JPH10101558A - Medicine for treating ischemic diseases - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine containing an oxygen-containing heterocyclic derivative as an active ingredient and enabling to treat ischemic diseases. SOLUTION: This medicine for treating ischemic diseases contains an oxygen- containing heterocyclic derivative of the formula (R<1> is R<4> -CO, R<4> -O-CO, R<4> -SO2 ; R<4> is an alkyl, an aryl, a cycloalkyl; R<2> is a 1-6C alkyl; R<3> is H, an acyl), its salt or its solvate or hydrate as an active ingredient. The comound includes (3R)-3-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)-2-tetrahydrofu ranol. The content of the compound of the formula is 1-90wt.%. The compound is orally administered at a daily dose of 0.01-1000mg for an adult or injected at a daily dose of 0.001-100mg for an adult. The medicine is useful for treating apoplexy, ischemic brain diseases, cerebral thrombosis, cerebral embolism, cardiac infarction, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel therapeutic agent for ischemic disease.

[0002]

BACKGROUND OF THE INVENTION Cerebral vascular disorders, which are widely known as strokes, have various types of hemorrhagic and ischemic diseases, and are one of the three leading causes of death in Europe, the United States and Japan. And its prevention and treatment is 21
This is an important medical problem in the aging society of the 21st century. In recent years, fatal cerebral hemorrhage has been decreasing, but ischemic brain disease is said to be increasing, and it is thought that in the aging society, patients in the chronic phase of ischemic brain disease will further increase. Can be Such patients may suffer from cerebrovascular dementia, and the importance of appropriate treatment is expected to increase further in the future, and the development of effective drugs for this is desired.

[0003] Also, coronary vascular disorders such as myocardial infarction have been a problem in Europe and the United States, but in Japan as well, the number of people with advanced arteriosclerosis has rapidly increased with the westernization of diet. The number of people who develop myocardial infarction, a blood disease, is also increasing. Since myocardial infarction is a fatal disease, it is desired to develop a drug that is surely effective against the attack. The present invention addresses such a need.

[0004]

The therapeutic agent for ischemic disease according to the present invention has the following general formula (I):

[0005]

Embedded image

(In the above general formula, R¹Is R^Four-CO-, R
^Four-O-CO- or R^Four-SO _Two− (R^FourIs a substituent
C which may have₆~ C₁₄Substituted with an aryl group of
May be C₁~ C₂₀An alkyl group of C_Three~ C₈No
A cycloalkyl group; or a C which may have a substituent₆
~ C₁₄Represents an aryl group of the formula:^TwoIs C₁~
C₆Represents an alkyl group of^ThreeIs a hydrogen atom or R^Five
-CO- (R^FiveIs C₁~ C_TenRepresents an alkyl group)
Where A is C₁~ C_ThreeMay have an alkyl group of
C₁~ C_ThreeRepresents an alkylene group)
Heterocyclic derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
Or a hydrate as an active ingredient.

Hereinafter, the present invention will be described in detail. Up
In the general formula (I), R^FourC defined by₁~ C₂₀
Examples of the alkyl group include a methyl group, an ethyl group, and a propyl
Group, isopropyl group, butyl group, isobutyl group, sec
-Butyl group, tert-butyl group, pentyl group, isope
Ethyl group, neopentyl group, tert-pentyl group, f
Xyl group, isohexyl group, heptyl group, octyl group,
Nonyl, decyl, undecyl, dodecyl, tri
Decyl group, tetradecyl group, pentadecyl group, hexade
Sil group, heptadecyl group, octadecyl group, nonadecyl
Group, icosyl, etc., preferably a methyl group or
Lidecyl group, tetradecyl group, pentadecyl group, hexa
C such as decyl group₁₃~ C₁₆Alkyl group. This
These alkyl groups are phenyl, naphthyl, ant
C such as a ril group₆~ C₁₄Even if it is substituted with an aryl group of
Good. In addition, these aryl groups are described further below.
Other substituents may be present. C_Three~ C ₈Cycloa
As the alkyl group, cyclopropyl group, cyclobutyl
Group, cyclopentyl group, cyclohexyl group, cyclohep
Examples include a tyl group and a cyclooctyl group. C₆~ C₁₄
Examples of the aryl group include a phenyl group, a naphthyl group, an an
And a tolyl group. These aryl groups further include
Halogen atoms such as a fluorine atom, a chlorine atom and a bromine atom;
Chill, ethyl, propyl, isopropyl, buty
Group, isobutyl group, sec-butyl group, tert-butyl group
Tyl group, pentyl group, isopentyl group, neopentyl
C, tert-pentyl group, etc.₁~ C_FiveThe alkyl of
Group; trifluoromethyl group; carboxyl group; nitro
A hydroxyl group; a methylenedioxy group; and a methoxy group;
Ethoxy, propoxy, isopropoxy, butoxy
Si group, isobutoxy group, tert-butoxy group, pliers
C such as a ruoxy group and an isopentyloxy group₁~ C_FiveNo
Having one or more substituents selected from alkoxy groups
You may.

When R ¹ represents R ⁴ CO—, R ⁴
Is a C ₁ -C ₂₀ alkyl group which may be substituted with a C ₆ -C ₁₄ aryl group which may have a substituent,
Unsubstituted alkyl group having ₁₄ -C ₁₆ or is preferably an aryl group optionally C ₆ -C ₁₄ which may have a substituent. Also, A is preferably an alkylene group of C ₁ -C _3. Particularly preferred are those in which R ⁴ is a C ₁₄ -C ₁₆ alkyl group and A is a C ₁ -C ₃ alkylene group.

When R ¹ represents R ⁴ OCO—, R ^1
4 is a C ₁ -C ₂₀ alkyl group which may be substituted with a C ₆ -C ₁₄ aryl group which may have a substituent, particularly a C ₁₃ -C ₁₅ unsubstituted alkyl group; ₃ is preferably a cycloalkyl group -C _8. A is C _1-
Preferably an alkylene group of C _3. Especially preferred, R ⁴ is an alkyl group of C ₁₃ ~C _15, A is C ₁
To C ₃ alkylene groups.

When R ¹ represents R ⁴ SO ₂ —, R 1
⁴ is preferably a C ₁ -C ₂₀ alkyl group or a C ₆ -C ₁₄ aryl group which may have a substituent. Particularly preferred among the alkyl groups, an alkyl group of C ₁₄ -C _16. Examples of the C ₁ -C ₆ alkyl group defined by R ² include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and an isopentyl group. , A neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, and the like.

The C ₁ -C ₁₀ alkyl group defined by R ⁵ includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group,
Examples include a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group.

Examples of the C ₁ -C ₃ alkylene group defined by A include a methylene group, an ethylene group and a propylene group. Such an alkylene group includes a methyl group, an ethyl group,
It may have one or two C ₁ -C ₃ alkyl groups such as a propyl group. Generally, A is preferably an unsubstituted alkylene group.

Particularly preferred compounds include (3S)-
3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol,
(2S, 3S) -2-acetoxy-3-((S) -4-
Methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran, (3S) -3-{(S) -4
-Methyl-2- (2,4,6-trimethylphenylsulfonylamino) valerylamino} -2-tetrahydrofuranol, (2S, 3S) -2-acetoxy-3-
{(S) -4-methyl-2- (2,4,6-trimethylphenylsulfonylamino) valerylamino} tetrahydrofuran,

(3S) -3-((S) -4-methyl-2
-Pentadecanoylaminovalerylamino) -2-tetrahydrofuranol, (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecanoylaminovalerylamino) tetrahydrofuran, (3S )-
3-((S) -2-hexadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol,
(2S, 3S) -2-acetoxy-3-((S) -2-
Hexadecanoylamino-4-methylvalerylamino)
Tetrahydrofuran, (3S) -3-((S) -2-heptadecanoylamino-4-methylvalerylamino)-
2-tetrahydrofuranol,

(2S, 3S) -2-acetoxy-3-
((S) -2-heptadecanoylamino-4-methylvalerylamino) tetrahydrofuran, (3S) -3-
((S) -4-methyl-2-tridecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, (2S, 3S) -2-acetoxy-3-((S)-
4-methyl-2-tridecyloxycarbonylaminovalerylamino) tetrahydrofuran, (3S) -3-
((S) -4-methyl-2-tetradecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, (2S, 3S) -2-acetoxy-3-((S)
-4-methyl-2-tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran,

(3S) -3-((S) -4-methyl-2
-Pentadecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, (2S, 3S)-
2-acetoxy-3-((S) -4-methyl-2-pentadecyloxycarbonylaminovalerylamino) tetrahydrofuran, (3S) -3-((S) -4-methyl-2-tetradecylsulfonylaminovale Lilamino)
-2-tetrahydrofuranol, (2S, 3S) -2-
Acetoxy-3-((S) -4-methyl-2-tetradecylsulfonylaminovalerylamino) tetrahydrofuran, (3S) -3-((S) -4-methyl-2-pentadecylsulfonylaminovalerylamino) -2-tetrahydrofuranol,

(2S, 3S) -2-acetoxy-3-
((S) -4-methyl-2-pentadecylsulfonylaminovalerylamino) tetrahydrofuran, (3S)-
3-((S) -2-hexadecylsulfonylamino-4
-Methylvalerylamino) -2-tetrahydrofuranol, (2S, 3S) -2-acetoxy-3-((S)-
2-hexadecylsulfonylamino-4-methylvalerylamino) tetrahydrofuran, (3S) -4-methyl-3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol, And their salts, solvates, and hydrates thereof. In addition, as a compound related to the compound represented by the general formula (I), a compound represented by the following general formula (A) is known (Japanese Patent Application Laid-Open No. Hei 8-104686).

