WO1998004539A1

WO1998004539A1 - Oxygenic heterocyclic derivatives

Info

Publication number: WO1998004539A1
Application number: PCT/JP1997/002598
Authority: WO
Inventors: Ryoichi Ando; Hirokazu Masuda; Keiichi Aritomo; Narihiko Yoshii; Ken-Ichi Saito
Original assignee: Mitsubishi Chemical Corporation
Priority date: 1996-07-29
Filing date: 1997-07-28
Publication date: 1998-02-05

Abstract

Oxygenic heterocyclic derivatives of general formula (I), salts thereof, and solvates or hydrates of those [wherein R1 is formula (II) (wherein R4 is C¿11?-C20 alkyl or the like) or the like; R?2 is C¿1-C10 alkyl or the like; R3 is H or formula (III) (wherein R5 is C1-C10 alkyl); and A is C1-C3 alkylene or the like]. These compounds exhibit a potent inhibitory activity against cysteine proteases such as calpain.

Description

Description Oxygen-containing complex ring conductor Technical field

The present invention relates to a novel oxygen-containing heterocyclic derivative. More specifically, the present invention relates to an oxygen-containing heterocyclic derivative, a salt thereof, a solvate thereof or a hydrate thereof, which has a strong inhibitory activity on cysteine protease, especially calpain. Background art

As papain, cathepsin B, cathepsin H, cathepsin L, calpain, interleukin-1 converting enzyme, and other cysteine proteases work in vivo, their abnormal redoxing causes various diseases. Increasingly, cysteine protease inhibitors have been reported to be effective in animal models of these diseases.

In skeletal muscle breakdown seen in muscular diseases such as muscular dystrophy and muscular atrophy, cysteine proteases such as kyrupain and cathepsin B are involved in early processes such as loss of Z-rays through degradation of muscle fiber proteins. It is considered (Metabolism, Vol. 25, extra edition "Metabolic Disease Highlight", p. 183, 1988). E-64-d, a cysteine protease inhibitor, has been reported to have a prolonged survival effect in muscular dystrophy hamsters (Journa 1 of Pharma cobio Dyn amics, Vol. 10, p. 678). , 1987). Therefore, cysteine protease inhibitors are considered to be therapeutic agents for muscular dystrophy, muscular atrophy and the like.

In ischemic diseases such as myocardial infarction and stroke, the main cause of cell damage after ischemia is active oxygen produced by xanthine oxidase. Converted to oxidase hexane Chin dehydrogenase elevated C a ² + concentration in the O connexion activated Chikararu z fin is a precursor of xanthine oxidase in the course of ischemia limited proteolysis to There is a theory that there is

En gland J ournalofedicine, 3 1 Volume 2, 1 5 9 pages, 1 985). It is also believed that calpain activation can be a direct cause of cardiomyocyte and brain neuronal cell death (Latest Medicine, 43, 783, 1988). A calpain inhibitor, NCO-700, has been reported to be effective in animal models of myocardial infarction (Arzneimittel Forschung / Drug Research, 36, 190, 671, E-64-c inhibits the breakdown of microtubule-associated protein after cerebral ischemia (Brain Research, 526, 177, pp. 1990). Therefore, calpain inhibitors may be therapeutic agents for ischemic diseases such as myocardial infarction and stroke.

Amyloid is a protein deposited in the senile plaques specific to the brain of patients with Alzheimer's disease, and it is known that this amyloid is formed by the degradation of the amyloid protein pre-specialized body (APP). I have. Amyloid is not produced by normal metabolism of APP, but amyloid is activated by abnormal metabolism by abnormally increased protease, which is considered to be senile plaque (Scientific American, 1 99 1 year 1 January issue, page 40). Therefore, inhibitors of proteases are expected to be therapeutics for Alzheimer's disease.

It has been reported that calpain is activated in rabbit head injury models (Neurochical Research, Vol. 16, p. 483, pp. 1991), and rat head injury models. In the Journal of Neurosurgery, Vol. 65, 92, 1986, administration of leptin, a calpain inhibitor, has been observed. Therefore, it is considered that calpain inhibitors are effective in improving consciousness disorder and movement disorder in head trauma.

It has been reported that myelin-binding protein present in dendrites of nerve cells is degraded by calpain (JournalofNeeurochemistry, vol. 47, p. 2007, p. 1986). Therefore, calpain inhibitors are thought to be effective for diseases that are said to be caused by neuronal demyelination, such as multiple sclerosis and peripheral nerve neuropathy.

Many of the cataracts are crystallin, a water-soluble protein in the lens. It is said that the lens is opaque due to hydrolysis by the action of the mouth thease. Cataracts in experimental models and certain types of human cataracts have elevated concentrations of calcium in the lens (Inv estigative Opthal mology & Visual Science, Vol. 28, 1702-1). 1987, Experimantal Eye Research, Vol. 34, pp. 413,〗 982), and because the most proteases in the lens are calpain ( L ensand Ey e Toxicity Research, Vol. 6, 725 ぺ, 1989), it is considered that abnormal dying of calpain is one of the causes of cataract. Report that E-64, a calpain inhibitor, was effective in an experimental model of cataract (Inv esti ga ti V e Oph thal mologgy & Visual Science, 32, 533, 1999) Therefore, calpain inhibitors are considered to be therapeutic agents for cataracts.

In relation to inflammation, neutrophils are known to respond to stimulation by chemotactic factors and phorbol ester by degranulation and production of superoxide. Is thought to be mediated by protein kinase C (PKC). It has been reported that calpain acts to activate this PKC, and that it promotes degranulation and suppresses superoxide production (Journa 1 of Biological Chemistry, 263, 1915, 1988). It has also been reported that the concentration of cathepsin B in rat macrophages is 30 to 40 times higher than that of leukocytes and neutrophils, and that the enzyme concentration of inflammatory macrophages is 6 times higher than that of normal macula phages. (J ournalof Biooch em istry, Vol. 98, p. 87, 1985). More recently, an enzyme that converts pre-interleukin 1S to interleukin 1/3 (interleukin 1/3 converting enzyme) was found to be a cysteine protease (Nature, 356, 768, (1992), it became clear that activation of cysteine protease plays an important role in the development of inflammation. For these reasons, it is believed that inhibitors of cysteine protease can be used as anti-inflammatory agents. ―

The type I allergic reaction progresses through immunoglobulin E (IgE) produced by sensitizing a living body to an antigen. It has been reported that essutin A, a cystine protease inhibitor, specifically inhibits IgE production and has no effect on IgG production (The Journal of Antibiotics, Vol. 42). , 1362, 11989). Therefore, it is considered that a cysteine protease inhibitor can be used as an antiallergic agent.

When hepatocytes are necrotic, damage to the cell membrane increases the permeability of ^{Ca 2+} , increasing the intracellular Ca ²⁺ concentration and activating calpain. It is thought that cell death occurs as a result of decomposition. Therefore, inhibitors of calpine can be used as therapeutics for fulminant hepatitis.

Cathepsins, such as cathepsin B and cathepsin L, are involved in the degradation of bone collagen in osteoclasts. Administration of E-64, a cathepsin inhibitor, or Estatin A, to rats with increased bone destruction by administration of parathyroid hormone may decrease blood calcium and hydroxyproline concentrations. It has been reported (Biochemical and Biophysical Research Research, Vol. 125, 1 Page, 1984, JP-A-2-218610). Therefore, inhibitors of cathepsins are considered to be therapeutic agents for osteoporosis and hypertensive lucidemia.

