JPH06298737A - Pyrrazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new pyrazole derivative, having inhibiting activity against the Maillard reaction and useful for preventing and/or treating various diabetic complications and diseases due to aging. CONSTITUTION:The compound is expressed by formula I [R<1> and R<2> are lower alkyl; R<3> is (i) amino which may be substituted with F, NO2, >=3C alkyl, lower alkanoyl or lower alkoxycarbonyl, (ii) lower alkyl substituted with halogen, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl or formula II (R<4> to R<6> are H, NH2, NO2, lower alkyl, lower alkoxy, lower alkoxycarbonyl or aralkyloxy or further R<5> and R<6> together form lower alkylendioxy) or (iii) carbonyl substituted with any of OH, lower alkyl, aralkyloxy, amine which may be substituted with alkyl or alkoxy which may be substituted with alkoxy or further R<2> and R<3> together form >=3C alkylene], e.g. 3,5-dimethyl-4-propyl-1H- pyrazole-1-carboxamidine hydrochloride.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has a Maillard inhibitory activity and prevents various complications of diabetes and diseases due to aging and / or
Or, it relates to a therapeutically useful pyrazole derivative or a salt thereof.

In recent years, protein denaturation by glucose has been widely highlighted as one of the onset factors of diabetic complications, and it is considered to be due to the Maillard reaction occurring in the living body. In the Maillard reaction, the amino group of a protein is non-enzymatically saccharified with glucose (glycosylation), an Amadori transfer product is formed as an initial glycosylation product, and further glycosylation proceeds to crosslink and denature the protein, An advanced glycosylated end product (AGE: brown, sparingly soluble and difficult to decompose by protease)
Advanced Glycation End Pr
It is a series of reactions that are believed to lead to The progress of non-enzymatic glycosylation or the production of AGE protein due to this reaction is remarkable particularly in hyperglycemic conditions, protein sites with slow or unmetabolized metabolism, and various protein sites in diabetic patients such as hemoglobin, serum albumin, and binding. Tissue collagen, elastin, myelin,
It is considered to be one of the causes that cause the degeneration of proteins such as ocular lens crystallin, functional deterioration and abnormalities, and cause diabetic complications such as retinopathy, nephropathy, cardiovascular system disorders, neuropathy and cataracts. ing. The in vivo Maillard reaction is considered to be one of the mechanisms of aging, and it is presumed that it is closely related to aging-related diseases. Therefore, inhibition of the non-enzymatic glycosylation and inhibition of AGE production by inhibiting the Maillard reaction is considered to be extremely effective for diseases such as various complications of diabetes and senile diseases. Research and development of compounds having reaction inhibitory activity have been attempted.

Conventionally, various compounds have been reported as compounds having Maillard inhibitory activity. For example, Japanese Patent Laid-Open No. 62-62, which was first reported as a Maillard reaction inhibitor.
Examples thereof include aminoguanidine, α-hydrazinohistidine, lysine and a mixture thereof described in Japanese Patent No. 142114. These agents are capable of inhibiting secondary glycosylation by reacting with the carbonyl moiety of the Amadori transfer product, which is an initial glycosylation product, and thus inhibiting protein cross-linking and AGE production. I am trying.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have created a pyrazole derivative having a chemical structure completely different from that of a conventional Maillard reaction inhibitory compound and having an excellent effect as a Maillard reaction inhibitor. Has been completed.

[0005]

That is, the present invention provides a compound represented by the general formula (I)

[0006]

[Chemical 3]

(The symbols in the formulas have the following meanings: R ¹ : lower alkyl group R ² : lower alkyl group R ³ : (i) fluorine atom, nitro group, unsubstituted lower alkyl having 3 or more carbon atoms Group, or an amino group which may be substituted with a lower alkanoyl group or a lower alkoxycarbonyl group, or (ii) a halogen atom, a lower alkanoyl group,
Lower alkoxy group, lower alkoxycarbonyl group and formula

[0008]

[Chemical 4]

[0009] (R ^4, R ⁵ or R ^6:. Same or different and each represents a hydrogen atom, an amino group, a nitro group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, lower alkoxycarbonyl group or aralkyl group further, R ^5, R ⁶ together may form a lower alkylenedioxy group.) Or a lower alkyl group substituted by any of the phenyl groups represented by: or (iii) a hydroxyl group, a lower alkyl group, an aralkyloxy group, A carbonyl group substituted with any of an amino group optionally substituted with a lower alkyl group and a lower alkoxy group optionally substituted with a lower alkoxy group. Furthermore, R ²
And R ³ may together form a lower alkylene group having 3 or more carbon atoms. ) Is a pyrazole derivative or a salt thereof.

The present invention will be described in detail below. In the definitions of the general formulas in the present specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. As the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, Examples thereof include a tert-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group and an isohexyl group.

Examples of the "lower alkanoyl group" include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like. The "lower alkoxycarbonyl group" includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t.
An ert-butoxycarbonyl group, a pentyl (amyl) oxycarbonyl group, an isopentyl (amyl) oxycarbonyl group, a hexyloxycarbonyl group, an isohexyloxycarbonyl group and the like can be mentioned. As the "lower alkoxy group", a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group,
sec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, t
ert-pentyloxy group, neopentyloxy group, 2
-Methylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group and the like.

