JPH10101560A - Medicine for preventing or treating neurodegenerative diseases - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine containing a specific oxygen-containing heterocyclic derivative as an active ingredient, capable of inhibiting the action of carpaine in the brain and effective for preventing and treating neurodegenerative diseases. SOLUTION: This medicine contains an oxygen-containing heterocyclic derivative of the formula [R<1> is R<4> -CO, R<4> -O-CO, etc., (R<4> is a 1-20C alkyl which may be substituted by a 6-14C aryl which may have a substituent); R<2> is a 1-6C alkyl; R<3> is H, R<5> -CO; (R<5> is a 1-10C alkyl); A is a 1-3C alkylene which may have a 1-3C alkyl], its pharmaceutically permissible salt, etc., as an active ingredient. The compound includes (3R)-3-((S)-4-methyl-2- phenylsulfonylaminovalerylamino)-2-tetrahydrofuranol. The compound of the formula is obtained e.g. by a method comprising reacting an amino acid derivative with a suitable condensing agent, reacting the product with a lactone derivative, and subsequently treating the product with a reducing agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel agent for preventing or treating a neurodegenerative disease.

[0002]

2. Description of the Related Art Diseases caused by degeneration of nerve cells include diseases caused by demyelination of nerve cells such as Alzheimer's disease, neuropathy of peripheral nerves, multiple sclerosis, and impaired consciousness or movement during head injury. Etc. are known. Alzheimer's disease is in old age (45-65 years old)
Is a progressive dementia that develops in the brain, and pathologically shows numerous senile plaques and neurofibrillary tangles in the brain. As for the senile dementia caused by the so-called natural aging that occurs in the senile period of 65 years or older, there is no essential difference in pathology,
It is called Alzheimer's disease. The number of patients with this disease has increased with the increase in the elderly population, and has become a socially important disease.

[0003]

At present, there are no drugs that can cure Alzheimer's disease, and many drugs that are being tested for Alzheimer's disease patients, such as cholinesterase inhibitors, act on the neurotransmission system. Most of them aim to improve. Therefore, there is a strong demand for the development of a drug that can reliably treat or prevent Alzheimer's disease.

The causes of neuropathy of peripheral nerves are various, such as complications of diabetes and side effects of anticancer drugs. Diabetes patients have increased rapidly in the era of satiety, and the number of cancer patients has continued to increase after a long time since cancer appeared in the top mortality rate. Therefore, an increasing number of people suffer from neuropathy, and there is a demand for the development of a drug effective for neuropathy so that they can conduct a normal social life as much as possible. Multiple sclerosis is considered to be an autoimmune disease, and neuropathy appears when the myelin of nerve cells is disrupted. Although the number of patients in Japan is not very large, it is designated as one of the incurable diseases for which there is no reliable treatment,
The development of an effective drug as soon as possible is desired.

In the past, serious injuries to the head due to traffic accidents and the like often resulted in death in the past, but with the recent advances in emergency medical care, it has become possible to save lives even with considerable injuries. . However, fortunately, even if they can survive their lives, consciousness disorders and motor disorders often remain, and they may not be able to return to society. Therefore,
Developing drugs that improve impaired consciousness or movement during head trauma is of great social value. Currently, cerebral metabolism enhancers and the like are used for consciousness disorder during head injury, and central muscular relaxants are used for movement disorder, but these are not always satisfactory, so development of more effective drugs is not possible. Is desired. As mentioned above,
Since the development of a drug that is truly effective against neurodegenerative diseases is desired, the present invention seeks to meet that need.

[0006]

The preventive or therapeutic agent for neurodegenerative diseases according to the present invention has the following general formula (I):

[0007]

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. R¹Is R^FourWhen CO- is represented,^FourIs
C which may have a substituent₆~ C₁₄With an aryl group of
C which may be replaced₁~ C₂₀Alkyl group, especially C₁₄
~ C₁₆Having an unsubstituted alkyl group or a substituent
May be C₆~ C₁₄Is preferably an aryl group.
A is C₁~ C_ThreePreferably an alkylene group of
No. Particularly preferred is R^FourIs C₁₄~ C₁₆Alkyl group
And A is C₁~ C_ThreeWhich is an alkylene group of
You.

