RU2040525C1 - 1,3-dioxane derivatives of alkenoic acid or their pharmaceutically acceptable salt - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 1,3-dioxane derivatives of alkenoic acid of the formula (I) where A¹-C₁-C₆-alkylene; R¹-C₁-C₆-alkyl, trifluoromethyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl or a group: R³-A² at R³ pyridyl, phenyl, non- or mono- or disubstituted with hydrogen, trifluoromethyl, nitro or cyano-group, and A² 0 C₁-C₆-alkylene, hydroxy-C₁-C₆-alkylene, C₂-C₆-alkenylene or direct bond with R³; R² - hydroxy-group, or physiologically acceptable alcohol moiety; X hydrogen, hydroxide or C₁-C₄-alkoxy-group; Y vinylene, n=1 or 2, or their pharmaceutically salt. For substances of the formula (I) the value pA₂ showing antagonism TXA₂ capability is 5.4-7.95 rel. units. Synthetase inhibition is carried out by using microsomatic method, and results are 0.05-0.31 μm. Synthesized compounds were used in medicine. The formula (I) is given in the description of invention. EFFECT: increased effectiveness of synthesized compounds.

Description

 The invention relates to new pyridine-containing heterocyclic compounds, in particular to a new 1,3-dioxan-5-yl derivative of alkenoic acids containing a pyridyl residue attached to the 4-position of the 1,3-dioxane ring. The acids of the invention have valuable pharmaceutical properties.

It is known that thromboxane A ₂ metabolite of arachidonic acid (hereinafter referred to as TXA ₂ ) has a pronounced vasoconstrictor effect and is a potent platelet aggregator. In addition, TXA ₂ has a strong constrictive effect on the smooth muscles of the bronchi and trachea. Thus, TCA ₂ can be used to treat various diseases, for example, coronary heart disease, such as myocardial infarction, tonsillitis, diseases related to cerebrovascular accident, for example, temporary cerebral ischemia, migraine attacks, peripheral circulatory disorders blood vessels, such as atherosclerosis, microangiopathy, hypertension, and thrombosis caused by impaired lipid metabolism.

It is believed that TXA ₂ exerts its physiological effect through a thromboxane receptor, under the influence of which the receptors of other prostanoid substances formed from arachidonic acid, such as prostaglandins H ₂ , prostaglandin F _{2 α} and prostaglandin D ₂ , which have contractility, can exhibit contracture . There are two main ways in which you can increase the activity of TXA ₂ . The first method is to administer a drug that predominantly acts on the thromboxane receptor, although it does not create the constrictor effect that appears after binding to TXA ₂ (or prostaglandins H ₂ , F _{2 α} and / or D ₂ ). This tool has the properties of a TXA ₂ antagonist. The second way is to administer a drug that inhibits one or more of the enzymes involved in the formation of TXA ₂ , in particular, which inhibits the enzyme known as thromboxane synthase (TXA ₂ synthase). Such a substance is an inhibitor _of TXA ₂ synthase. This suggests that agents possessing the properties of a TXA ₂ antagonist and inhibiting TXA ₂ synthase may be of therapeutic value in the treatment of one or more of the above and other diseases in which TCA ₂ is involved in the pathological process. In addition, agents that possess the properties of a TXA ₂ antagonist can be used in the treatment of such diseases in which prostaglandins H ₂ , P _{2 α} and / or D ₂ are involved, mainly, for example, in the treatment of asthmatic diseases and inflammatory processes. Although it is known to use 1,3-dioxane compounds as antagonists of TXA ₂ (see, for example, Europatent, N 94239B1) [1] which are to some extent inhibitors _of TXA ₂ synthase (see, for example, application for Europatent, N 98690A2) [ 2] nowhere is disclosed the preparation of compounds which, to the required degree, would exhibit both of these properties simultaneously.

However, in the course of research it was established (and this conclusion is the basis of the present invention) that the 1,3-dioxan-5-yl derivatives of alkenoic acids of the formula (1), shown together with other chemical structures at the end of the description, contain a pyridyl residue attached to the position four 1,3-dioxane rings, are good inhibitors _of TXA ₂ synthase, and to all exhibit a pronounced effect as an antagonist of TXA ₂ .

The invention provides a 1,3-dioxane derivative of alkenoic acids of the formula (1) shown together with other chemical formulas in the description below in Roman numerals, where A ¹ is C ₁ -C ₆ alkylene; R ¹ means C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₄ alkoxy-C ₁ -C ₄ -alkyl, or a group of the formula R ³ , A ² , where R ³ means pyridyl, phenyl or phenyl having 1 or 2 substituents selected from the group of hologen, trifluoromethyl, nitro and cyano groups, and A ² is C ₁ -C ₆ alkylene, hydroxy-C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or a direct link to R ³ ; R ² is an oxy group, a physiologically acceptable alcohol residue or a C ₁ -C ₄ alkanesulfonamido, X is hydrogen, an oxy group or a C ₁ -C ₄ alkoxy, Y is vinylene, and n is 1 or 2 or a pharmaceutically acceptable salt thereof.

It should be borne in mind that the compounds of formula (1) contain asymmetric carbon atoms and can exist or can be isolated in racemic or optically active forms. The proposed compounds are presented both in the form of racemates and in any optically active form (or its mixtures), which is capable of counteracting one or more of the effects of TXA ₂ or inhibiting the synthesis of TXA ₂ . Known methods for producing individual optical isomers (for example, in the synthesis of optically active starting materials or chromatographic separation of racemates) and methods for determining the activity of a compound as an antagonist of TXA ₂ and the inhibitory effect on TXA ₂ synthase using one or more standard tests, which are given below in description.

 It should be borne in mind that the groups at positions 2,4 and 5 of the 1,3-dioxane residue of formula (1) have the relative cis stereoisomerism that the groups adjacent to the vinyl group V have (i.e., the latter compounds exist in the form Z isomer). Although the specific configuration is shown in the attached chemical formulas (FIGS. 1 and 2), it does not necessarily correspond to the absolute configuration.

 It should also be borne in mind that the generic term “alkylene” means alkylene groups with both branched and unbranched chains, for example, ethylene and ethylidene, the same can be said of other generalizing terms. However, if a qualifying term is used, for example, “butyl”, this is understood to mean a straight chain group or a normal butyl group, the names of branched chain isomers, for example tert-butyl, are specifically indicated when necessary.

Particular values for R ¹ when it means C ₁ -C ₆ -alkyl include, for example, methyl, ethyl, isopropyl and tert-butyl, the latter two of which are preferred when R ¹ is C ₃ -C ₆ -cycloalkyl, as suitable groups are used, for example, cyclopentyl or cyclohexyl when R ¹ is C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl; suitable groups include, for example, 1,1-dimethyl-2-methoxyethyl and 1-methyl-1 propoxyethyl.

Particular values for R ² when it represents a physiologically acceptable alcohol residue are groups that lead to biological decomposition of esters selected, for example, from C ₁ -C ₆ alkyl, possibly containing hydroxy or C ₁ -C ₄ substituting groups such as methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl or 3-hydroxypropyl, phenyl and benzyl, the two of which may not necessarily contain 1 or 2 possible substituents selected from the hologen group (e.g. fluorine, chlorine , bromine or iodine), C ₁ -C ₄ alkyl (e.g. methyl or ethyl) and C ₁ -C ₄ alkoxy (e.g. methoxy and ethoxy).

When A ¹ is C ₁ -C ₆ alkylene, suitable groups include, for example, methylene, ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene and 1,1-dimethyltrimethylene.

When A ² is C ₁ -C ₆ alkylene, suitable groups include, for example, C ₁ -C ₄ alkylene (e.g. methylene, ethylene, trimethylene, isopropylene and 1,1-dimethylethylene) and 3,3-pentylidine, when A ² means C ₂ -C ₆ alkenylene to suitable groups include, for example, vinylene, 1,3-propenylene and 1,4-buten-2-ylene, when A ² means hydroxy-C ₁ -C ₆ alkylene to suitable groups for example, hydroxymethylene, oxytetramethylene (i.e., a group of the formula -O˙ (CH ₂ ) ₄ -), 1-hydroxy-1-methylethyl (i.e. a group of the formula -O -C (CH ₃ ) ₂ -) and 2-hydroxy-1,1-dimethylethyl (i.e. a group of formula -O˙S (CH _{3) 2} -, should et in mind that the oxy link refers to the group R ^3, instead of the 1,3-dioxane ring.

When R ³ is pyridyl, for example, 3-pyridyl is a suitable group.

A suitable optional halogen substitution group when R ³ is halo phenyl includes, for example, fluorine, chlorine or bromine.

A suitable group X, when X is C ₁ -C ₄ alkoxy, includes, for example, methoxy and ethoxy. Preferably, when X is, for example, hydrogen.

By way of example, a usually preferred value for -1, Y is cis-vinylene, and A ^{1 is} ethylene or trimethylene.

In the group of compounds of the invention that are of particular interest are compounds of formula (II), wherein A ³ is C ₁ -C ₄ alkylene. R ⁴ means trifluoromethyl, branched C ₃ -C ₆ alkyl or a group of the formula R ⁵ .A ⁴ where R ⁵ means pyridyl, phenyl or phenyl containing 1 or 2 substituents selected from the group of halogen, trifluoromethyl, nitro and cyano, and where A ⁴ means C ₁ -C ₄ alkylene, hydroxy C ₁ -C ₄ alkylene or a direct bond to R ⁵ ; Y is vinylene, O is a 3-pyridyl or 4-pyridyl residue, and X, R ² and n have any of the above meanings, and pharmaceutically acceptable salts thereof, where R ² is an oxy group or C ₁ -C ₂ alkanesulfonamido.

In the above group of compounds, it is preferred that Y is cis-vinylene, R ^{2 is} hydroxy, n-1, and X is hydrogen.

Another group of compounds of interest include compounds of formula (III), wherein A ³ is C ₁ -C ₄ alkylene, R ⁵ is pyridyl, phenyl or phenyl containing 1 or 2 substituents selected from the gologen group, trifluoromethyl, nitro, and cyano, and A ⁴ is C ₁ -C ₄ alkylene, hydroxy-C ₁ -C ₄ alkylene, or a direct mixture with R ⁵ , together with their pharmaceutically acceptable salts.

Suitable groups for A ³ include, for example, the groups having the meanings given above for A ¹ when A ¹ is C ₁ -C ₄ alkylene, for example ethylene, trimethylene and 1,1-dimethylene, of which ethylene is usually preferred.

Suitable values for A ⁴ include, for example, the above values for A ² when A ² means a direct bond, C ₁ -C ₄ alkylene or hydroxy-C ₁ -C ₄ alkylene, for example, with a direct bond, isopropylidene, 1,1-dimethylethylene and 1-hydroxy-1-methyl (i.e., a group of the formula —O˙C (CH ₃ ) ₂ -, and suitable groups for R ⁵ include, for example, 3-pyridyl, phenyl, 4- halo phenyl (e.g. 4-chloro or 4-bromophenyl), 2-halo phenyl (e.g. 2-fluoro or 2-chlorophenyl), dihalo phenyl (e.g. 3,4-difluoro, 3,4-dichloro or 2 , 4-dichlorophenyl), nitrophenyl (e.g. 2-nitro, 3-nitro or 4-nitrophenyl), 2-cyanoph enyl, 4-cyanophenyl, 2-trifluoromethylphenyl and 4-trifluoromethylphenyl.

As an example of suitable values for R ¹ , trifluoromethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, 2-chlorophenyl groups are represented. 3-chlorophenyl, 2-cyanophenyl, 4-cyanophenyl, 4-nitrophenyl, 2-chloro-5-nitrophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-phenoxy-1- methylethyl (the phenoxy group may optionally contain substituents selected from the groups 2-fluoro, 2-nitro, 2-trifluoromethyl, 3-fluoro, 3-bromo, 3-nitro, 4-fluoro, 4-bromo, 4-cyano, 4-nitro , 2,4-dichloro, 3,4-difluoro or 3,4-dichloro), 3-pyridyl, 4-pyridyl, 1-methyl-1- (3-pyridyloxy) ethyl, 1-propoxy-1-methylethyl and 1 , 1-dimethyl-2-phenylethyl (the phenyl moiety may optionally contain substituents selected from the groups 3-bromo, 3-nitro, 4-fluoro , 4-nitro, 4-trifluoromethyl, 3,4-difluoro or 3,4-dichloro), styryl or 2-nitrostyryl.

In the above compounds of the invention, a particularly preferred value for R ² when R ² , for example, is an oxy group, and for 3, when X, for example, means hydrogen.

 Specific new compounds of the present invention are disclosed in the examples, while, as an additional feature of the invention, they are presented together with their pharmaceutically acceptable salts. Particularly preferred compounds include those described in Examples 4.8, 11 and 28.