[0018]

Embedded image

(Wherein, R ¹ and R ² are the same or different and each represents hydrogen or a hydrocarbon group which may be substituted, R ³ represents a carboxyl group or an acyl group which may be esterified; Represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1, provided that m and n
When both are 0, R ³ represents a carboxyl group or an acyl group which has 7 or more carbon atoms and may be esterified.) However, the compounds of the above general formula (A) are used for cathepsin L inhibitors, bone It is an absorption inhibitor, a preventive and therapeutic agent for bone litigation, and it is not known that the compound represented by the general formula (I) has calpain inhibitory activity and can be used as a therapeutic agent for ischemic disease.

The therapeutic agent for ischemic disease of the present invention represented by the above general formula (I) can be used as a pharmaceutically acceptable salt. Specific examples of such salts include lithium salts,
Metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt and the like, or ammonium salts such as ammonium salt, methyl ammonium salt, dimethyl ammonium salt, trimethyl ammonium salt, dicyclohexylammonium salt and the like can be formed. Further, the therapeutic agent for ischemic disease of the present invention represented by the above general formula (I) can be used as a solvate or hydrate.

The stereochemistry of the asymmetric carbon present in the therapeutic agent for ischemic disease of the present invention represented by the general formula (I) is independently (R) -form, (S) -form or (RS-form). ) Can take body. Specific examples of the therapeutic agent for ischemic disease of the present invention represented by the above general formula (I) include, when R ³ is a hydrogen atom, compounds shown in Table 1 below, and R ³ is not a hydrogen atom. In such a case, the compounds shown in Table 2 below can be mentioned.

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

[0028]

[Table 7]

[0029]

[Table 8]

[0030]

[Table 9]

[0031]

[Table 10]

[0032]

[Table 11]

[0033]

[Table 12]

[0034]

[Table 13]

[0035]

[Table 14]

[0036]

[Table 15]

[0037]

[Table 16]

[0038]

[Table 17]

[0039]

[Table 18]

[0040]

[Table 19]

[0041]

[Table 20]

[0042]

[Table 21]

[0043]

[Table 22]

[0044]

[Table 23]

[0045]

[Table 24]

[0046]

[Table 25]

[0047]

[Table 26]

[0048]

[Table 27]

[0049]

[Table 28]

[0050]

[Table 29]

[0051]

[Table 30]

[0052]

[Table 31]

[0053]

[Table 32]

[0054]

[Table 33]

[0055]

[Table 34]

[0056]

[Table 35]

[0057]

[Table 36]

[0058]

[Table 37]

[0059]

[Table 38]

[0060]

[Table 39]

[0061]

[Table 40]

[0062]

[Table 41]

[0063]

[Table 42]

[0064]

[Table 43]

[0065]

[Table 44]

[0066]

[Table 45]

[0067]

[Table 46]

[0068]

[Table 47]

[0069]

[Table 48]

[0070]

[Table 49]

[0071]

[Table 50]

[0072]

[Table 51]

[0073]

[Table 52]

[0074]

[Table 53]

[0075]

[Table 54]

[0076]

[Table 55]

The active ingredient of the therapeutic agent for ischemic disease represented by the above general formula (I) can be produced, for example, by the following method.

[0078]

Embedded image

(In the above general formula, R ¹ , R ² and A are as defined above.) The amino acid derivative represented by the above general formula (II) is optionally substituted with a base such as triethylamine or pyridine. under,
The carboxylic acid is activated by reacting with a condensing agent such as dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, oxalyl chloride, isobutyl chloroformate, thionyl chloride, and then reacting the lactone derivative represented by the above general formula (III). Then, the compound represented by the above general formula (IV) is obtained. As a solvent used for the condensation reaction, a solvent suitable for each condensing agent may be appropriately selected and used, and the reaction conditions may be performed under conditions suitable for each condensing agent. Next, the obtained compound (IV) was treated with diisobutylaluminum hydride, sodium borohydride /
When treated with a reducing agent such as cerium chloride, the above general formula (V)
Can be obtained.

[0080]

Embedded image

(In the above general formula, R ¹ , R ² ,
R ⁵ and A are as defined above. Compound (V) produced by Production Method 1 was converted to methylene chloride, 1,2-dichloroethane, dimethylformamide,
N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetonitrile, dissolved in an organic solvent such as toluene,
By reacting the acid anhydride represented by the above general formula (R ⁵ CO) ₂ O in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, etc., the compound represented by the above formula (VI) can be obtained. it can. This reaction can be performed without a solvent.

In the above series of operations, protection and deprotection of a functional group may be required in some cases. In this case, a protecting group suitable for the functional group is selected, and an experimental operation is performed by a method known in the literature. What is necessary is just to perform using. Among the compounds represented by the above general formula (I), compounds (V) wherein R ³ is a hydrogen atom
Shows strong inhibitory activity against calpain, one of the cysteine proteases. R ³ is R ⁵ —CO—
(R ⁵ represents an alkyl group of C ₁ -C ₁₀₎ the compound of (VI) may be used as prodrugs of lactol derivatives showing strong inhibitory activity against calpain (V). That is, when the compound (VI) is orally administered, the lactol derivative (V), which is the active substance, is immediately released by the action of enzymes in the body after being absorbed from the intestinal tract and the like.

[0083]

Embedded image

When the brain becomes ischemic, such as a cerebral thrombus or a cerebral embolus, excitatory amino acids such as glutamic acid are released from the presynaptic terminal in large quantities, and the excitatory amino acid receptor at the postsynaptic terminal is activated. Na ⁺ and Ca ²⁺ flow into the cell through the ion channel. When Na ⁺ enters the cell, depolarization proceeds and the Ca ²⁺ channel of the nerve cell is opened, causing further influx of Ca ²⁺ . This results in a very high Ca ²⁺ concentration in the cells, activating calpain. Known as calpain substrates are microtubule-associated proteins and cytoskeletal proteins such as fodrin. Activated calpain degrades these proteins, which breaks cell membranes and leads to brain cells (Dementia, Vol. 7). , 161 pages, 1993
Year). It is thought that if a calpain inhibitor is present in nerve cells during cerebral ischemia, it is possible to prevent the cell membrane from being degraded. Therefore, calpain inhibitors are expected to be therapeutic agents for cerebral ischemic diseases.

In the case of myocardial infarction, which is an ischemic disease in the heart, the same effect as in nerve cells during cerebral ischemia also occurs in cardiomyocytes and calpain is activated. It is considered prone to get up. Myofin proteins such as myosin heavy chain, troponin T, troponin I, tropomyosin, α-actinin and the like are known as calpain substrates (Muscular Dyst).
rophy, 265 pages, University of Tokyo Press, 1980
), Activated calpain degrades these proteins, leading to cardiomyocyte death. Therefore, calpain inhibitors are considered to be therapeutic agents for myocardial infarction.

In applying the drug of the present invention to clinical applications, the ratio of a therapeutically effective ingredient to a carrier ingredient is usually 1% by weight to 90% by weight. The drug of the present invention may be orally administered in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, or intravenously as injections. It may be administered intramuscularly, intramuscularly or subcutaneously. It can also be used as a suppository. In addition, it may be used as powder for injection and prepared for business. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral use can be used to prepare the agents of the present invention. As an excipient used for producing a solid preparation, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as water or vegetable oils. The formulation may contain, in addition to the inert diluent, auxiliaries such as wetting agents, suspending auxiliaries, sweetening agents, fragrances, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Examples of the preparation for parenteral administration, that is, a solvent or a suspension used for producing an injection, a suppository, etc. include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. As the base used for suppositories, for example, cocoa butter, emulsified cocoa butter, laurin fat, witepsol and the like can be mentioned. The preparation method of the preparation may be a conventional method.

The clinical dose, when used orally, is generally 0.01 to 1000 mg per day as an active ingredient compound for an adult, but may be appropriately adjusted depending on age, disease state and symptoms. Is more preferable. The daily dose of the agent of the present invention may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently. When used as an injection, the compound of the present invention may be administered to an adult in a daily dose of 0,1.
It is desirable to administer 001 to 100 mg continuously or intermittently.

[0088]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto unless it exceeds the gist thereof.

Reference Example 1 (S) -3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino)
Preparation of -2-tetrahydrofuranone 6 ml of thionyl chloride was cooled to -5 ° C, and 998 mg of N-phenylsulfonyl-L-leucine was added.
After stirring for 0 minutes, the mixture was returned to room temperature and further stirred for 3 hours.
Next, the reaction solution was concentrated under reduced pressure, 10 ml of toluene was added to the obtained residue, and the mixture was concentrated to obtain crude N-phenylsulfonyl-L-leucyl chloride as a residue. The obtained crude N-phenylsulfonyl-L-leucyl chloride was dissolved in 20 ml of methylene chloride, and 443 mg of L-homoserine lactone hydrochloride and 0.9 ml of triethylamine were added under ice-cooling.
46 ml were added. The reaction solution was stirred for 15 minutes under ice cooling, and further stirred at room temperature for 1.5 hours. After completion of the reaction, dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with methylene chloride. Extract water with water,
After washing with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in that order, drying over magnesium sulfate was performed, followed by filtration. Concentrate the filtrate,
10 ml of ethyl acetate and hexane 20 were added to the obtained residue.
The resulting crystals were collected by filtration and filtered to obtain 861 m of the desired product.
g was obtained.

