JPH06345722A - Thioacetal derivative - Google Patents

Abstract

PURPOSE:To obtain a new thioacetal derivative, capable of manifesting strong inhibiting activity against thiol proteases and usable as a therapeutic agent for Alzheimer disease, myodystrophia, cardiac infarction and cataract. CONSTITUTION:This compound is expressed by formula I [R<1> is H, R<6>-O-CO or R<6>-CO (R<6> is substitutive 6-14C aryl, substitutive 6-14C aryloxy, substitutive 1-20C alkyl or substitutive 6-14C aryl); R<2> and R<3> are 1-20C alkyl substitutive with 6-14C aryl; R<4> and R<5> are 1-10C alkyl substitutive with heterocyclic group or substitutive 6-14C aryl; n is 0 or 1] or its salt, e.g. (S)-1,1-bis(methylthio)-3-tert- butoxycarbonylamino-5-phenyl-2-pentanone. The compound expressed by formula I in which n is 0 and R<1> is R<6>-O-CO (formula VII) is obtained by using a diazomethyl ketone derivative expressed by formula II (Boc is tert- butoxycarbonyl) as a raw material according to a pathway indicated by the reactional formula.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thioacetal derivative, and more particularly to a novel thioacetal derivative having a strong inhibitory activity against thiol proteases such as papain, calpain and cathepsins.

[0002]

2. Description of the Related Art With the elucidation of the in vivo function of thiol proteases to which papain, calpain, cathepsins, etc. belong, it has been found that their abnormal promotion is the cause of various diseases. Is being used as a remedy for these diseases. For example, inhibitors of calpain are effective against animal models such as muscular dystrophy, cataracts, myocardial infarction, and delayed neuronal cell death after cerebral infarction.Inhibitors of cathepsins include cancer metastasis and muscle atrophy. It has been reported to be effective against dysfunction, osteoporosis, hypercalcemia and the like.
However, known thiol protease inhibitors such as peptidyl aldehyde and epoxysuccinic acid derivatives are
Since oral absorbability, tissue transferability, and cell membrane permeability are not so good, there is a demand for the development of a new thiol protease inhibitor that solves these problems.

[0003]

Therefore, the present inventors have arrived at the present invention as a result of conducting research on a thiol protease inhibitor which is excellent in oral absorbability, tissue translocation and cell membrane permeability.

[0004]

That is, the gist of the present invention is to provide a compound represented by the following general formula (I)

[0005]

[Chemical 2]

(R⁶Is C which may have a substituent₆~
C₁₄An optionally substituted aryl group or C
₆~ C₁₄C optionally substituted by an aryloxy group of
₁~ C ₂₀May have an alkyl group or a substituent
I C₆~ C₁₄Represents an aryl group of R)²And R
³Are each independently C₆~ C₁₄Substituted with an aryl group of
May be C₁~ C₂₀Represents an alkyl group of R,^FourOver
And R^FiveAre each independently substituted with a heterocyclic group
Good C₁~ C_TenHaving an alkyl group or a substituent of
May be C₆~ C₁₄Represents an aryl group, and n is 0 or
Which represents 1) or a thioacetal derivative represented by
Exists in salt.

The present invention will be described in detail below. Examples of the C _{1 to} C ₂₀ alkyl group defined by R ⁶ in the above general formula (I) include a methyl group, an ethyl group, a propyl group,
Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group , Undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group,
Examples of the alkyl group include phenyl group, naphthyl group, anthryl group, and other C _{6 to} C ₁₄ aryl groups or phenoxy groups, 1-naphthoxy group, 2-naphthoxy group, and other C _{6 to} C ₁₄ alkyl groups. It may be substituted with an aryloxy group. Further, examples of the C _{6 to} C ₁₄ aryl group include the above-mentioned substituents.

The C ₁ -C ₂₀ alkyl group represented by R ² and R ³ includes the same groups as defined for R ⁶ , and the alkyl group is the same as defined for R ^6. C
_It may be substituted with a _{6 to} C ₁₄ aryl group. Examples of the C _{1 to} C ₁₀ alkyl group represented by R ⁴ and R ⁵ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group. , Isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group, and the like, and the alkyl group is a furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring. , Dihydropyran ring, tetrahydropyran ring, benzofuran ring, isobenzofuran ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring,
Pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring,
Pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring,
Benzimidazole ring, purine ring, quinolidine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring,
Isoxazolidine ring, thiazole ring, thiazolidine ring,
1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom such as isothiazole ring, isothiazolidine ring, dioxane ring, dithian ring, morpholine ring and thiomorpholine ring, and the total number of atoms constituting the ring May be substituted with 5 to 10 heterocyclic residues. Examples of the C _{6 to} C ₁₄ aryl group include the same groups as defined for R ⁶ .

