JPH06192089A - Inhibitor of mailard reaction - Google Patents

Abstract

PURPOSE:To obtain the subject medicine, comprising a specific amidino- heterocyclic derivative as an active ingredient, having low toxicity and useful for preventing and treating various diabetic complications, atherosclerosis, senile cataract, etc., and further as a functional food, etc. CONSTITUTION:The objective medicine comprises an amidino-heterocyclic derivative expressed by the formula [R<1> is H, lower alkyl or phenyl; R<2> is H, phenyl or aminosugar; X is CR<3>=(R<3> is H, lower alkyl, halogen, etc.)] or its salt as an active ingredient. 1-Amidino-3,5-dimethylpyrazole or its salt is preferred as the compound expressed by the formula. The daily dose of the compound expressed by the formula for an adult is preferably 10-200mg. Furthermore, this medicine is preferably blended in an amount of 0.05-10 pts.wt. based on the whole pharmaceutical preparation when preparing the medicine as a cosmetic or a skin external preparation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a Maillard reaction inhibitor containing an amidinoheterocycle derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

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: Adva)
nced GlycationEnd Products). 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. It causes degeneration of proteins such as collagen, elastin, myelin, and ocular lens crystallin in tissues, and causes functional decline and abnormalities, and causes diabetic complications such as retinopathy, nephropathy, cardiovascular system disorders, neuropathy and cataracts. It is considered to be one.
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. In particular, as a compound of interest in the context of the present invention, JP-A-6-1994 was first reported as the Maillard reaction inhibitor.
2-142114, aminoguanidine, α-
Examples include hydrazinohistidine, lysine and mixtures thereof. 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.

On the other hand, the amidinoheterocycle derivative, which is the active ingredient of the drug provided by the present invention, is CA, 69: 592.
51k, J. Am. Chem. Soc., 74 , 4562 (1952), CA, 78: 297
68c, CA, 87: 196219s, Helv.Chim.Acta, 58 , 761 (197
5), J. Heterocyclic. Chem., 11 , 691 (1974), JP-A-50-1
51872, Arch.Immunol.Ther.Exp., 24 , 871 (197
6), Heterocycles, 22 , 2013 (1984), Zh.Obshch.Khim.,
57, 584 (1987), and J.Indian.Chem.Soc., 13, 509 (1936 )
The basic compounds are disclosed in, and most of them are known compounds. However, these references do not describe that the amidinoheterocycle derivative has Maillard reaction inhibitory activity.

[0005]

Under these circumstances, the present inventors have shown the following general formula (I) (Chemical Formula 2), which has a structure different from that of compounds conventionally known as Maillard reaction inhibiting compounds. It was found that the amidinoheterocyclic derivative described above has an excellent effect as a Maillard reaction inhibitor, and the present invention has been completed.

[0006]

That is, the present invention comprises a Maillard reaction inhibitor containing, as an active ingredient, an amidinoheterocyclic derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, The purpose is to provide the inhibitor.

[0007]

[Chemical 2]

(The symbols in the formulas have the following meanings: R ¹ : hydrogen atom, lower alkyl group or phenyl group. R ² : hydrogen atom, lower alkyl group, phenyl group, amino group, lower alkoxy group, carboxy group. , or a lower alkoxycarbonyl group X:. a nitrogen atom or the formula -CR ³ = a group represented R ^3:. a hydrogen atom, a lower alkyl group, a phenyl group, a halogen atom or a lower alkanoyl group).

The drug of the present invention will be described in detail below. (Compound) Unless otherwise specified, in the definition of the general formula in the present specification, the term "lower" means a linear or branched carbon chain having 1 to 6 carbon atoms. Therefore, examples of the "lower alkyl group" specifically include 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, and a neopentyl group. Group, tert-
Examples thereof include a pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group and an isohexyl group. Also, "lower alkoxy group"
Are, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec.
-Butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, tert
-Pentyloxy group, neopentyloxy group, 2-methylpropoxy group, 1,2-dimethylpropoxy group, 1-
Examples thereof include an ethylpropoxy group and a hexyloxy group. As the "lower alkoxycarbonyl group", a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group,
Examples thereof include a pentyl (amyl) oxycarbonyl group, an isopentyl (amyl) oxycarbonyl group, a hexyloxycarbonyl group and an isohexyloxycarbonyl group.

