CS245796B2 - Production method of 4-hydroxyphenyl-1,3-dioxan-cis-5-ylalkene acids - Google Patents

Description

SUMMARY OF THE INVENTION The present invention provides a process for the production of novel 1,3-dioxan-5-ylalkenoic acids and derivatives thereof that antagonize one or more of the types of thromboxane A2 (TXA2) and are valuable therapeutic agents. TXA2 is known to be an effective blood clotting agent platelets and a strong vasoconstrictor. TXA2 is also a potent agent for contracting (constricting) smooth muscle in the bronchi and trachea. Thus, TXA2 can be implicated in a wide variety of disease states such as ischemic heart disease such as myocardial infarction and angina, cerebrovascular diseases such as transient cerebral ischemia, migraine, stroke, peripheral vascular diseases such as atherosclerosis, microangiopathy, hypertension and blood disorders coagulation due to lipid imbalance, and lung diseases such as pulmonary embolism, bronchial asthma, bronchitis, pneumonia, dyspnoea and emphysema. Accordingly, TXA2 antagonist compounds are expected to be therapeutically effective in preventing or treating one or more of the above-mentioned diseases, or any other disease states in which antagonizing the effects of TXA2 is desired.

Certain 4-substituted 1,3-dioxan-trans-5-ylalkenoic acids, a typical example of which is a compound of formula A

are known (see British Patent No. 2,046,733) as inhibitors of the enzyme responsible for the synthesis of TXA2. Similarly, it is known that certain 6-alkynyl-1,3-dioxan-cis-4-ylalkenoic acids, which are typically represented by the compound of formula B

(B) where

BA is a tert-butyl group, inhibiting various enzymes involved in the biosynthesis and degradation of arachidonic acid (Fried et al., Adv. Prostaglandin and Thromboxane Research, 1980, 6, 427-438). However, none of these 1,3-dioxanylalkenoic acid groups have been reported to be antagonistic to the effects of TXA.

It has now been found that the novel, chemically distinct 4-substituted 1,3-dioxan-5-ylalkenoic acids and their derivatives, of formula I

unexpectedly, they exhibit the ability to antagonize one or more of the effects of TXA2.

Accordingly, the present invention provides a process for the preparation of 4-hydroxyphenyl-1,3-dioxan-cis-5-yl-alkenoic acid derivatives of the above general formula (I), wherein:

R a and R b are each independently hydrogen, C 2 -C 6 alkenyl, C 1 -C 8 alkyl optionally substituted with up to three halogen atoms, pentafluorophenyl, C 1 -C 4 aryl or arylalkyl alkyl moieties wherein the aryl moiety is a phenyl or naphthyl group optionally bearing up to three substituents selected from the group consisting of halogen atoms, alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, alkylenedioxy groups of 1 to 4 carbon atoms, trifluoromethyl cyano, nitro, hydroxyl, alkylthio of 1-6 carbon atoms, alkanesulfonyl of 1-6 carbon atoms, alkanoylamino of 1-6 carbon atoms and oxapolymethylene of 2-4 carbon atoms, provided that both Ra and R b are alkyl or alkenyl groups, then the total number of carbon atoms in together both are not more than 8, or R a and R b together form a C 2 -C 7 polymethylene radical optionally substituted by one or two C 1 -C 4 alkyl groups,

R c is hydroxyl, C 1 -C 6 alkoxy or C 1 -C 6 alkanesulfonamido, n is 1 or 2,

A represents an ethylene or vinylene group,

Y represents a C 2 -C 5 polymethylene group optionally substituted with a C 1 -C 4 alkyl group, the benzene ring B is substituted with a hydroxy group and optionally carries one additional substituent selected from the group consisting of halogen atoms, C 1 -C 6 alkyl groups, (C 1 -C 6) alkoxy, hydroxyl, (C 1 -C 6) alkanoylamino, trifluoromethyl and nitro groups, and the substituents at the 4 and 5 positions of the dioxane ring are cis to each other, and salts of those compounds wherein R c is hydroxy, with bases providing a physiologically acceptable cation.

The compounds of formula I contain at least two asymmetric carbon atoms (i.e., carbon atoms C4 and C5 of the dioxane ring) and can therefore exist and be isolated in racemic form or in optically active forms.

In addition, those compounds of formula I wherein A is a vinylene group exist and can be isolated in separate stereoisomeric forms ("E" and "Z") on that group. It is to be understood that the invention encompasses all racemic, optically active and stereoisomeric forms (or mixtures thereof) of the above compounds that are capable of antagonizing one or more of the effects of TXA2, and it is well known in the art how individual optical isomers can be prepared (e.g. by synthesis from optically active starting materials or by resolution of the racemic form) and individual "E" and "Z" stereoisomers (for example, by chromatographic separation of their mixture), and how their antagonistic properties can be determined using TXA2 using the standard assays described below.