The "aralkyloxy group" is preferably a phenyl lower alkoxy group, specifically, a benzyloxy group, a phenethyloxy group, a phenylpropoxy group, a phenylbutoxy group, a phenylpentyloxy group, a phenylhexyloxy group and the like. And is preferably a benzyloxy group. The "lower alkylenedioxy group" is a group oxo group is bonded to both ends of the lower alkylene, methylenedioxy group (-OCH ₂ O-), ethylenedioxy group (-O (CH _{2) 2} O -), Propylenedioxy group and the like. As the "lower alkylene group having 3 or more carbon atoms", an alkylene group having 3 to 6 carbon atoms is preferable, and specifically, propylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group. Group, 3-methyltrimethylene group, ethylethylene group, dimethylethylene group, pentamethylene group, methyltetramethylene group, dimethyltrimethylene group, pentamethylene group, hexamethylene group and the like, preferably propylene group and tetramethylene group. A methylene group and a pentamethylene group.

The "halogen atom" is preferably a fluorine atom, a chlorine atom, a bromine atom or the like. In R ³ (i)
As the "unsubstituted lower alkyl group having 3 or more carbon atoms",
The lower alkyl group is an alkyl group having 3 to 6 carbon atoms, specifically, a propyl group, a butyl group, an isobutyl group, a pentyl group or a hexyl group. As the "amino group which may be substituted with a lower alkanoyl group or a lower alkoxycarbonyl group", a lower alkanoyl group or a lower alkoxycarbonyl group may be 1 in addition to an amino group.
It means an individually substituted amino group, and specifically it is an acetylamino group, a propionylamino group, a butyrylamino group, a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group or the like. (Ii) "Lower alkyl group" of substituted lower alkyl group
Of these, a methyl group, an ethyl group and a propyl group are preferable. Further, the substituents are as described above, specifically, acetyl group and propionyl group as "lower alkanoyl group", methoxy group as "lower alkoxy group",
As the ethoxy group, the "lower alkoxycarbonyl group" is preferably a methoxycarbonyl group or an ethoxycarbonyl group. The following formula

[0014]

[Chemical 5]

R ⁴ , R ⁵ or R in the phenyl group represented by
"Lower alkyl group" of ^6, the "lower alkoxy group", "lower alkoxycarbonyl group" or "aralkyloxy group" are as described above. (Iii) The "amino group which may be substituted with a lower alkyl group" among the substituents of the substituted carbonyl group means an amino group in which one lower alkyl group is substituted in addition to the amino group, Specifically, it is a methylamino group, an ethylamino group, a propylamino group, a butylamino group, or a pentylamino group. The “lower alkoxy group which may be substituted with a lower alkoxy group” means, in addition to the above lower alkoxy group, a group in which a lower alkoxy group is substituted at any position of the lower alkoxy group, such as methoxyethoxy group and ethoxy group. Ethoxy groups are preferred. Inventive Compound (I)
Forms a salt with an acid. As a salt with such an acid, hydrochloric acid
Mineral acids with hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid Examples thereof include acid addition salts with organic acids such as tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. Furthermore, the compound (I) of the present invention may be isolated as a hydrate, a solvate of ethanol or the like, or a crystalline polymorphic substance, and the present invention also includes these inventions. (Production Method) The compound of the present invention can be produced by applying various synthetic methods. The typical manufacturing method is illustrated below. First manufacturing method

[0016]

[Chemical 6]

(The symbols R ¹ , R ² or R ³ in the formula are as described above. X means halogen.) Examples of the halogen atom in X include a chlorine atom and a bromine atom. The compound (I) of the present invention is produced by subjecting a pyrazole compound represented by the general formula (II) and a halogenoformamidine salt represented by the general formula (III) or cyanamide (IV) to an N-amidination reaction. This reaction is carried out by heating the pyrazole compound (II) and a corresponding amount of the halogenoformamidine salt (III) or cyanamide (IV) in a solvent while heating or heating under reflux. Examples of the solvent include benzene, tetrahydrofuran (THF), chloroform, ethyl acetate, toluene, 1,4-dioxane and the like. When using cyanamide, the pyrazole compound (I
I) is preferably an acid addition salt such as hydrochloric acid, hydrobromic acid or nitric acid. Second manufacturing method

[0018]

