JPH11171881A - Oxygen-containing heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a cysteine protease inhibitor excellent in oral absorbability, tissue migration properties, cell wall permeability, etc. SOLUTION: This compound is represented by formula I [R<1> is a (substituted) 6-14C aryl or a (substituted) heterocyclic residue; R<2> is H or an (aryl-substituted) 1-10C alkyl; R<3> is H or a group represented by the formula; R<4> -CO (R<4> is a 1-10C alkyl); A is an (alkyl-substituted) 1-3C alkylene], e.g. (3S)-3- (S)-2-(4,6- dimethoxy-2-pyrimidinyl)amino-4-methylvalerylamino}-2-tetrahydrofuranol. The compound represented by formula I in which R<3> is H is obtained by reacting a compound represented by the formula R<1> X with an amino acid salt represented by formula II, providing an amino acid derivative represented by formula III, then reacting the resultant compound with an aminolactone derivative represented by formula IV and treating the resultant lactone derivative represented by formula V with a reducing agent such as diisopropylaluminum hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel oxygen-containing heterocyclic derivative.

[0002]

2. Description of the Related Art Papain, cathepsin B, cathepsin H, cathepsin L, calpain, interleukin 1β
As the functions of cysteine proteases such as convertases in vivo have been elucidated, it has been found that their abnormal enhancement is the cause of various diseases, and cysteine protease inhibitors are effective in animal models of those diseases. Reports have been increasing.

[0003] In skeletal muscle breakdown observed in muscle diseases such as muscular dystrophy and muscular atrophy, cysteine proteases such as calpain and cathepsin B are considered to be involved in early processes such as disappearance of Z-rays through degradation of muscle fiber proteins. (Metabolism, Vol. 25, extra edition "Metabolic Disease Highlights", p. 183, 1988). E-64-d, a cysteine protease inhibitor, has been reported to have a life-extending effect in muscular dystrophy hamsters (Journal of PharmacobioDynamic).
s, 10, 678, 1987). Therefore, cysteine protease inhibitors are considered to be therapeutic agents for muscular dystrophy, muscular atrophy and the like.

[0004] In ischemic diseases such as myocardial infarction and stroke, the main cause of cell damage after ischemia is the active enzyme produced by xanthine oxidase. C increased during the process of ischemia
There is a theory that calpain activated by a ²⁺ concentration converts xanthine dehydrogenase, a precursor of xanthine oxidase, to oxidase by limited degradation (New En
gland Journal of Medicine, 312, 159, 1985). It is also believed that calpain activation can be a direct cause of cardiomyocyte death and brain neuronal cell death (Latest Medicine, 43, 783, 198).
8 years). NCO-700, a calpain inhibitor, has been reported to be effective in animal models of myocardial infarction (Arzneimittel Forschung / Drug Research, 36,
190 pages, 671 pages, 1986) and E-
64-c inhibits the degradation of microtubule-associated protein after cerebral ischemia (Brain Research, 526, 177, 1
990). Therefore, calpain inhibitors are considered to be therapeutic agents for ischemic diseases such as myocardial infarction and stroke.

[0005] A protein called amyloid is deposited on senile plaques which are peculiarly found in the brain of Alzheimer's disease patients.
This amyloid is known to be produced by the degradation of amyloid protein precursor (APP). Amyloid is not produced in the normal metabolism of APP, but amyloid is produced by abnormal metabolism by an abnormally enhanced protease, which is considered to be senile plaque (Scientific Americ
an, November 1991 issue, p. 40). Therefore,
Protease inhibitors are expected to be therapeutic agents for Alzheimer's disease.

It has been reported that calpain is activated in a rabbit head injury model (Neuroc).
chemical Research, Vol. 16, p. 483, 1991
In a rat head injury model, administration of the calpain inhibitor leupeptin has been observed to protect the axon (Journal of Neurosu)
rgery, 65, 92, 1986). Therefore, it is considered that calpain inhibitors are effective in improving consciousness disorder and movement disorder in head trauma.

[0007] There is a report that myelin-binding protein present in dendrites of nerve cells is degraded by calpain (Journal of Neurochemistry, 47, 1007, 1986). Therefore, it is considered that calpain inhibitors are effective for diseases that are said to be caused by demyelination of nerve cells, such as multiple sclerosis and peripheral nerve neuropathy.

It is said that many cataracts cause crystal opacity due to hydrolysis of crystalline water-soluble protein in the lens by the action of protease. Cataracts in experimental models and certain human cataracts have elevated calcium levels in the lens (Investigative Ophthalmology & Visual Scienc
e, Vol. 28, p. 1702, 1987, Experimenta
l Eye Research, 34, 413, 1982
Years), and because the most protease in the lens is calpain (Lens and Eye
Toxicity Research, 6, 725 pages, 1989
), It is thought that the abnormal increase of calpain is one of the causes of cataract. E-6, an inhibitor of calpain
No. 4 was effective in an experimental model of cataract (In
vestigative Ophthalmology & Visual Science, 3
2, pp. 533, 1991), and calpain inhibitors are considered to be therapeutic agents for cataracts.

Neutrophils, which are closely related to inflammation, are known to respond to stimulation by chemotactic factors and phorbol esters by degranulation and production of superoxide, which is caused by protein kinase C (PKC). ) Is believed to be mediated by Calpine is this P
It has been reported that it acts to activate KC, promotes degranulation and suppresses superoxide production (Journal of Biological Chemistr).
y, 263, 1915, 1988). Also,
It has been reported that the concentration of cathepsin B in rat macrophages is 30 to 40 times higher than that of leukocytes or neutrophils, and that the enzyme concentration of inflammatory macrophages is 6 times higher than that of normal macrophages (Journal of Japan).
Biochemistry, 98, 87, 1985).
More recently, an enzyme that converts pre-interleukin 1β to interleukin 1β (interleukin 1β converting enzyme) was found to be a cysteine protease (Na
Nature, 356, 768, 1992). It was revealed that activation of cysteine protease plays an important role in the expression of inflammation. From these, it is considered that an inhibitor of cysteine protease can be used as an anti-inflammatory agent.

A type I allergic reaction is caused by immunoglobulin E (IgE) produced by sensitizing a living body to an antigen.
Proceed through. Estatin A, a cysteine protease inhibitor, specifically inhibits IgE production,
G production is reported to have no effect (The J
ournal of Antibiotics, 42, 1362 pages,
1989). Therefore, it is considered that cysteine protease inhibitors can be used as antiallergic agents.

[0011] When hepatocytes are necrotic, the permeability of Ca ²⁺ increases due to damage to the cell membrane, and the concentration of Ca ²⁺ in the cells increases to activate calpain. It is thought that cell death occurs as a result of decomposition. Therefore, calpain inhibitors can be used as therapeutic agents for fulminant hepatitis. Cathepsins such as cathepsin B and cathepsin L are involved in the degradation of bone collagen in osteoclasts. When rats administered with parathyroid hormone and promoted bone destruction are administered E-64 or estatin A, which is an inhibitor of cathepsins,
Decreased blood calcium and hydroxyproline levels have been reported (Biochemical and Biop
hysical Research Communication, 125, 441
1984, JP-A-2-218610). Therefore, inhibitors of cathepsins are considered to be therapeutic agents for osteoporosis and hypercalcemia.

As a substrate for calpain, there are sex hormone receptors such as estrogen receptor and androgen receptor. Calpain is known to activate these receptors, and abnormally elevated calpain is considered to be due to abnormal activation of sex hormone receptors, such as breast cancer,
It is said to cause prostate cancer and prostatic hypertrophy.
Therefore, calpain inhibitors would be therapeutic agents for the above diseases.

With the development of cancerous cells, epidermal growth factor (EG)
F) It is said that the receptor is activated, and calpain is known to activate the EGF receptor using the substrate as a substrate. Adult T-cell human leukemia virus (A
It has been reported that calpain was activated in cells infected with TLV / HTLV-1) (biochemistry, 5
7, 1202 pages, 1985). On the other hand, cathepsin B promotes collagen degradation, which is an important stage of cancer metastasis, or directly degrades collagen,
Due to its close relationship with the plasma membrane of neoplastic cells, it is said to be greatly involved in the process of cancer metastasis.
(Tumor Progressionand Markers, p. 47, 19
1982, Journal of Biological Chemistry, 256
Vol., Page 8536, 1984). From these facts, it is considered that a cysteine protease inhibitor is effective in suppressing cancer growth and preventing metastasis.

[0014] When platelets are activated, they aggregate and cause thrombus. E-64-, an inhibitor of calpain
d has been reported to inhibit thrombin-induced platelet aggregation (Thrombosis Research, 57, 847).
Page, 1990). Therefore, calpain inhibitors can be used as platelet aggregation inhibitors. As described above, abnormal enhancement of cysteine protease causes various diseases, and some cysteine protease inhibitors have been reported to be effective in animal models and the like.