Yield: 76% Melting point: 183-184 ° C. IR (KBr, cm ⁻¹ ): 3331, 3256, 177
2,1649. NMR (CDCl ₃ , δ): 0.67 (d, J = 6.0)
Hz, 3H), 0.84 (d, J = 6.3 Hz, 3
H), 1.45-1.56 (m, 3H), 2.01
(M, 1H), 2.63 (m, 1H), 4.26 (m, 1H)
1H), 4.36 (m, 1H), 4.45 (ddd, J
= 9.3Hz, 9.3Hz, 1.8Hz, 1H), 5.
28 (d, J = 8.1 Hz, 1H), 6.67 (d, J
= 6.0 Hz, 1H), 7.52 (m, 2H), 7.6
0 (m, 1H), 7.88 (dd, J = 7.2 Hz,
1.5 Hz. 2H).

Example 1 (3S) -3-((S) -4-
Production of methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol (Compound No. 135 in Table 1) (S) -3-((S) -2-phenylsulfonylamino obtained in Reference Example 1 -4-methylvalerylamino) -2
413 mg of tetrahydrofuranone in methylene chloride 60
and cooled to -78 ° C. Next,
3.81 ml of a 01 mol / l diisobutylaluminum hydride in toluene solution was added. Three hours later, a saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the mixture was returned to room temperature, filtered through celite, and the celite was thoroughly washed with ethyl acetate. The filtrate was washed with saturated saline, dried over magnesium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 30% hexane) to obtain 191 mg of the desired product.

Yield: 46% Melting point: 162 ° C. IR (KBr, cm ⁻¹ ): 3337, 3260, 164
9. NMR (CDCl ₃ + DMSO-d ₆ , δ): 0.72
(D, J = 6.6 Hz, 2.7 H), 0.78 (d, J
= 6.3 Hz, 0.3 H), 0.84 (d, J = 6.6).
Hz, 2.7H), 0.86 (d, J = 6.3 Hz,
0.3H), 1.46 (t, J = 7.2 Hz, 2H),
1.63 (m, 2H), 2.09 (m, 0.9H),
2.25 (m, 0.1H), 3.68-3.81 (m,
2H), 3.99-4.12 (m, 2H), 4.95
(S, 0.1H), 5.03 (d, J = 3.6 Hz,
0.1H), 5.15 (dd, J = 3.9 Hz, 3.9
Hz, 0.9H), 5.63 (d, J = 3.9 Hz,
0.9H), 6.68 (d, J = 9.3 Hz, 0.1
H), 6.81 (d, J = 8.1 Hz, 0.9H),
6.89 (d, J = 7.8 Hz, 0.9H), 7.14
(D, J = 7.2 Hz, 0.1 H), 7.46-7.5.
8 (m, 3H), 7.85 (m, 2H).

Example 2 (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran (Table 2)
(S) -3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2 obtained in Reference Example 1.
-244 mg of tetrahydrofuranone in methylene chloride 35
and cooled to −78 ° C., 1.01 mol / l
Solution of diisobutylaluminum hydride in toluene
91 ml were added. After stirring at −78 ° C. for 3 hours, a saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the mixture was returned to room temperature, filtered through celite, and the celite was thoroughly washed with ethyl acetate. After washing the filtrate with saturated saline,
After drying over magnesium sulfate, it was filtered. The filtrate was concentrated and the crude (3S) -3-((S) -4-methyl-
2-phenylsulfonylaminovalerylamino) -2-
Tetrahydrofuranol (the compound of Example 1) was obtained.
This was dissolved in 1 ml of pyridine and 1.5 ml of acetic anhydride was added under ice cooling.
After stirring for 9 hours under ice-cooling, 1.5 ml of methanol was added and concentrated. The obtained residue was dissolved in ethyl acetate, washed sequentially with dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was added with 2.5 mL of ethyl acetate.
Then, 2.5 ml of hexane and 2.5 ml of hexane were added, and the mixture was stirred.

Yield: 44% Melting point: 177-178 ° C. IR (KBr, cm ⁻¹ ): 3409, 3100, 175
3,1659. NMR (CDCl ₃ , δ): 0.54 (d, J = 6.3)
Hz, 3H), 0.80 (d, J = 6.3 Hz, 3
H), 1.37 (m, 2H), 1.59 (m, 1H),
1.81 (m, 1H), 2.16 (s, 3H), 2.2
4 (m, 1H), 3.61 (m, 1H), 3.95 (d
dd, J = 9.3 Hz, 9.0 Hz, 7.5 Hz, 1
H), 4.14 (ddd, J = 9.3 Hz, 9.0H)
z, 3.0 Hz, 1H), 4.53 (m, 1H), 4.
87 (d, J = 6.6 Hz, 1H), 6.16 (d, J
= 4.5 Hz, 1H), 6.56 (d, J = 8.7H)
z, 1H), 7.54 (m, 2H), 7.62 (m, 1
H), 7.86 (dd, J = 7.2 Hz, 1.5 Hz,
2H).

The compounds of Example 3 to Example 42 were produced in the same manner as in Reference Example 1, Example 1, and Example 2. The physical properties are described below. Example 3 (3S) -3-((S) -4-methyl-2-
Tetradecyloxycarbonylaminovalerylamino)
-2-tetrahydrofuranol (compound number 2 in Table 1)
Production of 6) IR (KBr, cm ^-1 ): 3410, 3301, 169
6,1649,1543. NMR (CDCl ₃ , δ): 0.83-0.98 (m,
9H), 1.25 (m, 22H), 1.43-1.70.
(M, 5H), 1.70-1.95 (m, 1H), 2.
23-2.52 (m, 1H), 3.89 (m, 0.7
H), 3.95-4.24 (m, 5H), 4.34.
(M, 1H), 4.50 (s, 0.3H), 5.22-
5.44 (m, 2H), 6.72 (d, J = 7.7H)
z, 1H).

Example 4 (3S) -3-((S) -2-)
Preparation of benzyloxycarbonylamino-4-methylvalerylamino) -2-tetrahydrofuranol (Compound No. 30 in Table 1) Melting point: 40-43 ° C IR (KBr, cm ⁻¹ ): 3306, 1705, 165
7. NMR (CDCl ₃ , δ): 0.92 (d, J = 6.1)
Hz, 3H), 0.94 (d, J = 5.9 Hz, 3
H), 1.52 (m, 1H), 1.64 (m, 2H),
1.78 (m, 1H), 2.29 (m, 0.5H),
2.41 (m, 0.5H), 3.51 (s, 0.5
H), 3.74 (s, 0.5H), 3.85 (ddd,
J = 8.0 Hz, 8.0 Hz, 8.0 Hz, 0.5
H), 3.97 (m, 0.5H), 4.10 (m, 2
H), 4.32 (m, 1H), 5.09 (s, 1H),
5.10 (s, 1H), 5.24 (s, 0.5H),
5.29 (s, 0.5H), 5.35 (d, J = 6.5)
Hz, 0.5H), 5.38 (d, J = 8.2 Hz,
0.5H), 6.45 (d, J = 6.0 Hz, 0.5
H), 6.57 (d, J = 6.0 Hz, 0.5H),
7.33 (m, 5H).

Example 5 (3S) -3-｛(S) -2-
Preparation of (2-chlorobenzyloxycarbonylamino) -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 34 in Table 1) Melting point: 46-49 ° C IR (KBr, cm ⁻¹ ): 3308, 1707,165
7,1541. NMR (CDCl ₃ , δ): 0.94 (m, 6H),
1.48-1.86 (m, 4H), 2.32 (m, 0.
6H), 2.48 (m, 0.4H), 2.90 (s,
0.4H), 3.09 (s, 0.6H), 3.88 (d
dd, J = 7.8 Hz, 7.8 Hz, 7.8 Hz, 0.
6H), 4.01 (m, 0.4H), 4.11 (m, 2
H), 4.34 (m, 1H), 5.23 (s, 2H),
5.25 (m, 2H), 6.18 (s, 0.4H),
6.45 (d, J = 7.6 Hz, 0.6H), 7.26
(M, 2H), 7.40 (m, 2H).

Example 6 (3S) -3-｛(S) -4-
Preparation of methyl-2- (4-methylbenzyloxycarbonylamino) valerylamino} -2-tetrahydrofuranol (Compound No. 42 in Table 1) IR (KBr, cm ^-1 ): 3310, 1703, 165
7, 1539. NMR (CDCl ₃ , δ): 0.93 (m, 6H),
1.52 (m, 1H), 1.58-1.86 (m, 3
H), 2.29 (m, 0.5H), 2.35 (s, 3
H), 2.43 (m, 0.5H), 2.91 (s, 0.
5H), 3.03 (s, 0.5H), 3.87 (dd
d, J = 7.8 Hz, 7.8 Hz, 7.8 Hz, 0.5
H), 3.97 (m, 0.5H), 4.10 (m, 2
H), 4.33 (m, 1H), 5.06 (s, 2H),
5.14 (m, 1H), 5.26 (m, 1H), 6.2
0 (s, 0.5H), 6.44 (s, 0.5H), 7.
16 (m, 2H), 7.23 (m, 2H).

Example 7 Preparation of (3S) -3-((S) -2-cyclohexyloxycarbonylamino-4-methylvalerylamino) -2-tetrahydrofuranol (Compound No. 47 of Table 1) Melting point: 28 -30 ° C IR (KBr, cm ^-1 ): 3310, 1696, 165
7, 1539. NMR (CDCl ₃ , δ): 0.95 (m, 6H),
1.29 (m, 2H), 1.36 (m, 4H), 1.5
3 (m, 2H), 1.69 (m, 4H), 1.85
(M, 2H), 2.36 (m, 0.5H), 2.48
(M, 0.5H), 2.85 (s, 0.5H), 3.0
6 (s, 0.5H), 3.89 (ddd, J = 7.8H)
z, 7.8 Hz, 7.8 Hz, 0.5 H), 4.02
(M, 0.5H), 4.14 (m, 2H), 4.36
(M, 1H), 4.63 (m, 1H), 4.99 (m, 1H)
1H), 5.26 (m, 0.5H), 5.32 (m,
0.5H), 6.22 (s, 0.5H), 6.47.
(S, 0.5H).

