of peptic ulcers.

The compounds of the invention can be also antitumoral agents.

It is known, for example, that a selective inhibition of TxA2 synthesis has been demonstrated to reduce the number of lung methastases and to slow down tumor growth [Nature (1982), 295, 188].

In view of the correlation between TxA3 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. postmenopausal osteoporosis [Prostaglandins (1981), 21,401].

Moreover the compounds of the invention are indicated for the treatment of angina pectoris.

In this respect, it is known, for example, that high levels of TxB3 have been found in patients with Prinzmetal's angine [Prostaglandins and Med. (1 979), 2, 243] and in patients with recurrent angina attacks [Sixth Intern. Congress on Thrombosis, Monte Carlo October 1 980 Abs n 140].

Moreover, especially the compounds of this invention wherein one of RI, R2, R3 and R4 is

wherein R, R' and R" are as defined above, are active in lowering serum cholesterol and triglycerides, in increasing the total serum HDL cholesterol and in increasing the ratio between a-lipoprotein and ss-lipoprotein total cholesterol and are therefore useful in the prevention and therapy of atherosclerosis and dislipidaemias.

The dosage level suitable for oral administration to adult humans of the compounds of the invention, e.g., 2-(1-imidazolyl)-7-carboxy-naphthalene may range from about 5 mg to about 500 mg per dose 1 to 3 times a day, preferably from about 20 mg to about 1 50 mg per dose 1 to 3 times a day depending on the disease, age and weight of the patients involved.

The toxicity of the compounds of the invention is negligible, therefore they can be safely used in therapy. Nine hours food deprived mice and rats were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LDso) was assessed on the seventh day after the treatment and resulted to be negligible.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions, rectally, in the form of suppositories, parenterally, e.g. intramuscularly, or by intravenous injection or infusion. In emergency situations the preferred one is intravenous. As stated above, the exact dosage depends on the disease, age, weight, conditions of the patient and administration route.

The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or 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, sugar-coating, 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; in particular a syrup to be administered to diabetic patients can contain as carrier only products which cannot be metabolized to glucose, or metabolized only in very small amount, For example sorbitol.

The suspensions and the emulsion may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension 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 injections or infusions 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. cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The N.M.R. spectrum was measured preferably in solution of dimethyl sulphoxide-d6 or of CDCI3, using a 90 M-hertz Bruker HFX apparatus.

The R, values were determined by thin layer chromatography on ready-to-use silica gel plates of 0.25 mm coating, thickness.

The following examples illustrate but do not limit the invention.

Example 1 A mixture of 1,2-dihydro-3-(1-imidazolyl)-6-ethoxycarbonyl-naphthalene (5 g) and sulfur (30 g) was heated at 1 30 C for 36 hours, with vigorous stirring.

The reaction mixture was taken up with ethyl acetate (200 ml), stirred for 2 hours, and filtered. The filtrate was extracted with 8% HCI (3 X 100 ml). The acidic solution, neutralized with 20% NaOH was extracted with ethyl acetate (3 X 100 ml).

After drying and evaporation of the solvent, the crude product was chromatographed on silica gel, eluant AcOEt + 0.25% NH4OH, giving 2 g of 2-(1-imidazolyl)-7-ethoxycarbonyl-naphthal- ene.

m.p. 113-11 5'C Elemental analysis: Found: C 71.98; H 5.28; N 10.50.

Calculated for C16H14N302 ; C 72.16 ; H 5.30; N 10.52.

N.M.R. (CDCl3) 8 p.p.m.: 1.44 (3H, t, CH3) 4.44 (2H, q, CH2) 7.27 (1 H, br s, 4 position of imidazole) 7.40 (1 H, br s, 5 position of imidazole) 7.59 (1H, dd, 3 position) 7.90 (4H, m, 1, 4, 5 position and 2 position of imidazole) 8.08 (1 H, dd, 6 position) 8.61 (1H, br s, 8 position) By proceeding analogously the following compounds were obtained.

2-(1 -imidazolyl)-7-carboxy-naphthalene; 2-( 1 -imidazolyl)-6-carboxy-naphthalene 2-(1 i m -imidazolyl)-7-(2-ethoxy-carbonyl-isopropoxy-naphthalene, m p. 60-63 'C, Elemental Analysis Found: C 69.06; A 6.25; N 8.86; Calculated for C19H20N203 : C 70.35; H 6.21; N 8.63; T.L.C. on silica gel Eluant: AcOEt + 0.5% conc. NH4OH Rf = 0.57

2-( 1 idazolyl)-7-(2-carboxy-isopropoxy)-naphthalene.