As used herein, the symbols Ra, Rb, Rc, and the like denote only the respective residues and have no other meaning.

A suitable alkyl group having 1 to 8 carbon atoms in the meaning of Ra or Rb is, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl or octyl and an alkyl group of 1 to 8 carbon atoms bearing up to three halogen substituents is, for example, chloromethyl, 2-chloroethyl, trifluoromethyl or 2,2,2-trifluoroethyl.

A particular aryl group represented by Ra or Rb is, for example, phenyl, 1-naphthyl or 2-naphthyl, for example, a (C1-C4) arylalkyl group such as benzyl, 1-phenylethyl or 2-phenylethyl and a C 2 -C 6 group such as vinyl or 2-methylallyl.

Suitable substituents which may optionally be present on the benzene ring B or on an aromatic radical which either acts as a radical Ra or Rb, or which form part of a more complex radical within the meaning of any of these symbols, include, for example:

243796

S for halogen atoms fluorine, chlorine, bromine or iodine;

for (1-6C) alkyl groups methyl, ethyl, propyl or isopropyl;

for (1-6C) alkoxy, methoxy, ethoxy or propoxy;

for (1-4C) alkylenedioxy, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

for (1-6C) alkylthio, methylthio or ethylthio;

for (1-6C) alkanesulfonyl groups a methanesulfonyl or ethanesulfonyl group;

for C 1 -C 6 alkanoylamino, acetamido or propionamino and for C 2 -C 4 oxapolymethylene the radical -CH 2 OCH 2 - or

-CH2CH2OCH2-.

Generally, when one of Ra and Rb is hydrogen, it is preferred that the other of Ra and Rb be cis in relation to the substituents at the 4 and 5 positions of the dioxane ring.

A suitable C 2 -C 7 polymethylene group, taken together with Ra and Rb, is, for example, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, and a suitable C 1 -C 4 alkyl substituent is, for example, methyl.

A suitable C 1 -C 6 alkanesulfonamido group is, for example, methanesulfonamido, ethanesulfonamido, propanesulfonamido or 1-methylethanesulfonamido.

A suitable C 1 -C 6 alkoxy group is, for example, methoxy or ethoxy.

A suitable Y radical is, for example, an ethylene, trimethylene or tetramethylene group, and a suitable optional substituent of this radical is, for example, a methyl group.

Particular examples of Ra and Rb include hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, octyl, vinyl, allyl, 2-methylallyl, trifluoromethyl, chloromethyl, 2-chloroethyl, phenyl, optionally substituted by fluorine, chlorine or bromine, methyl, methoxy, trifluoromethyl, methylthio, methanesulfonyl, nitro, hydroxy, cyano, acetamido, methylenedioxy - or methyleneoxymethylene (-CH 2 OCH 2 -), dichlorophenyl, dimethylphenyl, pentafluorophenyl, 1-naphthyl, 2-naphthyl and benzyl, and suitable radicals formed together by both are, for example, trimethylene, pentamethylene or hexamethylene optionally substituted by met hydroxyl group.

A preferred benzene ring for B is, for example, the 2-hydroxyphenyl radical.

A preferred radical for Rc is, for example, a hydroxyl group, a methoxy group, an ethoxy group, a methanesulfonamido group or an ethanesulfonamido group, of which a hydroxyl group is particularly preferred.

A preferred radical A is a vinylene group, a Y radical is a trimethylene group. Preferably, n is 1.

When A is a vinylene group, it is generally preferred that there is a cis-configuration on the adjacent carbon atoms, i.e., the “-configuration.

A preferred group of derivatives produced by the process of the invention are compounds of formula Ia

(fa) in which:

Ra and Rb either (and J independently represent a hydrogen atom or a C1-C4 alkyl group optionally substituted by one to three halogen atoms, or (ii) one of these symbols represents a hydrogen atom or a C1-C4 alkyl group and the other is phenyl, naphthyl or phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety optionally carrying one or two substituents selected from the group consisting of halogen atoms, alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 atoms C1 -C4 alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxyl, C1 -C4 alkylthio, C1 -C4 alkanesulfonyl, C1 -C4 alkanoylamino and C2 -C4 oxapolymethylene Or a pentafluorophenyl group; or (iii) one of the two l is hydrogen and the other is C 5 -C 8 alkyl or C 2 -C 6 alkenyl, or (IV) both together form a C 2 -C 7 polymethylene group, optionally substituted with C 1 -C 7 alkyl. 4 carbon atoms,

R c is hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkanesulfonamido and the benzene ring B optionally carries a hydroxyl substituent at the 2-position, the substituents at the 4 and 5 positions of the dioxane ring being cis to each other and the salts of those above said compounds wherein R c is a hydroxyl group with bases providing a physiologically acceptable cation.