Examples of calpain substrates include sex hormone receptors such as estrogen receptor and androgen receptor. Calpain is known to activate these receptors, and abnormal translation of calpain causes diseases that may be due to abnormal activation of sex hormone receptors, such as breast cancer, prostate cancer, and prostatic hypertrophy. It is said that. Therefore, calpain inhibitors would be therapeutic agents for the above diseases. It is said that epidermal growth factor (EGF) receptor is activated along with canceration of cells, and calpain is known to activate the EGF receptor using the EGF receptor as a substrate. In addition, it has been reported that calpain was activated in cells infected with the adult T-cell human leukemia virus (ATLVZHTLV-) (Biochemistry, 57, 1202, 1985). On the other hand, cathepsin B promotes collagen degradation, which is an important stage of cancer metastasis, or directly degrades collagen. And its close relationship with the plasma membrane of neoplastic cells, it is said to be greatly involved in the process of cancer metastasis (Tumor Progression and Markers, 47, 1982, J ournalof Bio 1 ogica 1 Chem istry, 256 volumes, 8536 pages, 【984). It is thought that inhibitors of cysteine protease are effective in suppressing cancer growth and preventing metastasis.

When platelets are activated, they aggregate, causing thrombus. It has been reported that platelet aggregation induced by E-64-d thrombin, an inhibitor of calpain, was inhibited by thrombin (Thrombosis Resealch, Vol. 57, pp. 87, 1990). Therefore, calpain inhibitors can be used as platelet aggregation inhibitors.

As described above, abnormal cysteine proteases cause various diseases, and some cysteine protease inhibitors have been reported to be effective in animal models and the like.

On the other hand, a lactol derivative similar to the compound of the present invention is represented by the following formula (II) (R ⁶ represents an isopropyl group, an isobutyl group, or a benzyl group, and R ⁷ represents a hydrogen atom or an acetyl group). Compounds have been reported (Japanese Patent Application Laid-Open (JP-A) No. H08-104685).

However, the structure of the compound (II) is significantly different from that of the compound of the present invention in that the group corresponding to R ⁴ of the present invention is a branched C ₇ alkyl group. In the above publication, d to d are used as the alkyl group corresponding to R ⁴ of the present invention. In the examples, the compounds of the above-mentioned C ₇ alkyl group and the compounds of the tert-butyl group are only described.

Known inhibitors include E-64 (Agrica Ituraland Biolo gica 1 Chemistry, Vol. 42, p. 529,] 978), E—64-d (Journalof Biochemistry, Vol. 93, p. 1305, 1983), NC 0-700 (special) Epoxy Succinic Acid Derivatives or Peptide Chloromethyl Ketones (Journa 1 of Biooch), Estatins A and B (The Journal of Antibiotics, Vol. 42, p. 1989) em istry, Vol. 99, p. 173, pp. 1986) Represented by bisoxymethyl ketone (Biooch em istry, Vol. 30, p. 4678, pp. 199). However, most of the irreversible inhibition. In general, irreversible inhibition II is said to be highly toxic because it easily reacts non-specifically with biological constituents other than the target enzyme, and few compounds have been used in clinical practice. Also, reversible inhibitors include leupeptin (The Journal of Antibiotics, Vol. 22, p. 283, 1969), and carpeptin (Journal of Enzyme Inh ibition, Vol. 3, p. 195, Peptidyl aldehyde is known, but it is said to have problems with chemical stability, stability in vivo, and permeability of cell membranes. Disclosure of the invention

An object of the present invention is to provide a novel cysteine protease inhibitor that can solve the above-mentioned conventional problems.

The gist of the present invention is the following general formula (I)

R

0

(In the above general formula (I), R ′ is R ⁴ — CR ⁴ or 0

II

R ^{4 represents} S— (R ⁴ represents a linear alkyl group of Cu C ^), and R ² represents

II

〇

Hydrogen atom or a C ₆ optionally substituted by Ariru group to CH C〗 -C _10,

0

II

Represents an alkyl group, R ³ represents a hydrogen atom or R ⁵ —C— (R ⁵ represents an alkyl group of C, to C ₁₀ ), and A may be substituted with an alkyl group of C, to C ₃ comprising a carrier acceptable same compounds and pharmaceutically; good maintenance oxygen-containing heterocyclic derivatives represented by an alkylene group of -C _3), a salt thereof, a solvate thereof or a hydrate thereof A pharmaceutical composition; and a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier for a disease caused by cystine protease overactivity. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the above general formula (I), CH to C ₂ defined by R ⁴ in R ¹ . Examples of the linear alkyl group include decdecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl. And straight-chain alkyl groups of ₁₃ to ₆ such as a tetradecyl group, a pendecyl group and a hexadecyl group.

The alkyl group of C! -C ₁₀ defined by R ^2, a methyl group, Echiru group, flop port propyl group, an isopropyl group, butyl group, isobutyl group, sec one butyl group, tert- butyl group, a pentyl group, Examples include isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, and decyl group. in the ₆ -C ₁₄ § Li Ichiru group may be substituted.

Examples of the d to C ₁₀ alkyl group defined by R ⁵ in R ³ include the same groups as defined for R ² , and preferably include C and C ₄ alkyl groups. You.

Examples of the d to C ₃ alkylene group defined by A include a methylene group, an ethylene group and a propylene group, and such an alkylene group is a d to C ₃ alkyl group such as a methyl group, an ethyl group, and a propyl group. 〗 May be substituted with two.

As R ² , an alkyl group of C ₆ to C ₁₄ which may be substituted with an aryl group of C ₆ to C ₁₄ is preferable, an alkyl group of C _{1 to} C ₁₀ is more preferable, and C 1 to C ₄ Alkyl base strength is particularly preferred, and isobutyl base strength is most preferred.

A is preferably a C 1, to C ₃ alkylene group.

As the compound represented by the general formula (I),

0

II

(1) R ¹ represents R ⁴ — C— (R ⁴ represents a linear alkyl group of CHC! ₆ ), R ² represents C, an alkyl group of 0, R ³ represents hydrogen Atom or

0

II

R ⁵ —C— (R ⁵ represents a C 1 to C ₁₀ alkyl group), and A represents a C 1 to C ₃ alkylene group;

0

II

(2) R ¹ is R ⁴ -0- C - represents the (. To table a linear Arukiru group R ⁴ Haji _{_13-15),} an alkyl group of R ² force "-C _10, R ³ Is a hydrogen atom or

0

! 1

R ⁵ -C— (R ⁵ represents an alkyl group of d to C ₁₀ ), and A represents a d to C ₃ alkylene group;

0

I!

(3) R ¹ is R ⁴ — S— (R ⁴ represents a C _{14 to} C ₁₆ linear alkyl group)

0

R ² represents a C 1, to C ₁₀ alkyl group, and R ³ represents a hydrogen atom or

0

II

R ⁵ one C one (R ⁵ represents an alkyl group having -C ₁₀₎ represent, compound A represents C, alkylene group of -C _3,

And their salts, their solvates and their hydrates are preferred and more preferred Or compounds represented by the conditions (2) or (3) above, salts thereof, solvates thereof, and hydrates thereof.