Example 2 A solution of 2-(1-imidazolyl)7-ethoxycarbonyl-naphthalene (1 g) and N/2 methanolic potassium hydroxyde (50 ml) was stirred at room temperature for 8 hours.

The organic solvent was evaporated under vacuum and the residue dissolved in water (100 ml).

After washing with ethyl acetate (2 X 100 ml) the aqueous solution was acidified with acetic acid.

Filtration of the solid precipitated and washing with water gave 780 mg of 2-(1-imidazolyl)-7carboxy-naphthalene.

m.p. 293-295 C (dec.) Elemental analysis: Found: C 70.31; H 4.23; N 11.66 Calculated for Cl4HloN202 C 70.58 ; H 4.23 ; N 11.75.

T.L.C.: eluent CHCl3 : CH3OH : CH3COOH = (90:10: 5) Rf 0.5 N.M.R. (DMDO-d6 fs p.p.m.

7.1 7 (1 H, br s, 4 position of imidazole) 7.92 (1H, br s, 5 position of imidazole) 8.00 (2H, m, 3 and 6 position) 8.08 (1 H, d, 4 or 5 position) 8.18 (1H, d, 4 or 5 position) 8.42 (2H, m, 1 and 8 position) 8.63 (1 H, br s, 2 position of imidazole) M.S. m/e/ 238 (m+) m/e/ 211 (m-CH = CH2 ±) m/e 193 (m-- COOHQ Example 3 A mixture of 1,2-dihydro-3-(1-imidazolyl)-6-carboxynaphthalene (3 g) and thionyl chloride (40 ml) was refluxed, under stirring, for 5 hours.

The thionyl chloride was evaporated under vacuum, the residue taken up with benzene (2 x 50 ml) and evaporated again to dryness.

The crude product was suspended in ether (80 ml) and dimethylethanolamine (3.74 ml) was added dropwise at room temperature.

The reaction mixture was stirred 2 hours, the solvent evaporated under vacuum and the residue dissolved in chloroform (150 ml).

After washing with water (2 X 100 ml), drying (Na2SO4) and evaporation of the solvent, the product was crystallized from ether/petroleum ether 1/1, giving 3.12 g of 1,2-dihydro-3-(1 imidazolyl)-6-(2-dimethylaminoethoxycarbonyl)-naphthalene.

m.p. 97 -78 C.

Elemental analysis: Found : C 69.28 ; H 6.85; N 13.47 Calculated for C18H21N3O2 : C 69.43; H 6.79; N 13.49 N.M.R. (CDCl3) 8 p.p.m.

2.71 (2H,t, CH2-N) 2.7-3-2 (4H, m,-CH2-CH2-) 4.42 (2H, t, CH2OCO)

Example 4 Tablets, each weighing 150 mg and containing 50 mg of the active substance were manufactured as follows: Compositions (for 10,000 tablets) 2-(1 -imidazolyl)-7-carboxy-naphthalene 500 g Lactose 710 9 Corn starch 237.5g Talc powder 37.5g Magnesium stearate 1 5 9 2-(1 -imidazolyl)-7-carboxy-naphthalene, lactose and a half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried, comminuted on a sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium was added, carefully mixed, and processed into tablets using punches of 8 mm diamether.

Claims (11)

1. A compound of general formula (I)

wherein a) each of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C,-C6 alkyl; C,-C6 alkoxy; a C2-C4 acyl or C2-C4 acylamino group; -SR',

-CH2OR', -COR or -CH2COR, wherein R is -OR' or

and each of R' and R", being the same or different, is hydrogen or C,-C6 alkyl; or b) one of R,, R2, R3 and R4 is a 5-tetrazolyl group;

wherein each of Ra and Rb, being the same or different is hydrogen or C,-C6 alkyl, or Ra and Rb, taken together with the nitrogen atom to which they are linked, form an unsubstituted morpholine or piperidine ring; -COCH2OR',

in which X is -0-, -S- or -NH- and R, R' and R" are as defined above, and the others are as defined above under a); Block 10 wherein Y completes a bond or is -O- or -CH2- and one of R5 and R6 is hydrogen and the other is hydrogen, C,-C6 alkyl, C3-C6 cycloalkyl, or a phenyl or pyridyl ring, wherein the phenyl or pyridyl ring is unsubstituted or substituted by one to three substituents chosen from hydroxy and C,-C4 alkoxy; and wherein, when kZJ is as defined above under a'), the symbol - - -- is a double bond and at least one of R1, R2, R3 and R4 is other than hydrogen; or, when kZJ is as defined above under b'), the symbol - - - - is a single or double bond, one of R,, R2, R3 and R4 is

wherein Ra and Rb are as defined above and the others of R1, R2, R3 and R4 are as defined above under a), and the pharmaceutically acceptable salts thereof.

