JPS62228061A - Substituted heterocyclic compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is acyl; R<2> is alkyl; Het is 5- or 6-membered heterocyclic group containing 1-3 N atoms and optionally one S or O atom; R<3> is carboxyl, amino, alkylamino, alkanoylamino, OH, alkoxy, SH, group of formula II (p is 1-5; R<4> is carboxyl, alkoxy, etc.), etc.; n is 0-3]. EXAMPLE:Ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazo-N-2- yl]thio]acetate. USE:SRS-A antagonistic agent. Useful for the prevention and remedy of allergic diseases, ischemic cardiopathy, inflammation, etc., caused by SRS-A. PREPARATION:The compound of formula I can be produced by reacting a substituted benzyl halide of formula III (X is halogen) with a mercaptosubstituted heterocyclic compound of formula IV (M is H or alkali metal).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is applicable to pharmaceuticals, especially SR8-A (Slow react
ingK' [wherein R1 is a lower acyl group; R2 is a lower alkyl group; a 5- or 6-membered heterocyclic group that may contain one sulfur atom or oxygen atom; R3 is a carboxy group; an amino group; a carboxy group a lower alkylamino group which may be substituted with; a lower alkanoylamino group which may be substituted with a carboxy group; a di-lower alkylamino group; a hydroxyl group; a lower alkoxy group which may be substituted with a carboxy group; a mercapto group; Lower alkylthio group optionally substituted with a carboxy group; formula -S -(CH2)p -C5
R' In both formulas, P is an integer from J to 5, and q is 0°1 or 2
, γ is an integer from 1 to 5.

R4 is a carboxyl group or a lower alkoxy group which may be substituted with a carboxyl group.

It means a lower alkyl group substituted with a carboxyl group and which may contain a sulfur atom or an oxygen atom in the carbon chain. ); n means 0.1.2 or 3, respectively; However, when R3 is a carboxyl group or a group substituted with a carboxyl group, the galboxy group may be in the form of an ester or a Taha salt. Also,
When n is 2 or 3, R3 can also be different groups. (Prior art) In allergic asthma and other atopic diseases in humans, or in anaphylactic shock in animals, nine different chemical mediators are released from the lungs and other tissues, and are released into the smooth muscles of bronchial muscles, pulmonary blood vessels, etc. It is thought to cause damage to living organisms by constricting blood vessels and restoring the permeability of skin blood vessels. Examples of such chemical mediators include histamine and 5R8-A. Although histamine plays an important role in anaphylactic shock in guinea pigs, it is a less important chemical mediator in human allergic asthma [Eiser
), Pharmacology and Therabeautics (Pharm.

Ther, ), 17.239-250 (1982)]
. On the other hand, there is a lot of evidence suggesting that 5R8-A is the most important chemical mediator in human allergic asthma [Brocklefurst].
Hurst), Journal Op Physiology (J, Physiol, ) +151, 416-435
(1960); Austen and Orange, American Rev.
Re5p.

Dis, ), 12, 423-436 (1975); Adams and Liechtenstein (L i
Journal of Immunology (J, Immunol, ), 122゜5
55-562 (1979)].

The development of drugs for preventing, eliminating, or alleviating the symptoms of allergic reactions has been aimed at inhibiting the production and release of such chemical mediators, or antagonizing their effects. Disodium cromoglycate (disodium cromoglycate) is a drug that suppresses the release of histamine.
Inm cromo-gl)rcate) is well known, and many antihistamines are commercially available as drugs that antagonize histamine. On the other hand, 5R8-A is a fast-acting and short-lasting chemical messenger, whereas histamine is a fast-acting and short-lasting chemical messenger.

It was known as a slow-acting and long-lasting chemical mediator, but it was recently revealed that it is a mixture of leukotrienes C4, D4, and E, whose structure was determined by Samuelsson. 5R8-A, or leukotriens, is a metabolite of polyunsaturated fatty acids (especially arachidonic acid) by glueboxygenase, and in addition to acting as a chemical mediator in the allergic reaction, it also has the effect of increasing mucus secretion, reducing ciliary movement, Coronary vasoconstrictor effect.

It has been revealed that it has effects such as reducing cardiac contractility. Therefore, it is desirable to develop a drug that suppresses the production and release of 5R8-A or antagonizes these effects.

The present inventors have been searching for drugs that suppress the production and release of 5R8-A or drugs that antagonize these effects.

As a result, it was discovered that the above compound (I) strongly antagonizes 5R3=-A, and the present invention was completed.

(Means for solving the problems) The chemical structure of the compound of the present invention has 1 to 3 nitrogen atoms.
and may further contain one sulfur atom or one oxygen atom. That is, the compound of the present invention represented by formula (I) (a) i (b+: (e)) is characterized in that the (C) moiety is the above-mentioned specific heterocyclic group, and that the specific heterocyclic group is the (b) moiety. It has chemical structural characteristics in that it is directly connected.

Various compounds have been known in relation to the compound of the present invention. For example, there is European Patent Publication No. 181779 filed by the present applicant, but the part corresponding to part (b) is different from -CH2-8- of the compound of the present invention! 1)-0-A
They differ in that -Y-. Part (a) and part (b) are directly connected in Japanese Patent Application Laid-Open No. 60-4894.
．． No. 4 is known. Although this patent also includes a compound directly connected to parts corresponding to parts (b) and (c) as a claim, all of the specifically produced compounds are parts (b) and (c). Between the moiety corresponding to the hunilene group (0) or alkylene group ((CH2)n
is intervening.

There is no direct connection. Furthermore, in this patent, if the moiety corresponding to the (C) moiety is a heterocyclic group, 5, that is, 9. At the time of filing this application, no specific compound in which the (b) moiety and the (c) moiety are directly connected is known. Furthermore, a compound in which the part (b) and the part corresponding to the (c) part are directly connected was known as a generic concept from the above patent, but the part corresponding to the (c) part is a 5-tetrazolyl group. It was limited to. Therefore, the compound of the present invention was not only unknown specifically, but also unknown as a general concept.

The meanings of the symbols of the compound of the present invention represented by formula (I) will be further explained.

"A 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms and optionally containing 1 sulfur atom or 1 oxygen atom" means a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms as heteroatoms. It is a 5- or 6-membered monocyclic heterocyclic group which contains at least one sulfur atom or one oxygen atom.

Typical examples of the heterocycles that make up these heterocyclic groups are pyrrole and imidazole.

triazole, oxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine,
They are pyrazine, pyrimidine, 1,3°5,-triazine, pyrrolidine, piperidine, and morpholine. These heterocycles have 1 group R3- on any carbon atom or nitrogen atom.
~3 can be replaced. When two or more R3s are substituted, these R3s can be different from each other. Next, the term "lower" refers to a straight or branched carbon chain having 1 to 8 carbon atoms.

Therefore, the "lower alkyl group" specifically includes, for example, a methyl group, an ethyl group, and a propyl group.

Impropyl group, butyl group, isobutyl group, see-
butyl group, tert-butyl group, pentyl group, isohentyl group, neopentyl group, tert-pentyl group,
1-methylbutyl group, 2-methylbutyl group, 1.2
-dimethylpropyl group, hexyl group.

Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group.

2.2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylphthyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1
, 2-trimethylpropyl group.

1.2.2-) Limethylpropyl group, 1-ethyl-1
Examples include -methylpropyl group, 1-ethyl-2-methylpropyl group, heptyl group, 1-methylhexyl group, 1-ethylpentyl group, 6-methylhexyl group, octyl group, and the like.

In addition, examples of the "lower acyl group" include formyl group, acetyl group, propionyl group, and butyryl group.

Isobutyryl group, valeryl group, invaleryl group.

Examples include pivaloyl group and hexanoyl group.

Furthermore, the term "lower alkyl which may be substituted with a carboxy group" or "lower alkanoyl which may be substituted with a carboxy group" is.

It is a lower alkyl group or a lower alkanoyl group that may have one carboxy group as a substituent on the alkyl group or the corresponding alkanoyl group listed in the above description of the lower alkyl group.

That is, "lower alkoxy group which may be substituted with a carboxy group" or "lower alkylthio group which may be substituted with a carboxy group" includes, for example, a methoxy group or a methylthio group, an ethoxy group or an ethylthio group, a propoxy group or Propylthio group, impropoxy group or isopropylthio group, n-butoxy group or n-butylthio group, carboxynemethoxy group or carboxymethylthio group (-8CH2COOH).

3-carboxypropoxy group (-QC) (2CH2C)
(,C0OH) or 3-carboxypropylthio group (
-5CH2CH, CI (2Coon).

Examples of "a lower alkylamino group substituted with a carboxy group" include, for example.

Methylamino group (-NHCH3), ethylamino group (-
raccoon CH2CH3), propylamino group (-NHCH2C
I(2CH,), carboxymethylamino group (-NHC
H2Coon) etc.