Example 8 (3S) -3-((S) -4-
Methyl-2-pentadecanoylaminovalerylamino)
-2-tetrahydrofuranol (compound number 6 in Table 1)
Production of 4) Melting point: 99 to 101 ° C. IR (KBr, cm ⁻¹ ): 3298, 1636, 154
3. NMR (CDCl ₃ , δ): 0.81-1.05 (m,
9H), 1.25 (m, 22H), 1.42-1.73.
(M, 5H), 1.83 (m, 1H), 2.12-2.
23 (m, 2H), 2.30 (m, 1H), 3.04
(M, 0.3H), 3.57 (m, 0.7H), 3.8
9 (m, 0.7H), 4.02 (m, 0.3H), 4.
12 (m, 1H), 4.23-4.53 (m, 2H),
5.27 (s, 0.3H), 5.33 (d, J = 4.3
Hz, 0.7H), 5.97 (d, J = 8.0 Hz, 1
H), 6.53 (d, J = 8.4 Hz, 0.3H),
6.61 (d, J = 8.3 Hz, 0.7H).

Example 9 (3S) -3-((S) -2-)
Hexadecanoylamino-4-methylvalerylamino)
-2-tetrahydrofuranol (compound number 6 in Table 1)
Production of 5) Melting point: 94-96 ° C IR (KBr, cm ^-1 ) 3414, 3297, 171
5,1543. NMR (CDCl ₃ , δ): 0.81-1.01 (m,
9H), 1.25 (m, 24H), 1.40-1.80.
(M, 5H), 1.85 (m, 1H), 2.10-2.
23 (m, 2H), 2.32 (m, 0.6H), 2.4
1 (m, 0.4H), 3.83 (m, 0.6H), 4.
02 (m, 0.4H), 4.10 (m, 1H), 4.3
1 (m, 1H), 4.43 (m, 1H), 5.27
(S, 0.4H), 5.32 (d, J = 4.6 Hz,
0.6H), 6.01 (d, J = 8.2 Hz, 1H),
6.57 (d, J = 7.5 Hz, 0.4H), 6.64
(D, J = 8.3 Hz, 0.6H).

Embodiment 10 (3S) -3-｛(S) -2
Preparation of-(2-fluorobenzoylamino) -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 75 in Table 1) Melting point: 62-64 ° C IR (KBr, cm ^-1 ): 3306, 1644 , 153
4. NMR (CDCl ₃ , δ): 0.80-1.07 (m,
6H), 1.59-2.01 (m, 4H), 2.40.
(M, 1H), 3.82 (m, 1H), 3.97-4.
20 (m, 1.6H), 4.24-4.45 (m, 1.
4H), 4.68 (m, 1H), 5.31 (d, J =
2.5 Hz, 0.6 H), 5.35 (dd, J = 4.2)
Hz, 4.1 Hz, 0.4H), 6.87 (m, 1
H), 7.02-7.20 (m, 2H), 7.25.
(M, 1H), 7.50 (m, 1H), 8.00 (m, 1H)
1H).

Embodiment 11 (3S) -3-｛(S) -2
Preparation of-(4-chlorobenzoylamino) -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 83 in Table 1) Melting point: 93-96 ° C IR (KBr, cm ^-1 ): 3295,1636 . NMR (CDCl ₃ , δ): 0.95 (d, J = 6.0)
Hz, 3H), 0.97 (d, J = 5.7 Hz, 3
H), 1.73 (m, 3H), 1.86 (m, 1H),
2.31 (m, 0.7H), 2.42 (m, 0.3
H), 3.41 (s, 0.3H), 3.86 (s, 0.
7H), 3.87 (ddd, J = 8.4 Hz, 8.4H
z, 8.4 Hz, 0.7H), 4.02 (ddd, J =
7.8Hz, 7.8Hz, 7.8Hz, 0.3H),
4.12 (m, 1H), 4.35 (m, 1H), 4.6
8 (m, 1H), 5.30 (s, 0.3H), 5.35
(D, J = 4.5 Hz, 0.7 H), 6.71 (d, J
= 8.1 Hz, 0.7H), 6.76 (d, J = 6.9)
Hz, 0.3H), 6.87 (d, J = 6.4 Hz,
0.7H), 6.95 (d, J = 8.1 Hz, 0.3
H), 7.39 (dd, J = 8.4 Hz, 1.8 Hz,
2H), 7.73 (dd, J = 8.4 Hz, 2.1H
z, 2H).

Embodiment 12 (3S) -3-｛(S) -4
Preparation of -methyl-2- (4-methylbenzoylamino) valerylamino} -2-tetrahydrofuranol (Compound No. 89 in Table 1) Melting point: 101-102 ° C IR (KBr, cm ^-1 ): 3304, 1634, 154
5,1504. NMR (CDCl ₃ , δ): 0.80-1.07 (m,
6H), 1.60-1.95 (m, 4H), 2.37.
(M, 1H), 2.39 (s, 3H), 3.45 (d,
J = 2.9 Hz, 0.6 H), 3.90 (m, 0.4
H), 3.97-4.19 (m, 2H), 4.38.
(M, 1H), 4.71 (m, 1H), 5.30 (d,
J = 2.9 Hz, 0.6 H), 5.35 (dd, J =
6.7 Hz, 6.7 Hz, 0.6 H), 6.74 (d,
J = 8.5 Hz, 0.4H), 6.80 (d, J = 8.
5 Hz, 1 H), 6.89 (d, J = 6.7 Hz, 0.
6H), 7.22 (d, J = 8.2 Hz, 2H), 7.
68 (d, J = 8.2 Hz, 2H).

Example 13 (3S) -3-((S) -2
Preparation of -hexadecylsulfonylamino-4-methylvalerylamino) -2-tetrahydrofuranol (Compound No. 131 in Table 1) IR (KBr, cm ^-1 ) 3337, 1647, 154
3. _{NMR (CDCl 3, δ):} 0.85-0.98 (m,
9H), 1.23-1.47 (m, 29H), 1.56
-1.61 (m, 2H), 1.78-1.88 (m, 2
H), 2.94-3.03 (m, 2H), 3.88-
4.21 (m, 4H), 4.25-4.53 (m, 1
H), 5.24-5.34 (m, 1H), 6.44.
(M, 0.6H), 6.75 (m, 0.4H).

Example 14 (3S) -3-｛(S) -2
Preparation of-(4-chlorophenylsulfonylamino) -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 141 in Table 1) Melting point: 112-115 ° C IR (KBr, cm ^-1 ): 3335,3264 , 164
9. NMR (CDCl ₃ , δ): 0.76 (d, J = 6.3)
Hz, 0.6H), 0.80 (d, J = 6.3 Hz,
2.4H), 0.87 (d, J = 6.9 Hz, 0.6
H), 0.89 (d, J = 6.6 Hz, 2.4H),
1.48 (m, 3H), 1.68 (m, 1H), 2.1
1 (m, 0.8H), 2.40 (m, 0.2H), 3.
67 (ddd, J = 6.9Hz, 6.9Hz, 6.9H
z, 1H), 3.85 (m, 0.8H), 3.94
(M, 0.2H), 4.05-4.21 (m, 2H),
5.18 (s, 0.2H), 5.25 (d, J = 4.5)
Hz, 0.8H), 5.31 (d, J = 9.9 Hz,
0.2H), 5.35 (d, J = 8.4 Hz, 0.8
H), 5.94 (d, J = 7.8 Hz, 0.2H),
6.23 (d, J = 7.8 Hz, 0.8H), 7.48
(D, J = 8.4 Hz, 2H), 7.80 (d, J =
8.4 Hz, 2H).

Example 15 (3S) -3-｛(S) -4
Preparation of -methyl-2- (2,4,6-trimethylphenylsulfonylamino) valerylamino} -2-tetrahydrofuranol (Compound No. 151 in Table 1) Melting point: 75-77 ° C IR (KBr, cm ^-1 ): 3328, 1657, 160
5,1541. NMR (CDCl ₃ , δ): 0.67 (d, J = 6.3)
Hz, 1.35H), 0.68 (d, J = 6.3 Hz,
1.65H), 0.83 (d, J = 6.4 Hz, 1.3
5H), 0.84 (d, J = 6.4 Hz, 1.65)
H), 1.38-1.72 (m, 4H), 2.11
(M, 0.65H), 2.29 (s, 3H), 2.31
(M, 0.45H), 2.63 (s, 6H), 3.61
(M, 1H), 3.72 (d, J = 3.0 Hz, 0.4
5H), 3.74-3.98 (m, 1H), 3.98-
4.24 (m, 2.55H), 5.23 (d, J = 3.
0 Hz, 0.45 H), 5.28 (dd, J = 3.9 H)
z, 3.9 Hz, 0.55 H), 5.46 (d, J =
8.6 Hz, 0.45 H), 5.60 (d, J = 8.0)
Hz, 0.55H), 6.38 (d, J = 7.4Hz,
0.45H), 6.54 (d, J = 8.0 Hz, 0.5
5H), 6.95 (s, 2H).