[0015]

However, a known inhibitor is E-64 (Agricaltural and Biological Chemistry).
mistry, vol. 42, p. 529, 1978), E-6
4-d (Journal of Biochemistry, 93, 130
5 page, 1983), NCO-700 (JP-A-58)
-126879), estatins A and B (The Jou
rnal of Antibiotics, 42, 1362 pages, 1
Epoxy succinic acid derivative or peptide chloromethylketone (Journal of Biochemistry)
Irreversible inhibitors such as α-substituted ketones of peptides represented by acyloxymethyl ketone (Biochemistry, 30, pp. 4678, 1991). Generally, irreversible inhibitors are said to be highly toxic because they readily react nonspecifically with biological constituents other than the target enzyme, and few compounds have been used in clinical practice. Leupeptin (The Journal of Antibiotics, vol. 22, 2
83, 1969), calpeptin (Journalof
Enzyme Inhibition, Volume 3, 195 pages, 1990
Peptidyl aldehyde is known, but it is said that there are problems with chemical stability, stability in vivo, permeability of cell membranes, and the like.

[0016] On the other hand, as the lactol derivatives similar to the compounds of the present invention, the following formula (II) (R ⁵ is esterified or unprotected carboxyl group or an acyl group, R ⁶
Represents an isopropyl group, an isobutyl group, or a benzyl group, and R ⁷ represents a hydrogen atom or an acetyl group).
No.).

[0017]

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However, the compound of the present invention is characterized in that the group corresponding to R ⁵ in the compound (II) is an aryl group which may be substituted or a heterocyclic ring which may have a substituent. ) Differs greatly in structure.

[0019]

Means for Solving the Problems Accordingly, the present inventors have studied on inhibitors of cysteine protease which are excellent in oral absorption, tissue transportability, cell membrane permeability and the like, and as a result, have completed the present invention. Was. That is, the gist of the present invention is represented by the following general formula (I)

[0020]

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(In the above general formula, R¹Has a substituent
May be C₆~ C₁₄Having an aryl group or a substituent
Represents an optionally substituted heterocyclic residue;^TwoIs a hydrogen atom, and
Is C₆~ C₁₄C which may be substituted with an aryl group of₁
~ C_TenRepresents an alkyl group of ^ThreeIs a hydrogen atom, or R
^Four-CO- (R^FourIs C₁~ C_TenRepresents an alkyl group)
And A is C₁~ C_ThreeEven if it is substituted with an alkyl group of
Good C₁~ C_ThreeRepresents an alkylene group)
Elementary heterocyclic derivatives or salts or solvates thereof
Or hydrates.

According to another aspect of the present invention, a medicament comprising the above-mentioned oxygen-containing heterocyclic derivative, a salt thereof, a solvate thereof or a hydrate thereof; There is provided a pharmaceutical composition comprising a salt, a solvate or hydrate thereof, and a pharmaceutically acceptable carrier. The above medicines and pharmaceutical compositions are useful for treating and / or preventing diseases and / or symptoms caused by abnormally elevated cysteine proteases in mammals including humans.
Hereinafter, the present invention will be described in detail.

In the above formula (I), the optionally substituted aryl group defined by R ¹ is a monocyclic or condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. Examples of the heterocyclic residue which may have a substituent include an oxygen atom, a sulfur atom, and 1 to 4 heteroatoms selected from nitrogen atoms, and the total number of atoms constituting the ring is 5
To 10 heterocyclic residues.

In the general formula (I), specific examples of the optionally substituted aryl group defined by R ¹ include a phenyl group, a naphthyl group and an anthryl group. Specific examples of the heterocyclic ring which may be included include a furan ring, a dihydrofuran ring, a tetrahydrofuran ring, a pyran ring, a dihydropyran ring, a tetrahydropyran ring, a benzofuran ring, an isobenzofuran ring, a chromene ring, a chroman ring, and an isochroman ring. , Thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine Ring, pyrazine ring, piperazine ring, pyrimidine ring, pyri Jin ring, a triazine ring, indolizine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, purine ring, quinolizine ring, quinoline ring,
Isoquinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, benzoxazole ring, benzoisoxazole ring, thiazole ring, Thiaziridine ring, isothiazole ring, isothiazolidine ring, thiadiazole ring, benzothiazole ring,
Benzoisothiazole ring, dioxane ring, dithiane ring,
A morpholine ring, a thiomorpholine ring, a pyridazinone ring and the like.

Preferred examples of the aryl group include a phenyl group and a naphthyl group. Preferred examples of the heterocyclic group include, for example, a 2-pyridyl group and a 3-pyridyl group.
Pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4
-Pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrazinyl group, 2-
Pyrrolyl group, 3-pyrrolyl group, 2-thienyl group, 3-thienyl group, 2-imidazolyl group, 4-imidazolyl group,
5-imidazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, isothiazolyl group, isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 2-
Oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 1,2,4-triazol-3-yl group, 1,
2,3-triazol-4-yl group, tetrazole-5
-Yl group, 1,2,4-oxadiazol-3-yl group, 1,2,4-oxadiazol-5-yl group,
2,4-thiadiazol-3-yl group, 1,2,4-thiadiazol-5-yl group, benzothiazol-2-yl group, benzoxazol-2-yl group, benzimidazol-2-yl group, benziso An xazol-3-yl group, a benzisothiazol-3-yl group, a benzisothiazol-3-yl-1,1-dioxide group, an indol-3-yl group, a 1H-indazolyl group, a syn-triazinyl group, as-triazinyl group, quinolinyl group,
Examples include an isoquinolinyl group, a quinoxalinyl group, a cinnolinyl group, a quinazolinyl group, a pyridazonyl group, and an indazonyl group.

The aryl group or heterocyclic residue may be a halogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₁ -C ₁₀ alkylthio group, a C ₁ -C ₁₀ alkylsulfinyl. A C ₁ -C ₁₀ alkylsulfonyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ haloalkoxy group, a C ₂ -C ₆ alkoxycarbonyl group, a C ₂ -C ₆ dialkylamino group , alkylcarbonylamino group of C ₂ -C _6, alkylsulfonylamino group C ₁ -C _4, an aromatic hydrocarbon ring group C ₆ -C _14, 1 or more selected from among a cyano group and a nitro group, It may have a substituent. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
Alkyl group of ₁ -C _10, alkoxy group of C _{1 ~C 10,} C
₁ -C ₁₀ alkylthio group, the alkyl chain moiety of the alkylsulfonyl group alkylsulfinyl group and C ₁ -C _10, of C ₁ -C _10, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl Or a linear or branched alkyl group such as a decyl group. Examples of the C ₁ -C ₄ haloalkyl group include a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, and a nonafluoro group. such as butyl group, the above C ₁ -C
The ₄ haloalkoxy group, a trifluoromethoxy group, difluoromethoxy group, 2,2,2-trifluoroethoxy group, or 1,1,2,2-like tetrafluoroethoxy group and the like, C ₂ -C Examples of the ₆ alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a pentyloxycarbonyl group, and the like.As the C _{2 to} C ₆ dialkylamino group, A dimethylamino group, a diethylamino group, or a dipropylamino group;
The in ₆ -C ₁₄ aromatic hydrocarbon ring group, for example, a phenyl group, and a naphthyl group.

The C ₁ -C ₁₀ 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,
A tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and the like, and such an alkyl group is a phenyl group, or it may be substituted with an aryl group of C ₆ -C ₁₄ such as a naphthyl group. An especially preferred group is an isobutyl group. As the C ₁ -C ₁₀ alkyl group defined for R ⁴ , the same groups as defined for R ² can be mentioned. A particularly preferred group is a methyl group.

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

The oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can form a pharmaceutically acceptable salt. Specific examples of such salts include, for acidic residues, lithium salts, sodium salts, potassium salts, metal salts such as magnesium salts and calcium salts, or ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts, Ammonium salts such as dicyclohexyl ammonium salt can be formed,
When a basic group is present, a hydrochloride, a bromate, a sulfate, a nitrate, a mineral salt such as a phosphate, or a methanesulfonate, a benzenesulfonate, a paratoluenesulfonate, an acetate, Organic acids such as propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate and lactate Salts 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 ) Can take body. 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 ¹ , R ² ,
And A are as previously defined. )
In particular, in a solution, the following general formula (IV) (wherein R ¹ , R ² ,
And A are as previously defined. There is an equilibrium with the hydroxyaldehyde derivative represented by This can be explained by the following experimental results. The NMR measurement results support the structure of the following general formula (III), but depending on the type of the solvent used, the ratio of the stereochemistry of the carbon atom to which the hydroxyl group on the lactol ring of the following general formula (III) is bonded may vary. Differences have been observed as differences in the ratio of stereoisomers of compound (III). It is believed that this difference in isomer ratios occurs because of the following equilibrium.

