WO1998008837A1 - Phenylbutanol derivatives, methods for their preparation and pharmaceutical compositions thereof - Google Patents

Abstract

The invention relates to novel phenylbutanol derivatives of formula (I), wherein R?1 and R2¿ are hydrogen or form together with the adjacent carbon atoms 6-membered saturated heterocycle containing one oxygen atom; R3 is lower alkyl, hydroxy(lower)alkyl or a group of formula (II) wherein Y is lower alkyl or lower alkoxy and m is 0, 1, 2, 3, 4 or 5; Z represents, independently from each other, hydroxy, lower alkyl, lower alkoxy, (lower)alkoxy(lower)alkoxy, halo or halo(lower)alkyl; n is 0, 1, 2, 3, 4 or 5 with the proviso that if R?1 and R2¿ are other than hydrogen, the value of n is at most 3; and (a) means a single or double chemical bond. The compounds of formula (I) are useful in treating toxic shock, multiple sclerosis, rheumatoid arthritis and Crohn's disease in mammals.

Description

PHENYLBUTANOL DERIVATIVES, METHODS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS

THEREOF

TECHNICAL FIELD

The invention relates to physiologically active phenylbutanol derivatives, methods for their preparation and therapeutically active compositions containing them. The phenylbutanol derivatives of the invention have beneficial effects on lipopolysaccharide (LPS)-induced TNFα and IL-6 plasma levels and are therefore useful, for example, for the treatment of septic shock, multiple sclerosis, rheumatoid arthritis and Crohn's disease. Thus, the invention relates to the use of the phenylbutanol derivatives of the invention in human medicine.

PRIOR ART

Several compounds are known in the art for the treatment of mammals, including human beings, that have been envenomated by poisonous snakes and insects. For example, the European patent specification No. 89229 describes pterocarpan compounds having the formula

wherein R - represents a hydrogen atom and R- represents a -CH C b- CH(CH3)-CH2θH group, or R¹ represents a H CH2OH

/

/

CH2 CH3 group and R^ represents a hydrogen atom.

Said pterocarpan compounds are obtained from aqueous alcoholic extract of the root of the South American cabeca de negra tree.

DISCLOSURE OF THE INVENTION

Our aim was to find compounds having similar or even better physiological activity in the treatment of, in general, septic shock and, as a matter of course, toxic shock than that of the above-mentioned pterocarpan compounds and being at the same time easily obtainable by simple synthetic methods from readily available starting materials.

The novel compounds of the formula (I) meet these requirements. In formula (I)

Rl and R^ are hydrogen or form together with the adjacent carbon atoms a 6- membered saturated heterocycle containing one oxygen atom; R is lower alkyl, hydroxy(lower)alkyl or a group of the formula (II)

wherein Y is lower alkyl or lower alkoxy and m is 0, 1, 2, 3, 4 or 5; represents, independently from each other, hydroxy, lower alkyl, lower alkoxy, (lower)alkoxy(lower)alkoxy, halo or halo(lower)alkyl; n is 0, 1, 2, 3, 4 or 5 with the proviso that if R - and R^ are other than hydrogen, the value of n is at most 3; and — means a single or double chemical bond.

Moreover, the compounds of the formula (I) can be used for the treatment of multiple sclerosis, rheumatoid arthritis and Crohn's disease in view of their activity against the pathogenic factor TNF.

Thus, in one aspect, the invention relates to the compounds of the formula

(I)-

In another aspect, the invention relates to pharmaceutical compositions, especially for treating toxic shock, multiple sclerosis, rheumatoid arthritis and

Crohn's disease, comprising a pharmaceutically acceptable carrier, diluent or adjuvant in admixture with an effective amount of at least one of the compounds of the formula (I).

In another aspect, the invention relates to a method of treating toxic shock, multiple sclerosis, rheumatoid arthritis and Crohn's disease in a mammal, including men, characterized by administering to said mammal an effective amount of at least one of the compounds of the formula (I).

In a still further aspect, the invention relates to processes for preparing compounds of the formula (I) which are described in greater detail hereafter.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the present invention, where R^, Z or Y represents a lower alkyl group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyi or hexyl groups. Of these, we prefer the methyl and ethyl groups.

Where R^ represents a hydroxy(lower)alkyl group, its alkyl moiety can be as defined above. Examples include the hydroxy methyl, 2-hydroxyethyl,

2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl groups. Of these, we prefer the hydroxymethyl and 2-hydroxyethyl groups. Where Z or Y represents a lower alkoxy group, its alkyl moiety can be as defined above. Examples include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy or hexyloxy groups. Of these, we prefer the methoxy and ethoxy groups. Where Z represents a (lower)alkoxy(lower)alkoxy group, its alkoxy moieties can be as defined above. Examples include the methoxymethoxy, ethoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 4-meth- oxybutoxy, 5-methoxypentoxy or 6-methoxyhexyloxy groups. Of these, we prefer the methoxymethyl, ethoxymethyl, 2-methoxyethyl and 2-ethoxyethyl groups.

Where Z represents a halogen atom, it may be a fluoro, chloro, bromo or iodo atom. Of these, we prefer the chloro or bromo atoms.

Where Z represents a halo(lower)alkyl group, its alkyl moieties and halo atoms can be as defined above. Examples include the chloromethyl, bromo- methyl, difluoromethyl, trifluoromethyl, iodomethyl, 2-chloroethyl, 1,2-dichloro- ethyl, 2,2-dichloroethyl or 3-chloropropyl groups. Of these, we prefer the trifluoromethyl group.

In the formula (I) the value of n is equal to 0, 1 , 2, 3, 4 or 5 provided that there is no sterical hindrance between the individual substituents of the benzene ring. If R- and R-2 form with the adjacent carbon atoms a 6-membered saturated heterocyclic group, the value of n can be, as a matter of course, at most 3. The value of n is preferably 1, 2 or 3.

In the formula (II) the value of m is equal to 0, 1, 2, 3, 4 or 5 provided that there is no sterical hindrance between the individual substituents of the benzene ring. The value of m is preferably 1, 2 or 3.

Where — represents a double bond, the compounds of the formula (I) may form stereoisomers of Z and E configuration. The scope of the compounds of the present invention extends to the individual stereoisomers and to their mixtures of any ratio. Where stereospecific synthesis techniques are employed or stereo- isomers are used as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.

Of the compounds of the present invention, a preferred class of compounds are those compounds of formula (I) in which R- and R^ are each hydrogen; R^ is lower alkyl or a group of the formula (II) wherein Y is lower alkoxy and m is 2; Z is hydroxy, lower alkyl or lower alkoxy and n is 1, 2 or 3.

Of the compounds of the present invention, another preferred class of compounds are those compounds of formula (I) in which Rl and R~ form together with the adjacent carbon atoms a 6-membered saturated heterocycle containing an oxygen atom; R^ is lower alkyl; Z is hydroxy, lower alkoxy or (lower)alkoxy(lower)aIkoxy; and n is 1.

Of the specific compounds of the present invention, preferred compounds are:

2 -methy l-4-(2 , 6-dimethoxypheny l)-butano 1 ; E-2-ethyl-4-(2,6-dimethoxyphenyl)-2-butene- 1 -ol; E-2-propyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol;

2,4-[bis-(2,6-dimethoxyphenyi)]-2-butene-l-ol; 2,4-[bis-(2,6-dimethoxyphenyl)]-butanol; Z-2-methy l-4-(2,6-dimethoxyphenyl)-2-butene- 1 -ol; E-2-methyl-4-(2,6-diethoxyphenyl)-2-butene-l-ol; E-2-methyl-4-(2-ethoxy-6-methoxyphenyl)-2-butene- l-ol;

E-2-methyl-4-(2,4-dihydroxyphenyl)-2-butene-l-ol; 7-hydroxy-8-(3-hydroxymethy 1-buty 1- 1 )chromane; E-2-methyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol; Z-2-methy l-4-(2-hydroxy-6-methoxypheny I)-2-butene- 1 -ol; E-2-methyl-4-(2,4,6-trimethoxyphenyl)-2-butene- l-ol;

E-2-methyl-4-(2,6-dimethoxy-4-methylphenyl)-2-butene- 1 -ol; E-2-methyl-4-(2,6-dimethoxy-4-n-propylphenyl)-2-butene-l -ol; 2-hydroxymethyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol; E-7-methoxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane; E-7-(methoxymethoxy)-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane; and E-7-hydroxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane.

The compounds of the present invention may be prepared by a variety of processes well known in the art for the preparation of compounds of this type. In the following these processes are elucidated in detail. Compounds of the formula (I) containing a double bond, i.e. the compounds of the formula (I¹) can be prepared according to Reaction Scheme A. In the above formulae Rl, R2, R3, Z and n are as defined at formula (I), "Hal" represents a halogen atom and "Ac" represents an acyl group.

Thus, in accordance with reaction scheme A the compounds of the formula (I') can be prepared through ester hydrolysis of a compound of the formula (III) by removing the acyl group.

As an acyl group one can use any kind of acyl groups derived from appropriate alkanoic acids, preferably lower alkanoic acids having 2 to 6 carbon atoms, like acetic acid. The ester hydrolysis can be performed by using a base or acid.

As base for this purpose one can use inorganic bases like alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide.

Again, as acid for this purpose one can use organic acids or inorganic acids. As organic acid e.g. acetic acid or trifluoroacetic acid can be mentioned. As inorganic acid e.g. hydrogen chloride or sulfuric acid can be mentioned.

The reaction is carried out suitably in a solvent. In some cases the acid itself can serve as a solvent but more frequently an inert, polar solvent is used. As such solvents e.g. water or a mixture of water and lower alcohols, for example, methanol or ethanol, can be mentioned. The reaction is performed suitably at a temperature of 0°C to 100°C, preferably 10°C to 50°C, most preferably at ambient temperature. REACTION SCHEME A

(IV)

(III)

d')

The intermediates of the formula (III) can be made in a two-step procedure by starting from a compound of the formula (V), introducing the side chain and then oxidizing the thus-obtained compound of the formula (IV) to obtain an intermediate of the formula (III). The compounds of the formula (V) are well known or can be prepared by methods known in the art.

The introduction of the side chain into the compounds of the formula (V) can be performed, for example, by converting a compound of the formula (V) first into its lithium derivative and reacting the latter with an allyl-type halide of the formula (VI).

The conversion of a compound of the formula (V) into its lithium derivative can be performed by using an organic lithium compound such as a lower alkyl lithium, preferably n-butyl lithium. The conversion is carried out in an inert solvent, preferably in an ether, more preferably diethyl ether, at a temperature between ambient temperature and the boiling point of the reaction mixture. The lithiated derivative is reacted with a halide of the formula (VI). "Hal" in this formula represents e.g. bromo, chloro or iodo atom, preferably bromo atom. The reaction is carried out in an inert solvent like aromatic hydrocarbons, e.g. benzene or toluene. The compounds of the formula (III) are obtained through oxidation of the compounds of the formula (IV). This oxidation can be performed by well known oxidizing agents like hydrogen peroxide, organic peroxides or metal oxides, e.g. Seθ2- The oxidation is performed in an organic solvent like acetic anhydride at a temperature of 80 to 150°C. Compounds of the formula (I) can be prepared according to Reaction

Scheme B. In the above formulae R-, R^, , Z and n are as defined at formula (I) and R4 represents a hydrogen atom or a lower alkoxy group. REACTION SCHEME B

(VII)

(!')

