JPS62252784A - Thianaphthene derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [Y is imidazolyl or pyridyl; Z is methylene, ethylene, trimethylene or vinylene which may have lower alkyl, etc., as a substituent group; W is direct bond or methylene, methine, ethylene or vinylene which may have lower alkyl, etc., as a substituent group; R1 and R2 are H, lower alkyl or (substituted) aryl; n is 1 or 2; dotted line is single or double bond; when W is methine, the dotted line is single bond], its salt and ester. EXAMPLE:Methyl 4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate of formula II. USE:Remedy for myocardial infarction, cerebrovascular thrombosis, ischemic peripheral angiosis, etc. PREPARATION:The compound of formula III [X is halogen, lower alkane- sulfonyloxy, etc.; Z1 is (substituted) methylene, etc.] is made to react with the compound of formula Y1H (Y1 is 1-imidazolyl) and, if necessary, the product is hydrolyzed to obtain the objective compound.

Description

[Detailed description of the invention]

Industrial Field of Application and Purpose of the Invention The present invention provides a method for inhibiting platelet aggregation and thromboxane A.
2 (hereinafter abbreviated as TXA2) has biosynthetic properties and harmful effects,
The present invention relates to a novel thianaphthene derivative that is useful as a medicine for the prevention and treatment of circulatory disorders such as thrombosis, stroke, myocardial infarction, and angina pectoris, and a method for producing the same. Constitution of the Invention The thianaphthene derivative of the present invention is a compound represented by the general formula. In the above formula, Y represents an imidazolyl group or a pyridyl group, and each Z optionally has a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted Ryl group, or a heterocyclic group as a substituent. Good methylene group, ethylene group,
Represents a trimethylene group or a vinylene group, W is a direct bond, a methylene group, a methine (=CH-) group, an ethylene group, each of which may optionally have a lower alkyl group or a substituted or unsubstituted aryl group. or a vinylene group, R1 and town are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted Ryl group, n represents 1 or 2, and the dotted line portion is a single bond or a double bond. shows. However, when W is a methine group,
Dotted lines indicate single bonds. In the general formula (11), Y preferably represents a 1-imidazolyl group or a 3-pyridyl group, and each Z optionally represents, for example, methyl, ethyl, n-propyl, isopropyl, n
- Straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as butyl, indutyl, 5ec-butyl, tert-butyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl having 3 to 4 carbon atoms A cycloalkyl group having 6 atoms, an aryl group such as phenyl, 1-s7tyl, 2-naphthyl, which may have a substituent as described below in the aromatic ring or heterocycle, or furyl, chenyl, imidazolyl, Thiazolyl, oxasilyl, inoxasilyl, pyridyl,
Methylene group, ethylene group which may have a monocyclic or bicyclic heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms, such as quinolyl, isoquinolyl, and indolyl, as a substituent. , trimethylene group or vinylene group, and the substituents on the aromatic ring or heterocycle are linear or branched chains having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and impropyl. alkyl groups such as methoxy, ethoxy, n-
Straight-chain or branched alkoxy groups having 1 to 3 carbon atoms such as propoxy and impropoxy, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, n-butyryloxy, imbutyryloxy, For example, benzo, yloxy, o+, m+,
p-) luoyloxy, o-, m+. p-7 ninyloxy, o +, m+, p −
An acylamoxy group such as an aromatic acyloxy group such as chlorobenzoyloxy, a lower aliphatic acylamino group such as acetylamino, globionylamino, n-butyrylamino, imbutyrylamino or e.g. benzoylamino, 0-lm -, p-) luoylamino, o
Acylamino groups such as aromatic acylamino groups such as aromatic acylamino groups such as +, m+, p-anisoylamino, o+, m+, p-chlorobenzoylamino, trifluoromethyl groups or e.g. fluorine, chlorine, bromine, etc. These substituents may be the same or in combination and may be substituted with 1 to 3 halogen atoms. W is a methylene group, methine (=CH
-) group, ethylene group or vinylene group, R1 and R2 are the same or different and represent a hydrogen button, an alkyl group having 1 to 4 carbon atoms or an aryl group having the same meaning as the group for Z described above, and n represents 1 or 2, and the dotted line portion represents an AAA bond or an a double bond. Specific examples of the thianaphthene derivative having the general formula (1) obtained by the present invention include, for example, the compounds listed in Table 1 and Section 2 below. Table 2 The novel compound (1) according to the present invention can be synthesized by the method shown below. Production method +11 (In the formula, R1, a2. W, n and the dotted line represent the same meanings as described above, Y represents a 1-imidazolyl group, and Z represents the same meaning as the corresponding substituent of Z. Optionally, as a substituent, a lower alkyl group, a cycloalkyl group,
It represents a methylene group, an ethylene group, or a trimethylene group which may have a substituted or unsubstituted Ryl group or a heterocyclic group. ) The thianaphthene derivative having
The general formula
. Subatomic halogen atoms, lower atom atoms such as methanesulfonylonoxy, ethanesulfonyloxy, etc.
Perkannulfonyloxy group: mabenzenesul
Carbohydroxy, p-)luninsulfonyloxy
Indicates an arylsulfonyloxy group such as a,
to λ is a hydrogen atom, methyl, ethyl, n-7
Oobiru, isopropyl, n-butyl, inbutyl,
Indicates a carboxyl protecting group such as tert-butyl. )
Compounds and formulas with subordinate
Engineering Y, H (31 salt (in the formula, Y represents the same meaning as above)
It can be obtained by reacting a compound containing a compound or its salt with an alkali metal such as lithium, sodium, or potassium, and hydrolyzing the resulting compound as necessary. In carrying out this method, the solvents used are tyrene coolide, chloroform, and carbon tetrachloride halogenated hydrocarbons; alcoholic compounds such as methanol, nital, and t-butanol; aromatic hydrogens such as toluene, toluene, and xylene; Acetonitrile; dimethylformamide, etc. are used. The reaction temperature is 10"C or around the boiling point of the solvent used. The reaction time varies depending on the temperature, etc.