[0031]

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Specific examples of the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) include, when R ³ is a hydrogen atom, compounds shown in Tables 1 and 3 below. When R ³ is not a hydrogen atom, the compounds shown in Tables 2 and 4 below can be mentioned.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

[Table 6]

[0039]

[Table 7]

[0040]

[Table 8]

[0041]

[Table 9]

[0042]

[Table 10]

[0043]

[Table 11]

[0044]

[Table 12]

[0045]

[Table 13]

[0046]

[Table 14]

[0047]

[Table 15]

[0048]

[Table 16]

[0049]

[Table 17]

[0050]

[Table 18]

[0051]

[Table 19]

[0052]

[Table 20]

[0053]

[Table 21]

[0054]

[Table 22]

[0055]

[Table 23]

[0056]

[Table 24]

[0057]

[Table 25]

[0058]

[Table 26]

[0059]

[Table 27]

[0060]

[Table 28]

[0061]

[Table 29]

[0062]

[Table 30]

[0063]

[Table 31]

[0064]

[Table 32]

[0065]

[Table 33]

[0066]

[Table 34]

[0067]

[Table 35]

[0068]

[Table 36]

[0069]

[Table 37]

[0070]

[Table 38]

[0071]

[Table 39]

[0072]

[Table 40]

[0073]

[Table 41]

[0074]

[Table 42]

[0075]

[Table 43]

[0076]

[Table 44]

[0077]

[Table 45]

[0078]

[Table 46]

[0079]

[Table 47]

[0080]

[Table 48]

[0081]

[Table 49]

[0082]

[Table 50]

[0083]

[Table 51]

[0084]

[Table 52]

[0085]

[Table 53]

[0086]

[Table 54]

[0087]

[Table 55]

[0088]

[Table 56]

[0089]

[Table 57]

[0090]

[Table 58]

[0091]

[Table 59]

[0092]

[Table 60]

[0093]

[Table 61]

[0094]

[Table 62]

[0095]

[Table 63]

[0096]

[Table 64]

[0097]

[Table 65]

[0098]

[Table 66]

[0099]

[Table 67]

[0100]

[Table 68]

[0101]

[Table 69]

[0102]

[Table 70]

Among the compounds represented by the general formula (I), compounds particularly suitable for the active ingredient of the medicament of the present invention include: (1) R ¹ is a phenyl group, a thiophene ring, a pyrazole ring, a triazole ring, a tetrazole ring; Ring, pyridine ring, pyrazine ring, pyrimidine ring, pyrimidinone ring, pyridazine ring, pyridazinone ring, triazine ring, indole ring, indazole ring, quinoline ring, isoquinoline ring, phthalazine ring, quinoxaline ring, quinazoline ring, oxazole ring, isoxazole ring A heterocyclic residue selected from oxadiazole ring, benzoxazole ring, benzoisoxazole ring, thiazole ring, isothiazole ring, thiadiazole ring, benzothiazole ring, benzoisothiazole ring and benzoisothiazole-1,1-dioxide Group (however, these Eniru group or a heterocyclic residue, C ₁ -C alkyl group of _10, alkoxy group of C ₁ ~C _10, C ₁ ~C alkylthio group _10, an alkylsulfonyl group having C ₁ -C _10, phenyl group, halogen Atom, C ₁ -C
₄ , haloalkyl groups, nitro groups, cyano groups, C ₂ -C ₆
A dialkylamino group, may be substituted with a group selected from the alkylsulfonylamino group of C ₂ -C ₆ alkylcarbonylamino group, and C ₁ -C ₄ a), R
² is a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted by a phenyl group, and R ³ is a hydrogen atom or R ⁴ —CO— (R ⁴ is a C ₁ -C ₄ alkyl group; is represented), a is an alkylene group of C ₁ -C optionally substituted with ₃ alkyl groups C ₁ -C ₃ compound;

(2) In the above compound (1), R ¹ is a phenyl group, a pyridine ring, a pyrimidine ring, a triazine ring, a tetrazole ring, a benzoxazole ring, a benzoisoxazole ring, a benzothiazole ring, a benzoisothiazole ring, Heterocyclic residues selected from benzoisothiazole-1,1-dioxide and quinoxaline rings (provided that these phenyl groups or heterocyclic residues are C ₁
Alkyl -C _10, alkoxy group of C ₁ ~C _10, C ₁
Alkylthio groups -C _10, an alkylsulfonyl group having C ₁ -C _10, phenyl group, a halogen atom, a haloalkyl group of C ₁ -C _4, nitro group, cyano group, a dialkylamino group of C ₂ ~C _6, C ₂ optionally substituted with a group selected from the sulfonylamino group alkylcarbonylamino group and C ₁ -C ₄ in -C ₆ also may) compound;

(3) In the above compound (1) or (2), the phenyl group or heterocyclic residue represented by R ¹ is
A C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group,
C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfonyl group, phenyl group, halogen atom, C ₁ -C ₄ haloalkyl group, nitro group, cyano group, dimethylamino group, acetylamino group and methylsulfonyl A compound having a substituent selected from an amino group or unsubstituted;

(4) R ¹ is a C ₁ -C ₄ alkyl group;
_{1 to} C ₄ alkoxy, halogen, trifluoromethyl, phenyl, nitro, dimethylamino,
Acetylamino group, methylsulfonylamino and methylsulfonyl chosen a phenyl group which may be substituted with a group from group, pyrimidinyl group, a tetrazolyl group or a benzoxazolyl group, R ² is isobutyl, R ³ Is a hydrogen atom or R ⁴ —CO— (R ⁴ is C ₁ to
A represents an alkyl group of C _4), it can be exemplified compounds wherein A is an ethylene group. However, the active ingredient of the medicament of the present invention is not limited to the compounds specifically mentioned above.

[0107]

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

Production method 1

[0109]

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(In the above formula, R ¹ and R ² are as defined above, X represents a halogen atom, a trichloromethyl group, a methylthio group or a methylsulfonyl group, and M represents an alkali metal or an alkaline earth metal. And a compound represented by the general formula (V) and a compound represented by the general formula (VI):
Is reacted with a solvent such as ethyl acetate, methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, or N-methylpyrrolidone to obtain an amino acid derivative represented by the general formula (VII). Can be done.

Production method 2

[0112]

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(In the above general formula, R ¹ , R ² , and A are as defined above.) In the same manner as in the method described in the patent (JP-A-9-169752), the above-mentioned general formula (VII) )) And an aminolactone derivative represented by the general formula (VIII).
When the lactone derivative represented by X) is dissolved in a solvent such as methylene chloride, toluene, heptane, or tetrahydrofuran, and treated with a reducing agent such as diisobutylaluminum hydride, sodium borohydride / cerium chloride, the above formula (III) is obtained. The oxygen-containing heterocyclic derivative represented can be obtained.

Production method 3

[0115]

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(In the above general formula, R ¹ , R ² ,
R ⁴ and A are as defined above. The oxygen-containing heterocyclic derivative produced by Production Method 2 was converted to methylene chloride, 1,2-dichloroethane, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetonitrile, Alternatively, by dissolving in an organic solvent such as toluene and reacting the acid anhydride represented by the above general formula (R ⁴ CO) ₂ O in the presence of a base such as pyridine, triethylamine or 4-dimethylaminopyridine, the above formula is obtained. The oxygen-containing heterocyclic derivative represented by (X) can be obtained. This reaction can be performed without a solvent.

Among the oxygen-containing heterocyclic derivatives of the present invention thus obtained, the compound (III) wherein R ³ is a hydrogen atom shows a strong inhibitory activity against cysteine protease. Also,
The compound (X) in which R ³ is R ⁴ —CO— (R ⁴ represents a C ₁ -C ₁₀ alkyl group) is a compound of the oxygen-containing heterocyclic derivative (III) having a strong inhibitory activity against cysteine protease. Can be used as a drug. That is, when the compound (X) is orally administered, after being absorbed from the intestinal tract or the like, the oxygen-containing heterocyclic derivative (III), which is the active substance, is immediately released by the action of enzymes in the living body.

[0118]

Embedded image

In clinical application of the compound of the present invention, 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, emulsions, suspensions or liquids, or injected. 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. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral use can be used to prepare the agents of the present invention. As an excipient used for producing a solid preparation, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as water or vegetable oils. The formulation may contain, in addition to the inert diluent, auxiliaries such as wetting agents, suspending auxiliaries, sweetening agents, fragrances, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Examples of preparations for parenteral administration, that is, solvents or suspensions used in the production of injections, suppositories and the like include 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 of the compound of the present invention for an adult, when used orally, is generally 0.01 to 1000 mg per day for an adult.
It is more preferable to increase or decrease as appropriate according to the symptoms. The daily dose of the agent of the present invention may be administered once a day or divided into two or three times a day at appropriate intervals,
It may be administered intermittently. When used as an injection, the compound of the present invention for an adult is administered in a daily dose of 0.00.
It is desirable to administer 1 to 100 mg continuously or intermittently.

[0121]

EXAMPLES The present invention will be described in detail with reference to Examples and Examples, but the present invention is not limited to these Examples.

