JPH06501684A - Retinoid-like active acetylene di-substituted with a heterocyclic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] a heterocyclic group and a 2-substituted chromanyl, thiochromanyl or 1.2.3.4-tet The present invention provides a retinoid-like active acetylene disubstituted with a hydroxylinyl group. The present invention relates to novel compounds with retinoid species activity. especially , the present invention combines an ethynyl heterocyclic acid moiety with a 2-substituted tetrahydroquinolinyl, thio chromanyl or a chromanyl moiety. The acid part is alco may be converted into alcohols, aldehydes or ketones or their derivatives, and may be reduced to -CH3 may also be used.

Related technology 4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid (X is Tetrahydroquinolinyl, chromanyl or thiochromanyl. ) structure A carboxylic acid derivative useful for inhibiting cartilage degeneration has been disclosed in the publication published on January 9, 1985. It is disclosed in European Patent Application No. 0133795. Released on April 2, 1986 European Patent Application No. 176034A discloses that Lonaphthalene compounds are disclosed in U.S. Pat. No. 4,739,098. Replacement of three olefinic units of the acid-containing portion of noic acid with ethynylphenyl groups It is stated that.

Summary of the invention The present invention is based on the formula 1 Formula 1 [In the formula, X is S10.

R1-R3 are hydrogen or lower alkyl; R4 and R5 are hydrogen or lower Alkyl, but R4 and R5 cannot both be hydrogen at the same time: A is pyridinyl, chenyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl , thiazolyl or oxasilyl; n is 0-5; B is Hl -COOH, or a pharmaceutically acceptable salt, ester or amide thereof, -C H20H, or its ether or ester derivative, -CHol or its Acetal derivative, -COR1 (R+ is alkyl having 1 to 5 carbon atoms, cycloalkyl or alkenyl group), or its ketal derivatives. ] Regarding the compound represented by.

Furthermore, the present invention can treat skin diseases such as acne, Darier's disease, psoriasis, ichthyosis, eczema, acne, etc. The present invention relates to the use of compounds of formula 1 for the treatment of topical dermatitis and epithelial cancer. Formula 1 The compounds are useful in the treatment of arthritic diseases and other immune diseases (e.g. lupus erythematosus), in wounds. Also promotes wound healing, treats dry eye syndrome, and restores sun-induced skin damage. Useful.

The present invention provides pharmaceutical formulations comprising a compound of formula 1 together with pharmaceutically acceptable excipients. It also relates to

The present invention further provides a method for the synthesis of compounds of formula 1, comprising cupric iodide and Pd(P Q3) In the presence of 2C12 (Q is phenyl) or similar complex, as shown in formula 2 By reacting the compound represented by formula 1 with the compound represented by formula 1, the corresponding compound represented by formula 1 is obtained. obtain a compound, [In the formula, R1-R5 have the same meanings as above, and X" is)\logen, preferably I Yes: n and A have the same meanings as above: B is Hl or protected acid, alkaline Cole, aldehyde or ketone. ] or In the presence of Pd(PQ3)4 (Q is phenyl) or similar complex, formula 4: [ In the formula, R1-R5 and X have the same meanings as above. The zinc salt shown below and the formula 3 to obtain the corresponding compound of formula 1 by reacting with a compound of Formula 5 [In the formula, n is 0 to 4. ] The acid of formula 1 is obtained by homologizing the compound represented by, or the acid of formula 1 is convert to salt, or Form acid addition salts: or Converting the acid of formula 1 to an ester: or Converting the acid of formula 1 to an amide: or reducing the acid of formula 1 to an alcohol or aldehyde; or reducing the alcohol of formula 1 to an alcohol or aldehyde; or oxidize the alcohol of formula 1 to an aldehyde. ; or converting the aldehyde of formula 1 to an acetal and converting the aldehyde of formula 1 to an acetal; convert to file A method comprising:

In the present invention, "ester" refers to the classical definition of ester in organic chemistry. Including all compounds included. When B (in formula 1) is -COOH, esthetics By alcohol, we mean that this group is treated with an alcohol, preferably an aliphatic alcohol having 1 to 6 carbon atoms. It includes products obtained by processing. Esters from compounds where B is -CH20H When deriving Substituted aliphatic, aromatic or alicyclic group, preferably having 1 to 1 carbon atoms in the aliphatic part 6).

Preferred esters include saturated aliphatic alcohols having 10 or fewer carbon atoms. or cyclic or saturated alicyclic alcohols and acids having 5 to 10 carbon atoms. to induce. Particularly preferred aliphatic esters are lower alkyl acids or alcohols. It is derived from. In the present invention, lower alkyl has 1 to 6 carbon atoms. means an alkyl group. Phenyl or lower alkyl phenyl esters are also preferred. stomach.

Amide has the classical meaning of amide in organic chemistry. Amide has no Included are substituted amides as well as aliphatic and aromatic mono- and di-substituted amides.

Preferred amides include saturated aliphatic groups having 10 or fewer carbon atoms or 5 carbon atoms. With mono- and di-substituted amides derived from ~10 cyclic or saturated alicyclic groups be. Particularly preferred amides are those derived from lower alkyl amines.

Mono- and di-substituted derivatives derived from phenyl or lower alkylphenylamines Amides are also preferred. Unsubstituted amides are also preferred.

Acetals and ketals have the group -CK, where K is (-OR)2 (R is a lower atom or K is -OR+ O (R+ is a straight chain having 2 to 5 carbon atoms or branched lower alkyl).

Pharmaceutically acceptable salts include salt-forming functional groups (e.g. acid or amine groups). can be prepared for any compound of the invention that has a Pharmaceutically acceptable salts are , which retains the activity of the parent compound and is not harmful or inconvenient to the recipient or the environment. It is a salt that does not have any harmful effects.

Such salts may be derived from organic or inorganic acids or bases. salt like this can be generated from - or multivalent ions. Particularly preferred for acid groups are: Inorganic ions such as sodium, potassium, calcium and magnesium Ru. Organic amine salts include amines, especially ammonium salts, such as mono-, di- and Obtained from trialkylamines or ethanolamines. caffeine, toro Salts can also be produced from molecules such as methamine. enough to form acid addition salts If sufficient basic nitrogen is present, any inorganic or organic acid or alkali Acid addition salts may be formed with killing agents (eg methyl iodide). Hydrochloric acid, sulfuric acid or is preferably a salt with an inorganic acid such as phosphoric acid. Many simple organic acids, e.g. bases It is also possible to use either basic, dibasic or tribasic acids.

Preferred compounds of the invention are those in which the ethynyl group and the group B are each 2 of the pyridine ring. The 6th and 3rd positions in the cotinic acid nomenclature are the 2nd and 5th positions in the pyridine nomenclature. or corresponding to the 5-position and 5-position of the thiophene group. bonded to the 2-position: n is 0, B is -C00H1, its alkali metal salt, organic amine salt or lower alkyl ester, or -CH20H, its lower alkyl ester Kill ester or ether, or -CHO or its acetal derivative It is a compound that is More preferred compounds are the following compounds represented by formula 6: Ethyl 6-[(2,2,4,4-tetramethylthiochroman-6-y) ) ethynyl] nicotinate (compound 1: X=S, R3=H, R4=CH3, R5=CH3, R”=C2H3); 6-[(2,2,4,4-tetramethylthiochroman-6-yl)ethynyl]ni Cotinic acid (compound 2; X-3, Rs=H, R4=CH3, R5=CH3, R” =H): ethyl 6-[(2,2,4,4-tetramethylchroman-6-yl)ethyl Tinylconicotinate (compound 3: X=O, R3=H, R4=CH3, R5=C H3, R”=C2Hs):6-[(2,2,4,4-tetramethylchroma n-6-yl)ethynyl]nicotinic acid (compound 4; X=O, Rs=H, Ra= CH5, R5=CH3, R”=H); ethyl 6-[<2.2.4.4.7-pen tamethylthiochroman-6-yl)ethynylconicotinate (compound 5; X= S, R5=CH5, R,=CH,, Rs=CHs, R”=C2Hs); 6-[(2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl ] Nicotinic acid (Compound 6: X=SSRs=CHs, R,=CH3, R5=CH 3, R”=H): 6-[(2,2,4,4,7-pentamethylchroma) at x-f- n-6-yl)ethynyl]nicotinate (compound 7; x=o, R3=CH3, R4=CH5, R,=CH3, R”=C2Ha); 6-[(2,2,4,4,7-pentamethylchroman-6-yl)ethynyl]ni Cotinic acid (compound 8; X=O, R5=CH5, R4=CH,, R5=CH3, R”=H).

Ethyl 6-[(2,4,4-trimethyl-6-thiochromanyl)-ethynylconi Cotinate (Compound 62: X=S, R3=HSR4=H, R5=CH3, R” =C2H3),.

The compounds of the present invention can be used in a comprehensive manner, taking into account symptoms, need for organ-specific treatment, dosage, etc. It may be administered physically or locally.

In the treatment of skin diseases, it is usually preferable to administer drugs locally; Oral administration may be used in cases such as treatment of severe cystic acne. Topical administration Any of the usual dosage forms for stomach. The preparation of such topical formulations is well documented in the literature in the pharmaceutical field, e.g. Remington's Pharmaceutical Sciences Pharrrra-ceutical 5science), 17th edition, Matsugu. Mack Publishing Company Detailed explanation is given in (Ston, Pennlevania). Topical administration of compounds of the invention Administer as a powder or spray (especially in aerosol form) to You can also.

When administering the drug of the present invention systemically, it may be administered as a powder, pill, tablet, etc. It can be prepared in the form of a cream or elixir and administered orally.

For intravenous or intraperitoneal administration, the compound may be administered in a solution or solution that can be administered by injection. or can be prepared as a suspension. Suppository form or subcutaneous sustained release formulation or intramuscular injection In some cases, it may be useful to formulate the drug into a dosage form.

To treat dry skin, to block light, to treat skin diseases by other means, to prevent infection. Local injections such as those mentioned above may be used for secondary purposes such as to relieve irritation or inflammation. Other drugs can be added to the dosage formulation.

By administering a therapeutically effective amount of one or more compounds of the invention, Skin diseases or other conditions known to be treatable by noic acid-like compounds can be treated. Treatment concentrations reduce specific symptoms or eliminate disease states. This is the concentration that slows progression. In some cases, the agents of the invention may be used to treat certain conditions. There is also the possibility that it could be used prophylactically to prevent its development. Treatment concentration depends on symptoms. the severity of the condition being treated and the sensitivity of the patient to treatment. may vary depending on Therefore, routine tests should be used to determine treatment concentrations on a case-by-case basis. It is best to specify For example, in the treatment of acne or similar skin diseases, 0 A formulation with a concentration of 0.001% to 5% by weight, preferably about 0.001% to 1% is effective for treatment. It is thought that When administered systemically, 0.01 to 100, preferably about 0 Amounts of 1 to 1 Q mg/kg body weight/day may be effective in many cases.

The retinoic acid-like activity of the compounds of the present invention is due to their retinoic acid-like activity on ornithine decarboxylase. This was confirmed by the conventional method of measuring retinoic acid activity using noic acid.

A study on the correlation between retinoic acid and cell growth inhibition was published by Verma. and Boutvell [Cancer Research (Research), 1977, ornithine decarboxylation occurs prior to biosynthesis. It has been described that the enzyme (ODC) activity is increased. Separately, increased polyamine synthesis has been shown to be associated with cell proliferation. In other words, ○ inhibits DC activity. If so, cell hyperproliferation can be controlled. All causes of increased ODC activity Although it is not known, 12-O-tetradecanoylphorbol-13-acete (TPA) has been shown to induce ODC activity. Retinoic acid is Inhibits ODC activity induction by TPA.

Persons substantially listed in Cancer Research (1662-1670, 1975) Assays according to the method also showed that the compounds of the present invention inhibited the induction of ODCs by TPA. found to be harmful.

