HUT63405A - Process for producing acetylene derivatives substituted with chromanyl, thiochromanyl or tetrahydroquinolinyl group and having retinoid-like activity, as well as pharmaceutical compositions comprising same as active ingredient - Google Patents

Abstract

Retinoid-like activity is exhibited by compounds of formula (I), where X is S, O; R1, R2 and R3 are hydrogen or lower alkyl; R4 and R5 are hydrogen or lower alkyl with the proviso that R4 and R5 cannot both be hydrogen, R6 is hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl or halogen; n is 0 - 5, and B is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal derivative, or -COR1 or a ketal derivative where R1 is -(CH2)mCH3 where m is 0-4, or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to novel 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl and phenyl substituted retinoid-like acetylene derivatives, to pharmaceutical compositions containing them as active ingredients, and to the preparation of new compounds. One of the molecules of the compounds of the present invention is an ethynyl benzoic acid and the other part is a 2-substituted 1,2,3,4-tetrahydroquinolinyl, thiochromanyl or chromanyl group, while the acid function, i.e. the carboxyl group, is converted to an alcohol, aldehyde or it can be converted to a ketone or it can be reduced to a methyl group.

4- (2- (4,4-Dimethyl-6-X) -2-methyl-vinyl) -benzoic acid, wherein X is a tetrahydroquinolinyl, chromanyl or thiochromanyl carboxylic acid derivative, is an inhibitor of cartilage degeneration. Published on 9 January 1985 in European Patent Publication No. 0133795. European Patent Publication No. 176034A, published April 2, 1986, discloses tetrahydronaphthalene derivatives containing an ethynyl benzoic acid group, and U.S. Patent 4,739,098 discloses compounds wherein the styrenecarboxylic acid [3,7- The three olefinic units of the dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraenecarboxylic acid] carboxylic moiety are replaced by ethynylphenyl.

It has now been found that the novel compounds of formula (I) are curative. In the general formula (1)

X is O or S;

R ', R ₂ and R ₃ is hydrogen or lower alkyl group, independently;

R4 and R5 are each independently hydrogen or lower alkyl, provided that they are not simultaneously hydrogen;

Rg is lower alkyl, lower alkenyl or lower cycloalkyl, n is 0, 1, 2, 3, 4 or 5; and

B is hydrogen or -COOH, or a pharmaceutically acceptable salt, ester, or amide thereof, -CH ₂ OH, or an ether or ester derivative thereof, -CHO or an acetal derivative thereof; or -COR 4 (where Ry 'is alkyl, cycloalkyl or alkenyl containing up to 5 carbon atoms) or a ketal derivative thereof.

The compounds of formula (I) are useful in the treatment of skin disorders such as hair follicles, Darier's disease, psoriasis, scaling, eczema, atopic skin disease and epithelial cancer. These compounds are also useful in the treatment of arthritis and other immunological disorders (e.g., lupus erythematosus), in promoting wound healing, in the treatment of dry eye syndrome, and in the elimination of the sun's deleterious effects on the skin.

Thus, the present invention also relates to pharmaceutical compositions comprising as active ingredient a compound of formula (1) in admixture with excipients and / or other excipients commonly used in the pharmaceutical production.

The present invention also relates to a process for the preparation of compounds of formula (I). The procedure consists in:

a) a compound of formula 2 wherein R 1 to R 5 and X are as defined above and a compound of formula 3 wherein R 8 and n are as defined above, X 'is halogen, preferably iodine and B' is hydrogen or a protected acid, alcohol, aldehyde or ketone group is reacted in the presence of copper (I) iodide and complexed suitably in the presence of Pd (PQ3) ₂ Cl2 (wherein Q is phenyl) or

b) reacting a zinc salt of formula (4) wherein ^R 1 'R 5 and X are as defined above, with a compound of formula (3) wherein R g, η, X' and B 'are as defined above, conveniently In the presence of Pd (PQ3) 4 (where Q is phenyl) or

c) converting a compound of Formula 5 into a homologue of Formula 1 wherein R 1 to R 8 and X are as defined above and n 'is 0, 1, 2, 3 or 4, and optionally

(i) converting an acid of formula (1) into a salt, or • (ii) converting a free base of formula (1) into an acid addition salt, or (iii) converting an acid of formula (1) into an ester, or (iv) converting an acid of formula I into an amide, or

(v) reducing an acid of formula (1) to an alcohol or aldehyde; or (vi) converting an alcohol of formula (1) into an ether or ester; or (vii) oxidizing an alcohol of formula (1) to an aldehyde; converting an aldehyde of formula (II) into an acetal, or (ix) converting a ketone of formula (1) into a ketal.

The term ester refers to esters well known in organic chemistry. When B is -COOH in formula (1), esters are understood to mean esters of compounds and alcohols having such a group, preferably aliphatic alcohols having from 1 to 6 carbon atoms. When the esters are derivatives of compounds having B as -CH ₂ OH, the functional group is -CH ₂ OOCR, wherein R is any optionally substituted aliphatic, aromatic or aliphatic-aromatic group, preferably in the aliphatic moiety 1-6 carbon atoms. containing an aliphatic group.

Preferred esters of up to 10 carbon atoms are from <RTI ID = 0.0> 4,4 </RTI> * 4444 · saturated aliphatic alcohols or acids or

Esters derived from cyclic or saturated aliphatic cyclic alcohols or acids containing from 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkane carboxylic acids or alcohols. As used herein and hereinafter, "lower alkyl" means C 1-6 alkyl. Further preferred are phenyl and lower alkyl phenyl esters.

The term amide also refers to groups well known in organic chemistry. In the present case, the unsubstituted amides and all aliphatic or aromatic mono- and disubstituted amides are included. Preferred amides are mono- or disubstituted amides derived from aliphatic groups having up to 10 carbon atoms or from cyclic or saturated aliphatic cyclic groups having from 5 to 10 carbon atoms. Particularly preferred are amides derived from lower alkyl amines. Further preferred are mono- and disubstituted amides derived from phenyl or (lower) alkylphenylamines. Unsubstituted amides are also preferred.

Acetals and ketals include compounds having the formula -CK, in which K is (-OR) 2 and in the latter R is lower alkyl. K may also be a group -OR10 where Rp is a straight or branched alkyl group containing from 2 to 5 carbon atoms.

• ·

A pharmaceutically acceptable salt can be prepared from any compound of the invention having a functional group suitable for salt formation, such as an acid group or an amine group. The pharmaceutically acceptable salt may be any salt which retains the efficacy of the parent compound and does not adversely or adversely affect the subject.

Such a salt may be derived from any organic or inorganic acid or base. The salt may be derived from monovalent or polyvalent ions. When the starting compound contains an acid group, salts with inorganic ions such as sodium, potassium, calcium and magnesium are important salts. Examples of salts with organic amines include salts with mono-, di- and trialkylamines or ethanolamine. Salts may also be prepared with caffeine, 2-amino-2- (hydroxymethyl) -1,3-propanediol and the like. If the compound contains a sufficient amount of a basic nitrogen atom to form an acid addition salt, the acid addition salts may be prepared with inorganic or organic acids or alkylating agents such as methyl iodide. Of the acid addition salts, salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid are preferred. Salts with simple organic acids such as mono-, di- or tricarboxylic acids may also be used.

Preferred compounds of the present invention are those wherein the ethynyl group and the B group are attached at the 1- or 4-position of the phenyl ring (i.e., the phenyl portion of the compounds of the invention is para-substituted); n is 0; and B is -COOH or an alkali metal salt or an organic amine salt thereof, or a lower alkyl ester, or -CH 2 OH or a lower alkyl ester or ether thereof, or -CHO or an acetal formed therein. Most preferred are the compounds of formula (6): ethyl 4 - [(2,2,4,4-tetramethylthiochroman-6-yl) ethynyl] benzoate (Compound 1, X = S, R ₃ = H, R 4 = CH ₃ , R 5 = CH ₃ ,

R = C ₂ H ₅ ),

4 - [(2,2,4,4-tetramethylthiochroman-6-yl) ethynyl] benzoic acid (Compound 2, X = S, R ₃ = H, R ₄ = CH ₃ , R ₅ = CH ₃ .

R = H) Ethyl 4 - ((2,2,4,4-tetramethyl-chroman-6-yl) -ethyl] -benzoate (Compound 3, X = O, R ₃ = H, R 4 = CH ₃ , R 5 = CH ₃ ,

R = C ₂ H ₅ )

4 - [(2,2,4,4-tetramethyl-chroman-6-yl) -ethyl] -benzoic acid (Compound 4, X = O, R ₃ = H, R ₄ = CH ₃ , R ₅ = CH ₃ , R = H) Ethyl 4 - [(2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl] -benzoate (Compound 5, X = S, R ₃ = CH ₃ , R 4 = CH ₃ , R 5 = CH ₃ , R = C ₂ H ₅ )

4 - [(2,2,4,4,7-Pentamethylthiochroman-6-yl) ethynyl] -benzoic acid (Compound 6, X = S, R ₃ = CH ₃ , R ₄ = CH ₃ , R ₅ = CH ₃ , R = H) Ethyl 4 - [(2,2,4,4,7-pentamethylchroman-6-yl) ethynyl] benzoate (Compound 7, X = O, R ₃ = CH ₃ , R ₄ = CH ₃ , R ₅ = CH ₃ ,

R = C ₂ H ₅ )

4 - [(2,2,4,4,7-Pentamethyl-chroman-6-yl) -ethyl] -benzoic acid (Compound 8, X = O, R ₃ = CH ₃ , R ₄ = CH ₃ , R ₅ = CH ₃ , R = H) • · • · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 9 ethyl 4 - [(2,4,4-trimethyl-6-thiochromanyl) ethynyl] -benzoate (Compound 56, X = S, R ₃ = H, R ₄ = H, R ₅ = CH ₃ , R = C ₂ H ₅ ) 4- (2,4,4-Trimethyl-1-6-thiochromanyl) ethynyl] -benzoic acid (Compound 57, X = S, R ₃ = H, R ₄ = H, R ₅ = CH ₃ , R = H)

The compounds of the invention may be administered systemically or topically, depending on a number of factors such as the nature of the disease being treated, the need for site-specific treatment, or the amount of active ingredient to be administered.