[Chemical 7] (The symbols R ¹ , R ² and R ³ in the formula have the above meanings.)
The compound (I) of the present invention is produced by subjecting a diketone compound represented by the general formula (V) and an aminoguanidine salt (VI) to a ring closure reaction. This reaction is carried out in a solvent at room temperature or under heating with a diketone compound (V) and a corresponding amount of an aminoguanidine salt (VI). Examples of the solvent include water, methanol, ethanol, tetrahydrofuran (TH
F), 1,4-dioxane and the like. Examples of the acid addition salt of aminoguanidine include hydrochloride, hydrobromide, nitrate and the like. Third Production Method (Nitration Reaction) Among the compounds of the present invention represented by the general formula (I), those in which R ³ is a nitro group can be produced by a conventional nitration reaction. For example, the compound of the present invention in which R ³ is a hydrogen atom and the corresponding amount of reaction or an excess amount of the nitrating reagent are stirred in an inert solvent under ice cooling or at room temperature to obtain a compound in which R ³ is a nitro group. You can As the inert solvent, acetonitrile, acetic acid and the like are preferable. Fourth Production Method (Reduction Reaction) Among the compounds of the present invention represented by the general formula (I), those in which R ³ is an amino group are produced by reducing a compound in which R ³ is a nitro group. This reduction reaction may be carried out according to a conventional method. For example, in catalytic reduction, palladium carbon, in the presence of a noble metal catalyst such as platinum oxide, methanol, ethanol,
It is carried out under normal pressure or increased pressure in a solvent usually used for catalytic reduction such as ethyl acetate. Fifth Production Method Among the compounds of the present invention represented by the general formula (I), those in which R ³ is a carboxylic acid are produced by removing the benzyl group of the benzyl ester compound. The method for removing the benzyl group may be carried out according to the above-mentioned fourth production method, by hydrogenation, in the presence of a noble metal catalyst such as palladium carbon, platinum oxide or the like, by a conventional hydrogenation method such as methanol, ethanol or ethyl acetate. Easily removed by.

[0019]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention or a salt thereof has a Maillard reaction inhibitory activity and has various diabetic complications such as retinopathy, nephropathy, coronary heart disease, peripheral circulatory disorder and cerebrovascular disorder. It is useful for the prevention and / or treatment of cardiovascular disorders, diabetic neuropathy, arteriosclerosis, arteriosclerosis, etc. which are considered to be involved in cataracts and Maillard reaction. Further, it is expected to be useful as a preventive and / or therapeutic drug for atherosclerosis, senile cataract and cancer, which are considered to be caused by protein aging. further,
Since it is possible to prevent cross-linking of proteins such as collagen and elastin, it can be used as a cosmetic or a skin external preparation. Furthermore, the Maillard reaction is not only in vivo,
It is well known that the compounds of the present invention are related to the deterioration of proteins and amino acids of foods and drinks, and the compounds of the present invention are not only functional foods for the above-mentioned pharmaceutical and cosmetic purposes, but also foods and drinks containing proteins and amino acids. It can also be used as a Maillard reaction inhibitor for food and drink.

(Pharmacological effect) The Maillard reaction inhibitory activity of the compound of the present invention was confirmed by the following experimental method and has an excellent effect. Experimental method for Maillard reaction inhibitory activity Lysozyme and ribose were dissolved in 0.1 M sodium phosphate buffer (pH 7.4) containing 3 mM sodium azide to a concentration of 6 mg / ml and 100 mM, respectively, and the mixture was incubated at 37 ° C for 7 hours. After incubation for a day, a fixed amount was taken out and subjected to electrophoresis using SDS-PAGE. After electrophoresis, 0.04% Coomassie
After staining with Briiiiant Blue R-250,
The amount of dimers and trimers produced was quantified by a densitometer. Compounds of the invention are
M was added so as to be 3 mM, 10 mM or 30 mM, and the inhibitory effect on the formation of dimer and trimer at each concentration was examined to determine the IC ₅₀ value.

(Formulation Items) One or more of the compounds of the present invention represented by the general formula (I), pharmaceutically acceptable salts thereof, pharmaceutically acceptable hydrates, etc. are effective. The pharmaceutical composition contained as an ingredient is a carrier, an excipient, or other additive for a formulation that is usually used, and tablets, powders, fine granules, granules, capsules, pills, liquids, It is prepared into an injection, a suppository, an ointment, a patch, etc. and administered orally or parenterally. The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which it is applied, but it is usually 0.
1 to 500 mg, preferably 10 to 200 mg,
This is administered once or in several divided doses. Since the dose varies depending on various conditions, a dose smaller than the above dose range may be sufficient. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. In addition to the inert diluent, this composition may contain solubilizing or solubilizing agents, humectants, auxiliary agents such as suspending agents, sweeteners, flavors, fragrances and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-water soluble solution and suspension include propylene glycol,
Polyethylene glycol, vegetable oils such as olive oil,
Alcohols such as ethanol, polysorbate 80
(Product name) etc. Such a composition may further contain additives such as an isotonicity agent, a preservative, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer (eg lactose), and a solubilizing or solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use. When the Maillard reaction inhibitor of the present invention is prepared as a cosmetic or an external preparation for skin, the compound (I) of the present invention or a salt thereof is added so as to be contained in an amount of 0.05 to 10 parts by weight based on the whole preparation. Cosmetics and external preparations for skin can be prepared by a conventional method using general cosmetic bases and external bases. Further, the Maillard reaction inhibitor of the present invention can be prepared as a food / drink, a favorite food, a functional food, etc. by a conventional method.

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The chemical structural formulas of the compounds of the present invention obtained in Examples are shown in the table below.

Example 1 A solution of 1.56 g of aminoguanidine hydrochloride in 5 ml of water, 30 ml of methanol and 1 ml of concentrated hydrochloric acid was added to 3-propyl-
2,4-Pentanedione 2.06 g of methanol 10 m
1 solution was added little by little, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent: chloroform: methanol = 5:
After purification in 1), it was recrystallized from ethanol-ether to obtain 1.70 g of 3,5-dimethyl-4-propyl-1H-pyrazole-1-carboxamidine hydrochloride.