"Lower alkanoylamino group which may be substituted with a carboxyl group" is, for example, a formylamino group, an acetylamino group, a propionylamino group, an oxaloamino group (-NHCOCOOH), a carboxyacetylamine group (-NHCOCH2COOH), 3- Carboxypropionylamino group (-NHCOCH2CH,C0OH)
etc.

The "lower alkyl group substituted with a carboxy group and which may contain a sulfur atom or an oxygen atom in the carbon chain" as meant by R4 refers to a straight or branched carbon atom having 1 to 6 carbon atoms. It's a chain.

The carbon chain is substituted with one carboxy group, and the carbon chain further has one oxygen atom or sulfur atom at the end or in the middle. Typical groups included in this definition are as follows.

Carboxymethoxy group (-0CI (, Cool-I),
Carboxymethylthio group (-3CH2COOH),
, 1-carboxyeth (-CH, CH2C00H),
Carboxymethylthiomethyl group (-CH2SCH2Co
on), carboxymethoxymethyl group (-CH,0CR
2COOH), 3-carboquine propoxy group (-0C
H2CH, CH2C00H), 2-carboxypropoxy group (-0(CH2), C00H), 3-(carboxymethylthio)propyl group (-(CH2)38C)
I, C00H), 2-(2-carboxyethylthio)
Ethyl group (-(CH2)2 s (cut )t C0
OH).

3-(2-carboxyethylthio)propyl group ((CH
z)s S (Cut)z C00H).

These groups R4 can be substituted at any position on the phenyl ring.

Next, P and γ are integers of 1 to 5 as described above. Therefore, (CH2)p and <ch>γ are
They are a methylene group, an ethylene group, a propylene group, a tetramethylene group (butylene group), and a pentamethylene group, respectively.

(0)q Moreover, -8- is a thio group (-S-) depending on the number of q.

Y q-0), sulfinyl group (-8-, q=1), and the formula are as follows.

-3(CH2)25CI(2Coo)(, -S (CH
2) 35C) 12COOH.

The two compounds of the present invention have been explained above, and among these,
Compounds having a carboxy group as a substituent can form esters or salts. The compounds of the present invention also include their esters or salts. Examples of esters include lower alkyl esters such as methyl ester, ethyl ester, and furoyl ester, as well as phenyl lower alkyl esters which may be substituted with lower alkoxy groups such as benzyl ester and p-methoxybenzyl ester; .

Examples of salts include salts with inorganic bases such as sodium salts and potassium salts, as well as salts with organic bases such as ethylamine salts, propylamine salts, diethylamine salts, triethylamine salts, dimorpholine salts, and jetanolamine salts. .

The compounds of the present invention include optical isomers based on asymmetric carbon atoms and tautomers based on heterocycles, oxo groups, hydroxy groups, thioxo groups, and mercapto groups. The present invention includes separated versions of these isomers as well as mixtures of each isomer.

(Production method) The compound (I) of the present invention is produced, for example, by the method shown in the following reaction formula.

First manufacturing method Z (II) CIIT) Second manufacturing method Third manufacturing method Fourth manufacturing method [The symbols in the formula represent the following meanings.

Het, R', R2, R3, n: Same as above X:
Halogen atom M: hydrogen atom or alkali metal A: oxygen atom, sulfur atom or imino group (-NH-) B: lower alkyl group optionally substituted with a carboxy group.

Lower alkanoyl group optionally substituted with a carboxy group 9 -(CH2) p 6''' or (however, in formula 9, p
, q, γ and R4 are the same as above) Group Y: lower alkylene group, lower alkanoyl group, carbonyl group 9 Formula -(cH2)p()' or group represented by formula R5=carboxy group or substituted with carboxy group Optionally substituted lower alkyl group R6: ester residue (however, when substituted with a carboxy group, the carboxy group can also be an ester)] First production method The present compound (I) is: It is produced by reacting a substituted benzyl halide represented by the general formula ([) with a mercapto-substituted heterocyclic compound represented by the general formula C11) or an alkali metal substituted product thereof.

The reaction is carried out using approximately equal moles of Compound (II) and Compound (Hl) or slightly excess mole of one of them in dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propatool, acetone, methyl ethyl ketone, and tetrahydrofuran.

It is carried out in an organic solvent such as chloroform or dioxane.

When a mercapto-substituted heterocyclic compound is used as compound (III), the reaction is usually carried out in the presence of a base, and such a base is potassium carbonate.

Triton B, potassium hydroxide, sodium hydride, etc. are suitable. Further, in order to promote the 9 reaction, a catalytic amount of potassium iodide, tetra-n-butylammonium bromide, etc. may be added.

The reaction temperature is not particularly limited, but is usually set at room temperature or under heating.

Second Production Method To carry out this method, a compound (IV) of the present invention (I) in which R1 is a hydroxyl group, a mercapto group, or an amine group is used as a raw material, and is reacted with an alkyl halide or an acyl halide (V). This reaction can be carried out in substantially the same manner as the first production method.

3M Method To carry out this production method, compounds in which R3 is an amino group (V
I) to carboxylic acid (■)'-! or its reactive derivatives. The reactive derivatives of carboxylic acids used in this case include acid halides, acid azides, active esters, and acid anhydrides. Also.

When reacting the free carboxylic acid (■), it is advantageous to carry out the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide. Each reaction component is used in approximately equimolar amounts;
Excess amounts of one component (eg, the carboxylic acid component) may be used. When the carboxylic acid (■) is a dicarboxylic acid (for example, ciuric acid, malonic acid, etc.), one of the dicarboxylic acids used is one in which one carboxy group is protected in the form of an ester or the like. The reaction solvent used is one that is inert to this reaction, such as pyridine, tetrahydrofuran, and dioxane.

Fourth production method This production method deesterifies the compound (■) in which R3 is an esterified carboxy group among the nine compounds (I) of the present invention to obtain the target compound (Ic) having the corresponding free carboxy group. It is something.

In the deesterification reaction, carbonic acid) is used.

A method of hydrolysis in the presence of a base such as sodium hydroxide or trifluoroacetic acid, hydrochloric acid, etc. can be adopted.

The compounds of the present invention produced by these various methods are:
It is isolated and purified by applying chemical operations commonly used in this field, such as extraction, recrystallization, and column chromatography.

(Effects of the Invention) As mentioned above, the compound (I) of the present invention strongly antagonizes 5R8-A and is therefore effective against various allergic diseases caused by 5R8-A (e.g. bronchial asthma, allergic rhinitis, hives) and 5R8-A. -It is useful for the prevention and treatment of ischemic heart disease, inflammation, etc. caused by A.

In addition to 5R8-A antagonistic activity, one of the compounds of the present invention has
Also included are compounds that have 5R8-A production and release suppressing effects and bronchodilator effects. Furthermore, the compounds of the present invention are useful as anti-inflammatory agents and anti-ulcer agents.

(1) 5R8-A and LTD, a method for suppressing the constrictive effect of isolated ileum and isolated trachea in guinea pigs Two male Hartley guinea pigs weighing 500-700 g were killed by head contusion. Ileum and Con
Tracheal specimens prepared according to the method of Tantine (1965) were aerated with 95% CO2 + 5% CO37.
1 in Tyrode's solution (Magnus tank volume 10 m1) at °C.
It was suspended with a tension of g. The tissue was allowed to equilibrate for 60 minutes.

During this time, the Tyrode solution was replaced every 15 minutes, and the tension was adjusted to 1.0 g each time. 5t isometric contraction
It was recorded on a recti coder via a rain gauge transducer. ileal subm
Contractile responses to axial concentrations of 5R8-A (prepared from guinea pig lungs) and 10 MLTD4 of the trachea were measured in the absence of drug and subsequently in the presence of various concentrations of the test compound. Inquiry time for test compound is 2
It was set to 0 minutes.

Results: As shown in Table 1, many compounds of the present invention exhibited very strong anti-5R8-A effects in isolated ileum. Furthermore, Examples 2.32.33°34, 35.36.
Compounds 37, 43 and 44 strongly inhibited LTD-induced contraction in isolated guinea pig tracheas (Table 1).

Table 1 Anti-5R8-A and anti-LTD4 effects of representative compounds of the present invention in isolated guinea pig ileum and isolated trachea (2) Method for suppressing LTD4-induced vascular hyperpermeability in guinea pigs: 270-305 g body weight fasted for 16 hours Ha
rt] 1% Evans blue for ey male guinea pigs
1 ml of e solution was administered intravenously. After 2 minutes, administer 5 ng/0.1 LTD to 2 areas on the back where 9 hairs were shaved.
mg/5ite was administered. In addition, to examine non-specific stimulation to animals, we added 0.1 m of LTD4 solvent.
lml intramembrane administration.

Animals were sacrificed 30 minutes after LTD4 administration, and the dye that leaked into the LTD4 or vehicle administration site was collected using Harada.
(1971) and colorimetrically determined at 620 nm. Increased vascular permeability due to LTD is called LT
D, and the difference in the amount of dye leaked by the solvent. Test compounds were administered orally 30 minutes before LTD4 administration.