Topical administration of the active ingredient is generally preferred for the treatment of dermatological disorders, although oral administration may also be appropriate in some cases, such as severe cystitis. Any conventional pharmaceutical preparation for topical administration such as a solution, suspension, gel, cream or ointment may be used. Preparation of this type of formulation is well known to those skilled in the art, such as those described in Remington's Pharmaceutical Science. 17th edition of the book (published by Mack Publishing Company, Easton, Pennsylvania, USA). For topical treatment, the compounds of the invention may also be in the form of powders or sprays, especially aerosols.

When an active ingredient is to be administered systemically, it may be administered orally, for example, in the form of a powder, pill, tablet, syrup or elixir. For intravenous or intraperitoneal administration, injectable solutions or suspensions may be prepared. In some cases, suppositories for subcutaneous administration or intra-articular administration may also be useful.

- Preparation of 10 muscular injections.

For topical application of this type, additional therapeutic agents may be added for secondary purposes such as treating dry skin, protecting against radiation, treating other skin complaints, preventing infection, reducing irritation or inflammation, and the like.

Skin complaints or other symptoms sensitive to treatment with other retinoic acid type compounds may be affected by administration of a therapeutically effective amount of one or more of the compounds of the invention. By therapeutically effective amount is meant an amount of the active ingredient which is capable of reducing or inhibiting the development of a particular symptom. In some cases, the active ingredient may be potentially used prophylactically to prevent the development of a particular symptom. A particular therapeutically effective concentration will vary from symptom to symptom and in some cases will vary depending on the severity of the symptom being treated and the patient's sensitivity to treatment. Thus, a particular therapeutically effective concentration is best determined by routine experimentation at a given site and time. However, it is believed that, for example, in the case of dermatitis or other skin complaints, 0.001 wt. and 5% by weight, preferably 0.01% by weight. and 1 weight! Formulations containing from 1 to 10% of the active ingredient satisfy the requirement of a therapeutically effective concentration. When administered systemically, in most cases, therapeutic results will be obtained with 0.01 mg to 100 mg, preferably 0.1 mg to 10 mg, per kg body weight per day.

The effect of the compounds of the present invention on retin carboxylic acid can be studied by determining the effect of retin carboxylic acid on ornithine decarboxylase in a known manner. The original work on the correlation between retin carboxylic acid and cell proliferation reduction is the work described by Verma and Boutwell in Cancer Research, 37, 2196-2201 (1977). This publication discloses an increase in ornithine decarboxylase (ODC) activity prior to polyamine biosynthesis. Others have also found that an increase in polyamine synthesis correlates or is related to cell proliferation. Thus, if ODC activity can be inhibited, cell proliferation (hyperproliferation) can be modified. Although not all the reasons for the increase in ODC activity are known, 12-O-tetradecanoylphorbol-13-acetate (TPA) is known to induce ODC activity. The compounds of the present invention also inhibit TPA-induced ODC activity, as confirmed by analysis by the method described in Cancer Slit, 35, 1662-1670 (1975).

Regarding the retinoic acid-like activity, it is noted that some of the preferred compounds of the invention, namely the compounds 1, 3, 7, 56 and 57 mentioned above, are the TPA-induced ODCs when tested by Verma and Boutwell. activity is inhibited by 80% at the following concentrations (IC ₈₀ ):

• * »· • 4

Test compound

IC30 (nanomolar)

First

1.2

0.1

7th

56th

.

2.2

0.24

The compounds of the present invention can be prepared by a variety of synthetic chemical methods. In the following, such methods will be described, provided that one skilled in the art of synthetic organic chemistry may appropriately adapt the reaction conditions specifically described below to prepare any compound of Formula (I) and modify the following process steps to provide the desired target compound.

Compounds of formula (I) wherein X is sulfur, and R4 and R5 are each independently hydrogen or lower alkyl (with the proviso that R4 and R5 are other than hydrogen) may be prepared as shown in Scheme 1. In this scheme, R., _R2 and R3 are independently hydrogen or lower alkyl, R is as defined in formula (1), n is 0, 1, 2, 3, 4 or 5 and B 'is hydrogen or a protected acid , alcohol, aldehyde or ketone. X 'is chlorine, bromine or iodine when n is 0, but preferably bromine or iodine when n is 1, 2, 3, 4 or 5.

Compounds of formula (I) wherein X is oxygen, and R4 and R5 are independently hydrogen or lower alkyl (with the proviso that R4 and R5 are other than hydrogen) may be prepared as shown in Scheme 2. In this scheme, R 1, R 2, R 3, R 4, R 5, R 8, n, B 'and X' are as defined in Scheme 1.

Methods for carrying out the synthesis steps of Schemes 1 and 2 are described below.

In the first step of Scheme 1, a 4-bromothiophenol derivative (9) is acylated with an acylating agent (10), such as acid chloride, which can be derived from an appropriately substituted acrylic acid. The acylation may be carried out in an inert solvent such as tetrahydrofuran in the presence of a strong base such as sodium hydride. The resulting thioester (11) containing the olefinic double bond of the acrylic acid moiety is then cyclized in the presence of a Friedel-Crafts catalyst such as aluminum chloride in a suitable solvent such as methylene chloride. The 2-oxo-6-bromothiochroman derivative (12) thus obtained is usually isolated in crystalline form.

The R4 and / or R5 substituents (which at the same time are other than hydrogen according to the invention) are then introduced by reacting a 2-oxo-6-bromothiochroman derivative of formula (12) with a Grignard compound having alkyl substituents R4 and R5. for example, when R4 and R5 are methyl, methyl magnesium bromide. If an excess of Grignard reagent, such as methyl magnesium bromide, • · * · »<·» a • · 4 4 «> ·

4 · 4 aa • 4 44444 44 • ·· a · · «4 ·······

14, the thiochroman ring is opened to form the tertiary alcohol derivative of 4-bromothiophenol (13).

The ring closure of the compound of formula 13 having the desired substituents R1, R2, R3, R4 and R5 is accomplished by heating under acidic conditions, preferably by heating a compound of formula 13 in aqueous acid. This gives a suitable compound of formula (14) wherein R1, R2, R3, R4 and R5 are the desired alkyl groups (or hydrogen).

The molecule to introduce the acetylene (etinrész), a formula (14) substituted 6-bromo-thiochroman derivative trimethylsilyl-acetylene is reacted with copper (I) iodide and a suitable catalyst, preferably Pd (PQ Level 3) ₂ C12 ^(wherein Q in the presence of phenyl). This reaction is typically carried out as a catalyst by heating in a reaction tube sealed in the presence of bis (triphenylphosphine) palladium (II) chloride and an acid binder such as triethylamine in an inert gas atmosphere such as argon.

The trimethylsilyl group of the thus obtained 6- (trimethylsilylethynyl) thiochroman (15) is then removed under basic conditions, preferably under an inert gas atmosphere, to give a 6-ethynylthiochroman (16).

To form an optionally substituted phenyl substituent on the acetylene portion of the compound of formula (16), the compound of formula (16) with a reagent of formula (3) wherein X ', n and B' are as previously defined and Q is di- or a multisubstituted phenyl moiety is added to it, i.e., the optionally substituted phenyl substituent is introduced by Compound III is reacted with a halogen substituted phenyl compound, i.e. a reagent of formula (3). For the latter compound, the phenyl ring is either substituted with the desired - (CH2) _n ^-B 'substituent or can be converted to another suitable substituent by methods well known in the art of organic chemistry.

The coupling reaction of the compound of formula (16) with the reagent of formula (3) can be carried out directly in the presence of copper (I) iodide, a suitable catalyst, preferably Pd (PQ ₃ ) 2 Cl 2, and an acid acceptor such as triethylamine in an inert gas atmosphere. for example by heating in an argon atmosphere.

The compound of formula (18) thus obtained may itself be the target compound of the invention or be converted to another target compound in steps such as salt formation, esterification, desesterification, conversion to a higher homologue or amidation. These operations will be described later.

The compounds of Formula 18 may also be prepared by first converting a thiochroman derivative of Formula 16 into a suitable metal salt, such as a zinc salt of Formula 17, followed by coupling with a reagent of Formula 3 (in which (optionally substituted phenyl) in the presence of a catalyst such as Pd (PQ ₃ ) ₄ (where Q is phenyl) or the like.

The conversion of compounds of formula (18) into various derivatives is referred to in Scheme 1 as homologues and derivatives of formula (19).

The following are described below for the conversion or deprotection of protected functional groups in the compounds of Formula 18 and the preparation of the phenyl derivatives of Formula 3 (which can be directly converted into the target compounds in the coupling reaction or further converted into the target compounds in a simple operation).

If a protected phenyl derivative is to be coupled with a compound of formula (2), i.e., a compound of formula (16) in Scheme 1, such protected compounds may be prepared from the corresponding acids, alcohols, ketones or aldehydes. These starting compounds, i.e. protected acids, alcohols, aldehydes or ketones, are all commercially available or can be prepared by known methods. Typically, the carboxylic acids can be esterified by refluxing the acid in a solution with the appropriate alcohol in the presence of an acidic catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid may be condensed with a suitable alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester may be isolated and purified in conventional manner. Acetals and ketals can be easily prepared by the method described by March on page 810 of Advanced Organic Chemistry (2nd edition, published by McGraw-Hill Book Company, United States Publisher). Alcohols, aldehydes, and ketones can all be protected by ethers and esters, and acetals and ketals by known methods, such as those published by McOmie in Plenum Publishing Press in the United States in 1973 or Protecting Groups. (edited by Greene in 1981 under the care of John Wiley and Sons, a US publisher).

Prior to carrying out a coupling reaction, the value of n may be increased (if the corresponding compounds are not commercially available) by subjecting the phenyl derivative containing B 'to -COOH to a chain-extending reaction and then treating it under Arndt-Eister conditions. , or other known chain augmentation reactions. Alternatively, heteroaromatic compounds bearing a group B 'other than a carboxyl group may be converted to higher homologues. The homologated acids can then be esterified as described in the previous paragraph.

An alternative method for preparing compounds of formula (1) having n = 1, 2, 3, 4 or 5 and wherein B is carboxyl or another functional group is to subject a suitable shorter chain homologue to a chain extension reaction by the aforementioned Arndt-Eister method or other known method. .

The acids and salts of formula (1) can be readily prepared by saponification of the corresponding esters. Alkaline saponification with an alkali metal base gives the acid. For example, an ester of formula (1) may be dissolved in a polar solvent, such as an alkanol, preferably under an inert gas atmosphere at room temperature, in a triple molar excess of a base such as potassium hydroxide. The resulting solution is stirred for an extended period of 15-20 hours, then cooled, acidified and the hydrolyzate isolated in a known manner.