Usually between 1 and 20. The optional hydrolysis step is carried out in a conventional manner. The hydrolysis reaction is carried out by bringing the ster compound obtained by the above reaction into contact with a hydrolyzing agent, ie, a group. The acids or bases used are those used in ordinary hydrolysis reactions without particular limitation, but include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid;
Suitable reagents include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The reaction is usually carried out in the presence of a solvent. Solvents used include alcohols such as methanol and ethanol,
A mixed solvent of these alcohols and water is suitable. There is no particular limitation on the reaction temperature, but it is usually carried out at room temperature to about 110°C. The reaction time varies mainly depending on the reaction temperature, the hydrolysis reagent used, etc., but is approximately 10 minutes to 6 hours. After the reaction is completed, the reaction mixture is treated in a conventional manner to obtain a compound having the general formula (1a). If further necessary,
It can be purified by column chromatography, recrystallization or distillation. In addition, a compound having the general formula (wherein R1,11L2. W, Y, z, and n represent the same meanings as described above) has a structure in which the dotted line portion on the structural formula represents a double bond. It can also be obtained by reduction reaction of compound (1a) or ester of (1a). The reduction reaction is carried out in the presence of a catalyst that does not participate in the reaction (for example, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, and tetrahedron). After reduction, the reaction mixture is treated according to a conventional method, and when an ester is used, the target compound (1b
) can be obtained. Production method (2) A thianaphthene derivative having the general formula (1a) 'e is a compound having the general formula (wherein, R1, R2, Zl, W, 'n and ``individual'' have the same meanings as above) and Y -3-Y. +1 (N represented by 41 (in the formula, Yl represents the same meaning as above),
It is obtained by reacting N'-thionyldiimidazole and hydrolyzing the resulting compound as required. The reaction of compounds (3) and (4) is carried out using methylene chloride, halogenated hydrocarbons such as roform, ether, tetrahydrofuran, dioxane ethers, pendane, toluene, ≧furan, etc. as a solvent. Aromatic hydrocarbons* such as carbon dioxide and carbon dioxide are used. Although this reaction can be carried out in the presence of a base such as 4-dimethylaminopyridine, the reaction temperature is from 0°C to around the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, etc., but usually
The duration ranges from 1 minute to 12 hours. After the reaction is complete, it is poured into water, treated by conventional methods, and purified by column chromatography, recrystallization, or distillation, if necessary. The hydrolysis reaction, which is carried out as necessary, is carried out according to a conventional method. That is, the reaction can be carried out in exactly the same manner as the reaction using production method (1) at ℃. Production method (3) (In the formula, J + R2HZ HW and n have the same meanings as described above, Yl represents pyridyl.) n and human have the same meanings as described above, R5 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an atomyl group or a heterocyclic group which may have a substituent, and m is 0. (indicates an integer from 2 to 2) and a compound having the general formula % (61 (wherein, Yl has the same meaning as described above)), resulting in a general formula % formula % It can be obtained by reducing or dehydrating a compound that contains a compound (n represents the same meaning as described above), and then hydrolyzing the compound as necessary. The reaction between compounds (51 and (6)) uses ethers such as ether and tetrahydrofuran as a solvent.The reaction temperature ranges from 13"C to 30"C1, and the reaction time ranges from 30 minutes to 5
It's time. After the reaction is complete, add an aqueous salt solution,
Treat by conventional methods and purify by column chromatography, recrystallization, or distillation if necessary. The reduction reaction of compound (7) can be carried out using organic solvents that do not participate in the reaction (for example, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol), E gold, etc. What! In the presence of 5 conspiracies, with contact reduction sea I,, after the completion of anti-2, anti; A target compound (1C) exhibiting a methylene group, an ethylene group, or a trimethylene group which may have a switching valve can be added. The dehydration reaction of compound (7) (in the formula, m represents 1) is as follows:
A catalytic amount of para-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid in an organic solvent that does not participate in the reaction (e.g., octa-aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as dioxane and tetrahydroctane). , by adding a mineral acid such as sulfuric acid, heating azeotropically, and optionally hydrolyzing as described above, the desired compound (1c ) can be obtained. After the completion of the reaction, the reaction mixture is treated according to a conventional method, and if necessary, subjected to column chromatography or recrystallization. represents the same meaning as above, and Z2 represents a vinylene group which may have a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or a heterocyclic group as a substituent). A derivative is a compound having the general formula (wherein, R1, R2, R,, W, A and n represent the same meanings as described above, and 2' represents 1) and (wherein, Yl is Synonymous with the above-mentioned comparison f2r: Represents the compound "9J".