Particular values for the individual substituents in the above preferred group of compounds are:

for (1-4C) alkyl, methyl, ethyl, propyl, isopropyl or butyl;

for (C 1 -C 8) -alkyl, pentyl, hexyl, heptyl or octyl;

for (C 1 -C 4) alkoxy, methoxy or ethoxy;

for (C 1 -C 4) alkyl, (C 1 -C 3) -substituted, chloromethyl, 2-chloroethyl, 2,2,2-trifluoroethyl or trifluoromethyl;

for (C 1 -C 4) -phenylalkyl, benzyl, 2-phenylethyl or 1-phenylethyl; for halogen atoms fluorine, chlorine or bromine;

for (1-4C) alkylenedioxy, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

for (C 1 -C 4) alkylthio, methylthio or ethylthio;

for (C 1 -C 4) alkanesulfonyl groups a methanesulfonyl or ethanesulfonyl group;

for (C 1 -C 4) alkanoylamino, acetamido or propionamido; and for (C 2 -C 4) oxapolymethylene (methyleneoxyethylene) (-CH 2 OCH 2 -) or ethyleneoxy (-CH 2 CH 2 O-).

Specific preferred combinations of the meanings of Ra and Rb include, for example:

(i) R a and R b are both hydrogen, methyl, ethyl, propyl, butyl or trifluoromethyl;

(ii) one of Ra and Rb is hydrogen and the other is trifluoromethyl, chloromethyl, benzyl, isopropyl, hexyl, octyl, phenyl (optionally having 1 or 2 substituents selected from fluoro, chloro and bromo, methyl, trifluoromethyl, hydroxyl, cyano, methylthio or acetamido), a phenyl group bearing a methylenedioxyl or methylenoxymethylene (-CH 2 OCH 2 -) substituent, a pentafluorophenyl group, a 1-naphthyl or a 2-naphthyl group, and (iii) Ra and Rb together a trimethylene, tetramethylene, pentamethylene, hexamethylene or -CH 2 CH 2 -CHCH 3 -CH 2 CH 2 - radical.

Particularly preferred mono- or disubstituted phenyl groups Ra or Rb are, for example, 2-fluoro-, 3-fluoro-, 4-fluoro-, 2-chloro-, 3-chloro-, 4-chloro-, 2-bromo- , 3-bromo-, 4-bromo-, 2-methyl-, 3-methyl-, 4-methyl-, 2-methoxy-, 3-methoxy-, 4-methoxy-, 2-trifluoromethyl-, 3-trifluoromethyl- 4-trifluoromethyl-, 3-hydroxy-, 4-cyano-, 4-methylthio-, 4-acetamido-, 3,4-dichloro, 2,4-dimethyl-, 3,4-methylenedioxy- and 3,4- (methyleneoxymethylene) phenyl group.

A further preferred group of substances produced by the process of the invention is represented by the compounds of formula Ib

wherein (i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl, or trifluoromethyl; or (ii) both together form a tri10 methylene, tetramethylene, pentamethylene or hexamethylene group, or -GHxCHa-GHCH5. -CH 2 CHa-, or R 11 represents a C 3 -C 8 alkyl group, a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a pentafluorophenyl group, a phenyl, a benzyl or a naphthyl group optionally substituted by one or two halogen atoms, alkyl groups (C1-C4) alkoxy, (C1-C4) alkoxy, trifluoromethyl, hydroxy, cyano, (C1-C4) alkylthio or (C1-C4) alkanoylamino, or methylenedioxy or methylenoxymethylene, and Rb is hydrogen , and the benzene ring B is ring 2 -hydroxyphenyl wherein R a and the substituents at the 4 and 5 positions of the dioxane ring are cis to each other and the carbon atom adjacent to the vinylene group has the indicated cis arrangement, and their salts with bases providing a physiologically acceptable cation, or methyl or ethyl esters thereof, or their methanesulfonamido-, ethanesulfonamido- or 1-methylethanesulfonamido derivatives.

A preferred C 3 -C 8 alkyl group is, for example, isopropyl, butyl, hexyl or octyl.