The amides may be prepared from the corresponding esters or carboxylic acids by any of the well known methods of amidation. For example, an acid can be converted to an acid chloride and then reacted with ammonium hydroxide or a suitable amine. For example, the acid may be treated with an alcoholic solution of a base such as potassium hydroxide in ethanol (approximately 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue is taken up in an organic solvent such as diethyl ether and the resulting solution is treated with a dialkylformamide and ten times excess oxalyl chloride. All of these operations are carried out at slightly reduced temperatures, i.e., -10 ° C to + 10 ° C. After the addition of oxalyl chloride, the resulting solution is stirred at said reduced temperature for 1-4 hours, preferably for 2 hours, then the solvent is removed and the residue is taken up in an inert organic solvent such as benzene. The resulting solution was cooled to about 0 ° C and concentrated aqueous ammonium hydroxide was added. The resulting reaction mixture was stirred at reduced temperature for 1-4 hours and then isolated in known manner.

The alcohols may be prepared by converting a suitable acid to the acid chloride by thionyl chloride or otherwise (March, J. Advanced Organic Chemistry, Vol. 2, McGrawHill Book Company, United States Publisher) followed by the acid chloride, sodium boron. -hydride (see page 1124 of March, cited herein) to give the corresponding alcohol. Alternatively, the esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylation of these alcohols with the appropriate alkyl halides under the conditions of the Williamson reaction (see March 35, p. 357) affords the corresponding ethers. These alcohols can be converted into esters by reaction with appropriate acids in the presence of acidic catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding alcohols by mild oxidizing agents, for example pyridinium dichromate in methylene chloride [Corey, E.J. and Schmidt, G .: Tet. Lett. 399 (1979)] or a mixture of dimethylsulfoxide and oxalyl chloride in methylene chloride (Omura, K. and Swern, D., Tetrahedron, 34, 1651 (1978)).

Ketones may be prepared from a suitable aldehyde by treatment with an Grignard reagent or the like containing an alkyl group followed by oxidation.

The acetals or ketals may be prepared from the corresponding aldehydes or ketones in the manner described by March, page 810, herein.

Compounds having B as the hydrogen atom may be prepared from the corresponding halogenated benzene derivatives, preferably iodine compounds.

Turning to Scheme 2, a phenol of Formula 20 or a phenol having a ₃ -substituent R _{3 is} acylated with an acylating agent of Formula 10, such as acid chloride, which may be derived from an appropriately substituted acrylic acid. As in Scheme 1, Scheme 2, the substituents R 1 and R _{3 of} the target compounds are introduced with the acrylic acid derivative (10). The acylation may be carried out in an inert solvent such as tetrahydrofuran in the presence of a strong base such as sodium hydride.

The phenylacrylate (21) thus obtained is then ring-closed in the presence of a Friedel-Crafts catalyst such as aluminum chloride in a suitable solvent such as methylene chloride. There is thus obtained a 2-oxochroman derivative of the formula (22) which has the substituents R 1 and R 2 at the 4-position and the R ₃ (if any) substituent at the 6-position. In a similar manner to the analogous 2-oxothiochroman derivatives of Formula 12, the R 4 and R 5 substituents (which are simultaneously hydrogen according to the present invention) are then introduced by reacting a 2-oxochroman of Formula 22 A solution of a derivative of a derivative thereof in a suitable solvent, such as anhydrous diethyl ether, is reacted with a solution of a Grignard compound bearing alkyl substituents R 4 and R 5, preferably when R 4 and R 5 are methyl, in tetrahydrofuran. The chroman ring is then opened to form a tertiary alcohol derivative of formula (23).

Ring closure carrying the desired R _lf R _2, R _3, R 4 and R 5 substituents (compound 23) is performed by heating under acidic conditions, for example, a (23) was prepared by heating in aqueous sulfuric acid when a chroman derivative (24) was obtained. It should be noted that up to this point, both thiochroman derivatives (Scheme 1) and chroman derivatives (Scheme 2) have been prepared from similar or identical steps in the synthesis sequence (which is only advantageous but not the only way to prepare the compounds of the invention). The only difference is that in Scheme 2, the starting phenolic derivative does not carry a halogen atom such as a bromine atom.

In the preferred synthesis sequence for the preparation of the chroman derivatives of the invention, the preferred steps for introducing an acetylene group at the 6-position of the chroman ring and the scheme shown in Scheme 2 differ from the step of introducing an acetylene group

Thus, in Scheme 2, a substituted chroman derivative of formula (24) is subjected to a Friedel-Crafts reaction to introduce the acetylene moiety into the 6-position, preferably by reacting the chroman derivative with acetyl chloride in nitromethane as the solvent. in the presence of a 6-acetylchroman derivative of formula (25).

The 6-acetyl group of a chroman derivative (25) is then converted to an acetylene group to form an acetylene-like, i.e. triple bond, preferably by treatment with lithium diisopropylamide at low temperatures, e.g. place. The intermediate enol (not shown in Scheme 2) is then esterified by treatment with diethyl chlorophosphate (or similar reagent) and reacted again with lithium diisopropylamide at a low temperature, for example -78 ° C a triple bond (presumably by elimination reaction) and a 6-ethynylchroman derivative of formula (26).

Subsequently, a 6-ethynylchroman derivative (26) is converted to the target compound of the present invention in steps analogous to the steps for converting the 6-ethynylthiochroman derivative (16) to the corresponding target compound according to Scheme 1. Briefly, the coupling reaction of formula (26) compound and the reagent (wherein Q is an optionally substituted phenyl residue), the formula (3) is accomplished with direct copper (I) iodide, a suitable catalyst, preferably Pd (PQ Level 3) 2C12 ^(wherein Q is a phenyl group or the like) and heating with an acid acceptor such as triethylamine. The compound of formula (28) thus obtained may itself be the target compound of the invention or be converted to another target compound in steps such as deprotection, deprotection, esterification, conversion to a higher homologue or amidation as described in Scheme 1. . The compounds of formula (28a) are thus obtained.

Compounds of formula (28) may also be prepared by first converting a chroman derivative (26) to a suitable metal salt, such as a zinc salt (27), and then reacting the latter with a reagent (3), wherein Q is optionally substituted phenyl) under the reaction conditions described in Scheme 1 for the coupling reaction with compounds of formula (18).

Schemes 3 and 4 illustrate methods for the preparation of compounds of formula (14).

In Scheme 3, 6-bromothiochroman derivatives of formula (14) wherein R 4 and R 5 are substituted at one site and hydrogen at another site are prepared by first reacting a compound of formula (12) with Scheme 1. The 2-oxo-6-bromothiochroman derivative was treated with Grignard reagent. Specifically, the 2-oxothiochroman derivative of formula (12) is treated with an excess of a Grignard reagent such as methylmagnesium bromide when R4 or R5 is methyl, which contains the required R 4 substituent as an alkyl group. The reaction is held at a relatively low but constant temperature (about 14 ° C) for a relatively short period of time (about half an hour) when a hemiacetal derivative (49) is obtained. This is then converted to the corresponding 6-bromothiolefin derivative (50) under acidic conditions, preferably with aqueous sulfuric acid. The latter is then reduced with a carbon-based substrate · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Hydrogenation at medium pressure, i.e., 2.1 x 10 ⁵ Pa, in the presence of 24 palladium sulfide catalysts. Thus, the appropriate substituents R ₁ , R ₂ , R ₃ , R 4 and R 5 are 6-bromothiochroman of formula (14) having the desired hydrogen atoms and alkyl groups (more particularly one of R 4 and R 5 is hydrogen).

In Scheme 4, 6-bromothiochroman derivatives of formula (14) having both alkyl and different alkyl groups are prepared by reacting the hemiacetal derivative (49) with the Grignard reagent used in the appropriate step of Scheme 3. reaction with a different Grignard reagent. In this step, the thiochroman ring is opened in the presence of the Grignard reagent to form the tertiary alcohol derivative of 4-bromothiophenol 13. The ring closure of the desired tertiary alcohol having the desired R _1x R ₂ , R ₃ , R ₄ and R 5 substituents is then carried out as described above by heating the compound of formula 13 under acidic conditions, preferably in aqueous sulfuric acid, R ₂ , R ₃ , R ₄ , and R 5 to give the desired compound of formula (14) having the desired alkyl and hydrogen substituents.

As in Scheme 3, Scheme 5, one of the R 4 and R 5 substituents of the chroman derivatives of Formula 24 represents an alkyl group and the other represents a hydrogen atom. Similarly to the analogous 2-oxothiochroman derivative (12) in Scheme 3, the oxochroman derivative (22) in Scheme 5 is reacted with excess Grignard reagent in R4 and

For introducing R5 substituents. As previously mentioned, at controlled reaction temperature and reaction time, as shown in Scheme 5, the hemiacetal derivative (51) can be isolated. The hemiacetal derivatives of formula (51) can then be converted to the corresponding olefin derivatives of formula (52) by heating under standard acidic conditions, such as aqueous sulfuric acid. The olefin derivatives (52) are then subjected to the same procedure as described in Scheme 3 for reducing compounds of formula (49) or other generally known reductions. The method can be used to reduce the chroman derivatives (24). It should be noted that up to this point, the synthesis sequence (which is advantageously, but not necessarily exclusively, used to prepare the compounds of the invention) includes similar or analogous steps to both thiochroman derivatives (Scheme 3) and chroman derivatives (Scheme 5). in Scheme 5, the main difference being that in Scheme 5, the starting lactone does not carry a halogen such as bromine as a substituent.

Referring to Scheme 6, is reacted a compound of formula (51) other than those utilized above Grignard reagent Grignard reagent to produce carrier differing alkyl compounds of formula (24) R4 and R5, when the desired Ri, _R2, R3 The tertiary alcohols (23) having substituents R 4, R 4 and R 5 are obtained. The ring closure of the compound of formula (23) is performed under acidic conditions when the compound of formula (24) is cyclically closed.

- We get 26 shots. To obtain the final product having one of the substituents R 4 and R 5 having an alkyl group and the other having a hydrogen atom or a different alkyl group at R 4 and R 5, compounds 14 and 24 are subjected to the steps described in Schemes 1 and 2, respectively. .

The following examples illustrate the preparation of the compounds of the present invention and the intermediates used.