Examples of retinoic acid-like activities include substantially all of Vuelma and Boutwell (op. cit.). According to the assay according to the method of and 7) inhibited TPA-induced ODC activity by 80% at the following concentrations (IC,.) : Compound I Cgo (stop O1) Compounds of the invention may be synthesized by a variety of chemical synthetic routes. DESCRIPTION OF THE INVENTION For this purpose, we outline the sequence of steps known to yield compounds of formula 1. Ru. Those skilled in the art will appreciate that the conditions described herein apply to any compound of formula 1. It will be readily recognized that this is a specific aspect that can be generalized. Furthermore, this Those skilled in the art will appreciate that the synthetic steps described herein may be modified without departing from the scope of the invention. It will be readily appreciated that the changes and/or adjustments may be made.

X is -S-, R4 and Rs are hydrogen or lower alkyl, and R4 and Compounds of Formula 1 in which both R and R5 are simultaneously hydrogen are synthesized according to Scheme I.

Reaction formula 1 In reaction formula 1, R1-R3 are hydrogen or lower alkyl groups, and A is the same as that of formula 1. have the same meaning, n is 0 to 5, B is hydrogen or a protected acid, alcohol, It is an aldehyde or a ketone. X' is CI! when n is 0. , Br or preferably Br or I when n is 1 to 5.

X is oxygen, R4 and R3 are hydrogen or lower alkyl, R4 and Compounds of formula 1 in which R5 are not both hydrogen at the same time are synthesized according to scheme 2.

Reaction formula 2 %formula% In reaction formula 2, R0 to R6, nSA, B and Xo have the same meanings as in reaction formula 1. be.

The steps shown in Reaction Formulas 1 and 2 will be explained next.

In reaction formula 1, 4-bromothiophenol (compound 9) was appropriately substituted. Acylating agents such as acid chloride derived from acrylic acid (compound 10) become Acylation is carried out in an inert solvent (e.g. tetrahydrofuran) with a strong base ( For example, in the presence of sodium hydride). Olefinic bonds in the acrylic acid moiety A thioester (compound 11) with a combination of A suitable solvent (e.g. methyl chloride) in the presence of a type catalyst (e.g. aluminum chloride) The ring is closed by stirring in a molten glass. The resulting 2-oxo-6-bromothy Ochroman (compound 12) is typically isolated in crystalline form.

2-oxo-6-bromothiochroman (compound 12) can be substituted with an alkyl substituent R4 or and a Grignard reagent with R5 (e.g., when R4 and R5 are methyl, methylmagnesium bromide). Introduce Rs (according to the invention, both cannot be hydrogen at the same time). Grinya If the reagent (e.g. methylmagnesium bromide) is in excess, the thiochroman ring is ring-opened, and a tertiary alcohol derivative of 4-bromothiophenol (compound 13) is formed. generate.

Ring closure of the thiophenol derivative (compound 13) with the desired groups R1 to R6 can be performed using an acid Compound 13 is preferably heated in aqueous acid by heating under normal conditions. This is done according to the following. obtained with the desired alkyl (or hydrogen) substituents R1 to R5 The 6-bromothiochroman obtained is shown as Compound 14 in Reaction Formula 1.

To introduce an acetylene (ethyne) moiety into the molecule, substituted 6-bromothioc Roman (compound 14) was prepared using cupric iodide and a suitable catalyst [usually Pd(PQ 2CA'2 (Q is phenyl)], reacted with trimethylsilylacetylene. make them respond. This reaction is typically carried out in a sealed tube with bis(triphenylphosphine) para Dium (If) chloride catalyst, in the presence of an acid acceptor (e.g. triethylamine) , by heating in an inert gas (argon) atmosphere. 6 obtained -Trimethylsilylethynylthiochroman is shown as compound 15 in reaction scheme 1. did.

As shown in reaction formula 1, in the next step, 6-trimethylsilylethynylthiochloro Removal of the trimethylsilyl moiety from man (compound 15) creates a ring-substituted 6-nitinyl A thiochroman derivative (compound 16) is obtained. This step is preferably carried out under basic conditions. Alternatively, it may be carried out in an inert gas atmosphere.

To introduce a heteroaryl group into the acetylene (ethyne) moiety of compound 16, Compound 16 was added with reagent X' A-(CHz)n-B (Formula 3) (X', A and B couples the above definition and agreement with respect to Equation 3. In other words, the desired with a substituent [(CH,)n-B] or by an organic reaction known to those skilled in the art. A heterocycle (A) having a group (CHz)nB that can be easily converted into a desired substituent by By reaction with a halogen-substituted heterocyclic compound (formula 3) containing 6-thiochromanyl A heteroaryl group is introduced into ethyne (compound 16).

6-thiochromanilethine (compound 16) and reagent X'A (CH2)nB The coupling is carried out in a closed tube in an inert gas (argon) atmosphere. Copper, a suitable catalyst [usually Pd(PQ3)2CIJ and an acid acceptor (e.g. directly by heating in the presence of methylamine).

The resulting disubstituted acetylene compound (compound 18) is the target compound according to the present invention. or salt formation, esterification, ester decomposition, homologation, amide formation, etc. It can be easily converted into the target compound by two methods such as Regarding these processes , will be described further below.

Compound 18 converts 6-thiochromanylethyne derivative (compound 16) into the corresponding gold first converting it into a zinc salt (compound 17) and then converting it into a zinc salt (compound 17). is tested in the presence of catalyst Pd(PQs)4 (Q is phenyl) or similar complex. Also by coupling with the drug X'-A-(CH2)nB (formula 3) can get.

The derivatization of Compound 18 is described in Reaction Scheme 1 as "homologues and derivatives" (compound It is shown as a conversion to product 19).

For derivatization or deprotection of compound 18 or heterocyclic compound X 'A (CHz)nB (which gives the compound of the present invention directly after coupling) , or which can be easily converted into the compounds of the present invention). I will clarify.

In the reaction with the compound of formula 2 (compound 16 in reaction formula 1), a protected heterocyclic compound If required, replace it with the corresponding acid, alcohol, ketone or aldehyde It can be prepared from Such starting materials (protected acids, alcohols, aldehydes or ketones) are commercially available or can be synthesized by methods described in the literature. Ru. Carboxylic acids are typically treated in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride. , esterification by refluxing the acid in a suitable alcohol solution. Also, Calcium in the presence of dichlorohexyl luposiimide and dimethylaminopyridine. Rubonic acid may be condensed with a suitable alcohol. The ester is converted in a conventional manner. harvest and purify. Acetals and ketals are described by March, r. Advanced Organic Chemistry Che+5istry) J, 2nd edition, ? -/Grow-Hill Book Co. (McG) rav-Hill Book Company), page 810. easily obtained. Alcohols, aldehydes and ketones are (McOmie), Plenum Publishing Press (PlenumPubl) Publishing Press), 1973 and Proticting Groups ( Protecting G roups), edited by G reene, Noyon Wiley & Thump (John Wiley & 5ons), ethers and esters, respectively, by known methods such as those described in 1981. may be protected by forming acetal, acetal or ketal.

In order to increase the value of n before the coupling reaction (such compounds are commercially available) ), the heterocyclic compound in which B is -COOH is by continuous treatment under normal reaction conditions or by other homologation methods. become homologues. Heterocyclic compounds in which B is not C0OH can be converted into homologs by appropriate means. may be converted into The homologated acid can then be esterified as described above. Ru.

Compounds of formula 1, where B is an acid group or other group, can be prepared by adding alkyl-acrylates as described above. By subjecting it to homologation by the Telt method or other methods, compounds in which n is 1 to 5 can also be obtained. compound can be obtained.

Acids and salts of formula 1 are readily obtained from the corresponding esters. alkali An acid is obtained by basic saponification with a metal base. For example, preferably with about 3 molar excess of base (e.g. potassium hydroxide) in an active gas atmosphere at room temperature. Stir for 5-20 hours, cool, acidify and recover the hydrolyzate in a conventional manner.

Amides can be prepared from the corresponding esters or carboxylic acids by any suitable method known to those skilled in the art. It may be produced by the amidation method. In one method of preparing such compounds converts the acid to the acid chloride and then converts it with ammonium hydroxide or a suitable amine. Process. For example, an acid can be mixed with an alcoholic solution of a base, such as KOH (approximately 10 mol % peroxide). (excess) ethanol solution for about 30 minutes at room temperature. Remove the solvent and distill the residue into Dissolved in an organic solvent such as methyl ether, treated with dialkylformamide, and then and a 10-fold excess of oxalyl chloride. These are all about -10 to +1 It is carried out at a moderately low temperature of 0°C. The resulting solution is heated at a low temperature for 1 to 4 hours, preferably 1 hour. Stir for an hour. The residue obtained by solvent removal is treated with an inert solvent (e.g. benzene) Cool to about 0° C. and treat with concentrated ammonium hydroxide. Reduce this mixture to Stir at warm temperature for 1-4 hours. The product is recovered in conventional manner.

Alcohols can be converted to acid chlorides by converting the corresponding acids into acid chlorides by thionyl chloride or other means. [Jay March, Advanced Organic Chemistry, Vol. 2nd edition, Matsugrow-Hill Book Co., Ltd., then acid chloride to sodium borohydride. [March, op. cit., p. 1124]. Also, The ester may be reduced with lithium aluminum hydride at low temperatures. this alcohols with appropriate alkyl halides under Williamson reaction conditions. By alkylation, the corresponding ethers are obtained [March, op. cit., 3. page 57]. These alcohols can be treated with acid catalysts or synchhexylcarbonimide. by reacting with a suitable acid in the presence of dimethylaminopyridine and dimethylaminopyridine. , can be converted into esters.

Aldehydes can be removed using mild oxidizing agents, e.g. pyridinium dichromene in methylene chloride. [Corey, E. J., Schmidt, G. (S. chmidt.

G.), Tetrahedron Letters (Tet, Lett.), 399.1979 ] or dimethyl sulfoxide/oxalyl chloride in methylene chloride [Omura, Ke I (Omura.

K.), Stern, D.), Tetrahedron (Tetra hedron), 1978.34.1651], the corresponding primary alcohol It can be prepared from

Ketones can be prepared by combining the appropriate aldehyde with an alkyl Grignard reagent or similar reagent. It can be prepared by processing and then oxidizing.

The acetal or ketal can be prepared by the method described in March, supra, p. 810. Obtained from the corresponding aldehyde or ketone.

Compounds in which B is hydrogen may be substituted with the corresponding haloheteroplexy, preferably in which the halogen is I. Derived from ring compounds.

To explain reaction formula 2, phenol or an alkyl group at the 3-position (meta-position) A substituted phenol (compound 20) having a substituent (R3) is added to an appropriate substituted acrylic acid. Acylation with an acylating agent such as an acid chloride derived from (compound 10).

In Reaction Formula 2, as in Reaction Formula 1, the groups R and R1 of the target compound are acrylic acid derivative (compound 10). Acid chloride (compound 10) Acylation with a strong base (e.g. It is preferable to carry out the reaction in the presence of sodium hydride). Substituted phenyl obtained -Acrylate is shown as Compound 21 in Reaction Scheme 2.

Substituted phenyl-acrylate (compound 21) can be prepared using Friedel-Krach type reaction conditions. ring closure under conditions (using filc13 catalyst in an inert solvent such as methylene chloride). 2-oxochloro having R and R2 in the 4th position and (optionally) R3 in the 6th position. It is referred to as Mann's compound (compound 22). 2-oxothiochroman ( Similarly to compound 12), 2-oxochroman (compound 22) of reaction formula 2 was Upon reaction with Jarl's reagent, groups R4 and R5 are introduced. As mentioned above, R 4 and R, cannot both be hydrogen at the same time. R4 and R6 are methyl Grignard reagent is methylmagnesium chloride [tetrahydrofuran]. (dissolved in THF)] is preferable. This Grignard reagent , for example, by adding a solution of compound 22 in a suitable solvent such as dry diethyl ether. Ru. Phenol with tertiary alcohol side chain (molecule with open chroman ring) (Compound 23 in Reaction Formula 2) is obtained.