Thus, in accordance with process B the compounds of the formula (I) can be prepared by selective reduction of the oxo function in the -COR4 group of the compounds of the formula (VII) into an alcoholic function, i.e. a hydroxymethyl group. If the carbon-carbon double bond in the alkene portion of the molecule is to be saved, the reduction must be selective. Said oxo group can be either part of an aldehyde (if R^ represents hydrogen) or an ester (if R^ represents a lower alkoxy group) function. In some cases one can use a mixture of an aldehyde and an ester of the formula (VII) as starting material.

The (selective) reduction can be carried out by known methods, using reducing agents known in the art (c.f. Larock: "Comprehensive Organic Transformations", pp. 527-552, VCH Publishers, Inc., New York, 1989). In order to perform the desired transformation lithium aluminum hydride is particularly preferable as reducing agent but one can use other reducing agents like different metal hydrides. The reduction is carried out usually in an inert organic solvent. As solvent one can use protic and aprotic solvents, preferably ether type solvents, most preferably diethyl ether or tetrahydrofuran. The reaction is carried out at a temperature between 20 °C and the boiling point of the solvent used, preferably between 20 °C and 70°C. The intermediates of the formula (VII) can be prepared from aldehydes of the formula (VIII) by reacting the latter with corresponding phosphonium salts or phosphonic acid esters, i.e. by performing a Wittig or Wittig-Horner reaction (c.f. supra, pp. 173-180).

The aldehydes of the formula (VIII) can be prepared by well known methods. Without giving an exhaustive list of these methods the following two are briefly described.

(i) A benzene derivative of the formula (V) is reacted with an alkyl lithium and subsequently with dimethyl or diethyl acetate of bromoacetaldehyde, followed by hydrolysis. (ii) The C=C double bond of a compound of the formula (IV) is oxidized in a known manner, preferably by using sodium periodate in the presence of a catalytic amount of osmium tetroxide.

Compounds of the formula (I) containing a single bond as the dotted line can be prepared by hydrogenating a compound of the formula (I) containing the exocyclic double bond or by hydrogenating an intermediate of formula (VII) and reducing the COR⁴ group. This reduction can be carried out by catalytical hydrogenation. As catalyst one can use noble metal catalysts, like platinum, palladium or palladium oxide, preferably on a support like charcoal, etc. The hydrogenation is carried out at a pressure of 1 to 100 bar, at a temperature of 20°C to 80 °C in an inert organic solvent like alcohols. The target compounds of the formula (I) and the key intermediates of the formulae (III), (IV), (VII) and (VIII) can be separated and purified by methods well known in the art like filtration, crystallisation and chromatography, e.g. column chromatography.

The compounds of the formulae (III) and (VII) are novel and therefore form a further aspect of the present invention. The majority of the compounds of the formula (IV) are also novel except those wherein R- and R^ are hydrogen, R^ is methyl, n is equal to 2, Z represents methoxy or hydroxy and the _ZZI means a single or double chemical bond. [3,5-Dimethoxy-n-propylbenzene is described in Sonn: Chem. Ber., 5_7, 960 (1924); 2,6-dimethoxyprenylbenzene is known from Cotteril et al: J. Chem. Soc. Perk. Trans. 1, (1974), 2423 and 2,4-dihydroxyprenylbenzene is known from Yamada et al.: Bull. Chem. Soc. Jap., 50, 750 (1970)].

As already referred to above, the compounds of the formula (I) of the present invention effect on lipopolysaccharide (LPS)-induced TNFα and IL-6 plasma levels and are therefore useful, for example, for the treatment of septic shock.

As it is well known, severe infections, particularly with gram-negative bacteria, have resulted in an increasing incidence of sepsis and septic shock among hospitalized patients. Also, high mortality associated with sepsis and septic shock persist despite appropriate antibiotic therapy. According to recent publications [c.f. Remick D.G.: "Cytokines and septic shock", Clin. Infect Dis., i, 37-50 (1994)], "Septicemia is the 13th leading cause of death in the United States. Data from the National Hospital Discharge Survey of the Centers for Disease Control's National Center for Health Statistics have demonstrated a 139 % increase in the rate of septicaemia from 73.6/100,000 persons. Although the rate increased among all age groups, the increase was greatest for persons over 65 years of age. In addition, septic shock is the most common cause of death among intensive care unit patients in the United States [Parrillo, J. E., Parker, M. M., Natanson, C. et al: "Septic shock in humans: Advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy", Ann. Intern. Med, 1 13, 227-242 (1990)]. Mortality rates from septic shock range from 40 to 90 % [Bone, R. C, Balk, R. A., Cerra, F. B. et al: "Definitions for sepsis and organ failure and guidelines for innovative therapies in sepsis". The ACCP/SCCM Consensus Conference Committee; American College of Chest Physicians/Society of Critical Care Medicine, Crit. Care Med., 20, 864-874 (1992) and Parrillo, J. E.: "Pathogenetic mechanisms of septic shock" N. Engl. J. Med., 328, 1471-1477 (1993)]. More recently it has become clear that cytokine cachectic/tumor necrosis factor (TNF) occupies a key role in the pathophysiology associated with diverse inflammatory states and other serious illnesses including septic shock and cachexia. Several studies have shown that tumor necrosis factor (TNF) plays an important role as a prime mediator of the inflammatory response seen in sepsis management in the future will include immune modulating therapy directed against the deleterious effects of cytokines, specifically TNF (c.f. Remick supra).

Since TNF neutralization in the treatment of septic shock [Pennington J.E: "Therapy with antibody to tumor necrosis factor in sepsis", Clin. Infect Dis, J_7, 515-9 (1993)] and in the treatment of rheumatoid arthritis [Elliot M.J., Maini R.N., Feldmann M., Kalden J.R., Antoni C, Smolen J.S., Leeb B., Breedveld F.C., Macfarlane J.D., Bijl H., Woody J.N.: "Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis", Lancet, 344, 1105-10 (1994] is now well known as the result of double-blind, placebo-controlled phase III clinical trials in which monoclonal antibodies against TNF were administered, and TNF seems to be the main pathogenic factor in multiple sclerosis and Crohn's disease [Raine C: "Multiple sclerosis: TNF revisited, with promise", Nature Medicine, L 211- 14, (1995)], therefore the compounds of the invention can be used in the treatment of these diseases. Method (ELISA)

1. TNF ELISA

ELISA kit for murine TNF-alpha was obtained from Genzyme (Cambridge, MA). ELISA was performed by a four-stage procedure in a microtiter plate coated the previous day with monoclonal antibody specific for TNF-alpha. Plasma samples (dilution 1 :6) or TNF standards and control solutions were placed in the wells and incubated according to the manufacturer's instructions. Each sample was measured in duplicate. The wells were washed rigorously between each step.

After the initial incubation, polyclonal gout anti-murine TNF antibody was added to each well. A third antibody, horseradish peroxidase-conjugated donkey antigout Ig, was then added. The substrate o-phenylenediamine was added for the last, or indicator step. Optical densities of the indicator then were determined at 492 nm by an automated ELISA reader (Bio-Rad, Richmond, CA). Absorbance was transformed into data (pg/ml) using the Microplate Manager/PC Data Analysis Software (BIO-RAD).

2. IL-6 ELISA

ELISA kit for murine IL-6 obtained from Endogen (Boston, MA). ELISA was performed by a three-stage procedure in a microtiter pre-coated anti-murine IL-6 96-well stripwell plate. Plasma samples (dilution 1 : 140), IL-6 standards and control solutions were placed in the wells (in duplicate) and incubated according to the manufacturer's instructions. The wells were washed 5 times rigorously between each step. After the initial incubation, pre-diluted conjugate reagent was added to each well. The substrate reagent was added for the last, indicator step. Absorbance was measured at 492 nm. Absorbance was transformed into data using the Microplate Manager/PC Data Analysis Software (BIO-RAD). RESULTS

Mice (20-26 g) were treated with bacterial lipopolysaccharide (LPS, endotoxin, 2 mg/kg, i.p.) in order to induce a production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Thirty minutes before the injection of LPS, the animals received different doses of Cabenegrin -Al known from the European patent specification No. 89 229 (5, 10 and 20 mg/kg, i.p.) or its derivatives in doses of 40 mg/kg. Ninety minutes after the mice had been treated with LPS, they were decapitated and the blood was collected in chilled tubes. After separation, the plasma was kept at -70 °C until assay. Both plasma TNF and IL-6 were measured with ELISA using commercially available kits for mouse TNF-α (Genzyme. Inc.,) and IL-6 (Endogen).

SUMMARY

Evidence was obtained that pretreatment of mice with Cabenegrin Al, furthermore the compounds of Examples 1 , 3, 8, 10, 14 and 17 significantly inhibited the effect of LPS to increase/induce TNF-α levels in the plasma. In contrast, Cabanegrin did not change or in a doses of 10 mg/kg even increased the

LPS-induced IL-6 levels in plasma.

Since increased TNF-α level has been suggested to be involved in the pathogenesis of the septic shock, these findings suggest that the phenylbutanol derivatives of the present invention might be beneficial for the treatment of the septic shock.

Mean ± standard error of means. Significance: *p > 0.05; **p > 0.01. Control value was taken as 100%. Control value of TNF-α and IL-6 levels means levels assayed in plasma taken from non-treated animals. Six animals were in each group.

A pharmaceutical composition which contains as its active ingredient one or a plurality of the compounds of the formula (I) is made into various dosage forms such as tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, plasters and the like, making use of conventionally used pharmaceutical carriers, excipients and other additives, and administered orally or parenterally. Clinical dose of the compounds of the present invention for human may be optionally decided taking symptoms, weight, age, sex and the like of each patient into consideration, but it may generally be in the range of from 5 to 1000 mg per adult (about 65 kg) per day in the case of oral administration, and the daily dose may be used in one portion or divided portions. Since the dose varies under various conditions, sufficient effects may be obtained in some cases with smaller dose than the above range.

As solid compositions for oral administration according to the present invention, tablets, powders, granules and the like may be used. In such solid compositions, one or a plurality of active ingredients may be mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, fine crystalline cellulose, starch, polyvinyl pyrrolidone or magnesium aluminate metasilicate. In accordance with the conventional way, the composition may contain other additives than the inert diluent, which include a lubricant such as magnesium stearate, a disintegrating agent such as fibrin calcium glycolate, a stabilizing agent such as lactose, vitamin E or ascorbic acid and a solubilizing agent or a solubilization aid such as glutamic acid or aspartic acid. As occasion demands, tablets or pills may be coated with a film of gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like.