To a suspension of ethyl 4-iodobenzoate (Compound 29) in g (40.32 mmol) of 4-iodobenzoic acid in 100 ml of anhydrous ethanol was added 2 ml of thionyl chloride, and the resulting mixture was refluxed for 3 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (100 mL). The ethereal solution was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to Kugelrohr distillation (100 ° C, 0.55 mm) to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 1.42 (3H, t, J = 7Hz), 4.4 (2H, q, J = 7Hz), 7.8 (4H).

By following the procedure described above, but employing an appropriate acid instead of 4-iodobenzoic acid, the following compounds can be prepared:

ethyl 4-iodophenyl acetate;

27 ethyl 3- (4-iodophenyl) propionate;

ethyl 4- (4-iodophenyl) butanoate; and ethyl 5- (4-iodophenyl) pentanoate.

S- (4-Bromophenyl) 3,3-dimethylthioacrylate (Compound 30)

Under an argon atmosphere, a solution of sodium hydride (1.92 g, 80 mmol) (obtained from a 60% mineral oil slurry by washing three times with 15 ml of hexane) in 30 ml of anhydrous tetrahydrofuran was added slowly over an hour. A solution of 4-bromothiophenol (15.1 g, 80 mmol) in anhydrous tetrahydrofuran (60 mL) was stirred at 0 ° C for an additional 30 minutes and then dimethyl acryloyl (10.1 g, 85 mmol) was added. chloride in 30 ml of anhydrous tetrahydrofuran. The cooling bath was removed and the reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into water (200 mL) containing glacial acetic acid (2 mL) and the organic layer was separated. The organic phase was then washed twice with water (75 ml), dried over magnesium sulfate and the solvent removed in vacuo. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.91 (3H, s), 2.14 (3H, s), 6.03-6.06 (1H, m), 7.28 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz).

4,4-Dimethyl-6-bromo-2-oxothiochroman (Compound 31)

A stirred suspension of aluminum chloride (15.9 g, 119 mmol) in methylene chloride (140 mL) was added under stirring under nitrogen and ice (21.64 g, 79.9 mmol) S- (4-bromophenyl) 3.3 dimethylthioacrylate (Compound 30) in 100 mL of methylene chloride. The reaction mixture was stirred at room temperature for 72 hours and then poured into 250 g of ice-cold sodium chloride solution. The mixture was extracted several times with methylene chloride, and the combined extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was recrystallized from hexane to give the title compound as white crystals.

NMR (CDC1 _3): δ 1.40 (6H, s), 2.67 (2H, s), 7.31-7.40 (3H, m).

Mass spectrum m / e calcd for C 19 H 16 SOBr 269.9714, found 269.9714.

4-Bromo-2- (1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 32)

To a solution of 3.49 g (32.8 mmol) of lithium perchlorate in argon gas is added 3.0 ml of methyl magnesium bromide (105 mmol) in 35 ml of diethyl ether, and 2.961 g is added dropwise to the reaction mixture with stirring. (10.926 mmol) of 4,4-dimethyl-6-bromo-2-oxothiochroman (Compound 31). The reaction mixture was refluxed for 70 hours, allowed to cool and then added to a mixture of 100 g of crushed ice and 8 ml of concentrated sulfuric acid. The organic layer was separated and the aqueous layer was extracted twice with 25 mL of diethyl ether. The combined organic layers were washed with saturated aqueous sodium bicarbonate (25-25 mL), once with water (25 mL) and once with saturated brine (25 mL), dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography to give the title compound as a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.05 (6H, s), 1.52 (6H, s), 2.30 (2H, s), 3.71 (1H, s), 7.22 (1H , dd, J = 8.5 Hz, 2.1 Hz), 7.28 (1H, d, J = 8.5 Hz), 7.35 (1H, d, J = 2.1 Hz).

Using methyl magnesium bromide instead of methyl magnesium bromide, the corresponding 4-bromo-2- (1,1-dimethyl-3-ethyl-3-hydroxypentyl) thiophenol can be prepared.

2,2,4 / 4-Tetramethyl-6-bromothiochroman (Compound 33)

A mixture of 500 mg (1.49 mmol) of 4-bromo-2- (1,1,3-trimethyl-3-hydroxybutyl) -thiophenol (Compound 32) and 8 mL of 20% aqueous sulfuric acid was refluxed. reflux for 1 hour and then extract with hexane. The organic extract was washed successively with water, saturated aqueous sodium bicarbonate solution, water again, and finally saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with hexane. The title compound was obtained as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.35 (6H, s), 1.40 (6H, s), 1.93 (2H, s), 7.17 (1H, dd, J = 8.4 Hz), 2.1 Hz), 7.23 (1H, d, J = 8.4 Hz), 7.26 (1H, d, J = 2.1 Hz)

Mass spectrum m / e calcd for C 13 H 17 S Br 284.0234, found 284.0221.

···· ·····································································•

2,2,4,4-Tetramethyl-6-trimethylsilylethynylthiochroman (Compound 34)

A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 mL of triethylamine was weighed into a thick-walled reaction tube and the air was evacuated under argon atmosphere. Trimethylsilylacetylene (1.4 g, 14.3 mmol) was added followed by copper (I) iodide (75 mg, 0.39 mmol) and bis (triphenylphosphine) palladium (150 mg, 0.21 mmol). (II) chloride powder mixture. The reaction mixture is then purged again, placed under an argon atmosphere and the reaction tube is sealed. After heating at 100 ° C for one hour, the reaction mixture was allowed to cool to room temperature, followed by addition of additional 1.4 g (14.3 mmol) trimethylsilylacetylene and 75 mg (0.39 mmol) copper ( I) iodide and 150 mg (0.21 mmol) of bis (triphenylphosphine) palladium (II) chloride powder. After aeration, the reaction mixture was placed under an argon atmosphere and the tube was sealed and heated at 100 ° C for 96 hours. The reaction mixture was cooled to room temperature and extracted with diethyl ether (3 x 10 mL). The combined organic extracts were washed with water (1 mL) followed by brine (25 mL), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was subjected to flash chromatography on silica gel eluting with hexane followed by 3% ethyl acetate in hexane. This gives the title compound as a yellow crystalline precipitate.

'T

31 H NMR (CDCl 3): δ 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 ( 1H, dd, J = 8.2 Hz, 1.8 Hz), 7.25 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J = 8.2 Hz).

MS calculated m / e gH26 C _X S Si calcd 382.1524, found 302.1519.

2,2,4,4-Tetramethyl-6-ethynylthiochroman (Compound 35)

To a solution of 527.6 mg (1.75 mmol) of 2,2,4,4-tetramethyl-6-trimethylsilylethynylthiochroman (Compound 34) in 4 mL of isopropanol was added 4 mL of 1 N potassium hydroxide solution under argon. and the resulting mixture was stirred at room temperature for 20 hours and then the isopropanol was removed in vacuo. The residue was extracted several times with diethyl ether, and the combined ethereal extracts were washed with water, then with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then removed in vacuo to afford the title compound as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.34 (6H, s), 1.37 (6H, s), 1.91 (2H, s), 2.99 (1H, s), 7.17 (1H, dd, J = 8.1 Hz, 1.8 Hz), 7.26 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J = 8.1 Hz).

Mass spectrum m / e C _X 5H _X8 S calcd 230.1129, found 230.1122.

Ethyl 4 - [(2,2,4,4-tetramethylthiochroman-6-yl) ethynyl] benzoate (Compound 1)

110.7 mg (0.481 mmol) of 2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 142.3 mg (0.516 mmol) of ethyl 4-iodobenzoate (Compound 29) in 2 ml of triethyl of the amine solution is weighed into a thick-walled glass tube and then in an argon gas atmosphere. * * 4 4 4 4!!!!! «· * · · · · · · · · · · · · · · · · A finely ground mixture of copper (I) iodide (42 mg, 0.221 mmol) and bis (triphenylphosphine) palladium (II) chloride (63 mg, 0.09 mmol) was then added. Air is then degassed again with argon and the glass tube is sealed. After stirring at room temperature for 40 hours, the triethylamine was removed in vacuo, and the resulting residue was purified by flash chromatography on silica gel using 3% ethyl acetate / hexane as eluent. This gave the title compound as a pale yellow precipitate.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.37-1.42 (15H, m), 1.96 (2H, s), 4.38 (2H, q, J = 7.0Hz), 7.25 (1H, dd, J = 8.2 Hz, 1.8 Hz), 7.33 (1H, d, J = 1.8 Hz), 7.37 (1H, J = 8.2 Hz), 7, 65 (2H, d, J = 8.6 Hz), 8.01 (2H, d, J = 8.6 Hz).

Mass spectrum m / e calcd for C ₂₄ H ₂₅ 6 ° 2 ^S 378.1653, found 378.1636.

In a manner similar to that described for the preparation of Compound 1, but from another suitable ethynylthiochroman derivative, i.e., the compound of formula (16) in Scheme 1, and a corresponding halo-substituted phenyl ester, which is a compound of formula (3) prepared as described for Compound 29) The following compounds of the invention may be prepared: Ethyl 4 - [(2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl] benzoate;

ethyl 4 - [(2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl) ethynyl] benzoate;

«·« <V * · · 4 ·· <· «· · • ♦ · ·« · • »9 * <* · · ♦ • * · ··« · »« ··· «·

33 ethyl 4 - [(2,2,4,4-tetramethyl-7-propylthiochroman-6-yl) ethynyl] benzoate;

ethyl 4 - [(2,2,4,4-tetramethyl-7-hexyl-thiochroman-6-yl) -ethyl] -benzoate;

ethyl 2- [4 - [(2,2,4,4-tetramethylthiochroman-6-yl) ethynyl] phenyl] acetate;

ethyl 2 - [[4- (2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl] phenyl] acetate;

ethyl 2- [4- (2,2,4,4-tetramethyl-7-ethyl-thiochroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl 2- (4- (2,2,4,4-tetramethyl-7-hexyl-thiochroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl 3- [4- (2,2,4,4-tetramethylthiochroman-2-yl) ethynyl) phenyl] propionate;

ethyl 3- (4- (2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl) phenyl] propionate;

ethyl 3- (4- 2- (2,2,4,4-tetramethyl-7-ethyl-thiochroman-6-yl) -ethyl) -phenyl] -propionate;

ethyl 3- [4- (2,2,4,4-tetramethyl-7-hexyl-thiochroman-6-yl) -ethyl] -phenyl] -propionate;

ethyl 5- [4- (2,2,4,4-tetramethylthiochroman-6-yl) ethynyl) phenyl] pentanoate;

ethyl 5- [4- (2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl) phenyl] pentanoate; and ethyl 5- [4- (2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl) ethynyl] phenyl] pentanoate.