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. R ¹ is R ⁴ S
When O ₂ — is represented, R 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.

The C ₁ -C ₆ alkyl group defined by R ² 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, and an isohexyl group. C ₁ to R ⁵ defined as
The alkyl group of C _10, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl and the like. As the C ₁ -C ₃ alkylene group defined for A, a methylene group,
An ethylene group, a propylene group, and such an alkylene group include a methyl group, an ethyl group, C ₁ -C and propyl group
_It may have 1 to 2 alkyl groups of ₃ . 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).

[0017]

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 known that the compound represented by the above general formula (I) has calpain inhibitory activity and can be used as a preventive or therapeutic agent for neurodegenerative diseases. Not.

The preventive or therapeutic agent for a neurodegenerative 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, sodium salts, potassium salts, magnesium salts, metal salts such as calcium salts, or ammonium salts, methyl ammonium salts, dimethyl ammonium salts,
Ammonium salts such as trimethylammonium salt and dicyclohexylammonium salt can be formed.
Further, the preventive or therapeutic agent for a neurodegenerative disease of the present invention represented by the above general formula (I) can also be used as a solvate or hydrate. Regarding the stereochemistry of the asymmetric carbon present in the preventive or therapeutic agent for a neurodegenerative disease of the present invention represented by the above general formula (I), the stereochemistry of the asymmetric carbon is independently (R) form,
(S) body or (RS) body can be taken. Specific examples of prophylactic or therapeutic agent for neurodegenerative diseases of the present invention represented by the aforementioned general formula (I), compounds shown in Table -1 if R ³ is a hydrogen atom, R ³ is hydrogen When it is not an atom, the compounds shown in Table 2 below can be mentioned.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

[0026]

[Table 7]

[0027]

[Table 8]

[0028]

[Table 9]

[0029]

[Table 10]

[0030]

[Table 11]

[0031]

[Table 12]

[0032]

[Table 13]

[0033]

[Table 14]

[0034]

[Table 15]

[0035]

[Table 16]

[0036]

[Table 17]

[0037]

[Table 18]

[0038]

[Table 19]

[0039]

[Table 20]

[0040]

[Table 21]

[0041]

[Table 22]

[0042]

[Table 23]

[0043]

[Table 24]

[0044]

[Table 25]

[0045]

[Table 26]

[0046]

[Table 27]

[0047]

[Table 28]

[0048]

[Table 29]

[0049]

[Table 30]

[0050]

[Table 31]

[0051]

[Table 32]

[0052]

[Table 33]

[0053]

[Table 34]

[0054]

[Table 35]

[0055]

[Table 36]

[0056]

[Table 37]

[0057]

[Table 38]

[0058]

[Table 39]

[0059]

[Table 40]

[0060]

[Table 41]

[0061]

[Table 42]

[0062]

[Table 43]

[0063]

[Table 44]

[0064]

[Table 45]

[0065]

[Table 46]

[0066]

[Table 47]

[0067]

[Table 48]

[0068]

[Table 49]

[0069]

[Table 50]

[0070]

[Table 51]

[0071]

[Table 52]

[0072]

[Table 53]

[0073]

[Table 54]

[0074]

[Table 55]

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

[0076]

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, when the obtained compound (IV) is treated with a reducing agent such as diisobutylaluminum hydride, sodium borohydride / cerium chloride, the compound represented by the above general formula (V) can be obtained.

[0078]

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. 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.

[0081]

Embedded image

Calpain is usually present in cells as a stable precursor. When the intracellular calcium concentration rises for some reason, calcium binds to calpain and changes into an activated form by autolysis to produce a proteolytic enzyme. To work as. β-amyloid is a major component of senile plaque, one of the characteristic pathological findings found in the brain of Alzheimer's disease patients, and its precursor, amyloid precursor protein (APP), is cleaved by proteolytic enzymes. Received and produced. It has been suggested that calpain is involved as the cleavage enzyme. (Biochemistry, 33 volumes, 45
50, 1994). As one of the proofs, A
It has been reported that calpain inhibitors suppressed β-amyloid secretion from cells overexpressing PP (Neu).
ron, vol. 14, p. 651, 1995).