Specific examples of preferred compounds include

(3S) -3-((S) -4-Methyl-1-2-pentadecanoylaminovalerylamino) 1-2-tetrahydrofuranoyl,

(2 S, 3 S) — 2-acetoxy 3 — ((S) _ 4-monomethyl-1-2-pentadecanoylamino novarelylamino) tetrahydrofuran,

(3 S) 1-3-((S)-2-Hexadecanoylamino 1-4-methylvalerylamino) 1-2-tetrahydrofuranoyl,

(2 S, 3 S) — 2-acetoxy-1- 3 ((S) — 2-hexadecanylamino — 4-methylvalerylamino) tetrahydrofuran,

(3 S) 1 3— ((S)-2—Heptadecanoylamino 4-methylvalerylamino) 1—2—Tetrahidrofuranoyl,

(2 S, 3 S) — 2-acetoxy 3— ((S) -2-heptadecanolylamino 4-methylvalerylamino) tetrahydrofuran,

(3S) -3-((S) -4-Methyl-2-tridecyloxycarbonylamino relylamino) 1-2-tetrahydrofrofanol,

(2 S, 3 S) — 2-acetoxy 3— ((S) -4-methyl-2-tridecyloxycarbonylamino valerylamino) tetrahydrofuran,

(3S) 13- ((S) 14-methyl-2-tetradecyloxycarbonylamino) relinoleamino) 1-2-tetrahydrofuranoyl,

(2 S, 3 S) — 2-acetoxy _ 3 — ((S) — 4-methyl-2-tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran,

(3 S)-3-((S) 1-4-methyl- 1-2-pentyldecyloxycarbonylamino-non-relinoleamino) _ 2-Tetrahydrofuranoyl,

(2 S, 3 S) — 2-acetoxy 3 — ((S) — 4-methyl-1-2-pentyldecyloxycarbonylaminovalerylamino) tetrahydrofuran,

(3 S) — 3— ((S) -4-methyl-2-tetradecylsulfonylaminovale lylamino) 1—2-tetrahydrodrofuranoyl, (2 S, 3 S) —2-Acetoxy 3-((S) —4-Methyl-2-tetradecylsulfonylaminovalerylamino) Tetrahydrofuran,

(3S) -3-((S) -4-methyl-2-pentyldecylsulfonylaminovalerylamino) 1-tetrahydrofuranoyl,

(2 S, 3 S) —2-Acetoxy— 3— ((S) — 4-Methyl-2-pentyldecylsulfonylaminoamino-relinoleamino) tetrahydrofuran,

(3S) — 3— ((S) — 2-hexadecylsulfonylamino-4-methylvalerylamino) 1-tetrahydrofuranol,

(2S, 3S) 1-2-acetoxy-13-((S) -12-hexadecylsulfonylamino-4-methylvalerylamino) tetrahydrofuran,

And their salts, their solvates, and their hydrates.

The oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can form a salt. Specific examples of such salts include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, or ammonium salt, methyl ammonium salt, dimethyl ammonium salt, trimethyl ammonium salt, and disc. Ammonia salts such as oral hexyl ammonium salt can be formed. Further, the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can also exist as a solvate or hydrate.

Regarding the stereochemistry of the asymmetric carbon present in the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I), the (R) -form, (S) -form or (RS) -form Can be taken.

In the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I), when R ³ is a hydrogen atom, the following general formula (III) (wherein R ′, R ² and A are as defined above) In particular, in a solution, there exists an equilibrium with a hydroxyaldehyde derivative represented by the following general formula (IV) (where R ¹ , R ² and A are as defined above). I do. This can be explained by the following experimental results. The NMR measurement results show that the force supporting the structure of the following general formula (ΠΙ) The ratio of the stereochemistry of the carbon atom bonded to the hydroxyl group on the lactol ring of the following general formula (ΠΙ) differs depending on the type of solvent used It has been strongly observed as a difference in the ratio of the stereoisomers of compound (III). This difference The difference in the sex ratio is considered to be caused by the following equilibrium. Η

(III) Specific examples of oxygen-containing heterocyclic derivatives of the present invention represented by the aforementioned general formula (I), the following table in the case of R ³ are hydrogen atoms - the compounds shown in 1, R ³ is hydrogen If it is not an atom, the compounds shown in Table 2 below can be mentioned.

(

Table 1

1 (continued)

1 (continued)

1 (continued)

Table I 1 (continued)

Table 1 (continued)

Table-] (continued)

IS Table-1 (continued)

R2 丫, 0

OH

/ 0

CH _s (CH ₂ ) i9 H ^— CH ^ HCCH 3) 2

, 0

OH

0

II

CHg (CH2) io— S— — CH ^ CH (CH 2

0 OH

0

II

CH Q (CA? 711— S— — CH 2CH (Ch 3

'' II

0 OH

0

II

CH ₃ (CH ₂ ) ₁₂ -S- ― CH c KCHg

0 OH

0

II

CH ₃ (CH ₂ ) ₁₃ -S- — CH ^ CI CH

0 OH

0

II

CH ₃ (CH ₂ ) i 4 S-- ― CH H (CHg) 9

0 OH

0

II

CH ₃ (CH ₂ ) ₁₅ -S- — CH ^ Ci CHg

0 OH 1 (continued)

2C 1 (continued)

Conversion

R2

¾ ■

OH

64 CH ₃ (CH ₂ ) ₁₄ ^--CH (CH ₃ ) CH ₃

0 OH people

65 CH ₃ (CH ₂ ) i3 Ιί -CH (CH ₃ ) CH2CH ₃

0

OH

0

II

66 CH ₃ (CH ₂ ) ₁₅ —S--CH (CH ₃ ) CH ^ CH ₃

0 OH

67 CH ₃ (CH ₂ ) ₁₃ Y-C

0 OH

68 3 ((¾ ₂ ) ₁₄丫--CH _2- >

0 OH

69 CH (CH ₂ ) i3 丫 -CH

0 _2-

OH

0

II

70 CH ₃ (CH2 i5— S—

II

0 OH Table 1] (continued)

Table-1 (continued)

1 (continued)

1 (continued)

.

Table-1 (continued)

Conversion

R2.,, 0 Brown OH

99 CH ₃ (CH ₂ 14 丫

0 OH

100 (1 ₃ (QI 2 ノ丫 -Cll2CH (CH ₃ ) ₂丄 / 0

T

0 OH

101 0Η ₃ (0Η ₂ ) ΐ6γ ― CH ^ H CH RE 0

0 OH z ⁰

102 CH ₃ (CH ₂ ) n H — CH ^ Cf CH 3) 2 J 丫 0

0

OH

103 CH ₃ (CH ₂ ) i2, — CH ^ HCCH 3) 2 丫 0

OH

, ο

104 CH ₃ (CH ₂ ) ₁₃ Y one CH Cl CHg)

0

0H

105 CH ₃ (CH ₂ ) i4 Y

OH Table-] (continued)

^^ ί

Rl R2

Completely

OH 0

106 CH ₃ (CH ₂ ) ₁₅ ί ^— CH 2CH (CH3) 2 people, 0

0

OH

0

107 CHs (CH2) 12-0 OH

0

II

108 CH ₃ (CH ₂ ) ₁₃ -S- CH CH (CH 3) 2

0 0H

0

109 CH ₃ (CH ₂ ) ₁₄ S-— CH ₂ CH (CH ₃ ) ₂

0 OH

0

II

110 CH ₃ (CH ₂ ) ₁₅ -S- — CH CH (CH3) 2

0 OH

Table 1 2

2 (continued)

2 (continued)

One 2 (continued)

Table 1 2 (continued)

Table 1 2 (continued)

Table 2 (continued)

2 (continued)

2 (continued)

2 (continued)

2 (continued)

Table 1 2 (continued)

3S

Table 1 2 (continued)

Table — 2 (continued)

2 (continued)

2 (continued)

Table 2 (continued)

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

Manufacturing method 1

(V) (VI)

Reducing agent R 1

(III)

(In the general formula, R ¹ , R ² and A are as defined above, and B oc represents a tert-butoxycarbonyl group.)