Reference Example 1 N- (4,6-dimethoxy-2-pyrimidinyl)-
(S) -leucine (in the formula (VII), R ¹ is 4,6-
Preparation of dimethoxy-2-pyrimidinyl group, compound in which R ² is an isobutyl group) 4.36 g (20.0 mmol) of 4,6-dimethoxy-2-methanesulfonylpyrimidine is dissolved in 50 ml of DMF, and L-leucine sodium salt 37g (22.0
mmol) and 3.04 g (22.0 mmol) of potassium carbonate
l) was added and the mixture was stirred at 80 to 90 ° C for 3 hours. After completion of the reaction, the reaction solution was added to 100 ml of ice water and stirred until the mixture became homogeneous, and then extracted with 100 ml of ethyl acetate, and the ethyl acetate layer was discarded. The pH of the aqueous layer was adjusted to about 4 using 1N hydrochloric acid, and then extracted twice with 200 ml of ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and 100 ml of hexane and diethyl ether 5 were added to the obtained residue.
After adding 0 ml and stirring, the generated crystals were collected by filtration to obtain 4.06 g (yield: 75%) of the title compound.

Melting point: 112-114 ° C. IR (KBr, cm ⁻¹ ): 3318, 2961, 172
3,1591,1373. 1H-NMR (CDCl ₃ , δ): 0.96 (d, J =
6.5 Hz, 3H), 0.98 (d, J = 6.5 Hz,
3H), 1.65-1.85 (m, 3H), 3.83.
(S, 6H), 4.50-4.58 (m, 1H), 5.
45 (s, 1H), 5.77 (d, J = 7.1 Hz, 1
H).

Reference Example 2 (S) -3-{(S) -2- (4,6-dimethoxy-2)
-Pyrimidinyl) amino-4-methylvalerylamino
Preparation of -2-tetrahydrofuranone (compound of formula (IX) in which R ¹ is a 4,6-dimethoxy-2-pyrimidinyl group, R ² is an isobutyl group, and A is an ethylene group) 3. The compound obtained in Reference Example 1. 91 g (14.5 mmol)
And 1.67 g (14.5 g) of N-hydroxysuccinimide
mmol) was dissolved in 60 ml of tetrahydrofuran, and 3.00 g of dicyclohexylcarbodiimide (1
(4.5 mmol) was added as a solution of 10 ml of tetrahydrofuran, and the mixture was returned to room temperature and stirred for 20 hours. The precipitated solid was removed by filtration, and the filtrate was concentrated to give N- (4,6-
The succinimide ester of dimethoxy-2-pyrimidinyl)-(S) -leucine was obtained. This was dissolved in dimethylformamide (80 ml), and L-homoserine lactone hydrochloride (2.20 g, 16.0 mmol) and triethylamine (4.25 ml, 30.5 mmol) were added under ice-cooling. The reaction solution was stirred for 1 hour under ice cooling, and further stirred at room temperature for 4 hours. After completion of the reaction, 60 ml of ice water was added to the reaction solution,
The pH was adjusted to about 4 using 1N hydrochloric acid, and ethyl acetate 2
Extracted with 50 ml. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 50% hexane), and further 50 ml of ethyl acetate
Crystallization was performed with 150 ml of hexane and the crystals were collected by filtration to obtain 3.91 g (yield: 76.4%) of the title compound.

Melting point: 131-133 ° C. IR (KBr, cm ⁻¹ ): 3449, 3310, 177
3,1657,1588,1196,1161. 1H-NMR (CDCl ₃ , δ): 0.94 (d, J =
6.2 Hz, 3H), 0.98 (d, J = 6.2 Hz,
3H), 1.60-1.66 (m, 2H), 1.75-
1.85 (m, 2H), 2.05-2.17 (m, 1
H), 2.75-2.82 (m, 1H), 3.85
(S, 6H), 4.22-4.31 (m, 1H), 4.
41-4.53 (m, 3H), 5.04 (d, J = 6.
8 Hz, 1H), 5.49 (s, 1H), 6.96
(D, J = 5.9 Hz, 1H).

Example 1 (3S) -3-{(S) -2- (4,6-dimethoxy-
Production of 2-pyrimidinyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 40 in Table 1) 3.01 g (8.54 mmol) of the compound obtained in Reference Example 2
l) was dissolved in 45 ml of methylene chloride and cooled to -78 ° C. Next, 27.0 ml of a 0.95 mol / l diisobutylaluminum hydride hexane solution (27.0 ml / l) was added to the reaction solution.
5.6 mmol) was added. After 3 hours, the reaction solution is
After 1 ml of methylene chloride and 150 ml of methylene chloride were added and the temperature was returned to room temperature, the pH of the aqueous layer was adjusted to about 4 using 1N hydrochloric acid. This was thoroughly stirred and separated, and the methylene chloride solution was washed with saturated saline, dried over sodium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 50% hexane) to obtain 1.60 g (yield 52.9%) of the title compound.

IR (KBr, cm ^-1 ): 3328, 29
57, 1657, 1591, 1537, 1458, 14
22. 1H-NMR (CDCl ₃ , δ): 0.92-0.99
(M, 6H), 1.55-1.70 (m, 1H), 1.
70-1.83 (m, 3H), 2.24-2.38
(M, 0.63H), 2.40-2.52 (m, 0.3
7H), 3.84 (s, 6H), 3.81-3.94.
(M, 1H), 4.06-4.16 (m, 1H), 4.
30-4.50 (m, 2H), 5.22 (brs, 0.
37H), 5.30 (m, 0.63H), 5.47
(S, 0.63H), 5.48 (s, 0.37H),
6.73 (d, J = 7.4 Hz, 0.37 H), 6.8
2 (d, J = 8.3 Hz, 0.63H).

Example 2 (2S, 3S) -2-acetoxy-3-{(S) -2-
(4,6-dimethoxy-2-pyrimidinyl) amino-4
-Methylvalerylamino} -tetrahydrofuran (Table 2
Preparation of Compound No. 300) 1.55 g (4.37 mmol) of the compound obtained in Example 1
1) was dissolved in methylene chloride (22 ml), and acetic anhydride (0.43 ml, 4.6 mmol) and 4-dimethylaminopyridine were added under ice-cooling. After the reaction solution was stirred at room temperature for 1 hour, it was diluted with 50 ml of methylene chloride. To this was added 10 ml of 0.5N hydrochloric acid, stirred, and separated. The obtained methylene chloride solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated, 5 ml of ethyl acetate and 14 ml of hexane were added to the obtained residue, and the mixture was stirred. The resulting crystals were collected by filtration to obtain 590 mg (yield: 34%) of the title compound.

Melting point: 140-141 ° C. IR (KBr, cm ⁻¹ ): 3333, 2957, 287
0, 1752, 1644, 1584. 1H-NMR (CDCl ₃ , δ): 0.94 (d, J =
6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz,
3H), 1.55-1.64 (m, 1H), 1.72-
1.88 (m, 2H), 2.25-2.32 (m, 1
H), 3.83 (s, 6H), 3.94 (q, J = 9.
0 Hz, 1 H), 4.10 (td, J = 2.8 Hz,
9.0Hz, 9.0Hz, 1H), 4.34-4.65
(M, 1H), 4.62-4.74 (m, 1H), 5.
49 (s, 1H), 6.07 (d, J = 4.5 Hz, 1
H), 6.55 (d, J = 8.9 Hz, 1H). The compounds of Example 3 to Example 26 were produced in the same manner as in Reference Example 1, Reference Example 2, Example 1, and Example 2. The physical properties are described below.

Example 3 (3S) -3-{(S) -2- (4,6-diethoxy-
Preparation of 2-pyrimidinyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 41 in Table 1) IR (KBr, cm ^-1 ): 3329,2957,165
5,1587,1178. 1H-NMR (CDCl ₃ , δ): 0.91-0.98
(M, 6H), 1.31-1.37 (m, 4H), 1.
50-1.85 (m, 4H), 2.24-2.36
(M, 0.64H), 2.40-2.55 (m, 0.3
6H), 3.80-3.96 (m, 1H), 4.04-.
4.48 (m, 7H), 5.20-5.40 (m, 1.
64H), 5.39-5.44 (m, 0.36H),
5.41 (s, 0.64H), 5.42 (s, 0.36
H), 6.77 (d, J = 8.1 Hz, 0.36H),
6.82 (d, J = 8.1 Hz, 0.64H).

Example 4 (3S) -3-{(S) -2- (4-chloro-6-methoxy-2-pyrimidinyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Table 1 Preparation of compound No. 42) IR (KBr, cm ^-1 ): 3409, 2957, 165
5,1580. 1H-NMR (CDCl ₃ , δ): 0.94-0.98
(M, 6H), 1.55-1.65 (m, 1H), 1.
65-1.88 (m, 3H), 2.25-2.38
(M, 0.6H), 2.40-2.55 (m, 0.4
H), 3.82-3.90 (m, 0.6H), 3.88.
(S, 3H), 3.90-3.98 (m, 0.4H),
4.08-4.18 (m, 1H), 4.32-4.46
(M, 2H), 5.25 (d, J = 2.4 Hz, 0.4
H), 5.32 (dd, J = 3.3 Hz, 4.2 Hz,
0.6H), 6.10 (s, 0.6H), 6.11.
(S, 0.4H), 6.60 (d, J = 7.4 Hz,
0.4H), 6.68 (d, J = 8.0 Hz, 0.6
H).