Physicochemical properties Elemental analysis value (as C ₉ H ₁₇ N ₄ Cl) C (%) H (%) N (%) Cl (%) theoretical value 49.88 7.91 25.85 16.36 experiment Value 49.88 7.92 25.97 16.26 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.88 (3H, t, J = 7 Hz), 1.25-
1.65 (2H, m), 2.20 (3H, s), 2.2
6-2.49 (2H, m), 2.45 (3H, s),
9.30 (4H, brs) In the same manner as in Example 1, the following compounds of Examples 2 to 24 were obtained.

Example 2 4-Butyl-3,5-dimethyl-1H-pyrazole-1
- carboxamidine hydrochloride starting compound 3-butyl-2,4-pentanedione physicochemical properties Elemental analysis (C ₁₀ H ₁₉ N ₄ as Cl) C (%) H ( %) N (%) Cl (%) Theoretical value 52.05 8.30 24.28 15.36 Experimental value 51.88 8.31 24.29 15.55 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.80-1.00 ( 3H, m), 1.17-1.
60 (4H, m), 2.20 (3H, s), 2.28-
2.49 (2H, m), 2.45 (3H, s), 9.3
1 (4H, brs)

Example 3 3,5-Dimethyl-4- (2-methylpropyl) -1H
- pyrazol-1-carboxamidine hydrochloride starting compound 3-isobutyl-2,4-pentanedione physicochemical properties Elemental analysis (C ₁₀ H ₁₉ N ₄ as Cl) C (%) H ( %) N (%) Cl ( %) Theoretical value 52.05 8.30 24.28 15.36 Experimental value 51.91 8.24 24.30 15.21 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.87 ( 6H, d, J = 6.6 Hz), 1.50
-1.85 (1H, m), 2.19 (3H, s), 2.
24 (2H, d, J = 8.6Hz), 2.43 (3H,
s), 9.26 (4H, brs)

Example 4 3,5-Dimethyl-4-pentyl-1H-pyrazole-
1-Carboxamidine hydrochloride Raw material compound 3-Pentyl-2,4-pentanedione Physicochemical property Elemental analysis value (as C ₁₁ H ₂₁ N ₄ Cl) C (%) H (%) N (%) Cl (%) theory Value 53.98 8.65 22.89 14.48 Experimental value 53.82 8.45 22.91 14.37 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.79-0.93 (3H, m), 1.15-1.
60 (6H, m), 2.20 (3H, s), 2.28-
2.48 (2H, m), 2.43 (3H, s), 9.2
6 (4H, brs)

Example 5 4-Benzyl-3,5-dimethyl-1H-pyrazole-
1-carboxamidine hydrochloride starting compound 3-benzyl-2,4-pentanedione physicochemical properties Elemental analysis (C ₁₃ H ₁₇ N ₄ as Cl) C (%) H ( %) N (%) Cl (%) Theoretical Value 58.98 6.47 21.16 13.39 Experimental value 58.84 6.44 21.21 13.48 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.11 (3H, s ), 2.50 (3H, s),
3.79 (2H, s), 7.14-7.31 (5H,
m), 9.31 (4H, brs)

Example 6 3,5-Dimethyl-4- (3-oxobutyl) -1H-
Pyrazole-1-carboxamidine hydrochloride starting compound 3-acetyl-2,6-heptane dione physicochemical properties Elemental analysis (C ₁₀ H ₁₇ N ₄ as _{OCl · 0.3H 2 O) C (} %) H (%) N (%) Cl (%) Theoretical value 48.02 7.09 22.40 14.17 Experimental value 47.87 7.16 22.58 14.33 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ : 2.08 (3H, s), 2.21 (3H, s),
2.43 (3H, s), 2.48-2.69 (4H,
m), 9.23 (4H, brs)

Example 7 1-amidino-3,5-dimethyl-1H-pyrazole-
Methyl 4-propionate hydrochloride Raw material compound 4-Acetyl-5-oxohexanoate methyl Physicochemical property Elemental analysis value (as C ₁₀ H ₁₇ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 46.07 6.57 21.49 13.60 Experimental value 45.88 6.53 21.51 13.72 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.22 (3H, s), 2.43 (3H, s),
2.44-2.77 (4H, m), 3.59 (3H,
s), 9.25 (4H, brs)

Example 8 3-Methyl-4,5,6,7-tetrahydro-1H-indazole-1-carboxamidine hydrochloride Raw material compound 2-Acetylcyclohexanone Physicochemical properties Elemental analysis value (as C ₉ H ₁₅ N ₄ Cl ) C (%) H (%) N (%) Cl (%) Theoretical value 50.35 7.04 26.10 16.51 Experimental value 50.27 7.14 26.06 16.29 Nuclear magnetic resonance spectrum ( DMSO-d ₆ , TMS internal standard) δ: 1.67-1.74 (4H, m), 2.18 (3
H, s), 2.37-2.42 (2H, m), 2.88.
-2.91 (2H, m), 9.16 (4H, brs)

Example 9 1-amidino-3,5-dimethyl-1H-pyrazole-
4-Carboxylic Acid Methyl Hydrochloride Raw Material Compound 2-Acetylacetoacetate Methyl Physicochemical Property Elemental Analysis Value (as C ₈ H ₁₃ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theory Value 41.30 5.63 24.08 15.24 Experimental value 40.90 5.57 24.07 15.16 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.40 (3H, s) ), 2.72 (3H, s),
3.82 (3H, s), 9.77 (4H, brs)