Although any of the compounds of formula (1) can form salts with the corresponding acids, it should be borne in mind that the compounds of formula (1) are amphoteric when R ² is an oxy group or alkanesulfonamido and can form salts with both acids and bases. Typical pharmaceutically acceptable salts of such compounds include, for example, alkali and alkaline earth metal salts, ammonium salts, salts with organic amines and quaternary bases forming physiologically acceptable cations, for example, salts with methylamino, dimethylamine, triethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, N-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide, as well as salts with acids that form physiologists anions, such as salts with mineral acids, for example halides (hydrogen chloride and bromide), sulfuric and phosphoric acids, and with strong organic acids, for example, para-toluenesulfonic and methanesulfonic acids, are acceptable.

Compounds of formula (1) can be obtained by traditional methods known in organic chemistry for the synthesis of synthetic analogues with the structure of natural compounds. Such methods are presented as an additional feature of the invention and are illustrated by the following methods for preparing the compounds of the invention, wherein R ¹ , R ² , X, Y, A ¹ and n are any of the above values.

(a) To obtain compounds of formula (1), where R ² is an oxy group, an aldehyde of formula (IV) is reacted with a Wittig reagent of formula R ³ P CH˙A ¹ ˙CO ₂ ⁼ M ⁺ , where R is C ₁ -C ₆ - alkyl or aryl (phenyl is particularly preferred), and M ⁺ means the corresponding metal cation, for example an alkali metal cation (lithium, sodium or potassium cation).

 In the proposed method, the desired compounds of formula (1) are obtained, where the substituents adjacent to the vinyl group Y preferably have predominantly relative cis stereoisomerism, i.e. in the form of a "Z" isomer. However, the proposed method also forms a small amount of similar compounds having relative trans-stereoisomerism (ie, in the form of the “E” isomer), which can be isolated using traditional methods, for example, chromatography or crystallization.

The proposed method for convenience can be carried out in an appropriate solvent or diluent, for example an aromatic solvent such as benzene, toluene or chlorobenzene, ether, for example 1,2-dimethoxyethane, tert-butyl methyl ether, dibutyl ether or tetrahydrofuran, in dimethyl sulfoxide or tetramethylene sulfone or in a mixture consisting of one or more of such solvents or diluents. The inventive method is usually carried out at a temperature ranging, e.g., from -80 ^to 40 ° C, but is preferably carried out said method at room or near-room temperature, e.g., in the range of 0-35 ° ^C.

 (b) To obtain compounds where X is an oxy group, in a compound of formula V, where R is a protected oxy group, deprotection is carried out by conventional methods.

Examples of particularly suitable protected oxy groups include C ₁ -C ₄ alkoxy (such as methoxy), benzyloxy, allyloxy, tetrahydropyran-2-yloxy, C ₁ -C ₄ alkanesulfonyloxy (especially methanesulfonyloxy) and trialkiosilyloxy containing up to 10 carbon atoms .

The conditions used for deprotection necessarily depend on the nature of the protected hydroxy groups. The removal of specific hydroxyl protective groups is described in detail in ordinary textbooks on organic chemistry and such traditional methods that are known in this field are included in the scope of the proposed method. Thus, specific groups can be removed by the following method:
(1), allyl or tetrahydropyran-2-yl group in the processing of a strong acid, such as trifluoroacetic acid, at a temperature, e.g., 10-40 ^{° C;}
(2) a trialkylsilyl group (e.g., tert-butyldimethylsilyl, which is preferred) when reacted with an aqueous solution of tetrabutylammonium fluoride or for the convenience of sodium fluoride in a suitable solvent or diluent, for example tetrahydrofuran or tert-butyl methyl ether, usually at or near ambient temperature environment, for example, in the range from 10 to 35 ^about C;
(3) alkanesulphonyl group hydrolysis reaction in the presence of base (such as NaOH or KOH) in a suitable aqueous solvent solution (e.g. aqueous solution of a C ₁ -C ₄ -alkanoda) at a temperature of, e.g., 0-60 ^{° C;}
(4) alkyl group or by treatment thioalkoxide difinilfosfidom alkali metal (e.g., sodium thioethoxide in a solvent such as N, N-dimethylformamide) at a temperature, e.g., 50-60 ^{° C,} or lithium diphenylphosphide at a temperature, e.g., ^about 0-60 WITH;
(5) a benzyl group in the case of palladium-catalyzed hydrogenolysis in alkanol, for example ethanol, at or close to ambient temperature or when using an alkali metal, for example, sodium in liquid ammonia.

(c) A derivative of a diol of formula (VI), wherein one of the values of T ¹ and T ² is hydrogen, and the other is a hydrogen or a group of the formula —CRaRb (OH (where Ra and Rb have the same or different C ₁ -C ₂ alvyl groups) interacts with an aldehyde derivative of the formula R ¹ ˙CHO or its acetal, hemiacetal or hydrate).

The aldehyde derivative (or its hydrate, or acetal or hemi-acetal in a C ₁ -C ₄ alkanol, for example methanol or ethanol) can be taken in excess in order to be convenient.

The reaction is usually carried out in the presence of an acid: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic acid or paratoluenesulfonic acid, preferably in the presence of a suitable solvent or diluent, for example dichloromethane, toluene, xylene or an ether, for example tetrahydrofuran dibutyl ether, tert-butyl methyl ether or 1,2-methyl ether -dimethoxyethane at a temperature in the range of, for example, from 0 to 80 ^about C.

The starting compounds of formula (VI), where T ¹ and T ^{2 are} both hydrogen, can be prepared, for example, by acid catalyzed mild hydrolysis or alcoholysis of the dioxane ring of a compound of formula (VII), wherein one of the values of Ra and Rb is hydrogen or C ₁ -C _4- alkyl (for example, methyl or ethyl), and the other C ₁ -C ₂ -alkyl obtained by a similar procedure with respect to the above-described method (a), for example, similarly as described in the application for Europatent N 93439. Hydrolysis or alcoholysis is usually carried out at a temperature in the range of 10-80 ° ^C under ispolz Vania aqueous inorganic acid, such as hydrochloric acid in an alkanol such as ethanol or 2-propanol or an ether (e.g. tetrahydrofuran).

The starting materials of formula (VI), where one of the values of T ¹ and T ² represents hydrogen, and the other group of the formula —CRaRb˙OH are intermediates in the preparation of the above starting compounds of the formula (VI), where T ¹ and T ^{2 are} both hydrogen. However, these intermediates are usually not isolated.

In accordance with the foregoing, the invention also provides an improved method (d) for implementing method (c), which comprises reacting a 1,3-dioxane of formula (VII), wherein one of the values of Ra and Rb is hydrogen, methyl or ethyl, and the other is methyl or ethyl with an excess of an aldehyde of formula R ¹ ˙CHO (or a hydrate, acetal or hemiacetal) in the presence of acid (e.g., one of the above) at a temperature in the range, for example, 10-80 ^{° C,} optionally in the presence of a suitable solvent or diluent (such as as one of the above).

In some cases, it is necessary to modify the methods of method (c) and (d), where the aldehyde of formula R ₁ ˙CHO does not have sufficient reactivity or tends to form an acyclic hemiacetate when reacted with a compound of formula (VI) or (VII), for example when 2,2,2-trifluoroacetaldehyde is used to prepare compounds of formula 1, wherein R ¹ is trifluoromethyl. Thus, the method (e) of the present invention consists in the interaction of the compounds of formula (VI), where T ² means hydrogen, and T ¹ means alkanesulfonyl (especially benzene or toluenesulfonyl) with an aldehyde of the formula R ¹ ˙CHO or its hydrate , acetal or hemi-acetal, for example with 2,2,2-trifluoroacetaldehyde or its hydrate in the presence of a suitable acid, usually under the same conditions as those described above in method (c) followed by base-catalyzed cyclization of the acyclic compound obtained, for example , Using a suitable base (e.g., potassium carbonate or sodium hydride) in a suitable solvent or diluent (such as an ether mentioned above) and at a temperature ranging, e.g., from 20 to 50 ° ^C. This method is illustrated in Example 34, the following, when using a compound of formula (VI), where R ² is methoxy, this group being converted to an oxy group upon hydrolysis after the formation of a dioxane ring.

The necessary starting alkanesulfonyl or arenesulfonyl esters of the formula (VI) described above can preferably be obtained from the corresponding diol of the formula (VI) (T ¹ T ² is hydrogen) by reaction with one molecular equivalent of the corresponding alkanesulfonyl or arenesulfonyl halide (e.g. methanesulfonyl chloride or para-toluenesulfonyl chloride) in a suitable solvent or diluent (e.g. ether or dichloromethane) at or near ambient temperature and in the presence of a base (e.g. triethylamine or pyridine).

(f) Decomposition of an ester of formula (VIII), wherein R ⁶ is C ₁ -C ₆ alkyl (especially methyl, ethyl, propyl or tert-butyl), phenyl or benzyl, which contain 1 or 2 substituents selected from the halogen group , C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

The decomposition reaction can be carried out using one or more conventional reagents and under conditions that are known in the art for the conversion of esters to acids. Thus, decomposition can be carried out, for example, by base-catalyzed hydrolysis, for example, using an alkali metal hydroxide such as potassium, lithium or sodium hydroxide in an aqueous system, preferably in the presence of an appropriate solvent or diluent, for example tetrahydrofuran, methanol, ethanol or tert butylmethyl ether at a temperature ranging, e.g., from 10 to ⁶⁰ ° C, preferably at or near ambient temperature. Alternatively, when R ⁶ is tert-butyl, the decomposition reaction can be carried out by heating by thermal formula (VIII) compound at a temperature in the range, for example, 80-150 ^{° C,} without or in the presence of the diluent, for example, diphenyl ether or diphenyl sulfone.

 The required starting materials for use in the above methods (a) to (f) can be obtained by known methods used to obtain structurally related compounds, for example, using similar methods described in Europatent N 94239В1 and application for Europatent N 98690А2 (2).

Aldehydes of formula (IV) can be prepared, for example, from allyl compounds of formula (XI), as shown in Schemes 1 and 2 (FIGS. 3 and 4) and illustrated in the examples below. It should be borne in mind that when it is necessary to obtain a specific stereoisomer, it may be necessary to control the sequence of selective purification, and any mixture of isomers is separated when using, for example, chromatography. Alternatively, when a particular isomer is desired, it can be prepared from the specific anantiomer of 3- [2- (1-hydroxy-1-pyridylmethyl) pent-4-enyl] oxazolidin-2-one of formula (XI), wherein R ⁷ is C ₁ -C ₄ -alkyl (especially isopropyl), which is obtained by aldol condensation of the corresponding 3- (4-pentenoyl) oxazolidin-2-one with polycarboxaldehyde, as shown below in scheme 3 (Fig. 5). [This method is especially for obtaining pure enantiomers of the compounds of formula 1]
Derivatives of the protected oxy groups of formula (V) can be obtained, for example, by carrying out process (c) or (d) with a corresponding compound similar to the 1,3-dioxane of formula (VII), but where X is preferably a protected oxy group. Such a compound is easily obtained using standard methods similar to those described above and presented in the examples.

 The diols of formula (VI) necessary for the preparation of dioxanes of formula (1) or (VII), where the pyridyl moiety contains X and the alkenic acid in the side chain has relative cis stereoisomerism, can be obtained, for example, by using a similar method described in the application at Europatent, N 142323 [3] using the corresponding pyridine-containing carboxaldehyde and succinic acid anhydride as starting material, and such as is used as a suitable base for aldol condensation in Scheme 3.

 Esters of formula (VIII) can be obtained, for example, by carrying out process (c) using the corresponding diol ester of formula (VI).

 The required Wittig reagents can be obtained by conventional methods, for example, by treating phosphonium halide with a strong base, such as sodium hydride, lithium, diisopropylamide, potassium tert-butoxide or butyl lithium. They are usually prepared in situ prior to performing the above condensation reaction (a).

It should be borne in mind that the compounds of formula (I), where R ² means an oxy group, can also be obtained by other methods known in the art, for example. base catalyzed hydrolysis of the corresponding amides or nitriles. In addition, compounds of formula (1), where R ² has other meanings besides an oxy group, can be prepared by conventional methods of esterification or sulfonamidation from compounds where R ² is an oxy- (or its reactive derivative), and the corresponding alcohol, phenol or C ₁ C ₄ alkanesulfonamide. Such methods are also within the scope of the invention.

 In the future, when it is necessary to obtain a salt of the compound of formula (1), it can be obtained by reacting with a suitable base with an acid that forms a physiologically acceptable ion, or any other conventional method used to prepare the salts.

In addition, when it is desired to obtain an optically active form of a compound of formula (1), one of the above reaction processes can be carried out using an optically active starting material (for example, which is disclosed in Scheme 3 and illustrated in Example 40). Alternatively, the racemic form of the compound of formula (1) can be prepared by reacting with the optically active form of a suitable organic base or acid, for example camphorsulfonic acid, ephedrine, N, N, N-trimethyl (1-phenylethyl) ammonium hydroxide or 1- phenylethylamine, followed by conventional separation of the implementation of the salts obtained in the form of diastereomeric mixtures, for example, fractional crystallization from a suitable solvent, for example C ₁ -C ₄ alkanol, and then an optically active form of a compound of formulas (1) can be isolated by treatment with acid (or base) by the conventional method, for example, using aqueous solutions of inorganic acids, for example, such as dilute hydrochloric acid (or aqueous alkali, such as aqueous NaOH solution).