The lactone derivative represented by the above general formula (V), which can be produced by the same operation as the method described in Japanese Patent Application No. 8-495666 (W096 / 25408), The protective group Boc was removed by dissolving in ethyl acetate, 1,4-dioxane, methylene chloride, and other solvents, and adding hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and other acids. Dissolve the mine salt in a solvent such as ethyl acetate, salted methylene, dimethylformamide, N-methylpyrrolidone, etc. and dissolve the base such as triethylamine and pyridine. By reacting the acid chloride represented by R ¹ —C 1 in the presence, a compound represented by the above formula (VI) is obtained. Next, the compound (VI) is dissolved in a solvent such as methylene chloride, toluene, heptane, tetrahydrofuran and the like, and treated with a reducing agent such as diisobutylaluminum hydride, sodium borohydride / cerium chloride. Is obtained.

Manufacturing method 2

In the (1) ^ formula, R ¹ , R ² , R ⁵ and A are as defined above.

)

The oxygen-containing heterocyclic derivative (製造) produced by Production Method 1 is converted to an organic solvent such as methylene chloride, 1,1-dichloroethane, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, etc. Dissolved in water and reacted with the acid anhydride represented by the above general formula (R ⁵ CO) 20 in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, and the like. Is obtained. This reaction can be performed without a solvent.

Among the oxygen-containing heterocyclic derivatives of the present invention thus obtained, the compound (ΙΠ) in which R ³ is a hydrogen atom shows strong inhibitory activity against cysteine protease. Also, R ³

0

II

The compound (VII) of R ⁵ -C-(R ⁵ represents an alkyl group of C ₁ , to C ₁₀ ) is an oxygen-containing heterocyclic derivative having a strong inhibitory activity against cysteine protease (III) Can be used as a prodrug. That is, when the compound (VII) is orally administered, after being absorbed from the intestinal tract or the like, the oxygen-containing heterocyclic derivative (ΠΙ), which is an active metabolite, is immediately released by the action of enzymes in the living body.

In applying such a compound of the present invention to clinical applications, the ratio of the therapeutically active ingredient to the carrier ingredient may be varied between 1% by weight and 90% by weight. For example, the compound of the present invention may be orally administered in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, milks, suspensions or liquids, or injected. The preparation may be administered 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 use. 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 the excipient used in the production of a solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, dextrin, calcium carbonate and the like. Liquid preparations for oral administration, that is, emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents such as water and vegetable oil. The formulation may contain, in addition to the inert diluent, auxiliary agents such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents or preservatives. Liquid preparations may be included in the form of absorbable substances, such as gelatin. Preparations for parenteral administration, i.e., solvents or suspensions used in the manufacture of injections, suppositories, etc. include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Can be Examples of bases used for suppositories include cocoa butter, emulsified cocoa butter, lauric fat, witepsol and the like. The pharmaceutical preparation may be prepared according to a conventional method.Clinical dose, when used by oral administration, is as a compound of the present invention for an adult, and is generally 0.01 to 100 mg per day for adults. It is more preferably 0.1 to 100 mg / day, which is more preferably adjusted appropriately according to age, pathological condition and symptom. The above-mentioned daily dose of the agent of the present invention may be administered once a day or at appropriate intervals in two or three doses per mouth, or may be administered intermittently.

When used as an injection, the compound of the present invention is continuously or intermittently administered to an adult in a daily dose of 0.000 to 100 mg / day, preferably 0.01 to 10 mg / day. It is desirable. Example

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples. However, the present invention is not limited to the following Reference Examples and Examples unless it exceeds the gist thereof. Reference Example 1 Production of (3 S) -3--((S) -2 -hepcandecanoylamino-4-methylvalerylamino) 1 -2-tetrahydrodrofuranone

(3S) -3-((S) -2-tert-butoxycarbonylamino-4-methyl valerylamino) -3-tetrahydrofuranone 3.04 g of ethyl acetate solution containing 4N hydrogen chloride 35m 35m After stirring at room temperature for 45 minutes, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 100 ml of methylene chloride, and 3.07 ml of heptadecanoyl chloride and 2.70 ml of triethylamine were added. After stirring at room temperature for 1 hour, 0.5 N aqueous hydrochloric acid (8 Om1) was added, the organic layer was separated, and the aqueous layer was extracted twice with methylene chloride. The extract was washed twice with a saturated saline solution, dried by adding sodium sulfate, and then the desiccant was filtered. The filtrate was concentrated to obtain 4.64 g of the desired product. Yield: 97%

Marauder R (CDC 1a, δ); 0.80-0.95 (m, 9H), 1.25 (m, 26H), 1.50-1.73 (m, 5Η), 2. 1 5-2. 38 (m, 3Η), 2.62 (m, 1Η), 4.27 (m, 1Η), 4.38-4.62 (m, 3Η), 6.47 ( d, J = 8.3 Η, 1 Η), 7.59 (d, J = 7.3 Η, 1 Η). Example 1 (3 S)-3-((S) 22-hepta Decanoylamino-1 4-methyl

Four & Production of valeryl amino) —2-tetrahydrofuranoyl (Compound No. 36 in Table 1)

(3S) -3-((S) —2_heptadecanoylamino-4-methylvalerylamino) obtained in Reference Example 1 1.9 g of tetrahydrofuranone 2-tetrahydrofuran 3 Dissolved in 0 Om 1 and cooled to −68 ° C. and slowly added dropwise 1.0 mo 1 Z 1 of hydrogenated diisobutylaluminum 2 Om 1. After stirring at 168 ° C for 1.5 hours, 5 ml of methanol was added, the temperature of the reaction solution was raised to 0 ° C, and 100 ml of 1N hydrochloric acid was added. The organic layer was separated, the aqueous layer was extracted twice with ethyl acetate, the extract was washed twice with saturated saline, dried over sodium sulfate, and the desiccant was filtered. Concentration gave 2.54 g of crude product. This was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 20% hexane) to obtain 93 g of the desired product.

Yield: 47%

Melting point: 79-82 ° C

I R (KB r, cm-ri: 3300, 1 6 3 7, 1 543.