Example 10 1-amidino-3,5-dimethyl-1H-pyrazole-
4-Methyl 4-acetate hydrochloride raw material compound 3-Acetyl-4-oxopentanoate methyl Physicochemical property Elemental analysis value (as C ₉ H ₁₅ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl ( %) Theoretical value 43.82 6.13 22.71 14.37 Experimental value 43.75 6.05 22.80 14.11 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.18 ( 3H, s), 2.44 (3H, s),
3.57 (2H, s), 3.63 (3H, s), 9.3
5 (4H, brs)

Example 11 3,5-Dimethyl-4- (4-nitrobenzyl) -1H
- pyrazol-1-carboxamidine hydrochloride starting compound 3- (4-nitrobenzyl) -2,4-pentanedione physicochemical properties Elemental analysis (as _{C 13 H 16 N 5 O 2} Cl) C (%) H (% ) N (%) Cl (% ) theoretical values 50.41 5.21 22.61 11.45 Found 50.07 4.86 22.70 11.45 nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard ) Δ: 2.12 (3H, s), 2.51 (3H, s),
3.98 (2H, s), 7.44 (2H, d, J = 8.
5 Hz), 8.18 (2H, d, J = 8.5 Hz),
9.32 (4H, brs)

Example 12 3,5-Dimethyl-4- (4-methoxybenzyl) -1
H- pyrazole-1-carboxamidine hydrochloride starting compound 3- (4-methoxybenzyl) -2,4-pentanedione physicochemical properties Elemental analysis (as _{C 14 H 19 N 4 OCl)} C (%) H (%) N (%) Cl (%) Theoretical value 57.04 6.50 19.01 12.03 Experimental value 56.80 6.48 19.02 12.02 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.10 (3H, s), 2.48 (3H, s),
3.71 (5H, s), 6.78-7.12 (4H,
m), 9.24 (4H, brs)

Example 13 1-amidino-3,5-dimethyl-1H-pyrazole-
Ethyl 4-carboxylate hydrochloride Raw material compound 2-Acetylacetoacetate ethyl Physicochemical property Elemental analysis value (as C ₉ H ₁₅ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theory Value 43.82 6.13 22.71 14.37 Experimental value 43.79 6.06 22.87 14.50 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.31 (3H, t , J = 7 Hz), 2.40 (3
H, s), 2.72 (3H, s), 4.28 (2H,
q, J = 7 Hz), 9.74 (4H, brs)

Example 14 1-amidino-3,5-dimethyl-1H-pyrazole-
4-carboxylic acid propyl hydrochloride starting compound 2-acetyl acetoacetate propyl physicochemical properties Elemental analysis (C ₁₀ H ₁₇ N ₄ as _{O 2 Cl) C (%)} H (%) N (%) Cl (%) Theoretical Value 46.07 6.57 21.49 13.60 Experimental value 45.83 6.85 21.59 13.55 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.97 (3H, t , J = 7 Hz), 1.69-
1.73 (2H, m), 2.40 (3H, s), 2.7
2 (3H, s), 4.20 (2H, t, J = 6.5H
z), 9.78 (4H, brs)

Example 15 1-amidino-3,5-dimethyl-1H-pyrazole-
4-Carboxylic acid butyl hydrochloride Raw material compound 2-Acetylacetoacetate butyl Physicochemical property Elemental analysis value (as C ₁₁ H ₁₉ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theory Value 48.09 6.97 20.39 12.90 Experimental value 47.91 6.95 20.41 12.92 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.93 (3H, t , J = 7 Hz), 1.37-
1.45 (2H, m), 1.65-1.70 (2H,
m), 2.40 (3H, s), 2.70 (3H, s),
4.24 (2H, t, J = 6.5Hz), 9.69 (4
H, brs)

Example 16 1-amidino-3,5-dimethyl-1H-pyrazole-
4-carboxylic acid benzyl hydrochloride starting compound 2-acetyl acetoacetate benzyl physicochemical properties Elemental analysis _{(C 14 H 17 N 4 O} 2 as Cl) C (%) H ( %) N (%) Cl (%) Theoretical Value 54.46 5.55 18.15 11.48 Experimental value 54.30 5.45 18.28 11.43 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.39 (3H, s ), 2.71 (3H, s),
5.32 (2H, s), 7.35-7.47 (5H,
m), 9.76 (4H, brs)

Example 17 3,5-Dimethyl-4- (3,4-methylenedioxybenzyl) -1H-pyrazole-1-carboxamidine hydrochloride Raw material compound 3- (3,4-methylenedioxybenzyl) -2 , 4-
Pentanedione physicochemical properties Elemental analysis _{(C 14 H 17 N 4 O} 2 Cl · 0.1H as _{2 O) C (%) H} (%) N (%) Theoretical values 54.14 5.58 18.04 Experimental Value 53.99 5.57 17.76 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.11 (3H, s), 2.46 (3H, s),
3.69 (2H, s), 5.96 (2H, s), 6.6
1-6.83 (3H, m), 9.11 (4H, brs)