Liquid compositions for use in oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like which contain commonly used inert diluents such as purified water and ethyl alcohol. In addition to the inert diluents, such compositions may also contain auxiliary agents such as a solubilizing agent or a solubilization aid, a moistening agent, a suspending agent and the like, as well as a sweetening agent, a flavouring agent, an aromatic agent and an antiseptic agent.

Injections for use in parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of diluent for use in aqueous solutions and suspensions include distilled water for injection use and physiological saline. Examples of diluent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, plant oils (e.g. olive oil), alcohols (e.g. ethyl alcohol) and Polysorbate 80 (trade name). Such compositions may also contain additives such as a tonicity agent, an antiseptic agent, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g. lactose) and solubilization aid, a solubilizing agent and the like. These compositions are sterilized by bacterial filtration through a bacteria-retaining filter, bactericide blending or irradiation. Alternatively, an aseptically produced solid composition may be used by dissolving, emulsifying or dispersing it in sterile water or a sterile solvent for injection use prior to its use. The above pharmaceutical compositions may contain the compounds of the formula (I) in the form of their inclusion complexes, too. For this purpose one can use e.g. cyclodextrin.

The following examples serve to illustrate the present invention without limiting, however, its scope. Example 1

E-2-MethyI-4-(2,6-diethoxyphenyl)-2-butene-l-oI a) 2,6-DiethoxypheπylacetaIdehyde

To a solution of 1,3-diethoxybenzene (4 g, 25 mmol) in anhydrous cyclohexane (50 ml) a 15 % solution of n-butyl lithium (20 ml) in cyclohexane was added dropwise under N2- The mixture was boiled for 1.5 h. The red suspension was cooled to room temp, and bromoacetaldehyde diethyl acetal (4.3 ml) was added and boiled for 1.5 h. After cooling, the reaction mixture was diluted with a solution of saturated NaHCO3 and separated. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The residue was dissolved in ethanol (50 ml) and stirred with aqueous HCl (5 ml, 1 : 1 ) at room temperature for 10 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. The residue was purified on a silica gel column with the eluent of hexane:ethyl acetate (10: 1) yielding 2,6-diethoxy- phenylacetaldehyde in 50 % yield, R_f = 0.5. ^ H-NMR (CDCI3) δ (ppm): 1.4 (t, 6H, 2xCH₃), 3.7 (d, 2H, CH₂-Ar), 4.0 (q, 4H, 2xCH₂), 6.5 (d, 2H, H-3, H-5, aromatic H), 9.6 (m, IH, CHO). b) E-Ethyl 2-methyl-4-(2,6-diethoxyphenyl)crotonate

4.9 mmol (1.03 g) of 2,6-diethoxyphenylacetaldehyde, 7.2 mmol (3.2 g) of phosphonium salt, prepared from triphenylphosphine and ethyl 2-bromo- propionate, was dissolved in abs. ethanol (50 ml) at room temperature and 1 N sodium ethylate in dry ethanol (15 ml) was added under N₂ atmosphere. The reaction mixture was stirred for 2 hours and then diluted with water and extracted with CH2C12- The organic phase was washed with water, dried and evaporated. The residue was purified using flash chromatography (50 g silica gel, hexane- ethyl acetate (10: 1) as eluent) yielding 0.95 g (66 %) of E-ethyl 2-methyl-4-(2,6- diethoxyphenyl)crotonate. Rf = 0.6. ΪH-NMR (CDCI3) δ (ppm): 1.2 (t, 3H, CH3), 1.4 (t, 6H, 2xCH3), 2.0 (s, 3H, CH3), 3.5 (d, 2H, CH₂-Ar), 4.0 (q, 4H, 2xCH2), 4.1 (q, 4H, CH₂), 6.5 (d, 2H, H-3, H-5 aromatic H), 6.8 (m, I H, CH), 7.1 (m, 1 H, H-4 aromatic H). c) E-2-Methyl-4-(2,6-diethoxyphenyI)-2-butene-l-ol

LiAlH4 (0.9 g) was suspended in abs. ether (25 ml) and cooled to 0 °C. A solution of E-ethyl 2-methyl-4-(2,6-diethoxyphenyl)crotonate (0.9 g, 3 mmol) in abs. ether (50 ml) was added to the suspension under stirring. The reaction mixture was stirred at room temperature for 2 hours and was poured into a solution of saturated NH4CI. After extraction with ethyl acetate, washing, drying and evaporation, 0.79 g of crude product was isolated which was chroma- tographed on silica gel (50 g, hexane-ethyl acetate, 5:2). 0.55 g (71 %) of E-2- methyl-4-(2,6-diethoxyphenyl)-2-butene-l-ol was obtained, m.p. 74-76 °C, Rf = 0.4. iH-NMR (CDCI3) δ (ppm): 1.35 (t, 6H, 2XCH3), 1.5 (br. s, IH, OH), 1.85 (s, 3H, CH3), 3.45 (d, 2H, CH₂-Ar), 4.0 (q, 4H, 2xCH₂), 4.05 (s, 2H, CH₂O), 5.5 (t, IH, =CH), 6.5 (d, 2H, H-3, H-5 aromatic H), 7.05 (m, IH, H-4 aromatic H). C _j 5H22O3 (250.30) Calculated C 71.97, H 8.84 Found C 71.86, H 8.65. Example 2 E-2-Methyl-4-(2-ethoxy-6-methoxyphenyl)-2-butene-l-ol a) 2-Ethoxy-6-methoxy-phenyiacetaldehyde diethyl acetal

Starting from l-ethoxy-3-methoxybenzene [Spitz: Monatshefte Chem. 5, 498 (1884)] (3.8 g, 25 mmol) and using the same procedure as described in Example 1, step a), 2.8 g (42 %) of acetal was obtained, Rf = 0.4. ^ΪH-NMR (CDC1₃) δ (ppm): 1 ,1 (t, 6H, 2XCH3), 1.4 (t, 3H, CH3), 3.05 (d, 2H, CH₂-Ar), 3.4 and 3.7 (m, 4H, 2xCH₂), 3,85 (s, 3H, CH3O), 4.0 (q, 2H, CH ), 4.9 (t, IH, CH), 6.5 (d, 2H, H-3, H-5, aromatic H), 7.1 (m, IH, H-4 arom.) b) 2-Ethoxy-6-methoxyphenylacetaIdehyde

2.6 g (10 mmol) of the acetal obtained in step a) above was stirred in ethanol (100 ml) in the presence of 1 : 1 HCl (10 ml) for 20 hours at room temperature. The ethanol was distilled in vacuo and the residue was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated yielding 1.8 g (92 %) of 2-ethoxy-6-methoxyphenylacetaldehyde, Rf = 0.4 (hexane-ethyl acetate, 10:1 ). *H-NMR (CDCI3) δ (ppm): 1.4 (t, 3H, CH3), 3.65 (d, 2H, CH₂-Ar), 3.85 (s, 3H, CH3O), 4.05 (q, 2H, CH ), 6.6 (d, 2H, H-3), H-5 aromatic H), 7.25 (m, IH, H-4 arom.), 9.65 (t, IH, CHO). c) E-Ethyl 2-methyl-4-(2-ethoxy-6-methoxypheny.)crotonate 0.37 g (2 mmol) of 2-ethoxy-6-methoxyphenylacetaldehyde, abs. ethanol

(15 ml), phosphonium salt (1.14 g, 2.5 mmol) (see Example 1 , step b) and IN NaOEt (5.3 ml) was stirred at room temperature under N2 atmosphere for 2 hours. The reaction mixture was diluted with water and then extracted with CH2CI2- Working up as earlier and purification on silica gel using hexane-ethyl acetate(10: l ) as eluent afforded 0.3 g (56 %) of pure E-ethyl 2-methyl-4-(2- ethoxy-6-methoxyphenyl)crotonate.

^ΪH-NMR (CDCI3) δ (ppm): 1.3 (t, 3H, CH3), 1.45 (t, 3H, CH3), 2.0 (s, 3H, CH3C), 3.65 (d, 2H, CH₂-Ar), 3.8 (s, 3H, OCH3), 4.0 and 4.15 (q, 4H, 2xCH2), 6.5 (d, 2H, H-3, H-5 arom.), 6.75 (m, IH, CH), 7.1 (m, IH, H-4 arom.) d) E-2-Methyl-4-(2-ethoxy-6-methoxyphenyI)-2-butene-l-ol

0.27 g (1 mmol) of E-ethyl 2-methyl-4-(2-ethoxy-6-methoxyphenyl)- crotonate in abs. ether (25 ml) was reduced with LiAlH4 as described previously. The crude product was chromatographed on silica gel using hexane-ethyl acetate (5:2) as eluent, yielding 0.15 g of E-2-methyl-4-(2-ethoxy-6-methoxyphenyl)-2- butene- 1-ol as colourless oil, Rf - 0.55. iH-NMR (CDCI3) δ (ppm): 1.4 (t, 3H, CH3), 1.5 (br.s., IH, OH), 1.85 (s, 3H, CH3C), 3.4 (d, 2H, CH₂-Ar), 3.8 (s, 3H, OCH3), 4.0 (q, 4H, 2xCH ), 5.5 (m, IH, CH), 6.5 (d, 2H, H-3, H-5 arom.), 7.05 (m, IH, H-4 arom.). Example 3

E-2-Methyl-4-(2,4,6-trimethoxyphenyl)-2-butene-l-ol a) 2-Methyl-4-(2,4,6-trimethoxypheny_)-2-butene

Phloroglucinol trimethyl ether (0.55 g, 3.2 mmol), abs. cyclohexane (10 ml) and n-butyl lithium (2.5 ml) was boiled for 1.5 hours. Prenyl bromide (0.5 mol) was added to the reaction mixture and it was boiled for another 1.5 hours. After working up the crude product was chromatographed on silica gel using hexane- ethyl acetate (9: 1) as eluent. 0.5 g (64 %) of 2-methyl-4-(2,4,6-trimethoxy- ρhenyl)-2-butene was obtained, Rf = 0.6. ^ΪH-NMR (CDCI3) δ (ppm): 1.6 and 1.75 (s, 6H, 2XCH3), 3.25 (d, 2H, CH2-Ar), 3.75 (s, 9H, 3xOCH3), 5.15 (t, IH, CH), 6.1 (s, 2H, H-3, H-5 arom.) b) l-Acetoxy-2-methyl-4-(2,4,6-trimethoxyphenyl)-2-butene and 2-for- myl-4-(2,4,6-tr_methoxyphenyl)-2-butene