Reaction 1 of C51 and (4): It is completely the same as the production method (2), and can be obtained by reaction treatment under the same conditions. To the manufacturing method'5) (In the formula, E(1, R2, Y, , W) represents the same meaning as described above, and z3 each optionally represents a lower alkyl group or a cycloalkyl group as a direct association. , a substituted or unsubstituted aryl group or an ethylene group, and a trimethylene group 12 represents a vinylene group. A, Y, and work n represent the same meanings as mentioned above, and p indicates two values for 11. ,, ; , odor purple, iodine (indicates a halogen atom)) can be obtained by reacting with a desired compound (in the formula, B, *
Compound (8) can be obtained by reducing or dehydrating a compound having R21R4, yll w, " + p and n have the same meanings as described above, and then subjecting the compound to water decomposition at the cutting edge as necessary. Compound (8) In the reaction of organic lithium compound (91), ethers such as ether and tetrahydrofuran are used as a t-solvent.The reaction temperature is -73°C to 30°C, and the reaction time is 30 minutes to 5 hours.After the reaction is completed, an aqueous ammonium chloride solution is used. is added and treated according to the conventional method: 'C, and if necessary, column coumadography, recrystallization, or distillation;
Ethers such as ether and tetrahydrofuran are used as the solvent, the reaction temperature is from 0° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 10 hours. After the reaction is completed (8
) and (9). In addition, reduction of compound (8) with a Zennoh hydride compound such as sodium borohydride or sodium cyanoborohydride can be carried out using ether, ethers such as tetrahydrofuran, or alcohols such as methanol as a solvent, and the reaction temperature is 0°C. It is carried out at the boiling point of the solvent used. Reaction time is 30 minutes to 5 hours. After the reaction is completed, it is treated by the conventional method (C) and purified by column chromatography, recrystallization, or distillation, if necessary. The reduction reaction of compound +111 is an organic solvent f that does not participate in the reaction.
j (%j: = ether, tetrahydrofuran two-ethers, benzene, toluene: aromatic hydrogens) l:i:, add sodium hydride and stir for 30 minutes to 2 hours, Reacts with carbon disulfide and methyl iodide. The reaction time is 10 minutes to 1 hour, and the reaction temperature is 0°C to the boiling point of the solvent used. Thus obtained (wherein R1+ R21a,, y4. AI 'j'
;'T; and n represent the same meanings as described above. ) with tributyltin hydride (n-Bu3Sr
, H) or by dehydration and, if necessary, hydrolysis. The radical reduction reaction of compound α2 with tributyltin hydride is carried out using organic solvents that do not participate in the reaction (e.g., ether, tetrahydrone, benzene,
L 5 of toluene 71 ”l IJy. Roasted arsenic compounds or a mixture of these #X＞田、α、α′
- In the presence of azobisin butyronitrile (λIBN) 1
By heating under reflux for 0 to 30 hours, the target compound (1e) in which Z represents a methylene group, an ethylene group, or a trimethylene group which may have the above-mentioned substituents can be obtained. The dehydration reaction of compound a'a is an organic compound that does not participate in the reaction! A catalytic amount of para-toluenesulfonic acid or hydrochloric acid, hydrobromic acid, sulfuric acid, etc. By adding a mineral acid, heating azeotropically, and optionally hydrolyzing as described above, the target compound (1e) in which Z represents a vinylene group optionally having the above-mentioned substituents is obtained. be able to. After the reaction is completed, the reaction mixture is treated according to a conventional method, and if necessary, it can be further purified by column chromatography or dark crystallization. Fruits::, for example, can be grown according to the following formulas::!take-~ fI3 C141as
(1e(5a)
(3a) In the above formula, A' represents the protection of carboxyl group in the above-mentioned person, and 1-1R4 represents a lower alkyl group, a cycloalkyl group, or an aryl group;
R5 represents a hydrogen atom contained in the two moieties described above divided by a lower alkyl group, a cycloalkyl group, an aryl group, or an atom ring group, and X has the same meaning as described above. 11 + Bottom 0 This reaction route is a production method when Z is a methylene group which may have a substituent and W shows a direct bond, but in the presence of compound (hydrogenating 131) IJium The compound (I41) is obtained by reaction with a dialkyl carbonate, and then the compound 151 is obtained by reduction reaction. This is heated under reflux in benzene medium using p-1 toluenesulfonic acid as a catalyst to obtain a dehydrated compound (US). Compound (l [9 to 7 Fr1edel-Crafts)
The reaction yields the acyl compound (5a), which is reduced to give the alcohol compound (3a), which is then rogenated or sulfonylated according to a conventional method to obtain the compound (2a). Manufacturing method B (5a) b t1ε (3b) (2b) In the above formula, n,
,, A/ and X have the same meanings as described above. In this reaction route, Z has a substituent (・

[This is a production method when W is a direct bond and W is a good ethylene group,
Compound (5a) is subjected to a Wittig reaction to obtain a compound tin with an elongated carbon chain, which is hydrolyzed to form an aldehyde IN8, and then reduced to obtain an alcohol form (3b). This is then halogenated or sulfonylated to give compound (2b). Manufacturing method C +18 R9 In the above formula,
Yl, λ', X and p have the same meanings as described above. In this reaction route, compound αG is subjected to a 7 LiDel-Crafts reaction to obtain an acylated compound α9, which is then reacted with imidazole to form a ketone body (LLllf:%). According to C, 4.5°6.7-
In order to obtain the titrahydride athianaphthene compound, the ester compound 12Ill' was synthesized by the catalytic reduction of the compound u610 or the Clemmensen reduction of the compound I according to the following formula, and the ester compound 12Ill' was synthesized by the above-mentioned method in place of the compound sieve. That objective is achieved by using compound +9. Manufacturing method D ■
Eclipse? 11AJ2C15 (5b) C3C) C2C) In the above formula, R, 4, R5, A' and X have the same meanings as described above. In this reaction route, 2 is a methylene group which may have a substituent, and W is a methine group.