Marauder R (CDC 13, δ): 0.90-1.03 (m, 9Η), 1.25 (m, 26H), 1.5-1.70 (m, 5H), 1.7 0-1.95 (m, 2 H), 2.10-2.22 (m, 2 H), 2.20-2.50 (m, 1 H), 3.78-4 .18 (m, 2H), 4.20-4.60 (m, 2H), 5.12-5.8.18 (m, 1H), 6.13 (d, J = 8.4 Hz, 0.6 H), 6.22 (d, J = 8.3 Hz, 0.4 H), 6.77 (d, J = 8.4 Hz, 0.6 H) , 6.82 (d, J = 7.0 Hz, 0.4 H). The compounds of Examples 2 to 7 were produced in the same manner as in Reference Example 1 and Example 1. The physical properties are described below. Example 2 Production of (3S) -3-((S) -2-dodecanoylamino-4-methylvalerylamino) -12-tetrahydrodrofuranoyl (Compound No. 31 in Table 1) IR (KBr , cm- '): 3 2 7 9, 1 6 4 9, 1 558. NMR (CDC 13, δ): 0.86-0.96 (m, 9II), 1.25 (m, 16H), 1.52-1.67 (m, 511) , 1.83 (m, 1 H), 2.16-2.22 (m, 2 H), 2.34 (m, 1 H), 3.86 (m, 0.6 H), 4.01—4.51 (m, 3.4H), 5.24-5.33 (m, III), 6.08-6.17 (m, 1H), 6 7 1-6.73 (m, 1 H). Example 3 (3 S) — 3— ((S) -4-methyl-2-phendecylaminovalerylamino) 1—2-tetrahydrodroflanol (Table) Melting point of Compound No. 34 of 1): 99 ~: 101 ° C

I R (KB r, cm-re: 3 2 9 8, 1 6 3 6, 1 543.

NMR (CDC 13, δ): 0.8 1-1.05 (m, 9 H), 1.25 (m, 22 H), 1.42-1.73 (m, 51-1 ), 1.83 (m, 1 H), 2.12-2.2.23 (m, 2H), 2.30 (m, 1 H), 3.04 (m, 0.3 H), 3 5 7 (m, 0.7 H), 3.89 (m, 0.7 H), 4.02 (m, 0.3 H), 4.12 (m, 1 H), 4.23 -4.53 (m, 2H), 5.27 (s, 0.3H), 5.33 (d, J = 4.3Hz, 0.7H), 5.97 (d , J = 8.0 Hz, 1 H), 6.53 (d, J = 8.4 Hz, 0.3 H), 6.61 (d, J = 8.3 Hz, 0.7 H Example 4 Preparation of (3S) -13-((S) 1-2-hexadecanoylamino-4-methylvalerylamino) -12-tetrahydrofurofanol (Compound No. 35 in Table 1) Melting point: 94-4-9 QV

I R (KB r, cm-re: 3 4 1 4, 3 29 7, 1 7 1 5, 1 54 3.

NMR (CDC 13, δ): 0.8 1-1.01 (m, 9 H), 1.25 (m, 24 H),]. 40 — 1.80 (m, 5 H) ), 1.85 (m, 1 H), 2.10-2.23 (m, 2 H), 2.32 (m, 0.6 H), 2.41 (m, 0.4 H) ), 3.83 (m, 0.6 H), 4.02 (m, 0.4 H), 4.10 (m, 0.6 H) 1 H), 4.31 (m, 1 H), 4.43 (m, 1 H), 5.27 (s, 0.4 H), 5.32 (d, J = 4. 6 Hz, 0.6 H), 6.01 (d, J = 8.2 Hz, I II), 6.57 (d, J = 7.5 Hz, 0.41-1), 6. 6 4 (d, J = 8.3 Hz, 0.6 H). Example 5 (3 S) — 3— ((S) —4-methyl-2-octadecanoylamino amino relylamino) Of 2-tetrahydrofuranol (compound No. 37 in Table 1)

I R (KB r, cm-R: 3 2 9 6, 1 63 9, 1 5 4 3.

NMR (CDC ", δ): 0.85-0.95 (m, 9H), 1.25 (m, 28H), 1.55-1.63 (m, 5H) , 1.85 (m, 1 H), 2.14 -2.41 (m, 3 H), 3.87 (m, 0.3 H), 4.0 1 -4.3 1 ( m, 1.7 H), 4.42-4.60 (m, 2 H), 5.27-5.31 (m, 1 H), 6.28-6.50 (m, 1 H), 7.73—7.75 (m, 1 H). Example 6 (3S) -3-((S) -4-Methyl-2-tetradecyloxycarbonylaminovalerylamino) Preparation of i-2-tetrahydrofuranol (compound No. 44 in Table 1)

IR CKB r, cm- ¹ ): 3 4 1 0, 3 3 0 1, 1 6 9 6, 1 6 4 9, 1 54

3.

NMR (CDC 13, δ): 0.83-0.98 (m, 9 Η), 1.25 (m, 22 Η), 1.43-1.70 (m, 5 Η), 1. 7 0-1.95 (m, 1 Η), 2.23-2.52 (m, 1 Η), 3.89 (m, 0.7 Η), 3.95-4.24 (m, 5Η), 4.34 (m, 1Η), 4.50 (s, 0.3Η), 5.22-5.44 (m, 2Η), 6.72 (d , J = 7.7Η, 1 (). Example 7 (3S) -3-((S) -2-hexadecylsulfonylamino-4-methylvalerylamino) 1-2-tetra Production of hydrofuranol (Compound No. 56 in Table 1) IR (KB r, cm): 3 3 3 7, 1 6 4 7, 1 5 4 3.

NMR (CDC 1 a, δ): 0.85-0.98 (m, 9H), 1.23-1.47 (m, 29H), 1.56-1.61 (m, 2 H), 1.78-1.88 (m, 2H), 2.94-3.03 (m, 2 H), 3.88-.2 1 (m, 4 H), 4.25-4.53 (m, 1 H), 5.24-5.3.4 (m, 1 H), 6.4.4 (m, 0.6 H), 6.75 Example 8 (2 S, 3 S) — 2-Acetoxy-I 3 — ((S) — 2-Heptadecanoylamino-4-methylvalerylamino) Tetrahydrodrofuran (Table 2) Of compound No. 150)

0.48 g of (3 S) — 3— ((S) — 2-heptadecanoylamino-4-methylvalerylamino) -1-tetrahydrofuranoyl obtained in Example 1 was converted to methylene chloride. The mixture was dissolved in 50 ml, cooled with ice water, and 125 mg of 4-dimethylaminopyridine and 0.097 ml of acetic anhydride were added. After stirring at room temperature for 3 hours, 0.5N aqueous hydrochloric acid was added, and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride, and the extract was washed twice with saturated saline, dried with sodium sulfate, filtered to remove the desiccant, and concentrated to give a crude product. Was done. This was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 33% hexane) to obtain the target compound.

20 g were obtained.

Yield: 62%

Melting point: 1 2 7 to 1 2 8

IR (KB r, cm- ¹ ): 3 2 9 7, 1 750, 1 6 42, 1 54 5.