Compound 23, which already has the desired groups R1 to R6, is prepared under acidic conditions (e.g. aqueous sulfuric acid). ring closure (by heating in a vacuum) to obtain the chroman derivative (compound 24). If synthesis routes (preferred, but not limited to, for the production of the compounds of the present invention) Up to this point, the thiochroman (Scheme 1) and the chroman-induced In either synthesis of the compound (Scheme 2), the same or similar steps are carried out and different The point is that in reaction formula 2, the starting material phenol derivative is a halogen (e.g. The only difference is that it does not have a substituent (for example, bromo).

In the preferred synthetic route of the chroman compound of the present invention, a halogen substituent is present. Therefore, it is preferable to introduce an acetylene (ethyne) group at the 6-position of the chroman moiety. The new step (reaction formula 2) is to introduce an acetylene moiety into the corresponding 1,000 chromans. This is different from the second process (reaction formula 1).

That is, in reaction formula 2, chroman-induced An acetyl group is introduced into the 6-position of the conductor (compound 24). This acetylation 1, Nito Acetyl chloride in the presence of aluminum chloride in lomethane solvent It is preferable. The resulting 6-acetylchroman derivative is designated as compound 25. did.

The acetylene (triple) bond acetates the 6-acetyl moiety of Taloman (compound 25). It is introduced into the molecule by converting it into a tyrene moiety. This is preferably 1. , with lithium diisopropylamide which enolizes the acetyl group (low temperature, e.g. This is done by treatment (at -78°C). Intermediate dinolic compound (reaction (not shown) in formula 2 is treated with diethyl chlorophosphate (or similar reagent). Stellate and react again with lithium isopropylamide at low temperature (e.g. -78°C) 6- A nitinylchroman derivative (compound 26) is obtained.

However, the present invention is not limited by such or other reaction mechanism theories. It is not intended that Without departing from the scope of the present invention, those skilled in the art will be able to: Modify and adjust synthetic conditions for specific intermediates to synthesize multiple compounds of the invention. To further enable and facilitate the production, a brief explanation of the reaction mechanism theory ( (as appropriate).

Continuing the explanation of reaction formula 2, 6-nitinylchroman derivative (compound 26>t'! , the corresponding desired thiochroman derivative from 6-nitinylthiochroman (compound 16) The target compound of the present invention ( Can be converted into two. That is, compound 26 is combined with cupric iodide, a suitable catalyst [usually P d(PQs)2C1z (Q is phenyl, etc.), and acid acceptors (e.g. trie thylamine) with reagent X'A (CH2)nB (formula 3). It is preferable to heat 1°. Due to this force/twisting reaction, the explanation regarding Reaction Equation 1 can be obtained. In the same way as explained above, whether the desired chroman compound (compound 28) is obtained or not, or can be easily converted into the target compound by protection, deprotection, esterification, homologation, etc. A derivative that can be obtained is obtained. The homologue is as compound 28a in reaction scheme 2. Indicated.

In addition, 6-nitinylchroman (compound 26) was first converted to the corresponding metal (zinc) salt ( Compound 27) and then reagent X'-A (CHJn-B (Formula 3) May be coupled with This coupling reaction is explained with respect to Equation 1. The coupling of compound 18 with similar reagents can be carried out under similar conditions.

Ward stem A -Record To explain about reaction formula 3, 2-oxo-6-promothiochroman (compound By treating ]2) with a Grignard reagent as in the case of reaction formula], Substituted 6-bromo in which one substituent of R4 or R3 is alkyl and the other is hydrogen Thiochroman 14 can be synthesized. That is, 2-oxo-thiochroma compound 2) with an excess of Grignard reagent having the necessary alkyl substituent R4. With drugs (e.g. methylmagnesium bromide when R4 or R, is methyl) Process.

This reaction is carried out for a relatively short period of time (approximately 0.0 5 hours), and as shown in reaction formula 3, the hemiacetal derivative (compound 55) was generate. The hemiacetal (compound 55) is then preferably subjected to acidic conditions. by heating with aqueous sulfuric acid), 6-bromothiolefin derivatives (by heating with aqueous sulfuric acid), 6-bromothiolefin derivatives (by heating with aqueous sulfuric acid), Compound 56) is obtained. 6-Bromothiolefin was treated with palladium sulfide catalyst. Reduce by hydrogenation at moderate pressure (approximately 30 psi) in the presence of . R1, R2, R3, R4 and R5 as desired hydrogen and alkyl substituents ( In particular, one of R4 and R5 is argyl and the other is H). Roman (compound 14) is obtained.

Regarding 6-promothiochroman 14 of reaction formula 4, as shown in reaction formula 4, Hezeta acetal derivative (compound 55) with a different Grignard than previously used. By treating the R4 and R3 substituents (both of which are alkyl), (but not the same group). In this reaction, Grignard The thiochroman ring is opened in the presence of a reagent to form the tertiary 4-promothiophenol. An alcohol derivative (compound 13) is produced. Desired R,, R2, R3, R4 and The ring closure of tertiary alcohols having RJI and RJI substituents is carried out under acidic conditions, as described above. By heating, preferably compound 13 is heated with aqueous sulfuric acid. Therefore, do it.

with desired alkyl and hydrogen substituents as R, R2, R,, R, and R5 6-bromothiochroman (compound 14) is obtained.

2A 5A1 Reaction formula 6 In Reaction Formula 5, similarly to Reaction Formula 3, R4 and R4 of the substituted chroman (compound 24) and one of the R5 substituents is alkyl and the other is hydrogen. In reaction equation 3, the corresponding Similarly to 2-oxo-thio-taloman (compound 12), the 2-oxo-thio-taloman of reaction scheme 5 -Treatment of chroman (compound 22) with excess Grignard reagent to produce R4 and R Introducing 5 substituents. By adjusting the temperature and time as described above, as shown in reaction formula 5, The hemiacetal derivative (compound 57) can be isolated. Normal acidic condition under conditions (e.g. by heating in aqueous sulfuric acid). ) is converted to the corresponding olefin derivative (compound 58). Next, reaction formula 3 using conditions similar to the reduction of compound 56 of The olefin (compound 58) can be reduced by conventional reduction methods. The resulting black The manne derivative is compound 24 of Reaction Scheme 5. Synthetic route up to this point (compound of the present invention) (preferred, but not limited to) for the production of products, thiol In the synthesis of both roman (reaction formula 3) and chroman derivatives (reaction formula 5) also carried out the same or similar steps, the main difference being the lactone release in reaction equation 5. The emitter must be free of halogens (eg bromo substituents).

Regarding compound 24 in Reaction Scheme 6, compound 57 is treated with a different group than previously used. By acting with Linard reagent, R4 and R5 substituents (both alkyl kill, but are not mutually the same group). As shown in reaction formula 6, where A tertiary alcohol (compound 23) is generated. Compound 23 was ring-closed under acidic conditions in the same manner as above to obtain Taloman. A derivative (compound 24) is obtained. One of the R4 and R5 substituents is alkyl and the other is hydrogen, or both R4 and R5 substituents are alkyl. However, in order to obtain a final product that is not the same group as each other, compounds 14 and 24 were subjected to reaction procedures substantially similar to those shown in Reaction Scheme 1 and Reaction Scheme 2, respectively. attach

Specific examples of compounds of the invention, as well as compounds of the invention and certain intermediates, below. The example synthesis steps are for illustrating the present invention and are not intended to limit the scope of the present invention. It's not something you can do.

15.75 g (0.1 mol) of 6-chloronicotinic acid, 6.9 g (0.1 mol) of ethanol 15 mol), 22.7 g (0.11 mol) of dicyclohexylcarbodiimide and A mixture of 3.7 g of dimethylaminopyridine in 200 ml of methylene chloride, The mixture was heated under reflux for 2 hours. Cool the mixture, remove the solvent under reduced pressure, and flush the residue. Chromatography gave the title compound as a low melting white solid.

PMR (CDC13): δ1.44 (3H, t, J-6, 2Hz), 4.44 ( 2HSQ.

J-4, 4Hz), 7.44 (IH, d, J-8, 1Hz), 8.27 (IHS dd, J-8°” Hz% 3 Hz), 9.02 (IHSd, J-3Hz).

Using the above procedure, other halo-substituted acids can be esterified to synthesize compounds such as can do: Ethyl 2-(2-chloropyrid-5-yl)acetate: Ethyl 5-(2-talo Ropyrider 5-yl)pentanoate: Ethyl 2-(2-iodofurur-5-yl) ) Acetate: Ethyl 5-(2-iodofurur-5-yl)pentanoate: Ethyl 2-(2-iotothien-5-yl)acetate: Ethyl 5-(2-iotothien-5-yl) en-5-yl)pentanoate: ethyl 2-(3-chloropyridazin-6-y) ) Acetate: Ethyl 5-(3-chloropyridazin-6-yl)pentanoether and the corresponding chloro- or other halogen-substituted pyrimidini of these esters; or pyrazinyl analogues. The above ester [ethyl 6-chloronicotinate (chemical Compound 29)] includes ethynyl compounds (e.g. compounds 16 and 26), or A sample which provides the target compound of the present invention by coupling with its zinc salt 17 and 27) Can be used as drug XI-A-(CH2), -B.

5-(4-bromophenyl)3,3-dimethylthioacrylate (compound 30) 1.92 g of NaH (80 mmol: (obtained from a 60% suspension in mineral oil by washing with 3 x 15 mA hexane) in water. 15.1 g (80 mmol) of 4-bromothiophenol in 60 liters of dry THF. ) solution was added slowly over a period of 1 hour. Stir the mixture for an additional 30 minutes at 0°C. After stirring, 10.1 g of dimethyl acryloyl chloride (85 mmol) solution. The cooling bath was then removed and the mixture was kept at room temperature for 40 hours. Stirred. The reaction mixture was poured into 200 d of water containing 2 ml of glacial acetic acid and the organic phase was separated. did. The organic phase was washed with 2x75174 water and dried over magnesium sulfate. solvent Removal in vacuo gave the title compound as a yellow oil.

PMR (CDC7!3) δ1.91 (3H, s), 2°14 (3H,, s), 6.03-6゜06 (IH, m), 7.28 (2H, d, J-8, 6Hz), 7 ．． 53 (2H, d, J-8°5Hz).

4.4-dimethyl-6-bromo-2-oxo-thiochroman (compound 31) nitrogen Aluminum chloride 1 in methylene chloride 140117+ with stirring in atmosphere 5.9 g (119 mmol) of 5-( 4-bromophenyl) 3,3-dimethyl-thioacrylate (compound 30) 21 ．． 64 g (799 mmol) solution was added. This mixture was then heated at room temperature for 72 hours. After stirring for a while, it was poured onto 250 g of ice/brine mixture. Extract the mixture with methylene chloride The combined organic extracts were washed with saturated sodium chloride solution and dried over magnesium sulfate. It was dry. The solvent was removed under reduced pressure and the residue was recrystallized from hexane to give the title compound as a white Obtained as crystals.

PMR (CDC1s) δ1.40 (6H, s), 2.67 (2H, s), 7. 31-7°40 (3H, m).

MS exact mass: m/e269.9714 (calculated value: Cl+H11S OB 269, 9714).

4-Bromo-2-(1,1,3-trimethyl-3-hydroxybutyl)thiophene Nol (compound 32) In an argon atmosphere, 3.49 g (32.8 mmol) of lithium perchlorate was added to 3.0M methylmagnesium bromide in solution was added 35/(105 mmol). I got it.

Add 4,4-dimethyl-6-bromo-2-oxo-thiochroman (chemical compound) to this mixture. Compound 31) A solution of 2.961 g (10,926 mmol) was added dropwise while stirring. , the reaction mixture was heated to reflux for 70 hours. The reaction mixture was then cooled and poured with 100 g of ice. /concentrated sulfuric acid 8 ml mixture. Separate the organic phase and soak the aqueous phase in ether 2X25mA ’ was extracted.

Combine the organic phases and add 2 x 25 ml of saturated sodium bicarbonate solution, 25 mA of water and 25 mA of saturated sodium bicarbonate solution. It was washed successively with 25 ml of sodium chloride solution and dried over magnesium sulfate. solvent was removed under reduced pressure and the residue was purified by crash chromatography to yield the title compound. The product was obtained as a pale yellow oil.