Further, as the "lower alkanoyl group",
Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like can be mentioned. The "halogen atom" is preferably a fluorine atom, a chlorine atom, a bromine atom or the like.

The amidinoheterocyclic compound (I) of the present invention forms an acid addition salt. The present invention also includes agents containing a pharmaceutically acceptable salt of compound (I) as an active ingredient, and examples of such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus. Acid addition salts with mineral acids such as acids, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid,
Examples thereof include acid addition salts with organic acids such as carbonic acid, glutamic acid and aspartic acid.

Further, the compound (I) may contain an asymmetric carbon atom depending on the kind of the substituent, and in the present invention, a drug containing an isolated optical isomer or a mixture thereof as an active ingredient. Is also included. Further, compound (I) may be isolated as a hydrate, a solvate such as ethanol, or a crystalline polymorphic substance, and the present invention also includes inventions containing these as active ingredients. Among the compounds (I) of the present invention, those particularly suitable as active ingredients of Maillard reaction inhibitors are
(1) 1-amidino-1,2,4-triazole or a pharmaceutically acceptable salt thereof, (2) 1-amidinopyrazole or a pharmaceutically acceptable salt thereof, (3) 1-amidino- 3,5-dimethylpyrazole or a pharmaceutically acceptable salt thereof, (4) 1-amidino-4-chloro-3,
5-dimethylpyrazole or a pharmaceutically acceptable salt thereof, (5) 1-amidino-4-bromo-3,5-dimethylpyrazole or a pharmaceutically acceptable salt thereof, (6)
1-amidino-3,5-dimethyl-4-phenylpyrazole or a pharmaceutically acceptable salt thereof, (7) 1-amidino-5-aminopyrazole or a pharmaceutically acceptable salt thereof, (8) 1-amidino-5-amino-3-methylpyrazole or a pharmaceutically acceptable salt thereof, (9) 1
-Amidino-5-amino-3-phenylpyrazole or a pharmaceutically acceptable salt thereof, (10) 1-amidino-
5-methoxy-3-methylpyrazole or a pharmaceutically acceptable salt thereof, (11) 1-amidino-5-ethoxy-3-methylpyrazole or a pharmaceutically acceptable salt thereof, (12) (1 -Amidino-3-methylpyrazole-
5-yl) carboxylic acid or a pharmaceutically acceptable salt thereof, (13) ethyl (1-amidino-3-methylpyrazol-5-yl) carboxylate or a pharmaceutically acceptable salt thereof, (14) ) 4-Acetyl-1-amidino-5-methylpyrazole or a pharmaceutically acceptable salt thereof, (15) 1-amidino-3,5-diphenylpyrazole or a pharmaceutically acceptable salt thereof, (16) ) 1-amidino-3,4,5-trimethylpyrazole or a pharmaceutically acceptable salt thereof, and (17) 1-amidino-
3,5-dimethyl-4-ethylpyrazole or a pharmaceutically acceptable salt thereof and the like can be mentioned. Among them, the above (2),
The compounds (3), (4), (5), (7), (8), (9), (13) and (14) are preferable, and the compound (3) is particularly preferable.

(Method of Obtaining) The main amidinoheterocycle derivative (I) and salts thereof of the present invention are those produced according to the method described in the above literature. In the active ingredient compound (I) of the present invention, a compound not specifically described in the above literature can be produced according to the method described in the above literature or by applying it.

[0014]

INDUSTRIAL APPLICABILITY The compound (I) and its pharmaceutically acceptable salt, which are the active ingredients of the present invention, are excellent as active ingredients of Maillard reaction inhibitors, such as having a Maillard reaction inhibitory activity and low toxicity. It has effects and is associated with various diabetic complications such as retinopathy, nephropathy, cardiovascular disorders such as coronary heart disease, peripheral circulatory disorders and cerebrovascular disorders, diabetic neuropathy, cataracts and Maillard reaction. It is useful for the prevention and / or treatment of arteriosclerosis, arteriosclerosis, etc. which are considered to occur. Further, it is expected to be useful as a preventive and / or therapeutic agent for atherosclerosis, senile cataract, and cancer, which are considered to be caused by protein aging. Furthermore, since it is possible to prevent protein cross-linking of collagen, elastin, etc., it can be used as a cosmetic or a skin external preparation. Furthermore, it is well known that the Maillard reaction is related to the deterioration of proteins and amino acids of foods and drinks as well as in vivo, and the drug of the present invention is a functional food for the above-mentioned pharmaceutical and cosmetic purposes. As well as
It can also be used as a Maillard reaction inhibitor for foods and drinks containing protein or amino acid, or for taste.