Example 18 4- (4-benzyloxybenzyl) -3,5-dimethyl-1H-pyrazole-1-carboxamidine hydrochloride raw material compound 3- (4-benzyloxybenzyl) -2,4-pentanedione nucleus Magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.10 (3H, s), 2.47 (3H, s),
3.71 (2H, s), 5.06 (2H, s), 6.9
3 (2H, d, J = 8.5Hz), 7.06 (2H,
d, J = 8.5 Hz), 7.30-7.43 (5H,
m), 9.17 (4H, brs)

Example 19 3,5-Dimethyl-4- (4-methoxycarbonylbenzyl) -1H-pyrazole-1-carboxamidine hydrochloride Raw material compound 3- (4-methoxycarbonylbenzyl) -2,4-pentanedione Physicochemical Properties Elemental analysis value (as C ₁₅ H ₁₉ N ₄ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 55.81 5.93 17.36 10.98 Experimental value 55 .71 5.86 17.44 11.00 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.10 (3H, s), 2.50 (3H, s),
3.83 (3H, s), 3.89 (2H, s), 7.3
1 (2H, d, J = 8Hz), 7.89 (2H, d, J
= 8 Hz), 9.32 (4H, brs)

Example 20 3,5-Dimethyl-4- (4-hydroxybenzyl)-
1H-pyrazole-1-carboxamidine hydrochloride raw material compound 3- (4-hydroxybenzyl) -2,4-pentanedione physicochemical properties elemental analysis value (as C ₁₃ H ₁₇ N ₄ OCl) C (%) H (%) N (%) Cl (%) Theoretical value 55.61 6.10 19.96 12.63 Experimental value 55.41 6.11 19.89 12.71 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.09 (3H, s), 2.47 (3H, s),
3.65 (2H, s), 6.68 (2H, d, J = 8.
3Hz), 6.93 (2H, d, J = 8.3Hz),
9.25 (4H, brs), 9.29 (1H, s)

Example 21 3,5-Dimethyl-4- (3,5-dimethyl-4-hydroxybenzyl) -1H-pyrazole-1-carboxamidine hydrochloride Raw material compound 3- (3,5-Dimethyl-4-hydroxy) Benzyl)-
2,4-Pentanedione Physicochemical properties Elemental analysis value (as C ₁₅ H ₂₁ N ₄ OCl) C (%) H (%) N (%) Cl (%) Theoretical value 58.34 6.85 18.14 11 .48 experimental value 58.12 6.82 18.29 11.47 nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.09 (3H, s), 2.10 (6H, s),
2.47 (3H, s), 3.59 (2H, s), 6.6
6 (2H, s), 8.04 (1H, s), 9.24 (4
H, brs)

Example 22 4- (3,5-di-tert-butyl-4-hydroxybenzyl) -3,5-dimethyl-1H-pyrazole-1
- carboxamidine hydrochloride starting compound 3- (3,5-di -tert- butyl-4-hydroxybenzyl) -2,4-pentanedione physicochemical properties Elemental analysis _{(C 21 H 33 N 4 OCl} · 0.2H 2 As O) C (%) H (%) N (%) Cl (%) Theoretical value 63.60 8.49 14.13 8.94 Experimental value 63.32 8.38 14.12 9.16 Nuclear magnetic resonance Spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.34 (18H, s), 2.18 (3H, s),
2.49 (3H, s), 3.65 (2H, s), 6.8
0 (1H, s), 6.90 (2H, s), 9.19 (4
H, brs)

Example 23 1-amidino-3,5-dimethyl-1H-pyrazole-
1- carboxylic acid 2-methoxyethyl hydrochloride starting compound 2-acetyl acetoacetate 2-methoxyethyl ester physicochemical properties Elemental analysis _{(C 10 H 17 N 4 O} 3 as Cl) C (%) H ( %) N ( %) Cl (%) Theoretical value 43.40 6.19 20.25 12.81 Experimental value 43.11 6.06 20.23 13.02 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.40 (3H, s), 2.71 (3H, s),
3.30 (3H, s), 3.64 (2H, t, J = 4.
6Hz), 4.36 (2H, t, J = 4.6Hz),
9.71 (4H, brs)

Example 24 1-amidino-3,5-dimethyl-1H-pyrazole-
1- carboxylic acid 2-ethoxyethyl hydrochloride starting compound 2-acetyl acetoacetate 2-ethoxyethyl ester nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.12 (3H, t , J = 7Hz) , 2.40 (3
H, s), 2.72 (3H, s), 3.49 (2H,
q, J = 7 Hz), 3.67 (2H, t, J = 4.9H)
z), 4.34 (2H, t, J = 4.9Hz), 9.7.
3 (4H, brs)

Example 25 (1) 3.0 g of triacetylmethane and 30 m of methanol
1.86 g of aminoguanidine hydrochloride was added to the solution of 1-10
The reaction mixture was stirred under ice-cooling for 1 day.
The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (eluent: chloroform: methanol =
After purification by 5: 1), it was recrystallized from ether-chloroform to obtain 4-acetyl-3,5-dimethyl-1H-pyrazole-1-carboxamidine (484 mg).