Preferred substituents on the phenyl, benzyl or naphthyl radical Ra are, for example:

in the case of halogens fluorine, chlorine or bromine, in the case of C1 -C4 alkyl groups, methyl, in the case of C1 -C4 alkoxy, in the case of C1 -C4 alkylthio, methylthio in the case of C1 -C4 alkylthio, in the case of C1 -C4 alkanoylamino groups 4 carbon atoms acetamido.

Preferred substituents on benzene ring B are, for example:

in the case of 2-halo, 2-fluoro, 2-chloro or 2-bromo, in the case of 3-halo, 3-fluoro or 3-chloro, in the case of a C 1 -C 4 -alkyl group, 2 methyl, 2-ethyl or 2-isopropyl and, in the case of a C 1 -C 4 -alkoxy group, 2-methoxy.

Suitable salts of compounds of formula I wherein R c is hydroxy are, for example, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium salts, aluminum and ammonium salts, and salts with organic amines or quaternary bases forming physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, N-methylglucamine, tetramethylammonium hydroxide and benzyitrimethylammonium hydroxide.

A particular compound of the invention is described below in an exemplary embodiment.

The process according to the invention is characterized in that the protected derivative of the general formula I in which the hydroxyl substituent on the benzene ring B is protected by a trimethylsilyl protecting group, an alkyl protecting group having 1 to 6 carbon atoms (such as methyl or ethyl) or an acyl protecting group such as acetoxy or benzoyloxy and the other substituents have the meaning given in formula I, deprotecting.

The conditions used to remove the protecting group necessarily depend on the nature of the respective protecting group. For example, if the protecting group is a methyl or ethyl group (i.e., the starting material is the corresponding methoxy or ethoxy compound of formula I), the cleavage of the protecting group can be accomplished, for example, by heating with sodium thioethoxide in a suitable solvent (such as N, N). dimethylformamide] to an elevated temperature, for example 90 to 160 [deg.] C. The acyloxy protecting group can be cleaved, for example, by hydrolysis in the presence of a base (such as sodium hydroxide or potassium hydroxide) in a suitable solvent (such as C 1 -C 4 alkanols) A temperature of, for example, 10 to 60 DEG C. The trimethylsilyl protecting group can be removed, for example, by reaction with aqueous tetrabutylammonium fluoride or sodium fluoride in a conventional manner.

The necessary starting protected derivatives can be prepared by processes analogous to other processes for the preparation of compounds of formula I described and protected in our related Czechoslovak patents Nos. 245,783 and 245,795, for example by reaction of an aldehyde of formula II

wherein the benzene ring B carries a hydroxyl substituent protected with a trimethylsilyl, C 1 -C 6 alkyl or acyl group with a Wittig reagent of formula

Ph 3 P = CH-Y-CO 2 -K + in dimethylsulfoxide or tetrahydrofuran at a temperature of 15 to 35 ° C. The necessary aldehydes of formula (II) can be prepared according to the following reaction schemes 1 and 2.

S c hé m a I

About me

(VU) (li) (12 = 1)

Reagents and conditions:

(iv) zinc borohydride, diethyl ether (i) sodium ethoxide, ethanol, allyl bromide (iii lithium aluminum hydride or lithium borohydride, tetrahydrofuran (iiii p-toluenesulfonic acid, compound of formula RaRb-CO or RaRb-C (0Me) 2 (v) ozone, ethylene , then triphenylphosphine, or osmium tetroxide, sodium periodate, t-butanol, water (vij sodium hydride, dimethylsulfoxide, BrCH 2 CH 2 OOMe compound (see acidic environment, water.

245706

Remarks: for example methyl or ethyl.

R = alkyl of 1 to 4 carbon atoms,

The term Me refers to a methyl group. Scheme II

Reagents and conditions:

(i) diborane, then hydrogen peroxide [ii) pyridium chlorochromate, dichloromethane; or dicyclohexylcarbodiimide, dimethylsulfoxide, pyridine, trifluoroacetic acid (iii) sodium borohydride, ethanol (iv) p-toluenesulfonyl chloride, pyridine; then sodium iodide, acetone, heating (v) 1,3-dithiane, lithium diisopropylamine, tetrahydrofuran, -78 ° C (vi) cerium ammonium nitrate, 0 ° C.

The above reaction schemes describe selective conversions of functional groups well known in the synthesis of structurally analogous compounds, such as prostaglandins and analogs thereof, and are generally carried out under reaction conditions similar to those known in the art. For example, in the presence of alkylthio groups, a non-specific oxidation reaction sequence is used [e.g., step (vj in Scheme I and step (vij in Scheme IIj). Similarly, a starting material of formula IV in which the hydroxyl substituent is protected, e.g. Analogously, when the benzene ring B carries an acyloxy substituent, such a product can be obtained by acylation of the corresponding derivative of general formula II, which is carried out in a conventional manner as the final reaction step before the Wittig reaction.