Further, in the above definition, the aryl ring located at the end of each substituent is further a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group. , Isobutyl group, sec
- butyl group, tert- butyl group, a pentyl group, an isopentyl group, an alkyl group of C ₁ -C _5, such as a neopentyl group; trifluoromethyl group; methoxy group, an ethoxy group,
A propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group,
C ₁ -C ₅ alkoxy groups such as isopentyloxy group;
Methylenedioxy group, ethylenedioxy group, propylenedioxy group, cyclic acetal residues of C ₁ -C _5, such as a butylene group; a hydroxyl group; an acetoxy group, propionyloxy group, butyryloxy groups, C such as a valeryloxy group an acyloxy group of ₂ -C _6; carboxyl group;
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, ter
t- butoxycarbonyl group, an alkoxycarbonyl group having C ₂ -C ₆ such as a pentyloxy group; an acetyl group, a propionyl group, a butyryl group, C ₂ such valeryl
To C ₆ acyl group; amino group; methylamino group, ethylamino group, propylamino group, isopropylamino group,
Butylamino group, isobutylamino group, tert- butylamino group, pentylamino group, monoalkylamino group of C ₁ -C _5, such as isopentyl amino group; a dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino Group, C ₂ such as diisopropylamino group
To C ₁₀ dialkylamino group; C _{2 to} C ₆ acylamino group such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group; carbamoyl group; methylcarbamoyl group; ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, tert- butylcarbamoyl group, an alkylcarbamoyl group of C ₂ -C ₆ such as a pentylcarbamoyl group; and a phenyl group, a tolyl group, a 1-naphthyl group, 2 - naphthyl group may have one or more substituents selected from aryl groups C ₆ -C _14, such as an anthryl group.

Further, in the general formula (I),
R², R³, R^Four, R^FiveAnd R⁶R²And R³
May each independently be substituted with a phenyl group.
I C₁~ C_TenAlkyl group of R^FourAnd R^FiveEach is German
And is substituted with a hetero ring such as a furan ring or a thiophene ring.
May be C₁~ C_FiveAlkyl group or phenyl
Group, R⁶Is a halogen atom, C₁~ C_FiveAlkoxy group
C which may be substituted with ₆~ C_TenIf the aryl group of
Or C optionally substituted with an aryloxy group₁~ C
_TenAlkyl group or halogen atom, trifluoro
C which may have a substituent such as a chill group₆~ C_TenThe ant
Group is mentioned as a preferred group.

The thioacetal derivative of the present invention represented by the general formula (I) can form a pharmaceutically acceptable salt. Specific examples of such salts include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, or ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium when an acidic group is present. Salts, ammonium salts such as dicyclohexyl ammonium salts can be formed, and when basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, or methanesulfonic acid. Salt, benzene sulfonate, paratoluene sulfonate, acetate, propionate, tartrate,
Can form organic acid salts such as fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate etc. .

Regarding the configurations of the asymmetric carbons present in the thioacetal derivative represented by the above general formula (I), the configurations (R), (S), or (RS) are independent of each other.
Can take body. Specific examples of the thioacetal derivative represented by the general formula (I) include compounds shown in Table 1 below when n = 0 and compounds shown in Table 2 below when n = 1. Is mentioned.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

[0016]

[Table 4]

[0017]

[Table 5]

[0018]

[Table 6]

[0019]

[Table 7]

[0020]

[Table 8]

[0021]

[Table 9]

[0022]

[Table 10]

[0023]

[Table 11]

[0024]

[Table 12]

[0025]

[Table 13]

[0026]

[Table 14]

[0027]

[Table 15]

[0028]

[Table 16]

[0029]

[Table 17]

[0030]

[Table 18]

[0031]

[Table 19]

[0032]

[Table 20]

[0033]

[Table 21]

[0034]

[Table 22]

[0035]

[Table 23]

[0036]

[Table 24]

[0037]

[Table 25]

[0038]

[Table 26]

[0039]

[Table 27]

[0040]

[Table 28]

[0041]

[Table 29]

[0042]

[Table 30]

[0043]

[Table 31]

[0044]

[Table 32]

[0045]

[Table 33]

[0046]

[Table 34]

[0047]

[Table 35]

[0048]

[Table 36]

Next, a method for producing the compound of the present invention will be described. The thioacetal derivative represented by the above general formula (I) can be produced, for example, by the following method.