After hydrolysis and decarboxylation, the compound is esterified. Next, the compound is reduced to an oxy compound according to a conventional method, and after acetylation according to a conventional method, the obtained compound = ↓ is subjected to an elimination reaction to obtain methine compound 6, compound o6 Friederu-Crafts. subjected to reaction and obtained n
The obtained compound (5b) is reduced to give an alkyl compound (3C), and then the compound (5b) is sulfonylated to give compound (2C). According to the above production method, in order to obtain a compound in which the substituent iw is a methylene group, the following formula is used:
3 Compound (■) is synthesized by catalytic reduction of compound O, and compound (■) is synthesized by the above-mentioned method.
The objective is achieved by using the obtained compound ① instead of . The thianaphthene derivative having the general formula (1) synthesized by the above production method can be obtained as a free base, free acid, or a pharmacologically acceptable salt depending on the production method. Pharmacologically acceptable acid addition salts include salts of mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, tartaric acid, citric acid, apple a, milk s, maleic acid, methanesulfonic acid, etc. Including mechanical O salt, as carbon Bq (=, two alkaline metal works of sodium and calcium,
Alternatively, organic bases such as alkaline earth metal salts, aluminum salts, ammonium salts, triethylamine, dicyclohexylamine, benzylamine, morpholine, and piperidine, or salts of basic amino acids such as lysine and arginine can be used. In addition, the thianaphthene derivative (11) of the present invention can be made into an ester that is easily hydrolyzed in vivo according to a conventional method. In this case, the ester group may be methyl, ethyl, propyl, isopropyl, butyl, etc. Lower alkyl groups, aliphatic acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1-methoxycarbonyloxyethyl,
lower alkoxycarbonyloxy, alkyl group or (5-methyl-2-
Oxin-1,3-dioxolen-4-yl)methyl group, etc.) In addition, when the thianaphthene position 7 ten derivative of the general formula fil O is obtained as a mixture of optical isomers, each isomer #- can be obtained by optical resolution using a conventional method. Although all optical isomers and mixtures of optical isomers in the compound having the general formula (1) are represented by a single formula, the scope of the description of the present invention is not limited thereby. Effects of the Invention The thianaphthene derivative of the present invention having the general formula (11) has been shown to have excellent platelet aggregation inhibiting action and a
It has an inhibitory effect on mboxane λ2 bioassay. That is, the compound of the X invention is, for example, rabbit PILP.
The positive effect of platelet aggregation induced by collagen using (platelet-rich plasma) was 10096 at 1o-mo/zt! TXλ2 at a molar concentration of ((,10−!
While inhibiting biosynthesis by 50%, it also inhibits cyclooxygenase and p-stacycline sineptase! The effect is very weak. In addition, in an in vivo experimental system, the effect of preventing death of rabbits and mice by Arachidon Injection was extremely strong by oral administration of the compound of the present invention. Thianaphthene derivatives having 1+ are useful as therapeutic agents for diseases caused by TX2, such as inflammation, hypertension, thrombosis, cerebral hemorrhage, and asthma, and in particular for the treatment of thrombophilia in open-hole animals including humans. For example, the compounds of the invention are useful for the treatment and prevention of myocardial infarction cold, cerebrovascular hemopathy, and ischemic peripheral blood disease; for the treatment and prevention of post-surgical hemopathy. : It is also useful for promoting the patency of the canal after surgery. Although the types of symptoms to be treated are different, the usual dose of 1aO for humans is 5a to 1130G"9, and IEi2
It can be administered by dividing between three days a week. Although the compound of unexploded 4 bows can be administered as is,
It is preferable to provide it as an energized, pharmaceutical preparation. The preparations include oral administration forms such as tablets, capsules, powders, aliquots, and Schifnobu preparations, and parenteral administration forms such as intravenous, subcutaneous, and intravenous injections. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example-1 0.75y of dilate methyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate in methanol:
and tetrahydrochloride = 7 runs each after adding 4 g to 1 OA mixed solvent, 3
°C; chloride dihydride a-1-human; oxymethylthianaphthene-6-carboxylate 0.75 f
t%t:. On the other hand, 2.98 y of imidazole and 20 Iq of 4
-60 ml of dimethylaminopyridine +7)”X4
'C 0.73 thionyl chloride in solution in methylene
m/ml solution of methylene chloride in IQml was added dropwise at room temperature.
Stirred for Q minutes. In the suspension thus obtained,
Methyl 4,5-dihydre a obtained by the above reaction
-2-Hydroxymethylthianaphthene-6-carboxylate) 0.75f of chloride □----- Dorozzo was subjected to silica gel column coomagography (dissolved in ethyl acetate: ethanol: triethylamine: 50:1:1). 0.211 of the target compound was obtained as an oily substance. Maki magnetic well 1 spectrum (weight: c1 form, δ compensation,
In TMS, E 壬m); 3.8Q (-1, 3H9
Coo CH5) v 542 (!%v 2Hv
H2' 16
50α-', 1550α-1 Elemental analysis 1st shift; Calculation as C15HHN202S2k H2O! I
:C, 51,+19; H, 3,79; ei,
s, 33; S, 1048% Experiment 11: Ri + 52.11: ) I * 37! l
: N * 9,43 :S, 10.25% Sara
% (=/V) methanol water-acetone Yosu M island,
Anhydrous pale yellow needles (m, p, >300'C)
Elemental analysis for frogs; total as C15H11N202SNa ** + i; C, 5
5,31; H, 3,93; N, 9.92; S
, 11.36 Chi experiment Ikoi; C, 55, 53; H, 3, 96; N, 10
．． 08; S, 11.24 Example-3 Methyl 2-benzoyl-4,5-dihydrothianaphthene-6-carboxylate) Q, 40 g After reduction with sodium borohydride in the same manner as in Example-1, imidazole group was introduced and treated in the following manner. Obtained crude Taakimono 3it-silica gel sword lamuku = madography (dissolved in ethyl acetate =) 1'! - to obtain compound a, 21q, which has a large E.sub. Shimiki, ;sound spectrum (weight loculum, δ constant, T
MS internal group m); 3.79 (-1 ratio, 3H9co
o CR2) * 6.65 (-1 woman, 2H,) (
-2 and H-1') (phenyl)methyl]thianaphthene-6-carboxylic acid.