PMR (CD (J’s): δ1.05 (6H, s), 1.52 (6HSs), 2 ．． 30 (2H.

S), 3.71 (IH, s), 7.22 (IH, ddSJ-8, 5Hz, 2.1 Hz), 7°28 (IH, d,, J-8,5Hz), 7.35 (LH, dSJ- 2.1Hz).

Using ethylmagnesium bromide instead of methylmagnesium bromide , the corresponding 4-bromo-2-(1,1-dimethyl-3-ethyl-3-hydroxy pentyl)-thiophenol is obtained.

2,2.4.4-tetramethyl-6-bromothiochroman (compound 33) 4-but Lomo-2-(1,1,3-trimethyl-3-hydroxybutyl)thiophenol (Compound 32) Mixture of 500 g (1.49 mmol) with 81 Il of 20% sulfuric acid The material was heated to reflux for 24 hours. This mixture was extracted with hexane and the organic extracts were combined. Wash with water, saturated sodium bicarbonate, water, and saturated sodium chloride, and rinse with sulfuric acid macerate. Dried with gnesium. The solvent was removed under reduced pressure and the residue was subjected to crash chromatography. The title compound was obtained as a colorless oil.

PMR (CDCA3): δ1.35 (6H, s), 1.40 (6H, s), 1. 93 (2H1S), 7.17 (IHSdd, J-8, 4Hz, 2.1 Hz), 7.23 (IH, d, J-34Hz), 7.26 (IH, d, J-2, 1Hz) .

MS exact mass: m/e284.0221 (calculated value: as C+3H+7SBr 284.0234).

2.2.4.4-Tetramethyl-6-bromotylene in 1.5 m/triethylamine Put 600 mg (2.11 mmol) solution of ochroman (compound 33) into a thick-walled tube. , degassed, and in an argon atmosphere, 1.4 g of trimethylsilylacetylene (14,3 mmol), and 75 mg (0.39 mmol) of cupric iodide and bis(trif. phenylphosphine) palladium(n) chloride 150+g (0.21 mmol) Treated with a powder mixture of

The reaction mixture was again degassed and the tube was sealed under an argon atmosphere. Mixture 1200 After heating at ℃ for 24 hours and cooling to room temperature, an additional amount of trimethylsilylacetylene 1. 4 g (14,3 mmol), and 75 mg (0,39 mmol) of cupric chloride and his(triphenylphosphine)palladium(II) chloride 150 mg (0 , 21 mmol). The mixture was then degassed and replaced with argon. Heated at 100° C. for 96 hours in a sealed tube under atmosphere. Cool the mixture to room temperature and Extracted with 3XIQgr. Combine the organic extracts and add water 2. )+r and saturated salt The mixture was washed successively with 25 ml of sodium chloride solution and dried over magnesium sulfate. Reduce solvent The pressure was removed and the residue was subjected to flash chromatography (liquid, hexane, then 3 % ethyl acetate/hexane) to give the title compound as a yellow crystalline solid.

PMR (CDCIa) δ0.23 (9H, s), 1.36 (6H,, s), 1 ．． 39 (6H1S), 1.94 (2H, s), 7.17 (LH, dd, J-8, 2Hz, 1.8Hz), 725 (IH, d, J-1,8Hz), 7.30 (IH , d, J-8, 2Hz).

MS accurate mass m/e302.1519 (calculated value as C+1HzSSi) 382.1524).

2,2.4.4-tetramethyl-6-nitinylthiochroman (compound 35) al 2.2.4.4-Tetramethyl-6 in 4 blades of isopropanol in a gaseous atmosphere -trimethylnolyruethynylthiochroman (compound 34) 527.6 g (1 75 mmol) solution, 4 apricots of IN-KOHOH solution was added. Reaction mixture at room temperature After stirring for 20 hours, the isopropanol was removed under reduced pressure. Extract the residue with ether The combined extracts were washed successively with water and saturated sodium chloride solution and soaked in a sulfuric acid magnet. dried with sium. The solvent was removed in vacuo to give the title compound as a yellow oil.

PMR (CDC7!3): δ1.34 (6H, s), 1.37 (6H, s), 1 ．． 91 (2H.

S), 2.99 (LH, s), 7.17 (IH, dd,, J-8, 1Hz, 1. 8Hz), 726 (IH, d, J-1, 8Hz), 7.30 (IH, d, J-8 , 1Hz).

MS exact mass + m/e230.1122 (calculated value: C + sH + 6S as 23 0°1129).

Ethyl 6-[(2,2,4,4-tetramethyl-thiochroman-6-yl)-ethyl [tinyl] nicotinate (compound 1) 2,2.4.4-tetramethyl-6-nitinylthiochroman (compound 35) 23 2 wings? (1,01 mmol) and ethyl 6-chloro-nicotinate (compound 29) A solution of 190 mg (1,03 mmol) of triethylamine in 2 liters of thick-walled Place in a glass tube, degas, and add cupric iodide 5319 (0,28 mmol) and bis(triphenylphosphine)palladium(II) chloride 84 mv (0.12 mmol). Degas the mixture again and The tube was sealed under Rougon atmosphere. The reaction mixture was heated at 55°C for 60 hours, then warmed to room temperature. Cooled. The mixture was treated with water and ether and the organic phase was separated. Aqueous phase The organic phases were combined, washed with saturated sodium chloride solution and extracted with magnesium sulfate. dried in a vacuum. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography. - (silica; 10% ethyl acetate/hexanes) to give the title compound a dark yellow color. Obtained as a colored oil.

PMR (CDC1,): δ1.32-1.43 (15H, m), 1.92 (2H , s), 4°38 (2HSQ, J-7, 1Hz), 7.28 (LH, dd, J- 8,3Hz, 1.8Hz), 7, 32-7.38 (2H, m), 7.53 (IH , d, J-8, 3Hz), 8.24 (LH.

dd, J-8, 2Hz, 2.2Hz), 9.16 (IH, dSJ-2, 2Hz) .

MS exact mass: m/e379.1594 (calculated value' Ct s H25N O z　S as 379, 1606).

an appropriate ethynylthiochroman (compound 16 of Reaction Scheme 1) and an appropriate halo-substituted complex. using a bare ring ester (formula 3; e.g. synthesized by the method described for compound 29). According to the method for synthesizing compound 1, the following compounds of the present invention can be synthesized: ethyl 6 -[(2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl ] Nicotinate; Ethyl 6-[(2,2,4,4-tetramethyl-7-ethylthiochroman-6- yl)-ethynyl] nicotinate; Ethyl 6-[(2,2,4,4-tetramethyl-7-propylthiochroman-6 -yl)-ethynyl]nicotinate: Ethyl 6-[(2,2,4,4-tetramethyl-7-hexylthiochroman-6 -yl)-ethynylconicotinate: Ethyl [((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl )-virigou-5-yl] acetate: Ethyl [((2,2,4,4,7-pentamethylthiochroman-6-yl)ethyl Nyl)-virigou-5-yl]acetate.

Ethyl [((2,2,4,4-tetramethyl-7-ethylthiochroman-6-y) (2,2,4,4 -tetramethyl-7-bequidylthiochroman-6-yl)ethynyl) birigou 5 -yl]acetate; ethyl 3-[((2,2,4,4-tetramethylthiochloro Man-6-yl)-ethynyl) birigu-5-yl]propionate: ethyl 3- [((2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl ) Pyrigu-5-yl]propionate: Ethyl 3-[((2,2,4,4-tet) lamethyl-7-ethylthiochroman-6-yl)ethynyl)pyrigu-5-yl] Propionate; ethyl 3-[((2,2,4,4-tetramethyl-7-hexy ruthiochroman-6-yl)-ethynyl)pyrigu-5-yl]propionate: Ethyl 5-[((2,2,4,4-tetramethylthiochroman-6-yl)ethyl ethyl 5-[((2,2,4,4 ,7-pentamethylthiochroman-6-yl)-ethynyl)pyrigu-5-yl] Pentanoate: Ethyl 5-[((2,2,4,4-tetramethyl-7-ethyl thiochroman-6-yl)-ethynyl)pyrigu-5-yl]pentanoate; thyl[5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl) )-furer 2-yl] acetate: Ethyl [5-((2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl)-furer-2-yl]acetate: Ethyl[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6 -yl)-ethynyl)furer-2-yl]acetate: ethyl[5-((2,2, 4,4-tetramethyl-7-hexylthiochroman-6-yl)-ethynyl)ph 2-yl]acetate: Ethyl 5-[((2,2,4,4-tetramethylthi ochroman-6-yl)ethynyl)-furer-2-yl]pentanoate: Ethyl 5-[5-((2,2,4,4,7-pentamethylthiochroman-6-y) (2, 2,4,4-tetramethyl-7-ethylthiochroman-6-yl)-ethynyl) Fuller 2-yl]pentanoate: Ethyl 5-[5-((2,2,4,4-tet) lamethyl-7-hexylthiochroman-6-yl)-ethynyl)furer-2-yl coventanoate ethyl [5-((2,2,4,4-tetramethylthiochroman -6-yl)ethynyl)-checy 2-ylcoacetate; Ethyl [5-((2,2,4,4,7-pentamethylthiochroman-6-yl) Ethyl[5-((2,2,4,4 -tetramethyl-7-ethylthiochroman-6-yl)-ethynyl) Checy 2 -yl]acetate: ethyl[5-((2,2,4,4-tetramethyl-7-beta) Kyzylthiochroman-6-yl)-ethynyl)chesy-2-yl coacetate: Ethyl 5-[5-((2,2,4,4-tetramethylthiochroman-6-yl) -ethynyl)-checy2-yl]pentanoate: ethyl 5-[5-((2, 2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl) Chessie 2-yl]pentanoate: ethyl 5-[5-((2,2,4,4-tetramethylate) -7-ethylthiochroman-6-yl)-ethynyl)chasyl-2-yl]pen Tanoate: Ethyl 5-[5-((2,2,4,4-tetramethyl-7-bekidi) ruthiochroman-6-yl)-ethynyl)chesy-2-ylcobentanoate: Ethyl[6-((2,2,4,4-tetramethylthiochroman-6-yl)ethyl yl)-pyridazin-3-yl]acetate: ethyl[6-((2,2,4,4 ,7-pentamethylthiochroman-6-yl)ethynyl)-pyridazin-3-y ]acetate: ethyl[6-((2,2,4,4-tetramethyl-7-ethyl thiochroman-6-yl)-ethynyl)pyridazin-3-yl]acetate thyl[6-((2,2,4,4-tetramethyl-7-hexylthiochroman-6 -yl)-ethynyl)pyridazin-3-ylcoacetate: ethyl 5-[6-( (2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)-pyrida Zin-3-yl]pentanoate: Ethyl 5-[6-((2,2,4,4,7- pentamethylthiochroman-6-yl)-ethynyl)pyridazin-3-yl]pe ethyl 5-[6-((2,2,4,4-tetramethyl-7-ethyl Thiochroman-6-yl)-ethynyl)pyridazin-3-ylcobentanoate ;ethyl 5-[6-((2,2,4,4-tetramethyl-7-hexylthiochloro Man-6-yl)-ethynyl)pyridazin-3-yl]pentanoate: ethyl [5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl) -pyrimidin-2-yl]acetate: ethyl[5-((2,2,4,4,7- pentamethylthiochroman-6-yl)ethynyl)-pyrimidin-2-yl]a Cetate: ethyl [5-((2,2,4,4-tetramethyl-7-ethylthioc roman-6-yl)-ethynyl)pyrimidin-2-yl]acetate; ethyl[ 5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl )-ethynyl)pyrimidin-2-yl]acetate; ethyl 5-[5-((2, 2,4,4-tetramethylthiochroman-6-yl)ethynyl)-pyrimidine- 2-ylcopentanoate; ethyl 5-[5-((2,2,4,4,7-pentanoate) methylthiochroman-6-yl)-ethynyl)pyrimidin-2-yl]pentano Ethyl 5-[5-((2,2,4,4-tetramethyl-7-ethylthio) chroman-6-yl)-ethynyl)pyrimidin-2-yl]pentanoate: Chyl 5-[5,-((2,2,4,4-tetramethyl-7-bequidylthiochroma) (6-yl)-ethynyl)pyrimidin-2-yl]pentanoate: ethyl[ 5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)- pyrazin-2-yl]acetate: Ethyl [5-((2,2,4,4,7-pentamethylthiochroman-6-yl) ethynyl)-pyrazin-2-yl]acetate; ethyl[5-((2,2,4, 4-Tetramethyl-7-ethylthiochroman-6-yl)-ethynyl)pyrazine -2-ylcoacetate: ethyl [5-((2,2,4,4-tetramethyl-7 -hexylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]acetate ethyl 5-[5-((2,2,4,4-tetramethylthiochroman-6- yl)ethynyl)-pyrazin-2-ylcopentanoate; ethynyl)virazine -2-yl]pentanoate: Ethyl 5-45-((2,2,4,4-tetramethane) thyl-7-ethylthiochroman-6-yl)-ethynyl)pyrazin-2-yl] Pentanoate: Ethyl 5-[5-((2,2,4,4-tetramethyl-7-beta) Kyzylthiochroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoe ethyl 6-[(2,2-diethyl-4,4-dimethylthiochroman-6- yl)-ethynyl]nicotinate; and Ethyl 6-[(2,2-diethyl-4,4,7-trimethylthiochroman-6- yl)-ethynyl]nicote.