NMR (CDC 13, δ): 0.82-0.98 (m, 9 Η), 1.25 (m, 26 II), 1.3-1.70 (m, 5 Η), 1 . 83 (m, 1Η), 2. 1

3 (s, 3Η), 2.20 (t, J = 7.2 Hz, 2Η), 2.32 (m, 1Η), 3.97 (m, 1Η), 4.1 4 (m, 1Η), 4.40 (m, 1Η), 4.55 (m, 1Η), 6.01 (d, J = 8.1 Hz, 1Η), 6. 1 7 (d,

J = 4.6 Hz, 1 H), 6.66 (d, J = 8.6 Hz, 1 H). The compounds of Examples 9 to 14 were produced in the same manner as in Example 8. The physical property values are described below. Example 9 Production of (2S, 3S) —2-acetoxoxy-3-((S) —2-dodecanoylamino-4-methylvalerylamino) tetrahydrofuran (Compound No. 11 in Table 1-2)

Marauder R (CDC 13, δ): 0.86-0.96 (m, 9H), 1.25 (m, 16 ，), 1.56-1.65 (m, 5Η), 1. 84 (m, 1 Η), 2.1

2 (s, 3Η), 2.16 -2.22 (m, 2Η), 2.32 (m, 1Η), 3.95 (m, 1Η), 4.11 (m, 1 Η), 4.42 (m, 1 Η), 4.58

(m, 1Η), 6.00 (d, J-8.ΟΗζ, 1Η), 6.18 (d, J = 4.7Ηζ, 1Η), 6.64 (d, J = 6 6 Hz, 1Η). Example 10 0 (2 S, 3 S) — 2-acetoxy — 3 _ ((S) — 4-methyl-2 monopentadecanoylaminovalerylamino) tetrahydrofuran ( Production of Compound No. 1444)

Melting point: 129 ~ 130 ° C

I R (KB r, cm-'): 3297, 1 748, 1642, 1545.

NMR (CDC 13, δ): 0.78-1.05 (m, 9 Η), 1.25 (m, 22 Η), 1.42-1.70 (m, 3 Η), 1.70- 2.00 (m, 2Η), 2.05 (m, 1Η), 2.07 (s, 3Η), 2.18 (t, J = 6.9 Hz, 2Η), 2.33 (m , 1Η), 3.95 (m, 1Η), 4.11 (m, 1Η), 4.45 (m, 1Η), 4.55 (m, 1Η), 6.04 ( d, J = 8. ΟΗζ, 1 Η), 6.18 (d, J = 4.5 Η, 1 Η), 6.69 (d, J = 8.4 Hz, 1 Η). 1 (2 S, 3 S) — 2-acetoxy — 3 — ((S) — 2-hexadecid Nylamino-14-methylvalerylamino) of tetrahydrofuran (Compound No. 1 45 in Table 1) Manufacture

S3 Melting point: 1 3 7 ° C

I R (KBr, cm-: 3 297, 1 748, 1 642, 1 543.

NMR (CDC 1 a, δ): 0.78-1.01 (m, 9 II), 1.25 (m, 24 H), 1.2-1.70 (m, 5 II), 1. 83 (m, 1 II), 2.09 (s, 3 H), 2.20 (t, J = 7.0 Hz, 2 H), 2.35 (m, 1 II), 3.95 (m, 1H), 4.13 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 5.9] (d, J = 8.3 Hz , 111), 6.17 (d, J = 4.6 Hz, 1 H), 6.57 (d, J = 10. OIIz, 1 H). Example 12 (2 S, 3 S) — 2-Acetoxy 3- ((S) — 4-Methyl-2 —Octadecanoylamino novalerylamino) Production of tetrahydrofuran (Compound No. 15 1 in Table 1)

NMR (CDC 13, δ): 0.85-0.96 (m, 9H), 1.18-1.39 (m, 30H), 1.8-1.82 (m, 4H), 2.12 (s, 3H), 2.) 6-2.34 (m, 3H), 3.93 (m, 1H), 4.12 (m, 1H), 4.25 ( m, 1 H), 4.43-4.58 (m, 1 H), 6.05 (d, J = 8.3 Hz, 1 H), 6.17 (d, J = 4.6 Hz) , 1 H), 7.15 (d, J = 6.9 Hz, 1 H). Example 13 (2 S, 3 S) — 2-acetoxy 3 — ((S) — 4-methyl — 2 — Production of tetradecyloxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 158 in Table 1)

Melting point: 1 14 to 1 15 ° C

IR (KB r, cm " ¹ ): 3304, 1 748, 1 696, 1653, 1 54

1.

NMR (CDC 13, <5): 0.82-1.01 (m, 9H), 1.26 (m, 22H), 1.42-1.75 (m, 5H), 1 86 (m, 1 H), 2.11 (s, 3 H), 2.37 (m, 1 H), 3.88-4.20 (m, 5 H), 4.59 (m, 1 H), 4.98 (m, 1 H), 6.) 6 (d, J = 4.6 Hz,

Four Example 1 4 (2 S, 3 S) — 2-acetoxy 3 — ((S) — 2-hexadecyl 1 H), 6.31 (d, J = 9.7 Hz, 1 H). Production of sulfonylamino-1-methylvalerylamino) tetrahydrofuran (Compound No. 176 in Table 1)

NMR (CDC 13, δ): 0.86-0.97 (m, 9H), 1.21-1.41 (m, 3OH), 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, 1 H), 4.60 (m, 1 H), 4.76 (d, J = 8.6 Hz, 1 H), 6.18 (d, J = 4.6 Hz, 1 H), 6.32 (d, J = 8.6 Hz, 1 H). The compounds of Examples 15 to 22 were produced in the same manner as in Reference Example 1, Example 1, and Example 8. The physical properties are described below. Example 15 (3S) -3-((S) —4-methyl-2-tridecyloxycarbonylcarbonylaminovalerylamino) -12-tetrahydrodrofuranoyl (compound No. 43 in Table 1) Manufacturing of

Melting point: 75-76C

I R (KB r, cm-: 3302, 1696, 1649, 1 545.

NMR (CDC 13, δ): 0.89-1.02 (m, 9Η), 1.15-1.40 (m, 19 9), 1.45-1.75 (m, 5Η) , 1.80 (m, 1Η), 2.05 (m, 1Η), 2.38 (m, 1Η), 3.86 (m, 1Η), 3.96-4.25 (m, 1Η) 4.6 6), 4.35 (m, 1Η), 4.48 (s, 0.), 5.27 (d, J = 2.4 Hz, 0.6Η), 5.33 ( dd, J = 3.8 Hz, 3.8 Η ζ, 0.4 Η), 5.40 (d, J = 7.8 Hz, 1 Η), 6.72 (d, J = 7.8 Η, Example 1 6 (2 S, 3 S) —2-Acetoxy—3 — ((S) -1-Methyl—2

SS —Production of tridecyloxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 157 in Table 1)

Melting point: 1 1 2 ° C

I R (KB r, cm-R: 3 3 0 4, 1 7 4 8, 16 9 6, 16 5 5,] 5 4

1.

NMR (CDC 13, δ): 0.88 (t, J = 6.4 Hz, 3 H), 0.91-0.99 (m, 6H), 1.15—1. 0 (m, 21H), 1.43—1.77 (m, 4H), 1.87 (m, 1H), 2.11 (s, 3H), 2.3 6 (m, 1 H), 3.95 (m, 1 II), 4.01-4.20 (m, 4 H), 4.58 (m, 1 H), 5.05 (d, J = 8.3 Hz, 1 H), 6.17 (d, J = 4.6 Hz, 1 H), 6.36 (d, J = 7.9 Hz, 1 H). Example 1 S (3 S) — 3— ((S) — 4-methyl-2-pentadecyloxy force rubonylaminovalerylamino) —2-tetrahydrofuranoyl (compound of Table 1) Manufacture of article number 4 5)

I R CKB r, cm-Re: 3 3 0 2, 1 6 9 5, 1 6 4 9, 1 5 4 3.