Sodium salt/trihydrate solution 1-3 Nistil compound Q, 21f reprecipitated from ethanol-ether to give the target compound 70
Color amorphous! I got it as a body. Red Tato absorption spectrum (Nujolmull):
1ta] -1,1463,, ff-1 Elemental fraction: C1gH=5N202SNa ・Calculation as 3H20 (I: C, 55,33; H, 5, 13; N, 6.
79; S, 7.77% Experimental value: c, 55.2
3; H, 4,85; N, 7.05; S, 7
．． 73? Example 5 - 1-oxoethyl]-4,5-dihydrothianaphthene 4.5-dihyde=thianaphthene-6-carboxylate) 15.0 da and aluminum chloride 2 (1,69 and bromo7tyl chloride 11 .3 at;?-sosonityl)-4,5-7 and thean-7-6-carboxylate were obtained. After dissolving the soaked =a= crystals in methanol 300□iZ and tetrahydrofuran 1501C: Togelahui (Sukyu Nichi, -2-5 Nor:
Elution with triethylamine:4G:1:1) gave 20.16% of the desired compound as an oily substance. Nuclear magnetic resonance spectrum (weight c20 form, δ厘, Tλ
! S internal standard) ; 3.85 (- double line, 3H9Co
o CH3), 5.20 (- double line, 21(
, >N-CH2-C0-). Reducing and treating with sodium borohydride in the same manner as in TL-NIKETO; The obtained unicoalcohol compound was dissolved and stirred at 3°C.
0.30g of sodium hydride was added at 50°C.
The mixture was stirred for 1 hour. After cooling to room temperature, carbon disulfide 1. ”
The product was subjected to silica gel column chromatography (eluted with vinegar, nityl:ethanol, and ditriethylamine = 8:1:1) to obtain 1.039 of the desired product, which was mixed with oily substance i. Nuclear magnetic resonance spectrum (deuterochloroform, δ<g,
Txs inside Tekote 5 flea 12.40 (- double line, 3H9SCH
5) t 3.79 (- double line, 3H, C00CH
,) Koman 71j-7. Xanthate ester obtained from Lupomosylate Example-6 1.
After dissolving OQ t in 15 ml of tetrahuman α-furan and 10 ml of toluene, 1.0 g of tributyltin hydride was added in the presence of a catalytic amount of α,α′-azobisinbutyronitrile.
The mixture was heated at reflux for one day and night under a stream of oxygen. After the reaction, the Sorimachi solution was reduced in diameter under reduced pressure, and the residue was dissolved in acetonitrile and washed with n-hexane. The acetonitrile layer was reduced under reduced pressure. Silica gel column with Jk diameter reduction remaining ball on the bottom;
Mudgraphy (bathing with ethyl acetate: ethanol: triethylamine: 30:1:1) with K, target object 0.5
1 page will be awarded the Oil Autumn Prize. Simi resonance spectrum (weight: =, Lum, δ(I, τ
VS Romi Jini) 3.15 (Mieki, 2H, H-2':<
2 L 3.30 (X collar, 3
H, C00CH5) to 4.19 (Mie temporary, 2H, H
-2"X 2 L 7.42 (- double line, IHX2
．． H-7, imidazole) Example 8゜゜Original example 0.451 of the ester obtained by T was hydrolyzed with sodium hydroxide in the same manner as in Example 2 to obtain 1 The body was reprecipitated from methanol-ether to obtain the desired product, 0.37 da, as a colorless paleomorphic hedron. Infrared image absorption spectrum (NujoJ mull):
1630c! 11-', 1550C! R-"Elemental analysis I C knee H93N202SN and O calculation °I:C,5
6,75; H, 4,42; N, 9.45; S
, 10.82 is also a trial compensation: C, 56, 511; H, 4, 7Q; N
, 9.44; S, 10.59% Example-9゜Lupoxylate Same as Example-1, except for methyl 2-olmyl-4,5,6,7-titrahydroCthianaphthene-6-
The desired amount of 0.20 da was obtained as an oily substance from 0.349 carboxylate.
; 3.77 (-heavy 4.3) 1゜Coo CH3
) v '20 (g 4v 2Ht
H2'
6f! was obtained by hydrolysis with sodium aqueous dispersion using the same method as Mt3-2! - was reprecipitated from Nit/'-ruether to obtain a desired power of 0.19F as a black amorphous solid. Red T-shaped absorption spectrum (knee, ;:t=・5;
:155Qcy-' Elemental analysis value':' 15::15J202S-: Calculation as a 'l:' H54,92: 5, 46.
09; Nico, 9.85; Mi, 11.28 Cicada *@, A --+ 5458', E
, 45. a7; 2: ,
9.91; Mi, 11.45% ・J,
! After bathing in acid 30 and ice vinegar 30, the mixture was heated under reflux for 3 hours. After the completion of the reaction, the reaction solution was dried to a concentrated leprosy under gas pressure.
v/-1) Ethanol water - crystalline, colorless needle-like crystals (2, ;,, 197-199 C> 2.55
gf:4. Absorption Spectrum (Ker dLs't) '1
720 Yen-1 Yuan f! , Analysis'1 Go13'':142;2F2s-=: Calculation as t゛I
;ko; 52.2a e nimi;
5.06, 2: : 9.311
. S; 1G, 73, :t; 11. sr% member @
IN: C: 52-15 g:':: 5.