Phenyl 3,3-dimethyl acrylate (compound 37) in an oxygen atmosphere, dried TH NaH in F2M (from a 60% suspension in mineral oil washing with hexane 3xlQ++1) ) in 50 mA of dry THF to a water-cooled solution of 1.29 g (54 mmol) of A solution of 5 g (53 mmol) of phenol was added slowly. Dry the mixture Treated with a solution of 7 g (59 mmol) dimethylacryloyl chloride in 30 m7 HF. I understood. The cooling bath was removed and the mixture was stirred for an additional 2.5 hours. The reaction mixture is Pour into 150 ml of water containing 1 liter of glacial acetic acid. The mixture was extracted with 150 ml of ether. The ethereal extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. It was dry. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography (silica: 5 % ether/hexane) to give the title compound as a yellow oil.

PMR (CDCA’s): δ1.99 (3H, s), 2.24 (3H, s), 5 ．． 93 (IH.

Broad S), 7.10 (2H, d, J-7, 8Hz>, 7.22 (IH, t, J-7,8Hz), 7.38 (2H,t, J-7,8Hz).

4.4-Dimethyl-2-oxo-chroman (compound 38) salt in argon atmosphere Water cooling of 10.4 g (78 mmol) of aluminum chloride in 160 liters of methylene chloride A suspension of phenyl 3,3-dimethyl acrylate ( A solution of 7 g (39.8 mmol) of compound 37) was slowly added with stirring. . The cooling bath was removed and the mixture was stirred for an additional 42 hours. Place the mixture on ice/brine. The mixture was poured and the organic phase was separated. The aqueous phase was extracted with methylene chloride and the organic extract was Combined, washed with saturated sodium chloride solution and dried over magnesium sulfate.

The solvent was removed under reduced pressure and the residue was subjected to flash chromatography (silica: 10% ether). Purification by dichloromethane/hexane) gave the title compound as a colorless oil.

PMR (CDCIs’): δ1.30 (6H, s), 2.56 (2H, s), 7 ．． 06 (IH.

dd, J-8,0Hz, 1.4Hz), 7.16(IH, td, J-8,0Hz , 1.4Hz), 7.26 (LH, td, J-8,0Hz, 1.7Hz), 7. 33 (IH, dd, J-8, 0Hz, 1.7Hz).

MS exact mass: m/e176.0852 (calculated value: Cr　r　Hr　y　O 2 as 176°0837).

2-(1,1,3-1-dimethyl-3-hydroxybutyl)phenol (compound 39) 3.0M methylmagnesium solution in THF cooled in a water bath in a nitrogen atmosphere. 11 (33 mmol) of 4,4-dimethylene in 11 (33 mmol) of loride in 35 1 (35 mmol) of dry ether 1.96 g (11.1 mmol) solution of Ru-2-oxo-chroman (compound 38) added. The cooling bath was removed and the mixture was stirred at room temperature for 72 hours. reaction mixture Pour into a mixture of 100g ice/3@l concentrated sulfuric acid and stir until the magnesium salt is dissolved. Ta. Separate the organic phase and soak the aqueous phase in ether 2X501A! Extracted with. Combine the organic phases , washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, Dry with magnesium sulfate. The solvent was removed under reduced pressure and the residue was flash chromatographed. Purification with roughy (silica; 20% ethyl acetate/hexane) gave the title compound a pale yellow color. Obtained as a colored solid.

PMR (CDCzs): δ1.13 (6HSs), 1.48 (6HSs), 1. 89 (IHLS), 2.23 (2H, s), 6.60 (LH, dd, J-7, 9 Hz, 1.4Hz), 6°83 (IH, s), 6.84 (IH, td, J-7, 9Hz, 1.4Hz), 7.07 (IH.

td, J-7,9Hz, 1.6Hz), 7.31(IH, ddSJ-7,9Hz , 1.6Hz).

MS exact mass m/e208.1458 (calculated value: as C+5HzoO2 208°1464).

2,2.4.4-tetramethylchroman (compound 40) 2-(1 , 1,3-trimethyl-3-hydroxybutyl)phenol (compound 39)2. A mixture of 98 g (14.3 mmol) and 49 ml of 20% sulfuric acid was heated under reflux for 4 hours. It flowed. The mixture was stirred for a further 72 hours at room temperature and then diluted with 5Q*l of water.

The mixture was extracted with hexane 3×20 mA'. Combine the organic extracts with water and saturate Washed successively with sodium chloride solution and dried over magnesium sulfate. Remove solvent under reduced pressure The title compound was obtained as a colorless oil.

PMR (CDCj’s) + 61.36 (6H, s), 1.37 (6H, s), 1 ．． 83 (2H.

S), 6.71 (IH, dd, J-8, 2Hz, 1.5Hz), 6.92 (IH , td, J-8,2Hz, 1.5Hz), 7.09 (IHStd%J-8,2 Hz, 1.5Hz), 7.29 (IH, dd, J-8, 2Hz, 1.5Hz).

2,2.4.4-tetramethyl-6-acetylchroman (compound 41) nitrogen atmosphere 2.2.4.4-tetramethylchroman (compound) in air, 25 m/nitromethane Into a water-cooled solution of 2 g (10.53 mmol) of substance 40), acetyl chloride 941 proverb 1 ( 11°99 mmol), followed by 1.59 g (11,92 mmol) aluminum chloride mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature for 16 hours. Mixed The mixture was cooled again in a water bath and treated with 25 ml of concentrated hydrochloric acid. Filter the mixture and remove the residue. Washed with methylene chloride. The filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography. - (silica; 10% ethyl acetate/hexane) to give the title compound a yellow color. Obtained as an oil.

PMR (CD (δ3): δ], 38 (6HSs), 1.39 (6HSs), 1 ．． 87 (2H.

S), 2-56 (3H, s), 6.83 (IH, d, J-8,7Hz), 7.7 1 (LH.

da, J-8, 7Hz, 2.1Hz), 7.98 (IH, d, J-2, 1Hz) .

MS exact mass: m/e232.1468 (calculated value: CIs H2002) 232°1464).

2,2.4.4-tetramethyl-6-nitinylchroman (compound 42) nitrogen atmosphere Dry THF 8mA in surrounding air! Diisopropylamine 522m+9 (5,17 1.6M n-butyl chloride in hexane was added to a cooled (-78°C) solution of 3.23 ml (5.17 mmol) of lithium were added slowly. 78% of the mixture After stirring for 40 min at 1.24 g (5.17 mmol) solution of Ru-6-acetylchroman (compound 41) Processed with. The mixture was stirred for an additional hour at -78°C and diluted with diethylchlorophosphate. The mixture was treated with 895 Tom A' (5.19 mmol). Warm the reaction mixture to room temperature , a solution of lithium diisopropylamine in THF [as described above, diisopropylamine 1.04 g (10.34 mmol) of pyramine and 1.6 M n-butylene in hexane. prepared from 6.46 mA (10.34 mmol) of chilllithium] at -78 °C. Transferred using a double-ended needle. The cooling bath was removed and the mixture was stirred at room temperature for 16 hours.

The mixture was treated with 10 μl of ice water and acidified to pH 2 with 10% hydrochloric acid. Separate the organic phase Separated and extracted the aqueous phase with 3×30+1 pentane.

Combine the organic extracts and add 2x30+sJ of dilute hydrochloric acid, water and 3 ml of saturated sodium bicarbonate solution. Wash sequentially with 30 ml of X and saturated sodium chloride solution and dry with magnesium sulfate. did.

The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica; 2% acetic acid ethyl chloride). Purification by methyl/hexane) gave the title compound as a pale yellow oil.

PMR (CDCA’s): δ1.31 (6H, s), 1.32 (6H, s), 1 ．． 50 (2H.

S), 3.00 (LH%　s), 6.72 (IH, d, J-8, 4Hz), 7. 20 (LH.

dd, J-8, 4Hz, 2.1Hz), 7.42 (IH, dlJ-2, 1Hz) .

MS exact mass: m/e 214.1251 (calculated value: 21 as C+sH+sO 4゜2,2.4.4-tetramethyl-6-nitinylchroman (compound 42) 23 3 mol (1°09 mmol) and ethyl 6-chloronicotinate (compound 29) 20 9-v (1,09 mmol) in 1 mJ of triethylamine was degassed, In an argon atmosphere, 50 g (0.26 mmol) of copper iodide and bis(trifle) phenylphosphine) palladium(n) chloride 100 mv (0.14 mmol) Treated with a powder mixture of The reaction mixture was heated at 55° C. for 80 h in an argon atmosphere. The mixture was heated for a while and cooled to room temperature. Remove triethylamine under reduced pressure and flush the residue Purification by chromatography (silica 25% ethyl acetate/hexanes) yielded the standard The compound was obtained as a yellow oil.

PMR (CD (Js): δ1.36 (12H, s), 1.42 (3H, tlJ- 7,2Hz), 1.85(2H,,s), 4.37(2H,Q,J-7,2Hz ), 6.79 (LH.

d, J-, 4Hz), 7.34 (LH, dd, J-8, 4Hz, 2.1Hz), 7.56 (IH.

dlJ-8,7Hz), 7.60(IH,d,J-2,1Hz), 8.27(L H, dd, J-8, 7Hz, 2.4Hz), 9.19 (LH, d, J-2, 4 Hz).

MS exact mass: m/e363.1837 (calculated value: as C25fhsOsN 363.1834).

3-Methyl-phenyl 3,3-dimethyl acrylate (compound 44) 6 in mineral oil A suspension of 0% sodium hydride (3.22 g; 81 mmol) was dissolved in hexane 3X1O +j? and treated with dry THF3Q*l. Cool the mixture in a water bath and dry Treated with a solution of 8.6 g (79.5 mmol) of m-cresol in 80 iff dry THF. I understood.

After stirring the reaction mixture for 10 min, dimethylacryloyl chloride in 40 ml of dry THF was added. It was treated with a solution of 10.5 g (88.5 mmol) of loride. The reaction mixture was heated at room temperature. The mixture was stirred for 6 hours and poured into a mixture of 150 l/l water/1 l/l glacial acetic acid. mix for 10 minutes The mixture was stirred for a while and the organic phase was separated. The aqueous phase was extracted with ether 2 x 50w, l. organic Combine the phases, wash successively with water and saturated sodium chloride solution, and dry over magnesium sulfate. It was dry. The solvent was removed under reduced pressure and flash chromatography (silica; 10% vinegar Purification by ethyl chloride/hexane) gave the title compound as a pale yellow oil.

PMR (CDCA’s): δ1.95 (3HSd, J-1,3Hz), 2.21 (3H, d.