NMR (CDC 13, <5): 0.85-0.96 (m, 9H), 1.25-1

.2 9 (m, 24 H), 1.50-1.89 (m, 6 Η), 2.29 (m, 0.7 Η), 2.42 (m, 0.3 Η), 3.8 1-4.25 (m, 5 Η), 4.28-4.41 (m, 1 Η), 5.24 (s, 1 Η), 5.26 (s, 0.3 Η)

, 5.32 (d, J = 4.6 Η ζ, 0.7 Η), 6.50 (s, 0.3 Η), 6

6 0 (d, J = 1.8 Hz, 0.7 Η). Example 18 (2 S, 3 S) — 2-acetoxy 3 — ((S) — 4-methyl — 2 — Pensyldecylo Preparation of (xoxycarbonylaminovalerylamino) tetrahydrofuran (Compound No. 16 2) in Table 1

Melting point: 1 1 4 to 1 1 5

I R (KB r, cm-ri: 3 3 0 4, 1 6 9 3, 1 6 5 5, 1 5 4 5.

NMR (CDC 13, δ: 0.88 (m, 3Η), 0.91—0.99 (m , 6 ID, 1.23-1.39 (m, 24H), 1.51-1.69 (m, 5H), 1.84 (m, 1H), 2. 10 (s, 3H), 2.36 (m, 1H), 3.92-4.17 (m, 5H), 4.58 (m, 1H), 4.98 (m, 1 H), 6.16 (d, J = 4.7 Hz, 1 H), 6.31 (d, J = 8.3 II z, 1 H). 3S) -3-((S) -4-Methyl-2-tetradecylsulfonylaminovalerylamino) -1-tetrahydrofuranol (Compound No. in Table 1)

5 4) Manufacturing

I R (KB r, cm- '): 3 346, 1 6 43, 1 5 33.

NMR (CDC 13, δ): 0.85-0.90 (m, 3Η), 0.9-0.98 (m, 6Η), 1.25-1.39 (m, 22) H), 1.56-1.83 (m, 5H), 2.20-2.38 (m, 1 H), 2.69-2.81 (m, 1 H), 2 98-3.04 (m, 2 H), 3.92-3.98 (m, 1 H), 4.6-4.58 (m, 2 H), 5.0 4-5. 0 7 (m, 1 H), 6.85-6.87 (m, 1 H). Example 2 0 (2 S, 3 S) — 2-acetoxy 3 — ((S) — Preparation of 4-Methyl-2- (tetradecylsulfonylaminovalerylamino) tetrahydrofuran (Compound No. 17 1 in Table 1)

Melting point: 84-85. C

I R (KB r, cm-: 3 3 1 5, 1 6 5 1, 1 5 4 5.

NMR (CDC 13, δ): 0.88 (m, 3 H), 0.94-0.98 (m, 6 H), 1.23-1.94 (m, 28 H) , 2. 1 2 (s, 3 H), 2. 3

6 (m, 1 H), 2.98 (m, 2 H), 3.85 (m, 1 H), 3.97 (m, 1 H), 4.15 (m, 1 H) , 4.59 (m, 1 H), 4.74 (m, 1 H), 6.17 (d, J = 4.5 Hz, 1 H), 6.32 (d, J = 8 5 Hz, 1 H). Example 2 Preparation of 1 (3S) -13-((S) -14-methyl-2-pentadecylsulfonylaminovalerylamino) -12-tetrahydrofuranoyl (Compound No. 55 in Table 1)

I R (KB r, cm-re: 3348,) 643, 1 54 1.

NMR (CDC 13, δ): 0.85-0.90 (m, 3Η), 0.94-0.98 (m, 6Η), 1.25-1.42 (m, 24Η), 1 58- 1.63 (m, 2Η), 1.72-1.86 (m, 3Η), 2.30-2.39 (m, 0.8Η), 2.40-2.58 (m , 0.2 Η), 2.94-3.02 (m, 2 Η), 3.80-3.94 (m, 2 Η), 4.04 (m, 0.2 Η), 4.1 0-4.17 (m, 0.8Η), 4.32-4.41 (m, 1Η), 5.00-5.5 (m, 1Η), 5.27 (m, 1Η) 0.2 Η), 5.34 (m, 0.8 Η), 6.22 (d, J-7.2 Hz, 0.2 H), 6.49 (d, J = 8.1 IIz Example 22 (2 S, 3 S) —2-Acetoxy 3-((S) —4-Methyl-12—Pentate Decylsulfonylaminovalerylamino) Tetrahydrofuran (Table 1) Preparation of Compound No. 1 72 of 2)

Melting point: 80 ~ 81 in 1

I R (KB r, cm-: 33 15, 1 651, 1548.

NMR (CDC 13, δ): 0.88 (m, 3Η), 0.92-0.98 (m, 6Η), 1.23-1.48 (m, 26Η), 1.50-1. 98 (m, 5Η), 2.12 (s, 3Η), 2.97 (dd, J = 6.9 Hz, 3.0 Hz, 2 H), 3.84 (m, 1 H), 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 Hz, 1 H). Test Example 1 Measurement of cystine protease inhibitory activity

m—Calpain is described in the rat brain (J0urna1ofBio1ogica1Chemistry, vol. 259, p. 3210, 1998).

5S The product was purified by the method described above, and its inhibitory activity was measured according to the method described in the literature (Journal of Biological Chemistry, vol. 259, p. 12489, 1998). The results are shown in Table 3.

Table 3 shows that the compound of the present invention exhibits a strong inhibitory activity against cysteine proteases such as papain, cathepsin B, cathepsin L, and lupain.

Table 1 3 (Inhibitory activity of calpain)

Industrial applicability

The oxygen-containing heterocyclic derivative of the present invention has a strong inhibitory effect on cysteine proteins such as papain, cathepsin B, cathepsin H, force tepsin L, calpain, and interleukin 1-converting enzyme, and has an oral absorption property. Muscular dystrophy, muscular atrophy, myocardial infarction, stroke, Alzheimer's disease, impaired consciousness and movement at the time of head trauma, multiple sclerosis, peripheral nervous system As a therapeutic agent for neuropathy, cataract, inflammation, allergy, fulminant hepatitis, osteoporosis, hypercalcemia, breast cancer, prostate cancer, prostatic hypertrophy, or as a cancer growth inhibitor, metastasis preventive, or platelet aggregation inhibitor Can be used.

Claims

Range of request

1. The following general formula (I)

0 0

II II

(In the above general formula (I), R ¹ is R ⁴ — C—, R ⁴ -0-C- or

0

II

R ⁴ -S— (R ⁴ represents a linear alkyl group of CH to C ₂₀ ), and R ² represents

II

0

A hydrogen atom, or d C ₁₀ which may be substituted with an aryl group of C _G -C

0

II

Represents an alkyl group, R ³ represents a hydrogen atom or R ⁵ —C— (R ⁵ represents a C ₁₀ alkyl group), and A may be substituted with a C ₃ alkyl group d to O ₃ represents an alkylene group represented by C ₃ ), a salt thereof, a solvate thereof or a hydrate thereof.