The position isomers and analogs of the compounds exemplified above can be prepared as described above * · · · 4 · · W4 · · 4 · · 4 · · 4 ·

1 »Ι« 4 ·· · «

- methods described herein or modifications of such methods apparent to those skilled in the art.

Phenyl 3,3-dimethylacrylate (Compound 37)

While cooling in an ice bath under an oxygen gas atmosphere, a suspension of 1.29 g (54 mmol) of sodium hydride (obtained from a 60% mineral oil slurry in 3 x 10 mL hexane) was slowly added 5 g (53 g) of anhydrous tetrahydrofuran. a solution of phenol in 50 ml of anhydrous tetrahydrofuran and a solution of 7 g (59 mmol) of dimethyl acryloyl chloride in 30 ml of anhydrous tetrahydrofuran are added. The cooling bath was removed and the reaction stirred for an additional 2.5 hours. The reaction mixture was then poured into 150 ml of water containing 1 ml of glacial acetic acid. The resulting aqueous mixture was extracted with diethyl ether (150 mL), and the extract was washed with saturated brine, dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting with 5% diethyl ether in hexane. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.99 (3H, s), 2.24 (3H, s), 5.93 (1H, broad s), 7.10 (2H, d, J = 7.8). Hz), 7.22 (1H, t, J = 7.8 Hz), 7.38 (2H, t, J = 7.8 Hz).

4,4-Dimethyl-2-oxochroman (Compound 38)

To a suspension of aluminum chloride (10.4 g, 78 mmol) in methylene chloride (160 mL) was stirred slowly under argon, 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 37) was added slowly. ml of methylene chloride. The cooling bath was removed and the reaction stirred for 42 hours. The reaction mixture was poured into a mixture of ice and a saturated aqueous sodium chloride solution, and the organic layer was separated. The aqueous phase was extracted with methylene chloride and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 10% diethyl ether in hexane. The title compound was obtained as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3): δ 1.30 (6H, s), 2.56 (2H, s), 7.06 (1H, dd, J = 8.0 Hz, 1.4 Hz), 7.16 (1H, td, J = 8.0 Hz, 1.4 Hz), 7.26 (1H, td, J = 8.0 Hz, 1.7 Hz), 7.33 (1H, dd, J = 8.0 Hz, - 1.7 Hz).

Mass spectrum m / e calculated for 176.0837, found 176.0852.

2- (1,1,3-Trimethyl-3-hydroxybutyl) phenol (Compound 39)

To a 3.0 M solution of methyl magnesium chloride in 11 mL of tetrahydrofuran (33 mmol) under ice-cooling under nitrogen was added 1.96 g (11.1 mmol) of 4,4-dimethyl-2-oxochroman (38 mL). (35 mL) in anhydrous diethyl ether (35 mL) was removed and the cooling bath was removed and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then poured into a mixture of 100 g of crushed ice and 3 ml of concentrated sulfuric acid and stirred until the magnesium salts were dissolved. The organic phase is then separated until

The aqueous phase is extracted twice with 50 ml of diethyl ether.

The combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate solution and finally saturated sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel, eluting with 20 volumes. using ethyl acetate in hexane. This gave the title compound as a pale yellow precipitate.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 1.13 (6H, s), 1.48 (6H, s), 1.89

(1H, s), 2.23 (2 H, s), 6.60 (1H, dd, J = 7.9 Hz, 1.4 Hz), 6.83 (1H, S), 6.84 (1H, td, J = 7.9 Hz, 1.4 Hz), 7.07 (1H, td, J = 7.9 Hz, 1.6 Hz), 7.31 (1H, dd, J = 7 , 9 Hz, 1.6 Hz).

Mass spectrum m / e calcd for C ₁₃ H 20 O 2 208.1464, found 208.1458.

2,2,4,4-Tetramethylchroman (Compound 40)

Under a nitrogen atmosphere, a mixture of 2.98 g (14.3 mmol) of 2- (1,1,3-trimethyl-3-hydroxybutyl) phenol (Compound 39) and 40 mL of 20 L aqueous sulfuric acid was refluxed. After refluxing for 4 hours, stirring at room temperature for an additional 72 hours, the reaction mixture was diluted with water (50 mL). The reaction mixture was extracted with hexane (3 x 20 mL), and the combined extracts were washed successively with water, brine, dried over magnesium sulfate, and the solvent removed in vacuo. The title compound was obtained as a colorless oil.

NMR (CDC1 _3): 8 1.36 (6H, s), 1.37 (6H, s), 1.83 · 4 · •

(2H, s), 6.71 (1H, dd, J = 8.2 Hz, 1.5 Hz), 6.92 (1H, td, J = 8.2 Hz, 1.5 HZ), 7.09 (1H, td J = 8.2 Hz, 1.5 Hz), 7.29 (1H, dd, J = 8.2 Hz, 1.5 Hz).

2.2.4.4- Tetramethyl-6-acetylchroman (Compound 41)

To a solution of 2 g (10.53 mmol) of 2,2,4,4-tetramethylchroman (Compound 40) in 20 ml of nitromethane was added 941 mg (11.99 mmol) of acetyl acetate while cooling with an ice bath. chloride followed by 1.59 g (11.92 mmol) of aluminum chloride. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then cooled again in an ice bath and 25 mL of concentrated hydrochloric acid was added. The reaction mixture was filtered and the residue was washed with methylene chloride. The filtrate and washings were evaporated in vacuo and the resulting residue was subjected to flash chromatography on silica gel eluting with 10% ethyl acetate / hexane. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.38 (6H, s), 1.39 (6H, s), 1.87 (2H, s), 2.56 (3H, s), 6.83 (1H , d, J = 8.7 Hz), 7.71 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.98 (1H, d, J = 2.1 Hz).

Mass spectrum m / e calcd for C ₁₃ H 20 O 2 232.1464, found 232.1468.

2.2.4.4- Tetramethyl-6-ethynylchroman (Compound 42)

To a solution of 522 mg (5.17 mmol) of diisopropylamine in 8 ml of anhydrous tetrahydrofuran, cooled to -78 ° C under nitrogen, 3.23 ml of a 1.6 M solution of n-butyllithium in hexane (5 ml) is added slowly. (17 mmol), the resulting mixture was stirred at -78 ° C for 40 min and then 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (41 mmol) was added. (2) in dry tetrahydrofuran (2 mL). The reaction mixture was then treated

After stirring at -78 ° C for an additional hour, diethyl chlorophosphate (895 mg, 5.19 mL) was added. The reaction mixture was allowed to warm to room temperature and then added with a double-ended needle at -78 ° C to lithium diisopropylamide (1.04 g, 10.34 mmol) in diisopropylamine and

6.66 ml of a 1.6 molar solution of n-butyllithium in hexane (10.34 mmol) was prepared as described above in tetrahydrofuran. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 16 hours. Then ice-cold water (10 ml) was added to the reaction mixture and the pH was adjusted to 2 with 10% hydrochloric acid. The organic phase is then separated and the aqueous phase is extracted three times with 30 ml of pentane each. The organic layers were washed successively with dilute hydrochloric acid (30 ml), water (once), saturated aqueous sodium bicarbonate (30 ml) and brine (1x), and dried over magnesium sulfate. the solvent was removed in vacuo. The residue was subjected to flash chromatography on silica gel, eluting with 2% ethyl acetate / hexane. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 1.31 (6H, s), 1.32 (6H, s), 1.50 (2H, s), 3.00 (1H, s), 6.72 (1H) , d, J = 8.4 Hz), 7.20 (1H, dd,

- 39 J = 8.4 Hz, 2.1 Hz), 7.42 (1H, d, J = 2.1 Hz).

Mass spectrum m / e: 214.1357, found 214.1251.

Ethyl 4 - [(2,2,4,4-tetramethylchroman-6-yl-ethynyl] -benzoate (Compound 3)

2,2,4,4-Tetramethyl-6-ethynylchroman (Compound 42) (233 mg, 1.088 mmol) and ethyl 4-iodobenzoate (Compound 29) (308 g, 1.087 mmol) in triethylamine (1 mL). solution is weighed into a thick-walled tube and then purged with argon gas. A finely ground mixture of copper (I) iodide (50 mg, 0.263 mmol) and bis (triphenylphosphine) palladium (II) chloride (100 mg, 0.142 mmol) is then added. The tube was then sealed and the reaction mixture was heated at 55 ° C for 48 hours. The triethylamine was then removed in vacuo and the residue was subjected to flash chromatography on silica gel using 5% ethyl acetate / hexane as eluent. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.33 (6H, s), 1.34 (6H, s), 1.37

(3H, t, J = 7.2 Hz), 1.83 (2H, s), 4.35 (2H, q, J = 7.2 Hz), 6.75 (1H, d j = = 8.4 Hz), 7.24 (1H, dd, J = 8.4) Hz , 2.1 Hz), 7.46 (1H, d, J = 2.1 Hz), 7.54 (2H, d, J + 8.1 Hz), 7 99 (2H, d, J = 8, 1 Hz).

Mass spectrum m / e calcd for C ₂₄ H ₂₆ 6 ° 3 362.1881, found 362.1880.

3-Methylphenyl 3,3-dimethylacrylate (Compound 44)

A suspension of 3.22 g (81 mmol) of sodium hydride in 60% w / w mineral oil was washed three times with 10 ml of hexane and

Anhydrous tetrahydrofuran (mL) was added. The resulting mixture was cooled in an ice bath and a solution of 8.6 g (79.5 mmol) of metacresol in 80 ml of anhydrous tetrahydrofuran was added. The resulting mixture was stirred for 10 minutes and then a solution of dimethyl acryloyl chloride (10.5 g, 88.5 mmol) in dry tetrahydrofuran (40 mL) was added. The reaction mixture was stirred at room temperature for 96 hours and then poured into a mixture of 150 ml of water and 1 ml of glacial acetic acid. The resulting aqueous mixture was stirred for 10 minutes and then the organic phase was separated. The aqueous layer was extracted with diethyl ether (2 x 50 mL), and the combined organic layers were washed successively with water and brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 10% ethyl acetate / hexane. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 1.9 δ (3H, d, J = 1.3 Hz), 2.21 (3H, d, J = 1.2 Hz), 2.34 (3H, s), 5.90 (1H, bs), 6.86-6.93 (2H, m), 7.01 (1H, d, J = 7.2Hz), 7.24 (1H, t, J = 7 , 2 Hz).