Further, it has been suggested that intracellular calcium homeostasis is disrupted as a mechanism of β-amyloid toxicity expression (P
rosedings of the Nationa
lAcademy of Sciences of t
he U.S. S. A. 90, 567 pages, 1993
It is believed that abnormally elevated levels of intracellular calcium cause abnormal activation of calpain, leading to cell death. On the other hand, examination of the ratio of calpain precursor to activator in the postmortem brains of Alzheimer's disease patients and normal subjects demonstrated that significantly activated calpain was increased in the brains of Alzheimer's disease patients (Proc
eatings of the National Ac
ademy of Sciences ofthe
U. S. A. 90, 2628 pages, 1993
Year). This result suggests that increased activation of calpain in Alzheimer's disease patients triggers neuronal cell death.

For the above reasons, compounds that suppress the activity of calpain in the brain are considered to be preventive or therapeutic agents for Alzheimer's disease. Since no animal model of Alzheimer's disease itself has been reported, we examined a model for suppressing the degradation of microtubule-associated protein 2 (MAP2). MA
P2 is one of the cytoskeletal proteins, present in very high concentrations in dendrites of neurons, is a major component of the cross-link between microtubules and between microtubules and neurofilaments, and Have a relationship (Scientif
ic American, 259, 56, 19
1988). In addition, MAP2 is one of the very good in vivo substrates of calpain, and it has been suggested that MAP2 degradation can be an indicator of calpain activation in the brain (An
nals of the New York Acad
emy of Sciences, 568, 198, 1989). Therefore, a substance that suppresses MAP2 degradation in the brain is highly likely to suppress the action of calpain in the brain, and for the reasons described above, it is considered that the substance is a prophylactic or therapeutic drug for Alzheimer's disease.

It has been reported that myelin binding protein present in dendrites of nerve cells is degraded by calpain (Journal of Neurochemistr).
y, 47, 1007, 1986). Therefore, it is thought that calpain inhibitors are effective for diseases that are said to be caused by demyelination of nerve cells, such as multiple sclerosis and neuropathy of peripheral nerves.

It has been reported that calpain is activated in a rabbit head injury model (Neu).
rochemical Research, 16 volumes, 4
83, 1991), and in a rat head injury model, administration of the calpain inhibitor leupeptin has been observed to protect neuronal axons (Journal of Neurosurg).
erry, 65, 92, 1986). Therefore, it is considered that calpain inhibitors are effective in improving consciousness disorder and motor disorder in head trauma.

In applying the agent of the present invention to clinical applications, the ratio of the therapeutically effective ingredient to the carrier ingredient is usually 1% by weight to 90% by weight. The drug of the present invention is granules, fine granules, powders, hard capsules, soft capsules, syrups,
It may be administered orally in the form of an emulsion, suspension or solution, or it may be administered as an injection intravenously, 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. Examples of excipients used in producing a solid preparation include 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. Preparations for parenteral administration, that is, injections, solvents or suspensions used in the production of suppositories, 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 daily 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.

[0089]

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, 1
H), 1.81 (m, 1H), 2.16 (s, 3H),
2.24 (m, 1H), 3.61 (m, 1H), 3.9
5 (ddd, J = 9.3 Hz, 9.0 Hz, 7.5H
z, 1H), 4.14 (ddd, J = 9.3 Hz, 9.
0 Hz, 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 =
8.7 Hz, 1H), 7.54 (m, 2H), 7.62
(M, 1H), 7.86 (dd, J = 7.2 Hz, 1.D).
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-
Production of methyl-2-tetradecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol (Compound No. 26 in Table 1) 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 (3S) -3-((S) -2-)
Cyclohexyloxycarbonylamino-4-methylvalerylamino) -2-tetrahydrofuranol (Table 1)
Preparation of Compound No. 47) 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).

Embodiment 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).