09g! ”: 9.sl 13110.63,
C1; 11.77% Example-12 Limethyl 4.5.6.7-Tetrahydrothiana 7ten-6-carboxylate 0.80y, Example-5
In the same manner as above, 0.54 da of the target compound was obtained as an oily substance. Temporary magnetic resonance spectrum (weight ae form, δ value, T
MS internal standard); 3.74 (-double line, 3H1 million cases - 13° From 0.54N of the keto compound obtained in Example-12, the target compound 0.429 was obtained in the same manner as in Example-6. was obtained as an oily substance. Nuclear magnetic resonance spectrum (weight Cl roform, δ value, TM
S17] part standard); 2.38 (- double line, 3H9S
CH5) t 3.77 (-double line, 3H, C0
0CH3) Example-1jL. Tisanthate ester obtained by Kumanretsu-13 0
．． 41 g was radically reduced with tri7tyltin hydride in the same manner as in Example 7, and then treated in the same manner to obtain 0.2 ap of the product. 75 & gas resonance spectrum (deuterochloroform, δ value, TMS internal standard) 3.18 (triplet line, 2H,H-2'X2 L 3.79 (- doublet line,
31(,C00CH3). 4.20 (Triple line, 2H, H-2" After the reaction was completed, the reaction solution was dried under reduced pressure, and the obtained solid was recrystallized with ethanol-ether to form a year-colored amorphous solid Q. ,1
I got 9'f. Infrared absorption spectrum (Nujol mull):
? 720cW1-' Elemental analysis value Calculated value as C14H16N202S-HCJ: C,
5178; H, 5,48; N, 8.96; S
, 1G, 25; C1, 11, 33% Experiment (1[: C, 53, 72; H, 5, 73; N
, 9.01; S, 9.95; C1,11,
3042-formyl-45,6,7-titrahydro-6
-methoxycarbonyl methylidene thianaphthene 1.50
In the same manner as in Example 1, 0.39f of the target compound was obtained as an oily substance. Nuclear magnetic resonance spectrum (deuterochloroform, 1.Tλ at δ
! Based on S; 3.611 (- double line, 3H5C0
09), 5.20 (- double line, 2H,H-2'X2
C6,25(-double line, IH,H-6')t
6.73 (-Double line. 1■ -Rho 1) Example-17゜The ester body obtained from Example-16, 0.299, was dissolved in sodium aqueous dispersion by the same method as Example-2:'c ″
``C hydrolyzed, precipitated by re-precipitation from nitano-ether, and made into a giant white'': material o, 20 das in pale yellow hand shape!
I got it as a body. Atmospheric absorption spectrum (NujoJ mull):
1580CM-' Elemental analysis value Calculated value as C14H13N202SNa: C956
, 75; H, 4, 42: N, 9.45: S,
10.82% Experimental value: C, 57,03; H, 4,18; N,
9.40;S, 11.08% Example-18°tJ? 1 3-Akihibiridine 2.17gt ether 4Qytl
Danji to the solution! ! 12 mins of n- at -78″C under ambient air
7 tyllitihum (15% n-hexane solution) After stirring for 30 minutes, ether of methyl 6-(2-formyl-4,5-dihydrothianaphthene)carcamosylate and tetrahydrofuran mixed solvent (2 each
A solution of 0 gJ) was added dropwise. After heating to room temperature for about 1 hour, two treatments were carried out in the usual manner, and a silica gel column was added.
The mixture was subjected to thornfine filtration (eluted with ethyl acetate) to obtain the desired compound 1.61 f as an oily substance. 2. Magnetic resonance spectrum (deuterochloroform. δ value, TMS internal standard); 3. +10 (-double line, 3H1COOCH5), 5.94 (-double line, IH,H2' C6,65 (-double line, 11(, H
-3) Lupoxylate Example - 1 g of methyl 4,5-dihydro-2-C(hydroxy)(3-pyridyl)methyl]thianaphthene-6-tylupoxylate, 1,0 da of ethanol solvent A, 3 Purification was performed by 10♂-balachromatography (eluting with hexane:ethyl acetate = 1 = 2) in the absence of an IN-term of .48ml under a hydrogen stream to obtain 0.48ml of the desired product.
15 g were obtained as an oil. Nuclear magnetic resonance spectrum (weight oc form. δ value, TλIs internal standard); 3.71 (- double line,
3H1COOCH5), 4.08 (- double line,
2H, H2'X 2 ) *6.44 (- double line, I
H, H-3) 0.151 g of the Nistyl body obtained in Example 1 was processed and further recrystallized from ethanol-ether. ,, 2 pieces 5~
208°C). Elemental analysis value C45H,5N028- Calculated value as HCI: C,
511,15; H, 5,21; N, 4.5
2;S. 10.35; CJ, 11.4a % experimental value: C, 57,89; H, 5,45; N, 4.