[0050]

[Chemical 3]

(In the above general formula, R ³ , R ⁴ , R ⁵
And R ⁶ are as previously defined, and B _OC is t
represents an ert-butoxycarbonyl group. ) Methods known in literature (Methods in Enzymology, Volume 80, 820)
Page, 1981), the diazomethylketone derivative represented by the above general formula (II) can be easily produced using methylene chloride, chloroform, 1,2-dichloroethane, dimethylformamide, 1,3-dimethylimidazolidinone. When dissolved in a solvent such as the above and added with the sulfenyl chloride derivative represented by R ⁴ SCl, the α-chloro-α-thiomethylketone derivative represented by the above general formula (III) is obtained. Next, the compound (III) is dissolved in diethyl ether, tetrahydrofuran, dioxane, dimethylformamide or the like, and R is added in the presence of a base such as pyridine, triethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide.
^{When the} thiol represented by ^5- SH is reacted, the compound represented by the above general formula (IV) is obtained. When the B _OC group of the compound (IV) is deprotected with acidic conditions such as hydrogen chloride-ethyl acetate, hydrogen chloride-dioxane, hydrogen chloride-ethanol, hydrobromic acid-acetic acid, etc., it is represented by the above formula (V). The amine salt is obtained. This compound (V) is added in the presence of an amine such as pyridine and triethylamine.

[0052]

[Chemical 4]

By reacting with an acyl chloride represented by the formula (VI), a compound represented by the above general formula (VI) is obtained.

[0054]

[Chemical 5]

By reacting the chloroformate represented by the formula (1), the compound represented by the above general formula (VII) is obtained.
Furthermore, the condensation reaction can be carried out by the following method.

[0056]

[Chemical 6]

(In the above general formula, R ² , R ³ ,
R ⁴ , R ⁵ , R ⁶ and B _OC are as defined above. ) In the presence of a base such as pyridine, triethylamine, sodium hydroxide, potassium hydroxide, etc., the carboxyl group of the B _OC -amino acid represented by the above general formula (VIII), in the presence of dicyclohexylcarbodiimide, oxalyl chloride,
Activated with a condensing agent such as carbonyldiimidazole, isobutyl chloroformate, diphenylphosphoryl azide,
Subsequently, if necessary, the compound represented by the general formula (IX) is obtained by reacting the compound represented by the general formula (V) in the presence of a base such as pyridine or triethylamine. Next, the B _OC group of the compound (IX) is deprotected under the acidic condition as described above to obtain the compound represented by the above formula (X). Further, the compound (X) is added in the same manner as described above.

[0058]

[Chemical 7]

By reacting with a chloroformate represented by the formula (1), the compound represented by the above general formula (XI) or (XII) is obtained. In clinical application of the compound of the present invention, the ratio of therapeutically effective ingredient to carrier ingredient is 1
It can vary between wt% and 90 wt%. For example, the compound of the present invention may be orally administered in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or other internal liquid preparations. Alternatively, it may be administered intravenously, intramuscularly or subcutaneously as an injection. It can also be used as a suppository. Alternatively, it may be made into powder for injection and prepared at the time of use. Oral,
Pharmaceutical organic or inorganic solid or liquid carriers or diluents suitable for enteral and parenteral administration can be used for preparing the medicament of the present invention. Excipients used when producing a solid preparation include, for example, lactose, sucrose, starch,
Talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid formulations for oral administration,
That is, emulsions, syrups, suspensions, other liquids for internal use and the like contain a generally used inert diluent such as water or vegetable oil. In addition to the inert diluent, this preparation may contain additives such as a wetting agent, a suspension aid, a sweetening agent, an aromatic agent, a coloring agent or a preservative. It may be made into a liquid formulation and contained in a capsule of an absorbent substance such as gelatin. Formulations for parenteral administration, that is, as a solvent or suspending agent used for producing injections, suppositories, etc., include, for example, water, propylene glycol, polyethylene glycol,
Examples thereof include benzyl alcohol, ethyl oleate, and lecithin. Examples of the base used in suppositories include cocoa butter, emulsified cocoa butter, laurin butter, Witepsol and the like. The preparation method of the preparation may be a conventional method.