 It is usually preferable to obtain the enantiomeric form of a compound of formula (1), wherein the groups on the dioxane ring have a 2S, 4S, 5R configuration.

Most of the intermediates disclosed above are novel, for example, compounds of formulas (IV), (V), (VII), (VIII), (IX) and (XI), representing additional, distinctive features of the present invention. It should be noted that in addition, some compounds of formula (VII) (such as compounds where Ra and Rb are both methyl or ethyl) have a pronounced inhibitory activity against TXA ₂ synthase and can essentially be used as drugs as in pure form, and in the form of pharmaceutical compositions, which are also included in the scope of the invention.

As indicated previously, the compound of formula (1) exhibits significant activity as a TXA ₂ antagonist and is also an inhibitor _of TXA ₂ synthase. Confirmation of the antagonistic effect of the compounds of formula (1) can be demonstrated on one or the other of the following standard tests:
(a) a thin layer on a model rat aorta, similarly to that known from work Nature, vyp.223, s.29-35, 1969 g. using as an antagonist of TXA ₂ mimetic agent known as V 46619 (described RLIones, and et al. in "Chemistry, Biochemistry and Pharmacological Activity of Trostanoids, p. 211, ed. IMRoberts and F. Scheinmann, Pergamon Press, 1979);
(b) a platelet aggregation assay performed according to the method described by Born (Nature, issue 194, pp. 927-929, 1962), namely that
(i) the aggregation is carried out on acidified with citric acid human plasma with an abundant number of platelets by adding a mimetic agent V 46619 as an antagonist of TXA ₂ , resulting in a dose-response curve;
(II) obtaining a dose-response curve for aggregation of platelets stimulated with a mimetic agent V 46619 is carried out with the introduction of increasing doses of the test compound (usually in the range from 10 ^-5 to 10 ^-10 M), and
(III) calculating the value of Kv, showing the activity of the test compound as a TXA ₂ antagonist, averaged over several concentrations, from the calculated value at a 50% response when aggregating with the mimetic agent V 46619 in the presence and absence of the test compound, or
(c) a bronchial vasoconstriction test is to determine the degree of inhibition of bronchial vasoconstriction by a test compound induced by Konzett-Kossler in a model of anesthetized guinea pig (according to a method modified by Collier and Iames, Brit.I. Pharmacol, vol. 30, p. 283-307, 1967) with the intravenous administration of the mimetic agent V 46619, a TXA ₂ antagonist, and includes
(I) obtaining a cumulative dose-response curve for bronchoconstriction induced by the mimetic agent V 46619 by intravenous infusion of V 46619 with an increase in its concentration (0.2-4 mg / kg) diluted in a constant volume of physiological saline and representing vasoconstriction bronchi as a maximum from theoretically calculated without air supply to the test animal;
(Ii) obtaining a cumulative dose-response curve for bronchoconstriction induced by the mimetic agent V 46619 at 30 minute intervals for 3 hours after oral administration of the test compound; and
(III) calculating a dose-dose ratio for a test compound (i.e., a concentration ratio of V 46619 required for 50% narrowing of the bronchial vessels in the presence or absence of the test compound), showing the activity of the TCA ₂ antagonism.

Test procedure (b) can be conveniently modified to demonstrate the antagonism of the effects of TXA ₂ in vivo when evaluating the effect of a test compound on platelet aggregation after administration of a test compound to a laboratory animal, such as a rabbit, rat, guinea pig or dog. However, when examining dog platelet aggregation, it is necessary to use adenosine diphosphate, a platelet aggregator at a set maximum allowable concentration (approximately 0.4-1.2x10x10 ^-6 M) together with the mimetic agent V 46619, a TXA ₂ antagonist.

The antagonism of the effects of TXA ₂ on the vascular system can also be demonstrated, for example, in a rat, using the following procedure:
(d) male rats (Alderley Park strain) are anesthetized with sodium pentobarbital and then blood pressure of the carotid artery is measured. Then, a TXA ₂ V 46619 antagonist agent is poured through the jugular vein at a concentration of 5 mg / kg to increase systolic blood pressure in the range of 20-30 mm / Hg (2640-3970 pascal), the process is repeated twice to ensure the adequacy of the response. Then, the test compound is administered either intravenously (through the jugular vein) or orally (through the cannula) directly into the stomach, and five minutes after administration of the test compound, a provocative test is administered using V 46619, and then every 9 minutes until a hypertensive effect is established Agent V 46619.

The inhibitory effect of the test compound on TXA ₂ synthase can be demonstrated using the standard in vitro test procedure [test (s)] described by Howa rth and others (Niochem.Soc.Transactions, issue 10, s, 293-240, 1982) using the preparation of microsomal TXA ₂ synthase with human platelets and to evaluate the conversion of (1 ^-14 C) arachidonic acid to thromboxane B ₂ (TXB ₂ ) of the metabolite TXA ₂ , quantitative thin-layer radiochromatography is performed.

The inhibitory effect of the test compound on TXA ₂ synthase can also be demonstrated using the standard method [test (f)] in which blood samples are taken in laboratory animals (usually rats, but also guinea pigs, rabbits or dogs) after administration of the test compounds are usually orally administered. The blood samples were treated with an anticoagulant, is first incubated at ³⁷ ° C with collagen (about 100 microns), then mixed with indomethacin, a cyclooxygenase inhibitor (at about 10 ^-3 M), centrifuged and determine the level of TXA ₂ metabolite, TXB ₂ by radioimmunoassay standard . The inhibitory activity with respect to TCA ₂ synthase can be assessed by comparative analysis of the amount of TCB ₂ contained in the plasma of animals administered with the test compound and the amount of TCB ₂ present in the plasma of the control group of animals with placebo.

Typically, compounds of formula (1), where R ¹ and R ^{2 are} hydroxy, show the following results in one or more of the above tests: test (a) pA ₂ >5.5; Test (b): K _at <1.5 x 10 ^-6 M; test (c): dose ratio> 5.1 1 hour after administration at a dose of 10 mg / kg; test (d): significant inhibition of hypertension provoked by V 46619 for at least 1 hour after oral administration at a dose of 50 mg / kg or at a lower dosage; Test (e): IR ₅₀ <1.0x10 ^-6 M; test (f): significant inhibition of TXB ₂ 1 hour after a dose of 100 mg / kg or less.

 In the tests, there was no toxic or other side effect of the test compounds of formula (1), which exhibited a pronounced effect in in vivo trials (c), (d) or (f) with repeated doses of the minimum effective dose.

Compounds of formula (1), wherein R ² is other than the hydroxy group, generally exhibits lower activity in the above in vitro tests, but exhibits similar activity when R ² is the oxy compounds of formula (1) in in vivo tests.

As an illustration, the compound described in example 2 has the ability of both a TXA ₂ antagonist and a TXA ₂ synthase inhibitor, confirmed by a K _in value of 6.5 x 10 ^-7 M in the test (b, IC ₅₀ 4.8 x 10 ^-8 M in test (e), and shows an almost complete inhibition of the formed TXB ₂ within 5 hours after oral administration of a dose of 25 mg / kg to rats in test (f) without any observed signs of toxic effects on the test animals.

As indicated earlier, due to the combined action of the compounds of formula (1) as a TXA ₂ antagonist and a TXA ₂ synthase inhibitor, they can be used to treat and prevent diseases or pathological processes in which TXA ₂ (or prostaglandins H ₂ , D ₂ and / or F ₂ ) ₂ in warm-blooded animals. Typically, the compound of formula (1) is administered for this purpose orally, rectally, intravenously, subcutaneously, intramuscularly or by inhalation so that the dose, for example, in the range of 0.01-15 mg / kg body weight, is divided into 4 doses day, varying the dosage during treatment, taking into account the method of administration, the severity of the disease, weight and age of the patient.

 The compounds of formula (1) are usually used in the form of pharmaceutical compositions consisting of a compound of formula (1) or, as indicated above, a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable dilution or carrier. Such a composition is presented as an additional feature of the invention and can be formulated in various dosage forms. For example, the composition may be in the form of tablets, capsules, solutions or suspensions for oral administration, in the form of suppositories for rectal administration, in the form of sterile solutions or suspensions for intravenous and intramuscular injections, in the form of an aerosol or solution or suspension used from a nebulizer for inhalation, in the form of a powder containing a pharmaceutically acceptable diluent, such as lactose for insufflation.

 Pharmaceutical compositions can be prepared by conventional methods using pharmaceutically acceptable diluents or carriers known in the art. Oral tablets and capsules may conveniently be coated with an enteric coating, for example, from cellulose triacetate phthalate, to reduce the contact of the active ingredient of formula (1) with stomach acids.

The pharmaceutical compositions of the invention may also contain one or more known agents that play a huge role in the treatment of diseases or pathological conditions, for example, a known platelet aggregation inhibitor, lipid-lowering agent, antihypertensive agent. a bronchodilator, a beta-adrenergic blocker or a vasodilator may also be included in the pharmaceutical composition of the invention for the treatment of cardiovascular diseases or conditions. Similarly, as an example, in the treatment of pulmonary diseases, an antihistamine, a steroid (e.g. beclomethasone dipropionate), sodium cromoglycate, phosphodiesterase inhibitor, or beta-adrenergic stimulant can also be included in the composition of the invention. In addition, a known TXA ₂ antagonist, for example, as the preferred compound disclosed in the application for Europatent, N publication 201354 (4), or a known TXA ₂ synthase inhibitor, for example, as basoxibene or furegrelate (V 63557) can also be included with the compound of formula (1) or its acceptable salt in the proposed composition for changing the total equilibrium under the action of a TXA ₂ antagonist and a TXA ₂ synthase inhibitor to obtain the desired therapeutic effect in any of the above diseases or pathological conditions.

In addition to the above use of the compounds of formula (1) in human internal medicine, they can also be successfully used in veterinary medicine for the treatment of similar conditions in warm-blooded animals that are of commercial interest, for example, dogs, cats, horses and cattle. In general, for such treatment, the compounds of formula (1) are usually administered in the same dosages or in the same manner as described above when used in humans. The compounds of formula (1) are also of value as a pharmacological tool in the development and standardization of test systems in assessing the effects of TXA ₂ in laboratory animals, for example, cats, dogs, rabbits, monkeys, rats and mice, as part of an ongoing search to develop new and improved medications. The compounds of formula (1) can also be used because of their ability to act as a TXA ₂ antagonist and a TXA ₂ synthase inhibitor to maintain the viability of blood vessels in warm-blooded animals (or in separate parts of them) during artificial (extracorporeal) circulation, for example in transplants of limbs or internal organs. When using a compound of formula (1) or a pharmaceutically acceptable derivative thereof for this purpose, it is usually administered in such a way as to achieve a stable concentration in the blood, for example 0.1-10 mg / L.

The invention is further illustrated by the following non-limiting examples, in which Examples 1-17 describe the preparation of intermediates used and, unless otherwise indicated:
(I) concentration and evaporation are carried out by rotary evaporation in vacuo;
(Ii) operations are carried out at room temperature, i.e. in the range of 18-26 ^about C;
(Iii) flash chromatography was performed on kieselgel Fluka Kieselgel 60 (N catalog 60738), supplied by the company "Fluka Ab. Buchs, Switzerland, CH-9470);
(IV) the outputs, when given, are presented for reference only and are not necessarily the maximum achievable with the careful development of this method;
(V) The NMR spectra are usually determined at a frequency of 90-200 Hz in CDCl ₃ using tetramethylsilane (TMS) as the internal standard and are expressed as chemical shifts (delta value) in parts per million relative to TMS, using conventional abbreviations for main peaks: With singlet; M multiplet; t triplet; br shir. d doublet.

(VI) all target products are isolated in the form of racemates, which have a good microstructure;
(VII) for convenience, racemic end products are designated by the cis or trans nomenclature to reflect the relative configuration of substituents around the dioxane ring, i.e. in such racemates, the substituents at positions 4,5 are indicated as (4,5-cis) instead of the more precise notation (4SR, 5RS), the latter notation being used to indicate the enantiomeric forms described in Example 40.