0.44 g ( 1.8 mmol) of 2-methyl-4-(2,4,6-trimethoxyphenyl)-2-butene, AC2O (5 ml) and SeO₂ (0.25 g, 2.2 mmol) was boiled for 30 minutes. The reaction mixture was diluted with cold water and extracted with ethyl acetate. After washing, drying and evaporation the residue was chromatographed on silica gel using hexane-ethyl acetate (5:2) as eluent yielding 0.15 g of 2-formyl-4-(2,4,6- trimethoxyphenyl)-2-butene and 1 -acetoxy-2-methyl-4-(2,4,6-trimethoxyphenyl)- 2-butene, Rf = 0.5 and 0.4. The ratio of 2-formyl-4-(2,4,6-trimethoxyphenyl)-2- butene and l-acetoxy-2-methyl-4-(2,4,6-trimethoxyphenyl)-2-butene was found to be 2: 1 on the basis of the ^H-NMR spectrum. H-NMR (CDCI3) δ (ppm) of 2-formyl-4-(2,4,6-trimethoxyphenyl)-2-butene: 1.8 (s, 3H, CH3C), 3.6 (d, 2H, CH₂Ar), 3.85 (s, 9H, 3xOCH₃), 6.1 (s, 2H, aromatic), 6.5 (t, 1H, CH), 9.35 (s, IH, CHO). iH-NMR (CDCI3) δ (ppm) of l-acetoxy-2-methyl-4-(2,4,6-trimethoxyphenyl)-2- butene: 1.8 (s, 3H, CH3C), 1.9 (s, 3H, CH3CO), 3.35 (d, 2H, CH₂Ar), 3.85 (s, 9H, 3xOCH3), 4.4 (s, 2H, CH2O), 5.5 (t, IH, CH), 6.15 (s, 2H, aromatic H). c) E-2-Methyl-4-(2,4-6-trimethoxyphenyl)-2-butene-l-ol A mixture of 2-formyl-4-(2,4,6-trimethoxyphenyl)-2-butene and 1-acetoxy- 2-methyl-4-(2,4,6-trimethoxyphenyl)-2 -butene (150 mg) prepared above was reduced with LiAlH4 in abs. ether at room temperature for 1 hour. After working up in the usual way E-2-methyI-4-(2,4-6-trimethoxyphenyl)-2-butene-l-ol was obtained in 70 % yield as colourless oil. Rf = 0.3 (hexane-ethyl acetate, 5:2). iH-NMR (CDCI3) δ (ppm): 1.85 (s, 3H, CH3C), 3.45 (d, 2H, CH₂-Ar), 3.8 (s, 9H, 3xCH3), 5.45 (t, IH, CH), 6.2 (s, 2H, aromatic H). Example 4 E-2-Methyl-4-(2,6-dimethoxy-4-methylphenyI)-2-butene-l-oI a) 2,6-Dimethoxy-4-methylphenylacetaldehyde

Orcinol dimethyl ether (4.2 g, 27.6 mmol) was dissolved in abs. cyclo- hexane (50 ml) under N2 and was cooled to 0 °C; 19 ml (15 %) of n-butyl lithium was added dropwise to the solution at 0 °C temperature and then was boiled for 30 minutes. After cooling to room temperature bromoacetaldehyde diethyl acetal (4.25 ml, 28.2 mmol) was added and the mixture was boiled for 1.5 hours. After dilution with a solution of NaHCO3 and extraction with ethyl acetate the organic phase was washed, dried and evaporated. The residue was dissolved in ethanol (100 ml) and in the presence of 1 : 1 HCl (10 ml) was stirred for 24 hours at room temperature. The solvent was evaporated and the residue was extracted with ethyl acetate. Working up in the usual way 1.8 g (34 %) of

2,6-dimethoxy-4-methylphenylacetaldehyde was obtained, Rf = 0.4 (hexane- ethyl acetate, 10: 1). ^H-NMR (CDCI3) δ (ppm): 2.35 (s, 3H, CH3-A1), 3.65 (d, 2H, CH₂-Ar), 3.8 (s, 6H, 2xOCH ), 6.4 (s, 2H, H-2, H-6 arom.), 9.5 (t, IH, CHO). b) E-Ethyl 2-methyl-4-(2,6-dimethoxy-4-methylphenyI)crotonate

A mixture of 2,6-dimethoxy-4-methylphenylacetaldehyde (1.5 g, 7.8 mmol), abs. ethanol (70 ml), phosphonium bromide (4.2 g) (see Example 1 , step b) and IN NaOEt (22 ml) was stirred under N2 at room temperature for 2 hours.

After evaporation the residue was extracted with CH2CI2. The organic phase was washed, dried and evaporated yielding E-ethyl 2-methyl-4-(2,6-dimethoxy-4- methylphenyl)crotonate as crude product, which was chromatographed on silica gel with hexane-ethyl acetate (10: 12) as eluent, yielding 1.35 g (62 %) of E-ethyl

2-methyl-4-(2,6-dimethoxy-4-methylphenyl)crotonate as colourless oil, Rf = 0.4. iH-NMR (CDCI3) δ (ppm): 1.25 (t, 3H, CH3), 2.0 (s, 3H, CH3C), 2.3 (s, 3H,

ArCH₂), 3.5 (d, 2H, CH₂-Ar), 3.8 (s, 6H, 2xOCH₃), 4.15 (q, 2H, CH3), 6.35 (s.

2H, aromatic H), 6.75 (t, IH, CH). c) E-2-Methyl-4-(2,6-dimethoxy-4-methylphenyl)-2-butene-l-ol

To the suspension of L-AIH4 (1.35 g) in abs. ether (35 ml) 1.35 g (5.1 mmol) of E-ethyl 2-methyl-4-(2,6-dimethoxy-4-methylphenyl)crotonate was added in abs. ether (75 ml) during 30 minutes. After 2 hours stirring the excess of

L-AIH4 was decomposed with a solution of saturated NH4CI, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried and evaporated yielding the crude E-2-methyl-4-(2,6-dimethoxy-4- methylphenyl)-2-butene-l-ol which was chromatographed on a silica gel column with hexane-ethyl acetate (5:2) as eluent. The yield was 0.35 g (30 %), Rf = 0.4.

*H-NMR (CDCI3) δ (ppm): 1.5 (s, IH, OH), 1.8 (s, IH, CH3C), 2.35 (s, 3H, ArCH₃), 3.4 (d, 2H, CH₂Ar), 3.8 (s, 6H, 2XOCH3), 4.0 (s, 2H, CH₂O), 5,45 (t,

IH, CH), 6.4 (s, aromatic H).

Example 5

Z-2-Methyl-4-(2,6-d_methoxyphenyl)-2-butene-l-ol a) 1.3 g (5.2 mmol) of E-ethyl-2-methyl-4-(2,6-dimethoxyphenyl)crotonate in anhydrous benzene (280 ml) placed into a quartz pot was irradiated with a mercury lamp (450 W) for 3 hours.

The solvent was distilled and the residue was purified by silica gel column chromatography with toluene-methyl ethyl ketone (40:1) as the eluent, to give Z- ethyl-4-(2,6-dimethoxyphenyl)crotonate (180 mg, 15%). iH-NMR (CDCI3) δ (ppm): 1.35 (t, 3H, CH3), 1.9 (s, 3H, CH3C), 3.85 (s, 6H, 2xOCH ), 3.9 (d, 2H, CH₂Ar), 4.3 (q, 2H, CH₂), 5.9 (t, IH, CH), 6.6 (d, 2H, H- 3, H-5 aromatic H), 7.15 (t, IH, H-4 aromatic H). b) Z-ethyl-4-(2,6-dimethoxyphenyl)crotonate (0.17 g, 0.6 mmol) was reduced with L1AIH4 in anhydrous ether (50 ml) for 3 hours. After working up the residue was flash chromatographed on silica gel with hexane-acetone (5: 1) as the eluent affording 0.015 g (10 %, R_f = 0.4) of Z-2-methyl-4-(2,6- dimethoxyphenyl)-2-butene-l-ol. *H-NMR (CDCI3) δ (ppm): 1.7 (s, 3H, CH3- C), 1.95 (s, IH, OH), 3.4 (d, 2H, CH2Ar), 3.75 (s, 6H, 2XOCH3), 4.25 (s, 2H, CH₂OH), 5.45 (t, IH, CH), 6.5 (d, 2H, H-3, H-5 aromatic H), 7.1 (t, IH, H-4 aromatic H).

Example 6 2-Methyl-4-(2,6-dimethoxyphenyl)-butanol a) 2,6-Dimethoxyphenylacetaldehyde diethyl acetate 15 % Butyl lithium in cyclohexane (37.8 ml) was added dropwise to the solution of resorcinol dimethyl ether (6.38 ml, 0.05 mol) in anhydrous cyclohexane (100 ml) under N2 with stirring. The reaction mixture was boiled for 1.5 hours. To the cooled mixture 10 g (0.055 mol) of bromoacetaldehyde diethyl acetal was added and then was boiled for another 1.5 hours. After addition of NaHCO3 solution the mixture was extracted with CH2CI2. The organic phase was washed with water, dried and evaporated affording 10.7 g (84 %) of crude product (mixture of acetal and aldehyde ~ 1 : 1 on the basis of the NMR spectra). Acetal ^H-NMR (CDCI3) δ (ppm): 1.15 (t, 3H, CH3), 3.0 (d, 2H, CH₂Ar), 3.4 (q, 2H, CH₂), 3.7 (s, 6H, 2xOCH ), 4.85 (t, IH, CH), 6.55 (m, 2H, H-3, H-5 aromatic H), 7.2 (m, IH, H-4 aromatic H). Aldehyde ^H-NMR (CDCI3) δ (ppm): 3.7 (d, 2H, CH Ar), 3.8 (s, 6H, 2xOCH3), 6.6 (d, 2H, H-3, H-5 aromatic H), 7.25 (m, IH, H-4 aromatic H), 9.55 (t, IH, CHO). b) 2,6-Dimethoxyphenylacetaldehyde

The mixture of acetal and aldehyde (11.9 g) as obtained in step a) above was dissolved in ethanol (100 ml) and stirred with 10 % HCl (20 ml) at room temperature for 20 hours. The solvent was distilled and the aqueous phase was extracted with CH₂C1₂. The organic phase was washed, dried and concentrated in vacuum. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (5: 1) as the eluent yielding 3 g (33 %) of 2,6-dimethoxy- phenylacetaldehyde, m.p.: 37-38 °C. *H-NMR (CDC1₃) δ (ppm): 3.7 (d, 2H, CH2Ar), 3.8 (s, 6H, 2xOCH3), 6.6 (d, 2H, H-3, H-5 aromatic H), 7.25 (m, IH, H-4 aromatic H), 9.5 (t, IH, CHO). ClO^H12°3 (180.19) Calculated C 66.65, H 6.7