Embodiment 16 (3S) -3-｛(S) -2
-(4-tert-butylphenylsulfonylamino)
Preparation of -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 154 in Table 1) Melting point: 140-141 ° C IR (KBr, cm ⁻¹ ): 3362, 3161, 164
7, 1535. NMR (DMSO-d ₆ , δ): 0.74 (d, J =
6.5 Hz, 3H), 0.81 (d, J = 6.6 Hz,
3H), 1.15-1.41 (m, 3H), 1.29
(S, 9H), 1.54 (m, 1H), 1.95 (m,
1H), 3.46 (m, 1H), 3.62-3.82.
(M, 3H), 4.80 (d, J = 4.3 Hz, 1
H), 6.06 (d, J = 4.3 Hz, 1H), 7.5
3 (d, J = 8.5 Hz, 2H), 7.66 (d, J =
8.5 Hz, 2H), 7.82 (d, J = 9.4 Hz,
1H), 7.95 (d, J = 6.7 Hz, 1H).

Example 17 (3S) -3-｛(S) -2
Preparation of-(4-methoxyphenylsulfonylamino) -4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 157 in Table 1) Melting point: 153-155 ° C IR (KBr, cm ^-1 ): 3362, 3150,164
7, 1597, 1535, 1501. NMR (DMSO-d ₆ , δ): 0.69 (m, 0.6
H), 0.76 (d, J = 6.5 Hz, 2.7 H),
0.82 (d, J = 6.7 Hz, 2.7H), 1.15
-1.45 (m, 3H), 1.56 (m, 1H), 2.
01 (m, 1H), 3.54 (m, 1H), 3.60 −
3.90 (m, 3H), 3.81 (s, 3H), 4.8
9 (d, J = 4.6 Hz, 0.9H), 4.99 (m,
0.1H), 6.09 (d, J = 4.6 Hz, 0.9
H), 6.41 (d, J = 2.7 Hz, 0.1H),
7.04 (d, J = 8.8 Hz, 2H), 7.60 −
7.80 (m, 3.1H), 7.94 (d, J = 6.9)
Hz, 0.9H).

Example 18 (3S) -3-｛(S) -4
Preparation of -methyl-2- (2-naphthylsulfonylamino) valerylamino} -2-tetrahydrofuranol (Compound No. 166 in Table 1) Melting point: 102-104 ° C IR (KBr, cm ⁻¹ ): 3351, 1655, 154
1. NMR (DMSO-d ₆ , δ): 0.65 (d, J =
6.4 Hz, 1.5 H), 0.65-0.90 (m,
4.5H), 1.14-1.68 (m, 5H), 3.2
5 (m, 0.5H), 3.57-3.91 (m, 3.5
H), 4.73 (s, 0.5H), 4.89 (dd, J
= 4.3Hz, 4.3Hz, 0.5H), 5.98
(S, 0.5H), 6.32 (d, J = 4.3 Hz,
0.5H), 7.60-7.80 (m, 3.5H),
7.93 (d, J = 6.7 Hz, 0.5H), 7.98
−8.17 (m, 4H), 8.38 (d, J = 8.3H)
z, 1H).

Example 19 (3S) -4-methyl-3-
((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol (Table-
Preparation of Compound No. 180 of No. 1) Melting point: 116-121 ° C. IR (KBr, cm ⁻¹ ): 3356, 3272, 165
5. NMR (CDCl ₃ , δ): 0.70 (d, J = 6.0)
Hz, 2.1H), 0.71 (d, J = 6.0 Hz,
0.9H), 0.86 (d, J = 6.6 Hz, 3H),
0.95 (d, J = 6.6 Hz, 2.1H), 1.04
(D, J = 6.6 Hz, 0.9 H), 1.50 (m, 2
H), 1.62 (m, 1H), 2.12 (m, 1H),
3.43 (m, 1H), 3.70 (m, 1H), 3.9
1 (m, 1H), 4.17 (dd, J = 8.4 Hz,
8.4 Hz, 1 H), 5.12 (d, J = 4.5 Hz,
0.3H), 5.25 (d, J = 4.5 Hz, 0.7
H), 5.35 (d, J = 7.2 Hz, 0.7H),
5.40 (d, J = 7.2 Hz, 0.3H), 6.34
(D, J = 8.7 Hz, 0.3 H), 6.37 (d, J
= 8.7Hz, 0.7H), 7.49-7.62 (m,
3H), 7.88 (m, 2H).

Example 20 Preparation of (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 296 in Table 2) Melting point: 114-115 ° C IR (KBr, cm ^-1 ): 3304, 1748, 169
6,1653,1541. NMR (CDCl ₃ , δ): 0.82-1.01 (m,
9H), 1.26 (m, 22H), 1.42-1.75.
(M, 5H), 1.86 (m, 1H), 2.11 (s,
3H), 2.37 (m, 1H), 3.88-4.20
(M, 5H), 4.59 (m, 1H), 4.98 (m,
1H), 6.16 (d, J = 4.6 Hz, 1H), 6.
31 (d, J = 9.7 Hz, 1H).

Example 21 Preparation of (2S, 3S) -2-acetoxy-3-((S) -2-benzyloxycarbonylamino-4-methylvalerylamino) tetrahydrofuran (Compound No. 300 in Table 2) : 162-164 ° C IR (KBr, cm ^-1 ): 3310, 1637, 165
5,1535. NMR (CDCl ₃ , δ): 0.94 (d, J = 6.2)
Hz, 3H), 0.95 (d, J = 6.2 Hz, 3
H), 1.83 (m, 1H), 2.07 (s, 3H),
2.11 (m, 3H), 2.36 (m, 1H), 3.9
3 (ddd, J = 7.8Hz, 7.8Hz, 7.8H
z, 1H), 4.09 (m, 2H), 4.79 (m, 1
H), 5.12 (s, 2H), 5.32 (s, 1H),
6.04 (d, J = 4.2 Hz, 1H), 6.17
(D, J = 4.4 Hz, 1H), 7.25 (m, 5
H).

Example 22 (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecanoylaminovalerylamino) tetrahydrofuran (Table 2)
Preparation of compound No. 334) Melting point: 129-130 ° C. IR (KBr, cm ⁻¹ ): 3297, 1748, 164
2,1545. NMR (CDCl ₃ , δ): 0.78-1.05 (m,
9H), 1.25 (m, 22H), 1.42-1.70.
(M, 3H), 1.70-2.00 (m, 2H), 2.
05 (m, 1H), 2.07 (s, 3H), 2.18
(T, J = 6.9 Hz, 2H), 2.33 (m, 1
H), 3.95 (m, 1H), 4.11 (m, 1H),
4.45 (m, 1H), 4.55 (m, 1H), 6.0
4 (d, J = 8.0 Hz, 1H), 6.18 (d, J =
4.5 Hz, 1 H), 6.69 (d, J = 8.4 Hz,
1H).

Example 23 (2S, 3S) -2-acetoxy-3-((S) -2-hexadecanoylamino-4
-Methylvalerylamino) tetrahydrofuran (Table-2
Preparation of Compound No. 335) Melting point: 137 ° C. IR (KBr, cm ⁻¹ ) 3297, 1748, 164
2,1543. NMR (CDCl ₃ , δ): 0.78-1.01 (m,
9H), 1.25 (m, 24H), 1.42-1.70.
(M, 5H), 1.83 (m, 1H), 2.09 (s,
3H), 2.20 (t, J = 7.0 Hz, 2H), 2.
35 (m, 1H), 3.95 (m, 1H), 4.13
(M, 1H), 4.40 (m, 1H), 4.55 (m, 1H)
1H), 5.91 (d, J = 8.3 Hz, 1H), 6.
17 (d, J = 4.6 Hz, 1H), 6.57 (d, J
= 10.0 Hz, 1H).

Example 24 (2S, 3S) -2-acetoxy-3-{(S) -2- (2-fluorobenzoylamino) -4-methylvalerylamino} tetrahydrofuran (Compound No. 345 in Table 2) Melting point: 165-166 ° C. IR (KBr, cm ⁻¹ ): 3343, 3304, 174
8, 1694, 1640, 1551. NMR (CDCl ₃ , δ): 0.96 (d, J = 5.7)
Hz, 3H), 0.98 (d, J = 5.7 Hz, 3
H), 1.58-1.95 (m, 4H), 2.10
(S, 3H), 2.39 (m, 1H) 3.95 (dd
d, J = 9.0 Hz, 9.0 Hz, 7.4 Hz, 1
H), 4.14 (ddd, J = 9.0 Hz, 9.0H)
z, 2.9 Hz, 1H), 4.55-4.75 (m, 2
H), 6.19 (d, J = 4.8 Hz, 1H), 6.6.
1 (d, J = 8.2 Hz, 1H), 7.00 (d, J =
7.4 Hz, 0.5 H), 7.02 (d, J = 7.4 H)
z, 0.5H), 7.15 (dd, J = 8.2 Hz,
7.5Hz, 1H), 7.29 (ddd, J = 6.8H)
z, 6.8 Hz, 0.9 Hz, 1 H), 7.55 (m,
1H), 8.06 (ddd, J = 6.8 Hz, 6.8H
z, 1.9 Hz, 1H).

Example 25 (2S, 3S) -2-acetoxy-3-{(S) -2- (4-chlorobenzoylamino) -4-methylvalerylamino} tetrahydrofuran (Compound No. 353 in Table 2) Melting point: 204-205 ° C IR (KBr, cm ^-1 ): 3304, 1746, 167
4,1635. NMR (CDCl ₃ , δ): 0.96 (d, J = 6.1)
Hz, 3H), 0.97 (d, J = 6.0 Hz, 3
H), 1.58-1.78 (m, 3H), 1.85
(M, 1H), 2.13 (s, 3H), 2.31 (m,
1H) 3.95 (m, 1H), 4.14 (ddd, J =
8.6Hz, 8.6Hz, 2.9Hz, 1H), 4.5
5-4.70 (m, 2H), 6.20 (d, J = 4.6)
Hz, 1H), 6.62 (d, J = 8.3 Hz, 1
H), 6.81 (d, J = 7.8 Hz, 1H), 7.4
1 (d, J = 6.7 Hz, 2H), 7.73 (d, J =
6.7 Hz, 2H).