J4.2Hz), 2.34 (3H, s), 5.90 (IH, Broad S), 6. 86-6°93 (2HSm), 7.01 (H, d, J-7, 2Hz), 7.24 (IH, t, J-7, 2Hz).

13 g (97 g) of aluminum chloride in 200 ml of methylene chloride in an argon atmosphere 3-methyl-fluoride in 100 fiJ of methylene chloride was added to a water-cooled suspension of phenyl 3,3-dimethyl acrylate (compound 44) 9.0 g (47,4 mm ) solution was added dropwise. The reaction mixture was further incubated at 0° C. for 30 min and at room temperature for 15 h. Stir for a while. The reaction mixture was poured into ice water/salt mixture 200 mA and the organic phase was separated. . The aqueous phase was extracted with 5 Qml of ether. Combine the organic phases and add water and saturated sodium chloride. The mixture was washed successively with magnesium sulfate solution and dried over magnesium sulfate. Remove the solvent under reduced pressure and remove the residue. Purify by flash chromatography (silica; 5% ethyl acetate/hexane). 4.4.7-trimethyl-2-oxo-chroman and 4.4.5- An approximately 2.5:1 isomer mixture of trimethyl-2-oxo-chroman was produced as a pale yellow oil. I got it as a thing. 3.8 g (20 mmol) of this 2-oxo-chroman isomer mixture ) in 60 liters of ether in an argon atmosphere at 0°C. ．． One 20 cup (60 mmol) of 0M methylmagnesium bromide was added. reaction mixture The mixture was stirred at room temperature for 48 hours and poured onto a 1 ml ice/concentrated sulfuric acid mixture. Separate the organic phase and the aqueous phase was extracted with ether 2×50 mA'.

Combine the organic phases and add water, saturated sodium bicarbonate solution, water and saturated sodium chloride. It was washed successively with solutions and dried over magnesium sulfate. Remove the solvent under reduced pressure and clarify the residue. ・Purified by Sosch chromatography (silica; 15% ethyl acetate/hexane) The title compound was obtained as a colorless oil.

PMR (CDCA’s): δ1.14 (6H,s), 1.45 (6HSs), 2 ．． 19 (3H.

S), 2.21 (2HSs), 6.39 (LH, d, J-1,8Hz), 6.6 7 (IH.

ddSJ-7, 9Hz, 1.8Hz), 7.16 (IH, dSJ-7, 9Hz) , 7.44 (IH, s).

2,2.4.4.7-pentamethyl-chroman (compound 46) in nitrogen atmosphere, 2 -(1,1,3-1-dimethyl-3-hydroxybutyl)-5-methyl-pheno 2.16 g (11.7 mmol) of compound 45 was added with 50 ml of 20% sulfuric acid. added. The reaction mixture was heated under reflux for 13 hours and then cooled. Separate the organic phase and add water The phase was extracted with ether. Combine the organic extracts with water and saturated sodium bicarbonate solution. , washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate.

The solvent was removed in vacuo to give the title compound as a yellow oil.

PMR (CDCA'3): δ1.32 (6H, s), 1.34 (6H, s), 1 ．． 81 (2H1S), 2.26 (3H, s), 6.63 (LH, s), 6.72 (LH, d, J-7,9Hz), 7.15 (IHSdSJ-7,9Hz).

2,2.4.4.7-pentamethyl-6-acetyl-chroman (compound 47) a 2.2.4.4.7-Pentamethyl in 30 liters of nitromethane in a Rougon atmosphere - In a water-cooled solution of 1.96 g (9.6 mmol) of chroman (compound 46), acetic acid chloride was added. 1.059 g (13.5 mmol) of cetyl, followed by 1.05 g (13.5 mmol) of cetyl, followed by 1. 9 g (14.3 mmol) were added. The reaction mixture was stirred at room temperature for 14 hours and then transferred to a water bath. The mixture was cooled and treated with 25 ml of concentrated hydrochloric acid. The mixture was warmed to room temperature, ether and Diluted with water. The organic phase was separated and the aqueous phase was extracted with ether. Combine organic extracts , water, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution sequentially. Washed and dried with magnesium sulfate. Remove the solvent in vacuo and flash chromatize the residue. Purified by matography (silica: 5% ethyl acetate/hexane) and labeled The compound was obtained as a pale yellow oil.

PMR (CDCj’s): δ1.36 (6H, s), 1.37 (6H, s), 1 ．． 86 (2H.

S), 2.49 (3HSs), 2.56 (3H, s), 6.65 (LH, s), 7.74 (LH, s).

2, 2.4.4.7-pentamethyl-6-nitinylchroman (compound 48) a Diisopropylamine 455119 ( 4.5 mmol) solution was added with 3 Nl of 1.5 M n-butyllithium in hexane. Added at 78°C. The mixture was stirred for an additional 45 minutes at -78°C and then dissolved in dry THF. 2,2.4.4.7-pentamethyl-6-acetyl-chroman (chemical It was treated with a solution of 1.07 g (4.3 mmol) of compound 47). 78% of the reaction mixture After stirring for 1 hour at °C, 776 mg (4.5 mmol) of diethyl chlorophosphate Processed with. The mixture was warmed to room temperature and dissolved in dry THF 10 liters of lithium diisopropylene. A solution of pyramide [as described above, diisopropylamine 910 u (9.0 ml) mol), and 1°5M n-butyllithium 5i+j in hexane! (9,0mi The mixture was transferred using a double-ended needle at −78° C. Mixture at room temperature Stir for 15 hours, then pour into ice water (A). Acidified to 2. The organic phase was separated and the aqueous phase was extracted with pentane. Combine organic extracts and washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. , dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was transferred to an original tube (Kugelr ohr) distillation (82°C, 0.3 mm) to give the title compound as a pale yellow oil. I got it as a thing.

PMR (CDCzg): δ1.32 (6H, s), 1.34 (6H, s), 1. 81 (2H1S), 2.36 (3H, s), 3.18 (LH, s), 6.64 ( LH,s), 7.40 (LH%S).

MS exact mass: m/e228.1520 (calculated value + 22 as Cl6H200) 8°1514).

? Uta 1 sun master 11 uni Ekudojo" dish round three ■ Goeyo mountain 2, 2.4.4.7-pen tamethyl-6-nitinylchroman (compound 48) 300■9 (1,316 mm mol) and ethyl 6-talolonicotinate (compound 29) 245°6 p(1, 3276 mmol) in 2 liters of triethylamine was placed in a pressure tube; A stream of nitrogen was passed through the solution for 15 minutes. Flush the tube with argon and phenylphosphine) palladium (II) chloride 100 rich 9 (0,1425 mi) A fine powder mixture of 50 u (0.2625 mmol) of cupric iodide and added to the liquid. The pressure tube was sealed and the reaction mixture was heated at 60° C. for 72 hours. blend was cooled to room temperature and triethylamine was removed under reduced pressure. Flash chromatography of the residue Purification by chromatography (silica: 10% ethyl acetate/hexane) yielded the title compound. The product was obtained as a yellow solid.

PMR (CDCA’s): δ1.37 (6H, s), 1.38 (6H, s), 1.44 (3H1t, J-7,2Hz), 1.85 (2H,s), 2.49 (3 H1S), 4.43 (2H, q, J4.2Hz), 6.70 (IH, s), 7. 55-7.61 (2H, m), 8.28 (IH, dd, J-8, 2Hz, 2.1 Hz), 9.22 (LH, d, J-2, 1 Hz).

MS exact mass: m/e377.1982 (calculated value: Cz4HztOaN) 377.1991).

2-[2,2,4,4-tetramethylchroman-6-yl)ethynyl]-5-hyron Droxymethylpyridine (compound 50) Add a stirrer, dropping funnel, nitrogen inlet tube, and thermometer to a 250 ml tricycle. Attach. In a flask, add lithium hydride in 30 ml of dry diethyl ether. Add a solution of Luminium 379.5-9 (10 mmol). Solution under nitrogen atmosphere Ethyl 6-[(2,2,4,4 -tetramethylchroman-6-yl)ethynylcornicotinate (compound 43) 3.632 g (10 mmol) of the solution was added at such a rate that the temperature did not exceed 160°C. Drip. The mixture was stirred at -30°C for 1 hour and excess hydride was removed with ethyl acetate. Add 00u (3.4 mmol) and decompose. Then saturated ammonium chloride solution The reaction mixture is hydrolyzed by adding 3 mA' of liquid and allowed to warm to room temperature.

Filter the mixture and wash the residue with ether. Saturate the ether phase with sodium chloride solution Wash with water, dry with magnesium sulfate, and concentrate under reduced pressure. Chromatography of the residue , and then purification by recrystallization to give the title compound.

The same method can be used to convert the acids or esters of the invention to the corresponding primary alcohols. can be done.

2,2.4.4-Tetramethyl-6-[2-(5-hydroxymethylpyrigu 2 -yl) ethynyl fuchroman (compound 50) 3.09 g (10 mmol), ice vinegar acid 60019 (10 mmol), dicyclohexylcarbodiimide 2.06 g ( 10 mmol) and 4-dimethylaminopyridine 460 to 9 (3,765 mmol) mol) in methylene chloride 1501/ml is stirred at room temperature for 48 hours. reaction The mixture is filtered and the residue is washed with 50 ml of methylene chloride. The filtrate was concentrated under reduced pressure to obtain a residue. is purified by chromatography and then recrystallization to give the title compound. .

Other alcohols of the invention can be esterified in a similar manner.

Four-piece Rocrasco equipped with stirrer, thermometer, and two pressure-equalizing addition funnels with drying tubes. , 1.396 g (11 mmol) of freshly distilled oxalyl chloride in methylene chloride Add 25 ml of solution. The solution was cooled to -60°C and diluted with methylene chloride 511A! 1.875 g (24 ml) of dimethyl sulfoxide (distilled from calcium hydride) A solution of 5 min. The reaction mixture was heated at -60°C for an additional 1 Stir for 0 minutes.

2.2.4.4-Tetramethyl-6-[(5-hydro 3.10 g of oxymethylpyrigu-2-yl)ethynyl]-chroman (compound 50) (10 mmol) is added to the reaction mixture over a period of 5 minutes. Renew the mixture After stirring for 15 minutes, treat with 5.06 g (50 mmol) of triethylamine. Ru. Remove the cooling bath and allow the mixture to warm to room temperature. Add 30 IN of water to the mixture. Continue stirring for an additional 10 minutes. Separate the organic phase and add 20ml of methylene chloride to the aqueous phase. Extract with Combine the organic phases and wash sequentially with dilute hydrochloric acid, water and sodium chloride solution. , dry with magnesium sulfate. The solution was filtered, concentrated under reduced pressure, and the residue was chromatographed. Purification by roughy and then recrystallization gives the title compound.

By this method, the primary alcohol of the present invention can be oxidized to the corresponding aldehyde. Can be done.

2-[(2,2,4,4-tetramethylchroman-6-)ethynyl]-5-(1 -Hydroxypropyl)pyridine (compound 53) Stirrer, reflux protected with drying tube A three-loclasco equipped with a condenser and a pressure-equalizing dropping funnel protected by a drying tube. Add 4 ml (12 mmol) of 3M ethylmagnesium bromide solution in solution. . Cool the flask in a water bath and add 10 ml of dry ether! 2-[(2, 2, 4, 4-tetramethylchroman-6-yl)ethynylcopyridine 5-carboxal A solution of 2.98 g (10 mmol) of dehyde (compound 52) is stirred vigorously. Add slowly. Then, remove the cooling bath and add ml of the mixture for 3 hours. Ru. The mixture is stirred for a further hour, filtered and the residue washed with 2 x 10 Il of ether. . Separate the ether solution, dry over magnesium sulfate, and remove the ether under reduced pressure. . The residue was purified by chromatography and then recrystallization to give the title compound get.

Using the same procedure, other aldehydes of the invention can be converted to the corresponding secondary aldehydes. can be done.

Such secondary alcohols can be prepared using the method for preparing compound 52 or other oxidation procedures. can be converted to the corresponding ketone.