When used by oral administration, the clinical dose is generally 0.01 to 1000 mg per day for adults as the compound of the present invention, but depending on age, disease state and symptoms. It is more preferable to increase or decrease appropriately. The above-mentioned daily dose of the drug of the present invention may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently. When used as an injection, a single dose of the compound of the present invention for adults is 0.1.
It is desirable to administer 001-100 mg continuously or intermittently.

[0061]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these reference examples and examples as long as the gist thereof is not exceeded.

Example 1 (S) -1,1-bis (methylthio) -3-tert-butoxycarbonylamino-5
-Phenyl-2-pentanone (Compound No. 3 in Table-1
7) Production of 160 mg of dimethyl disulfide in 5 ml of methylene chloride
And cooled to 0 ° C., and 233 mg of sulfuryl chloride is added. After 15 minutes, tert-butoxycarbonyl-L
-Homophenylalanine diazomethyl ketone 1.03
g and stir at room temperature for 5 hours. Next, aqueous sodium hydrogen carbonate was added to the reaction solution, extraction was performed with methylene chloride, the extract was washed with saturated saline, and then the solvent was distilled off under reduced pressure.
3 g are obtained. This is dissolved in 10 ml of tetrahydrofuran, 238 mg of sodium methanethiolate is added, and the mixture is stirred overnight at room temperature, then water is added. Extraction with diethyl ether, washing the extract with saturated brine, drying over magnesium sulfate, filtration, concentration, and purification by silica gel column chromatography (developing solvent 10% ethyl acetate in hexane) gave 288 mg of the desired product. To be IR (KBr, cm ^-1 ) 3376, 1705, 1686. NMR (CDCl ₃ , δ) 1.46 (S, 9H), 1.89 (m, 1H), 2.02 (S, 3H), 2.07
(S, 3H), 2.20 (m, 1H), 2.68 (t, J = 8.1Hz, 2H), 4.63 (S, 1H), 4.
72 (m, 1H), 5.07 (d, J = 8.3Hz, 1H), 7.13-7.36 (m, 5H).

Example 2 (S) -3-Amino-1,1-
Bis (methylthio) -5-phenyl-2-pentanone
Production of Hydrochloride (Compound No. 34 in Table-1) (S) -1,1-bis (methylthio) -3-tert-butoxycarbonylamino-5-obtained in Example 1
278 mg of phenyl-2-butanone was dissolved in 1 ml of diethyl ether, and 4 m of ethyl acetate containing 4N hydrogen chloride was added.
l was added and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. Diethyl ether (4 ml) was added to the residue, and the produced powder was filtered and washed with diethyl ether.
mg is obtained. IR (KBr, cm ^-1 ) 3401,3243,1709. NMR (CD ₃ OD, δ) 2.03 (S, 3H), 2.16 (S, 3H), 2.08-2.42 (m, 2
H), 2.72 (m, 2H), 4.62 (m, 1H), 5.01 (S, 1H), 7.18-7.40 (m, 5
H).

Example 3 (S) -1,1-bis (methylthio) -3-((S) -2-tert-butoxycarbonylamino-4-methylvalerylamino) -5-phenyl-2-pentanone ( Preparation of compound No. 114) in Table-2 tert-butoxycarbonyl-L-leucine 210m
g was dissolved in methylene chloride 5 ml, cooled to -5 ° C, triethylamine 85 mg and isobutyl chloroformate 10 were added.
Add 6 mg. Obtained in Example 2 after 20 minutes (S)
-3-Amino-1,1-bis (methylthio) -5-phenyl-2-pentanone hydrochloride (215 mg) and triethylamine (71 mg) are added, and the mixture is further stirred for 1 hour, and water is added. After extraction with methylene chloride, the extract was washed with saturated brine, filtered, concentrated, and purified by silica gel column chromatography (developing solvent 10% ethyl acetate-containing hexane) to obtain 216 mg of the desired product. IR (KBr, cm ^-1 ) 3353,3272,1709,1688,1647.NMR (CDCl ₃ , δ) 0.88-1.02 (m, 6H), 1.44 (S, 9H), 1.38-1.55
(m, 1H), 1.58-1.78 (m, 2H), 1.97 (m, 1H), 1.99 (S, 3H), 2.06
(S, 3H), 2.26 (m, 1H), 2.66 (d, J = 7.9Hz, 2H), 4.09 (m, 1H), 4.
60 (S, 1H), 4.68-4.85 (m, 1H), 4.98 (m, 1H), 6.67 (m, 1H), 7.1
1-7.38 (m, 5H).