PRI me R 1. A solution containing 2 - [(4,5-cis) -2,2-dimethyl-4- (3-pyridyl) -1,3-dioxan-5-yl] acetaldehyde (1) , (0.20 g) in dry tetrahydrofuran (THF) (7 ml) is added under argon atmosphere to a stirred and ice-cooled solution of ylide obtained by the reaction of bromide (3-carboxypropyl) triphenylphosphine (0.91 g) with potassium tert-butoxide ( 0.48 g) in dry THF (30 ml). The resulting mixture was stirred for 2 hours and then treated with ice-cold water (50 ml). The solution was concentrated and more water (25 ml) was added, the pH was adjusted to 7 by the addition of several crystals of oxalic acid, followed by extraction of the solution with ethyl acetate (3 × 40 ml). The aqueous phase is acidified to pH 4 with oxalic acid and extracted with ethyl acetate (3x50 ml). These combined extracts were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography using a dichloromethane / methanol mixture (95: 5 v / v) as eluent in 4 (Z) -6- [2,2-dimethyl-4- (3-pyridyl) -1.3 yield dioxan-cis-5-yl] hexenoic acid as an oil (0.19 g); NMR: 1.55 (3H, s), 1.57 (3H, s) 1.5-2.6 (7H, m), 3.85 (1 Ndd, I 12 Hz, 1.5 Hz), 4, 15 (1H, dm I 12 Hz), 5.15-5.50 (3H, m), 7.3-7.4 (1H, m), 7.7-7.8 (1H, m) 8, 1 (1H, broad) and 8.45-8.60 (2H, m).

The required starting materials are prepared according to the following procedure:
(1) Methyl ester of 2- (nicotinoyl) acetic acid (17.9 g) prepared according to the method of E. Weuhert et al. I. Org. Chem. vyp.48, s.5006, 1983) was added under argon to a solution of sodium metal (2.3 g) in methanol (200 ml), followed by stirring the resulting mixture at ²⁵ ° C for 30 min. Then allyl bromide (12.0 g) was added and the mixture was stirred overnight. An additional amount (about 2 g) of allyl bromide was added, followed by stirring for 48 hours, and then evaporated. The resulting oil was partitioned between water and ether, and the aqueous layer was extracted three times with ether. The combined extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was washed with flash chromatography and then elution with a mixture of petroleum ether (b.p. 60-80 ^{° C.)} And ethyl acetate (1: 1, v / v) to give methyl 1-2-nicotinoyl-4-pentenoate (A) as a pale yellow oil (13.8 g); NMR: 2.6-2.9 (2H, m), 8.7 (3H, s), 4.4 (1H, m), 4.9-5.2 (2H, m) /, 5.5 -6.0 (1H, m), 7.2-7.5 (1H, m), 8.1-8.3 (1H, m), 8.7-8.8 (1H, m) and 9 1-9.2 (1H, m).

(II) A solution of A (8,8) in dry THF (40 ml) was added to a suspension of lithium aluminum hydride (1.8 g) in dry THF (80 ml) at an argon atmosphere, at which the temperature would not exceed ^about 10 C. After 2 hours, the mixture was cooled on ice. Ethyl acetate (20 ml) was then added to break up the excess reagent, followed by the introduction of an aqueous saturated solution of ammonium chloride (50 ml). The precipitate was filtered off and washed with ethyl acetate. The aqueous phase is separated and extracted with ethyl acetate (3x50 ml). The combined organic fractions were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography and after elution with ethyl acetate / methanol (95: 5, v / v), 2-allyl-1- (3-pyridyl) 1,3-propanediol (B) (5.3 g) was obtained as an oil (mixture of epimers); NMR: 1.8-2.2 (3H, m), 3.6-4.1 (4H, m), 4.7-5.2 (3H, m), 5.6-5.9 (1H , m), 7.2-7.4 (1H, m), 7.65-7.8 (1H, m) and 8.4-8.6 (2H, m).

(III) A mixture consisting of B (5.2 g) of para-toluenesulfonic acid (5.2 g) and 2,2-dimethoxypropane (50 ml) was stirred overnight at room temperature, the pH was adjusted to 8-10 by administration triethylamine, and then the solution is concentrated under reduced pressure. The residue was purified by flash chromatography and then elution with a mixture of petroleum ether (bp. 40-60 ^C.) and ethyl acetate (60:40, v / v) was obtained 5-allyl-2,2-dimethyl-4- (3 -pyridyl) 1,3-dioxane (C) (mixture of 4,5-cis and trans-isomers) as an oil (4.6 g); NMR: 1.4-1.6 (6H, m), 1.6-2.5 (3H, m), 3.65-4.25 (2H, m), 4.5-5.7 (4H , m), 7.2-7.4 (1H, m), 7.6-7.8 (1H, m), and 8.45-8.65 (2H, m).

(IV) Ozone in oxygen was bubbled through a solution containing C (3.4 g) in ethyl acetate (130 mL) at ^-70 ° C until a blue color appears. Argon is then passed through a solution to discharge excess ozone and a solution of triphenylphosphine (6 g) in ethyl acetate (50 ml) is added. The mixture was warmed overnight to room temperature, followed by stirring overnight. The solution was concentrated and ether (50 ml) was added to precipitate triphenylphosphine oxide. The mixture was then filtered and the filtrate was concentrated. An oil is obtained which is purified by flash chromatography. Elution with a mixture (60:40, v / v) ethyl acetate-petroleum ether (. B.p. 40-60 ° ^C) initially obtained 2 - [(4,5-cis] -2,2-dimethyl-4- ( 3-pyridyl) -1,3-dioxan-5-yl] acetaldehyde (1) as an oil (0.8 g); NMR: 1.5 (3H, m), 1.55 (3H, s). 2 , 0-2.3 (1H, m), 2.3-2.5 (1H, m), 2.8-3.0 (1H, m), 3.8 (1H, dd, I 12 Hz, 1.5 Hz), 4.3 (1H, dm, I 12 Hz), 5.25 (1H, d, I 3 Hz), 7.25-7.35 (1H, m), 8.45-8 60 (2H, m) and 9.61 (1H, s); and then the corresponding 4,5-trans isomer; NMR: 1.47 (3H, s), 1.57 (3H, s), 2, 0-2.6 (3H, m), 3.75-4.05 (2H, m), 4.68 (1H, d, I 10 Hz), 7.25-7.40 (1H, m), 7.70-7.80 (1H, m), 8.50-8.65 (2H, m) and 9.5 (1H, broad, s), in the form of an oil (0.7).

PRI me R 2. The mixture consisting of 4 (Z) -6- [2,2-dimethyl-4 (3-pyridyl) -1,3-dioxane-cis-5-id] hexenoic acid [0.458 g ] 2-chlorobenzaldehyde (0.84 ml) and p-toluenesulfonic acid (0.314 g) was stirred for 60 h at 25 ^C. The solution was basified by the addition of triethylamine and the entire reaction mixture was then purified by flash chromatography, eluting initially with dichloromethane to obtain unreacted aldehyde, and then with a mixture of dichloromethane: methanol (95: 5, v / v) with a yield of 4 (Z) -6 - [(2,4,5-cis) -2- (2-chlorophenyl) -4- (3 -pyridyl) -1,3-dioxan-5-yl] hexenoic acid (0, 16 g) as an oil; NMR: 1.6-2.7 (7H, m), 4.1-4.4 (2H, m), 5.20-5.55 (3H, m), 6.05 (1H, s), 7.2-7.5 (5H, m), 7.65-7.95 (2H, m) to 8.4-8.6 (2H, m).

 PRI me R 3. By a similar procedure described in example 2, but using as starting material 5 (Z) -7- [2,2-dimethyl-4- (3-pyridyl) -1,3-dioxane -cis-5-ul) heptenoic acid (E) and 2-chlorobenzaldehyde, get 5 (Z) 7 - [(2,4,5-cis) -2- (2-chlorophenyl) -4- (3-pyridyl) -1,3-dioxan-5-ul] heptenoic acid in the form of an oil at 47% yield; NMR: 1.5-2.7 (9H, m), 4.1-4.4 (2H, m), 5.2-5.5 (3H, m), 6.05 (1H, s), 7.2-7.5 (5H, m), 7.7-7.9 (2H, m) and 8.45-8.65 (2H, m).

 The starting heptenic acid (E) was obtained by a similar procedure as described in Example 1 to obtain the corresponding hexenoic acid, except that instead of (3-carboxypropyl) triphenylphosphonium bromide, (4-carboxybutyl) triphenylphosphonium bromide was used. Heptenic acid is obtained as an oil at 40% yield, NMR: 1.55 (3H, s), 1.57 (3H, s), 1.5-2.6 (9H, m), 3.85 (1H, dd, I 12 Hz; 1.5 Hz), 4.15 (1H, dm, I 12 Hz); 5.15-5.50 (3H, m), 6.6 (1H, br s), 7.3-7.4 (1H, m), 7.7-7.8 (1H, m) and 8.45-8.60 (2H, m).

 Example 4. By a similar procedure described in example 2, but using 2-phenoxy-2-methylpropanal as starting material instead of 2-chlorobenzaldehyde, 4 (Z) -6 - [(2,4,5 -cis) -2- (1-methyl-1-phenoxyethyl) -4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid as a colorless oil (28% yield) which solidifies upon storage ; NMR: 1.35 (3H, s), 1.40 (3H, s), 1.5-2.6 (7H, m), 3.9-4.3 (2H, m), 4.75 ( 1H, s), 5.1 (1H, d, I 2 Hz), 5.15-5.55 (2H, m), 6.95-7.15 (3H, m), 7.2-7, 4 (3H, m0, 7.60-7.75 (1H, m) and 8.5-8.6 (2H, m).

 The starting aldehyde is prepared according to the procedure described in the application for Europatent N 201351 A2, example 6.

PRI me R 5. 3-Pyridinecarboxaldehyde (0.365 ml) and p-toluenesulfonic acid (1.08 g) are added to a solution containing 4 (Z) -6- [2,2-dimethyl-4- (3-pyridyl -1,3-dioxan-cis-5-yl] hexenoic acid (0.393 g) in acetonitrile (8 ml) under argon atmosphere The reaction mixture was heated under reflux for 4 hours and then cooled. Ethyl acetate (10 ml) was added. ) followed by extraction with a mixture of 1 M NaOH solution (50 ml). The combined extracts are acidified to pH 4 with acetic acid and extracted with ethyl acetate (4x20 ml). -ethnic layer was dried (MgSO ₄₎ and concentrated to give an oil which was purified by flash column chromatography using as eluent a mixture of methanol / dichloromethane (1: 10-1: 5 v / v) to give 4 (Z) -6- [. (2,4,5-cis) -2,4-bis (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid, (0.231 g) as an oil. NMR: 1.6-1, 9 (2H, m), 2.3-2.7 (5H, m), 4.1-4.35 (2H, m), 5.2-5.55 (3H, m), 5.8 ( 1H, s), 7.3-7.4 (2H, m), 7.9-8.0 (1H, m) and 8.5-8.85 (4H, m).

PRI me R s 6-16. Using a similar procedure as described in Example 5, but replacing 3-pyridinecarboxaldehyde with the corresponding aldehyde of formula R ⁴ .CHO, the following acids of formula (III) (A ³ means ethylene) are obtained in the form of an oil in 14-86% yields:
R ^{4 1} H NMR (ppm) 6 (CH ₃ ) ₃ CH = 1.0 (9H, s), 1.5-1.75 (2H, m), 2.2-2.55 (5H, m)
3.85-3.95 (1H, m), 4.1-4.2 (1H, m), 4.35 (1H, s),
5.0-5.5 (3H, m), 7.3-7.4 (1H, m), 7.7-7.75 (1H, m),
8.5-8.6 (2H, m) 7 3-Ru˙О˙С (СН ₃ ) ₂ - 1.4 (3Н, s), 1.43 (3Н, s), 1.5-1, 8 (2H, m), 2.2-2.6
(5H, m), 3.95-4.3 (2H, m), 4.8 (1H, s), 5.1-5.55 (3H, m),
7.2-7.7 (4H, m), 8.3-8.6 (4H, m) 8 4CN-Ph 1.45-2.6 (7H, m), 4.05-4.25 ( 2H, m), 5.15-5.45 (3H, m), 5.9 (1H, s), 7.35-7.45 (1H, m), 7.7-7.9 (5H, m)
8.5-8.6 (2H, m) 9 2CN-Ph 1.5-2.7 (7H, m), 4.1-4.3 (2H, m), 5.15-5.5 ( 3H, m),
6.0 (1H, s), 7.35-7.95 (6H, m), 8.45-8.6 (2H, m). 10 3Br-PhO˙C (CH ₃ ) ₂ - 1.38 (3H, s, 1.42 (3H, s), 1.5-1.8 (2H, m),
2.2-2.6 (5H, m), 3.95-4, (2H, m), 4.75
(1H, s), 5.1-5.55 (3H, m), 6.9-7.75 (6H, m),
8.5-8.6 (2H, m). 11 4Br-PhO˙C (CH ₃ ) ₂ - 1.37 (3H, s), 1.4 (3H, s), 1.5-1.8 (2H, m),
3.95-4.25 (2H, m), 4.75 (1H, s),
5.05-5.5 (3H, m), 6.9-7.7 (6H, m), 8.5-8.6 (2H, m). 12 4F-PhO˙C (CH ₃ ) ₂ - 1.35 (3H, s0, 1.4 (3H, s), 1.55-1.8 (2H, m),
2.2-2.6 (5H, m), 3.95-4.25 (2H, m), 4.75 (1H, s),
5.05-5.5 (3H, m), 6.85-7.05 (4H, m), 7.3-7.7 (2H, m),
8.5-8.6 (2H, m). 13 4F-PhO˙C (CH ₃ ) ₂ - 1.38 (3H, s), 1.42 (3H, s0, 1.55-1.8 (2H, m),
2.2-2.55 (5H, m), 3.95-4.25 (2H, m), 4.8
(1H, s), 5.1-5.5 (3H, m), 6.75-6.85 (3H, m),
7.15-7.75 (3H, m), 8.5-8.6 (2H, m). 14 PhCH ₂ ˙C (CH ₃ ) ₂ - 1.0 (6H, s), 1.55-1.75 (2H, m), 2.25-2.55 (5H, m),
2.75 (2H, s), 3.85-4.2 (2H, m), 4.3 (1H, s),
5.0-5.5 (3H, m), 7.1-7.75 (7H, m), 8.5-8.6 (2H, m). 15 4CN-PhO˙C (CH ₃ ) ₂ - 1.43 (3H, s), 1.46 (3H, s), 1.55-1.8 (2H, m),
2.2-2.55 (5H, m), 3.95- (2H, m), 4.8 (1H, s),
5.1-5.5 (3H, m), 7.1-7.75 (6H, m), 8.5-8.6 (2H, m). 16 2NO ₂ -Ph˙CH = CH- 1.6-1.85 (2H, m), 2.2-2.9 (5H, m), 4.05-4.3 (2H, m),
5.15-5.5 (4H, m), 6.25-6.35 (1H, m), 7.3-8.0
(7H, m), 8.5-8.6 (2H, m).