To prepare a compound of formula (I) wherein Rc is alkoxy

245736 having from 1 to 6 carbon atoms, the corresponding acid of the general formula (I) in which R c is a hydro group or a reactive derivative thereof is esterified in a conventional manner.

For example, an acid of formula I wherein R c is hydroxy, or a reactive derivative thereof, can be esterified by reaction with an appropriate C 1 -C 6 alkanol.

It will be understood that when a free acid of formula (I) is used for the above reaction, water is formed during the reaction. Thus, in such cases it is particularly useful to carry out the reaction in the presence of a suitable dehydrating agent, for example dicyclohexylcarbodiimide, in the presence of a suitable solvent or diluent, for example tetrahydrofuran, acetone, methylene chloride or 1,2-dimethoxyethane, preferably at or near room temperature.

A suitable reactive acid derivative of the formula I is, for example, an acid chloride, an acid bromide, an anhydride or a mixed anhydride with formic acid, or an acid azide. These derivatives can be prepared from the free acid in a conventional manner. If such a derivative is used in the above reaction, no dehydrating agent is required and the C1 -C6 alkanol is conveniently used in large excess, optionally diluted with a suitable diluent or solvent such as an ether such as tetrahydrofuran or 1,2-dimethoxyethane.

When using a reactive acid derivative of the formula I, it is generally not necessary to heat the reaction mixture.

In order to obtain a compound of the formula I in which Rc is C1 -C6 -alkanesulfonamido, the corresponding compound of the formula I in which Rc represents a hydroxy group or a reactive derivative thereof is reacted with the corresponding alkanesulfonamide containing in the alkyl moiety 1. up to 6 carbon atoms.

For example, the free acid of formula I in which R c is a hydroxyl group may be reacted with a suitable dehydrating agent, for example dicyclohexylcarbodiimide, optionally together with an organic base such as 4-dimethylaminopyridine in the presence of a suitable solvent or diluent such as methylene chloride, at a temperature in the range of from 10 to 50 ° C, preferably at or near room temperature. Alternatively, a reactive acid derivative of the formula I wherein R c is a hydroxy group, for example an acid halide (such as an acid chloride), can be reacted with an alkali metal salt (such as a sodium salt) of the corresponding alkanesulfonamide containing from 1 to 6 carbon atoms. conveniently at or near room temperature, in a suitable solvent or diluent, e.g.

1fl in ether, Ν, Ν-dimethylformamide on methylene chloride.

In order to prepare a compound of formula I in which A is an ethylene group, the corresponding compound of formula I in which A is a woolen group is subjected to hydrogenation in the presence of a catalyst.

Hydrogenation may be carried out in a suitable solvent or diluent, for example in a C 1 -C 4 alkanol (such as ethanol or 2-propanol), optionally in the presence of water, at a temperature in the range, for example, 15 to 35 ° C. pressure of 0.1 to 0.2 MPa.

A suitable catalyst is, for example, a noble metal catalyst, such as palladium metal, suitably supported on an inert support such as carbon, barium sulfate or mountain carbonate.

A salt of a compound of formula I wherein R c is a hydroxyl group is obtained by reacting the compound with an appropriate base providing a physiologically acceptable cation, or by any other means.

If the optically active form of the compound of formula (I) is to be obtained, any of the above procedures are carried out using the appropriate optically active starting material. Alternatively, when R c is a hydroxyl group, the racemic form of the compound may be reacted with an optically active form of a suitable organic base such as ephedrine, Ν, Ν, Ν-trimethyl- (1-phenylethyl) ammonium hydroxide or 1-phenylethylamine, and the mixture of diastereomeric salts thus obtained is separated in a customary manner, for example by traction crystallization from a suitable solvent, for example a C1 -C4 alkanol, and then the optically active form of the aforementioned compound of formula I can be liberated in a conventional manner by acid treatment, e.g. acids such as dilute hydrochloric acid.

The optically active form of a compound of formula I in which Rc is not hydroxy can be obtained from the corresponding optically active form of the corresponding acid by the above-mentioned esterification or amidation procedures.

The above defined intermediates of formulas II and VII are novel and are also within the scope of the invention.