Results: The compounds of Examples 2, 34, and 37 dose-dependently suppressed the restoration of vascular permeability caused by LTD.

Its ED50 values were 11.3, 4.2 and 7.0 mg/kg p,o, respectively. These results indicate that the compounds of Examples 2.34 and 37 exhibit strong anti-leukotriene effects when administered orally.

(3) Acutely toxic male phylan in rats? - (Fisher) 344 rats (7 weeks old) were used. The compounds of Examples 2 and 37 showed no toxic effects at 1000 mg/kg p,o during the 14 day observation period.

The compound (I) of the present invention is the '! Pharmaceutical compositions mixed with pharmaceutically acceptable carriers, excipients, etc. [Example 2 tablets, capsules].

It can be safely administered orally or parenterally as powders, granules, pills, ointments, syrups, injections, inhalants, and halved doses. The dose depends on the subject, route of administration,
Although it varies depending on symptoms etc. 9 Normal adult daily allowance 90.1
-500 mg, or 1 to 200 mg, administered orally or parenterally in 2 to 3 divided doses a day.

EXAMPLES Below, the present invention will be described in detail with reference to Examples.

Example 1 0.42 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, ethyl [(5-medi.

Lucapto 1.3.4-thia≠azol-2-yl? .

thio]acetate 0.54g, anhydrous potassium carbonate 0.3
and 5 ml of methyl ethyl ketone, add catalytic amounts of potassium iodide and tetra-n-butylammonium bromide, and stir at 60° C. for 3 hours. The reaction solution was diluted with toluene and insoluble materials were filtered off. The P solution was washed with an aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (5:
Elute with a mixture of 1) and obtain oily ethyl [[5-[(4-
0.75 g of acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]acetate was obtained.

Nuclear magnetic resonance spectra (in CDCIs, TMS internal standard.

ppm): 1.18 (t, 3H), 1.28 (
t, 3H), 1.4-1.8 (2H), 2.60
(s, 3H), 2.6-2.8 (2H).

4.08 (s, 2H), 4.22 (q, 2H
), 4.54 (S.

2H), 6.90 (d, LH), 7.52 (d,
LH).

12.69 (s, LH).

Mass spectrum m/z: 426 (M+).

Example 2゜ Ethyl obtained in Example 1 [[5-[(4-acetyl-
3-Hydroxy-2-propylbenzyl)thio] -1
, 0.98 g of 3,4-thiadiazol-2-yl]thio]acetate was dissolved in 7.8 ml of 90% methanol by heating at 60°C, and then 6.1 g of IN aqueous sodium hydroxide solution was dissolved.
ml and stir at 60°C for 30 minutes.

An IN aqueous sodium hydroxide solution and ethyl acetate are added to the reaction mixture to separate the layers. The aqueous layer was acidified with IN hydrochloric acid.

Extracted with ethyl acetate. Add the extract to water and saturated saline.

After sequentially washing with water and drying with anhydrous magnesium sulfate.

The solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to give [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio] -1,3,
0.75 g of 4-thiadiazol-2-yl]thio]acetic acid
I got it. Melting point: 116-118℃ Elemental analysis value (Cl6H
18N204 As Ss) C (capital) H (capital) N (c) S (% theoretical value 48.22 4.55 7.03
24.14 Experimental value 48.11 4.56 6.96
24.31 Example 3゜4-acetyl-3-hydroxy-2-propylbenzyl chloride 0.30 g, ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyre)0 Using .42 g as raw material and following the same method as in Example 1, oily ethyl 4-[[5-[(4-
Acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]
0.59 g of butyrate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 0.99 (t, 3H), 1.36 (t,
3H), 1.4-1.8 (2H).

2.0-2.4 (2H), 2.4-2.8 (4H)
, 2.61 (s, 3H).

3.34 (t, 2H), 4.13 (q, 2H),
4.55 (s, 2H).

6.93 (d, IH), 7.54 (d, IH),
12.69 (s, LH) mass spectrum m/z
: 454 (M+) Example 4, n Ethyl obtained in Example 3 4-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio] -
Using 0.25 g of 1,3,4-thiadiazol-2-yl]thio]butyre as a starting material, it was treated in the same manner as in Example 2 to obtain 4-[[5-[(4-acetyl-3-hydroxy- 2-propylbenzyl)thio]-L3.4-
0.23 g of thiadiazol-2-yl]thibutyric acid was obtained.

Melting point 75-78℃ Elemental analysis value (C, 8H22N20.S3) C (%
) H(2))N(%)s(%) Theoretical value 50.68
5.20 6.57 22.55 Experimental value 50,55
5.32 6.56 22.36 Example 5゜4-7-1-3-hydroxy-2-propylbenzyl chloride 0.30 g, 2-amino-5-mercapto-1,3,4-thiadiazole 0. 22 g of anhydrous potassium carbonate and 3 ml of methyl ethyl ketone were added a catalytic amount of potassium iodide and tetra-n-bromide.
Add butylammonium and stir at 60°C for 2 hours. After adding ethyl acetate to the reaction solution and filtering off insoluble matter, F
The solution is washed with an aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 2-amino-5-[
(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole 0.4.4
I got g.

Melting point 143-147°C Nuclear magnetic resonance spectrum (DMS O-d6. TMS internal standard.

ppm): 0.92 (t, 3H), 1.3-1
．． 7 (21(), 2.3-2.8(2H).

2.62 (s, 3H), 4,32 (s, 2H),
6.88 (d, IH).

7.72 (d, IH), 12.7 (s, IH) mass spectrum m/z: 323 (M+) 31 Example 6° 2-Amino-5-[(4-acetyl) obtained in Example 5 −
3-Hydroxy-2-propylbenzyl)thio] -1
, 3,4-thiadiazole 0.14 g, mono p-methoxybenzyl malonate 0.15 g Woviridine 3 ml
dicyclohexylcarbodiimide in a solution of 0.
15 g and a catalytic amount of p-)luenesulfonic acid,
Stir at room temperature for 6 hours. During this time, 5 g of mono-p-methoxybenzyl malonate and dicyclohexylcarbodiimide was added over time. After the reaction was completed, ethyl acetate was added, and after separating the insoluble matter, the F solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed sequentially with IN hydrochloric acid, water, saturated deuterated water, and water, and dissolved in anhydrous sulfuric acid. Dry with magnesium. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, eluted with a mixture of chloroform and methanol (4:1), and further recrystallized from isopropyl alcohol.
p-methoxybenzyl 3-[[5-[(4-acetyl-3-hy)"fuxy-2-propylbenzyl)thio]-
1,3,4-thiadiazol-2-yl]amino]-3
-Oxopropione-1-0.04g was obtained.

Melting point 162-166°C Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 1.00 (t, 3H), 1.4-2.0
(2H), 2.58 (s, 3H).

2.6-2.9(2H), 3.71(s, 2I(),
3.77 (s, 3H).

4.46 (s, 2H), 5.14 (s, 2H), 6
．． 7-7.0 (3H).

7.2-7.4 (2H), 7.52 (d, LH),
12.3 (LH).

1, 2.7 (s, LH).

Example 7° Obtained in Example 6. p-Methoxybenzyl 3-[[5-
[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropione-) 0.27 g
was treated as the starting material in the same manner as in Example 2 to obtain f-[[
5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole-2-
0.16 g of yl]amino]-3-oxopropionic acid was obtained.

Melting point 184-187°C Nuclear magnetic resonance spectrum (in DMS O-d6, TMS internal standard.

ppm): 0.93 (t, 3H), 1.3-1.
7 (2H), 2.5-2.8 (2H).

2.63 (3,3H), 3.0-3.8 (2H),
3.53 (s, 2H).

4.54 (s, 2H), 6.96 (d, IH), 7
．． 74(d, IH).

12.73 (s, IH).

Example 8 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 2.5-dimethyl chloride)
-1,3,4-thiadiazole 0.24g, anhydrous dihydrium carbonate 0.20g and methyl ethyl ketone 4
ml of the mixture is added a catalytic amount of tetra-n-butylammonium bromide and stirred at 60°C for 1 hour. Add dilute hydrochloric acid to the reaction solution to make it neutral, and then extract with ethyl acetate. After drying the extract with anhydrous magnesium sulfate.

The solvent was distilled off. The residue was recrystallized from inglovir alcohol to give 2'-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1
, 0.20 g of 3,4-thiadiazole was obtained.

The crystals were subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (5:1) to obtain 0.03 g of the above product with even higher purity.

Melting point 133-135℃ Elemental analysis value (as CI4 HI6 N202 S3)
C (%) H) N (%) S (%) Theoretical value
49.39 4.74 8.23 28.25 Experimental value
49.41 4.60 8.17 28.19 Examples
9゜4-acetyl-3-hydroxy-2-propylbenzyl chloride 0.30 g, ethyl 5-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiocovalerate 0.39 g, anhydrous potassium carbonate 0 .2
Catalytic amounts of potassium iodide and tetra-n-butylammonium bromide are added to a mixture of 0 g and 4 ml of methyl ethyl ketone and stirred at 60° C. for 3 hours.