Example 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,
2H), 1.62 (m, 1H), 2.12 (m, 1
H), 3.43 (m, 1H), 3.70 (m, 1H),
3.91 (m, 1H), 4.17 (dd, J = 8.4H
z, 8.4 Hz, 1H), 5.12 (d, J = 4.5H)
z, 0.3H), 5.25 (d, J = 4.5 Hz, 0.
7H), 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, 1
H), 1.81 (m, 1H), 2.16 (s, 3H),
2.24 (m, 1H), 2.31 (s, 3H), 2.6
2 (s, 6H), 3.56 (m, 1H), 3.94
(M, 1H), 4.14 (m, 1H), 4.52 (m, 1H)
1H), 5.00 (d, J = 7.1 Hz, 1H), 6.
15 (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, 1
H), 1.84 (m, 1H), 2.16 (s, 3H),
2.22 (m, 1H), 3.56 (m, 1H), 3.8
8 (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 H)
z, 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 Production 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.

[0137]

[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 MAP2 Degradation Inhibition Test An 8-week-old male Wistar rat was anesthetized with pentobarbital (40 mg / kg), and kainic acid (0.4 μm) was added.
g) was injected into the lateral ventricle. The drug is kainic acid injection 6
Oral administration was performed 0 minutes before and 60 minutes later. Twenty-four hours after kainic acid injection, the dorsal half of the hippocampus was excised with 1 mM EDTA,
1 mM EGTA, 1 mM DTT, 1 mM benzamidine, 0.1 mM leupeptin and 0.1 mM pAPMS
F containing 10 mM Tris-HCl (pH 7.4)
3 ml, homogenized, and centrifuged at 4 ° C for 20 minutes (1
2000 × g). From the obtained cytoplasmic fraction, SDS-
The polypeptide portion was separated by PAGE and transferred to a PVDF membrane by Western blotting. MAP2 was immunostained with rat brain MAP2 monoclonal antibody and alkaline phosphatase, and the colored band was measured with a laser densitometer (PD-110, MD). The MAP2 degradation inhibitory effect was determined by whether or not the amount of MAP2 (usually reduced by 40 to 60%) reduced by intraventricular administration of kainic acid was significantly increased (ie, whether or not MAP2 degradation was significantly suppressed). . Table 4 shows the results. Table 4 shows that the compound of the present invention significantly suppressed MAP2 degradation, and thus suppressed calpain activity in the brain.

[0141]

[Table 57]

Test Example 4 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 LD ₅₀ values of the compounds of Example 2 and Example 29 were both> 2000 mg / kg.

Test Example 5 Formulation Example (1) Tablet The following ingredients were mixed according to 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 capsule The following components were mixed in a conventional manner, and filled in a soft capsule. Compound of Example 2 30 mg Olive oil 300 mg Lecithin 20 mg (3) Preparation for injection The following ingredients were mixed according to a conventional method to prepare a 1 ml ampoule. Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water for injection 1 ml

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07D 307/22 C07D 307/22 309/14 309/14 407/12 307 407/12 307 (31) Priority claim number special Nippon Hei 8-207012 (32) Priority Date Hei 8 (1996) August 6, (33) Priority Country Japan (JP)

Claims (38)