Found C 65.98, H 6.52. c) E-Ethyl 2-methyl-4-(2,6-dimethoxyphenyl)-crotonate

2,6-Dimethoxyphenylacetaldehyde (3 g, 16.6 mmol) was added to the mixture of phosphonium salt (see Example 1 , step b) (9.3 g, 22 mmol), anhydrous ethanol (140 ml) and IN NaOEt (43 ml, 42 mmol) under N₂ with stirring at room temperature. After 2 hours the ethanol was distilled and the residue was extracted with CH2CI2. The organic phase was washed, dried and evaporated and the residue was flash chromatographed on silica gel with toluene-dichloromethane (1 : 1) yielding 3.3 g (75 %) of pure E-ethyl 2-methyl-4- (2,6-dimethoxyphenyl)-crotonate (Rf = 0.7). ΪH-NMR (CDCI3) δ (ppm): 1.25 (t, 3H, CH3), 3.0 (s, 2H, CH₃-CH₂), 3.5 (d, 2H, CH₂-Ar), 3.8 (s, 6H, 2xOCH ), 4.15 (q, 2H, CH₂), 6.5 (d, 2H, H-3, H-5 aromatic H), 6.8 (t, IH, CH), 7.15 (m, IH, H-4 aromatic H). d) Ethyl 2-methyι- -(2,6-dimethoxyphenyl)-butyrate The methanolic solution (20 ml) of E-ethyl 2-methyl-4-(2,6-dimethoxy- phenyl)-crotonate ( 1.03 g) was added to the suspension of Pd/C catalyst (0.5 g) in methanol (15 ml) previously saturated with hydrogen. The reduction was finished using up 96 ml of H₂. After filtering off the catalyst the filtrate was evaporated and the residue was flash chromatographed on silica gel with hexane- acetone (5:2) as the eluent yielding 0.9 g (85 %) of ethyl 2-methyl-4-(2,6- dimethoxypheny -butyrate. (Rf = 0.7). ^ΪH-NMR (CDCI3) δ (ppm): 1.2 (m, 6H, CH3-C and CH3), 1.6, 1.9 and 2.4 (m, 3H, CH, CH₂), 2.7 (t, 2H, CH₂-Ar), 3.75 (s, 6H, 2XOCH3), 4.1 (q, 2H, CH2CH3), 6.5 (d, 2H, H-3, H-5 aromatics), 7.15 (t, IH, H-4 aromatic H). e) 2-Methyl-4-(2,6-dimethoxyphenyl)-butanol

A mixture of ethyl 2-methyl-4-(2,6-dimethoxyphenyl)-butyrate (0.47 g, 1.76 mmol), anhydrous ether (50 ml), L-AIH4 (0.47 g) was refluxed for 2 hours. After working up the residue was chromatographed on silica gel with hexane- acetone (5:2) as the eluent affording 0.33 g (83 %) of 2-methyl-4-(2,6- dimethoxyphenyl)-butanol as colourless oil. (Rf = 0.4) - ^H-NMR (CDCI3) δ (ppm): 1.0 (d, 3H, 2-CH₃), 1.45, 1.65 and 2.75 (m, 5H, 1-CH₂, 2-CH, 3-CH₂), 1.9 (s, IH, OH), 3.5 (m, 2H, ArCH₂), 3.85 (s, 6H, 2XOCH3), 6.5 (d, 2H, H-3, H- 5 aromatics), 7.1 (t, IH, H-4 aromatic H).

Example 7 E-2-Methyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol

0.1 g of E-ethyl 2-methyl-4-(2,6-dimethoxyphenyl)-crotonate in anhydrous ether (25 ml) was reduced with L-AIH4 (0.1 g) with reflux for 3 hours. After usual working up, the residue was flash chromatographed on silica gel with the eluent of hexane-acetone (5:2) affording E-2-methyl-4-(2,6-dimethoxyphenyl)-2- butene-1-ol. (Rf = 1.4). ^H-NMR (CDCI3) δ (ppm): 1.85 (s, 3H, CH₃), 2.0 (br. s, IH, OH), 3.4 (d, 2H, CH₂-Ar), 3.8 (s, 6H, 2xOCH₃), 3.95 (s, 2H, CH₂-0), 5.45 (t, IH, CH), 6.55 (d, 2H, H-3, H-5 aromatics), 7.15 (t, IH, H-4 aromatic H). M.p.: 39.5-41 °C.

Example 8 l-Hydroxy-2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene a) 2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene-l-al 2,6-Dimethoxyphenylacetaldehyde (1.04 g, 5.7 mmol) prepared in Example 6, anhydrous ethanol (50 ml) and IN NaOEt in dry ethanol (15 ml) was stirred at room temperature for 2 hours. The solvent was distilled and the residue was extracted with ethyl acetate. The organic phase was washed, dried and evaporated and the residue was purified using column chromatography on silica gel with hexane-ethyl acetate (5: 1 ) as eluent, yielding 0.55 g (56 %) of crystalline product, m.p. 133-134 °C. H-NMR (CDCI3) δ (ppm): 3.5 (d, 2H. CH₂Ar), 3.7 and 3.8 (s, 6H, 2XOCH3), 6.55 and 6.7 (d, 4H, 2xH-3, H-5 aromatic H), 6.95 (t, IH, CH), 7.15 and 7.35 (t, 2H, 2xH-4 aromatic H), 9.6 (s, IH, CHO) - Ms (m e); 342 (75), 313 (100), 151 (95), 91 (80). C oH₂₂O₅ (342.37) Calculated C 70.16, H 6.47

Found C 71.28, H 6.72. b) l-Hydroxy-2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene Reduction of 2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene-l-al (0.25 g, 0.7 mmol) with L.A1H4 (0.5 g) in anhydrous ether (45 ml) at room temperature for 3 hours afforded 0.2 g (80 %) of crystalline l-hydroxy-2,4-[bis-(2,6-dimethoxy- phenyl)]-2-butene, m.p. 138-140 °C, Rf = 0.3 in hexane-ethyl acetate 5:2. 1H-NMR (CDCI3) δ (ppm): 2.0 (br. s, IH, OH), 3.15 (d, 2H, CH₂Ar), 3.65 and 3.75 (s, 6H, 2xOCH3), 4.25 (s, 2H, CH₂O), 6.05 (t, IH, CH), 6.45 and 6.65 (d, 4H, 2xH-3, H-5 aromatic H), 7.05 and 7.2 (t, 2H. H-4 aromatic H). Ms (m e); 344 (5), 327 (20), 313 (25), 151 (65), 91 (70).

C20H24O5 (344.37) Calculated C 69.75, H 7.03

Found C 70.03, H 6.95.

Example 9 2,4-[bis-(2,6-Dimethoxypheny.)]-butano, a) 2,4-[bis-(2,6-Dimethoxyphenyl)]-butanaI

The solution of 2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene-l-al (0.3 g, 0.1 mmol) in glacial acetic acid (25 ml) was added to the suspension of 10 % PαVC catalyst (0.5 g) in glacial acetic acid (10 ml) previously saturated with hydrogen.

The hydrogenation was continued for 20 hours using 50 ml of H₂. The catalyst was filtered off and the filtrate was evaporated in vacuum. The residue was chromatographed on silica gel with hexane-ethyl acetate (5: 1) as the eluent, yielding 230 mg (67 %) of 2,4-[bis-(2,6-dimethoxyphenyl)]-butanal (Rf = 0.4). iH-NMR (CDCI3) δ (ppm): 1.8 and 2.5 (m, 4H, 2xCH₂), 3.7 and 3.75 (s, 6H, 2XOCH3), 4.0 (dd, IH, CH), 6.45 and 6.55 (d, 4H, 2xH-3), H-5 aromatic H), 7.1 and 7.2 (t, 2H, 2xH-4 aromatic H), 9.71 (d, IH, CHO). b) 2,4-[b_s-(2,6-Dimethoxyphenyl)]-butanoI

2,4-[bis-(2,6-Dimethoxyphenyl)]-butanal (0.23 g, 0.6 mmol), L.AIH4 (0.5 g) and anhydrous ether (30 ml) was refluxed for 30 minutes. After working up in the usual way the residue was crystallized from hexane-ethyl acetate yielding 0.15 g (65 %) of 2,4-[bis-(2,6-dimethoxyphenyl)]-butanol, m.p. 96-97 °C, Rf = 0.2 (hexane-ethyl acetate 5: 1). ^H-NMR (CDCI3) δ (ppm): 1.8 and 2.5 (m, 4H, 2xCH₂), 2.0 (s, IH, OH), 3,65 (d, 2H, CH₂), 3.7 and 3.8 (s, 6H, 2xOCH₃), 3.95 (m, IH, CH), 6.5 and 6.6 (d, 4H, 2xH-3, H-5 aromatic H), 7.1 and 7.2 (t, 2H, 2xH-4 aromatic H). C20H26O5 (346.4) Calculated C 69.34, H 7.56

Found C 69.72, H 7.48.

Example 10 E-2-Methyl-4-(2,6-dimethoxy-4-n-propyIpheπyI)-2-butene-l-ol a) l-(3,5-DimethoxyphenyI)-l-propanol To the ethylmagnesiumbromide [prepared freshly from magnesium (0.6 g), ethylbromide (2 ml) and anhydrous ether (20 ml)] was added a solution of 3,5- dimethoxybenzaldehyde (4.15 g, 21 mmol) in anhydrous ether (40 ml) with stirring at room temperature during 30 minutes. The reaction mixture was boiled for 2 hours. To the cooled mixture NH4CI solution was added and then extracted with ether. The organic phase was washed, dried and evaporated yielding the crude product which was purified by flash chromatography with hexane-ethyl acetate (5: 1). 4.35 g (88 %) of l-(3,5-dimethoxyphenyl)-l-propanol was obtained (Rf = 0.4). 1H-NMR (CDCI3) δ (ppm): 0.95 (t, 3H, CH3), 1.7 (m, 2H, CH₂), 2.2 (s, IH, OH), 3.8 (s, 6H, 2XOCH3), 4.5 (t, I H, CH), 6.35 (dd, I H, H-2 aromatic H), 6.5 (d, 2H, H-4, H-6 aromatic H). b) 3,5-Dimethoxy-n-propyl-benzene

4.2 g (21.4 mmol) of l-(3,5-dimethoxyphenyl)-l -propanol was reduced with H₂ in glacial acetic acid (70 ml) in the presence of 10 % Pd/C (3.5 g). After 30 hours (using 550 ml of H₂) the catalyst was filtered off, the solvent was evaporated and the residue was flash chromatographed on silica gel with hexane- ethyl acetate (5:2) as the eluent yielding 2.6 g (68 %) of 3,5-dimethoxy-n- propyl-benzene. ^H-NMR (CDC1₃) δ (ppm): 1.0 (t, 3H, CH3), 1.7 (m, 2H, CH₂), 2.55 (t, CH2Ar), 3.8 (s, 6H, 2XOCH3), 6.3 (dd, IH, H-2 aromatic H), 6.4 (d, 2H, H-4, H-6 aromatic H). c) 2,6-Di ethoxy-4-n-propylphenyl acetaldehyde