The reaction solution was diluted with ethyl acetate, and insoluble materials were filtered off.

The r solution was washed with an aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography.

Elute with a mixture of hexane-ethyl acetate (5:1).

Oily ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4
-thiadiazol-2-yl]thio]valerate 0.5
2 g was obtained.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 0.99 (t, 3H), 1.25 (
t, 3H), 1.4-1.7 (2H).

1.7-2.0 (4H), 2.34 (t, 2H),
2.61 (s, 3H).

2.5-2.8 (2H), 3.30 (t, 2H), 4
．． 12(q, 2H).

4.56 (s, 2H), 6.94 (d, IH), 7
．． 54(d, IH).

12.68 (s, IH).

Mass spectrum m/z: 468 (M+).

Example 10゜4-acetyl-3-hydroxy-2-propylbenzyl chloride 0.30 g, ethyl 6-[(5-mercap)-1,3,4-thiadiazol-2-yl)
Using 0.46 g of thio]hexanate as a raw material and following the same method as in Example 9, oily ethyl 6-[[5-[(
059 g of 4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,,3,4-thiadiazol-2-yl]thio]hexanate was obtained.

Nuclear magnetic resonance spectra (in CDCl3, TMS internal standard.

ppm) 20, 99 (t, 3H), 1.25 (t,
3H), 1.3-2.0 (8H).

2.30 (t, 2H), 2.62 (s, 3H), 2
．． 5-2.8 (2H).

3.28 (t, 2H), 4.12 (q, 2H), 4
．． 57 (s, 2H).

6.93 (d, LH), 7.54 (d, ], H),
12.68 (s, LH) mass spectrum m/z:
482 (M+).

Example 11 Ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1 obtained in Example 9
, 0.20 g of 3,4-thiadiazol-2-yl]thio]valerate was dissolved in 2 m of 90% methanol by heating at 60°C, and then 1.5 g of 1N aqueous sodium hydroxide solution was dissolved.
Add +++l and stir at 60°C for 30 minutes.

An IN aqueous sodium hydroxide solution and ethyl acetate are added to the reaction mixture to separate the layers. The aqueous layer was made acidic with 2N hydrochloric acid.

Extracted with ethyl acetate. Add the extract to water and saturated saline.

Washed sequentially with water, dried over anhydrous magnesium sulfate, and distilled off the solvent to obtain an oily 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-L3,4-thiadiazole-2. 018 g of -yl]thio]valeric acid was obtained.

Nuclear magnetic resonance spectrum (DMSO-d, medium, TMS internal standard.

ppm): 1.00 (t, 3H), 1.3-1
．． 9 (6H), 2.24 (t, 2H).

2.63 (s, 3H), 2.4-2.8 (2H),
3.27 (t, 2H).

4.58 (s, 2H), 7.00 (d, LH),
7.76 (d, IH).

12.05(s, II(), 12.73(s, IH)
Mass spectrum m/z: 4.40 (M) Example
12゜Ethyl 6-[[5-[(4,-acetyl-3-hydroxy-2-propylbenzyl)thio] obtained in Example 10
Example 11.
The solid obtained by the same treatment as above was recrystallized from isopropyl alcohol to give 6-[[5-[(4-acetyl-3
-Hydroxy-2-propylbenzyl)thioko 1.3
．． 4-thiadiazol-2-yl]thio]hexanoic acid 0
．． 02 g was obtained.

Melting point 67-74℃ Elemental analysis value (as C20H26N204S3) C (%
) H) N) S (%) Theoretical value 52,84
5.76 6.16 2], 16 experimental value 52,5
4 5.59 6.14. 2],,09 Example 13
゜2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto- obtained in Example 8
1,3,4-thiadiazole 0.20g, 7-bromoheptanoic acid 0.15g, anhydrous potassium carbonate 0.18
A catalytic amount of tetra-n-butylammonium bromide was added to a mixture of g and 5 ml of methyl ethyl ketone.

Stir at 60°C for 1 hour. Add an aqueous sodium hydroxide solution and ethyl acetate to the reaction solution and separate the layers. The aqueous layer was made acidic with 2N hydrochloric acid and extracted with ethyl acetate.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (2:1).
7-[[5-[(4-acetyl-3-hydroxy-
0.20 g of 2-propylbenzyl)thio]-1,3,4-thiadiazol-2-ylcothio]hebutanoic acid was obtained.

Melting point 63-68℃ Elemental analysis value (as C2, H28N20.S3) C (%
) H (%) N (%) S (%) Theoretical value 53.82
6.02 5.98 20.53 Experimental value 53.95
6.19 5.88 20.35 Example 14 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.20 g of 4-hydroxy-2-mercaptopyrimidine, 0.2 g of anhydrous potassium carbonate
0 g and 4 ml of methyl ethyl ketone.

adding a catalytic amount of tetra-n-butylammonium bromide;
Stir at 60℃ for 1 day. An aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction mixture to separate the layers.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (1:2).
'2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-4-hydroxypyrimidine 0.1
Obtained 0g.

Melting point 177℃ Elemental analysis value (C+e II8 N20s S)C
(%) H (%) N (%) S (%) Theoretical value
60,36 5,70 8.80 10.07 Experimental value
60,33 5,70 8.63 9.90 Example 1
5゜0.06 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-4-hydroxypyrimidine + ethylbromoacetate obtained in Example 14)
A catalytic amount of tetra-n-butylammonium bromide is added to a mixture of 0.06 g of anhydrous potassium carbonate, 0.04 g of anhydrous potassium carbonate, and 3 ml of methyl ethyl ketone and stirred at 60'C for 1 hour. Add water to the reaction solution and extract with ethyl acetate.

The extract was dried over anhydrous magnesium sulfate -Aζ-, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (6:1).
Elute with a solution of ethyl [[2-[(4-acetyl-
0.06 g of 3-hydroxy-2-propylbenzyl)thio]pyrimidin-4-yl]oxy]acetate was obtained.

Melting point 112-117°C Nuclear magnetic resonance spectrum (in CDCl2, TMS internal standard.

ppm): 1.00 (t, 3H), 1.25 (t
, 3H), 1.4-1.8 (2H).

2.59 (s, 3H), 2.5-2.9 (2H), 4
．． 22(q, 2H).

4.38 (s, 2H), 4.87 (s, 2H), 6
．． 56(d, IH).

6.94 (d, IH), 7.53 (d, II (),
8.30 (d, LH).

12.7 (s, IH) Mass spectrum m/z: 404 (M+).

46-Example 16゜n Ethyl obtained in Example 15 [[2-[(4-acetyl-
0.06 g of 3-hydroxy-2-propylbenzyl)thio]hyrimidin-4-yl]oxy]acetate
% methanol 2mZ at 60°C, and further IN
Add 1 ml of sodium hydroxide aqueous solution and heat at 60°C for 15 minutes.
Stir for a minute. Add an aqueous sodium hydroxide solution and ethyl acetate to the reaction solution and separate the layers.

The aqueous layer was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to obtain 0.02 g of [[2-[(4-acetyl-3-hydroxy-2-furobylbenzyl)thiolopyrimidin-4-yl]oxy]acetic acid. Ta.

Melting point 174-178℃ Elemental analysis value (as Cls N20 N205 S) C
(%) I((%) N(%) S(%) Theoretical value 57.43 5.36 7.44 8.52 Experimental value
57.20 5.28 7.28 8.42 Example 1
7゜2-[(4- 0.33 g of acetyl-3-hydroxy-2-propylbenzyl)thio]-3-hydroxypyridine was obtained.

Melting point 126°C Elemental analysis value (as C+7H+oNOs S) C (%)
I ((%) N (%) S (%) Theoretical value 64-.33
6.03 4.4110.10 Experimental value 64,16
5,95 4.43 9.96 Example 18° According to the 2-[(4-acetyl-3- obtained in Example 17), ethyl[[2-[(4-acetyl-3-hydroxy-2-propylbenzyl ) thiokopyridin-3-yl]
0.09 g of oxy]acetate was obtained.

Melting point 98-100℃ Elemental analysis value (as C21N25 No!l S) C (
%) H (%) N (%) S (%) Theoretical value 62.
51 6.24 3.47 7.95 Experimental value 62.2
9 6,14 3,42 8.06 Example 19° Ethyl obtained in Example 18 [[2-[(4-acetyl-
[[2-[(
4-acetyl-3-hydroxy-2-propylbenzyl)thiokopyridin-3-yl]oxy]acetic acid 0.02
I got g.

Melting point 157℃ Elemental analysis value (C, 9I (2, No, S) C (%)
) H (%) N (%) S (%) Theoretical value 60,7
8 5.64 3.73 8.54 Experimental value 60.66
5.61 3.70 8.63 The following was obtained in the same manner as in Example 14.

Example 20 2-Hydroxy-3-propyl-4-[[(1 ,2,4-4H-triazole-3
-yl)thio]methyl]acetophenone was obtained.