Example 26 Preparation of (2S, 3S) -2-acetoxy-3-((S) -2-hexadecylsulfonylamino-4-methylvalerylamino) tetrahydrofuran (Compound No. 401 in Table 2) NMR (CDCl ₃ , δ): 0.86-0.97 (m,
9H), 1.21-1.41 (m, 30H), 1.45.
-1.89 (m, 3H), 2.12 (s, 3H), 2.
98 (m, 2H), 3.85 (m, 1H), 3.98
(M, 1H), 4.15 (m, 1H), 4.60 (m, 1H)
1H), 4.76 (d, J = 8.6 Hz, 1H), 6.
18 (d, J = 4.6 Hz, 1H), 6.32 (d, J
= 8.6 Hz, 1H).

Embodiment 27 (2S, 3S) -3-
Production of ((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2-pivaloyloxytetrahydrofuran (Compound No. 410 in Table 2) Melting point: 165-166 ° C IR (KBr, cm ⁻¹⁾ ): 3293, 1640. NMR (CDCl ₃ , δ): 0.64 (d, J = 5.9)
Hz, 3H), 0.81 (d, J = 6.1 Hz, 3
H), 1.26 (s, 9H), 1.48 (m, 3H),
1.72 (m, 1H), 2.23 (m, 1H), 3.6
4 (m, 1H), 3.94 (ddd, J = 9.1 Hz,
9.1 Hz, 9.1 Hz, 1 H), 4.10 (ddd,
J = 9.1 Hz, 9.1 Hz, 3.1 Hz, 1H),
4.45 (m, 1H), 5.07 (d, J = 7.7H)
z, 1H), 6.10 (d, J = 4.5 Hz, 1H),
6.21 (d, J = 8.4 Hz, 1H), 7.51
(M, 2H), 7.61 (m, 1H), 7.86 (d,
J = 7.1 Hz, 2H).

Example 28 (2S, 3S) -2-acetoxy-3-{(S) -2- (4-chlorophenylsulfonylamino) -4-methylvalerylamino} tetrahydrofuran (Compound No. 416 in Table 2) Melting point: 136-137 ° C IR (KBr, cm ⁻¹ ): 3335, 3258, 174
4,1651,1535. NMR (CDCl ₃ , δ): 0.61 (d, J = 6.2)
Hz, 3H), 0.83 (d, J = 6.3 Hz, 3
H), 1.35-1.62 (m, 3H), 1.80.
(M, 1H), 2.15 (s, 3H), 2.21 (m,
1H), 3.61 (m, 1H), 3.97 (ddd, J
= 9.1 Hz, 9.1 Hz, 9.1 Hz, 1H), 4.
14 (ddd, J = 9.1 Hz, 9.1 Hz, 2.9H
z, 1H), 4.50 (m, 1H), 5.09 (d, J
= 7.3 Hz, 1H), 6.15 (d, J = 4.6H)
z, 1H), 6.42 (d, J = 8.8 Hz, 1H),
7.51 (d, J = 8.6 Hz, 2H), 7.80
(D, J = 8.6 Hz, 2H).

Example 29 (2S, 3S) -2-acetoxy-3-{(S) -4-methyl-2- (2,4,6-
Trimethylphenylsulfonylamino) valerylamino @ tetrahydrofuran (Compound No. 426 in Table 2)
Melting point: 158-159 ° C IR (KBr, cm ^-1 ): 3416, 3191, 175
5,1661,1605,1535. NMR (CDCl ₃ , δ): 0.56 (d, J = 6.3)
Hz, 3H), 0.79 (d, J = 6.3 Hz, 3
H), 1.39 (m, 2H), 1.58 (m, 1H),
1.81 (m, 1H), 2.16 (s, 3H), 2.2
4 (m, 1H), 2.31 (s, 3H), 2.62
(S, 6H), 3.56 (m, 1H), 3.94 (m,
1H), 4.14 (m, 1H), 4.52 (m, 1
H), 5.00 (d, J = 7.1 Hz, 1H), 6.1
5 (d, J = 4.6 Hz, 1H), 6.61 (d, J =
8.7 Hz, 1H), 6.97 (s, 2H).

Embodiment 30 (2S, 3S) -3-
Production of {(S) -2- (4-tert-butylphenylsulfonylamino) -4-methylvalerylamino} -2-pivaloyloxytetrahydrofuran (Compound No. 434 of Table-2) Melting point: 166-167 ° C IR (KBr, cm ^-1 ): 3360, 1728, 168
2,1665,1547. NMR (CDCl ₃ , δ): 0.55 (d, J = 6.0)
Hz, 3H), 0.78 (d, J = 6.0 Hz, 3
H), 1.25 (s, 9H), 1.32 (s, 9H),
1.38-1.82 (m, 4H), 2.25 (m, 1
H), 3.60 (m, 1H), 3.95 (m, 1H),
4.12 (ddd, J = 9.0 Hz, 9.0 Hz, 3.
0 Hz, 1H), 4.46 (m, 1H), 5.05
(D, J = 7.1 Hz, 1H), 6.10 (d, J =
4.5 Hz, 1 H), 6.41 (d, J = 8.3 Hz,
1H), 7.52 (d, J = 8.6 Hz, 2H), 7.
78 (d, J = 8.6 Hz, 2H).

Example 31 (2S, 3S) -2-acetoxy-3-{(S) -2- (4-methoxyphenylsulfonylamino) -4-methylvalerylamino} tetrahydrofuran (Compound No. 437 in Table 2) ): 157-158 ° C IR (KBr, cm ^-1 ): 3329,3273,174
6,1659,1597,1544,1501. NMR (CDCl ₃ , δ): 0.54 (d, J = 6.1)
Hz, 3H), 0.81 (d, J = 6.3 Hz, 3
H), 1.38 (m, 2H), 1.56 (m, 1H),
1.84 (m, 1H), 2.16 (s, 3H), 2.2
2 (m, 1H), 3.56 (m, 1H), 3.88
(S, 3H), 3.95 (m, 1H), 4.15 (m,
1H), 4.56 (m, 1H), 4.81 (d, J =
6.4 Hz, 1 H), 6.16 (d, J = 4.5 Hz,
1H), 6.68 (d, J = 9.2 Hz, 1H), 6.
99 (d, J = 8.6 Hz, 2H), 7.79 (d, J
= 8.6 Hz, 2H).

Example 32 Preparation of (2S, 3S) -2-acetoxy-3-{(S) -4-methyl-2- (2-naphthylsulfonylamino) valerylamino} tetrahydrofuran (Compound No. 446 in Table 2) Melting point: 158-159 ° C IR (KBr, cm ^-1 ): 3337, 3275, 172
3,1676,1543. NMR (CDCl ₃ , δ): 0.48 (d, J = 6.1)
Hz, 3H), 0.76 (d, J = 6.2 Hz, 3
H), 1.33-1.75 (m, 4H), 1.97.
(M, 1H), 2.15 (s, 3H), 3.68 (m,
1H), 3.87 (m, 1H), 4.05 (m, 1
H), 4.42 (m, 1H), 5.19 (d, J = 7.
1 Hz, 1 H), 6.12 (d, J = 4.6 Hz, 1
H), 6.53 (d, J = 8.7 Hz, 1H), 6.5.
3 (d, J = 8.7 Hz, 2H), 7.58-7.71
(M, 2H), 7.82 (dd, J = 8.7 Hz, 1.D).
9Hz, 1H), 7.87-8.03 (m, 3H),
8.44 (s, 1H).

Embodiment 33 (3S) -3-((S) -2
Preparation of -Heptadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol (Compound No. 66 in Table 1) Melting point: 79-82 ° C IR (KBr, cm ^-1 ): 3300, 1637, 154
3. NMR (CDCl ₃ , δ): 0.90-1.03 (m,
9H), 1.25 (m, 26H), 1.45-1.70.
(M, 5H), 1.70-1.95 (m, 2H), 2.
10-2.22 (m, 2H), 2.20-2.50
(M, 1H), 3.78-4.18 (m, 2H), 4.
20-4.60 (m, 2H), 5.12-5.18
(M, 1H), 6.13 (d, J = 8.4 Hz, 0.6
H), 6.22 (d, J = 8.3 Hz, 0.4H),
6.77 (d, J = 8.4 Hz, 0.6H), 6.82
(D, J = 7.0 Hz, 0.4H).

Example 34 (2S, 3S) -2-acetoxy-3-((S) -2-heptadecanoylamino-4
-Methylvalerylamino) tetrahydrofuran (Table-2
Preparation of Compound No. 336) Melting point: 127-128 ° C. IR (KBr, cm ⁻¹ ): 3297, 1750, 164
2,1545. NMR (CDCl ₃ , δ): 0.82-0.98 (m,
9H), 1.25 (m, 26H), 1.43-1.70.
(M, 5H), 1.83 (m, 1H), 2.13 (s,
3H), 2.20 (t, J = 7.2 Hz, 2H), 2.
32 (m, 1H), 3.97 (m, 1H), 4.14
(M, 1H), 4.40 (m, 1H), 4.55 (m, 1H)
1H), 6.01 (d, J = 8.1 Hz, 1H), 6.
17 (d, J = 4.6 Hz, 1H), 6.66 (d, J
= 8.6 Hz, 1H).