Example 4 (S) -3-((S) -2-Amino-4-methylvalerylamino) -1,1-bis (methylthio) -5-phenyl-2-pentanone hydrochloride (Table- Preparation of Compound No. 112 of 2) (S) -1,1-bis (methylthio) -3-((S) -2-tert-butoxycarbonylamino-4-methylvalerylamino) obtained in Example 3) 207 mg of 5-phenyl-2-pentanone was dissolved in 2 ml of ethyl acetate containing 4N hydrogen chloride, stirred at room temperature for 20 minutes, added with 2 ml of diethyl ether, and the formed crystals were filtered and washed with diethyl ether. 114 mg of the product are obtained. NMR (CD ₃ OD, δ) 1.01 (d, J = 5.9Hz, 3H), 1.03 (d, J = 5.9Hz, 3
H), 1.60-1.83 (m, 3H), 1.97 (m, 1H), 1.99 (S, 3H), 2.06 (S, 3
H), 2.21 (m, 1H), 2.68 (m, 2H), 3.93 (t, J = 8.1Hz, 1H), 4.83
(S, 1H), 4.98 (dd, J = 7.7Hz, 2.8Hz, 1H), 7.13-7.31 (m, 5H).

Example 5 (S) -1,1-bis (methylthio) -3-[(S) -4-methyl-2- (4-trifluoromethylbenzoylamino) valerylamino] -5
-Phenyl-2-peptanone (Compound No. 12 in Table-2
Preparation of 9) 28 mg of 4-trifluoromethylbenzoic acid was dissolved in 2 ml of methylene chloride and cooled to 0 ° C., and triethylamine 1 was added.
Add 5 mg and 18 mg isobutyl chloroformate. 1
After 5 minutes, (S) -3-((S) -2 obtained in Example 4).
-Amino-4-methylvalerylamino) -1,1-bis (methylthio) -5-phenyl-2-pentanone hydrochloride (56 mg) and triethylamine (14 mg) were added, and the mixture was further stirred for 2 hours, water was added, and methylene chloride was added. Extract. The extract is washed with saturated brine, dried over magnesium sulfate, filtered, concentrated, and recrystallized from hexane-ethyl acetate to obtain 28 mg of the target product. Melting point 186-188 ° C. IR (KBr, cm ^-1 ) 3312, 1721, 1636. NMR (CDCl ₃ , δ) 0.98 (d, J = 5.3Hz, 6H), 1.60-1.85 (m, 3H), 2.
01 (m, 1H), 2.04 (S, 3H), 2.09 (S, 3H), 2.25 (m, 1H), 2.65 (t, J
= 8.1Hz, 2H), 4.59 (S, 1H), 4.64 (m, 1H), 5.02 (m, 1H), 6.59
(d, J = 8.9Hz, 1H), 6.63 (d, J = 8.3Hz, 1H), 7.08-7.35 (m, 5H),
7.70 (d, J = 8.3Hz, 2H), 7.90 (d, J = 8.3Hz, 2H). By the same method as in Examples 1, 2, 3, 4 and 5, the following compounds were produced. The physical properties will be described below.

Example 6 Preparation of (S) -1,1-bis (methylthio) -3-isobutoxycarbonylamino-5-phenyl-2-pentanone (Compound No. 36 in Table 1) IR (neat, cm ^{− _{1) 3326,1699,1603. NMR (CDCl 3}} , δ) 0.93 (d, J = 6.7Hz, 6H), 1.80-2.35 (m, 3H), 2.
02 (S, 3H), 2.08 (S, 3H), 2.69 (t, J = 8.5Hz, 2H), 3.88 (d, J = 6.
7Hz, 2H), 4.60 (S, 1H), 4.81 (m, 1H), 5.26 (d, J = 7.8Hz, 1H),
7.16-7.38 (m, 5H).

Example 7 (1RS, 3S) -3-ter
t-butoxycarbonylamino-1-methylthio-4-
Preparation of phenyl-1-phenylthio-2-butanone (Compound No. 26 in Table 1) NMR (CDCl ₃ , δ) 1.43 (S, 9H), 1.89 (S, 1.5H), 2.02 (S, 1.5H),
2.95-3.18 (m, 2H), 4.58 (S, 0.5H), 4.75 (S, 0.5H), 4.75-5.2
0 (m, 2H), 7.10-7.36 (m, 9H), 7.36-7.45 (m, 1H).