Melting point 150-151°C Elemental analysis value (C,, H, as 7N302S) C (%)
H (%) N (%) S (%) Theoretical value 57.71
5.88 14.42 11.09 Experimental value 57.76
5.84 14.50 10.84 Example 21° 2-Amino-5-[(4-acetyl-
3-Hydroxy-2-propylbenzyl)thio] -1
, 0.30 g of 3,4-thiadiazole to 6.5 g of pyridine
0.20 g of ethyl oxalyl chloride is added dropwise to the solution dissolved in the solution at -30°C, and the mixture is stirred at room temperature for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate.

The solvent was distilled off. The residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (8:1).
Elute with a mixture of ethyl [5-[(4-7 cetyl-3
-hydroxy-2-7”ropyrupenzyl)thio] -1
,3,4-thiadiazol-2-yl]oxamate 0
．． 15g was obtained.

Melting point 189°C Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 1.00 (t, 3H), 1.44 (t
, 3H), 1.3-1.8 (2H).

2.59(s, 3I(), 2.6-2.9(2H),
4.46(q, 2H).

4.54 (s, 2H), 6.92 (d, IH), 7
．． 52(d, IH).

12.67 (s, IH) Mass spectrum m/z: 423 (M-Example 2
2゜ Ethyl [5-[(4-acetyl-
3-Hydroxy-2-propylbenzyl)thio] -1
,3,4-thiadiazol-2-yl]oxame-)0
．． Suspend 14 g in 8 ml of 90% methanol, add 2 liters of IJum aqueous solution + Z, and stir at room temperature for 20 minutes. Add an aqueous sodium hydroxide solution and ethyl acetate to the reaction solution and separate the layers. One layer of water was acidified with IN hydrochloric acid and extracted with ethyl acetate.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from isopropyl alcohol, and the resulting crystals were dissolved in an aqueous sodium hydroxide solution. This solution was made acidic by adding IN hydrochloric acid, and the precipitated solid matter was collected and dried under reduced pressure to obtain "5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio] -1,3,4
-Thiadiazol-2-yl]oxamidic acid 0.02g
I got it.

Melting point 208°C (decomposed) Nuclear magnetic resonance spectrum (DMSO-d, medium, TMS internal standard.

ppm): 0.94 (t, 3H), 1.3-1.
8 (2H), 2.64 (s, 3H).

2.5-2.8 (2H), 4.56 (s, 2H),
6.98 (d, IH).

7.85 (d, IH), 12.74 (s, IH) Mass spectrum m/z: 396 ((M+H)') Example 23 2-Amino-5-[(4-acetyl-3-hydroxy-
2-propylbenzyl)thio] -1,3,4-thiadiazole 0.20 g, ethylsuccinyl chloride 0.
Using 15 g as raw material, following the same method as Example 21,
Ethyl 4-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-ylcoamino'' nuclear magnetic resonance spectrum in CDCl2, TMS internal standard.

ppm): 0.99 (t, 3H), 1.23
(t, 3H), 1.4-1.9 (2H).

2.62 (s, 3H), 2.6-2.9 (4H), 2
．． 9-3.2 (2H).

4.13 (q, 2H), 4.50 (s, 2H), 6
．． 90(d, IH).

7.53 (d, LH), 12.69 (s, IH) mass spectrum m/z: 451 (M+) Example 2
4゜ Ethyl [[5-[(4-acetyl-3
-hydroxy-2-7'-pyrubenzyl)thio]-1,
0.27 g of 3,4-thiadiazol-2-ylcoamino-4-oxobutyrate in 8 m of 90% methanol
1, and to this was added 22 mL of IN aqueous sodium hydroxide solution.
Add the ingredients and stir at room temperature for 20 minutes.

Add thorium hydroxide aqueous solution and ethyl acetate to the reaction solution and separate the layers. The aqueous layer was made acidic with IN hydrochloric acid and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from isopropyl alcohol to give 4-[[5-[(4-acetyl-3-hydroxy-
2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amine-4-oxobutyric acid 0.1
．． 1g was obtained.

Melting point 194°C (decomposition) Elemental analysis value (as CIIIH21N305S2) C (
%) H (%) N (%) S (%) Theoretical value 5
1,05 5.00 9.92 15.14 Experimental value 5
1.11 5.08 9.75 14.92 Reference example 1
．． (Raw material of Example 25) Br(CH2)3CI H8CH2Co□C2H3CI(CH2)3SCH2C
00C2H5 ethyl mercaptoacetate2. OOg
, 3.13 g of 1-bromo-3-chloropropane,
A mixture of 2.29 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide is stirred at room temperature for 3 hours. The reaction solution was diluted with toluene, and insoluble matter was filtered off. The P solution was washed successively with an aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography.

Elute with n'lll of hexane-ethyl acetate (15:1).

2.65 g of oily ethyl [(3-chloropropyl)thio]acetate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 1.28 (t, 3H), 1.9-2.
2 (2H), 2.7-2.9 (2H).

3.20 (s, 3H), 3.64 (t, 2H), 4
．． 19(q, 2H) mass spectrum/L/m/z:
196 (M+).

Reference example 2. (Raw materials for Example 26) p-hydroxybenzyl alcohol2. OOg, ethyl bromoacetate) 3.23 g, anhydrous potassium carbonate 2.45 g and N,N-dimethylformamide 15
ml of the mixture is added a catalytic amount of tetra-n-butylammonium bromide and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and insoluble materials were filtered off. After washing with IJum aqueous solution and water in sequence and drying over anhydrous magnesium sulfate, the solvent was distilled off.

The residue was subjected to silica gel column chromatography,
Elution was performed with a mixture of hexane and ethyl acetate (3:2) to obtain 2.16 g of oily ethyl [p-(hydroxymethyl)phenoxy]acetate.

Nuclear magnetic resonance spectra (in CDCl2, TMS internal standard.

ppm): 1.27 (t, 3H), 1.6~
1.8 (LH), 4.25 (q, 2H).

4.58 (s, 2H), 4.60 (d, 2H), 6
．． 8-7.0 (2H).

7.2-7.4 (2H) Mass spectrum m/z: 210 (M+).

To a solution in which 0.30 g of ethyl [p-(hydroxymethyl)phenoxy]acetate obtained in (a) was dissolved in 3 ml of benzene (1K), 0.13 ml of thionyl chloride was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution is diluted with toluene, and cold water is added to the solution to separate the liquid. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (6:1) to give an oily ethyl [
p-(chloromethyl)phenoxy]acetate 0.31
I got g.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 1.29 (t, 3H), 4.26 (
q, 2H), 4.54 (s, 2H).

4.60 (s, 2H), 6.8-7.0 (2H), 7
．． 2-7.4 (2H) mass spectrum/l/m/z
: 228 (M”).

Reference example 3. (Raw materials for Example 27) p-hydroxybenzyl alcohol 1.00 g,
Using 1.61 g of ethyl 2-bromopropione-
-(Hydroxymethyl)phenoxy]propionate 1
．． 44g was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 1.22 (t, 3H), 1.59 (d
, 3H), 1.6-1.8 (IH).

4.19 (q, 2H), 4.59 (d, 2H), 4.
73 (q, IH).

6.8-7.0 (2H), 7.2-7.4 (2H) Mass spectrum m/z: 2'24 (M).

Ethyl 2-[p-(hydroxymethyl) obtained in (a)
Using 1.39 g of phenoxy]propionate as a raw material,
According to the same method as in Reference Example 2 (b), ethyl 2-[p
-(chloromethyl)phenoxy]propionate 1.3
3g was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 1.23 (t, 3H), 1.60 (
d, 3H), 4.20(q, 2H).

4.52 (s, 2H), 4.72 (q, IH), 6.
7-7.0 (2H).

7.1-7.4 (2H) Mass spectrum A/m/z: 242 (M”)
.

Reference example 4. (Raw material of Example 28) 4 ml of an aqueous solution of 0.39 g of sodium metaperiodate
Ethyl [(3-chloro1
- Add 3 ml of a methanol solution of 0.30 g of lobrovir)thio]acetate dropwise and stir at room temperature for 100 minutes.

30 ml of saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. Dry the extract with anhydrous magnesium sulfate.

The solvent was distilled off. The residue was subjected to silica gel column chromatography, eluted with a mixture of hexane and ethyl acetate (1:3), and 0.31 g of ethyl (3-chloropropylsulfinyl) acetate was obtained. )C(%)
H (%) S (%) Ct (%) Theoretical value 39.53
6.16 15.08 16.67 Experimental value 39.2
5 6.42 15.04 16.78 Reference example 5 (raw material of Example 29) CI(CH2)3SO□CH2C00C2H5 Reference example 1
Dissolve 0.30 g of ethyl [(3-chloropropyl)thioloacetate] obtained in 2 ml of acetic acid.

Add 1 ml of 30% hydrogen peroxide solution to this at 0°C,
Stir for 1 hour at C. 40 ml of saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and extracted with ethyl acetate.