To the solution of 3,5-dimethoxy-n-propyl-benzene (2.5 g, 13.8 mmol) in anhydrous cyclohexane (60 ml) was added dropwise the solution of butyl lithium in cyclohexane (13 ml) at 0 °C with stirring under N2 atmosphere. The reaction mixture was boiled for 1.5 hours. After cooling bromoacetaldehyde diethyl acetal (2.6 ml, 17.2 mmol) was added to the mixture and boiled for another 1.5 hours. After extraction, washing, drying and evaporation the residue was stirred with the mixture of ethanol (20 ml) and 1 : 1 HCl (5 ml) at room temperature for 20 hours. The solvent was evaporated and the residue was extracted with CH2CI2, washed with water, dried and evaporated yielding the crude 2,6-dimethoxy-4-n- propylphenyl acetaldehyde which was column chromatographed on silica gel with hexane-acetone (9:1). 0.6 g (20 %) of pure 2,6-dimethoxy-4-n-propylphenyl acetaldehyde was obtained (Rf = 0.6). ^Ϊ H-NMR (CDCI3) δ (ppm): 1.0 (t, 3H, CH3), 1.7 (m, 2H, CH₂), 2.55 (m, 2H, CH₂), 3.65 (d, 2H, CH₂Ar), 3.8 (s, 6H, 2XOCH3), 6.45 (s, 2H, H-3, H-5 aromatic H), 9.6 (t, IH, CHO). d) Ethyl 2-methyI-4-(2,6-d_methoxy-4-n-propylphenyl)-crotonate

The mixture of 2,6-dimethoxy-4-n-propylphenyl acetaldehyde (0.5 g, 2.2 mmol) and phosphonium salt prepared in Example 1 (1.3 g, 3 mmol), abs. ethanol (25 ml) and IN NaOEt in dry ethanol (3.3 ml, 3.3 mmol) was stirred under N₂ atmosphere for 2 hours at room temperature. After working up in the usual way the residue was chromatographed on silica gel with CH₂C1₂ -benzene (3:1) yielding 0.28 g (40 %) of ethyl 2-methyl-4-(2,6-dιmethoxy-4-n-propyl- phenyl)-crotonate (Rf = 0.3). ^H-NMR (CDCI3) δ (ppm):0.9 (t, 3H, propyl- CH3), 1.3 (s, 3H, ethyl-CH3), 1.7 (m, 2H, propyl-CH₂), 2.0 (s, 3H, CH3), 2.6 (t, 2H, ethyl-CH ), 3.5 (d, 2H, CH₂Ar), 3.8 (s, 6H, 2XOCH3), 4.2 (q, 2H, CH₂), 6.4 (s, 2H, H-3, H-5 aromatic H), 6.8 (t, IH, CH). e) E-2-Methyl-4-(2,6-dimethoxy-4-n-propyIphenyI)-butene-l-ol 0.28 g ethyl 2-methyl-4-(2,6-dimethoxy-4-n-propylphenyl)-crotonate (0.9 mmol) was reduced with LiAlH4 (0.5 g) in abs. ether (30 ml) with reflux. After working up an oily product was obtained which was purified by column chro- matography on silica gel with the eluent of hexane-acetone (4:1). 121 mg (50 %) of E-2-methyl-4-(2,6-dimethoxy-4-n-propylphenyl)-2-butene-l-ol was obtained as colourless oil. (Rf = 0.4). ^H-NMR (CDCI3) δ (ppm): 0.9 (t, 3H, CH3), 1.3 (br. s, IH, OH), 1.6 (m, 2H, CH2), 1.8 (s, 3H, CH3), 2.55 (t, 2H, CH₂), 3.4 (d, 2H, CH2Ar), 3.75 (s, 6H, 2xOCH₃), 3.95 (s, 2H, CH₂O), 5.5 (t, IH, CH), 6.4 (s, 2H, H-3, H-5 aromatic H). Example 11 E-2-Ethyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol a) Wittig reagent

The mixture of triphenylphosphine (7.86 g, 0.03 mmol), abs. benzene (15 ml) and ethyl 2-bromobutyrate (4.42 ml, 0.03 mol) was boiled for 4 hours under N₂ atmosphere. After cooling the precipitated product was filtered off, washed with abs. ether and dried in a vacuum desiccator. 1.3 g (9.5 %) of Wittig reagent was obtained, m.p. 158-160 °C. ²H-NMR (CDCI3) δ (ppm): 1.0 (t, 3H, CH3), 1.35 (t, 3H, CH3), 2.0 (m, 2H, CH₂), 4.1 (m, 2H, CH2OCO), 5.8 (t, IH, CH), 7.9 (m, 15H, aromatic H). b) E-Ethyl 2-ethyl-4-(2,6-dimethoxyphenyl)-crotonate

The mixture of 2,6-dimethoxyphenylacetaldehyde (0.5 g, 2.75 mmol),

Wittig ester (1.59 g, 3.47 mmol), abs. ethanol (25 ml) and IN NaOEt in dry ethanol (7.1 ml) was stirred at room temperature for 3 hours under N₂ atmosphere. The usual workup followed by column chromatography on silica gel with toluene : acetone (20:1) as eluent yielded 0.1 g (12 %) of E-ethyl 2-ethyl-4- (2,6-dimethoxyphenyl)-crotonate (Rf = 0.7). ΪH-NMR (CDCI3) δ (ppm): 1.1 and 1.25 (t, 6H, 2xOCH₃), 2.5 (q, 2H, CH2), 3.55 (d, 2H, CH₂Ar), 3.8 (s, 6H, 2XOCH3), 4.15 (q, 2H, CH2O), 6.55 (d, 2H, H-3, H-5 aromatic H), 6.7 (t, IH. CH), 7.2 (t, IH, H-4 aromatic H). c) E-2-Ethyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol Reduction of E-ethyl 2-ethyl-4-(2,6-dimethoxyphenyl)-crotonate (0.205 g, 0.73 mmol) with LiAlH4 (0.205 g) in abs. ether (20 ml) was carried out at room temperature with stirring for 30 minutes. After working up, the product obtained was purified by column chromatography on silica gel with hexane-acetone (5:2) as the eluent yielding 77.7 mg (46 %) of E-2-ethyl-4-(2,6-dimethoxyphenyl)-2- butene-1-ol as colourless oil. (Rf = 0.6). H-NMR (CDCI3) δ (ppm): 1.05 (t, 3H, CH3), 1.6 (br. s, IH, OH), 2.3 (q, 2H, CH₂), 3.4 (d, 2H, CH₂Ar), 3.75 (s, 6H, 2xOCH3), 3.95 (s, 2H, CH2O), 5.45 (t, IH, CH), 6.55 (d, 2H, H-3, H-5 aromatic H), 4.15 (t, 1 H, H-4 aromatic H). Example 12 E-2-Propyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol a) Wittig ester

The mixture of triphenylphosphine (7.86 g, 0.03 mmol), abs. benzene (15 ml), and ethyl 2-bromovalerate was boiled for 9 hours under N2 atmosphere. The precipitated product was filtered off and washed with abs. ether, then dried in vacuum. 2.09 g (15 %) of Wittig ester was obtained, m.p. 167-170 °C. ^[H-NMR (CDCI3) δ (ppm): 0.91 and 1.05 (2xt, 6H. 2XCH3), 1.5 and 2.0 (m, 4H, 2xCH₂), 4.05 (q, 2H, CH ), 5.9 (m, IH, CH), 7.8 (m, 15H, aromatic H). b) E-Ethyl 2-n-propy.-4-(2,6-dimethoxyphenyl)-crotonate

2,6-Dimethoxyphenylacetaldehyde (0.6 g, 3.3 mmol) was added to the mixture of Wittig ester (2.09 g, 4.4 mmol) abs. ethanol (35 ml) and IN NaOEt in dry ethanol (8.5 ml, 8.5 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred for 6 hours. Next day it was worked up and the crude product was column chromatographed on silica gel with hexane-acetone (10: 1) as the eluent. 0.13 g (8.5 %) of E-ethyl 2-n-propyl-4-(2,6- dimethoxyphenyl)-crotonate was obtained. ^H-NMR (CDCI3) δ (ppm): 0.95 and 1.25 (t, 6H, 2xCH3), 1.5 (m, 2H, CH2), 6.0 (d, 2H, H-3, H-5 aromatic H), 6.8 (t, IH, CH), 7.2 (t, IH, H-4 aromatic H). c) E-2-Propyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol

0.133 g (0.45 mmol) of E-ethyl 2-n-propyl-4-(2,6-dimethoxyphenyl)- crotonate in abs. ether (20 ml) was reduced with LiAlH4 (0.133 g) at room temperature with stirring for 30 minutes. The reaction mixture was worked up and the residue was column chromatographed on silica gel with hexane-acetone (5:2) as the eluent. 90 mg (80 %) of E-2-propyl-4-(2,6-dimethoxyphenyl)-2- butene-1-ol was obtained as colourless oil (Rf = 0.5) - ^H-NMR (CDCI3) δ (ppm): 0.95 (t, 3H, CH3), 1.4 (br. s, IH, OH), 2.2 (m, 2H, CH ), 2.2 (t. 2H, CH₂), 3.45 (d, 2H, CH₂Ar), 3.8 (s, 6H, 2xOCH₃), 5.5 (t, IH, CH), 6.6 (d, 2H, H-3, H-5 aromatic H), 7.15 (t, IH, H-4 aromatic H). Example 13

2-Hydroxymethyl-4-(2,6-dimethoxyphenyI)-2-butene-l-ol a) l-Acetoxy-2-(acetoxymethyl)-4-(2,6-dimethoxyphenyl)-2-butene 2,6-Dimethoxy-prenylbenzene [Cotterill et al: J. Chem. Soc. Perk. Trans I,

2423 (1974)] (2 g, 10 mmol) was boiled in Ac₂O (10 ml) in the presence of Se0₂ ( 1.5 g) and then with another amount of Se0₂ (0.5 g) for 2 hours. The reaction mixture was poured into cold water, extracted with CH C1₂. The organic phase was washed, dried and evaporated and the residue was chromatographed on silica gel with hexane-ethyl acetate as the eluent. 0.45 g (14.2 %) of l-acetoxy-2-(acetoxymethyl)-4-(2,6-dimethoxyphenyl)-2-butene was obtained (R_f = 0.5). *H-NMR (CDCI3) δ (ppm): 2.05 and 2.1 (s, 6H, 2xOAc), 3.5 (d, 2H, CH₂Ar), 3.80 and 3.85 (s, 6H, 2XOCH3), 4.55 and 4.9 (s. 4H, 2xOCH₂), 5.9 (t, IH, CH), 6.5 and 6.6 (d, 2H, H-3, H-5 aromatic H), 7.15 (t, IH, H-4 aromatic H). b) 2-Hydroxymethyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol The mixture of diacetate (0.4 g, 1.2 mmol), abs. methanol (20 ml) and IN NaOMe in dry methanol (3 ml) was stirred under N₂ atmosphere for 20 hours. The solvent was evaporated; the residue was diluted with water, neutralized with AcOH and extracted with ethyl acetate. The crude product was chromatographed on silica gel column, with hexane-acetone (2: 1). 120 mg (41 %) of 2- hydroxymethyl-4-(2,6-dimethoxyphenyl)-2 -butene- l-ol (Rf = 0.3) was obtained, m.p. 71 -73 °C. *H-NMR (CDC1 ) δ (ppm): 2.15 and 2.6 (br. s, 2H, OH), 3.45 (d, 2H, CH₂Ar), 3.85 (s, 6H, 2 OCH3), 4.2 and 4.4 (s, 4H, 2xCH 0), 5.65 (t, IH, CH), 6.6 (d, 2H, H-3, H-5 arom.), 7.15 (t, IH, H-4 aromatic H). C13H18O4 (238.27) Calculated C 65.53, H 7,61 Found C 65,42, H 7,29.