As mentioned above, the compounds of formula I are antagonists of one or more of the effects of TXA2, for example, some effects on the platelets, on the vascular system and / or on the lung. This antagonism can be demonstrated by any of the following tests:

a j Standard model trial with rabbit aorta stripe [Piper and Vane, see Nature,

1969, 233, 29-35], using a freshly prepared sample of TXA2 prepared as an agonist by adding 25 µg of arachidonic acid to 250 μ1 of platelet rich plasma krfi245796 with citric acid addition and leaving the mixture completely precipitate within 90 seconds before use.

bj Standard platelet aggregation test based on the experiment described by Born (Nature, 1962, 194, 927-929), which measures the inhibition of platelet-rich human plasma aggregation with citric acid addition induced by a submaximal concentration of arachidonic acid (in the range of 25-100 µg / ml) caused by administration of the test compound.

c) Standard bronchoconstriction trick, consisting of measuring the inhibition (caused by a test compound) of bronchoconstriction induced in the Konzett-Rossler guinea pig model (Collier and James modification, British J. Pharmacol., 1967, 30, 283-307) by intravenous administration of a mimetic agent to TXA? base, known as U 46 619, at a dose of 1 to 1.5 gg / ml.

By way of illustration only, the structurally related 5 (Z) -7- (2,2-dimethyl-4-phenyl-1,3-dioxan cis-5-yl) heptenic acid corresponding to formula I exhibits the following in the tests described above Properties:

a) to 6.28;

b) IC 50 about 6.7 X 10 -5 m a

c) intravenously administered dose of 5 mg / kg 90 ° / o reduction of bronchoconstriction.

In general, the other compounds of formula I produced by the method of the invention exhibit similar or better efficacy in test (a) (pA2 5.0) and at least one of tests (b) and (c) without any apparent toxicity when administered at a dose in test c).

Antagonizing the effects of TXA? the vascular system can be demonstrated as follows.

Male rats (Alderley Park strain) are anesthetized with sodium pentobarbital and their blood pressure is monitored in the carotid artery. A TXA-based mimetic agent known as U46619 is intravenously applied to the juminal vein (see, for example, RL Jones et al., "Chemistry, Biochemistry and Pharmacological Activity of Prostanoids", eds. SM Roberts and F. Scheinmann, p. 211, Pergamon Press, 1979) and the ED 50 (dose required to achieve 50% of maximal hypertensive effect) was determined (n = 3). The ED 50 for U46619 is about 5 µ / kg.

The test compound is then injected either intravenously into the jugular vein or orally via the cannula directly into the stomach by administering JJ46619 at the ED50 dose at 5 minutes after the test compound and then every 10 minutes thereafter until it does not block the hypertensive effect of U46619.

By way of illustration only, in this test, the laevorotatory form structurally related to 5 (Z) - (2,2-diethyl-4-phenyl-1,3-dioxan-cis-5-yl) heptenic acid when administered orally at a dose of 50 mg / kg significantly more (more than 30%) the hypertensive effects of a TXA2-based mimetic (U46619) for 120 minutes after this oral administration In general, preferred compounds of formula I significantly reduce after intravenous administration at a dose of 10 mg / kg or less. hypertensive effect of U46619 for at least 60 minutes without any signs of toxicity.

As mentioned above, the compounds of formula (I) may be used for the treatment or prevention of diseases or adverse conditions in warm-blooded animals where it is desirable to antagonize one or more of the effects of TXA. In general, the compound of formula (I) is administered orally, rectally, intravenously, subcutaneously, intramuscularly, or by inhalation, so that the patient receives a dose ranging, for example, from 0.5 to 20 mg / kg body weight, depending on the route of administration, the severity of the disease, and the weight and age of the patient.

The compounds of formula I are generally used in the form of pharmaceutical preparations comprising a compound of formula I, or optionally a salt thereof, together with a pharmaceutically acceptable diluent or carrier. These compositions can be presented in a variety of dosage forms. For example, the compositions may take the form of tablets, capsules, solutions or suspensions for oral administration, suppositories for rectal administration, sterile solutions or suspensions for intravenous or intramuscular injection, aerosols or nebulisable solutions or suspensions for inhalation, or powders. in which the active ingredients are present together with pharmaceutically acceptable inert solid diluents, such as lactose, for insulphation administration.

These pharmaceutical compositions may be prepared by conventional techniques using pharmaceutically acceptable diluents or carriers known in the art. Tablets and capsules for oral administration may conveniently be provided with a coating which protects them from disintegration in the stomach and is, for example, cellulose acetate phthalate in order to minimize contact of the active compound of the formula I with stomach acids.

The pharmaceutical compositions may also contain one or more agents known to be used in the treatment of the aforementioned diseases or conditions, such as known platelet aggregation inhibitors, hypolipldemic agents, antihypertensive agents, adrenergic β-receptor blockers or vasodilators. . These known compositions may be present, for example, in the disclosed pharmaceutical compositions for treating cardiac or vascular diseases or disorders.