The extract was washed successively with a saturated aqueous sodium bicarbonate solution, a 10% aqueous sodium bisulfite solution, and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

The residue was subjected to silica gel column chromatography,
Elution was performed with a mixture of hexane and ethyl acetate (2:1) to obtain 0.30 g of oily ethyl (3-chloropropylsulfonyl)acetate.

Nuclear magnetic resonance spectra (in CDCl2, TMS internal standard.

ppm): 1.37 (t, 3H), 2.2-2
．． 5 (2H), 3.4-3.6 (2H).

3.71 (t, 3H), 4.01 (s, 2H), 4
．． ．． 29(q, 2H) mass spectrum m/z: 2
29 ((M+1)+).

Example 25゜2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto- obtained in Example 8
1,3,4-thiadiazole 0.20 g, Reference Example 1
Ethyl [(3-chloropropyl)thioloacetate obtained in
) 0.14 g, anhydrous potassium carbonate 0.09 g and N
.

A catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 5 ml of N-dimethylformamide.

Stir at 60°C for 10 hours. The reaction solution was diluted with toluene, and insoluble materials were filtered. The solution was washed successively with an aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (5:1) to give an oily ethyl [[3([5-[(4-acetyl-3-hydroxy-2-propylbenzyl)]. )thio] −
0.15 g of 1,3°4-thiadiazol-2-ylcothio]propyl]thio]acetate was obtained.

Nuclear magnetic resonance spectrum (CDCl, medium, TMS internal standard.

ppm): 0.99 (t, 3H), 1.26 (
t, 3H), 1.4-1.8 (2H).

1.9-2.3 (2H), 2.58 (s, 3H),
2.6-2.9 (4H).

3.19 (s, 2H), 3.40 (t, 2H), 4
．． 18 (s, 2H).

4.54 (s, 2H), 6.93 (d, IH), 7
．． 54(d, IH).

12.67 (s, IH) Mass spectrum, II/ m/z: 500 (M+)
.

Example 26゜2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-merca7'-1゜3.4-
Thiadiazole 0.20 g, ethyl [(p-chloromethyl)phenoxy]acetate obtained in Reference Example 2 0
．． A catalytic amount of tetra-n-butylammonium bromide is added to a mixture of 16 g of anhydrous potassium carbonate, 0.09 g of anhydrous potassium carbonate, and 4 ml of 2-butanone, and the mixture is stirred at 60° C. for 30 hours. The reaction solution was diluted with ethyl acetate, and insoluble materials were filtered.

After washing with an aqueous solution of IJ and water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (4:1) to give an oily ethyl [p-[[5-[(4-acetyl-3-hydroxy-2-propyl 0.2'1 g of benzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]acetate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): 1.00 (t, 3H), 1.29
(t, 3H), 1.4-1.8 (2H).

2.63 (s, 3H), 2.6-2.8 (2H),
4.27(q, 2H).

4.47 (s, 2H), 4.56 (s, 2H), 4
．． 61 (s, 2H).

6.8-7.0, 7.2-7.4 (2H), 7.54
(d, tH).

12.7 (s, IH) Mass spectrum m/z: 532 (M).

Example 27 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-merca7”)-1°3.4-thiadiazole 0.20 g, ethyl obtained in Reference Example 3
Using 0.17 g of 2-[(p-chloromethyl)phenoxy]propionate as a raw material, ethyl 2-[p-[[[5-[(4-acetyl-3-hydroxy-2- propylbenzyl)thio] -
0.23 g of 1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]propionate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.

ppm): o, 9c+(t, 3H), 1.2
2(t, 3r(), 1.4-1.8(2HL1.5
9 (d, 3H), 2.58 (s, 3H), 2.6~
2.9 (2H).

4.20 (q, IH), 4.44 (s, 2H), 4
．． 54 (s, 2H).

4.70 (q, IH), 6.7-7.0 (3H),
7.2. ~7.4 (2H).

7.53 (d, IH), 12.67 (s, IH) mass spectrum m/z: 546 (M+).

Example 28 0.24 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thioko-5-mercapto-1°3.4-thiadiazole, ethyl (3-chloropropylsulfinyl) obtained in Reference Example 4 Acete・-)0.18g
Using as a raw material, oily ethyl [3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thioko 1.3.4-thiadiazol-2-yl] was prepared in the same manner as in Example 25. 0.22 g of thio]propylsulfinyl]acetate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard s ppm): 100 (t, 3 H), 0
−30 (t + 3 H), 1.4 to 1.8 (2
H), 2.2-2.6 (2H), 2.60 (s, 3H)
.

2.6-2.9 (2H), 2.9-3.2 (2H)
, 3.48 (t, 2H).

3.70 (s, 2H), 4.25 (Q, 2H) 4.55
(8, 2H).

6.94 (d, 1) (), 7.55 (d, IH), 12
．． 68(s, IH).

Mass spectrum m/z: 516 (M+).

Example 29 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thioyo5-mercapto-1°3.4-thiadiazole 0.25 g, ethyl (3-chloropropylsulfonyl) obtained in Reference Example 5 Using 0.20 g of acetate as a raw material, oily ethyl [
3-[[5-[(4-acetyl-3-hydroxy-2-
0.21 g of brobylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propylsulfonyl]acetate was obtained.

Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard, ppm): 1.00 (t, 3H),
1.31 (t, 3I(), 1..4~1.8(2
H), 2.3-2.9 (4H), 2.60 (s, 3H)
, 3.3-3.7(4H), 3.98(s, 2T(
), 4=27(q, 21().

4.59 (s, 2H), 6.93 (d, IH), 7.5
5 (d, LH) + 12.68 (s, IH).

Mass spectrum m/z: 533 ((M+1)”
).

Example 30 4-acetyl-3-hydroxy-2-propylbenzyl chloride 0.30 g, 3-amino-5-mercapto-
Using 0.18 g of 1,2,4-triazole as a raw material, 4'-[[(5-amino-
0.25 g of 1,2,4-1-riazol-3-yl)thio]methyl]-2'-hydroxy-3'-propylacetophenone was obtained.

Nuclear magnetic resonance spectrum (CDCI3CDCl5-D, l
During.

TMS internal standard, ppm): 0.99 (t,
3H), 1.3-1.8 (2H), 2.59 (s,
3H), 2.6-2.8 (2H), 4.28 (s, 2H
), 4.8-5.3 (2H), 6.92 (d, IH),
7.53(d, IH), 11.5(1)I), 12. (
IH).

Mass spectrum m/z: 306 (M+).

Example 31 4′-[[(5-amino-], 2°4 obtained in Example 30
-Triazol-3-yl)thio]methyl]-27-hydroxy-3'-propylacetophenone (0.15 g) was dissolved in 3 ml of pyridine, and 0.31 g of ethyl oxalyl chloride was added thereto at 0°C. = Stir for 1 hour. Cold water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed successively with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The white solid obtained by distilling off the solvent was suspended in 5 ml of 90% methanol, and I
Add 4 ml of N aqueous sodium hydroxide solution and stir at room temperature for 2 hours. hydroxide in the reaction solution) IJium aqueous solution,
Add ethyl acetate and separate the liquid. The aqueous layer was made acidic with 2N hydrochloric acid, and the precipitated white solid was separated in a furnace and dried under reduced pressure.
0.14 g of [(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-L2,4-)lyazol-3-yl]amine]oxamic acid was obtained.

Melting point 220°C (decomposition) Elemental analysis value (C+a) (as IlI N40+ S) C (%) H (%) N (%) S (%) Theoretical value 50,79 4. ．． 79 14. ．． 81 8.4
7 Experimental value 50.84 4.80 14.54. 8
．． 46=72 Example 32 Ethyl [[3-[[5-[(4-acetyl-3-hydroxy-2--jropylbenzyl)thio]-1,3,4-thiadiazole-2] obtained in Example 25 -yl]thio]propyl]thio]acetate) is suspended in 2 ml of 90% methanol, 1 ml of IN aqueous sodium hydroxide solution is added thereto, and the mixture is stirred at room temperature for 45 minutes. Add an aqueous sodium hydroxide solution and ethyl acetate to the reaction solution and separate the layers. The aqueous layer was made acidic with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane-ethyl acetate (1:2) to give an oily [[3-[[5-[(4-acetyl-
3-Hydroxy-2-propylbenzyl)thio]-L3
, 0.14 g of 4-thiadiazol-2-ylcothiocoprobylcothio]acetic acid was obtained.

Nuclear magnetic resonance spectrum (in CDC1j, TMS internal standard.

ppm): 1.00 (t, 3H), 1.3~
1.8 (2H), 1.9-2.4 (2H), 2.5
9 (s, 3H), 2.6-3.0 (4H).

3.26 (s, 2H), 3.40 (t, 2HL 4.5
'4(s, 2H).

4.8-5.6(1)(), 6.92(a, IH),
7.54(a, IH).

12.67 (8, IH) + Mass spectrum m/z: 472 (M”).