 (Note: Ru pyridyl and Ph phenyl optionally substituted as indicated).

The starting aldehyde for example 7, 2-methyl-2- (3-pyridyl-hydroxy) propionaldehyde is prepared according to the following procedure:
(1) A solution containing 3-hydroxypyridine (4.75 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPV) (10 ml) was added dropwise over a period of 30 minutes to a stirred, ice-cooled suspension of sodium hydride (50% w / w dispersion in mineral oil, 2.4 g) in DMPV (40 mL), The mixture was heated ^to 50 ° C to give a clear solution which was then cooled to 4 ^o C. Then 2-bromo-2-methylpropionate (4.38 ml) and potassium iodide (100 mg) are added, followed by stirring of the reaction mixture at ambient temperature for 16 hours. Then, the mixture is poured into water (50 ml) and extracted with ether (3x50 ml). The combined extracts were washed successively with water (2x25 ml), brine (25 ml), dried (MgSO ₄ ) and evaporated. After purification using flash chromatography eluting with a simple ether / hexane (1: 1, v / v) mixture, ethyl 2-methyl-2- (3-pyridyloxy) propionic acid (A) is obtained as a clear oil (34%) NMR: 1.27 (3H, t, I 7 Hz), 1.61 (6H, s), 4.25 (2H, q, I 7 Hz), 7.19 (2H, m), 8.27 (2H, m).

(II) 1.5 M solution of diisobutylaluminum hydride in toluene (21 ml) was added dropwise under argon to a stirred solution of A (2.09 g) in toluene (75 mL) at -70 ^C. Stirring was continued for 5 min after completion of the addition. Then, a 10% (v / v) solution of methanol in toluene (15 ml) was added to the reaction mixture. The resulting mixture was poured into water (300 ml), stirred vigorously for 30 minutes and filtered through kieselguhr. The organic phase is separated, and the aqueous phase is saturated with sodium chloride, followed by extraction with ether (2x100 ml). The combined organic salts were washed with saturated brine (3 x 100 ml), dried (MgSO ₄ ) and evaporated. After purification of the obtained residue by liquid chromatography at medium pressure, eluting with a mixture of ethyl acetate / hexane (1: 1, v / v), 2-methyl-2- (3-pyridyloxy) propionaldehyde is obtained as a clear oil (56%); NMR: 1.46 (6H, s), 7.20 (2H, m), 8.31 (2H, m), 9.34 (1H, s).

 The starting aldehyde for Example 10 2- (3-Bromophenoxy) -2-methylpropanal was prepared according to the following procedure.

(I) A solution containing dichloroacetic acid methyl ester (77.18 g, 0.54 mol) in anhydrous ether (50 ml) is added to a stirred solution of methyl magnesium iodide obtained from magnesium chips (32.8 g, 1.35 mol ) and methyl iodide (84.1 ml, 1.35 mol) in anhydrous ether (750 ml) at ⁰ ° C under argon at such a rate at which the temperature of the mixture would not exceed 15 ° ^C. The mixture was stirred at 25 ^o C. for 30 min followed by cooling to 0 ° ^C. water (100 mL) and then acidified to a pH of 4 with concentrated hydrochloric sour oh. The organic layer was separated, and the aqueous layer was washed with ether (3x100 ml). The combined organic layers were dried (MgSO ₄ ) and evaporated. After distillation of the residual oil under reduced pressure, 1,1-dichloro-2-hydroxy-2-methylpropane (A) (57.81 g) is obtained in the form of an oil: mp. 48-50 ^about M at 20 mmHg; NMR: 1.45 (6H, s), 2.15 (1H, br s) and 5.65 (1H, s).

(II) Cetyltrimethylammonium bromide (0.28 g, 0.77 mmol) is added to a solution of m-bromophenol (6.66 g, 38.5 mmol) in a 3.85 M aqueous NaOH solution (10 ml), followed by solution A ( 1.37 g, 9.6 mmol) in ether (20 ml). The resulting mixture was stirred under argon for 18 hours, followed by dilution with ether (50 ml). To isolate unreacted phenol, the mixture was extracted with a 2M aqueous NaOH solution (4 x 30 ml). The combined aqueous extracts were treated with ether (50 ml) and the organic phase was washed first with a 2M aqueous NaOH solution (20 ml) and then with 50 ml water. The combined organic layers were dried (MgSO ₄ ) and evaporated. Purification by flash column chromatography, eluting with ethyl acetate / hexane (1: 1, v / v), gives 2- (3-bromophenoxy) -2-methylpropanal (0.89 g) as an oil: NMR: 1.45 (6H) , s), 6.75-7.20 (4H, m), 9.8 (1H, s).

 Using the same procedure as described in the preparation of 2- (3-bromophenoxy) -2-methylpropionic aldehyde, except that phenol substituted accordingly is taken as the starting material, the following aldehydes are obtained, which are used in Examples 11,12,13 and 15 2- (4-bromophenoxy) -2-methylpropionic aldehyde; NMR: 1.4 (6H, s), 6.7-7.4 (4H, m), 9.8 (1H, s).

2- (4-fluorophenoxy) -2-methylpropionic aldehyde; NMR: 1.4 (6H, s), 6.8-7.0 (4H, m), 9.8 (1H, s);
2- (3-fluorophenoxy) -2-methylpropionic aldehyde; NMR: 1.45 (6H, s), 6.55-7.3 (4H, m), 9.8 (1H, s); and
2- (4-cyanophenoxy) -2-methylpropionic aldehyde; NMR: 1.5 (6H, s), 6.85-7.6 (4H, m), 9.75 (1H, s).

 The starting aldehyde for Example 14 was prepared according to the procedure described by H.K. Diefl, K.C. Brannock, Tetrahedron Letters, chap. 14, p. 1273, 1973.

PRI me R 17. In accordance with the procedure described in example 1, except that as the starting material use 2 - [(4,5-cis) -2,2-dimethyl-4- (4- pyridyl) -1,3-dioxan-5-yl] acetaldehyde, 4 (Z) -6- [2,2-dimethyl-4- (4-pyridyl) -1,3-dioxan-cis-5-yl] is obtained hexenoic acid in the form of an oil that solidifies upon storage, in 7% yield; 167-169 ^about With (after recrystallization from a mixture of ethyl acetate / petroleum ether); NMR: 1.42 (3H, s), 1.49 (3H, s), 1.7-2.5 (7H, m), 3.66 (1H, d, I12 Hz), 4.12 (1H d, I 12 Hz), 5.1-5.42 (3H, m), 7.30 (2H, d) and 8.52 (2H, d).

 The above starting material is obtained as an oil at a 50% yield in accordance with the procedure described in Example 1; NMR: 1.5 (3H, s), 1.55 (3H, s), 2.0-2.3 (1H, m), 2.3-2.5 (1H, m). 2.8-3.0 (1H, m), 3.8 (1H, dd, I 12 Hz, 1.5 Hz), 4.3 (1H, dm, I12 Hz), 5.2 (1H, d , I 3 Hz), 7.25 (2H, d), 8.6 (2H, d) and 9.62 (1H, s) to obtain it, methyl 3- (4-pyridyl) -3-oxo- propionic acid obtained by a similar methodology, which is described by E. Wenkert and others I. Org. Chem, vol. 48, p. 5006, 1983.

The following analogs of the intermediates of example 1 are obtained in the form of oils that are used without further purification:
(I) methyl-2-isonicotinoyl-4-pentenoate, yield 65%
(II) 2-allyl-1- (4-pyridyl-1,3-propanediol), yield 77%
(III) 5-allyl-2,2-dimethyl-4 (4-pyridyl) -1,3-dioxane (mixture of 4,5-cis and trans isomers), 44% yield
PRI me R 18. In accordance with the procedure described in example 5, but as the starting material using 4 (Z) -6- [2,2-dimethyl-4- (4-pyridyl) -1,3- dioxan-cis-5-yl] hexenoic acid and 2-chlorobenzaldehyde give 4 (Z) -6- [2,4,5-cis) -2- (2-chlorophenyl) -4- (4-pyridyl-1, 3-dioxan-5-yl] hexenoic acid as an oil at 21% yield; NMR: 1.6-2.7 (7H, m), 3.59 (1H, d, I10.7 Hz), 4.35 (1H, dd, I 10.7 Hz, 4.8 Hz), 4.6 (1H, d, I 10.7 Hz), 5.18-5.5 (2H, m), 5.98 (1H , s), 7.2-7.8 (6H, m) and 8.63 (2H, br s).

PRI me R s 19-29. In accordance with the methodology. described in Example 5, except that instead of 3-pyridinecarboxaldehyde the corresponding aldehyde of formula R ⁴ ˙CHO is used, the following acids of formula (III) are obtained (A ³ is ethylene).

R ^{4 1} H NMR (ppm) 19 4NO ₂ -Ph 1.5-2.6 (7H, m), 4.1-4.3 (2H, m), 5.15-5.5 (3H , m)
5.95 (1H, s), 7.35-8.6 (8H, m). 20 2.4-Cl ₂ -Ph 1.5-2.5 (7H, m), 4.05-4.25 (2H, m), 5.15-5.45 (3H, m),
6.05 (1H, s), 7.35-7.85 (5H, m), 8.45-8.55 (2H, m). 21 3.4-Cl ₂ -Ph 1.6-2.65 (7H, m), 4.05-4.3 (2H, m), 5.2-5.5 (3H, m),
5.7 (1H, s). 7.3-7.8 (5H, m); 8.5-8.65 (2H, m). 22 2-Cl, 5-NO ₂ -Ph 1.7-2.7 (7H, m), 4.15-4.4 (2H, m), 5.2-5.55 (3H, m),
6.05 (1H, s); 7.3-8.7 (7H, m). 23 3Br-BhCH ₂ C (CH ₃ ) ₂ - 1.0 (6H, s), 1.5-1.75 (2H, m), 2.3-2.8 (7H, m),
3.8-4.2 (2H, m), 4.25 (1H, s), 4.95-5.5 (3H, m),
7.05-7.4 (5H, m), 7.65-7.7 (1H, m), 8.5-8.6
(2H, m). 24 3,4-Cl ₂ -PhO˙C (CH ₃ ) ₂ - 1.38 (3H, s), 1.4 (3H, s), 1.6-1.8 (2H, m),
2.2-2.6 (5H, m), 3.95-4.24 (2H, m), 4.75 (1H, s),
5.1-5.5 (3H, m), 6.9-7.75 (5H, m), 8.5-8.6 (2H, m). 25 4F-PhCH ₂ C (CH ₃ ) ₂ - 1.0 (6H, s), 1.55-1.75 (2H, m), 2.2-2.55 (5H, m),
3.8-4.2 (2H, m), 4.3 (1H, s), 4.95-5.5 (3H, m),
6.9-7.75 (6H, m); 8.5-8.65 (2H, m). 26 4NO ₂ PhO˙C (CH ₃ ) ₂ - 1.45 (6H, s), 1.8-2.5 (7H, m), 3.95-4.1 (2H, m),
4.9 (1H, s), 5.05-5.5 (3H, m), 7.2-7.7 (4H, m),
8.1-8.2 (2H, m), 8.45-8.5 (2H, m). 27 2F-PhO˙C (CH ₃ ) ₂ - 1.38 (3H, s), 1.42 (3H, s), 1.55-1.8 (2H, m),
2.2-2.55 (5H, m) 3.95-4.3 (2H, m), 4.85 (1H, s),
5.1-5.5 (3H, m), 6.95-7.7 (6H, m), 8.45-8.6 (2H, m). 28 3,4-F ₂ -PhO˙C (CH ₃ ) ₂ - 1.35 (3H, s), 1.38 (3H, s), 1.55-1.8 (2H, m),
2.2-2.55 (5H, m), 3.95-4.25 (2H, m), 4.75 (1H, s),
5.1-5.5 (3H, m), 6.7-7.75 (5H, m), 8.5-8.6 (2H, m). 29 4CF ₃ -Ph 1.6-2.65 (7H, m), 4.15-4.35 (2H, m), 5.2-5.5 (3H, m),
5.78 (1H, s), 7.3-7.8 (6H, m), 8.5-8.7 (2H, m).