2-[(2,2,4,4-tetramethylchroman-6-yl)ethynyl]-5- Dimethoxymethylpyridine (compound 54) Attach a Dean-8tark apparatus to a round-bottomed flask; Above it is fitted a reflux condenser protected by a drying tube. 2-[(2,2,4,4 -tetramethylchroman-6-yl)ethynylcopyridine 5-carboxalde Hyde (compound 52) 3.58 g (12 mmol), anhydrous methanol 4.801 g ( 15 mmol), p-toluenesulfonic acid hydrate 2 irises 9 and anhydrous benzene 1 Pour the mixture of Heat to reflux in a nitrogen atmosphere until it collects in the Stark trap. Bring the reaction mixture to the chamber Cool to room temperature and extract sequentially with 5 ml of 10% sodium hydroxide solution and 2 x 5 i/ml of water. and dry with magnesium sulfate. Filter the solution and remove the solvent under reduced pressure. residue Purification by chromatography and then recrystallization gives the title compound.

In a similar manner, the aldehydes or ketones of the present invention can be converted into acetals or ketals. can be converted.

2.4.4-Trimethyl-6-bromo-2-hydroxy-thiochroman (compound Mutual”l 62 mf (186 mmol) of 3M methylmagnesium bromide in ether and and cerium chloride in 160 ml of THF (incubated for 4 days in a high vacuum line at 135°C). A solution of 68 g (182,5 mmol) of 4,4- Dimethyl-6-bromo-2-oxo-thiochroman 5 g (18.45 mmol) solution was added at -14°C. After stirring the mixture for 0.5 h, concentrated sulfuric acid IQmJ was poured into an ice/water mixture containing 300 mA'. Separate the phases and dissolve the aqueous phase in ether 1 Extracted at 00 mA'. Combine the organic phases, add 2 x 250 mA of water, saturated sodium chloride Washed with solution IX 100 mA and dried over magnesium sulfate. Remove the solvent under reduced pressure, The residue was subjected to Cla Soss chromatography (silica: 10% ethyl acetate/hexane). ) to give the title compound as a yellow oil.

PMR (CDC4): δ1.35 (3H, s), 1.47 (3H, s), 1.7 1 (3H.

S), 2.09-2.18 (AB double line), 2.42 (IH, s), 7.17- 7.24 (2H, m), 7.27 (IHSd, J=8.1Hz).

2.4.4-)dimethyl-6-bromo-4H-1-benzothiobilane (compound 5 2,4.4-1-dimethyl-6-bromo-2-hydroxythiochroman (compound 55) A mixture of 2.03 g (7.1 mmol) and 20% sulfuric acid 20@I was added to 4 The mixture was heated to reflux for an hour. The mixture was extracted with ether. The combined organic extracts were mixed with water 2X. After washing with 25 mA' and 25 ml of saturated sodium chloride solution, dried with sium.

The solvent was removed under reduced pressure and the residue was subjected to flash chromatography (silica:hexane). Purification to give the title compound as a colorless oil.

PMR (CD (δ3): δ1.34 (6H, s), 2.00 (3HSd, J = 1.4Hz), 5.45 (IH, J = 1.4Hz), 7.19-7.38 ( 3H, m).

2.4.4-Trimethyl-6-promothiochroman (compound 59) ethyl acetate 2.4.4-trimethyl-6-bromo-(4H)-1-benzothio in 5 ml A solution of pyran (compound 56) 50011G+ (1.9 mmol) was added to a solution of 10% ( treated with radium sulfide/carbon 500119 and then bar (P a rr) in a hydrogen atmosphere (30 psi) for 24 hours. mixture It was filtered through Celite and the solvent was removed under reduced pressure. Crash chromatography of the residue Purification by (silica; hexane) gave the title compound as a colorless oil.

PMR (CDCj!,): 61.21 (3H%s), 1.33 (3HSd, J = 6.6Hz), 1, 36 (3H, s), 1.64-1.89 (2H, m) , 3.37-3.50 (IH,, +m), 7, 10 (LH, dd, J = 8. 4Hz, 2.1Hz), 7.19 (IHSd, 8.4Hz), 7.20 (LH , d, 2.1 Hz).

2,4.4-1-dimethyl-6-trimethylsilyl-ethynyl-thiochroman ( Compound 60) Distilled trimethylamine 1*I! 2.4.4-1-dimethyl-6-promo in - A solution of thiochroman (compound 59) 20119 (74 mmol) was placed in a thick-walled tube. I put it in and degassed it. The mixture was then diluted with trimethylsilylacetate under an argon atmosphere. tyrene (0.53-1c3.72 mmol), and bis-triphenylphosphine Radium (II) chloride 52-9 (0,074 mmol) and iodide It was treated with a powder mixture with 28 u (0.15 mmol) of copper. argon atmosphere The tube was sealed under air. The mixture was heated at 55°C for 72 hours. Cool the mixture to room temperature The mixture was filtered through Celite, and the residue was washed with methylene chloride. The filtrate was concentrated under reduced pressure to obtain a residue. was purified by flash chromatography (silica:hexane) and labeled The compound was obtained as a yellow oil.

PMR (CDCA’a): δ0.24 (9HJs), 1.22 (3H,s), 1.33 (3H.

dSJ=6.6Hz), 1.37 (3H, s), 1.71 (IHSt, J-13 , 0Hz), 1°86 (IH, ddSJ-13, 0Hz, 3.0Hz), 3.3 8-3.50 (IH, m), 7°07 (IHSdd, J-8, 1Hz, 1.8H z), 7.18 (IHld, J = 1.8Hz), 7, 26 (IH, d, J = 8.1Hz).

2,4.4-trimethyl-6-nitinylthiochroman (compound 61) 2.4 ．． 4-) Dimethyl-6-trimethylsilyl-ethynyl-thiochroman (compound 6 0) KOH ethanol solution 114/ added. The reaction mixture was stirred at room temperature for 16 hours. Then, remove the ethanol under reduced pressure. and the residue was extracted with ether. Combine the ether extracts and add water and saturated sodium chloride. Washed with thorium solution and dried with magnesium sulfate. Remove the solvent under reduced pressure and remove the residue. Purification by bulk distillation gave the title compound as a colorless extract.

PMRCCDCIs): 61.21 (3H, s), 1.32 (3HSd%J= 6Hz), 1°40 (3H, s), 1.70 (LH, t, J-13,0Hz), 1.88 (IHSdd, J-13, 0Hz, 3.0Hz), 3.0 (IH, s), 3.39-3.51 (IH%m), 7.13 (IH, dd, J=9.1H z, 2.1Hz), 7.21 (IH, dSJ-2, 1Hz), 7°28 (IH, d, J-9,0Hz).

Ethyl 6-[(2,4,4-trimethyl-6-thiochromanyl)-ethynyl]ni Cotinate (compound 62) 2,4.4-trimethyl-6-nitinylthiochroman (compound 61) 55u (0°26 mmol) and ethyl 6-chloro-nicotinate (compound 29) 47 mg (0.26 mmol) in 2 wl of distilled triethylamine was added to the thick-walled I put it in a tube. Argon was passed through the mixture for 20 minutes under slight vacuum. then , the mixture was treated with bis-triphenylphosphinepalladium(n) chloride 18mp (0,051 mmol) and cupric iodide 9.7-9 (0,051 mmol) Processed with. The mixture was stirred at 55°C for 72 hours. Then cool the mixture to room temperature did. The reaction mixture was diluted with methylene chloride and treated with a small amount of silica. Then, The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica 32% ethyl acetate). ethyl acetate/hexane) followed by HPLC (4% ethyl acetate/hexane, Fatman ・Attach to Whatman partisil 10) and mark it The compound was obtained as a colorless oil.

PMR (CDCA’3): δ1.25 (3H, s), 1.35 (3HSd, J = 6.6Hz), 1.41 (3HSS), 1.42 (3H, tSJ = 7.0Hz ), 1.72 (IHSt, J = 15Hz), 1.89 (IH, dd, J = 1 5Hz, 4Hz), 3.40-3. ．． 51 (IHlm), 4.40-4.46 ( 2H, q, J=7.0Hz), 7.25(LH, dd, J=8.1Hz, 1. 8Hz), 7.33 (IH, s), 7.35 (LH, d, J=8.1Hz), 7.56 (LH, d, J = 8.4Hz), 8.28 (IHSdd, , J = 8.4 Hz, 2.1Hz), 9°19 (IH, d, J = 2.1Hz).

Following the above procedure, common changes in the field of synthetic organic chemistry in light of the disclosure of the present invention The following example compounds can be further synthesized by adding: 2,2.4.4-tet Lamethyl-6-acetyl-7-ethylchroman: 2,2.4.4-tetramethyl -6-acetyl-7-brobylchroman: 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- Hexyl chroman; 2,2-diethyl-4,4-dimethyl-6-acetyl-chroman 2,2-diethyl-4,4,7-trimethyl-6-acetyl-chroman; Ethyl 6-[(2-methyl-2-ethyl-4,4-dimethyl-chroman-6-y ) ethynyl] nicotinate: Ethyl 6-[(2,2,4,4-tetramethyl-7-ethylchroman-6-yl ) ethynyl] nicotinate: Ethyl 6-[(2,2,4,4-tetramethyl-7-propylchroman-6-y) ) ethynyl] nicotinate: Ethyl 6-[(2,2,4,4-tetramethyl-7-hexylchroman-6-y ) ethynyl] nicotinate: Ethyl[2-((2,2,4,4-tetramethylchroman-6-yl)ethynyl ) birigou-5-yl] acetate; Ethyl [2-((2,2,4,4,7-pentamethylchroman-6-yl)ethyl pyrigu 5-ylcoacetate: Ethyl [2-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) )ethynyl)pyrigu-5-yl]acetate: ethyl[2-((2,2,4, 4-Tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrigu 5- yl] acetate: ethyl 3-[2-((2,2,4,4-tetramethylchroma) (2-yl)ethynyl)pyrigu-5-ylcopropionate: Ethyl 3-[2-((2,2,4,4,7-pentamethylchroman-6-yl) ethynyl)pyrigu-5-yl]propionate: ethyl 3-[2-((2,2, 4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl) birigou 5 -yl]propionate; ethyl 3-[2-((2,2,4,4-tetramethyl -7-hexylchroman-6-yl)ethynyl)pyrigu-5-yl]propione ethyl 5-[2-((2,2,4,4-tetramethylchroman-6-yl ) ethynyl) birigou 5-ylcopentanoate: Ethyl 5-[2-((2,2,4,4,7-pentamethylchroman-6-yl) ethynyl)pyrigu-5-ylcobentanoate: ethyl 5-[2-((2,2, 4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrigu 5 -yl]pentanoate: ethyl 5-[2-((2,2,4,4-tetramethyl chroman-6-yl)ethynyl)pyrigu-5-ylcopentanoate.

Ethyl 5-[2-((2,2,4,4-tetramethylchroman-6-yl)ethyl nyl)furer-2-yl]acetate; Ethyl [5-((2,2,3,3,7-pentamethylchroman-6-yl)ethyl Nyl) fuller 2-ylcoacetate: Ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) )ethynyl)furer-2-ylcoacetate; ethyl[5-((2,2,4,4 -tetramethyl-7-bexylchroman-6-yl)ethynyl)furer-2-yl ] Acetate; Ethyl 5-[5-((2,2,4,4-tetramethylchroman- 6-yl)ethynyl)furer-2-yl]pentanoate: Ethyl 5-[5-((2,2,4,4,7-pentamethylchroman-6-yl) ethynyl)furer-2-yl]pentanoate; ethynyl)furer-2-yl] Pentanoate; ethyl 5-[5-((2,2,4,4-tetramethyl-7- xylchroman-6-yl)ethynyl)furer-2-yl]pentanoate: ethyl [5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)thi 2-ylcoacetate; Ethyl [5-((2,2,4,4,7-pentamethylchroman-6-yl)ethyl nil) Chasyl 2-yl] acetate; Ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) ) ethynyl) checy 2-yl] acetate.