Example 33 Ethyl [p-[, [[5-(1(4-
Acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]
Suspend 0.20 g of methyl]phenoxy]acetate in 2 ml of 90% methanol and add IN hydroxide)
Add 1 mZ of IJum aqueous solution and stir for 1 minute at room temperature. Add an aqueous sodium hydroxide solution and ethyl acetate to the reaction solution and separate the layers. The aqueous layer was made acidic with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to give [p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl. ]thio]methyl]phenoxy]acetic acid 0. I got tsg. Melting point 13
1~134°C Elemental analysis value (as C23H24N20.S3) C (%
) H (%) N (%) O (%) Theoretical value 54,7
4 4.79 5.55 19.06 Experimental value 54
．． 45 4. ．． 74 5.35 18.89 Example 3
4 Ethyl obtained in Example 27 2-[p-[[[5-[(4
-acetyl-3-hydroxy-2-propylhensyl)
[thio]-L3,4-thiadiazol-2-yl]thio]
2-[p-[[[5
0.11
I got g.

Melting point 138-142°C Elemental analysis value (as C24H26N2o5s3) C (%
) H (%) N (%) o (%) Theoretical value 55,
58 5,05 5.40 18.55 Experimental value 55
．． 54 5.04 5.32 18.55 Example 35 Ethyl[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thioko 1.3.4 to thiadiazole] obtained in Example 28 Using 0.20 g of -2-yl]thio]propylsulfinyl]acetate as a raw material, it was treated in the same manner as in Example 33 to obtain [3-[(5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]). ]
0.16 g of -1,3,4-thiadiazol-2-yl]thio]propylsulfinyl]acetic acid was obtained.

Melting point 107~110"C Elemental analysis value (as C,, H24N20.S) C (
%) H (%) N (%) s (%) Theoretical value 46.
70 4,95 5.73 26.25 Experimental value 46
．． 56 5.23 5.47 26.04 Example 36 n Ethyl [3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-
Using 0.19 g of L 3,4-thiadiazol-2-yl]thio]propylsulfonyl]acetate as a raw material, it was treated in the same manner as in Example 33 to obtain [3-[[5-[(4-acetyl-3-hydroxy- 2-propylbenzyl)thio: ]
-1,3,4-thiadiazol-2-yl]thio]furobylsulfonyl]acetic acid (obtained 113 g. Melting point 12
2-125℃ elemental analysis value (Cl9H24N206 S4
) C (%) H (%) N (%) S (%) Theoretical value 4.5.22 4-. 79 5.55 25.4
2 Experimental value 45.0'l 4.99 5.38 2
5.60 Example 37 2-[(4-acetyl-3-hydroxy-2-probylbenzyl)thio]-5-mercapto-1°3.4-thiadiazole 0.49 g, p-bromomethyl)benzoic acid 0
．． A catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 36 g of anhydrous potassium carbonate, 0.48 g of anhydrous potassium carbonate, and 12 m of 2-butanone, and stirred at 60 DEG C. for 45 minutes. Add IJum aqueous solution and ethyl acetate to the reaction solution and separate the layers. The aqueous layer was made acidic with IN hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying with anhydrous magnesium sulfate.

The solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to give p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-
0.50 g of 1,3,4-thiadiazol-2-yl]thiomethyl]benzoic acid was obtained.

Melting point 163-166°C Elemental analysis value (as C22H2□N204S3) C (%
) H (%) N (%) S (%) Theoretical value 5
5.67 4.79 5.90 20.27 Experimental value
55,63 4.65 5.73 20.14 Reference example
6 2,5-dimercapto-1,3,4-thiadiazole 1
．． ．． 2 g, anhydrous potassium carbonate 1. ．． 1 g, N,
Add ethyl p- to a mixture of 10 m4 of N-dimethylformamide.
(bromomethyl)benzony) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution is made acidic with dilute hydrochloric acid, extracted with ethyl acetate, the extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using toluene-ethyl acetate (9:1).
) was eluted with a mixture of The obtained crystals were recrystallized from toluene-n-hexane to obtain 230 mg of ethyl l)-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoate. Melting point 11
4-115°C elemental analysis value (C, 2) (HN202S3
) C (%) H (%) N (%) s (%) Theoretical value 4.6.13 3,87 8.97 30.79
Experimental value 46.20 3.84 8.81 30.8
9 Reference Example 7 2.5-dimercapto-1,3,4-thiadiazole 1
．． 5 g of anhydrous potassium carbonate, and 10 ml of N,N-dimethylformamide, 1 g of p-(bromomethyl)benzoic acid was added and stirred at room temperature for 3 hours. 30 ml of water was added to the reaction solution, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using toluene-ethyl acetate (1:1).
) was eluted with a mixture of + p [(5-mercapto-1
, 400 mg of 3,4-thiadiazol-2-yl)thiomethyl]benzoic acid was obtained.

Melting point 230-232°C Elemental analysis value (C,n as H8N20□S3) C (%
) H (%) N (%) S (%) Theoretical value 42.24
2.84 9.85 33.83 Experimental value 42,1
8 2.91 9.68 33.86 Example 38 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1°3.4-thiadiazole 3401T1g, anhydrous potassium carbonate 150r
1 g, 220 g of ethyl p-(bromomethyl)benzoate in a mixture of 5 mZ of N,N-dimethylformamide
was added and stirred at room temperature for 3 hours. 30 ml of toluene was added, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of triene-ethyl acetate (9:1).
Oily ethyl p-[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3.4-thiadiazol-2-yl]thiomethyl]benzoate 0
．． 38 g was obtained.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm'): 1.0 (t, 3H), 1.5
9(t, 3T().

1,: 2-1.9 (m, 4H), 2.62 (s, 3H)
, 2.6-2.8 (m.

2H), 4.37 (q, 2H), 4.54 (8, 2H)
, 4.56 (s, 2H).

6.92(d, IT(), 7.51(dd, 4H
), 8.0 (d, LH).

12.69 (s, IH) Example 39 Ethyl p-[(5-mercapto-1,3
,4-thiadiazol-2-yl)thiomethyl]benzony)23Orl1g, anhydrous potassium carbonate 110■,
Add 4- to a mixture of 5 ml of N,N-dimethylformamide.
160 mg of acetyl-3-hydroxy-2-propylbenzyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Add 30n+t of toluene to the reaction solution and wash with water.

It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1) to give an oily ethyl p-[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]. ]-1,3,4-thiadiazol-2-yl]thiomethyl]benzony) 3301TIg
I got it. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 38.

Example 40 p-[(5-mercapto-1,3°4-
Thiadiazol-2-yl)thiomethyl]benzoic acid 20
0mg, anhydrous potassium carbonate 200 rllg, N,N
- 1 part of 4-acetyl-3-hydroxy-2-propylbenzyl chlorand in a mixture of 5 ml of dimethylformamide.
Add 70 rllg and stir at room temperature for 2 hours. water 20
Add m1, wash with ethyl acetate, and acidify with dilute hydrochloric acid.

Extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from isopropyl alcohol to give p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio] −
1,3,4-thiadiazol-2-yl]thiomethyl]
130 n1 g of benzoic acid was obtained. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 37.

Example 41 Reference Example 8 Ethyl p-[5-[(4-acetyl-3-hydroxy-
2-propylbenzyl)thio]-1,3゜4-thiadiazol-2-yl]thiomethyl]benzoate 380m
g, methanol 2mZ, tetrahydrofuran 2ml,
IN - A mixture of 2 ml of sodium hydroxide aqueous solution at 60-7
The mixture was stirred at 0°C for 1 hour. After cooling.

20 ml of water was added, washed with ethyl acetate, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. Wash the extract with water.

It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was recrystallized from isopropyl alcohol-water.
p-[[5-[(4-acetyl-3-hydroxy-2
100 mg of -propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thiomethyl]benzoic acid was obtained. The physical properties of the obtained compound were consistent with those of the compound obtained in Example 37.

7.33 (s, 4H) ethylthioglycolic acid 1.22 g, anhydrous potassium carbonate 1.4 g, N,N-dimethylformamide 20
Add 5.3 g of p-xylene dichloride to ml of the mixed solution.

Stir overnight at room temperature. 50 ml of toluene was added to the reaction solution, washed with water, and dried over anhydrous magnesium sulfate.

Concentrate under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1) to obtain 1.61 g of oily ethyl [(p-chloromethylbenzyl)thio]acetate.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 1.28 (t, 3H), 3.05
(s, 2H).

3.82 (s, 2H), 4.18 (q, 2H), 4.5
6 (s, 2H).

Example 42 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1°3.4-thiadiazole 1100rI1. Anhydrous potassium carbonate 50■
90 mg of ethyl [(p-chloromethylbenzyl)thio]acetate) obtained in Reference Example 8 was added to a mixture of 5 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 3 hours.

Add 30 mZ of toluene to the reaction solution, wash with water, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (9:1) to give an oily ethyl [[p-[
[[s-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole-
100 mg of 2-yl]thio]methyl]benzyl]thio]acetate was obtained.