2. A compound of formula (I) according to claim 1 wherein a") each of R" R2, R3 and R4 is independently hydrogen, hydroxy, halogen, hydroxymethyl, C1 -C4 alkyl, C1 -C4 alkoxy, or a group -COORc or

wherein each of R, and Rd is independently hydrogen, or C,-C4 alkyl; or one of R1, R2, R3 and R4 is a substituent chosen from b") C2-C4 alkanoyl, -CH2COORcZ

wherein Rc and Rd are as defined above, and the others are as defined above under a"); 'Zv is as defined above under a') in claim 1; the symbol -~-- is a double bond, and at least one R,, R2, R3 and R4 is other than hydrogen, and the pharmaceutically acceptable salts thereof.

3. A compound of formula (I) according to claim 1 wherein: one of R1, R2, R3 and R4 is

-CH2COORd or ~CORg, wherein Rg is -ORC or -NH2 and Rc and Rd are as defined in claim 2, and the others are hydrogen; #Z#is as defined above under a') in claim 1; and the symbol - - - - is a double bond; and the pharmaceutically acceptable salts thereof.

4. A compound of formula (I) according to claim 1 wherein: one of R1, R2, R3 and R4 is

wherein Rc and Rd are as defined in claim 2 and-Rg is as defined in claim 3, and the others are hydrogen; kZY is as defiuned under a') in claim 1; the symbol - - - - is a double bond; and the pharmaceutically acceptable salts thereof.

5. A compound selected from the group consisting of: 2-(1 -imidazolyl)-7-ethoxycarbonyl-naphthalen 2-(1 -imidazolyl)-7-(2-ethoxy-carbonyl-isopropoxy)-naphthalene; 2-(1 -imidazolyl)-7-carboxy-naphthalene; 2-(1 -imidazolyl)-6-carboxy-naphthalene; 1 , 2-dihydro-3-( 1 -imidazolyl)-6-(2-dimethylamino-ethoxycarbonyl)-naphthalene, the pharmaceutically acceptable salts thereof and, when appropriate, the C,-C4 alkyl esters thereof.

6. A process for the preparation of a compound of formula (I) according to claim 1, the process comprising: A) converting a compound of formula (II)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined in claim 1; and M is hydrogen or an acyl group, into a compound of formula (1), wherein R1, R2, R3 and R4 are as defined in claim 1, < Z/is as defined under b') in claim 1; and the symbol - - - - represents a double bond; or B) reducing a compound of formula (II), as defined above, thus obtaining a compound of formula (I), wherein R,, R2, R3 and R4 are as defined in claim 1, kzJ is as defined under b') in claim 1; and the symbol ---- represents a single bond; or C) reducing a compound of formula (III)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined in claim 1, thus obtaining a compound of formula (I), wherein R1, R2, R3 and R4 are as defined in claim 1, #Z# is as defined under b') in claim 1, and the symbol -~~- represents a single bond; or D) reducing a compound of formula (IV)

wherein R1, R2, R3, R4, R5, R6 and Y are as defined in claim 1, thus obtaining a compound of formula (I) wherein R1, R3, R3 and R4 are as defined in claim 1,'is as defined under b') in claim 1, and the symbol - - - - represents a single bond; or E) oxidizing a compound of formula (V)

wherein R1, R2, R3 and R4 are as defined in claim 1, thus obtaining a compound of formula (I), wherein R1, R2, R3 and R4 are as defined in claim 1,Z2is as defined under a') in claim 1, and the symbol-L=r is a double 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 formula (I) into the single isomers.

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

8. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

9. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, other than one wherein one of R1, R2, R3 and R4 is -O-CR'R"-COR and the three others of R1, R2, R3 and R4 are as defined in claim 1, for use as an inhibitor of thromboxane A2 synthetase.

10. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, R3 and R4 is -O-CR'R"-COR and the three others of R1, R2. R3 and R4 are as defined in claim 1, for use in the prevention or treatment of dislipidaemias or atherosclerosis.

11. A process for the preparation of a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 3.

1 2. A pharmaceutical composition substantially as hereinbefore described in Example 4.