Likewise, for example, known antihistamines, steroids (such as beclomethasone dipropionate), cromglycic acid sodium salt, phosphodiesterase inhibitors or adrenergic β-receptor stimulants may conveniently be present in the disclosed compositions for treating pulmonary diseases or disorders.

In addition to therapeutic use, the compounds of Formula I are also useful as pharmacological adjuvants in the development and standardization of test systems for evaluating the effects of TXA2 on laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice in search of new therapeutic agents. Since the compounds of formula I antagonize the effects of TXA 2, they can also be used as adjuncts to maintain blood, vascular and venous system viability in warm-blooded animals under conditions of artificial extracorporeal circulation, for example during limb or organ transplantation. When used for this purpose, the compound of formula (I) or a physiologically tolerable salt thereof is generally applied so as to achieve and maintain a constant blood concentration in the range, for example, from 0.5 to 50 mg / l.

The invention is illustrated by the following non-limiting example. In this example, unless otherwise noted, the

(i) all evaporations are carried out in a rotary evaporator under vacuum 11a;

(ii) the operations are carried out at room temperature, that is at a temperature in the range of 18 to 26 ° C;

iii) column chromatography is carried out on Merck 60 silica gel using about 50 to 70 g silica gel for each gram of sample, followed by thin layer chromatography using Merck 60F 254 plates and a 0.25 mm layer;

(iv) yields are given for illustration only and do not necessarily mean the highest achievable yields;

(v) NMR spectra measured at 90 MHz in deuterochloroform using tetramethylsilane as an internal standard, the results being expressed as chemical shifts (values <5) over tetramethylsilane and the shape of the principal signals is described by abbreviations as follows:

s = singlet m = multiplet t - triplet br - broad signal d - doublet;

if for a multiplet (m) a single chemical shift value is given, this value corresponds to the center of the signals forming that multiplet;

vi) all resulting products isolated as racemates; and vii) those compounds of formula I wherein A is a vinylene group may contain 3 to 5% by weight of the stereoisomeric E-form.

Example

To 104 mg of 5 (Z) -7- [2,2-dimethyl-4- (2-methoxyphenyl) -1,3-dioxan-cis-5-yl] heptenic acid, 2.1 ml of 0.5 ml are added under nitrogen. M solution of sodium thioethoxide in N, N-dimethylformamide, refluxed for 1.1 hours and then diluted with ice-water to a total volume of 25 ml. The aqueous mixture was acidified to pH 4 with acetic acid and extracted twice with 15 ml of ethyl acetate each time. The extracts were washed with a saturated sodium chloride solution and, after drying over magnesium sulfate, evaporated. The oily residue was purified by column chromatography on 12 g of silica gel, eluting with toluene / ethyl acetate / acetic acid (80: 20: 2 by volume). 25 mg of oily 5 (Z) -7- [2,2-dimethyl-4- (2-hydroxyphenyl) -1,3-dioxan-cis-5-yl] heptanoic acid are obtained.

NMR:

1.50 (6 H, s),

2.22 (9H, m).

3.97 (2 H, m),

5.31 (3 H, m),

6.98 (4H, m);

8.38 (2H, s) ppm.

The desired starting material was obtained as a solid product, m.p. 112 DEG-114 DEG C. in a yield of 59% by reaction of [2,2-dimethyl-4- (2-methoxyphenyl) -1,3-dioxan-cis-5-yl]. of acetaldehyde (A) with a ylide, prepared by reacting (4-kaiboxybutyl) triphenylphosphonium bromide with a sodium derivative of dimethylsulfoxide, in dry dimethylsulfoxide, followed by conventional work-up and purification of the crude product by column chromatography.

Acetaldehyde A is obtained as an oily material satisfactorily. of purity by ozonolysis of (4,5-cis) -5-allyl-2,2-dimethyl-4- (2-methoxyphenyl) -1,3-dioxane, which itself is obtained as a solid melting at 77-79 ^° C according to the procedures described in Scheme 1, using ethyl 3- (2-methoxyphenyl) -3-oxopropionate as the starting material, via the intermediate oily ethyl 2-allyl-3- (2-methoxyphenyl) -3-oxopropionate.

NMR:

1.17 (3 H, m),

2.69 (2H, m), using a similar manufacturing method,

4.10 (6H, m), as described poorly in the example, gave a further 5.00 (2H, IU, more compounds of the general formula)

5.81 (1H, mj, I), which are characterized by their physiology 6.95 (2H, m), the caliant properties described in 7.37 (1H, m), and Czechoslovak Patent Nos. 245,783

7.51 (1 H, m) ppm. and 245,795.