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 2.38 (3H, s), 2.42 (3H, s),
2.76 (3H, s), 6.54 (3H, brs)

(2) 4-acetyl-3,5-dimethyl-
To a solution of 484 mg of 1H-pyrazole-1-carboxamidine in 1 ml of ethanol and 5 ml of ether, 0.7 ml of 4N hydrochloric acid-1,4-dioxane solution was added dropwise. The precipitated crystals were collected by filtration and 4-acetyl-3,5-dimethyl-
1H-pyrazole-1-carboxamidine hydrochloride 488
mg was obtained.

Physicochemical properties

Example 26 3,5-Dimethyl-1H-pyrazole-1-carboxamidine nitrate 2.01 g anhydrous acetonitrile 150 m
To the suspension of 1 l, 2 g of nitronium tetrafluoroporate was added little by little under ice cooling and argon atmosphere, and the reaction mixture was stirred under ice cooling for 30 minutes. After the solvent was distilled off under reduced pressure, the residue was washed with chloroform, and 3,5-dimethyl-4-nitro-1H-pyrazole-1-carboxamidine nitrate 2.
43 g were obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 2.51 (3H, s), 2.77 (3H, s),
9.83 (4H, brs)

Example 27 3,5-Dimethyl-4-nitro-1H-pyrazole-1
-Carboxamidine nitrate 984 mg methanol 20
To the solution of ml, add 500 mg of 10% palladium carbon,
The mixture was stirred under atmospheric pressure of hydrogen atmosphere under ice cooling for 45 minutes. After the reaction solution was filtered to remove insoluble matter, the solvent was distilled off under reduced pressure.
The obtained residue is dissolved in 5 ml of water and sodium hydroxide 1
60 mg was added and extracted with chloroform.

After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 5 ml of ethanol and 2 ml of 4N hydrochloric acid-1,4-dioxane solution, and the solvent was evaporated under reduced pressure. The obtained residue is ethanol-
Recrystallized from ether-chloroform, 4-amino-
810 mg of 3,5-dimethyl-1H-pyrazole-1-carboxamidine dihydrochloride were obtained.

Physicochemical properties Elemental analysis value (as C ₆ H ₁₃ N ₅ Cl ₂ .0.5H ₂ O) C (%) H (%) N (%) Theoretical value 30.65 6.00 29.79 experiment Value 30.74 5.97 30.10 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.34 (3H, s), 2.62 (3H, s),
9.58 (7H, brs)

Example 28 The following compound was obtained in the same manner as in Example 27. 4- (4-aminobenzyl) -3,5-dimethyl-1H
-Pyrazole-1-carboxamidine dihydrochloride raw material compound 3,5-dimethyl-4- (4-nitrobenzyl) -1H
-Pyrazole-1-carboxamidine hydrochloride Physicochemical property Elemental analysis value (as C ₁₃ H ₁₉ N ₅ Cl ₂ .0.2H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 48 .82 6.11 21.90 22.17 experimental value 48.75 6.12 21.66 22.16 nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.12 (3H, s), 2.50 (3H, s),
3.54 (2H, brs), 3.81 (2H, s),
7.24-7.30 (4H, m), 9.25 (3H, b
rs), 10.31 (2H, brs)

Example 29 4- (3-chloropropyl) -3,5-dimethyl-1H
To a solution of 0.46 g of pyrazole hydrochloride in 5 ml of ethanol was added a solution of 0.17 g of cyanamide in 0.3 ml of water and the reaction mixture was stirred at 80 ° C. for 1 day. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from isopropanol-diisopropyl ether to give 4- (3-chloropropyl)-
0.13 g of 3,5-dimethyl-1H-pyrazole-1-carboxamidine hydrochloride was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 1.69-2.11 (2H, m), 2.22 (3
H, s), 2.44 (3H, s), 2.48-2.60.
(2H, m), 3.50-3.11 (2H, m), 9.
27 (4H, brs)

Example 30 The following compound was obtained in the same manner as in Example 29. 3,5-dimethyl-4- (3-methoxypropyl) -1
H-pyrazole-1-carboxamidine hydrochloride raw material compound 3,5-dimethyl-4- (3-methoxypropyl) -1
Physicochemical properties of H-pyrazole hydrochloride Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.48-1.78 (2H, m), 2.20 (3
H, s), 2.33-2.54 (2H, m), 2.42.
(3H, s), 3.24 (3H, s), 3.21-3.
35 (2H, m), 9.22 (4H, brs)

Example 31 1-amidino-3,5-dimethyl-1H-pyrazole-
A catalytic amount of 10% palladium carbon was added to a solution of 1.74 g of benzyl 4-carboxylate hydrochloride in 40 ml of methanol, and the mixture was stirred at room temperature for 15 minutes under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered to remove insoluble materials, and then the solvent was distilled off under reduced pressure.
The obtained residue was recrystallized from ethanol-ether,
1-amidino-3,5-dimethyl-1H-pyrazole-
1.11 g of 4-carboxylic acid hydrochloride was obtained.

Physicochemical properties Elemental analysis value (as C ₇ H ₁₁ N ₄ O ₂ Cl.0.1H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 38.14 5. 12 25.42 16.08 Experimental value 38.05 5.01 25.70 16.35 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.39 (3H, s), 2.72 ( 3H, s),
9.76 (4H, brs)

Example 32 N-Butyl 3,5-dimethyl-1H-pyrazole-4
To a solution of 0.82 g of carboxamide in 30 ml of dioxane, 0.49 g of chloramidine hydrochloride was added and the reaction mixture was heated at 100 ° C. for 4 hours. After cooling to room temperature, the product was collected by filtration. The obtained crude crystals were recrystallized from ethanol-diethyl ether to give N-butyl 1-amidino-
0.54 g of 3,5-dimethyl-1H-pyrazole-4-carboxamide hydrochloride was obtained.