2- (1,3-Trimethyl-3-hydroxybutyl) -5-methylphenol (Compound 45)

To a suspension of aluminum chloride (13 g, 97.5 mmol) in methylene chloride (200 mL) was added dropwise 9.0 g (47.4 mmol) of 3-methylphenyl 3,3-dimethylacrylate under argon atmosphere while cooling in an ice bath. (Compound 44) in methylene chloride (100 mL). This is how it got • ·

- The reaction mixture was stirred at 0 ° C for an additional 30 minutes and then at room temperature for 15 hours. The reaction mixture was poured into ice-water / sodium chloride solution (200 mL) and the organic layer was separated. The aqueous phase is extracted with 50 ml of diethyl ether. The combined organic phases were washed successively with water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 5% ethyl acetate / hexane. This gives a mixture of isomeric products, i.e., 4,4,7-trimethyl-2-oxochromane and 4,4,5-trimethyl-2-oxochromane in a ratio of about 2.5: 1 by weight as a pale yellow oil. To a solution of the isomeric 2-oxochromans thus obtained in a solution of 3.8 g (20 mmol) in diethyl ether (60 ml) was added 3.0 ml of methyl magnesium bromide in diethyl ether at 0 ° C under argon. (60 mmol) and the resulting mixture was stirred at room temperature for 48 hours and then poured into a mixture of ice and 1 mL of concentrated sulfuric acid. The organic phase is then separated and the aqueous phase is extracted twice with 50 ml of diethyl ether. The combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate solution, water again, and finally saturated sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 15% ethyl acetate / hexane. This gives the title compound as a colorless · ·

s), 2.19 (1H, dd,

- 42 as oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.14 (6H, s), 1.45 (6H, (3H, s), 2.21 (2H, s), 6.39 (1H, d, J = 1 , 8 Hz), 6.67

J = 7.9 Hz, 1.8 Hz), 7.16 (1H, d, J = 7.9 Hz), 7.44 (1H, s).

2 _z 2,4,4,7-Pentamethyl-chroman (Compound 46)

Under nitrogen atmosphere, 2- (1,1,3-trimethyl-3-hydroxybutyl) -5-methylphenol (Compound 45) (2.16 g, 11.7 mmol) was added with 50 ml of 20% aqueous sulfuric acid solution. and the resulting mixture was refluxed for 13 hours and then cooled. The organic phase is then separated and the aqueous phase is extracted with diethyl ether. The combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate solution, water again, and finally saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The title compound was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s), 2.26 (3H, s), 6.63 (1H, s), 6.72 (1H, d, J = 7.9 Hz), 7.15 (1H, d, J = 7.9 Hz).

2,2,4,4,7-Pentamethyl-6-acetylchroman (Compound 47)

To a solution of 1.96 g (9.6 mmol) of 2,2,4,4,7-pentamethylchroman (Compound 46) in 30 mL of nitromethane under argon atmosphere was added 1.059 g (13.5 mmol). acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 14 hours, cooled in an ice bath, and concentrated hydrochloric acid (25 mL) was added. Following • · · 4 ·

The reaction mixture was warmed to room temperature and diluted with diethyl ether / water. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate solution, water again, and finally saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 5% ethyl acetate / hexane. The title compound was obtained as a pale yellow oil.

NMR (CDC1 _3): <5 1.36 (6H, s), 1.37 (6H, s), 1.86 (2H, s), 2.49 (3H, s), 2.56 ( 3H, s), 6.65 (1H, s), 7.74 (1H, s).

2,2 _/ 4,4 _/ 7-Pentamethyl-6-ethynylchroman (Compound 48)

To a solution of diisopropylamine (455 mg, 4.5 mmol) in anhydrous tetrahydrofuran (5 mL) at -78 ° C under argon was added 3 mL of a 1.5 molar solution of n-butyllithium in hexane and the resulting mixture, After stirring at 78 ° C for 45 minutes, a solution of 1.07 g (4.3 mmol) of 2,2,4,4,7-pentamethyl-6-acetylchroman (Compound 47) in 4 ml of anhydrous tetrahydrofuran was added. . The resulting reaction mixture was stirred at -78 ° C for 1 hour and then diethyl chlorophosphate (776 mg, 4.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and lithium diisopropylamide (910 mg, 9.0 mmol) in diisopropylamine and 6 mL of 1.5M n-bu44 in hexane was added via a double-ended needle. lithium solution (9.0 mmol) in a solution of 10 ml of anhydrous tetrahydrofuran at -78 ° C. The reaction mixture was stirred at room temperature for 15 hours and then poured into 10 ml of ice-cold water. The pH of the aqueous mixture was then adjusted to 2 with 10% aqueous hydrochloric acid, and the organic layer was separated and the aqueous layer was extracted with pentane. The combined organic layers were washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate and the solvent removed in vacuo. The residue was purified by Kugelrohr distillation (82 ° C, 0.3 mm) to give the title compound as a pale yellow oil.

NMR (CDC1 _3): δ 1.32 (6H, s), 1.34 (6H, s), 1.1 (2H, s), 2.36 (3H, s), 3.18 (1 H , s), 6.64 (1H, s), 7.40 (1H, S).

Mass Spectrum m / e calcd for Ciggoid ⁰ 228.1514, found 228.1520.

Ethyl 4 - ((2,2,4,4,7-pentamethyl-chroman-6-yl) -ethyl] -benzoate (Compound 7)

2,2,4,4,7-Pentamethyl-6-ethynylchroman (Compound 48) (200 mg, 877 mmol) and ethyl 4-iodobenzoate (Compound 29) in 245.3 mg (0.888 mmol) in 2 mL A solution of triethylamine was bubbled with nitrogen for 15 minutes and the reaction mixture was placed under argon and 50 mg (0.2625 mmol) of copper (I) iodide and 100 mg (0.1425 mmol) of bis (triphenylphosphine) were added. ) -Palladium (II) chloride finely ground. The reaction vessel was then refluxed and heated at 55 ° C under argon for 72 hours. The triethylamine was then removed in vacuo and the residue was subjected to flash chromatography on silica gel using 5% ethyl acetate / hexane as eluent.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.32 (12H, s), 1.37 (3H, t, J = 7.0Hz), 1.80 (2H, S), 2.40 (3H, s), δ , 36 (2H, q, J = 7.0Hz), 6.66 (1H, s, 7.42 (1H, s), 7.54 (2H, d, J = 8.6Hz, 7.9) (2H, d, J = 8.6 Hz).

Mass spectrum m / e calcd for C ₂₅ H ₂ gO ₃ 376.2038, found 376.2038.

2,4,4-Trimethyl-6-bromo-2-hydroxythiochroman (Compound 49) g (182.5 mmol) cerium chloride (previously dried under high vacuum at 135 ° C for 4 days) in 160 mL of tetrahydrofuran and To a solution of 62 ml of a 3 molar solution of methyl magnesium bromide in diethyl ether (186 mmol) at -14 ° C was added 5 g (18.45 mmol) of 4,4-dimethyl-6-bromo-2- oxothiochroman in 20 ml of anhydrous tetrahydrofuran was added and the reaction mixture was stirred for 30 minutes and then poured into 300 ml of ice water containing 10 ml of concentrated sulfuric acid. The phases are then separated and the aqueous phase is extracted with 100 ml of diethyl ether. The combined organic layers were washed with water (2 x 200 mL), once with saturated brine (100 mL), dried over magnesium sulfate, and the solvent removed in vacuo. The residue was purified by silica gel flash chromatography using 10% ethyl acetate / hexane as eluent. This gives the title compound as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.35 (3H, s), 1.47 (3H, s), 1.71 (3H, s), 2.09 -2.18 (AB doublet), 2.42 (1H, s), 7.17-7.24 (2H, m), 7.27 (1H, d, J = 8.1 Hz).

2,4,4-Trimethyl-6-bromo-4H-1-benzothiopyran (Compound 50)

A mixture of 2.03 g (7.1 mmol) of 2,4,4-trimethyl-6-bromo-2-hydroxythiochroman (Compound 55) and 20 ml of 20% aqueous sulfuric acid was refluxed for 4 hours, then extracted several times with diethyl ether. The combined organic extracts were washed with water (2 x 25 mL) and once with brine (25 mL), dried over magnesium sulfate and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane. The title compound was obtained as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 1.34 (6H, s), 2.00 (3H, d, J = 1.4 Hz), 5.45 (1H, J = T, 4 Hz), 7.19 -7.38 (3 H, m).

2 _/ 4 _/ 4-Trimethyl-6-bromothiochroman (Compound 53)

To a solution of 500 mg (1.9 mmol) of 2,4,4-trimethyl-6-bromo-4H-1-benzothiopyran (Compound 56) in 5 mL of ethyl acetate was added 500 mg of a carbon support containing 10% by weight of palladium sulfide, followed by Hydrogenation was carried out in a Parr apparatus with hydrogen gas (2.1 x 105 Pa) for 24 hours with shaking. The reaction mixture was then filtered through Celite filtration aid and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with hexane. The title compound was obtained as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 1.21 (3Η, s), 1.33 (3Η, d, J = 6.6

Hz), 1.36 (3H, s), 1.64-1.89 (2H, m), 3.37 to 3 , 50 (1H, in), 7.10 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.19 (1H, d, 8.4 Hz), 7.20 (1H, d, 2, , 1 Hz).

2.4.4- Trimethyl-6-trimethylsilylethynylthiochroman (Compound 54)

A solution of 2,4,4-trimethyl-6-bromothiochroman (201 mg, 74 mmol) in freshly distilled triethylamine (201 mg, 74 mmol) was added to a thick-walled tube and degassed. Trimethylsilylacetylene (0.53 mL, 3.72 mmol) was added to the reaction mixture under argon, followed by bis (triphenylphosphine) palladium (II) chloride (52 mg, 0.074 mmol) and , 15 mmol) of copper (I) iodide powder mixture. The reaction mixture was then placed under an argon atmosphere and the tube was sealed. The reaction mixture was heated at 55 ° C for 72 hours, then allowed to cool to room temperature, filtered through Celite (filter aid) and washed with methylene chloride. Finally, the filtrate was concentrated in vacuo and the residue was subjected to flash chromatography eluting with hexane. The title compound was obtained as a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 0.24 (9H, s), 1.22 (3H, s), 1.33 (3H, d, J = 6.6 Hz), 1.37 (3H, s) , 1.71 (1H, t, J = 13.0 Hz),

1.86 (1H, dd, J = 13.0 Hz, 3.0 Hz), 3.38-3.50 (1H, m), 7.07 (1H, dd, J = 8.1 Hz, 1 , 8 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.26 (1H, d, J = 8.1 Hz).