Example 5 (3S) -3-{(S) -2- (2-methanesulfonyl-4-methoxy-6-pyrimidinyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Table 1) IR (KBr, cm ^-1 ): 3368, 2959, 173
6, 1659, 1584, 1313, 1149. 1H-NMR (CDCl ₃ , δ): 0.93-1.00
(M, 6H), 1.64-1.85 (m, 4H), 2.
22-2.35 (m, 0.6H), 2.35-2.50
(M, 0.4H), 3.11 (s, 1.2H), 3.1
3 (s, 11.8H), 3.80-3.90 (m, 1
H), 3.95 (s, 3H), 4.06-4.15.
(M, 1H), 4.28-4.45 (m, 2H), 5.
22 (d, J = 2.2 Hz, 0.4H), 5.27
(T, J = 4.3 Hz, 0.6 H), 5.65 (br
s, 1H), 6.37 (brs, 0.4H), 6.57.
(D, J = 8.1 Hz, 0.6 H), 6.72 (s,
0.6H), 6.74 (s, 0.4H).

Example 6 (3S) -3- {2- (4-Dimethylamino-6-methoxy-2-pyrimidinyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 43 in Table 1) IR (KBr, cm ^-1 ): 3350, 2955, 165
5,1597,1572. 1H-NMR (CDCl ₃ , δ): 0.91-0.98
(M, 6H), 1.50-1.86 (m, 4H), 2.
20-2.35 (m, 0.6H), 2.35-2.50
(M, 0.4H), 3.00 (s, 6H), 3.81
(S, 3H), 3.80-3.95 (m, 1H), 4.
02-4.10 (m, 1H), 4.25-4.45
(M, 2H), 4.96 (d, J = 6.5 Hz, 0.3
H), 5.02 (d, J = 6.5 Hz, 0.4H),
5.12 (d, J = 6.5 Hz, 0.3 Hz), 5.2
0 (s, 1H), 5.18-5.20 (m, 0.4
H), 5.27-5.30 (m, 0.6H), 6.90.
-6.96 (m, 1H).

Example 7 (3S) -3-{(S) -2- (2-nitro-4-trifluoromethylphenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (compound of Table 1) Production of No. 23) Melting point: 166-170.5 ° C. IR (KBr, cm ⁻¹ ): 3283, 2957, 165
7, 1597, 1541, 1368. 1H-NMR (CDCl ₃ , δ): 0.89-1.00
(M, 3H), 1.00-1.10 (m, 3H), 1.
69-1.98 (m, 4H), 2.29-2.54
(M, 1H), 3.82-4.13 (m, 3H), 4.
30-4.46 (m, 1H), 5.07-5.11
(M, 0.3H), 5.17-5.22 (m, 0.7
H), 6.11 (d, 0.3H, J = 8.0 Hz),
6.58 (d, 0.7H, J = 8.7 Hz), 6.81
−6.92 (m, 1H), 7.59−7.71 (m, 1
H), 8.27 (d, 0.3H, J = 4.8 Hz),
8.34 (d, 0.7H, J = 5.4Hz), 8.51
(Bs, 1H).

Example 8 (2S, 3S) -2-acetoxy-3-{(S) -2-
Preparation of (2-nitro-4-trifluoromethylphenyl) amino-4-methylvalerylamino} -2-tetrahydrofuran (Compound No. 283 in Table 2) Melting point: 140-141 ° C IR (KBr, cm ^-1 ): 3374, 1746, 165
7, 1578, 1539, 1364. 1H-NMR (CDCl ₃ , δ): 0.94 (d, 3
H, J = 6.0 Hz), 1.04 (d, 3H, J = 6.0).
0 Hz), 1.56 (s, 3H), 1.72-1.99
(M, 4H), 2.28-2.40 (m, 1H), 3.
89-4.13 (m, 3H), 4.57-4.72
(M, 1H), 6.07 (d, 1H, J = 4.8H
z), 6.31 (d, 1H, J = 9.0 Hz), 6.7
9 (d, 1H, J = 8.7 Hz), 7.68 (dd, 1
H, J = 8.7 Hz, 2.1 Hz), 8.27 (d, 1
H, J = 4.8 Hz), 8.51 (d, 1H, J = 2.
1 Hz).

Example 9 (3S) -3-{(S) -2- (4,6-dimethyl-2)
-Pyrimidinyl) amino-4-methylvalerylamino
-2-tetrahydrofuranol (compound number 3 in Table 1)
Preparation of 9) Melting point: 40.8-48.3 ° C IR (KBr, cm ^-1 ): 3335, 2957, 165
9, 1591, 1570, 1458. 1H-NMR (CDCl ₃ , δ): 0.84-1.02
(M, 6H), 1.53-1.67 (m, 1H), 1.
70-1.95 (m, 2H), 2.00-2.09
(M, 1H), 2.17-2.30 (m, 6H), 2.
31-2.39 (m, 1H), 3.75-3.95
(M, 1H), 4.00-4.17 (m, 1H), 4.
20-4.63 (m, 2H), 5.15 (d, 0.2
H, J = 3.3 Hz), 5.20-5.35 (m, 1.
8H), 6.36 (d, 1H, J = 5.4 Hz), 6.
92-6.97 (m, 0.2H), 7.01-7.08
(M, 0.8H).

Example 10 (3S) -3-{(S) -2- (2-benzoxazolyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 74 in Table 1) Production Melting point: 105-110 ° C IR (KBr, cm ^-1 ): 3275, 2959, 164
4,1586,1555. 1H-NMR (CDCl ₃ , δ): 0.97 (d, 3
H, J = 6.0 Hz), 1.00 (d, 3H, J = 6.0).
0 Hz), 1.60-2.00 (m, 4H), 2.21
-2.48 (m, 1H), 3.81-4.00 (m, 1
H), 4.05-4.22 (m, 1H), 4.24-
4.58 (m, 2H), 5.33 (s, 0.15H),
5.50 (d, 0.85H, J = 4.5Hz), 6.0
3-6.21 (m, 1H), 6.93-7.08 (m, 1H)
1H), 7.09-7.40 (m, 3H), 7.49.
(D, 1H, J = 7.5 Hz).

Example 11 (2S, 3S) -2-acetoxy-3-{(S) -2-
Preparation of (2-benzoxazolyl) amino-4-methylvalerylamino} -2-tetrahydrofuran (Compound No. 334 in Table 2) Melting point: 206.7-208.1 ° C. IR (KBr, cm ⁻¹ ): 3216, 3038, 295
9, 1753, 1660, 1587. 1H-NMR (CDCl ₃ , δ): 0.85-1.02
(M, 6H), 1.60-1.91 (m, 4H), 1.
95 (s, 3H), 2.23-2.35 (m, 1H),
3.87-3.98 (m, 1H), 4.05-4.17
(M, 1H), 4.32-4.45 (m, 1H), 4.
55-4.64 (m, 1H), 5.77 (d, 1H, J
= 7.6 Hz), 6.17 (d, 1H, J = 1.9H)
z), 6.73 (d, 1H, J = 8.5 Hz), 7.0
8 (dd, 1H, J = 7.3 and 7.3 Hz),
7.18 (dd, 1H, J = 7.3 and 7.3H
z), 7.25 (d, 1H, J = 7.3 Hz), 7.3
5 (d, 1H, J = 7.3 Hz).

Example 12 (3S) -3-{(S) -2- (1-phenyl-1H-
Tetrazolyl) amino-4-methylvalerylamino
2-tetrahydrofuranol (compound number 64 in Table 1)
Melting point: 73-76 ° C. IR (KBr, cm ⁻¹ ): 3287, 2959, 178
2,1659,1604. 1H-NMR (CDCl ₃ , δ): 0.80-1.02
(M, 6H), 1.55-1.82 (m, 3H), 1.
87-1.94 (m, 1H), 2.20-2.29
(M, 1H), 3.75-3.85 (m, 0.5H),
3.93-4.19 (m, 1.5H), 4.24-4.
34 (m, 1H), 4.52-4.64 (m, 1H),
5.09-5.16 (bs, 0.5H), 5.20
(D, 0.5H, J = 8.2 Hz), 5.27 (d, 1
H, J = 7.0 Hz), 7.07 (d, 1H, J = 7.
0 Hz), 7.40-7.65 (m, 5H).

Example 13 (3S) -3-{(S) -2- (4-bromo-2-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 625 in Table 3)
Melting point: 149-160 ° C. IR (KBr, cm ⁻¹ ): 3362, 2955, 164
7, 1616, 1505, 1346, 1265. 1H-NMR (CDCl ₃ , δ): 0.90-0.94
(M, 3H), 1.01-1.04 (m, 3H), 1.
73-1.86 (m, 4H), 2.20-2.42
(M, 1H), 2.60-2.80 (m, 1H), 3.
85-3.94 (m, 2H), 4.05-4.10
(M, 1H), 4.21-4.39 (m, 1H), 5.
07 (d, J = 2.7 Hz, 0.3 H), 5.19 (d
d, J = 4.5, 3.0 Hz, 0.7H), 6.22-
6.30 (m, 0.3H), 6.62-6.71 (m,
1.7H), 7.50-7.58 (m, 1H), 7.9
5-8.10 (m, 1H), 8.35-8.37 (m,
1H).