[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 preventive or cure for neurodegenerative diseases containing hydrate as an active ingredient
Remedy. 2. R ¹ is R ⁴ —CO— (R ⁴ is a C _{1 to} C ₂₀ alkyl group optionally substituted with a C _{6 to} C ₁₄ aryl group which may have a substituent or 2. The prevention of a neurodegenerative disease according to claim 1, wherein A represents a C ₆ -C ₁₄ aryl group which may have a substituent, and A represents a C ₁ -C ₃ alkylene group. Or therapeutic drugs. 3. The preventive or therapeutic agent for a neurodegenerative 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 preventive or therapeutic agent for a neurodegenerative disease according to claim 1, which represents ₃ alkylene groups. 5. The preventive or therapeutic agent for a neurodegenerative disease according to claim 4, wherein R ⁴ represents a C _{13 to} 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
Prophylactic or therapeutic agents according to claim 1 neurodegenerative diseases, wherein a representative of the representative) an aryl group C _14. 7. The preventive or therapeutic agent for a neurodegenerative disease according to claim 6, wherein R ⁴ represents a C _{14 to} C ₁₆ alkyl group. 8. C ₆ to R ⁴ may have a substituent.
Prophylactic or therapeutic agents according to claim 6 neurodegenerative diseases, wherein the 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 preventing or treating a neurodegenerative disease. . 10. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-phenylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof, Or a prophylactic or therapeutic agent for a neurodegenerative disease, which is a solvent or hydrate thereof. 11. The active ingredient is (3S) -3-｛(S)-
Neurology characterized in that it is 4-methyl-2- (2,4,6-trimethylphenylsulfonylamino) valerylamino} -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. Drug for preventing or treating degenerative diseases. 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 preventing or treating a neurodegenerative disease. 13. The method according to claim 1, wherein the active ingredient is (3S) -3-((S)-
Prevention or treatment of a neurodegenerative disease characterized by being 4-methyl-2-pentadecanoylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. medicine. 14. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecanoylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Or a preventive or therapeutic agent for a neurodegenerative disease characterized by being a hydrate. 15. The active ingredient is (3S) -3-((S)-
Prevention or treatment of a neurodegenerative disease characterized by being 2-hexadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. medicine. 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 preventing or treating a neurodegenerative disease. 17. The method according to claim 16, wherein the active ingredient is (3S) -3-((S)-
Prevention or treatment of a neurodegenerative disease characterized by being 2-heptadecanoylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. medicine. 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 preventing or treating a neurodegenerative disease. The active ingredient may be (3S) -3-((S)-
4-methyl-2-tridecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof, for preventing or preventing a neurodegenerative disease; Therapeutic drugs. 20. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tridecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. An agent for preventing or treating a neurodegenerative disease, which is a solvent or a hydrate. 21. The active ingredient is (3S) -3-((S)-
4-methyl-2-tetradecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or a hydrate thereof, for preventing or preventing a neurodegenerative disease; Therapeutic drugs. 22. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. An agent for preventing or treating a neurodegenerative disease, which is a solvent or a hydrate. The active ingredient is (3S) -3-((S)-
4-methyl-2-pentadecyloxycarbonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof, for preventing a neurodegenerative disease. Or therapeutic drugs. 24. An active ingredient comprising (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecyloxycarbonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable salt thereof. An agent for preventing or treating a neurodegenerative disease, which is a solvent or a hydrate. 25. An active ingredient comprising (3S) -3-((S)-
Prevention or treatment of a neurodegenerative disease characterized by being 4-methyl-2-tetradecylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. medicine. 26. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-tetradecylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Or a hydrate for preventing or treating a neurodegenerative disease. 27. The active ingredient is (3S) -3-((S)-
Prevention of a neurodegenerative disease characterized by being 4-methyl-2-pentadecylsulfonylaminovalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a salt or solvent or hydrate thereof. Or therapeutic drugs. 28. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -4-methyl-2-pentadecylsulfonylaminovalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Or a preventive or therapeutic agent for a neurodegenerative disease characterized by being a hydrate. 29. The active ingredient is (3S) -3-((S)-
Prevention or treatment of a neurodegenerative disease characterized by being 2-hexadecylsulfonylamino-4-methylvalerylamino) -2-tetrahydrofuranol, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof. medicine. 30. The active ingredient is (2S, 3S) -2-acetoxy-3-((S) -2-hexadecylsulfonylamino-4-methylvalerylamino) tetrahydrofuran, or a pharmaceutically acceptable solvent thereof. Or a preventive or therapeutic agent for a neurodegenerative disease characterized by being 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, a neurodegeneration characterized in that: Drugs for preventing or treating diseases. 32. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is Alzheimer's disease. 33. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is a disease caused by demyelination of nerve cells. 34. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is multiple sclerosis. 35. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is neuropathy. 36. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is a disorder at the time of head injury. 37. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is impaired consciousness during head injury. 38. The preventive or therapeutic agent for a neurodegenerative disease according to any one of claims 1 to 31, wherein the neurodegenerative disease is a movement disorder at the time of head injury.