 In accordance with the method described by R. Subramanian. Chem. and Ind, s, 731, 1978, which is used to produce 2,2-dimethyl-3-phenylpropionic aldehyde, except that appropriately substituted benzyl halide is used as the starting material, the following aldehydes are obtained, which are used in Examples 23 and 25 : 3- (3-bromophenyl) -2,2-dimethylpropionic aldehyde; NMR: 1.05 (6H, s), 2.75 (2H, s), 7.0-7.4 (4H, m), 9.55 (1H, s); 3- (4-fluorophenyl) -2,2-dimethylpropionic aldehyde; NMR: 1.05 (6H, s), 2.75 (2H, s), 6.9-7.1 (4H, m), 9.55 (1H, s).

 In accordance with a similar procedure described for the preparation of 2- (3-bromophenoxy) -2-methylpropionic aldehyde, but correspondingly substituted phenol was used as the starting material, the following aldehydes were obtained, which are used in Examples 24.27 and 28: 3- (3 , 4-dichlorophenoxy) -2-methylpropionic aldehyde; NMR: 1.45 (6H, s), 6.7-7.35 (3H, m), 9.75 (1H, s); 2 (2-fluorophenoxy) -2-methylpropionic aldehyde; NMR: 1.45 (6H, s), 6.9-7.15 (4H, m), 9.8 (1H, s).

 The starting aldehyde for Example 26, 2- (4-nitrophenoxy) -2-methylpropionic aldehyde, was prepared according to a similar procedure described for the preparation of 2-methyl-2- (3-pyridyloxy) propionic aldehyde, except that instead of 3- hydroxypyridine use 4-nitrophenol. NMR: 1.55 (6H, s), 6.9 (2H, d, I 7 Hz), 8.15 (2H, d, I 7 Hz), 9.8 (1H, s).

PRI me R 30. R-para-toluenesulfonic acid (0.33 g) is added to a solution containing 4 (Z) -6- [2,2-dimethyl-4- (3-pyridyl) -1,3- dioxan-cis-5-yl] hexenoic acid (0.482 g) in acetonitrile (15 ml) and the mixture was stirred for 30 minutes. Then diethyl 2-fenoksiatsetaldegid (1.04 g) was added to the reaction mixture, followed by heating it to 90 ^{° C} for 15 hours. The mixture was then cooled and evaporated. Residual oil consisting of a mixture of the desired acid product and ethyl ester are dissolved in methanol (6 ml). A 2M aqueous sodium hydroxide solution (3 ml) was added, and then the resulting mixture was stirred for 1 hour. Ethyl acetate (25 ml) and water (25 ml) were added, and then the mixture was acidified with acetic acid and extracted with ethyl acetate (4 x 25 ml). The combined organic extracts were dried (MgSO ₄ ) and evaporated. After purification of the obtained oil by flash chromatography with elution, first in dichloromethane and then in a mixture of methanol / dichloromethane (7:93, v / v), 4 (Z) -6 - [(2,4,5-cis4) -2 -phenoxymethyl-4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid (0.146 g) as an oil: NMR: 1.65-1.85 (2H, m), 2.2- 2.6 (5H, m), 4.0-4.25 (4H, m), 5.1-5.45 (4H, m), 6.9-7.45 (6H, m), 7, 75-7.8 (1H, m) and 8.5-8.6 (2H, m).

The starting material, diethylacetal of 2-phenoxyacetaldehyde, was prepared by the following procedure:
Sodium hydride (5.83 g, 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMTR (DMPV) (25 ml) at ⁵ ° C, followed by stirring the resulting mixture for 30 min. Deetilatsetal bromoacetaldehyde (10.05 ml) was added to the reaction mixture and then heated to 110 ^{° C} for 5 hours followed by cooling. The mixture was separated with ethyl acetate (100 ml) and water (100 ml), the organic phase was separated and washed successively with a 2M aqueous NaOH solution (2x50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO ₄ ) and evaporated. The resulting oil was purified by flash chromatography and using ethyl acetate / hexane (1:10, v / v) as the eluent, 2-phenoxyacetaldehyde diethyl acetal (9.43 g) was obtained as an oil; NMR: 1.25 (6H, t, I 7.0 Hz), 3.6-3.85 (4H, m), 4.05 (2H, d, I 6.0 Hz), 4.85 (1H , t, I 6.0 Hz) and 6.9-7.35 (5H, m).

PRI me R 31. p-Para-toluenesulfonic acid (0.358 g) is added to a solution containing 4 (Z) -6- [2,2-dimethyl-4- (3-pyridyl -2,3-dioxan-cis -5-yl] hexenoic acid (0.522 g) in acetonitrile (12 ml), followed by stirring for 30 minutes, Add a solution containing 2- (2,4-difluorophenoxy) -2-methylpropionic aldehyde (1.02 g) in acetonitrile and then trimethylorthoformate (0.21 ml), followed by heating the mixture under reflux for 3 hours under argon atmosphere.To complete the esterification, methanol (1 ml) is added and then the solution is refluxed refrigerator for another 2 hours. Then the reaction mixture was gradually cooled and extracted with 1M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (25 ml). The organic layer was separated, dried (MgSO ₄ ) and evaporated. After purification of the resulting oil by flash chromatography eluting with methanol / dichloromethane (1: 100-1: 20, v / v), methyl 4 (Z) -6 - [(2,4,5-cis) -2- (1-methyl-1- (3,4-difluorophenoxy) ethyl-4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid (0.333 g) as an oil; NMR: 1.37 (3H, s), 1.40 (3H, s), 1.5-1.8 (2H, m), 2.2-2.6 (5H, m), 3.65 ( 3H, s), 3.9-4.3 (2H, m), 4.75 (1H, s). 5.05-5.5 (3H, m), 6.7-7.7 (5H, m) and 8.5-8.6 (2H, m).

PRI me R 32. A mixture consisting of 4 (Z) -6- [2,2-dimethyl-4 (3-pyridyl) -1,3-dioxancis-5-yl] hexenoic acid ( 0.500 g), 2-methyl-2-propoxypropionic aldehyde (2.13 g) and para-toluenesulfonic acid monohydrate (0.342 g), stirred for 18 h, 0.2 M sodium hydroxide solution (20 ml) was added to the reaction mixture, followed by washing it with ether (2x10 ml), acidification to pH 5 with acetic acid and extracting it with ether (3x25 ml). The combined ether extracts were washed with water (2x10 ml), saturated sodium chloride solution (10 ml) and then dried over anhydrous magnesium sulfate. The organic extracts were evaporated to give a brown oil, which was purified by medium pressure liquid chromatography (MLPC) using a mixture of ethyl acetate, hexane and acetic acid (80: 20: 1, v / v) as eluent to give a clear oil, which was obtained by powdering ether 4 (Z) -6 - [(2,4,5-cis) -2- (1-methyl-2-propoxyethyl-4- (3-pyridyl-1,3-dioxan-5-yl] hexenoic acid ., 0.25 hydrate (0.053 g) as a solid, mp 116-118 ^C; NMR. 200 MHz, d ₆ DMSO): 0,83 (3H, t, I = 7 Hz), 1.18 (3H, s), 1.20 (3H, s), 1.42 (3H, m0, 1.84 (1H, m), 2.14 (4H, m), 2.35 (1H, m), 3.40 (2H, t, I 6 Hz), 3.94 (2H, m), 4.65 (1H, s); 5.15 (1H, d, I 2 Hz). 5.18 (1H, m), 5.34 (1H, m), 7.38 (1H, m), 7.68 (1H, dm, I 7 Hz), 8.49 (2H, m); elemental analysis:
Found: C, 65.8; H 8.3; N 3.7
C ₂₁ H ₃₁ NO ₅ 0.25H ₂ O;
Calculated: C 66.0; H 8.3; N, 3.7.

 The starting aldehyde is prepared according to the procedure described in the application for Europatent, N 201351 A2, example 7.

PRI me R 33. In accordance with the procedure described in example 5, except that instead of 3-pyridinecarboxyaldehyde use cyclohexanecarboxaldehyde and the reaction is carried out at ambient temperature in the presence of only 1.1 equivalents of p-toluenesulfonic acid monohydrate, get 4 (Z) -6- [2,4,5-cis) -2-cyclohexyl-4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid hydrate as a white solid (47% yield ), mp 121-125 ^about C; NMR: (200 MHz, CDCl ₃ ); 1.22 (5H, m), 1.74 (8H, m), 2.29 (4H, m), 2.44 (1H, m), 3.89 (1H, d, I 11 Hz), 4.12 (1H, d I 11 Hz), 4.51 (1H, d, I 4 Hz), 5.00 (1H, d, I 1.5 Hz), 5.22 (1H, m), 5.38 ( 1H, m), 7.33 (1H, m), 7.72 (1H, d, I 7 Hz), 8.53 (2H, m); elemental analysis:
Found: C, 67.2; H 8.1; N 3.7%
Calculated for C ₂₁ H ₂₉ NO ₄ , 1H ₂ O: C, 66.8; H 8.2: N 3.7.

PRI me R 34. A 1M sodium hydroxide solution (6.28 ml) was added to a stirred solution containing 4 (Z) -6 - [(2,4,5-cis) -4- (3-pyridyl methyl ester) ) -2-trifluoromethyl-1,3-dioxan-5-yl] hexenoic acid (A) (563 ml) in methanol (10 ml). After 2 h, water (40 ml) was added and the resulting mixture was washed with diethyl ether (2x20 ml), acidified to pH 5 with acetic acid, followed by extraction with ethyl acetate (3x30 ml). The combined organic extracts were washed with water (20 ml), saturated sodium chloride solution (2x20 ml) and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, an oil is obtained which is purified by liquid chromatography at medium pressure, and using an ethyl acetate / methanol / acetic acid mixture (95: 5: 1, v / v) as eluent, 4 (Z) -6 - [(2 4,5-cis) -4- (3-pyridyl) -2-trifluoromethyl-1,3-dioxan-5-yl] hexenoic acid monoacetate adduct as an oil (587 mg); NMR: (200 MHz, CDCl ₃ ): 1.71 (1H, m), 1.83 (1H, m), 2.10 (3H, s), 2.30 (4H, m), 2.51 ( 1H, m), 4.05 (1H, dm, I 11 Hz), 4.30 (1H, d, I 11 Hz), 5.12 (1H, q, I 3 Hz), 5.20 (1H, d , I 2 Hz), 5.22 (1H, m), 5.46 (1H, m); 7.42 (1H, m), 7.80 (1H, d, I 7 Hz), 8.59 (2H, broad).

Elemental analysis for C ₁₆ H ₁₈ NO ₄ F ₃ , ICH ₃ COOH
Found: C, 53.3; H 5.6; N 3.4%
Calculated: C 53.5; H 5.4; N 3.5%
The starting material required for A is prepared by the following procedure:
(I) A 1M hydrochloric acid solution (10 ml) is added to a solution containing 4 (Z) -6- [2,2-dimethyl-4- (3-pyridyl) -1,3-dioxan-cis-5-yl] hexenoic acid (1.42 g in tetrahydrofuran (15 ml), followed by stirring for 2 hours. Water is added and the pH is adjusted to 12 with 2M sodium hydroxide solution. The mixture is washed with ethyl acetate (2x25 ml), acidified to pH 5 with acetic acid, and then saturated with solid sodium chloride.The aqueous mixture was then extracted with ethyl acetate (12 x 50 ml) and the combined fractions were dried using MgSO _4. After evaporation of the solvent, 4 (Z) -erythro-8-hydride was obtained roxy-7-hydroxymethyl-8- (3-pyridyl) -4-octenoic acid (B) as a brown oil (1.114 g), used without further purification To determine the characteristics, the sample was purified by flash chromatography eluting with methanol / dichloromethane (1: 5, v / v); NMR (200 MHz, CDCl ₃ ): 1.91 (3H, m), 2.23 (5H, m), 3.59 (2H, m), 5.02 (1H, m), 5.35 (3H, m); 7.30 (1H, m); 7.76 (1H, m), 8.46 (1H, dd, I 4 and 1 Hz). 8, 60 (1H, d, I 2Hz).