Example 14 (3S) -3-{(S) -2- (2-methyl-4-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 626 in Table 3)
IR (KBr, cm ^-1 ): 3389, 2957, 165
5,1591,1527,1497,1325,129
4. 1H-NMR (CDCl ₃ , δ): 0.92-0.96
(M, 3H), 1.01-1.05 (m, 3H), 1.
65-2.05 (m, 4H), 2.27 (s, 3H),
2.25-2.54 (m, 1H), 2.92 (bs, 1
H), 3.85-3.95 (m, 2H), 4.08-
4.14 (m, 1H), 4.28-4.52 (m, 2
H), 5.11-5.13 (m, 0.3H), 5.20.
−5.23 (m, 0.7H), 6.27 (d, J = 7.
8 Hz, 0.3 H), 6.45-6.51 (m, 1
H), 6.69 (d, J = 8.1 Hz, 0.7H),
8.00-8.05 (m, 2H).

Example 15 (3S) -3-{(S) -2- (4,5-dichloro-2)
Preparation of -nitrophenyl) amino-4-methylvalerylamino {-2-tetrahydrofuranol (Compound No. 627 in Table 3) Melting point: 187-195 ° C IR (KBr, cm ^-1 ): 3385,2955,164
5,1618,1560,1485,1248,122
6. 1H-NMR (CDCl ₃ , δ): 0.91-0.95
(M, 3H), 1.00-1.04 (m, 3H), 1.
60-1.95 (m, 4H), 2.22-2.52
(M, 1H), 2.66 (d, J = 2.7 Hz, 1
H), 3.82-3.97 (m, 2H), 4.05-
4.11 (m, 1H), 4.32-4.42 (m, 1
H), 5.12-5.14 (m, 0.3H), 5.25.
−5.28 (m, 0.7H), 6.18 (d, J = 7.
8Hz, 0.3H), 6.61 (d, J = 7.8Hz,
0.7H), 7.98-8.07 (m, 1H), 8.3.
2 (s, 0.7H), 8.33 (s, 0.3H).

Example 16 (3S) -3-{(S) -2- (4-nitrophenyl)
Preparation of amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 21 in Table 1) IR (KBr, cm ^-1 ): 3339,2957,165
5,1601,1530,1505,1478. 1H-NMR (CDCl ₃ , δ): 0.92-0.95
(M, 3H), 1.00-1.02 (m, 3H), 1.
63-1.84 (m, 4H), 2.25-2.54
(M, 1H), 3.19 (d, J = 2.8 Hz, 0.5
H), 3.24 (d, J = 2.8 Hz, 0.5H),
3.82-3.95 (m, 2H), 4.10 (m, 1
H), 4.37 (m, 1H), 4.73 (d, J = 5.
3 Hz, 0.5 H), 4.81 (d, J = 5.7 Hz,
0.5H), 5.10 (d, J = 2.6 Hz, 0.5
H), 5.22 (m, 0.5H), 6.36 (d, J =
7.8 Hz, 0.5 H), 6.74 (d, J = 8.1 H)
z, 0.5H), 6.58 (d, J = 9.3 Hz, 1
H), 6.59 (d, J = 9.2 Hz, 0.5H),
8.08 (d, J = 9.3 Hz, 1H), 8.09
(D, J = 9.2 Hz, 0.5H).

Example 17 (3S) -3-{(S) -2- (2-nitrophenyl)
Production melting point of amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 22 in Table 1): 1
40-142 ° C IR (KBr, cm ^-1 ): 3382,3299,295
7, 1649, 1620, 1512. 1H-NMR (CDCl ₃ , δ): 0.91-0.94
(M, 3H), 1.00-1.04 (m, 3H), 1.
75-1.92 (m, 4H), 2.32 (m, 1H),
2.48 (brs, 0.85H), 2.60 (brs,
0.15H), 3.82-3.97 (m, 2H), 4.
10 (m, 1H), 4.41 (m, 1H), 5.07
(M, 0.15H), 5.16 (m, 0.85H),
6.70-6.82 (m, 3H), 7.46 (t, J =
8.5 Hz, 1 H), 8.01 (d, J = 4.5 Hz,
0.15H), 8.08 (d, J = 4.5 Hz, 0.8
5H), 8.21 (d, J = 8.5 Hz, 1H).

Example 18 (2S, 3S) -2-acetoxy-3-{(S) -2-
(2-Nitrophenyl) amino-4-methylvalerylamino} -2-tetrahydrofuran (Compound No. 2 in Table 2)
82) IR (KBr, cm ^-1 ): 3383, 2959, 175
2,1655,1618,1507. 1H-NMR (CDCl ₃ , δ): 0.92 (d, J =
6.0 Hz, 3H), 1.03 (d, J = 6.0 Hz,
3H), 1.47 (s, 3H), 1.75-1.98.
(M, 4H), 2.30 (m, 1H), 3.90-3.
98 (m, 2H), 4.11 (m, 1H), 4.69
(M, 1H), 6.01 (d, J = 4.7 Hz, 0.1
5H), 6.53 (d, J = 9.3 Hz, 1H), 6.
66 (d, J = 8.2 Hz, 1H), 6.84 (t, J
= 8.2 Hz, 1H), 7.48 (t, J = 7.1H)
z, 1H), 8.05 (d, J = 4.3 Hz, 1H),
8.22 (d, J = 8.3 Hz, 1H).

Example 19 (3S) -3-{(S) -2- (4-Fluoro-2-nitrophenyl) amino-4-methylvalerylamino}-
2-tetrahydrofuranol (compound number 62 in Table 3)
Production of 1) Melting point: 120-124 ° C IR (KBr, cm ^-1 ): 3385, 1649, 158
6,1533,1240. 1H-NMR (CDCl ₃ , δ): 0.90-0.93
(M, 3H), 1.01-1.03 (m, 3H), 1.
60-1.90 (m, 4H), 2.33 (m, 0.7
H), 2.45 (m, 0.3H), 2.91 (d, J =
2.9 Hz, 0.7 H), 2.99 (d, J = 2.9 H)
z, 0.3H), 3.82-3.92 (m, 2H),
4.07 (m, 1H), 4.36 (m, 1H), 5.0
5. 7 (m, 0.3H), 5.18 (m, 0.7H),
35 (d, J = 8.3 Hz, 0.3H), 6.68-
6.76 (m, 1.7H), 7.27 (m, 1H),
7.88-7.97 (m, 2H).

Example 20 (3S) -3-{(S) -2- (4-methyl-2-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 622 in Table 3)
Melting point: 114-116 ° C. IR (KBr, cm ⁻¹ ): 3428, 1649, 152
8, 1348. 1H-NMR (CDCl ₃ , δ): 0.89-0.91
(M, 3H), 1.00-1.02 (m, 3H), 1.
70-1.89 (m, 4H), 2.29 (s, 1.5
H), 2.30 (s, 1.5H), 2.25-2.50.
(M, 1H), 2.66 (d, J = 2.4 Hz, 0.5
H), 2.79 (d, J = 2.4 Hz, 0.5 H),
3.84-3.94 (m, 2H), 4.07 (m, 1
H), 4.35 (m, 1H), 5.07 (m, 0.5
H), 5.17 (m, 0.5H), 6.41 (d, J =
8.0 Hz, 0.5 H), 6.62 (d, J = 8.6 H)
z, 0.5H), 6.66 (d, J = 8.6 Hz, 0.
5H), 6.81 (d, J = 8.0 Hz, 0.5H),
7.26-7.32 (m, 1H), 7.88 (d, J =
4.0 Hz, 0.5 H), 7.95 (d, J = 4.0 H)
z, 0.5H), 8.01 (brs, 1H).

Example 21 (3S) -3-{(S) -2- (3-methyl-4-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 632 in Table 3)
IR (KBr, cm ^-1 ): 3343, 2959, 161
0, 1586, 1532, 1501. 1H-NMR (CDCl ₃ , δ): 0.92-0.95
(M, 3H), 1.00-1.02 (m, 3H), 1.
60-1.85 (m, 4H), 2.30-2.50
(M, 1H), 2.59 (s, 1.8H), 2.60
(S, 1.2H), 3.26 (d, J = 2.7 Hz,
0.4H), 3.33 (d, J = 2.7 Hz, 0.6
H), 3.80-3.95 (m, 2H), 4.10
(M, 1H), 4.35 (m, 1H), 4.55 (d,
J = 5.6 Hz, 0.4 H), 4.64 (d, J = 5.
6 Hz, 0.6 H), 5.11 (d, J = 2.4 Hz,
0.4H), 5.22 (m, 0.6H), 6.35-
6.48 (m, 2.4H), 6.78 (d, J = 8.2)
Hz, 0.6H), 8.03 (d, J = 8.9 Hz,
0.6H), 8.03 (d, J = 8.9 Hz, 0.6
H).

Example 22 (3S) -3-{(S) -2- (5-methyl-2-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 633 in Table 3)
Melting point: 153-155 ° C. IR (KBr, cm ⁻¹ ): 3380, 3293, 164
9, 1624, 1582, 1497. 1H-NMR (CDCl ₃ , δ): 0.89-0.94
(M, 3H), 1.00-1.03 (m, 3H), 1.
67-1.90 (m, 4H), 2.33 (s, 1.8
H), 2.34 (s, 1.2H), 2.30-2.5
5 (m, 1H), 2.88 (d, J = 3.0 Hz, 0.
6H), 2.97 (d, J = 3.0 Hz, 0.4H),
3.80-4.00 (m, 2H), 4.08 (m, 1
H), 4.35 (m, 1H), 5.09 (d, J = 3.
0 Hz, 0.4H), 5.19 (m, 0.6H), 6.
40 (d, J = 7.8 Hz, 0.4 H), 6.47
(S, 0.4H), 6.51 (s, 0.6H), 6.5
8 (d, J = 9.9 Hz, 0.6H), 6.62 (d,
J = 9.9 Hz, 0.4H), 6.79 (d, J = 7.
8Hz, 0.6H), 8.00-8.14 (m, 2
H).

Example 23 (3S) -3-{(S) -2- (2-chloro-4-nitrophenyl) amino-4-methylvalerylamino} -2
Preparation of tetrahydrofuranol (Compound No. 25 in Table 1) IR (KBr, cm ^-1 ): 3382, 2959, 165
5,1593,1528,1503,1329,129
4. 1H-NMR (CDCl ₃ , δ): 0.92-0.96
(M, 3H), 1.01-1.05 (m, 3H), 1.
65-1.97 (m, 3H), 2.27-1.56
(M, 1H), 3.02-3.17 (m, 1H), 3.0.
81-3.98 (m, 2H), 4.03-4.17
(M, 1H), 4.37 (m, 1H), 5.11 (d,
J = 2.4 Hz, 0.3 H), 5.22 (m, 1 H),
5.27 (d, J = 5.4 Hz, 0.7H), 6.27
(D, J = 8.0 Hz, 0.3 H), 6.55-6.6.
5 (m, 1H), 6.67 (d, J = 8.0 Hz, 0.
7H), 8.07 (m, 1H), 8.24 (m, 1
H).

Example 24 (3S) -3-{(S) -2- (4-nitro-2-trifluoromethylphenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (compound of Table 1) Production of No. 24) IR (KBr, cm ^-1 ): 3406, 2961, 165
7, 1620, 1595, 1537, 1508, 132
9. 1H-NMR (CDCl ₃ , δ): 0.92-0.96
(M, 3H), 1.02-1.05 (m, 3H), 1.
59-1.98 (m, 4H), 2.35 (m, 0.6
H), 2.47 (m, 0.4H), 2.88 (s, 1
H), 3.89 (m, 1H), 4.00 (m, 1H),
4.08 (m, 1H), 4.35 (m, 1H), 5.0
8 (d, J = 2.7 Hz, 0.4H), 5.20 (m,
1H), 5.27 (brs, 0.7H), 6.10
(D, J = 7.8 Hz, 0.4 H), 6.61 (d, J
= 8.3 Hz, 0.6 H), 6.68 (dd, J = 9.
3, 3.0 Hz, 1H), 8.26 (m, 1H), 8.
43 (m, 1H).

Example 25 (3S) -3-{(S) -2- (5-Chloro-2-nitrophenyl) amino-4-methylvalerylamino} -2
-Tetrahydrofuranol (compound number 623 in Table 3)
IR (KBr, cm ^-1 ): 3378, 3293, 164
9, 1615, 1570, 1491, 1332. 1H-NMR (CDCl ₃ , δ): 0.91-0.95
(M, 3H), 1.00-1.03 (m, 3H), 1.
67-1.95 (m, 4H), 2.31 (m, 0.65)
H), 2.45 (m, 0.35H), 2.76 (d, H
= 2.7 Hz, 0.65 H), 2.79 (d, J = 2.
7 Hz, 0.35 H), 3.79-3.98 (m, 2
H), 4.05 (m, 1H), 4.38 (m, 1H),
5.12 (d, J = 2.7 Hz, 0.35 H), 5.2
3 (m, 0.65H), 6.27 (d, J = 4.5H)
z, 0.35H), 6.65 (d, J = 4.5 Hz,
0.65H), 6.68-6.82 (m, 2H), 8.
08 (d, J = 4.5 Hz, 1H), 8.15 (dd,
J = 9.0, 3.3 Hz, 1H).

Example 26 (3S) -3-{(S) -2- (2-fluoro-4-nitrophenyl) amino-4-methylvalerylamino}-
2-tetrahydrofuranol (compound number 62 in Table 3)
Production of 4) IR (KBr, cm ^-1 ): 3364, 2959, 165
5,1614,1539,1331. 1H-NMR (CDCl ₃ , δ): 0.85-0.95
(M, 3H), 0.97-1.05 (m, 3H), 1.
63-1.95 (m, 4H), 2.35 (m, 0.62
H), 2.44 (m, 0.38H), 2.88 (br
s, 1H), 3.80-4.00 (m, 2H), 4.1
3 (m, 1H), 4.39 (m, 1H), 4.79
(M, 0.38H), 4.87 (m, 0.62H),
5.11 (brs, 0.38H), 5.23 (m, 0.
62H), 6.27 (d, J = 8.1 Hz, 0.38
H), 6.60 (m, 1H), 6.68 (d, J = 8.
1 Hz, 0.62 H), 7.85-8.02 (m, 2
H),.

Reference Example 3 Production of (S) -3-{(S) -2- (2-amino-4-trifluoromethylphenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranone Reference Example 2 (S) -3-｛(S)-obtained in the same manner as
2- (2-nitro-4-trifluoromethylphenyl)
2.28 g (5.65 mmol) of amino-4-methylvalerylamino} -2-tetrahydrofuranone are dissolved in a mixed solvent of 20 ml of tetrahydrofuran and 30 ml of ethanol, and 0.8 g of 10% palladium-carbon and 3 drops of 1 N hydrochloric acid Was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 3 hours, the insolubles were filtered off, and the filtrate was concentrated to give 2.09 g (yield 99%) of the title compound.

1H-NMR (CDCl ₃ , δ): 0.9
1 (d, J = 6.0 Hz, 3H), 0.99 (d, J =
6.0 Hz, 3H), 1.58-1.94 (m, 3
H), 2.10-2.24 (m, 1H), 2.60-
2.78 (m, 1H), 3.0-3.6 (bs, 2
H), 3.78-3.82 (m, 1H), 4.18-
4.45 (m, 4H), 6.57 (d, J = 8.4H)
z, 1H), 6.97 (d, J = 1.2 Hz, 1H),
7.08 (d, J = 8.4 Hz, 1H), 7.22 (b
rs, 1H).

Reference Example 4 (S) -3-{(S) -2- (2-acetylamino-4)
Production of -trifluoromethylphenyl) amino-4-methylvalerylamino {-2-tetrahydrofuranone 0.73 g (1.96 mm) of the compound obtained in Reference Example 3
ol) and 254 mg of 4-dimethylaminopyridine
(2.08 mmol) was dissolved in 10 ml of methylene chloride. Acetic anhydride 200ml (2.12mmo) under ice cooling
l) was added and the mixture was stirred at the same temperature for 15 minutes. After completion of the reaction, ice water and a 10% aqueous citric acid solution were sequentially added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was purified by column chromatography (developing solvent: ethyl acetate containing 50% methylene chloride) to give 0.63 g (yield 78%) of the title compound.
) Got.

IR (KBr, cm ^-1 ): 3290, 23
61, 1780, 1667, 1620, 1532, 13
33, 1161, 1115. 1H-NMR (CDCl ₃ , δ): 0.91 (d, J =
5.8 Hz, 3H), 0.97 (d, J = 5.8 Hz,
3H), 1.58-1.90 (m, 3H), 2.24
(S, 3H), 2.25-2.38 (m, 1H), 2.
41-2.56 (m, 1H), 4.00-4.09
(M, 1H), 4.12-4.34 (m, 2H), 4.
38-4.46 (m, 2H), 6.72 (d, J = 8.
6 Hz, 1H), 7.28 (s, 1H), 7.40
(D, J = 8.6 Hz, 1H), 7.61 (s, 1
H), 7.99 (d, J = 6.9 Hz, 1H).

Reference Example 5 (S) -3-{(S) -2- (4-methanesulfonylaminophenyl) amino-4-methylvalerylamino}
Production of -2-tetrahydrofuranone (S) -3-｛(S)-obtained in the same manner as in Reference Example 3.
1.00 g of 2- (4-aminophenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranone
(3.28 mmol) in 30 ml of tetrahydrofuran
Was dissolved. 515 ml of triethylamine under ice cooling
(3.69 mmol), methanesulfonyl chloride
275 ml (3.54 mmol) were added sequentially. After 20 minutes, a 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and the obtained residue was purified by column chromatography (developing solvent: ethyl acetate containing 50% methylene chloride).
1.25 g (100% yield) of the title compound were obtained.