Example 14 E-2-Methyl-4-(2,4-dihydroxyphenyI)-2-butene-l-oI a) l-Acetoxy-4-(2,4-d.acetoxyphenyI)-2-methy_-2-butene 4-(3-Methyl-2-butenyl)-l ,3-benzenediol (1.5 g) [Yamada et al: Bull Chem. Soc. Jap. 50, 750 (1987)] was acetylated by AC2O in pyridine at room temperature to give 4-(2,4-diacetoxyphenyl)-2-methyl-2-butene ( 1.8 g, 82 %) as colourless oil, which was reacted with Seθ2 as described in Example 3 to afford l-acetoxy-4-(2,4-diacetoxyphenyl)-2-methyl-2-butene (800 mg, 36 %). b) E-2-Methyl-4-(2,4-dihydroxyphenyI)-2-butene-l-ol l-Acetoxy-4-(2,4-diacetoxyphenyl)-2-methyl-2-butene (800 mg, 2,63 mmol) was saponified by 1 N sodium methylate at room temperature. After usual work up the title compound was isolated by column chromatography on silica gel (toluene: ethanol / 10: 1) as a colourless oil (140 mg, 30%). iH-NMR (CDCI3) δ (ppm): 1.59 (s, 3H, 2-Me), 3.32 (d, J = 7 Hz), 2H, Ar-CH2-CH=). 4.08 (d, J = 4 Hz, 2H, -CH2-OH), 4.1 1 (t, J = 4 Hz, IH, 1-OH), 4.79 and 5.00 (2xs, 2xlH, 2,4-OH), 5.10 (t, J = 7 Hz, I H, =CH-), 6.35 (m, 2H, 3.5-H), 6.95 (d, J = 8 Hz), IH, 6-H). Example 15 E-7-Methoxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane a) 7-AIIyloxychromane

To a stirred solution of 7-hydroxychromane [Naylor et al: J. Chem. Soc, 1 190 (1958)] (0.45 g) in abs. DMF (10 ml) NaH (0.2 g) was added under N2 atmosphere at 0 °C temperature. After 15 minutes allylbromide (0.5 ml) in abs. DMF (5 ml) was dropped in it and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ether. The organic phase was washed with 5 % NaOH, then with water and dried over MgSO4- The solvent was evaporated and the residue was purified by flash chromatography on silica gel with hexane- ethyl acetate (9: 1) as eluent, to afford 0.4 g (72 %) of 7-allyloxychromane, Rf = 0.7. iH-NMR (CDCI3) δ (ppm): 2.0 (m, 2H, C-4-H), 2.7 (t, 2H, C-4-H), 4.1 (t, 2H, C-2-H), 4.5 (d, 2H, CH₂-OH), 5.35 (m, 2H, CH₂ = CH), 6.0 (m, IH, CH), 6.4 (m, 2H, 6,8-Ar-H), 6.9 (d, IH, 5-Ar-H). b) 7-Hydroxy-8-a_lylchromane

A solution of 7-allyloxychromane (4.8 g) in 1 10 ml xylene was heated in a closed glass tube at 200 °C for 10 hours. The xylene was evaporated and the residue purified by flash chromatography on silica gel with toluene to afford 2.56 g (52 %) of 7-hydroxy-8-allylchromane as colorless oil, Rf = 0.4 (toluene). c) 7-Methoxy-8-al_ylchromane

To a stirred mixture of 7-hydroxy-8-allylchromane (1.9 g), water (25 ml) and KOH (2.5 g) at room temperature was added after 15 minutes dimethyl sulphate (3.5 ml) and the mixture stirred for 10 hours. The product was extracted with CH₂C1₂, washed with 10 % KOH, water and dried over Na₂SO4- The evaporation of the solvent gave 1.8 g (90 %) of 7-methoxy-8-allylchromane as oil, R_f = 0.7 (hexane-acetone, 9: 1). ^H-NMR (CDCI3) δ (ppm): 1.95 (m, 2H,

C-3-H), 2.7 (t, 2H, C-4-H), 4.2 (t, 2H, C-2-H), 3.4 (d, 2H, CH₂=CH), 3.8 (s, 3H.

OCH3), 5.0 (m, 2H, CH₂-Ar), 5.95 (m, IH, CH), 6.5 and 6.9 (d, 2H, 5,6-Ar-H). d) 7-Methoxychroman-8-yl-acetaldehyde To the solution of 7-methoxy-8-allylchromane (0.9 g) in dioxane (60 ml) was added a solution of OSO4 (0.23 g) in dioxane (5 ml) at room temperature and the mixture was stirred for 30 minutes. Subsequently NaIO4 (2.35 g) in water (180 ml) was added to the solution during 1 hour. A solid product precipitated which dissolved after a short time and a clear solution was obtained. After 30 minutes the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 50 ml). The organic phase was washed with a solution of sodium thiosulphate, with water, and dried over MgSO4. The evaporation gave 0.79 g (87 %) of 7-methoxychroman-8-yl-acetaldehyde as an oil, Rf = 0.4 (hexane-acetone, 10:1). ^H-NMR (CDCI3) δ (ppm): 2.0 (m, 2H, C-3-H), 2.75 (t, 2H, C-4-H), 3.65 (d, 2H, Ar-CH₂), 3.8 (s, 3H, OCH3), 4.2 (d, 2H, C-2-H), 6.5 (d, IH, 6-Ar-H), 7.0 (d, IH, 5-Ar-H), 9.65 (t, IH, CHO). e) E-7-Methoxy-8-(2-ethoxycarbonyl-2-butene-4-yi)-chromane 0.8 g of 7-methoxychroman-8-yl-acetaldehyde and 3.6 g of phosphonium salt (prepared from triphenylphospine and ethyl 2-bromopropionate) was dissolved in abs. ethanol (50 ml) at room temperature and IN NaOEt in dry ethanol (18 ml) was added under N₂ atmosphere. The reaction mixture was stirred for 1 hour and then diluted with water and extracted with CH₂Cl2- The organic phase was washed with water, dried and evaporated. The residue was purified by flash chromatography on silica gel, using hexane-acetone, 10:1 as eluent to yield 0.66 g (60 %) of 7-methoxy-8-(2-ethoxycarbonyl-2-butene-4-yl)- chromane as an oil, Rf = 0.5. iH-NMR (CDCI3) δ (ppm): 1.3 (t, 3H, CH3-CH2), 1.95 (m, 2H, C-3-H), 2.0 (s, 3H, CH3), 2.75 (t, 2H, C-4-H), 3.5 (d, 2H, CH₂-Ar), 3.8 (s, 2H, OCH3), 4.2 (m, 4H, C-2-H, OCH2), 6.45 (d, I H, 6-Ar-H), 6.75 (t, IH, CH=), 6.9 (d, IH, 5-Ar-H). f) E-7-Methoxy-8-[(2-hydroxymethyl)-2-butene-4-yl|-chromane

A solution of E-7-methoxy-8-(2-ethoxycarbonyl-2-butene-4-yπ-chromane (0.6 g) in abs. ether (10 ml) was dropped to the suspension of LiAlH4 (0.4 g) in abs. ether (10 ml) under N2 atmosphere under stirring. After 30 minutes the reaction mixture was worked up as usual and the resulting product was purified by column chromatography on silica gel with the eluent of toluene/ethyl acetate (4: 1) to give E-7-methoxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane (0.33 g, 65 %) as an oil, Rf = 0.4. ^ΪH-NMR (CDCI3) δ (ppm): 1.5 (br, IH, OH, deuterable), 1.85 (s, 3H, CH3-C=), 2.0 (m, 2H, C-3-H), 2.75 (t, 2H, C-4-H), 3.35 (d, 2H, CH₂-Ar), 3.75 (s, 3H, OCH3), 3.95 (s, 2H, CH₂-0), 4.2 (t, 2H, C-2-H), 5.5 (t, IH, CH=), 6.45 (d, IH, 6-Ar-H), 6.9 (d, IH, 5-Ar-H). Example 16 E-7-Hydroxy-8-[(2-hydroxymethyI)-2-butene-4-yl]-chromane a) 7-Methoxymethoxy-8-a__ylchromane

A solution of 7-hydroxy-8-allylchromane (1.66 g) in abs. DMF (20 ml) was reacted with NaH (0.8 g) under N₂ atmosphere at 0 °C with stirring for 15 minutes. A solution of chloromethylmethyl ether (2 ml) in abs. DMF (5 ml) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ether. The organic phase was washed with 10 % NaOH and then with water. After evaporation of the solvent 7-methoxymethoxy-8-allylchromane was obtained (1.95 g, 95 %), as an oil (Rf = 0.75 (hexane-acetone, 9: 1). ^ΪH-NMR (CDCI3) δ (ppm): 1.95 (m,