(II) para-toluenesulfonic acid monohydrate (1.06 g) is added to a solution containing B (1.114 g) in methanol (25 ml), followed by stirring for 3 hours. Triethylamine (0.83 ml) is added and then the mixture evaporated. After evaporation, a saturated sodium chloride solution (20 ml) was added, followed by extraction with ethyl acetate (4x25 ppm). The combined organic extracts were washed with saturated sodium chloride (10 ml), dried using MgSO ₄ and the solvent was evaporated. The resulting oil was purified by liquid chromatography at medium pressure, and using methanol / dichloromethane (1:12, v / v) as eluent, 4 (Z) -erythro-8-hydroxy-7-hydroxymethyl-8- ( 3-pyridyl) -4-octenoic acid (C) as an oil (1.044 g): NMR: (250 MHz, CDCl ₃ ): 1.82 (2H, m), 2.16 (1H, m), 2.44 ( 4H, m), 4.91 (2H, br.), 3.67 (3H, s), 3.81 (2H, d, I 3 Hz), 5.20 (1G, d. I 2 Hz). 5.30 (2H, m), 7.33 (1H, m), 7.79 (1H, m), 8.51 (1H, m), 8.61 (1H, m).

(III) A solution of methanesulfonyl chloride (0.32 ml) in dichloromethane (2.0 ml) is added over 10 minutes to a stirred solution containing compound C (995 mg) and triethylamine (0.59 ml) in dichloromethane (20 ml). The mixture was stirred for another 1 h and then diluted with ethyl acetate (50 ml). The resulting mixture was washed with water (2x15 ml), saturated sodium chloride solution (15 ml), and dried using (MgSO ₄ ). Evaporation of the solvent gave an oil which was purified by liquid chromatography at medium pressure, and eluting with a methanol / dichloromethane mixture (1:32, v / v), 4 (Z) -erythro-8-hydroxy-7- (methylsulphonyloxy- tyl) -8- (3-pyridyl-4-octenoic acid (D) as a colorless oil (886 mg); NMR: (250 MHz, CDCl ₃ ): 2.24 (8H, m), 3.01 (3H, s ), 3.68 (3H, s), 4.10 (1H, m), 4.31 (1H, m), 5.02 (1H, d, I 2 Hz), 5.38 (2H, m) 7.34 (1H, m), 7.77 (1H, d, I 7 Hz), 8.57 (2H, m).

(IV) Anhydrous potassium carbonate (994 mg) and trifluoroacetaldehyde hydrate (1.13 g) are added to a solution containing compound D (857 mg) in dry tetrahydrofuran (10 ml). The mixture was stirred for 15 minutes at ambient temperature and then at ⁶⁰ ° C for 5 hours. The mixture was then diluted with ethyl acetate (75 mL) and washed with water (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was dried (MgSO ₄ ) and the solvent was evaporated. After purification of the obtained oil by liquid chromatography at medium pressure, eluting with ethyl acetate [hexane (7: 3, v / v), methyl 4 (Z) -6- [2,4-trans, 4,5-cis) - 4- (3-pyridyl-2-trifluoromethyl-1,3-dioxan-5-yl] hexenoic acid as a colorless oil (137 mg). NMR: (250 MHz), CDCl ₃ ): 1.66 (1H , m), 2.02 (1H, m), 2.29 (4H, m), 2.43 (1H, m), 3.66 (3H, s), 3.96 (1H, dd, I = 11 and 2 Hz), 4.36 (1H, dm, I 11 Hz), 5.20 (1H, m), 5.30 (1H, q, I 6 Hz), 5.42 (1H, m), 5, 48 (1H, d, I 2 Hz). 7.35 (1H, m), 7.71 (1H, m), 8.59 (2H, m), and then methyl ester 4 (Z) -6 - [(2,4,5-cis) -4 - (3-pyridyl-2-trifluoromethyl-1,3-dioxan-5-yl] hexenoic acid (A) as a colorless oil (578 mg); NMR: (250 MHz, CDCl ₃ ): 1.60 (1H, m), 1.81 (1H, m), 2.30 (4H, m), 2.55 (1H, m), 3.66 (3H, s), 4.04 (1H, dm, I 11 Hz), 4.29 (1G, d, I 11 Hz), 5.12 (1H, q, I 3 Hz), 5.19 (1H, d, I 2 Hz), 5.22 (1H, m), 5, 45 (1H, m), 7.38 (1H, m), 7.74 (1H, m), 8.58 (2H, m).

PRI me R s 35-39. In accordance with a similar procedure described in Example 5, except that an aldehyde of the formula R ⁴ ˙CHO is used instead of 3-pyridinecarboxaldehyde, the following acids of the formula (III) are obtained (A ³ means ethylene).

R ^{4 1} H NMR (ppm) 35 3NO ₂ -PhO˙C (CH ₃ ) ₂ - 1.45 (3H, s), 1.47 (3H, s), 1.55-1.8 (2H , m)
2.2-2.55 (5H, m), 3.95-4.3
(2H, m), 4.8 (1H, s), 5.1-5.55 (3H, m), 7.3-8.0 (6H, m),
8.5-8.6 (2H, m). 36 2NO ₂ -PhO˙C (CH ₃ ) ₃ - 1.45 (6H, s), 1.5-1.8 (2H, m), 2.15-2.5 (5H, m),
3.9-4.2 (2H, m), 4.85 (1H, s), 5.1% 5.5 (3H, m),
7.1-7.8 (6H, m), 8.4-8.6 (2H, m). 37 2,4-Cl ₂ -PhO˙C (CH ₃ ) ₂ - 1.46 (3H, s), 1.48 (3H, s), 1.55-1.8 (2H, m),
2.15-2.55 (5H, m); 3.95-4.25 (2H, m). 4.95 (1H, s),
5.1-5.55 (3H, m), 7.1-7.65 (5H, m), 8.45-8.65 (2H, m). 38 4NO ₂ -PhCH ₂ C (CH ₃ ) ₂ - 1.0 (3H, s), 1.02 (3H, s), 1.5-1.75 (2H, m),
2.25-2.6 (5H, m), 2.85 (2H, s), 3.8-4.2 (2H, m),
4.3 (1H, s0, 5.0-5.55 (3H, m), 7.25-8.1 (6H, m),
8.5-8.65 (2H, m) 39 3NO ₂ -PhCH ₂ C (CH ₃ ) ₂ - 1.02 (3H, s), 1.04 (3H, s), 1.5-1.75 (2H, m),
2.25-2.6 (5H, m), 2.85 (2H, s), 3.85-4.25 (2H, m),
4.3 (1H, s), 5.0-5.55 (3H, m), 7.35-8.1
(6H, m), 8.5-8.65 (2H, m).

 According to the procedure described for the preparation of 2-methyl-2-3-pyridyloxy / propionic aldehyde, except that appropriately substituted phenol is used as the starting material, the following aldehydes are obtained, which are used in Examples 35-37.

 2- (3-nitrophenoxy) -2-methylpropionic aldehyde; NMR: 1.5 (6H, s), 7.15-7.95 (4H, m), 9.85 (1H, s) 2- (2-nitrophenoxy) -2-methylpropionic aldehyde; NMR: 1.5 (6H, s), 6.9-7.8 (4H, m), 9.85 (1H, s). 2- (2,4-dichlorophenoxy) -2-methylpropionic aldehyde; NMR: 1.45 (6H, s), 6.8-7.4 (3H, m), 9.85 (1H, s).

 Following a similar technique disclosed by R. Subramanian, Chem. ans Ind. p.731, 1978 to obtain 2,2-dimethyl-3-phenyl-propionic aldehyde, except that the correspondingly substituted benzyl halide is used as the starting material, the following aldehydes are obtained, which are used in examples 38 and 39: 3- ( 4-nitrophenyl) -2,2-dimethylpropionic aldehyde; NMR: 1.1 (6H, s), 2.9 (2H, s), 7.3 (2H, d, I 8 Hz), 8.15 (2H, d, I 8 Hz), 9.55 ( 1H, s). 3- (3-nitrophenyl) -2,2-dimethylpropionic aldehyde; NMR: 1.1 (6H, s), 2.9 (2H, s), 7.45-8.15 (4H, m), 9.6 (1H, s).

PRI me R 40. By a similar procedure described in example 5, but as starting material using 4 (Z) -6 - [(4S, 5R) -2,2-dimethyl-4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid and 2- (4-bromophenoxy) -2-methylpropionic aldehyde, 4 (Z) -6 - [(2S, 4S, 5R) -2- [1- ( 4-bromophenoxy) -1-methylethyl] -4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid as an oil with 25 [α] _D -113.3 ethanol C 0.465, and NMR data coincide with those obtained by the racemic compound described in example 11.

The starting 2,2-dimethyl-1,3-dioxane derivative was prepared by the following procedure:
(I) a 1.53 M solution containing butyllithium in hexane (23.9 ml). was added to a solution of 4S - (-) - isopropyl-2-oxazolidinone (4.68 g) in dry THF (75 mL) cooled to ^-78 ° C under argon. The mixture was gradually warmed to -50 ^{° C} and then stirred for 30 min. The mixture was then recooled to ^-78 ° C and added dropwise to a solution of 4-pentenoyl chloride (4.33 g) in dry tetrahydrofuran (10 ml). After finished administration, the mixture was stirred at ^-78 ° C for 30 min followed by warming to -20 ° ^C. Saturated aqueous ammonium chloride solution (20 ml) and the mixture was extracted with ethyl acetate (3.times.100 ml). The combined organic layers were dried (MgSO ₄ ) and evaporated. After purification of the precipitate by flash chromatography, eluting with ethyl acetate / hexane (20: 80, v / v), (4S) -4-isopropyl-3- (4-pentenoyl) oxazolidin-2-one (A) is obtained (6, 34 g) as an oil. NMR: 0.85-0.95 (6H, m), 2.3-2.5 (3H, m), 2.9-3.2 (2H, m), 4.15-4.5 (3H, m) ), 4.95-5.15 (2H, m), 5.75-6.0 (1H, m).

(II) A 1M solution of dibutylborotrifthalate in dichloromethane (32.7 ml) is added to a solution containing compound A (6.28 g) in dry dichloromethane (110 ml), cooled to 5 ^° C under argon atmosphere, followed by addition of diisopropylethylamine (6, 25 ml). The reaction mixture was stirred for 30 min at ⁵ ° C and then cooled to -78 ° ^C was added dropwise 3-pyridinecarboxaldehyde (3.1 ml). The mixture was stirred for 30 min at ^-78 ° C followed by gradual warming to -50 ^{° C} for 30 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then cooled ^to 5 ° C and add hydrogen peroxide (11.5 ml, 30% aqueous solution). The mixture was stirred for 30 minutes and then poured into water (50 ml) and extracted with dichloromethane (3x100 ml). The combined extracts were dried (MgSO ₄ ) and evaporated. After purification of the residue by flash column chromatography, eluting with ethyl acetate / hexane (1: 1, v / v), gradually increasing to 100% ethyl acetate), (4S) - (3 - [(2S) -2 - [(1S -1-hydroxy-1- (3-pyridyl) methyl] pent-4-enoyl) -4-isopropyloxazolidin-2-one (B) as a solid, mp. mp. 112-113 ^C (after recrystallization from toluene ); 25 [α] +136.0 (EtOH, s.0.311); NMR: 0.85 (6H, dd, I 7 Hz), 2.15-2.7 (4H, m), 4.0- 4.2 (2H, m), 4.3-4.55 (2H, m), 4.95-5.1 (3H, m), 5.65-5.9 (1H, m), 7.25- 7.35 (1H, m), 7.75-7.85 (1H, m), 8.5-8.65 (2H, m).

(III) 30 wt. a solution of sodium methoxide in methanol (3.65 ml) was added to a solution containing compound B (5.76 g) in methanol (40 ml) cooled to 5 ^° C. The mixture was stirred for 15 minutes, and then a saturated aqueous solution was added. ammonium chloride (10 ml) and ether (50 ml). The required amount of water is added to dissolve any unreacted inorganic reagent. The mixture was then extracted with diethyl ether (3x50 ml). The combined layers were dried (MgSO ₄ ) and evaporated. After purification of the residue by flash chromatography, eluting with ethyl acetate, (2S) -2 [(1S) -1-hydroxy-1- (3-pyridyl) methyl] pent-4-enoic acid (C) methyl ester (3.245 g) was obtained as oils; NMR: 2.3-2.6 (2H, m), 2.8-2.9 (1H, m), 3.6 (3H, s), 4.95-5.1 (3H, m), 5.65-5.85 (1H, m), 7.25-7.35 (1H, m), 7.7-7.75 (1H, m), 8.45-8.6 (2H, m) )

(IV) A solution containing compound C (3.88 g) in THF (10 ml) is added dropwise to a cooled suspension of lithium aluminum hydride (767 mg) in THF (50 ml) at such a rate that the temperature is maintained at - 10 ^C. After complete addition the mixture was stirred at ⁵ ° C for 4 hours. ethyl acetate (20 ml) followed by addition of saturated aqueous ammonium chloride solution (10 ml and 10 ml). The mixture was extracted with ethyl acetate (3x50 ml). The combined extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography using ethyl acetate as eluent, which was gradually diluted with methanol to give a methanol / ethyl acetate mixture (1: 9). Get (1S, 2R) -2-allyl-1- (3-pyridyl) -1,3-propanediol (D) (2.69 g) as an oil; NMR: 1.65-1.8 (1H, m), 1.95-2.15 (2H, m), 3.15-3.45 (2H, m), 4.4-4.5 (1H , m), 4.75-5.0 (3H, d, I 7 Hz), 5.6-5.85 (1H, m), 7.3-7.4 (1H, m). 7.65-7.7 (1H, m), 8.4-8.5 (2H, m).