Example 35 (3S) -3-((S) -4
Preparation of -methyl-2-tridecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol (Compound No. 25 in Table 1) Melting point: 75-76 ° C IR (KBr, cm ^-1 ): 3302, 1696,164
9, 1545. NMR (CDCl ₃ , δ): 0.89-1.02 (m,
9H), 1.15-1.40 (m, 19H), 1.45.
-1.75 (m, 5H), 1.80 (m, 1H), 2.
05 (m, 1H), 2.38 (m, 1H), 3.86
(M, 1H), 3.96-4.25 (m, 4.6H),
4.35 (m, 1H), 4.48 (s, 0.4H),
5.27 (d, J = 2.4 Hz, 0.6 H), 5.33
(Dd, J = 3.8 Hz, 3.8 Hz, 0.4 H),
5.40 (d, J = 7.8 Hz, 1H), 6.72
(D, J = 7.8 Hz, 1H).

Example 36 Preparation of (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tridecyloxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 295 in Table 2) Melting point: 112 ° C. IR (KBr, cm ⁻¹ ): 3304, 1748, 169
6,1655,1541. NMR (CDCl ₃ , δ): 0.88 (t, J = 6.4)
Hz, 3H), 0.91-0.99 (m, 6H), 1.
15-1.40 (m, 21H), 1.43-1.77
(M, 4H), 1.87 (m, 1H), 2.11 (s,
3H), 2.36 (m, 1H), 3.95 (m, 1
H), 4.01-4.20 (m, 4H), 4.58.
(M, 1H), 5.05 (d, J = 8.3 Hz, 1
H), 6.17 (d, J = 4.6 Hz, 1H), 6.3.
6 (d, J = 7.9 Hz, 1H).

Example 37 (3S) -3-((S) -4
-Methyl-2-pentadecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol (Table 1)
Of compound No. 27) IR (KBr, cm ^-1 ): 3302, 1695, 164
9, 1543. _{NMR (CDCl 3, δ):} 0.85-0.96 (m,
9H), 1.25 to 1.29 (m, 24H), 1.50
-1.89 (m, 6H), 2.29 (m, 0.7H),
2.42 (m, 0.3H), 3.81-4.25 (m,
5H), 4.28-4.41 (m, 1H), 5.24
(S, 1H), 5.26 (s, 0.3H), 5.32
(D, J = 4.6 Hz, 0.7 H), 6.50 (s,
0.3H), 6.60 (d, J = 7.8 Hz, 0.7
H).

Example 38 Preparation of (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecyloxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 297 in Table 2) Melting point: 114-115 ° C IR (KBr, cm ^-1 ): 3304, 1693, 165
5,1545. NMR (CDCl ₃ , δ): 0.88 (m, 3H),
0.91-0.99 (m, 6H), 1.23-1.39
(M, 24H), 1.51-1.69 (m, 5H),
1.84 (m, 1H), 2.10 (s, 3H), 2.3
6 (m, 1H), 3.92-4.17 (m, 5H),
4.58 (m, 1H), 4.98 (m, 1H), 6.1
6 (d, J = 4.7 Hz, 1H), 6.31 (d, J =
8.3 Hz, 1H).

Embodiment 39 (3S) -3-((S) -4
Preparation of -methyl-2-tetradecylsulfonylaminovalerylamino) -2-tetrahydrofuranol (Compound No. 129 in Table 1) IR (KBr, cm ^-1 ): 3346, 1643, 153
3. _{NMR (CDCl 3, δ):} 0.85-0.90 (m,
3H), 0.94-0.98 (m, 6H), 1.25-
1.39 (m, 22H), 1.56-1.83 (m, 5
H), 2.20-2.38 (m, 1H), 2.69-
2.81 (m, 1H), 2.98-3.04 (m, 2
H), 3.92-3.98 (m, 1H), 4.46-
4.58 (m, 2H), 5.04-5.07 (m, 1
H), 6.85-6.87 (m, 1H).

Example 40 Preparation of (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecylsulfonylaminovalerylamino) tetrahydrofuran (Compound No. 399 in Table 2) : 84-85 ° C IR (KBr, cm ^-1 ): 3315, 1651, 154
5. NMR (CDCl ₃ , δ): 0.88 (m, 3H),
0.94-0.98 (m, 6H), 1.23-1.94
(M, 28H), 2.12 (s, 3H), 2.36
(M, 1H), 2.98 (m, 2H), 3.85 (m, 1H)
1H), 3.97 (m, 1H), 4.15 (m, 1
H), 4.59 (m, 1H), 4.74 (m, 1H),
6.17 (d, J = 4.5 Hz, 1H), 6.32
(D, J = 8.5 Hz, 1H).

Example 41 (3S) -3-((S) -4
Preparation of -methyl-2-pentadecylsulfonylaminovalerylamino) -2-tetrahydrofuranol (Compound No. 130 in Table 1) IR (KBr, cm ^-1 ): 3348, 1643, 154
1. _{NMR (CDCl 3, δ):} 0.85-0.90 (m,
3H), 0.94-0.98 (m, 6H), 1.25-
1.42 (m, 24H), 1.58-1.63 (m, 2
H), 1.72-1.86 (m, 3H), 2.30-
2.39 (m, 0.8H), 2.40-2.58 (m, 0.8H)
0.2H), 2.94-3.02 (m, 2H), 3.8
0-3.94 (m, 2H), 4.04 (m, 0.2
H), 4.10-4.17 (m, 0.8H), 4.32
-4.41 (m, 1H), 5.00-5.05 (m, 1
H), 5.27 (m, 0.2H), 5.34 (m, 0.
8H), 6.22 (d, J = 7.2 Hz, 0.2H),
6.49 (d, J = 8.1 Hz, 0.8H).

Example 42 Preparation of (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecylsulfonylaminovalerylamino) tetrahydrofuran (Compound No. 400 in Table 2) : 80-81 ° C IR (KBr, cm ^-1 ): 3315, 1651, 154
8. NMR (CDCl ₃ , δ): 0.88 (m, 3H),
0.92-0.98 (m, 6H), 1.23-1.48
(M, 26H), 1.50-1.98 (m, 5H),
2.12 (s, 3H), 2.97 (dd, J = 6.9H)
z, 3.0 Hz, 2H), 3.84 (m, 1H), 3.
96 (m, 1H), 4.15 (m, 1H), 4.61
(M, 1H), 4.69 (m, 1H), 6.18 (d,
J = 4.5 Hz, 1 H), 6.30 (d, J = 9.0 H)
z, 1H).

Test Example 1 Measurement of Calpain Inhibitory Activity m-calpain was obtained from rat brain by the literature (Journa).
l of Biological Chemistr
y, volume 259, p. 3210, 1984), and its inhibitory activity was determined by the literature (Journa).
l of Biological Chemistr
y, 259, 12489, 1984). Table 3 shows the results. Table-
3 shows that the compound of the present invention shows a strong inhibitory activity on calpain.

[0136]

[Table 56]

Test Example 2 Production of active metabolite in blood (2S, 3S) -2-acetoxy- obtained in Example 2
3-((S) -4-Methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran was dissolved in acetonitrile and added to rat serum to a final concentration of 100 μM. After incubation at 37 ° C for 5 minutes, acetonitrile was added, and the solution obtained by centrifugation was measured by HPLC. As a result, added (2S, 3S) -2-acetoxy-3-((S) -4-
97% of methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran is hydrolyzed and the active metabolite (3S) -3-((S) -4-methyl-2)
-Phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol (compound of Example 1). Similar operations were performed on human and dog sera to confirm that active metabolites were produced. HPLC conditions are as follows.

Column Nucleosil 100 ₅ C ₁₈ 4.6 × 250 mm (manufactured by Nagel) Column temperature 50 ° C. Mobile phase CH ₃ CN: H ₂ O: PIC A Low UV (manufactured by Waterrs) 22: 78: 1 Flow rate 1 ml / min Detection wavelength UV 222 nm From these results, it was found that the compound of the general formula (I) had R ³
It can be seen that a compound in which R ³ is not a hydrogen atom is immediately converted into a lactol derivative in which the active metabolite R ³ is a hydrogen atom in a living body.

Test Example 3 Investigation of Improvement of Passive Avoidance Response Impairment after Short-Term Forebrain Ischemia Bilateral male vertebral arteries were electrocauterized under pentobarbital anesthesia, and a thread was applied to both bilateral common carotid arteries. Animals that did not exhibit neurological symptoms such as paralysis were used for the experiment. In addition, animals in which only vertebral artery was cauterized were used as a sham operation group. During ischemia and after reperfusion, the body temperature of the animals was maintained on a warming mat until the righting reflex was restored.

For the experiment on passive avoidance reaction disorder, an apparatus composed of a bright room (50 × 50 × 50 cm) equipped with a 100 W light bulb and a dark room (20 × 14 × 20 cm) was used. Rats whose bilateral vertebral arteries were cauterized 48 hours before were placed in a light room, and the transition time to a dark room was measured to determine the response latency at the time of the acquisition trial. However, animals with a transit time of 90 seconds or more were excluded from this experiment. When the rat entered the dark room, the guillotine door was closed and an electric shock (2.9 mA, 5 seconds) was immediately applied from the floor grid to terminate the acquisition trial.
Subsequently, ischemic load (bilateral common carotid artery occlusion) was performed for 5 minutes under ether anesthesia, and a regeneration trial was performed 48 hours after reopening. Here, as in the case of the acquisition trial, the rats were placed in a bright room, and the transition time to the dark room (reaction latency) was observed up to 300 seconds. Animals that did not enter the dark for more than 300 seconds had a response latency of 300 seconds. The response latencies of the acquisition trial and the regeneration trial were compared to determine whether there was an effect of improving passive avoidance response disorder. The drug was orally administered 30 minutes before the ischemic load. Flunarizine, a calcium antagonist, was used as a control.