Nuclear magnetic resonance spectrum (CDCl3. TMS internal standard.

ppm): 1.00 (t, 3H), 1.28 (t,
3H) +1.40 to 1.80 (m, 2H), 2.60 (
s, 3H).

2.50-2.84 (m, 2H), 3.04 (s, 2H
) 13.81 (s, 2H), 4.18 (q, 2H), 4
．． 50 (s, 2H).

4.56 (s, 2H), 6.94 (d, IH), 7.3
1(s, 2H).

7.34 (S, 2 H), 7.55 (d, I H
), 12.67 (s, I H) Example 43 Obtained in Example 42. Ethyl [[pr[[5-[(4-
Acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]
Using 100 mg of methyl]benzyl]thio]acetate as a starting material, 50 mg of -1,3,4-thiadiazol-2-yl]thiocomethylcobenzyl]thio]acetic acid was obtained in the same manner as in Example 41.

Melting point 102~104°C Elemental analysis value (as C24H2ON20484) C (%
) H (%) N (%) S (%) Theoretical value 53.91
4.90 5.24 23.99 Experimental value 54.02
5.03 5.23 23.81 Example 44 4-acetyl-3-hydroxy-2-propylbenzyl chloride 0.20 g, 3-oxide-5-sulfide-4-inchazolecarboxylic acid tripotassium 0.19
g, anhydrous potassium carbonate 0.05 g and 2-butanone 5
A catalytic amount of tetra-n-butylammonium bromide was added to the mixture of mZ, stirred at 60°C for 2 days, and treated in the same manner as in Example 9 to obtain 5-[(4-acetyl-3-hydroxy-2 0.04 g of 3-hydroxy-4-inchazolecarboxylic acid (propylbenzyl)thioyo was obtained.

Melting point 210°C (decomposed) Nuclear magnetic resonance spectrum (in DMSOda, TMS internal standard, ppm): 0.94 (t, 3H), 1
．． 3-1.8 (2H).

2.64 (s, 3H), 2.5-2.8 (2H), 4.
32 (S, 2H).

7.08 (d, LH), 7.80 (d, IH),
12.75 (s, IH) mass spectrum m/z
: 367 (M+).

Reference Example 9 One drop of piperidine is added to a mixed solution of 13.4 g of paratoaldehyde, 5 g of malonic acid, and 50 ml of pyridine, and the mixture is heated under reflux until the generation of carbon dioxide gas stops. The reaction solution was concentrated under reduced pressure, and water was added to 200 m7. Add 12 g of sodium hydrogen carbonate, wash with ethyl acetate, and acidify with concentrated hydrochloric acid.

Collect the precipitated crystals in a furnace, wash thoroughly with water, and dry.

6.6 g of p-formylcinnamic acid was obtained.

Melting point: 250℃ or higher.

Reference Example 10 Obtained in Reference Example 9. 4 g of p-formylcinnamic acid, 3.5 g of iothomethyl, 3.3 g of anhydrous potassium carbonate, N, N
- A mixture of 30 ml of dimethylformamide is stirred at room temperature overnight. Add 200 ml of toluene to the reaction solution to make 5%
It was washed with an aqueous sodium bicarbonate solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.8 g of methyl p-formylcinnamate.

Melting point 82-84°G Reference Example 11 Methyl p-formyl cinnamate obtained in Reference Example 10 3.
8g, ethanol 30ml1. 10% palladium-carbon 0.1% in a solution of 10 ml of tetrahydrofuran.
g is added, and catalytic reduction is carried out at room temperature and pressure until hydrogen absorption stops. The catalyst was removed, and sodium borohydride [g] was added to the P solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 200 ml of ethyl acetate was added, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

3.5 g of oily ethyl 3-(p-hydroxymethylphenyl)propionate was obtained.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

1, i5 7.0-7.40 (m, 4.H)
\2, Reference Example 12 Oily ethyl:(-(p-chloromethylphenyl) ) 3.4 g of propionate was obtained.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 1.20 (t, 3H), 2.40-2.
7'6 (m, 2H).

2.76-3.10 (m, 2H), 4.11 (Q, 2H
), 4.54 (s, 2H).

7.0-7.40 (m, 4H) Example 45 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-5-mercapto-1 obtained in Example 8
, 3,4-thiadiazole 130rl1g and Reference Example 12
Using 100 mg of ethyl 3-(p-chloromethylphenyl)propionate obtained in Example 42 as a raw material, the same treatment as in Example 42 was carried out to obtain oily ethyl 3-[p-[[[5-[[4
-acetyl-3-hydroxy-2-propylbenzyl)
thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenyl]propionate 1601I1 g
I got it.

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm'): 1.00 (t, 3H), 1-. 20
(t, 3I().

1.36-1.80 (m, 2H) + 2.59
(s, 3H).

2.4.0-3.10 (m, 4H), 4.
11. (q, 2H).

4.46 (s, 2H), 4.54 (s, 2H), 6.9
2(d, IH).

7.00-7.40 (m, 4.H), 7.54 (d,”
LH), 12.6(s, 1.i() mass spectrum m/
z -(M++ 1 ) Example 46 Ethyl 3-[p-[[[5-[(4-
Using 160 g of acetyl-3-hydroxy-2-propylbenzyl)thio]-L3,4-thiadiazol-2-yl]thio]methyl]phenyl]propionate as a starting material, the same procedure as in Example 41 was used to obtain an oily 3 −
120 nIg of [p-JT[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenyl]propionic acid was obtained. .

Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard.

ppm): 1.0 (t, 3H), 1.2-1
．． 8 (m, 2H).

2.60 (s, 3H), 2.5-3.2 (m, 4H),
4.46 (s, 2H).

4.54 (s, 2H), 6.92 (d, IH), 7.0
~7.4 (m, 4H).

7-52 (d, I H), 12-69 (8, I H
) Mass spectrum m/z = 503 (M”+1
) The following compounds were obtained in the same manner as in Example 14.

Example 47 Using 5-mercaptotetrazole and 4-acetyl-3-hydroxy-2-propylbenzyl chloride,
2-Hydroxy-3-propyl-4,-[[(5-tetrazolyl)thio]methyl]acetophenone was obtained. Melting point 170-172°C Elemental analysis value (C+ s H+e
N4 (as O□S) %) H(%) N(
%) S (%) Theoretical value 53.41 5.52 1
9.16 10.27 Experimental value 53.61 5.57
19.21 10.60 Prescription example 1 (tablet) Compound of Example 37 30 mg milk
Sugar 10tn1g
Cornstarch 57mg Hydroxypropyl cellulose 4mg Carboxymethylcellulose calcium 4mg Magnesium stearate 1mg 30g of the compound of Example 37, 104g of lactose and 57g of cornstarch were uniformly mixed, 40ml of 10% (w/v) hydroxypropylcellulose aqueous solution was added to this mixture, Granules were prepared by wet granulation method.

4g of carboxymethyl cellulose calcium in this granule
After adding and mixing 1 g of magnesium stearate, the mixture was compressed into tablets (200 mg per tablet).

Formulation Example 2 (Capsule) Compound of Example 37 301T1g Crystalline Cellulose 40mg Crystalline Lactose
129+r+g Magnesium stearate
1mg total 200
After mixing 1000 times the amount of each of the above ingredients in a conventional manner, the mixture was filled into gelatin capsules to prepare capsules (200 mg per capsule).

Formulation example 3 (inhalant) 0.1 g of the compound of Example 37 was mixed with ethanol-propylene glycol-purified water (weight ratio 30:10:60)
) The mixture was dissolved in a liquid mixture of 90 mZ, and the mixture was further added to make the total volume 100 mZ, and each 100 ml of the mixture was filled into a designated container and sealed to obtain an inhalant.

Claims (1)

[Claims] General formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a lower acyl group; R^2 is a lower alkyl group; ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ is a nitrogen atom 1 to 3
a 5- or 6-membered heterocyclic group which may further contain one sulfur atom or one oxygen atom; R^3 is a carboxyl group; an amino group; a lower alkylamino which may be substituted with a carboxyl group; Group; Lower alkanoylamino group which may be substituted with a carboxy group; Di-lower alkylamino group; Hydroxyl group; Lower alkoxy group which may be substituted with a carboxy group; Mercapto group; Lower which may be substituted with a carboxy group Alkylthio group; Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In both formulas, P is an integer from 1 to 5, q is 0, 1 or 2, γ is an integer of 1 to 5, R^4 is a carboxyl group, a lower alkoxy group which may be substituted with a carboxyl group, even if it is substituted with a carboxyl group and contains a sulfur atom or an oxygen atom in the carbon chain. a good lower alkyl group); n means 0, 1, 2 or 3, respectively; However, when R^3 is a carboxy group or a group substituted with a carboxy group, the carboxy group may be in the form of an ester or a salt. Moreover, when n is 2 or 3, R^3 can also be mutually different groups. ] A substituted heterocyclic compound represented by: