JPH1045588A - Alpha-glucosidase inhibitor containing pyrazolone-based compound or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor having excellent α-glucosidase inhibiting activities useful for treatment of metastatis of cancer, virus disease, diabetes mellitus, etc., by including a pyrazolone-based compound or its salt having a specific structure. SOLUTION: This inhibitor includes a pyrazolone-based compound of formula I (R<1> is an alkyl, phenyl, etc.; R<2> is H, a halogen, etc.) or its salt. The compound of formula I in which R<2> is a group of phenylcarbonylamino or R<1> is a group of alkylcarbonyloxyalkyl is the new one. 4,4-Dibromo-3-benzoylamino-1-phenyl-2- pyrazolin-5-one is preferable as the former and 4,4-dibromo-1-(2-acetoxyethyl)-3- methyl-2-pyrazolin-5-one is preferable as the latter. The compound of formula I is, for example, obtained by reacting a compound of formula II with a brominating agent such as bromine at 5-100 deg.C for 0.5-24hr. The daily dose of the compound of formula I is usually 50-5,000mg for an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to an inhibitor of an enzyme involved in sugar chain processing in a living body, a reagent for researching glycoprotein sugar chain processing, and further, cancer metastasis, viral diseases such as AIDS, diabetes, The present invention relates to an α-glucosidase inhibitor containing a pyrazolone compound or a salt thereof, which is useful as a therapeutic drug for hyperlipidemia, inflammatory diseases, autoimmune diseases, rejection during organ transplantation, and allergic diseases.

[0002]

2. Description of the Related Art Castanospermine, 1-deoxynojirimycin and the like are known as α-glucosidase inhibitors. However, the α-glucosidase inhibitor of the present invention differs from those in the chemical structure of the active ingredient.
As represented by castanospermine, which is an α-glucosidase inhibitor, inhibitors of enzymes involved in sugar chain processing are cancer metastasis suppressors (Humphries et al., Can).
cer Research 46, 5251-522
2, 1986), suppression of development in an autoimmune encephalomyelitis animal model (Willenburg et al., J. Neuro.
l. Sci, 90, 77-85, 1989), suppression of onset in arthritis animal models (Willenborg et al.,
Immunol. Cell Biol. 70,369-
377, 1992), suppression of the expression of major histocompatibility class I molecules on cell membranes that are important for the immune response (Moore et al.,
J. Biologic. Chem. 268,3809-
3812, 1993). In addition, Japanese Patent Publication (A) Hei 4-5
00959 has an effect of improving the pathological condition in an autoimmune encephalomyelitis animal model, an adjuvant arthritis model, a tissue graft rejection model, and a delayed hypersensitivity reaction model. Anti-inflammatory and / or immunosuppressive therapeutic methods have been proposed. Further, International Patent Specification WO 8709033 discloses the use of castanospermine as a therapeutic agent against retroviral pathogens such as the AIDS virus. Its effects have been described as interfering with retroviral replication in infected cells resulting from inhibition of glycan processing and reducing the pathogenic effects associated with the presentation of viral envelope glycoproteins on infected cells. Also, European Patent Specification No. 202661 proposes the use of castanospermine for the prevention of hyperlipidemia and excessive lipid accumulation and the treatment of diabetes. This is because of the inhibition of digestive enzymes, the inhibition of lipid biosynthesis,
This is due to the inhibition of glucose formation by hydrolysis of complex sugars.

Many of the pyrazolone compounds represented by the following general formula (I) or salts thereof in the present invention are known. For example, 4,4-dibromo-1,3-dimethyl-2-pyrazolin-5-one is disclosed in JP-A-62-281.
No. 865 and No. 62-281866,
4,4-Dibromo-1-methyl-3-phenyl-2-pyrazolin-5-one is a product of Journal of University Kuwait Science (J. Univ. Kuwait, Sci) 197.
6,3, pp. 39-56, 4,4-dibromo-3-methyl-1-phenyl-2-pyrazolin-5-one is published in Journal of the Indian Chemical Society (J. Indian Chem. Soc). .) 1977, 54, No. 5, 485 −
On page 487, 4,4-dibromo-1,3-diphenyl-
2-Pyrazolin-5-one is a Zite Schrift Fur Chemie (Z. Chem) 1980, Volume 20, No. 12, 437.
-Page 438, 4,4-dibromo-3-methyl-1-
(P-Nitrophenyl) -2-pyrazolin-5-one was obtained from Zurnal Fur Practice Chemie (J.P.
rakt. Chem) 1984, Vol. 326, No. 3, pages 367-373. JP-A-2-225469 describes that many of the compounds of the formula (I) or salts thereof have antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, Trichophyton, fungi and the like. . However, there is neither description nor suggestion in the prior art that the compound of the general formula (I) or a salt thereof has an α-glucosidase inhibitory activity.

[0004]

[Problems to be Solved by the Invention] Glycan processing in the treatment of cancer metastasis, viral diseases such as AIDS, diabetes, hyperlipidemia, inflammatory diseases, autoimmune diseases, rejection during organ transplantation and allergic diseases It is thought that it is important to inhibit the enzyme related to. Under such a concept, there is a demand for the development of a pharmaceutical having an α-glucosidase inhibitory action.

[0005]

Means for Solving the Problems As a result of intensive investigations by the present inventors for compounds having α-glucosidase inhibitory activity, the compound represented by the following general formula (I) or a salt thereof has an excellent inhibitory action. And found that the present invention was completed. That is, the present invention has the general formula (I):

[0006]

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(Wherein R ¹ is an optionally substituted alkyl group, an optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group An optionally substituted alkylcarbonyloxyalkyl group or an optionally substituted pyrimidinyl group, wherein R ² is a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted alkyl group, Optionally an alkoxy group,
An optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonylamino group,
An optionally substituted phenyl group, an optionally substituted phenylcarbonylamino group, or an optionally substituted pyridinyl group) or a salt thereof. Agent.

Examples of the salt of the pyrazolone compound represented by the general formula (I) include mineral salts such as hydrochloride, sulfate and nitrate, p-toluenesulfonate, propanesulfonate and methanesulfonate. Organic acid salts.

[0009] The general formula (I) an optionally substituted alkyl group contained in R ¹ in, an optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, a substituted An optionally substituted pyridinyl group, an optionally substituted alkylcarbonyloxyalkyl group and an optionally substituted pyrimidinyl group, and an optionally substituted alkyl group contained in R ² , an optionally substituted alkoxy group, Optionally substituted alkylthio group, optionally substituted cycloalkyl group, optionally substituted alkoxycarbonyl group, optionally substituted alkylcarbonylamino group, optionally substituted phenylcarbonylamino group, optionally substituted phenyl group And a substituent of the optionally substituted pyridinyl group include a halogen atom; a nitro group; a cyano group; Hon group; carboxy group; alkyl group optionally substituted by halogen atom; alkoxy group optionally substituted by halogen atom; alkylthio group optionally substituted by halogen atom; alkoxycarbonyl group optionally substituted by halogen atom An alkylsulfinyl group optionally substituted with a halogen atom; an alkylsulfonyl group optionally substituted with a halogen atom; a phenyl group optionally substituted with a halogen atom, and the number of these substituents is 1 Or two or more same or different, and each of the above specific groups which may be substituted with the above halogen atom may be substituted with one or two or more same or different halogen atoms. Good.

The alkyl group or alkyl moiety contained in R ¹ and R ² in the general formula (I) generally has 1 to 10 carbon atoms, and may be linear or branched. For example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, octyl group,
Nonyl group, decyl group, etc., and R ¹ and R
^The cycloalkyl group contained in ² generally has 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Examples of the halogen atom contained in R ¹ and R ² in the general formula (I) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

R ¹ in the above general formula (I) is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, a substituted An optionally substituted alkylcarbonyloxyalkyl group and an optionally substituted pyrimidinyl group are desirable. R ² is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted phenylcarbonyl An amino group or an optionally substituted pyridinyl group is preferred.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (I '):

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(Wherein R ¹ is an optionally substituted alkyl group, an optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group Or an optionally substituted alkylcarbonyloxyalkyl group or an optionally substituted pyrimidinyl group, and R ² ′ is an optionally substituted phenylcarbonylamino group) or a salt thereof, and a compound represented by the general formula (I ''):

[0014]

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(In the formula, R ¹ 'is an optionally substituted alkylcarbonyloxyalkyl group, R ² is a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted alkyl group, or an optionally substituted alkyl group. Optionally alkoxy group, optionally substituted alkylthio group, optionally substituted cycloalkyl group, optionally substituted alkoxycarbonyl group, optionally substituted alkylcarbonylamino group, optionally substituted phenyl group, A compound represented by an optionally substituted phenylcarbonylamino group or an optionally substituted pyridinyl group or a salt thereof is a novel compound.

The compound represented by the general formula (I ') includes an alkyl group in which R ¹ may be substituted, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, A compound which is an optionally substituted alkylcarbonyloxyalkyl group or an optionally substituted pyrimidinyl group is desirable, and 4,4-dibromo-3
-Benzoylamino-1-phenyl-2-pyrazolin-
5-one is particularly preferred.

Examples of the compound of the general formula (I ″) are those in which R ² is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, or a substituted A phenyl group which may be substituted, a phenylcarbonylamino group which may be substituted or a pyridinyl group which may be substituted is preferred, and 4,4-dibromo-1- (2-acetoxyethyl) -3-methyl-
2-Pyrazolin-5-one is particularly desirable.

The pyrazolone compound represented by the general formula (I) or a salt thereof can be produced, for example, by the following method.

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(Wherein R ¹ and R ² are as described above) The above reaction is usually carried out in the presence of a solvent, and any solvent may be used so long as it does not inhibit the above reaction. Examples thereof include carboxylic acids such as acetic acid and propionic acid, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, and water. Brominating agents such as bromine, pyridinium bromide perbromide, 4
-Dimethylaminopyridinium bromide perbromide, N-bromosuccinimide, dioxane dibromide, phenyltrimethylammonium tribromide, pyrrolidone hydrotribromide and the like.

The compound represented by the general formula (II), which is a starting material for the above reaction, can be produced by a known method such as the following method. (1) Method of reacting R ² COCH ₂ CO ₂ C ₂ H ₅ with R ¹ NHNH ₂ (Chemical Abstract, 1978, 89, 43765h: ibid., 1
983, Volume 99, 122368r etc.). (2) Method of reacting R ² C≡CCO ₂ C ₂ H ₅ and R ¹ NHNH ₂ [Journal of American Chemical Society (J. Am. Chem. Soc.), 1941, 63, 1151. -1 Page, etc.]. Incidentally, typical production examples of the compound of the general formula (II) are described in Table 2 of JP-A-2-225469.

The pyrazolone compound represented by the general formula (I) or a salt thereof has an α-glucosidase inhibitory activity. The α-glucosidase inhibitor can be used as a cancer metastasis inhibitor, a viral disease, diabetes, hyperlipidemia, inflammatory disease, autoimmune disease, rejection and allergic disease therapeutic agent. The general formula (I)
In the case of using a pyrazolone compound represented by the formula or a salt thereof as an active ingredient of a medicament, the patient's age, body weight, the nature and degree of the disease, the administration route and the like, cannot be specified unconditionally, but the dosage is Usually, the dose is about 50 mg to 5000 mg per day for an adult, and is administered orally or parenterally. The drug can be administered orally, intravenously, intramuscularly, intraarticularly, in tissue, by the skin route, the mucosal route, and the like. Dosage forms include powders, powders, fine granules, granules, tablets, dragees, capsules, injections, nasal drops, suspensions, drops, ointments, syrups, sublingual tablets, suppositories. Agents, sustained-release preparations and the like. These can be produced by a conventional method using a usual pharmaceutically acceptable carrier for the preparation, as in the case of the usual medicine.

[0022]

DETAILED DESCRIPTION OF THE INVENTION

(1) An α-glucosidase inhibitor, which comprises a pyrazolone compound of the general formula (I) or a salt thereof. (2) R ^{1 in} the compound of the general formula (I) is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, An alkylcarbonyloxyalkyl group or a pyrimidinyl group which may be substituted,
R ² is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted phenylcarbonylamino group, Or the α-glucosidase inhibitor of (1), which is an optionally substituted pyridinyl group.

(3) A pyrazolone compound of the general formula (I ') or a salt thereof. (4) R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted alkylcarbonyloxyalkyl group or The pyrazolone-based compound of (3), which is a pyrimidinyl group which may be substituted, or a salt thereof. (5) The pyrazolone-based compound of (3) or a salt thereof, wherein R ¹ is a phenyl group and R ² ′ is a phenylcarbonylamino group. (6) The α-glucosidase inhibitor of (1), which comprises the compound of general formula (I ′) or a salt thereof.

(7) A pyrazolone compound of the formula (I ″) or a salt thereof. (8) R ² is a hydrogen atom, an alkyl group which may be substituted,
Pyrazolone of (7) which is an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted phenylcarbonylamino group or an optionally substituted pyridinyl group Compounds or salts thereof. (9) The pyrazolone compound of (7), wherein R ¹ 'is an acetoxyethyl group, and R ² is a methyl group, or a salt thereof. (10) The α-glucosidase inhibitor according to (1), comprising the compound of the general formula (I ″) or a salt thereof.

(11) A cancer metastasis inhibitor comprising a pyrazolone compound of the general formula (I) or a salt thereof. (12) A therapeutic agent for a viral disease, which comprises a pyrazolone compound of the general formula (I) or a salt thereof. (13) A therapeutic agent for diabetes, comprising a pyrazolone compound of the general formula (I) or a salt thereof. (14) A therapeutic agent for hyperlipidemia, comprising a pyrazolone compound of the general formula (I) or a salt thereof. (15) A therapeutic agent for an inflammatory disease, comprising a pyrazolone compound of the general formula (I) or a salt thereof. (16) A therapeutic agent for an autoimmune disease, which comprises a pyrazolone compound of the general formula (I) or a salt thereof. (17) A therapeutic agent for rejection and allergic disease, comprising a pyrazolone compound of the general formula (I) or a salt thereof

[0026]

The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention.

Synthesis Example 1 4,4-dibromo-3-benzo
Ilamino-1-phenyl-2-pyrazolin-5-one
Synthesis of (Compound No. 53) (1) 3-Amino-1-phenyl-2-pyrazoline-5
To 3.5 g of -one, 100 ml of tetrahydrofuran was added, and the mixture was ice-cooled, 3.1 g of benzoyl chloride was added, and the mixture was reacted at room temperature for 23 hours with stirring. After completion of the reaction, the reaction product was put into water and extracted with methylene chloride. The extract layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride / ethyl acetate = 9).
/ 3-), 3-benzoylamino-1-phenyl-2-pyrazoline-5-having a melting point of 225 to 227 ° C.
1.6 g of on was obtained.

(2) After 0.9 g of 3-benzoylamino-1-phenyl-2-pyrazolin-5-one obtained in the above step (1) was added to 30 ml of acetic acid as a solvent, 1.08 of bromine was added.
g was added, and the mixture was reacted for 1 and a half hours at room temperature with stirring. After completion of the reaction, the reaction product was put into water and extracted with methylene chloride. The extract layer was washed with water and dried over sodium sulfate.
Methylene chloride was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: methylene chloride) to obtain 1.1 g of the desired product having a melting point of 190 ° C. (decomposition).