IR (KBr, cm ^-1 ): 3378, 29
59, 1777, 1657, 1518, 1325, 11
52. 1H-NMR (CDCl ₃ , δ): 0.92 (d, J =
6.0 Hz, 3H), 0.99 (d, J = 6.0 Hz,
3H), 1.54-1.88 (m, 3H), 2.12
2.26 (m, 1H), 2.60-2.74 (m, 1
H), 2.86 (s, 3H), 3.69-3.73.
(M, 1H), 3.93 (bs, 1H), 4.26-
4.31 (m, 1H), 4.42-4.50 (m, 1
H), 4.60-4.77 (m, 1H), 6.30 (b
s, 1H), 6.60 (d, J = 8.6 Hz, 2H),
7.02 (d, J = 8.6 Hz, 2H), 7.42
(D, J = 7.2 Hz, 1H).

Example 27 (3S) -3-{(S) -2- (2-acetylamino-
4-trifluoromethylphenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Table 3
Production of Compound No. 628) The title compound was produced in the same manner as in Example 1 using the compound obtained in Reference Example 4. IR (KBr, cm ^-1 ): 3378, 2961, 165
1,1622,1528,1333,1115. 1H-NMR (CDCl ₃ , δ): 0.92-1.02
(M, 6H), 1.52-1.93 (m, 4H), 2.
27 (s, 3H), 2.08-2.39 (m, 1H),
2.90-3.03 (m, 0.5H), 3.14-3.
33 (m, 0.5H), 3.73-3.88 (m, 1
H), 3.90-4.55 (m, 5H), 4.93 (b
s, 0.5H), 5.10-5.14 (m, 0.5
H), 6.65-6.72 (m, 1H), 7.22-
7.55 (m, 4H).

Example 28 Preparation of (3S) -3-{(S) -2- (2-acetylaminophenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 629 in Table 3) The title compound was produced in the same manner as in Reference Example 1, Reference Example 2, Reference Example 3, Reference Example 4, and Example 27.

IR (KBr, cm ^-1 ): 3279, 29
57, 1658, 1523, 1453, 1310, 10
42. 1H-NMR (CDCl ₃ , δ): 0.93-1.02
(M, 6H), 1.50-1.88 (m, 4H), 2.
24 (s, 3H), 2.03-2.34 (m, 1H),
2.91-3.02 (m, 1H), 3.71-4.28
(M, 6H), 4.80-5.12 (m, 1H), 6.
62-6.76 (m, 2H), 6.95-7.56
(M, 4H).

Example 29 (3S) -3-{(S) -2- (4-methanesulfonylaminophenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 630 in Table 3) Production The title compound was produced in the same manner as in Example 1 using the compound obtained in Reference Example 5. IR (KBr, cm ^-1 ): 3376, 2957, 165
7,1514,1327,1152,1036,97
4. 1H-NMR (CDCl ₃ , δ): 0.76 (d, J =
6.6 Hz, 1 H), 0.82 (d, J = 6.6 Hz,
1H), 0.91 (d, J = 5.7 Hz, 2H), 1.
00 (d, J = 5.7 Hz, 2H), 1.48-1.8
4 (m, 4H), 2.21-2.44 (m, 1H),
2.95 (s, 2H), 2.97 (s, 1H), 3.2
6-3.77 (m, 1H), 3.80-4.07 (m, 1H)
3H), 4.22-4.38 (m, 1H), 5.01-
5.07 (m, 0.65H), 5.32-3.37
(M, 0.35H), 6.54-6.65 (m, 3
H), 7.07-7.21 (m, 3H).

Example 30 (3S) -3-{(S) -2- (2-methanesulfonylaminophenyl) amino-4-methylvalerylamino} -2-tetrahydrofuranol (Compound No. 631 in Table 3) Production The title compound was produced in the same manner as in Reference Example 1, Reference Example 2, Reference Example 3, Reference Example 5, and Example 29. IR (KBr, cm ^-1 ): 3416, 2957, 166
2,1481,1352,1163,968,747. 1H-NMR (CDCl ₃ , δ): 0.97 (d, J =
6.2 Hz, 3H), 1.02 (d, J = 6.2 Hz,
3H), 1.63-1.98 (m, 4H), 2.04-
2.17 (m, 1H), 2.75 (s, 3H), 3.0
4 (bs, 1H), 3.62-3.79 (m, 2H),
4.03-4.14 (m, 2H), 5.18 (d, J =
8.9 Hz, 1 H), 6.53 (d, J = 7.7 Hz,
1H), 6.76-6.82 (m, 1H), 7.10-
7.14 (m, 1H), 7.33-7.36 (m, 2
H).

Test Example 1 Measurement of m-calpain Inhibitory Activity m-calpain was purified from pig kidney by CA.
It was purchased from LBIOCHEM and its inhibitory activity was measured according to the method described in the literature (Journal of Biological Chemistry, vol. 259, page 12489, 1984). The results are shown in Table-5. Table 5 shows that the compounds of the present invention show strong inhibitory activity against cysteine proteases such as calpain.

[0166]

[Table 71]

Test Example 2 Acute toxicity test The compound of the present invention was added to SD male and female rats in 0.5% CMC-N.
The solution suspended in the aqueous solution (a) was orally administered by gavage, and symptoms were observed for 7 days. As a result, the approximate minimum lethal dose of the compound of Example 8 was> 2000 mg / kg.

Test Example 3 Formulation Example (1) Tablet The following ingredients were mixed according to a conventional method and tableted with a conventional apparatus. Compound of Example 8 30 mg Crystalline cellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4 mg (2) Soft capsule The following ingredients were mixed according to a conventional method, and filled in a soft capsule. Compound of Example 8 30 mg Olive oil 300 mg Lecithin 20 mg

[0169]

Industrial Applicability The oxygen-containing heterocyclic derivative of the present invention has a strong inhibitory effect on cysteine proteases such as papain, cathepsin B, cathepsin H, cathepsin L, calpain, and interleukin-1β converting enzyme. , Dystrophy, muscular atrophy, myocardial infarction, stroke, Alzheimer's disease, impaired consciousness and movement such as head trauma, multiple sclerosis, neuropathy of peripheral nerves , Cataract, inflammation, allergy, fulminant hepatitis, osteoporosis, hypercalcemia, breast cancer, prostate cancer, prostate hypertrophy, etc., or as a cancer growth inhibitor, metastasis preventive, platelet aggregation inhibitor it can.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI A61K 31/00 615 A61K 31/00 615 619 619E 621 621D 625 625 625F 626 626N 627 627F 629 629 635 635 635B 637 637E 643 643D 31 / 335 602 31/335 602 31/34 601 31/34 601 31/35 31/35 31/38 31/38 31/41 31/41 31/415 31/415 31/42 31/42 31/425 31/425 31/44 31/44 31/47 31/47 31/495 31/495 31/50 31/50 31/505 31/505 31/53 31/53 C07D 307/22 C07D 307/22 309/14 309/14 405/12 209 405/12 209 213 213 215 215 217 217 231 231 237 237 239 239 241 241 241 249 249 251 251 251 25 257 409/12 307 409/12 307 413/12 305 413/12 305 307 307 417/12 305 417/12 305 307 307 (72) Inventor Akira Nakao 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Inside Yokohama Research Laboratory (72) Inventor Ryoichi Ando 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory (72) Inventor Shigehiko Yoshii 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Inside Yokohama Research Laboratory (72) Inventor Kenichi Saito 1000 Yokohama Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Inside Mitsubishi Chemical Research Laboratory

Claims (8)

[Claims] 1. A compound represented by the following general formula (I) (In the above general formula, R ¹ is a C ₆ to C ₅ which may have a substituent.
_{A 14-} membered aryl group or a heterocyclic residue which may have a substituent, wherein R ² is a hydrogen atom or a C ₁ -C ₁₀ alkyl which may be substituted by a C ₆ -C ₁₄ aryl group; R ³ represents a hydrogen atom or R ⁴ —CO— (R ⁴
Represents represents) an alkyl group of C ₁ -C _10, A is C
₁ -C good C ₁ optionally substituted with an alkyl group having ₃ -C
₃ represents an alkylene group) or a salt thereof, or a solvate or hydrate thereof. ^2. The compound according to claim _{1, wherein} R ² is a C ₁ -C ₁₀ alkyl group. 3. The compound according to claim 2, wherein R ² is an isobutyl group. 4. The compound according to claim ₃ , wherein A is a C ₁ -C ₃ alkylene group. 5. The compound according to claim 3, wherein A is an ethylene group which may be substituted by a C ₁ -C ₃ alkyl group. 6. The compound according to claim 3, wherein A is an ethylene group. 7. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition for a disease caused by abnormally elevated cysteine protease, comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.