(V) para-toluenesulfonic acid monohydrate (2.91 g) is added to a solution containing compound (D) (2.68 g) in 2,2-dimethoxypropane (15 ml), and then the mixture is stirred for 18 hours. Triethylamine is added. (10 ml), followed by separation of the mixture with the addition of ether (50 ml) and water (20 ml). The organic layer was dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography and using ethyl acetate / hexane (1: 1, v / v) as eluent, (4S, 5R) -5-allyl-2,2-dimethyl-4- (3-pyridyl) - 1,3-dioxane (E) (2.39 g) as an oil; NMR: 1.53 (3H, s), 1.55 (3H, s), 1.6-1.75 (1H, m), 1.9-2.0 (1H, m), 2.3- 2.5 (1H, m), 3.85-4.2 (2H, m), 4.9-5.0 (2H, m), 5.27 (1H, d, I 3 Hz), 5.45- 5.7 (1H, m), 7.25-7.35 (1H, m), 7.65-7.7 (1H, m), 8.5-8.6 (2H, m).

(VI) Ozone was passed through a solution containing the allyl compound (E) (530 mg) in methanol (30 mL) cooled to ^-78 ° C, until a blue coloration appears. The mixture was purged through argon before methyl sulfide (1.6 ml) was added. The reaction mixture was then stirred at room temperature for 18 hours, followed by evaporation in vacuo and separation using dimethyl ether (50 ml) and water (20 ml). The organic layer was dried (MgSO ₄ ) and evaporated. After purification of the residue by flash chromatography, eluting with methanol / methylene chloride (5:95, v / v), 2- [4S, 5R) -2,2-dimethyl-4- (3-pyridyl) -1,3-dioxane- 5-yl] acetaldehyde (F) as an oil; NMR: 1.53 (3H, s), 1.55 (3H, s), 2.15-2.4 (2H, m), 2.85-2.95 (1H, m), 3.8- 3.85 (1H, m), 4.25-4.35 (1H, m), 5.28 (1H, d, I3 Hz), 7.25-7.7 (2H, m), 8.5 -8.6 (2H, m), 9.6 (1H, s).

 Note: the optical purity is estimated as 99% by proton NMR with the introduction of (R) - (-) - 2,2,2-trifluoro-1- (9-antryl) ethanol and observation in the region of 2.7-2.9 (delta ), where 4 doublets were found, with the center at 2.77, 2.71. 2.82 and 2.85 (1H. CH-CHO).

(VII) Acetaldehyde (F) is then converted to 4 (Z) -6 - [(4S, 5R) -2,2-dimethyl-4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid having 25 [α] _D (EtOH, with 0.465) and NMR data matching those obtained according to the recipe described in example 1, using the same procedure as described in the first part of example 1.

PRI me R 41. The following illustrative examples of dosage unit forms include tablet, capsule, infusion and aerosol formulations, which can be obtained by conventional methods known in the pharmaceutical field for the treatment and prevention of diseases. (a) Tablet I mg / tablet Compound Z 1.0 Lactose 93.25 N ₂ -croscarmellose 4.0 Corn starch paste 0.75 Magnesium stearate m / v aqueous paste 1.0 (b) Tablet II mg / tablet Compound 50 Lactose 223.75 N ₂ -scrocarlylose 6.0 Cornstarch 15.0 Polyvinylpyrrolidone (5% w / v aqueous paste) 2.25 Magnesium stearate 3.0 (d) Capsule mg / capsule Compound 10 mg Lactose 488.5 Stearate magnesium 1.5 (e) Composition for injection (50 mg / ml) Compound Z (in the form of free acid) 5.0% m / v 1M sodium hydroxide solution 15.0% v / v Hydrochloric acid (to bring the pH to 7 , 6) Polyethylene glycol 400 4.5% m / v CT water up to 100% (f) Composition for injection II (10 mg / ml) Compound Z (in the form of free acid) 1.0% m / v Sodium phosphate EP 3.6% m / v 0.1 M sodium hydroxide diluent 15.0% v / v Sterile water up to 100% (g) Composition for injection III (1 mg / ml, buffered to pH 6) Compound Z (free acid form) 0.1% m / v Sodium phosphate EP 2.26% m / v Citric acid 0.38% m / v Polyethylene glycol 400 3.5% m / v Sterile water up to 100% (h) Aerosol I mg / ml Compound Z 10.0 Sorbitol trioleate 13.5 Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (I) Aerosol II mg / ml Compound Z 0.2 Sorbitol trioleate 0.27 Trichlo rfluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoromethane 1094.0 (j) Aerosol III mg / ml Compound Z * 2.5 Sorbitol trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (K) Aerosol IV Compound Z * 2.5 Soya lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6
NOTE * Compound Z is a compound of formula (I) or a salt thereof, for example a compound of formula (I), the disclosure in any of the examples presented and is especially described in examples 4, 8, 11 or 28.

 Compositions in the form of tablets (a) to (c) may contain an enteric coating made by conventional methods, for example, for coating cellulose triacetate phthalate. Aerosol formulations (h) - (k) can be used with standard aerosol dispensers in a specific dose, and suspending agents sorbitol trioleate and soya lecithin can be replaced with a preferred suspending agent, for example sorbitan monoleate, one-and-a-half sorbitol oleate, polysorbite 80, polyglycerol oleate or oleic acid.

 The microanalysis data are given in table 1.

Table 2 shows the biological tests which demonstiruyut ability of test compounds to act as antagonists of TXA ₂ and TXA ₂ synthase inhibitors.

The antagonism of TXA _{2 was} demonstrated using a blood platelet aggregation test based on the test described by Born (Nature, 1961, 194, 927-929), including:
(i) aggregation of platelet-rich, citrated human plasma by the addition of imitative TXA ₂ agent u 46619 so as to obtain a dose response curve;
(ii) obtaining a dose response curve for stimulated platelet aggregation of u 46619 in the presence of increasing amounts of the test compound (usually in the range of 10 ^-5 -10 ^{-1 0} M);
(iii) the calculation of the value of Kv, showing the possibility of antagonism of TXA ₂ for the test substance, the average of several concentrations from the calculated 50% aggregation value u 46619 in the presence and absence of the test substance.

In the table, the test results are presented in the form of pA ₂ , which is defined as the negative logarithm of the value of K _in .

Inhibition of TXA ₂ synthase was demonstrated using the standard in vitro test method described by Howarth et alia (Biochem. Soc. Transitions, 1982, 10, 239-240) using a microsomatic, platelet containing TXA ₂ synthase human platelet and using a quantitative thin layer radiochromatographic method estimates of the conversion of [I- ¹⁴ C] arachidonic acid to TXA ₂ metabolic thromboxane B ₂ (TXB ₂ ).

 In table 2, the results are given in units of M. M.

 Biological test data are provided for representative compounds of formula (I) and known compounds of similar structure. Known compounds are disclosed in examples EP-A-201351 (5), 201354 (4) and 202086 (6).

Compounds of formula (I) are antagonists of TXA ₂ inhibitors and TXA ₂ synthase. This desired biological activity could not be predicted from any cited reference. In particular, it was not possible to predict that when a 4-phenyl substituent is replaced by a 4-pyridyl substituent, the thromboxane antagonist activity will remain and a new thromboxane synthesis inhibition activity will arise. As test data confirm, known compounds are inactive as thromboxane synthase inhibitors.

 Table 3 shows comparative data for the compounds of the examples from EP-A-201351, 201354 and 202086.

Claims (8)

1. 1,3-dioxanone derivatives of alkenoic acid of the General formula

where A ₁ C ₁ -C ₃ alkylene;
R ₁ C ₁ -C ₆ -alkyl, trifluoromethyl, C ₃ -C ₆ -cycloalkyl, or C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, or a group of the general formula R ₃ · A ₂ -,
where R _{3 is} pyridyl, phenyl or phenyl containing 1 or 2 substituents selected from the group: halogen, trifluoromethyl, nitro or cyano;
A ₂ C ₁ -C ₆ alkylene, hydroxy-C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene or a direct bond to R ₃ ;
R _{2 is a} hydroxy group or a physiologically acceptable alcohol residue;
X is hydrogen, hydroxy or C ₁ -C ₄ alkoxy;
Y is vinylene;
n 1 or 2,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that in it A _{1 is} methylene, ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene or 1,1-dimethyltrimethylene, R _{1 is} methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopentyl, cyclohexyl, 1,1-dimethyl-2-methoxyethyl, 1-methyl-1-propoxyethyl or a group of the general formula
R ₃ · A ₂ -,
where R ₃ 3-pyridyl, phenyl or phenyl containing 1 or 2 substituents selected from the group: fluoro, chloro, bromo, trifluoromethyl, nitro or cyano;
A ₂ methylene, ethylene, trimethylene, isopropylidene, 1,1-dimethylethylene, 3,3-pentylidine, oxymethylene, oxytetramethylene, 1-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, vinylene, 1,3- propenylene, 1,4-buten-2-ylene or a direct bond to R ₃ ;
R _{2 is a} hydroxy, C ₁ -C ₆ alkoxy group, possibly containing an oxy or C ₁ -C ₄ alkoxy substituent, or R ₂ is a phenoxy or benzyloxy group, each of which may contain 1 or 2 substituents selected from groups halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy group;
X is hydrogen, hydroxy, methoxy or ethoxy. 3. Connection PP. 1 and 2, characterized in that in it R _{1 is} selected from the group: trifluoromethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 2-cyanophenyl, 4-cyanophenyl, 4-nitrophenyl, 2-chloro-5-nitrophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 1-phenoxy-1-methylethyl (the phenoxy radical of which may contain 2-fluoro, 2-nitro -, 2-trifluoromethyl, 3-fluoro, 3-bromo, 3-nitro, 4-fluoro, 4-bromo, 4-cyano, 4-nitro, 2,4-dichloro, 3,4-difluoro or 3,4 dichlorosubstituted groups, 3-pyridyl, 4-pyridyl, 1-methyl-1- (3-pyridyloxy) ethyl, 1-propoxy-1-methylethyl and 1,1-dimethyl-2-phen ethyl (the phenyl residue of which possibly contains 3-bromo, 3-nitro, 4-fluoro, 4-nitro, 4-trifluoromethyl, 3,4-difluoro or 3,4-dichloro substituted groups), styryl or 2-nitrostyryl . 4. Connection PP. 1 3, characterized in that in it A _{1 is} ethylene or trimethylene, Y is cis-vinylene, n 1, X is hydrogen, R _{2 is an} oxy group. 5. The compound according to claim 1 of the General formula

where A ₃ C ₁ -C ₄ alkylene;
R ₅ pyridyl, phenyl or phenyl containing 1 or 2 substituents selected from halogen, trifluoromethyl, nitro or cyano;
A ₄ C ₁ -C ₄ alkylene, hydroxy-C ₁ -C ₄ alkylene or a direct bond to R ₅ ,
and its pharmaceutically acceptable salts. 6. The compound according to claim 5, characterized in that it contains A ₃ ethylene, trimethylene or 1,1-dimethylethylene, A ₄ direct bond, isopropylene, 1,1-dimethylethylene or 1-hydroxy-1-methylethyl, R ₅ - 3-pyridyl, phenyl, 4-halo phenyl, 2-halo phenyl, dihalo phenyl, nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl or 4-trifluoromethylphenyl.  7. The compound according to claim 1, characterized in that it is selected from 4 (Z) -6 - [(2,4,5-cis) -2- (1-methyl-1-phenoxyethyl) -4- (3- pyridyl) -1,3-dioxan-5-yl] hexanoic acid, 4 (Z) -6 - [(2,4,5-cis) -2- (4-cyanophenyl) - 4 - (3-pyridyl-1 , 3-dioxan-5-yl] hexanoic acid, 4 (Z) -6 - [(2,4,5-cis) - 2- (1- [4-bromophenoxy] -1-methylethyl) -4- (3 -pyridyl) -1,3-dioxan-5-yl] hexenoic acid, 4 (Z) -6 - [(2,4,5-cis) -2- (1- [3,4-difluorophenoxy] -2- methylethyl) -4- (3-pyridyl) -1,3-dioxan-5-yl] hexenoic acid, and a pharmaceutically acceptable salt thereof.  8. The salt of the compound according to any one of paragraphs. 1-7, characterized in that it is a salt of alkali or alkaline earth metals, an ammonium salt, a salt with an organic amine or quaternary base forming a physiologically acceptable cation, or a salt with an acid forming a physiologically acceptable anion.

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