Claims (4)

SUBJECT A process for the preparation of 4-hydroxyphenyl-1,3 dioxan-cis-5-ylalkenoic acid derivatives of the general formula I in which: R a and R b are each independently hydrogen, C 2 -C 6 alkenyl, C 1 -C 8 alkyl optionally substituted with up to three halogen atoms, pentafluorophenyl, C 1 -C 4 aryl or arylalkyl alkyl moieties wherein the aryl moiety is a phenyl or naphthyl group optionally bearing up to three substituents selected from the group consisting of halogen atoms, alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms, alkylenedioxy groups of 1 to 4 carbon atoms, trifluoromethyl cyano, nitro, hydroxyl, alkylthio of 1-6 carbon atoms, alkanesulfonyl of 1-6 carbon atoms, alkanoylamino of 1-6 carbon atoms and oxapolymethylene of 2-4 carbon atoms, provided that both Ra and R b are alkyl or alkenyl groups, then the total number of carbon atoms in together both are not more than 8, or R a and R b together form a C 2 -C 7 polymethylene radical optionally substituted by one or two C 1 -C 4 alkyl groups, R c is hydroxyl, C 1 -C 6 alkoxy or C 1 -C 6 alkanesulfonamido, n is 1 or 2, A represents an ethylene or vinylene group, Y represents a C 2 -C 5 polymethylene group optionally substituted with a C 1 -C 4 alkyl group; the benzene ring B is substituted with a hydroxy group and optionally carries one additional substituent selected from the group consisting of halogen atoms, C 1 -C 6 alkyl groups , C 1 -C 6 alkoxy, hydroxyl, C 1 -C 6 alkanoylamino, trifluoromethyl and nitro, and substituents at the 4 and 5 positions of the dioxane ring are in the cis position with each other, and salts of those compounds in which R c is a hydroxy group with bases providing a physiologically acceptable cation, characterized in that from the corresponding compound of formula I in which the hydroxyl substituent on the benzene ring B is protected by a trimethylsilyl protecting group, an alkyl protecting group having 1 to 6 carbon atoms or an acyl protecting group and others su substituents having the meaning given above, this protecting group is cleaved, whereupon the optionally formed acid of formula I in which R c is hydroxy or a reactive derivative thereof is esterified in the usual manner to give the corresponding compound of formula I in which R c is alkoxy having 1 to Or the resulting acid of the formula I in which Rc is hydroxy is reacted with the corresponding C 1 -C 6 alkanesulfonamide in the presence of a dehydrating agent, or the reactive derivative of the acid of the formula I is reacted with the corresponding alkanesulfonamide with 1-6 carbon atoms. up to 6 carbon atoms or an alkali metal salt thereof to give the corresponding compound of formula I wherein R c is C 1-6 alkanesulfonamido, or a compound of formula I wherein A is vinylene is hydrogenated in the presence of a catalyst to form the corresponding compound of formula (I) wherein A is an ethylene group, and / or a compound of formula (I) wherein Rc is a hydroxyl group is converted to a salt by treatment with an appropriate base providing a physiologically acceptable cation; to obtain an optically active form of a compound of formula (I), either of the above methods using an optically active starting material, or the racemic form of a compound of formula (I) wherein R c is hydroxy is reacted with an optically active form of a suitable organic base, as follows the resulting diastereomeric salt mixture is separated and treated with an acid to liberate the desired optically active form of the compound of formula (I) which is then optionally subjected to the esterification or amidation described above to give the corresponding compounds in which Rc is not hydroxy. 2. The process of claim 1, wherein the hydroxyl substituent is protected with a trimethylsilyl, methyl, ethyl, acetyl or benzoyl group. 3. A process according to claim 1 or 2, wherein the starting material is a compound of formula I wherein the benzene ring B is substituted with methoxy or ethoxy and the reaction is carried out using sodium thioethoxide in a suitable solvent such as Ν, Ν-dimethylformamide, at a temperature of 90 to 160 ° C. 4. A process according to any one of claims 1 to 3, wherein the starting material is a compound of formula (I) in which Ra and Rb are either hydrogen, methyl, ethyl or trifluoromethyl, or Ra represents a trifluoromethyl, chloromethyl, 2-chloroethyl or pentafluorophenyl group and Rb represents a hydrogen atom, the benzene ring B is substituted with a protected hydroxy group attached at the 2-position. n is 1, Y represents a trimethylene group, A represents a vinylene group, wherein the carbon atoms adjacent to this group are cis, a Rc is as defined above.