As a result, flunarizine contained 30 mg / kg
The improvement effect was observed at po, whereas the compound of Example 2 of the present invention (Compound No. 405 of Table 2) and the compound of Example 24 (Compound No. 345 of Table 2) were each 1 mg. / Kg · po showed an improving effect. Therefore, the compounds of the present invention are considered to be therapeutic agents for stroke.

Test Example 4 Investigation of Myocardial Necrosis Inhibitory Effect in Rat Acute Myocardial Infarction Model An experiment was performed using SD female rats (14 weeks old).
Acute myocardial infarction was created by permanently ligating the branch of the coronary artery in the left ventricle under thoracotomy under mild ether anesthesia, and the heart was excised 24 hours after ligation to evaluate the infarct size. The animals were randomly divided into two groups, one group containing the compound 10m of Example 29 (Compound No. 426 in Table 2).
g / kg suspended in water with tween 80,
One hour before ligation of the coronary artery was orally administered at a volume of ml / kg (drug group), and the remaining one group was given an equal volume of tap water (control group). Successful thoracotomy, 2 from coronary artery ligation
Rats that survived up to 4 hours later were used as final evaluation targets, and the test was performed until both groups had eight rats.

Evaluation of myocardial infarction size was performed as follows. 2 mm from the apex toward the base of the heart
Sliced at intervals, the sections were taken at 37 ° C in TTC solution (1
%), And stained to determine necrotic and non-necrotic areas. Thereafter, a photograph of the cross-sectional image of the section was taken and image analysis was performed on a computer. The infarct size was expressed as% of the value obtained by dividing the total necrotic area of all slice sections by the total left ventricular area (including; septum, excluding; left ventricular cavity).

As a result, in the control group, 2 died during thoracotomy, and 9 died within 24 hours after the operation. On the other hand, in the drug group, 3 animals died during thoracotomy,
Ten died within 24 hours after surgery. There was no difference in the number of deaths between the two groups until the final evaluation reached eight cases. The total left ventricular area of the slice sections in both groups was 105.6 ± 6.3 m in the control group, respectively.
m ^2, the drug group was not significantly different between 114.6 ± 3.8 mm ² next both groups. On the other hand, the infarct size was 37.3 ± 3.5% in the control group, but 25.0 ± 1.7% in the drug group, and the compound of the present invention was orally administered before ligation of the coronary artery. Showed significant reduction (p <0.05) in myocardial infarction size. The infarct size reduction rate was 33.0% with respect to the control group. From the above results, it was revealed that the compound of the present invention suppressed the progress of myocardial necrosis in a rat acute myocardial infarction model.

Test Example 5 Acute Toxicity Test The active ingredient of the drug of the present invention was added to SD male and female rats at 0.5% C.
A suspension in an MC-Na aqueous solution was orally administered by gavage,
The symptoms were observed for 7 days. The LD50 values of the compounds of Example 2 and Example 29 were both> 2000 mg / kg.

Test Example 6 Formulation Example (1) Tablet The following ingredients were mixed in accordance with a conventional method and tableted with a conventional apparatus. Compound of Example 2 30 mg Crystalline cellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4 mg

(2) Soft Capsules The following components were mixed in a conventional manner and filled in soft capsules. Compound of Example 2 30 mg Olive oil 300 mg Lecithin 20 mg

(3) Formulation for Injection The following components were mixed in a conventional manner to prepare a 1 ml ampoule. Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water for injection 1 ml

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 309/14 C07D 309/14 407/12 307 407/12 307 (72) Inventor Atsushi Anabuki 1000 Kamoshidacho, Aoba-ku, Yokohama-shi, Kanagawa-ken Address: Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Ryoichi Ando 1000, Kamoshida-cho, Aoba-ku, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory

Claims (36)

[Claims] 1. A compound represented by the following general formula (I)(In the above general formula, R¹Is R^Four-CO-, R^Four-O-CO
-Or R^Four-SO _Two− (R^FourHas a substituent
Good C₆~ C₁₄May be substituted with an aryl group
C₁~ C₂₀An alkyl group of C_Three~ C₈The cycloalkyl
Group; or C which may have a substituent₆~ C₁₄Ants
And represents R^TwoIs C₁~ C₆Archi
And represents R^ThreeIs a hydrogen atom or R^Five-CO- (R
^FiveIs C₁~ C_TenA represents an alkyl group of
C₁~ C_ThreeC optionally having an alkyl group₁~ C_Three
An oxygen-containing heterocyclic derivative represented by
Body, a pharmaceutically acceptable salt thereof, or a solvent thereof.
Is a therapeutic drug for ischemic disease containing hydrate as an active ingredient. 2. R¹Is R^Four-CO- (R^FourIs a substituent
C that you may have ₆~ C₁₄Substituted with an aryl group of
May be C₁~ C₂₀Having an alkyl group or a substituent of
May be C₆~ C₁₄Represents an aryl group)
Then A is C₁~ C_ThreeCharacterized by representing an alkylene group of
The therapeutic agent for ischemic disease according to claim 1, wherein 3. The therapeutic agent for ischemic disease according to claim 2, wherein R ⁴ represents a C _{14 to} C ₁₆ alkyl group. ^{4. A} compound according to claim 1, wherein R ¹ is R ⁴ —O—CO— (R ⁴ is a C ₁ -C ₂₀ alkyl which may be substituted by a C ₆ -C ₁₄ aryl group which may have a substituent. Group or C ₃ -C ₈
A represents C ₁ -C
_3. The therapeutic agent for ischemic disease according to claim 1, which represents ₃ alkylene groups. 5. The therapeutic agent for ischemic disease according to claim 4, wherein R ⁴ represents a C ₁₃ -C ₁₅ alkyl group. 6. R ¹ is R ⁴ —SO ₂ — (R ⁴ is C ₁ -C
C _6- which may have ₂₀ alkyl groups or substituents
Ischemic diseases by claim 1, wherein a representative of the representative) an aryl group C _14. 7. The therapeutic agent for ischemic disease according to claim 6, wherein R ⁴ represents a C ₁₄ -C ₁₆ alkyl group. 8. C ₆ to R ⁴ may have a substituent.
Ischemic disease therapeutics according to claim 6, characterized by an aryl group of C _14. 9. The active ingredient is (3S) -3-((S) -4
-Methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof, for treating an ischemic disease. 10. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent or A therapeutic agent for ischemic disease, which is a hydrate. 11. The active ingredient is (3S) -3-｛(S)-
4-methyl-2- (2,4,6-trimethylphenylsulfonylamino) valerylamino} -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof, Hematological disease drug. 12. An active ingredient comprising (2S, 3S) -2-acetoxy-3-{(S) -4-methyl-2- (2,4,6).
-Trimethylphenylsulfonylamino) valerylamino ditetrahydrofuran, or a pharmaceutically acceptable solvent or hydrate thereof, for treating ischemic disease. 13. The method according to claim 1, wherein the active ingredient is (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-pentadecanoylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 14. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecanoylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Alternatively, a therapeutic agent for ischemic disease, which is a hydrate. 15. The active ingredient is (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 2-hexadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 16. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -2-hexadecanoylamino-
4-methylvalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent or hydrate thereof, for the treatment of ischemic disease. 17. The method according to claim 16, wherein the active ingredient is (3S) -3-((S)-
A therapeutic agent for ischemic disease, which is 2-heptadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 18. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -2-heptadecanoylamino-
4-methylvalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent or hydrate thereof, for the treatment of ischemic disease. The active ingredient may be (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-tridecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 20. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tridecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. A therapeutic agent for ischemic disease, which is a solvent or a hydrate. 21. The active ingredient is (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-tetradecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 22. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. A therapeutic agent for ischemic disease, which is a solvent or a hydrate. The active ingredient is (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-pentadecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 24. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. A therapeutic agent for ischemic disease, which is a solvent or a hydrate. 25. An active ingredient comprising (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-tetradecylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 26. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Alternatively, a therapeutic agent for ischemic disease, which is a hydrate. 27. The active ingredient is (3S) -3-((S)-
A therapeutic drug for ischemic disease, which is 4-methyl-2-pentadecylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 28. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Alternatively, a therapeutic agent for ischemic disease, which is a hydrate. 29. The active ingredient is (3S) -3-((S)-
A therapeutic agent for ischemic disease, which is 2-hexadecylsulfonylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. 30. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -2-hexadecylsulfonylamino-4-methylvalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Alternatively, a therapeutic agent for ischemic disease, which is a hydrate. 31. An active ingredient comprising (3S) -4-methyl-3
-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof, ischemic. Disease treatment drug. 32. The therapeutic agent for ischemic disease according to any one of claims 1 to 31, wherein the ischemic disease is stroke. 33. The therapeutic agent for ischemic disease according to claim 1, wherein the ischemic disease is ischemic brain disease. 34. The therapeutic agent for ischemic disease according to any one of claims 1 to 31, wherein the ischemic disease is cerebral thrombosis. 35. The therapeutic agent for ischemic disease according to claim 1, wherein the ischemic disease is cerebral embolism. 36. The therapeutic agent for ischemic disease according to any one of claims 1 to 31, wherein the ischemic disease is myocardial infarction.