50; S, 1G, 41; C1,11,5
5% ketone obtained in Example-5 1.02 V 9 Akira 8
%r-1 and O75ε were reduced and treated with hydrogen rt:sodium citric acid to obtain alcohol compound 0.875'. This alcoholic substance was dissolved in 100 ml of toluene, and subjected to p-tolunin; .5Bf
was obtained as an oil. Nuclear magnetic resonance spectrum (weight acx form, δ value,
TMS internal standard) 3.79 (- double line, 3H,C
o. CM, ), 6.5-7.3 (6H, olefin proton). 7.75 (1H, galefin proton) Example-21
0.38y of the ester obtained was dissolved in sodium hydroxide and water in the same manner as in Example 2, and one of the resulting esters was reprecipitated from nitano-ether.
0.291 of the target product was obtained as a colorless amorphous solid. Infrared absorption spectrum /l/ (NujoJ mull
) : lB55cm', 1560cIII-' Elemental analysis value Calculated value as C14H11N202SNa: C, 57
,14; H,3,77; N, 9.52; S,
10.119% Experiment'l: C, 56,89; H, 3,88; N
, 9.56; S, 11.21% 5.319 of hydrogenated sodium worm (Harimoto) was suspended in dimethylformamide of 100=7, and 20 f of 4
．． 5.6.7-Titrahydro-7-ketothianaphthene dimethylformamide solution in the chamber! '2 drops, 10
Stir for a minute. was obtained in the above reaction solution. This crude product was mixed with 10 (1g7 tetrahydrofuran and 100a+/
After dissolving in methanol and cooling to -15°C, 4.
I lost 98g of sodium borohydride in 1 hour. After completion of the anti-π treatment, the product was dissolved in 5QQtxl of benzene L, I) -) After adding 2.5 t of luninsulfenic acid, 1 water u a , the water produced azeotropically was dissolved for 30 minutes. Removal: Matography: With 'c' attached, the target compounds 2Q and 1 da were obtained as the first purchase by elution of Hecan-False Nithyl (1:1). Tatsumi Kiyoshi spectrum (weight ce: holm. δ value, TMS standard); 3. aO(- double line, 3
H2Cool: 'Town), 68A and 7.29'C each double line, cryptographic constant 5Hz, each IH, It-2 and H
-3), 7.54 (- double line, IH, H-7) Reference example -26 2g string 57 - replacement and salt Ihimechishinmi 00 pieces, after cooling the bath solution to -35°C, under nitrogen atmosphere , 60y of ethyl (3-+enyl)phthalate and the methylene 600-solution (1 bottle; : Methyl Methyl Nithyl bottled methylene 600ml 4-
A crude syrup containing [3-(2-formylnochenyl] phthalate was obtained.
- suspended in 18. ethyl alcohol under a nitrogen stream.
After adding 5- dropwise at room temperature, the reaction system was heated to 8fi℃&/ff
It was a long time ago. Toluene of crude syrup fried in the afternoon 25
0 ml b'El was added all at once to the reaction system. The crude syrup thus obtained was distilled under reduced pressure to obtain the target product 32.1101 Cb, p, 125-128°C/
2fflE, ;2 passed away. Nucleus @ Kiinari spectrum (] [Chloroform. 61 Direct, τ', iS Naija J); 1.31 (3l
Sacrificial, number of bond legs 7 Hz, -:0OCHz three-hole Es) e 4.24 (four X-rays,
＠＠Constant 7 Hz, -: CCH2 Gogos)
, 6. a9 o:hi7.29 (each double lung, number of combined legs 5
E:, F-22: and H-3 Reference Example -3゜ 50 ml of 10.3F aluminum chloride was suspended in methylene chloride and heated to -10'C under an atomic atmosphere.
At r, 5y methyl 4,5-dihydrothianaphthene-6-10,000 rupoxylate (30 ml) dissolved Zea! L
was forged. After 10 minutes, dichloromethylmethyl dichloride,
Silicate gel column; apply to MADROGRA ΣE (hexa/=ethyl acetate=2=1 and elute twice), and target object 8.21
f was obtained as an oil. Macroscopic resonance spectrum (weight - = 10, shim. δ value, TMS internal standard); 3.113 (-heavy line, 3H9COOCH5), 7.50 and 7.5
7 (each - double line, each IH,) i-3 and H-7),
9.86 (- double line. 1H, CI(O) Reference Example - Umbrella Same as Reference Example-3 (C11,7119 aluminum chloride, 1.17xt; D benyl chloride and 1.3O
Methyl 4,5-dihyde-thianaphthene-6-carbossylate of f: 1.65 Da of the desired product was obtained as a lump sum. g"E-weighted spectrum (weight!: IC form. δ direct, TMS internal standard); 3J1 (- heavy line,
3H9coo2) Reference Example-9 - Carbon catalyst 1.6f was shaken for 4 hours in an air stream. After completion of S, 1,3, 2 rings, 5, and IC silica gel column chromatography (hexane: ethyl acetate = 10:1): C was added, and 1.31 da of the target product was removed. Again as Jomonoga. Tawara miki resonance spectrum (1 = = nirum, δfI,
3.73 (-1i scale, 3H
9Coo CH4) * ε75 two and seven. OB (each two
-3) Thiophene derivative o, soy obtained from Reference Example-5
Therefore, the target object 0.34 was obtained using the same method as in Reference Example-Y.
g was obtained as an oil. Received magnetic resonance spectrum (weight T: 10 holm, δ lin, T
3.73 (- double line, 3H1
Coo CH Mi L r, t5 (-x Itukitsu, IH, H-3L9.83 (-Chugei, IH, C
1(O) Hajie] Sodium chloride 3.2Sl) Dimethyl?