2.4.4- Trimethyl-6-ethynylthiochroman (Compound 55)

186 mg (0.647 mmol) of 2,4,4-Trimethyl-6-trimethylsilyl »·

- To a solution of 48 ethinylthiochroman (Compound 60) in ethanol (11 ml) was added potassium hydroxide solution and the resulting mixture was stirred at room temperature for 16 hours. The ethanol is then removed in vacuo and the residue is extracted with diethyl ether. The ether extract was washed with water followed by saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. The residue was purified by Kugelrohr distillation to give the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 1.21 (3H, s), 1.32 (3H, d,

J = 6Hz), 1.40 (3H, s), 1.70 (1H, t, J = 13.0Hz), 1.88 (1H, dd, J = 13.0Hz, 3.0Hz) ), 3.0 (1H, s), 3.39-3.51 (1H, m), 7.13 (1H, dd, J = 9.1 Hz, 2.1 Hz), 7.21 (1H , d, J = 2.1 Hz), 7.28 (1H, d, J = 9.0 Hz).

Ethyl 4 - [(2,4,4-trimethyl-6-thiochromanyl) -ethyl] -benzoic acid (Compound 56) mg (0.26 mmol) 2,4,4-Trimethyl-6-ethynyl-thiochroman (Compound 55) ) and a solution of ethyl 4-iodobenzoate (70.5 mg, 0.26 mmol) (compound 29) in distilled triethylamine (1.5 mL) was weighed into a thick-walled tube and argon gas was bubbled through the solution under slightly reduced pressure. A mixture of bis (triphenylphosphine) palladium (II) chloride (18 mg, 0.051 mmol) and copper (I) iodide (9.7 mg, 0.051 mmol) was then added. The tube was then sealed and the reaction mixture was stirred at 55 ° C for 72 hours. The reaction mixture was then cooled to room temperature, diluted with methylene chloride and treated with a small amount of silica gel. The solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel using 1.5% ethyl acetate / hexane as eluent. This gave the title compound as a white crystalline precipitate.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 1.25 (3H, s), 1.35 (3H, d, J = 6.6

Hz_, 1.37 -1.44 (6H, m), 1.75 (1H, ,, J = 13Hz), 1.88 (1H, dd, J 13 HZ, 3.5 Hz), 3.40- 3.50 (1H, m), 4.38 (2H, q, J = 7Hz), 7.17 (1H, dd, J = 8.1 Hz, 1.8 Hz), 7.26 (1H, d, J = 1.5 Hz), 7.33 (1H, j + 8.1 Hz), 7, 55 (2H, d, , J = 8.4 Hz, 8.01 (2H, d, J = 8.4 Hz).

4- (2,4,4-Trimethyl-6-thiochromanyl) -ethylbenzoic acid (Compound 57) mg (0.102 mmol) of ethyl 4 - [(2,4,4-trimethyl-6-thiochromanyl) -ethyl] - A mixture of benzoic acid (compound 56) and 11 ml of ethanolic potassium hydroxide solution was stirred at room temperature for 16 hours and then the solvent was removed in vacuo. The residue was taken up in water and the aqueous solution was acidified with N hydrochloric acid. The mixture was extracted three times with diethyl ether, and the combined extracts were washed with water, brine, dried over magnesium sulfate and the solvent removed in vacuo. This gave the title compound as an orange precipitate.

NMR m.p. ektrum (CDCl3): 1, 17 (3H, s) , 1.26 (3H, d, J = 6.3 Hz), 1.34 (3H, s) , 1.58 (1H, t, J = 13 1 Hz), 192 (1H, dd, J 13 , 1 Hz, 2.4 H Z), 3.33-3, 48 (1H, m) , 7.20 (1H, d, J = 8.1 Hz), 7.21 (1H, s) , 7.45 (1H, d. J = 8 1 Hz), 7, , 62 (2H, d, 8, Hz), 7.95 (2H, d, J = 8.4 Hz).

According to the methods described above, but with modifications well known to those skilled in the art of synthetic organic chemistry, the following compounds may be prepared:

2.2.4.4-tetramethyl-6-acetyl-7-ethyl-chroman;

2.2.4.4-tetramethyl-6-acetyl-7-propylchroman;

2.2.4.4-tetramethyl-6-acetyl-7-butylchroman;

2.2.4.4-tetramethyl-6-acetyl-7-pentylchroman;

2.2.4.4-tetramethyl-6-acetyl-7-hexylchroman;

2,2-diethyl-4,4-dimethyl-6-acetylchroman;

2,2-diethyl-4,4,7-trimethyl-6-acetylchroman;

ethyl 4 - [(2,2,4,4-tetramethyl-7-ethyl-chroman-6-yl) -ethyl] -benzoate;

ethyl 4 - ((2,2,4,4-tetramethyl-7-propylchroman-6-yl) ethynyl] benzoate;

ethyl 4 - [(2,2,4,4-tetramethyl-7-hexyl-chroman-6-yl) -ethyl] -benzoate;

ethyl [2- (4- (2,2,4,4-tetramethyl-chroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl [2- (4- (2,2,4,4,7-pentamethyl-chroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl [2- (4- (2,2,4,4-tetramethyl-7-ethyl-chroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl [2- (4- (2,2,4,4-tetranethyl-7-hexyl-chroman-6-yl) -ethyl) -phenyl] -acetate;

ethyl 3- [4 - ((2,2,4,4-tetramethylchroman-2-yl) ethynyl) phenyl] propionate;

ethyl 3- (4 - ((2,2,4,4,7-pentamethyl-chroman-6-yl) -ethyl) -phenyl] -4

- 51 nyl] propionate;

ethyl 3- (4 - ((2,2,4,4-tetramethyl-7-ethyl-chroman-6-yl) -ethyl) -phenyl] -propionate;

ethyl 3- (4- (2,2,4,4-tetramethyl-7-hexyl-chroman-6-yl) -ethyl) -phenyl] -propionate;

ethyl 5- (4 - ((2,2,4,4-tetramethyl-chroman-6-yl) -ethyl) -phenyl] -pentanoate;

ethyl 5- (4 - ((2,2,4,4,7-pentamethyl-chroman-6-yl) -ethyl) -phenyl] -pentanoate;

ethyl 5- (4 - ((2,2,4,4-tetramethyl-7-ethyl-chroman-6-yl) -ethyl) -phenyl] -pentanoate;

ethyl 5- (4 - ((2,2,4,4-tetramethyl-chroman-6-yl) -ethyl) -phenyl] -pentanoate;

ethyl 4- (2,2-diethyl-4,4-dimethylchroman-6-yl) ethynyl] benzoate; and ethyl 4- (2,2-diethyl-4,4,7-trimethylchroman-6-yl) ethynyl] benzoate.

The following describes the preparation of a pharmaceutical composition for topical application, bearing in mind that the compounds of the invention are preferably administered topically. Such topical formulations may thus have the following composition:

Solution

Component Weight!

Hatóanyag0,1

BHT0,1

Ethanol (US Pharmacopoeia grade) 58.0

- Polyethylene glycol weighing 52,400 moles (US Pharmacopoeia grade)

Gel

component

agent

BHT

Ethanol (US Pharmacopoeia grade)

Hydroxypropyl cellulose

41.8

Crowd%

0.1

0.1

97.8

2.0

Claims (35)