Ethyl [5-((2,2,4,4-tetramethyl-7-bequidylchroman-6- yl) ethynyl) Checy 2-yl coacetate; ,4,4-tetramethylchroman-6-yl)ethynyl)chesy-2-yl]pe ntanoate; Ethyl 5-[5-((2,2,4,4,7-pentamethylchroman-6-yl) ethynyl) Checy 2-ylcobentanoate: ethyl 5-[5-((2,2, 4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl) Checy 2 -ylcopentanoate: ethyl 5-[5-((2,2,4,4-tetramethyl -7-hexylchroman-6-yl)ethynyl)chasyl-2-yl]pentanoe ethyl [6-((2,2,4,4-tetramethylchroman-6-yl)ethyl) pyridazin-3-ylcoacetate; Ethyl [6-((2,2,4,4,7-pentamethylchroman-6-yl)ethyl pyridazin-3-yl]acetate: Ethyl [6-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) )ethynyl)pyridazin-3-yl]acetate: ethyl[6-((2,2, 4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyridazi -3-yl]acetate: Ethyl 5-[6-((2,2,4,4-tetramethylate) chroman-6-yl)ethynyl)pyridazin-3-ylcopentanoate: Chyl 5-[6-((2,2,4,4,7-pentamethylchroman-6-yl)ethyl) pyridazin-3-ylcobentanoate: ethyl 5-[6-((2,2 ,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyridazi ethyl 5-[6-((2,2,4,4-tetra Methyl-7-bexylchroman-6-yl)ethynyl)pyridazin-3-ylco Pentanoate; ethyl [5-((2,2,4,4-tetramethylchroman-6 -yl)ethynyl)pyrimidin-2-yl]acetate; Ethyl [5-((2,2,4,4,7-pentamethylchroman-6-yl)ethyl pyrimidin-2-ylcoacetate: Ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) ethynyl)pyrimidin-2-ylcoacetate.

Ethyl [5-((2,2,4,4-tetramethyl-7-bequidylchroman-6- yl)ethynyl)pyrimidin-2-ylcoacetate: ethyl 5-[5”((2 ,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrimidine-2- yl]pentanoate: Ethyl 5-[5-((2,2,4,4,7-pentamethylate) chroman-6-yl)ethynyl)pyrimidin-2-ylcobentanoate; Chyl 5-[4-((2,2,4,4-tetramethyl-7-ethylchroman-6- yl)ethynyl)pyrimidin-2-ylcopentanoate.

Ethyl 5-[5-((2,2,4,4-tetramethyl-7-hexylchroman- 6-yl)ethynyl)pyrimidin-2-yl]pentanoate: ethyl[5-( (2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrazine-2 - Ilcoacetate; Ethyl [5-((2,2,4,4,7-pentamethylchroman-6-inoethyl) pyrazin-2-yl]acetate: Ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-y) )ethynyl)pyrazin-2-yl]acetate: ethyl[5-((2,2,4 ,4-tetramethyl-7-bexylchroman-6-yl)ethynyl)pyrazine- 2-ylcoacetate: ethyl 5-[5-((2,2,4,4-tetramethylchloride) roman-6-yl)ethynyl)pyrazin-2-yl]pentanoate; ethyl 5 -[5-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl ) pyrazin-2-ylcopentanoate: ethyl 5-[5-((2,2,4,4 -tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrazine-2-y ]pentanoate: Ethyl 5-[5-((2,2,4,4-tetramethyl-7 -bexylchroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate ethyl 6-[(2,2-diethyl-4,4-dimethylchroman-6-yl) ethynyl]nicotinate; and Ethyl 6-[(2,2-diethyl-4,4,7-trimethylchroman-6-yl ) ethynyl] nicotinate, as well as the corresponding thiochroman compounds.

Prescription example for local administration.

The compounds of the invention may preferably be administered topically using a variety of formulations. Use the following prescription. Can be used: Retinoid (active ingredient) 0.1 BHT　O,1 Alcohol USP 58.0 Polyethylene glycol 40ONF 41.8 gel Retinoid (active ingredient) 0. I BHT　O,1 Alcohol USP 97.8 Hydroxypropylcellulose 2.0 International Survey Report memewlal AeeklJm#-Light/US911069■PCT/υS 91106900 Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number C07D409106 213 8829-4C2a 7 8829-4C 2398829-4C 2418829-4C 3078829-4C 3118829-4C 3338829-4C 4131062638829-4C 3118829-4C 4171062779051-4C 3119051-4C // A61K 31/35 ABL 9360-4C31/38 ADD 9 360-4C 31/42 9360-4C 31/425 9360-4C 31/44 ADA 9360-4C 31/495 9360-4C 311509360-4C 3115059360-4C I (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, NL, SE), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN , TD, TG), AU, BB, BG, BR, CA, FI, HU , JP, KP, KR.

LK, MC, MG, MW, No, PL, RO, SD, S

Claims (33)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [wherein, X is S or O; R1, R2 and R3 are hydrogen or lower alkyl; R4 and R5 are hydrogen or lower alkyl, but (i) R4 and R5 are both hydrogen at the same time. (ii) R4 and R5 are not the same group; n is an integer from 0 to 5; And; A is pyridinyl, chenyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl , thiazolyl or oxazolyl; B is hydrogen; -COOH, or a pharmaceutically acceptable salt, ester or amide thereof -CH 2OH, or its ether or ester derivative, -CHO, or its ester derivative Setal derivatives, or -COR'' (R'' is alkyl having 1 to 5 carbon atoms, (roalkyl or alkenyl group), or its ketal derivative. ] The compound shown in 2. 2. A compound according to claim 1, wherein X is S. 3. 3. A is pyridyl or chenyl, and n is 0, 1 or 2. Compounds listed. 4. 4. The compound according to claim 3, wherein n is 0. 5. B is -COOH or a pharmaceutically acceptable salt, ester or amide thereof 4. The compound according to claim 3. 6. 4. A compound according to claim 3, wherein R3 is hydrogen or methyl. 7. 3. A compound according to claim 2, wherein R4 is hydrogen. 8. 2. A compound according to claim 1, wherein X is O. 9. 9. A is pyridyl or chenyl, and n is 0, 1 or 2. Compounds listed. 10. 10. The compound according to claim 9, wherein n is 0. 11. B is -COOH or a pharmaceutically acceptable salt, ester or amide thereof; 10. The compound according to claim 9, which is 12. 10. The compound according to claim 9, wherein R3 is hydrogen or methyl. 13. 10. The compound according to claim 9, wherein R4 is hydrogen. 14. Incorporated and mixed into a pharmaceutical composition containing pharmaceutically acceptable excipients One or more compounds according to claim 1. 15. 15. A pharmaceutical composition according to claim 14, useful for the treatment of skin diseases in mammals. 2. One or more compounds of claim 1 incorporated and mixed into a composition. 16. R4 is lower alkyl, R5 is also lower alkyl, but R4 and R5 are different. 3. The compound according to claim 2, which is a group. 17. R4 is lower alkyl, R5 is also lower alkyl, but R4 and R5 are different. 9. The compound according to claim 8, which is a group. 18. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [wherein R1, R2 and R3 are hydrogen or lower alkyl; R4 and R 5 is hydrogen or lower alkyl, but (i) R4 and R5 are both hydrogen at the same time (ii) R4 and R5 are not the same group: n is 0 to is an integer of 5; B is -COOH, or a pharmaceutically acceptable salt, ester or amide thereof; -CH2OH, or its ether or ester derivative, -CHO, or its acetal derivative, or -COR'' (R'' is alkyl having 1 to 5 carbon atoms) , cycloalkyl or alkenyl group), or a ketal derivative thereof. ] The compound shown in 19. 19. The compound according to claim 18, wherein n is 0. 20. B is -COOH or a pharmaceutically acceptable salt or ester derivative thereof 20. The compound according to claim 19. 21. 21. R1 and R2 are methyl, R4 is hydrogen, and R5 is methyl. Compound. 22. 22. The compound according to claim 21, wherein R3 is H or CH3. 23. 22. A compound according to claim 21, wherein B is COOC2H5. 24. 24. The compound according to claim 23, wherein R3 is H, or a pharmaceutically acceptable salt thereof. . 25. Formula (i): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X is S or O; R1, R2 and R3 are hydrogen or lower alkyl; R4 is lower alkyl can be: n is an integer from 0 to 5; A is pyridinyl, chenyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl , thiazolyl or oxazolyl; B is hydrogen; -COOH, or a pharmaceutically acceptable salt, ester or amide thereof, -C H2OH, or its ether or ester derivative, -CHO, or its Acetal derivative or -COR'' (R'' is alkyl having 1 to 5 carbon atoms, (roalkyl or alkenyl group), or its ketal derivative. ] A method for producing a compound represented by formula (ii), which comprises the following steps: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1, R2 and R3 are If X is S, Y is halogen, and if X is O, Y is hydrogen. Ru. ] A compound represented by, Grignard reagent R4-Mg-X' (X' is halogen) and is reacted to form formula (ii): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R1, R2, R3, R4 X and Y have the same meanings as above. ] Restrictions on compounds indicated by: The compound of formula (iii) can be expressed as formula (iv): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I V) [wherein R1, R2, R3, R4, X and Y have the same meanings as above. ]in Converting to the indicated compound; By saturating the compound of formula (iv), formula (v): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V) [wherein R1, R2, R3, R4, X and Y have the same meanings as above. ] Obtain the compound shown by: The compound of formula (v) is converted to the compound of formula (i), and this conversion is performed by converting the compound of formula (vi): ▲ number There are formulas, chemical formulas, tables, etc. ▼ (VI) [In the formula, R1, R2, R3, R4 and X has the same meaning as above. ] and the compound represented by formula (vii): X'-A-(CH2)n-B(VII) [wherein, X' is a halogen, A, B and n have the same meanings as above. ] By reacting with the compound shown in I will do it. 26. 26. The method of claim 25, wherein X is S. 27. 27. The method of claim 26, wherein R4 is CH3. 28. 28. The method of claim 27, wherein R1 and R2 are CH3. 29. 29. The method of claim 28, wherein R3 is H. 30. 26. The method of claim 25, wherein X is O. 31. Formula (i): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X is S or O; R1, R2 and R3 are each hydrogen or lower alkyl; R4 and R 5 is lower alkyl, but R4 and R5 are not the same group; n is 0 to is an integer of 5; A is pyridinyl, chenyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl , thiazolyl or oxazolyl; B is hydrogen; -COOH, or a pharmaceutically acceptable salt, ester or amide thereof, -C H2OH, or its ether or ester derivative, -CHO, or its Acetal derivative, or -COR'' (R'' is alkyl having 1 to 5 carbon atoms, chloroalkyl or alkenyl group), or its ketal derivative. ] A method for producing a compound represented by formula (ii), which comprises the following steps: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1, R2 and R3 are If X is S, Y is halogen, and if X is O, Y is hydrogen. Ru. ] and the Grignard reagent R4-Mg-X' (R4 has the same meaning as above). , X' is a halogen) to form the formula (iii): ▼(III) [In the formula, R1, R2, R3, R4, X and Y are the same as above. It is righteousness. ] Obtain a compound represented by; Compounds of formula (iii) were treated with Grignard reagent R5-Mg-X' (R5 and X' is the same meaning as above) and the formula (iv): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R1, R2, R3, R4, R5, X and Y have the same meanings as above. ] Obtain the compound shown by: A compound of formula (iv) is converted into a compound of formula (v): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R1, R2, R3, R4, R 5, X and Y have the same meanings as above. ] Convert to a compound represented by; The compound of formula (v) is converted to the compound of formula (i), and this conversion is performed by converting the compound of formula (vi): ▲ number There are formulas, chemical formulas, tables, etc. ▼ (VI) [In the formula, R1, R2, R3, R4, R5 and X have the same meanings as above. ] and the compound represented by formula (vii): X'-A-(CH2)n-B(VII) [wherein, X' is a halogen, A, B and n have the same meanings as above. ] By reacting with the compound shown in I will do it. 32. 32. The method of claim 31, wherein X is S. 33. 32. The method of claim 31, wherein X is O.