Dissolve 957 da of 4,5,6,7-tetrahydro-1-ketothianaphthene 9,0 dimethy, -h, 2 niimide 3021 in a suspension in 30 m/m of lumamide,
I dripped Ni. After cooling the reaction solution to 5° C., 16 ml of dimethyl carbonate was added dropwise, and the mixture was stirred at room temperature for 1 hour. Thereafter, 6.6 ml of bromoacetic acid methyl ester and dimethylformamide (10 ml) were added dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction completed solution was poured into ice water, extracted with ethyl acetate, extracted with 1"?J hydrochloric acid? 2 ml of ice, each ZOOz(n) After decomposition, the reaction was heated under reflux for 3 hours.The reaction'q, Dry it thoroughly under pressure, and add the residue to 500 g of methanol and 2 mt of ethyl.
: 1 :C Niri Somi), 4.5.6.7
-Titrahydride=-7-methoxycarbonylmethylthi7+7 f710.13F was used again as a letter. After dissolving 10.13 da of the keto form obtained in step 2 in 200 g of methanol, it was acetylated with sodium borohydride and 20 g of acetic anhydride.
TMS internal standard); 3.72 (-fi line, 3
H9COOCH, )t 6.33 (IH, H-6
), T, 4Q (- double line, IH,) (
-3) t 9.111 (- double line, IHlCHO)

Claims (5)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Y represents an imidazolyl group or a pyridyl group,
Z represents a methylene group, ethylene group, trimethylene group, or vinylene group, each of which may optionally have a lower alkyl group, cycloalkyl group, substituted or unsubstituted aryl group, or heterocyclic group as a substituent, and W represents a direct a methylene group, each optionally carrying a lower alkyl group or a substituted or unsubstituted aryl group as a substituent;
It represents a methine (=CH-) group, an ethylene group, or a vinylene group, R_1 and R_2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aryl group, n represents 1 or 2, and the dotted line portion indicates a single or double bond. However, when W is a methine group, the dotted line portion represents a single bond. ] A thianaphthene derivative having the following, and its pharmacologically acceptable salts and esters. (2) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, X represents a halogen atom, a lower alkanesulfonyloxy group, or an arylsulfonyloxy group, and Z_
1 represents a methylene group, an ethylene group, or a trimethylene group, each of which may optionally have a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or a heterocyclic group as a substituent; W represents a direct bond; Methylene group, methine (=C
H-) group, ethylene group or vinylene group, R_1
and R_2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aryl group, and n
represents 1 or 2, A represents a hydrogen atom or a protecting group for a carboxyl group, and the dotted line portion represents a single bond or a double bond. However, when W is a methine group, the dotted line portion represents a single bond. ] A compound having the formula Y_1H [wherein Y_1 represents a 1-imidazolyl group]. [In the formula, Y_1, Z_1, W, R_1, R_2] and n
has the same meaning as above. ] A method for producing a thianaphthene derivative having the following, and a pharmacologically acceptable salt and ester thereof. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z_1 each optionally has a lower alkyl group, cycloalkyl group, substituted or unsubstituted aryl group, or heterocyclic group as a substituent. a methylene group, ethylene group or trimethylene group, W is a direct bond, each of which may optionally have a lower alkyl group or a substituted or unsubstituted aryl group as a substituent;
It represents a methine (=CH-) group, an ethylene group, or a vinylene group, R_1 and R_2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aryl group, n represents 1 or 2, and A represents It shows a protecting group for a hydrogen atom or a carboxyl group, and the dotted line part shows a single bond or a double bond. However, when W is a methine group,
Dotted lines indicate single bonds. ] A compound having the formula Y_1-SO-Y_1 [In the formula, Y_1 represents a 1-imidazolyl group. [In the formula, Y_1, Z_1, W, R_1, R_2] and n
has the same meaning as above. ] A method for producing a thianaphthene derivative having the following, and a pharmacologically acceptable salt and ester thereof. (4) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R_3 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or a heterocyclic group, and W represents a direct bond, Each represents a methylene group, a methine (=CH-) group, an ethylene group, or a vinylene group which may optionally have a lower alkyl group or a substituted or unsubstituted aryl group as a substituent, and R_1 and R_2
are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aryl group, m represents 0, 1 or 2, n represents 1 or 2, and A represents a hydrogen atom or a protecting group for a carboxyl group. The dotted line indicates a single bond or a double bond. However, when W is a methine group, the dotted line portion represents a single bond. ] A compound having the formula Y_2-Li [In the formula, Y_2 represents a pyridyl group. [In the formula, Y_2, R_3, W, R_1, R_2, m, n
and A have the same meanings as described above. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by subjecting a compound having the following to a reduction or dehydration reaction and then hydrolyzing it as necessary ▼ [In the formulas, each Z is an optional substituent. lower alkyl group,
Y_2, W
, R_1, R_2 and n have the same meanings as described above. ], and a method for producing a pharmacologically acceptable salt and ester thereof. (5) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. represents a methylene group, a methine (=CH-) group, an ethylene group or a vinylene group, which may be
R_1 and R_2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aryl group, n and p represent 1 or 2, A represents a hydrogen atom or a protecting group for a carboxyl group, and the dotted line portion is Indicates a single or double bond. However, when W is a methine group, the dotted line portion indicates a single bond.
represents a substituted or unsubstituted aryl group or heterocyclic group,
X' represents a halogen atom. ] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. obtained by reacting with a compound having
has the same meaning as defined above, and R4 represents a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or a heterocyclic group. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by subjecting a compound having the following to a reduction or dehydration reaction and then hydrolyzing it as necessary ▼ [In the formula, each Z_3 is an optional substituent. Y_1, R_1, R
_2, n and W have the same meanings as described above. ] A method for producing a thianaphthene derivative having the following, and a pharmacologically acceptable salt and ester thereof.