Compounds of formula (1): wherein: X is O or S; Rl, _R2 and R3 are independently hydrogen or lower alkyl; R 4 and R 5 each independently represent hydrogen or lower alkyl, provided that (i) they are simultaneously different from hydrogen and (ii) different from each other; Rg is hydrogen, halogen, lower alkyl, lower alkenyl or lower cycloalkyl, n is 0, 1, 2, 3, 4 or 5; and B is hydrogen or -COOH, or those with a pharmaceutically acceptable salt, -COORg, -COONR _{g of} R _10, -CH ₂ OH, -CH ₂ OR, -CH ₂ OCOR _{11 11z,} CHO, CH _{(OR12) 2,} -CHOR ₁₃ O, COR, CR (OR _{12) 2,} or O ^ -CR'OR group of formula and in which formulas R is alkyl having up to 5 carbon atoms, cycloalkyl or alkenyl, Rg is alkyl of 1 to 10 carbon atoms or cycloalkyl of 5 to 10 carbon atoms, or Rg is phenyl or lower alkyl, R9 and R10 are each independently hydrogen or alkyl of 1 to 10 carbon atoms, Represents a cycloalkyl, phenyl or (lower) al54kylphenyl group containing 5-10 carbon atoms, represents a lower alkyl, phenyl or (lower) alkylphenyl group, R _X2 represents a lower alkyl group and R _X3 represents a 2-5 carbon atom , a divalent alkyl group. Compounds of formula (1) according to claim 1, characterized in that X represents a sulfur atom. Compounds of formula (1) according to claim 2, characterized in that n is 0, 1 or 2. Compounds of formula (1) according to claim 3, characterized in that n is 0. Compounds of formula (1) according to claim 3, characterized in that B is a carboxylic acid or a pharmaceutically acceptable salt thereof, or B is -COOR g or -COONR g R 4 Q. Compounds of formula (1) according to claim 3, characterized in that R 3 represents a hydrogen atom or a methyl group. Compounds of formula (1) according to claim 2, characterized in that R 4 is hydrogen. Compounds of formula (1) according to claim 1, characterized in that X represents an oxygen atom. Compounds of formula (1) according to claim 8, characterized in that the phenyl ring is selected from the group consisting of 1- and a It is disubstituted at the 4-position while n is 0, 1 or 2. Compounds of formula (1) according to claim 9, characterized in that n is 0. Compounds of formula (I) according to Claim 9, characterized in that B is a carboxylic acid or a pharmaceutically acceptable salt thereof, or B is -COOR g or -COONR 9 R 10. Compounds of formula (I) according to claim 9, characterized in that R 3 represents a hydrogen atom or a methyl group. 13. A compound of formula (1) according to claim 9, wherein R4 is hydrogen. 14. A pharmaceutical composition comprising one or more compounds of formula (I) as an active ingredient, wherein: X is O or S; Rl, _R2 and R3 are independently hydrogen or lower alkyl; R 4 and R 5 are each independently hydrogen or lower alkyl, provided that (i) they are simultaneously different from hydrogen and (ii) are different from each other; Rg is hydrogen, halogen, lower alkyl, lower alkenyl or lower cycloalkyl, n is 0, 1, 2, 3, 4 or 5; and B is hydrogen or -COOH, or those with a pharmaceutically acceptable salt, -COORg, -COONR ₉ R _10, -CH ₂ OH, -CH ₂ OR, -CH ₂ OCOR _{11z 11z} -CHO, -CH (OR ₁₂ ) ₂ , -CHOR ₁₃ O, -COR, -CR (OR ₁₂ ) ₂ , or -CROR ₁₃ O, wherein R is an alkyl of up to 5 carbon atoms, cycloalkyl or alkenyl, R ₈ is C 1 -C 10 alkyl or C 5 -C 10 cycloalkyl, or R 8 is phenyl or (lower) alkylphenyl, R 8 and R 10 are each independently hydrogen or C 1 -C 10 alkyl-; , cycloalkyl of 5-10 carbon atoms, phenyl, or lower) alkyl-phenyl group, R represents a lower alkyl, phenyl or (lower) alkylphenyl, R12 is lower alkyl and _R33 is C2-5 alkyl, containing a divalent alkyl group together with a carrier and / or other excipients commonly used in the manufacture of pharmaceuticals. A pharmaceutical composition according to claim 14, characterized in that it is in a form for treating skin disorders in a mammal. Compounds of formula (1) according to claim 2, characterized in that R 4 and R 5 are different lower alkyl groups. Compounds of formula (1) according to claim 8, characterized in that R 4 and R 5 are different lower alkyl groups. 18. A compound of formula (29): wherein R 1, R ₃ and R ₃ are each independently hydrogen or lower alkyl; R4 and R5 are each independently hydrogen or a moiety; - denotes 57 carbons, with the proviso that (i) they are simultaneously different from hydrogen and (ii) are different from each other; n is 0, 1, 2, 3, 4 or 5; and B is hydrogen or -COOH, or those with a pharmaceutically acceptable salt, -COORg, -COONRgR _10, -CH ₂ OH, -CH2ORH, C ^ OCOR, CHO, CH _{(OR12) 2,} -CHOR ₁₃ O, COR, CR (OR _{12) 2,} or O ^ -CR'OR group of formula and in which formulas R is alkyl having up to 5 carbon atoms, cycloalkyl or alkenyl, Rg is alkyl of 1 to 10 carbon atoms or cycloalkyl of 5 to 10 carbon atoms, or Rg is phenyl or lower alkyl, Rg and R10 are each independently hydrogen or alkyl of 1 to 10 carbon atoms, C 5 -C 10 cycloalkyl, phenyl or lower alkyl) phenyl, R 1 j is lower alkyl, phenyl or (lower) alkyl phenyl, R 12 is lower alkyl, and R ₁₃ is bivalent to 5 to 5 carbon atoms. alkyl. 19. A compound of formula 29 according to claim 18, wherein n is 0. Compounds of formula (29) according to claim 19, characterized in that B is a carboxyl group or a pharmaceutically acceptable salt thereof, or B is -COORg or -COONRgRiQ. Compounds of formula (29) according to claim 20, wherein R ₁ , R ₂ and R 5 are methyl and R 4 is hydrogen. 22. A compound of formula 29 according to claim 21 wherein R3 is hydrogen or methyl. 23. A compound of formula (29) according to claim 21 wherein B is a carboxyl group or a pharmaceutically acceptable salt thereof. 24. A compound of formula (29) according to claim 23 wherein R3 is hydrogen or a pharmaceutically acceptable salt thereof. 25. A compound of formula 29 according to claim 21 wherein B is ethoxycarbonyl. 26. A compound of formula 29 according to claim 25, wherein R3 is hydrogen. 27. A process for the preparation of a compound of formula (I): wherein X is O or S; ^R 1, ^r 2 ® ^sr 3 independently of one another are hydrogen or lower alkyl; R 4 and R 5 are each independently hydrogen or lower alkyl, provided that (i) they are simultaneously different from hydrogen and (ii) are different from each other; »· - 59 Rg is hydrogen, halogen, lower alkyl, lower alkenyl or lower cycloalkyl, n is 0, 1, 2, 3, 4 or 5; and B is hydrogen or -COOH, or those with a pharmaceutically acceptable salt, -COORg, -COONRgR _10, -CH ₂ OH, -CH ₂ OR _{1 X,} CH ₂ OCOR _11, -CHO, -CH (OR ₁₂ ) ₂ , -CHO R ₁₃ O, -COR, -CR (OR ₁₂ ) ₂ , or -CROR _{X 30} O, wherein R is alkyl, cycloalkyl having up to 5 carbon atoms, or alkenyl, Rg is alkyl of 1-10 carbon atoms or cycloalkyl of 5-10 carbon atoms, or Rg is phenyl or lower alkyl phenyl, Rg and R10 are each independently hydrogen or alkyl of 1-10 carbon atoms; cycloalkyl containing 10 carbons, phenyl or (lower) alkyl-phenyl group, R _xx is a lower alkyl, phenyl or (lower) alkyl group having _RX2 is lower alkyl and R _X3 is 2-5 carbon atoms, a divalent wherein R _x , R ₂ and R ₃ are as defined above and Y is halogen; if X is S, or Y is hydrogen when X is O - a R ₄ -Mg-X 'with a Grignard reagent of the formula: - wherein R ₄ is as defined above, and X' is halogen atom - to * · · · And reacting the resulting compound of formula (31) wherein R ₁ , R ₂ , R 3, R 4, X and Y are as previously defined, with a compound of formula (32) wherein R ₁ , R ₂ , R 3 , R4, X and Y are as defined above - is eliminated saturated with a latter compound, and thus preparing an intermediate compound of formula (33) formula: - wherein Rl, _R2, R3, R4, X and Y are as defined above - Y substitute is substituted with acetylene, so that when X represents a sulfur atom, a compound of formula 33 is reacted with a trialkylsilylacetylene and then the trialkylsilyl group is removed under basic conditions, or when X is oxygen, a compound of formula 33 under conditions of Friedel-Crafts reaction with an acetylating agent, the resulting intermediate is treated with a strong base to give a compound of formula (34). a compound of formula wherein R ₁ , R ₂ , R 3, R 4 and X are as defined above, with a compound of formula 3, wherein X ', R 8 and n are as previously defined and B' is hydrogen or a protected acid, an alcohol, an aldehyde or a ketone and optionally converting a compound of formula (1) thus obtained into a homologue or derivative thereof. 28. The process of claim 27 for the preparation of compounds of formula (I) wherein X is sulfur, wherein the appropriately substituted starting compounds are used. 29. The process of claim 28 for the preparation of compounds of formula (I) wherein R4 is methyl, wherein the substituted compounds are suitably substituted. 30. A process according to claim 29 for the preparation of compounds of formula (I) wherein R 1 and R _{2 are} methyl, wherein the starting compounds are suitably substituted. 31. The process of claim 30 for the preparation of compounds of formula (I) wherein R3 is hydrogen, wherein the appropriately substituted starting compounds are used. 32. A process according to claim 27 for the preparation of compounds of formula (I) wherein X is O, wherein the substituted compounds are suitably substituted. 33. A process for the preparation of a compound of formula (I): X is O or S; Rl, _R2 and R3 are independently hydrogen or lower alkyl; R4 and R5 are each independently lower alkyl, with the proviso that they are different; Rg is hydrogen, halogen, lower alkyl, lower alkenyl or lower cycloalkyl; n is 0, 1, 2, 3, 4 or 5; and B is hydrogen or -COOH, or those with a pharmaceutically acceptable salt, -COORg, -COONR ₉ R _10, -CH ₂ OH, -CH ₂ OR, -CH ₂ OCOR _{11z 11z} -CHO, -CH (OR _{12) 2,} -CHOR ₁₃ O, -COR, -CR (OR ₁₂ ) ₂ , or -CROR ₁₃ O, in which R is alkyl of up to 5 carbon atoms, cycloalkyl or alkenyl, R 8 is alkyl of 1 to 10 carbon atoms - either C 5 -C 10 cycloalkyl or R 8 is phenyl or lower alkyl, R 8 and ^R 10 are each independently hydrogen or C 1 -C 10 alkyl, C 5 -C 10 cycloalkyl, phenyl or ( is lower) alkyl group, a containing Rn is lower alkyl, phenyl or (lower) alkyl group, R ₂ represents lower alkyl and _R13 is 2-5 carbon atoms, a divalent group thereof, which character cooked the formula (30) compound of the formula: - wherein R _lz R ₂ and R ₃ are as defined above and Y is halogen when X is S, or Y is hydrogen when X is O - formula R4-Mg With a Grignard reagent of the formula -X 'wherein R 4 is as defined above and X' is a halogen atom, then a compound of formula 31 is obtained wherein R _{1 is} R ₂ , R ₃ , R 4, X and Y is as defined above with a Grignard reagent of formula R5-Mg-X ', wherein R5 and X' are as previously defined, to form a compound of formula (35) wherein , R 2, R 3, R 4, X and Y are as defined above, into a compound of formula 36 wherein R _{1 is} R 2, R 3, R 4, X and Y are as previously defined, the Y substituent of the latter compound being acetylated. n is substituted by reacting a compound of formula (33) with a trialkylsilylacetylene when X represents a sulfur atom, then removing the trialkylsilylacetyl group under basic conditions or, when X represents an oxygen atom, a compound of formula (33) is reacted by Friedel-Crafts reaction is an acetylating agent and a resulting intermediate is treated with a strong base, and a resulting compound of the general formula (2): - wherein R _lz R2, R3, R4 and X are as defined above - a (3 ) wherein X ', A and n are as defined above and B' is hydrogen or a protected acid, alcohol, aldehyde or ketone group, and if desired, a compound of formula (1) is obtained. homologue or derivative thereof. 34. A process according to claim 33 for the preparation of compounds of formula (I) wherein X is sulfur, wherein the substituted compounds are suitably substituted. 35. A process according to claim 33 for the preparation of compounds of formula (I) wherein X is O, wherein the substituted compounds are suitably substituted.