2H, C-3-H), 2.75 (t, 2H, C-4-H), 3.4 (d, 2H, CH₂=CH), 3.5 (s, 3H, OCH3), 4.2

(d, 2H, C-2-H), 5.0 (m, 2H, CH₂-Ar), 5.15 (s, 2H, OCH 0), 6.0 (m, IH, CH),

6.6 and 6.85 (d, 2H, 5,6-Ar-H). b) 7-Methoxymethoxychroman-8-yI-acetaldehyde

7-Methoxymethoxychroman-8-yl-acetaldehyde was obtained from 7- methoxymethoxy-8-allyIchromane as described for 7-methoxychroman-8-yl-acet- aldehyde and gave 90 % of 7-methoxymethoxychroman-8-yl-acetaldehyde as an oil, Rf = 0.3 (hexane-acetone, 10: 1 ). H-NMR (CDCI3) δ (ppm): 2.0 (m, 2H, C- 3-H), 2.75 (t, 2H, C-4-H), 3.4 (s, 3H, OCH3), 3.7 (d, 2H, CH₂-Ar), 4.2 (t. 2H, C- 2-H), 5.15 (s, 2H, OCH₂O), 6.7 (d, I H, 6-Ar-H), 6.95 (d, IH, 5-Ar-H). 9.65 (t, IH, CHO). c) E-7-(Methoxymethoxy)-8-(2-ethoxycarbonyI-2-butene-4-yl)- chromane 7-(Methoxymethoxy)-8-(2-ethoxycarbonyl-2-butene-4-yl)-chromane as an oil was obtained from 7-methoxymethoxychroman-8-yl-acetaldehyde in the same manner as above. (70 %), Rf = 0.6 (toluene-ethyl acetate, 9: 1). ^H-NMR (CDCI3) δ (ppm): 1.3 (t, 3H, CH3-CH2), 1.95 (m, 2H, C-3-H), 2.0 (s, 3H, CH3), 2.75 (t, 2H, C-4-H), 3.45 (s, 3H, OCH3), 3.5 (d, 2H, CH₂-Ar), 4.15 (m, 4H, C- 2-H, OCH ), 5.2 (s, 2H, OCH₂O), 6.6 (d, I H, 6-Ar-H), 6.75 (t, IH, CH=), 6.9 (d, IH, 5-Ar-H). d) E-7-(Methoxymethoxy)-8-[(2-hydroxymethyl)-2-butene-4-yl]- chromane

E-7-(Methoxymethoxy)-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane was obtained by the reduction of 7-(methoxymethoxy)-8-(2-ethoxycarbonyl-2- butene-4-yl)-chromane in 90 % yield in the same manner as above, Rf = 0.3 (toluene-ethyl acetate, 9: 1). iH-NMR (CDCI3) δ (ppm): 1.5 (br, IH, OH), 1.85 (s, 3H, CH3-C=), 2.0 (m, 2H, C-3-H), 2.75 (t, 2H, C-4-H), 3.4 (d, 2H, CH₂-Ar), 3.5 (s, 3H, OCH3), 3.95 (s, 2H, CH₂-O), 4.2 (t, 2H, C-2-H), 5.2 (s, 2H, OCH₂O), 5.5 (t, IH, CH), 6.6 (d, IH, 6-Ar-H), 6.85 (d, IH, 5-Ar-H). e) E-7-Hydroxy-8-[(2-hydroxymethy.)-2-butene-4-yl]-chromane

0.7 g of E-7-(Methoxymethoxy)-8-[(2-hydroxymethyl)-2-butene-4-yl]- chromane in methanol (20 ml) was stirred with 1 : 1 aqueous HCl (1 ml) at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel with the eluent of toluene-ethyl acetate (4:1) to afford 7-hydroxy-8-[(2- hydroxymethyl)-2-butene-4-yl]-chromane (0.35 g, 60 %), with m.p. 84-86 °C, Rf

= 0.3. iH-NMR (CDCI3) δ (ppm): 1.85 (s, 3H, CH₃-C=), 2.0 (m, 2H, C-3-H), 2.4 (s, IH, OH), 2.75 (t, 2H, C-4-H), 3.4 (d, 2H, CH -Ar), 3.95 (s, 2H, CH O), 4.2 (t, 2H, C-2-H), 5.5 (t, IH, CH), 6.3 (d, IH, 6-Ar-H), 6.75 (d, IH, 5-Ar-H), 7.2 (m, IH, Ar-OH).

^C14^H 18°3 (234.28) Calculated C 71.77, H 7.74

Found C 71.62, H 7.62. Example 17 Z-2-Methyl-4-(2-hydroxy-6-methoxyphenyl)-2-butene-l-ol a) l-Acetoxy-2-(3-methyI-2-butenyl)-3-methoxybenzene

2-(3-Methyl-2-butenyl)-3-methoxyphenol [Hubuceh et al: Chem. Ind. (London) 1780 (1969)] (10 g, 48 mmol) was acetylated with Ac₂0 in pyridine at room temperature to afford the title compound as a colourless oil (4.5 g, 42 %). iH-NMR (CDCI3) δ (ppm): 1.65 and 1.75 (2xs, 6H, =CMe ), 2.30 (s, 3H, OAc), 3.25 (d, J = 7 Hz, ArCH₂-CH=) 3.90 (s, 3H, OMe), 5.60 (t, J = 7 Hz, IH, =CH-), 6.60-7.25 (m, 3H, ArH). b) Z-l-Acetoxy-2-methyl-4-(2-acetoxy-6-methoxyphenyl)-2-butene l-Acetoxy-2-(3-methyl-2-butenyl)-3-methoxybenzene (7 g, 32 mmol) was reacted in Ac₂O (40 ml) with SeO₂ (3 g, 27 mmol) as described in Example 3 to give the title compound (2.25 g, 30 %) as a colourless oil. iH-NMR (CDCI3) δ (ppm): 1.75 (s, 3H, 2-Me), 2.10 (s, 3H, OAc), 3.30 (d, J=7.5 Hz), 2H, Ar-CH₂-CH=), 3.85 (s, 3H, OMe), 4.45 (s, 2H, CH₂OAc), 5.50 (t, J=7.5 Hz, IH, =CH-), 6.65-7.30 (m, 3H, ArH). c) Z-2-MethyI-4-(2-hydroxy-6-methoxypheπyl)-2-butene-l-ol Saponification of Z-l-acetoxy-2-methyl-4-(2-acetoxy-6-methoxyphenyl)-2- butene (2.25 g, 9,6 mmol) with 0.68 NaOEt (45 ml) at room temperature resulted in the title compound (0.7 g) in 40 % yield. Rf = 0.12 (toluene: EtOAc=4:l). ^J H-NMR (CDCI3) δ (ppm): 1.88 (s, 3H, 3-Me), 3.41 (d, J=7.5Hz, 2H, Ar-CH .CH=), 3.82 (s, 3H, OMe), 4.05 (s, 2H, -CH₂OH), 5.12 (s, IH, OH), 5.55 (t, J=7.5Hz, IH, =CH-), 6.48 (t, J=8Hz, 2H, 4.6Hz), 7.05 (t, J=8Hz, IH, 5-H).

Claims

Patent Claims:

1. A compound of the formula (I),

wherein

Rl and R^ are hydrogen or form together with the adjacent carbon atoms 6- membered saturated heterocycle containing one oxygen atom; R3 is lower alkyl, hydroxy(lower)alky 1 or a group of the formula (II)

wherein Y is lower alkyl or lower alkoxy and m is 0, 1, 2, 3, 4 or 5; Z represents, independently from each other, hydroxy, lower alkyl, lower alkoxy, (lower)alkoxy(lower)alkoxy, halo or halo(lower)alkyl; n is 0, 1 , 2, 3, 4 or 5 with the proviso that if R - and R^ are other than hydrogen, the value of n is at most 3; and

— means a single or double chemical bond.

2. A compound as claimed in claim 1 , wherein R^, Z or Y is methyl or ethyl.

3. A compound as claimed in claim 1 , wherein R^ is hydroxymethyl or 2- hydroxyethyl.

4. A compound as claimed in claim 1 , wherein Z or Y is methoxy or ethoxy.

5. A compound as claimed in claim 1, wherein Z is methoxymethyl, ethoxymethyl, 2 -methoxy ethyl or 2-ethoxyethyl.

6. A compound as claimed in claim 1, wherein Z is chloro or bromo.

7. A compound as claimed in claim 1, wherein Z is trifluoromethyl.

8. 2-methyl-4-(2,6-dimethoxyphenyl)-butanol; E-2-ethyl-4-(2,6-dimethoxypheny l)-2-butene- 1 -ol;

E-2-propyl-4-(2,6-dimethoxyρhenyl)-2-butene-l-ol;

2,4-[bis-(2,6-dimethoxyphenyl)]-2-butene-l-ol;

2 ,4-[bis-(2 , 6-dimethoxypheny l)]-butanol ;

Z-2-methyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol; E-2-methyl-4-(2,6-diethoxyρhenyl)-2-butene-l-ol;

E-2-methyl-4-(2-ethoxy-6-methoxyphenyl)-2-butene-l-ol;

E-2-methyl-4-(2,4-dihydroxyphenyl)-2-butene-l-ol;

7-hydroxy-8-(3-hydroxymethyl-butyl-l)-chromane;

E-2-methyl-4-(2,6-dimethoxyphenyl)-2-butene-l-ol; Z-2-methyl-4-(2-hydroxy-6-methoxyphenyl)-2-butene-l-ol;

E-2-methyl-4-(2,4,6-trimethoxyphenyl)-2-butene-l-ol;

E-2-methyl-4-(2,6-dimethoxy-4-methylphenyl)-2-butene- 1 -ol;

E-2 -methy l-4-(2 , 6-dimethoxy-4-n-propy lpheny l)-2-butene- l-ol;

2-hydroxymethyl-4-(2,6-dimethoxyphenyl)-2-butene- 1 -ol; E-7-methoxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane;

E-7-(methoxymethoxy)-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane; and

E-7-hydroxy-8-[(2-hydroxymethyl)-2-butene-4-yl]-chromane.

9. A pharmaceutical composition, especially for treating toxic shock, multiple sclerosis, rheumatoid arthritis and Crohn's disease, comprising an effective amount of at least one compound of the formula (I) as defined in any of claims 1 to 8.

10. A method of treating toxic shock, multiple sclerosis, rheumatoid arthritis and Crohn's disease in a mammal, including men characterized by administering to said mammal an effective amount of at least one compound of the formula (I) as defined in any of claims 1 to 8.

1 1. A compound of the formula (III)

wherein

R - and R^ are hydrogen or form together with the adjacent carbon atoms 6- membered saturated heterocycle containing one oxygen atom; R3 is lower alkyl, hydroxy(lower)alkyl or a group of the formula (II)

wherein Y is lower alkyl or lower alkoxy and m is 0, 1 , 2, 3, 4 or 5; Z represents, independently from each other, hydroxy, lower alkyl, lower alkoxy, (lower)alkoxy(lower)alkoxy, halo or halo(lower)alkyl; and n is 0, 1, 2, 3, 4 or 5 with the proviso that if R - and R^ are other than hydrogen, the value of n is at most 3.

12. A compound of the formula (VII),

wherein

Rl and R^ are hydrogen or form together with the adjacent carbon atoms 6- membered saturated heterocycle containing one oxygen atom;

R3 is lower alkyl, hydroxy(lower)alkyl or a group of the formula (II)

wherein Y is lower alkyl or lower alkoxy and m is 0, 1 , 2, 3, 4 or 5; R⁴ represents a hydrogen atom or a lower alkoxy group; Z represents, independently from each other, hydroxy, lower alkyl, lower alkoxy, (lower)alkoxy(lower)alkoxy, halo or halo(lower)alkyl; and n is 0, 1, 2, 3, 4 or 5 with the proviso that if Rl and R- are other than hydrogen, the value of n is at most 3.