2. The compound according to claim 1, wherein R ² represents a d to C ₁₀ alkyl group which may be substituted with a C ₆ to C ₁₄ aryl group, a salt thereof, a solvate thereof, and the like. Or its hydrate.

3. R ² Chikaraku C, represent an alkyl group claim 1 compound of wherein the -C _10, a salt thereof, a solvate thereof or a hydrate thereof.

0 0 0

II II II

4. R ¹ is R ^4- C-, R ⁴ -0-C- or R ⁴ -S- (R ⁴

II

0

Represents a C ₃ -C ₁₆ linear alkyl group), the compound according to any one of claims 1 to 3, a salt thereof, a solvate thereof or a hydrate thereof.

5. A is C, claim, characterized in that represents an alkylene group of -C _3〗 1-4 Neu A compound, salt, solvate, or hydrate thereof according to any of the above.

0

II

6. R ¹ represents R "—C— (R ⁴ represents a C _{14 to} C ₁₆ linear alkyl ¾); R ² represents C, to C ₁₀ alkyl; R ³ Is a hydrogen atom, or

0

I!

R ⁵ one C-(R ⁵ is d -C, alkyl of ₀₎ represents, A is C, a compound of claim 1, wherein the represents an alkylene group having -C _3, a salt thereof, The solvate or hydrate thereof.

7. The compound according to claim 6, wherein R ³ represents a hydrogen atom, a salt thereof, a solvate thereof, or a hydrate thereof.

0

II

8. The compound according to claim 6, wherein R ³ represents R ⁵ —C— (R ⁵ represents an alkyl group of C, to d.), A salt thereof, a solvate thereof, or a solvate thereof. Hydrate

0

II

9. R ¹ represents R ⁴ -0-C- (R ⁴ represents a C _{13 to} C, ₅ linear alkyl group); R ² represents an alkyl group of ~ C ₁₀ ; R ³ is a hydrogen atom or

0

! 1

R ⁵ - C one (R ⁵ represents an alkyl group of d -C ₁₀₎ represent, A is C, a compound of claim 1, wherein a representative of the alkylene group ~ C _3, a salt thereof, Solvates or hydrates thereof.

10. The compound according to claim 9, wherein R ³ represents a hydrogen atom, a salt thereof, a solvate thereof or a hydrate thereof.

0

II

11. The compound according to claim 9, wherein R ³ represents R ³ -C- (R ⁵ represents a C, to C ₁₀ alkyl group), a salt thereof, a solvate thereof or a compound thereof. Hydrate. 0

II

1 2. R ¹ Power R ^4- S — (R ⁴ is a straight-chain alkyl S from CH to C ₁₆

〇

R ² represents a C- to C ₁₀ alkyl group; R ³ represents a hydrogen atom or

0

II

R ^⁵ - C- (R ⁵ represents an alkyl group having -C ₁₀₎ represent, A is C, a compound of claim 1, wherein the represents an alkylene group having -C _3, a salt thereof, Solvates or hydrates thereof.

13. The compound, salt, solvate or hydrate thereof according to claim 12, wherein R ³ represents a hydrogen atom.

0

II

13. The compound according to claim 12, wherein R ³ represents R ³ —R ⁵ —C 1 (R ⁵ represents an alkyl group of C 1 to C ₁₀ ), a salt thereof, a solvate thereof, or The hydrate.

1 5. (3S) -3-((S) -4-Methyl-2-pentadecanoylaminovalerylamino) —2-tetrahydrofuranol, its salt, solvate or hydrate thereof.

1 6. (2 S, 3 S) — 2-acetoxy-1 3 — ((S) — 4-methyl-2-pentantadecanoylaminovalerylamino) tetrahydrofuran, its salt, solvate or water Japanese food.

1 7. (3 S) — 3— ((S) — 2-Hexadecanoylamino-1-methylvalerylamino) — 2-tetrahydrofuranoyl, a salt, solvate or hydrate thereof.

1 8. (2 S, 3 S) —2-Acetoxy 3-((S) —2-Hexadecanoylamino-4-methylvalerylamino) tetrahydrofuran, its salt, solvate or hydrate thereof.

1 9. (3S) -3-((S) 1-2-Heptadecanoylamino-14-methylvalerylamino) -12-tetrahydrofuranoyl, salt, solvate or hydrate thereof .

20. (2 S, 3 S) — 2-acetoxy 3- ((S) — 2 decanoyl lumino 4-methylvaleryl amino) Tetrahydrofuran, its salt, solvate or hydrate thereof.

2 1. (3 S) — 3— ((S) — 4-methyl-2-tridecyloxycarbonylaminovalerylamino) -12-tetrahydrofuranoyl, its salt, solvate or Its hydrate.

2 2. (2 S, 3 S) — 2-acetoxy-3-((S) — 4-methyl-12-tridecyloxycarbonylaminovalerylamino) tetrahydrofuran, its salts, and its solvation Thing or its hydrate.

2 3. (3S) -3-((S) -4-Methyl-2-tetradecyloxycarbonylaminovalerylamino) -12-tetrahydrofuranol, its salt, solvate or hydration object.

2 4. (2 S, 3 S) — 2-Acetoxy — 3 — ((S) — 4-Methyl-1-2-tetradecyloxycarbonylaminovalerylamino) Tetrahydrofuran, its salt, its Solvates or hydrates thereof.

2 5. (3S) -3-((S) -4-methyl-2-pentyldecyloxycarbonylaminovalerylamino) -12-tetrahydrofuranoyl, its salt, its solvate or its Hydrate.

2 6. (2 S, 3 S) — 2-acetoxy-1- 3 — ((S) — 4-methyl-2-pentantadecyloxycarbonylaminovalerylamino) tetrahydrofuran, its salts, and its solvates Thing or its hydrate.

2 7. (3S) -3-((S) -4-Methyl-2-tetradecylsulfonylamino relylamino) -12-tetrahydrofuranol, a salt, solvate or hydrate thereof.

2 8. (2 S, 3 S) — 2-acetoxy 3- ((S) — 4-methyl-2-tetradecylsulfonylaminovalerylamino) tetrahydrofuran, its salt, its solvate or its Hydrate.

29. (3 S) — 3— (S) — 4-Methyl-2-pentenedecylsulfonylamino relylamino) 1-tetrahydrofuranoyl, its salts and solvates. Or its hydrate.

3 0. (2 S, 3 S) — 2-acetoxy 1 3 — ((S) — 4-methyl-2-quinone decylsulfonylamino novalerylamino) tetrahydrofuran, its salt, and its solvate Thing or its hydrate.

3 III. (3S) -3-((S) -2-1-hexadecylsulfonylamino-4-methyltylvalerylamino) -12-tetrahydrofuranoyl, its salt, solvate or Its hydrate.

32. (2 S, 3 S) — 2-Acetoxy — 3 — ((S) — 2-Hexadecyls- rufonylamino-1-methylvalerylamino) Tetrahydrofuran, its salt, its solvate or its Hydrate.

3 3. A pharmaceutical composition comprising the compound according to any one of claims 1 to 32 and a pharmaceutically acceptable carrier.

3 4. For a disease caused by abnormally elevated cystine protease, which comprises the compound according to any one of claims 1 to 32 and a pharmaceutically acceptable carrier. Pharmaceutical composition.