Physicochemical properties Elemental analysis value (as C ₁₁ H ₂₀ N ₅ OCl · 0.1H ₂ O) C (%) H (%) N (%) Theoretical value 47.95 7.39 25.41 12. 87 Experimental value 47.93 7.31 25.61 12.98 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.91 (3H, t, J = 7.3 Hz), 1.30.
−1.36 (2H, m), 1.45 to 1.52 (2H,
m), 2.31 (3H, s), 2.55 (3H, s),
3.19-3.24 (2H, m), 8.10 (1H,
t, J = 5.5 Hz), 9.50 (4H, brs)

Example 33 The following compound was obtained in the same manner as in Example 32. 3,5-dimethyl-4-fluoro-1H-pyrazole-
1-carboxamidine hydrochloride raw material compound 3,5-dimethyl-4-fluoro-1H-pyrazole nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.26 (3H, s), 2.47 (3H , D, J =
2.4 Hz), 9.42 (4H, brs)

Example 34 4-amino-3,5-dimethyl-1H-pyrazole-1
To a solution of carboxamidine dihydrochloride (0.86 g) in dimethylformamide (20 ml) was added pyridine (5 ml) under ice-cooling, and then valeryl chloride (0.5 ml) was added dropwise. After stirring the reaction mixture at 4 ° C. overnight, 2 ml of methanol was added. The solution was evaporated under reduced pressure, the obtained residue was diluted with 1N sodium hydroxide solution, and extracted with chloroform.
The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The resulting residue was purified by silica gel chromatography (eluent; chloroform: methanol = 5: 1) to give the hydrochloride salt, which was recrystallized from ethanol-diethyl ether to give 3,5-dimethyl-4-. 0.53 g of pentanamide-1H-pyrazole-1-carboxamidine hydrochloride was obtained.

Physicochemical properties Elemental analysis value (as C ₁₁ H ₂₀ N ₅ OCl) C (%) H (%) N (%) Cl (%) Theoretical value 48.26 7.36 25.58 12.95 experiment Value 48.00 7.27 25.71 13.21 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.91 (3H, t, J = 7.3 Hz), 1.29.
−1.38 (2H, m), 1.54 to 1.61 (2H,
m), 2.11 (3H, s), 2.32 (2H, t, J
= 7.3 Hz), 2.34 (3H, s), 9.31 (4
H, brs), 9.52 (1H, s)

Example 35 In the same manner as in Example 34, the following compound was obtained. 3,5-dimethyl-4-ethoxycarbonylamino-1
H-pyrazole-1-carboxamidine hydrochloride Raw material compound Ethyl chloroformate Physicochemical properties Elemental analysis value (as C ₉ H ₁₆ N ₅ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 41.30 6.16 26.76 13.55 Experimental value 41.07 6.06 26.75 13.56 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20-1.26 ( 3H, m), 2.14 (3
H, s), 2.36 (3H, s), 4.08-4.13.
(2H, m), 8.96 (1H, brs), 9.34
(4H, brs)

[0070]

[Table 1]

[0071]

[Table 2]

[0072]

[Table 3]

[0073]

[Table 4]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 231/56 405/06 231 7602-4C // A61K 7/00 D 9051-4C 31/415 ADP 7431-4C (72) Inventor Hisaka Takashi 2-3-1 Kaga, Itabashi-ku, Tokyo 420 Kaga Garden Heights 420 (72) Inventor Toshiyuki Takasu 2-5-9 Ninomiya, Tsukuba, Ibaraki Prefecture Rumi Tsukuba No. 229 (72) Invention Person Masako Umeda 1-1-14-2 Ninomiya Tsukuba, Ibaraki Prefecture Bonur Tsukuba 308 (72) Inventor Yuko Hirasaki 1-14-2 Ninomiya Tsukuba, Ibaraki Prefecture 311 Bonur Tsukuba

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (The symbols in the formulas have the following meanings: R ¹ : lower alkyl group R ² : lower alkyl group R ³ : (i) fluorine atom, nitro group, unsubstituted lower alkyl group having 3 or more carbon atoms, or An amino group which may be substituted with a lower alkanoyl group or a lower alkoxycarbonyl group, or (ii) a halogen atom, a lower alkanoyl group, a lower alkoxy group, a lower alkoxycarbonyl group and a formula: (R ⁴ , R ⁵ or R ^{6 are the} same or different and are a hydrogen atom, an amino group, a nitro group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an aralkyloxy group. Further, R ⁵ and R ⁶ are And a lower alkyl group substituted with any of the phenyl groups represented by () may form a lower alkylenedioxy group together.
i) A carbonyl group substituted with any of a hydroxyl group, a lower alkyl group, an aralkyloxy group, an amino group optionally substituted with a lower alkyl group and a lower alkoxy group optionally substituted with a lower alkoxy group. Further, R ² and R ³ may be integrated to form a lower alkylene group having 3 or more carbon atoms. ] The pyrazole derivative shown by these, or its salt.