Synthesis Example 2 4,4-dibromo-1- (2-
(Acetoxyethyl) -3-methyl-2-pyrazoline-5
Synthesis of 1-one (Compound No. 56) (1) To 3.8 g of 2-hydrazinoethanol, 10 ml of methanol was added and ice-cooled, 6.5 g of ethyl acetoacetate was added, and the mixture was reacted at room temperature for 17 hours while stirring. . After completion of the reaction, the solvent was distilled off and the residue was dried, and the melting point of 68-72 ° C was 1-.
6.36 g of (2-hydroxyethyl) -3-methyl-2-pyrazolin-5-one was obtained. (2) 1-obtained in the step (1) in 50 ml of acetic acid
After dissolving 1.0 g of (2-hydroxyethyl) -3-methyl-2-pyrazolin-5-one, 5.1 g of 4-dimethylaminopyridinium bromide perbromide was added, and the mixture was reacted at room temperature for 22 hours with stirring. It was After completion of the reaction, the reaction product was put into water and extracted with ethyl acetate. The extracted layer was washed with an aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/1).
Purified by 4) to give 1.49 g of the desired product as an oil.
Got

Table 1 shows typical examples of the pyrazolone compound represented by the general formula (I) according to the present invention, which is synthesized according to the above-mentioned production method and synthesis example.

[0031]

[Table 1]

[0032]

[Table 2]

[0033]

[Table 3]

Test Example 1 [α-Glucosidase Inhibitory Activity] Using 4-nitrophenyl-α-D-glucopyranoside as a substrate, α-glucosidase is allowed to act, and 4-nitrophenol liberated by hydrolysis is quantified by a colorimetric method. Was measured. That is, 0.01 ml of a 40 mU / ml α-glucosidase solution (dissolved in 10 mM phosphate buffer, pH 7.2) and 0.01 ml of a sample-containing solution (dissolved in 10 mM phosphate buffer, pH 7.2) were mixed. rear,
1.5 mg / ml substrate solution (10 mM phosphate buffer,
(dissolved in pH 7.2) 0.08 ml was added to start the reaction. After reaction at 37 ° C. for 60 minutes, 1M sodium carbonate was added.
The reaction was stopped by adding 1 ml, and the absorbance at 405 nm was measured. The absorbance (A) of the reaction solution containing the sample and the absorbance (B) of the reaction solution not containing the sample were measured, and the inhibition rate was calculated as (B-
The concentration (IC ₅₀ ) at which α-glucosidase activity was inhibited by 50% was calculated by calculating A) / B × 100. The test results are shown in Table 3. The α-glucosidase used was derived from Saccharomyces sp. The results in Table 2 show that the active ingredient compounds of the present invention have α-glucosidase inhibitory activity.

[0035]

[Table 4]

According to the present invention, a pyrazolone compound or a salt thereof can be provided as an α-glucosidase inhibitor.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/415 ADN A61K 31/415 ADN 31/44 ADY 31/44 ADY 31/505 ADP 31/505 ADP // C07D 231/20 C07D 231/20 Z 401/04 231 401/04 231 403/04 231 403/04 231

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is an optionally substituted alkyl group, an optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, or an optionally substituted An alkylcarbonyloxyalkyl group or an optionally substituted pyrimidinyl group, and R ² is a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted alkyl group, or an optionally substituted An alkoxy group, an optionally substituted alkylthio group, an optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonylamino group, an optionally substituted phenyl group, Is a phenylcarbonylamino group which may be substituted or a pyridinyl group which may be substituted) An α-glucosidase inhibitor comprising a lon-based compound or a salt thereof. 2. The compound of the formula (I) wherein R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridinyl group, An optionally substituted alkylcarbonyloxyalkyl group or an optionally substituted pyrimidinyl group, wherein R ² is a hydrogen atom, an optionally substituted alkyl group,
An optionally substituted cycloalkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted phenyl group, an optionally substituted phenylcarbonylamino group, or an optionally substituted pyridinyl group. α
-Glucosidase inhibitors.