Example 8 (S) -1,1-bis (methylthio) -3-[(S) -2- (4-methoxyphenoxyacetylamino) -4-methylvalerylamino] -5-
Phenyl-2-pentanone (Compound No. 12 in Table-2
4) Production IR (neat, cm ^-1 ) 3287,1713,1651,1605. NMR (CDCl ₃ , δ) 0.92 (d, J = 5.8Hz, 3H), 0.94 (d, J = 4.8Hz, 3
H), 1.45-1.80 (m, 3H), 1.95 (m, 1H), 2.01 (S, 3H), 2.08 (S, 3
H), 2.23 (m, 1H), 2.63 (t, J = 8.4Hz, 2H), 3.76 (S, 3H), 4.48
(S, 2H), 4.51 (m, 1H), 4.60 (S, 1H), 4.99 (m, 1H), 6.62 (d, J =
8.4Hz, 1H), 6.78-6.95 (m, 5H), 7.08-7.35 (m, 5H).

Example 9 (3S) -3-((S) -2-
Preparation of benzyloxycarbonylamino-4-methylvalerylamino) -1-methylthio-4-phenyl-1-phenylthio-2-butanone (Compound No. 93 of Table-2) IR (KBr, cm ^-1 ) 3410,3325 _{, 1712,1705,1655,1635. NMR (CDCl 3,} δ) 0.78-1.03 (m, 6H), 1.38-1.72 (m, 3H), 1.94
(S, 3H), 2.92-3.19 (m, 2H), 4.12 (m, 1H), 4.67 (S, 1H), 4.99
(S, 1H), 5.08 (S, 2H), 5.24 (d, J = 7.5Hz, 1H), 6.46 (d, J = 7.3H
z, 1H), 7.10-7.55 (m, 15H).

Example 10 (3S) -3-((S) -2
-Benzyloxycarbonylamino-4-methylvalerylamino) -1-furfurylthio-4-phenyl-1-phenylthio-2-butanone (Compound No. 98 of Table-2)
Manufacture of melting point 136-137 ℃ IR (KBr, cm ^-1 ) 3402,3250,1708,1632.NMR (CDCl ₃ , δ) 0.89 (d, J = 5.9Hz, 6H), 1.33-1.72 (m, 3H) , 2.
87 (dd, J = 14Hz, 7.2Hz, 1H), 3.04 (dd, J = 14Hz, 7.2Hz, 1H), 3.
73 (d, J = 15Hz, 1H), 3.95 (d, J = 15Hz, 1H), 4.08 (m, 1H), 4.75
(S, 1H), 4.96 (d, J = 7.8Hz, 1H), 5.08 (S, 2H), 5.23 (q, J = 7.2H
z, 1H), 6.17 (d, J = 2.9Hz, 1H), 6.31 (m, 1H), 6.45 (d, J = 7.4H
z, 1H), 6.99-7.10 (m, 2H), 7.15-7.43 (m, 14H).

Test Example Measurement of Calpain Inhibitory Activity From the rat brain, the method described in the literature (Journal of Biological Ch
m-calpain was purified by emistry, 259, 3210, 1984), and its inhibitory activity was determined by the method described in the literature (Journa
l of Biological Chemistry, 259, 12489, 1984
Year). The results are shown in Table-3.

From Table 3, it can be seen that the compounds of the present invention show inhibitory activity against thiol protease such as calpain.

[0074]

[Table 37]

[0075]

The thioacetal derivative of the present invention exhibits an inhibitory activity against thiol proteases such as papain, cathepsin B, cathepsin H, cathepsin L and calpain, and therefore, muscular dystrophy, cataract, myocardial infarction,
It can be used as a therapeutic agent for stroke, Alzheimer's disease, muscular atrophy, osteoporosis, hypercalcemia and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07C 323/29 7419-4H 323/32 7419-4H C07D 307/38 333/18 (72) Inventor Kaho Tamao 1000, Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Sanryo Kasei Co., Ltd.

Claims (1)

[Claims] 1. The following general formula (I):(R⁶Is C which may have a substituent₆~ C₁₄Ally
C which may have a substituent or a substituent₆~ C₁₄A
C optionally substituted with a reeloxy group₁~ C ₂₀A
Alkyl group or C optionally having substituent (s)₆~ C₁₄
Represents an aryl group of R)²And R³Are each
Independently C₆~ C₁₄May be substituted with the aryl group of
I C₁~ C₂₀Represents an alkyl group of R,^FourAnd R^FiveIs it
C each independently substituted with a heterocyclic group₁~
C_TenAn optionally substituted alkyl group or C₆
~ C₁₄Represents an aryl group, and n represents 0 or 1. )
A thioacetal derivative represented by or a salt thereof.