(Pharmacological effect) The Maillard reaction inhibitory activity of the present invention was confirmed by the following experimental method. I Maillard Reaction Inhibitory Activity Test Experimental Method 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. After incubating for 7 days, a fixed amount was taken out and subjected to electrophoresis using SDS-PAGE. After electrophoresis, 0.04% Coomassie Brilliant
After staining with Blue R-250, the production amount of dimers and trimers was quantified with a densitometer. The compounds of the present invention are pre-incubated with 1 mM, 3 mM, 10 mM or 30 m
M ₅₀ was added, and the inhibitory effect on the formation of dimers and trimers at each concentration was examined to determine the IC ₅₀ value. Experimental Results The Maillard reaction inhibitory activity of the compound (I) of the present invention obtained by the above experiment is shown in Table 1 below together with the compound list.

[0016]

[Table 1]

II Toxicity Test The active ingredient (I) of the present invention has low toxicity and is suitable for use as a Maillard reaction inhibitor. For example, Experimental Examples 3 and 7
Compound of 20 to male Wistar rats (6 weeks old)
It was intraperitoneally administered to 0 mg / kg, but no abnormal findings were observed.

(Formulation Items) One or more compounds such as a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrate is used as an active ingredient. The pharmaceutical composition to be contained contains tablets, powders, fine granules, granules, capsules, pills, liquids, injections by using carriers and excipients for pharmaceuticals which are usually used, and other additives. , Suppositories,
It is prepared into 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, weight, age, sex, etc. of the patient to whom it is applied, but it is usually 0.1 to 500 orally for adults per day.
mg, preferably 10-200 mg, which may be 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. Non-water soluble solutions and suspensions include, for example, 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 a skin external preparation, the active ingredient (I) of the present invention or a salt thereof is used in an amount of 0.05-10
It is blended so as to contain by weight. 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 or drink, a favorite food, a functional food or the like by a conventional method.

[0020]

EXAMPLES The present invention will be described in more detail below with reference to formulation examples. Naturally, the invention is not limited to the following examples. Prescription example Oral formulation (film-coated tablets)

[0021]

[Table 2]

The active ingredient (I) of the present invention or its pharmaceutically
Acceptable Salt 30 mg Tablet 150 g of the active ingredient (I) of the present invention or a pharmaceutically acceptable salt thereof, 340 g of anhydrous calcium hydrogen phosphate, 100 g of crystalline cellulose and 10 g of light anhydrous silicic acid are taken, and a fluidized granulation coating apparatus ( Okawara Seisakusho)
Mix evenly. 250 g of 10% hydroxypropyl cellulose solution is sprayed on this and granulated. After drying, 20
Pass through a sieve of mesh and carboxymethyl cellulose calcium 21g and magnesium stearate 4g.
7mm × with a rotary tableting machine (manufactured by Hata Seisakusho)
Using an 8.4R pestle, make tablets of 130 mg each. 19 g of hydroxypropylmethyl cellulose in a coating device (manufactured by Freund Sangyo),
Polyethylene glycol 6000 2.5 g, titanium oxide 10 g, iron sesquioxide 0.5 g, and 325 g of a coating liquid containing 0.5 g of talc are sprayed, and each tablet is 6.5 m.
g-coated film-coated tablets.

[Procedure amendment]

[Submission date] February 5, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0016

[Correction method] Change

[Correction content]

[0016]

[Table 1]

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 231/38 249/08 249/10 249/12 249/14 (72) Inventor Satoshi Hayashibe Tsukuba City, Ibaraki Prefecture 2-5-9 Ninomiya Rumi Tsukuba No. 215 (72) Inventor Hisaka Takashi Kama 2-3-1 Kaga, Itabashi-ku, Tokyo 420 Kaga Garden Heights 420 (72) Inventor Toshiyuki Takasu 2-5-9 Ninomiya, Tsukuba, Ibaraki Rumi -Tsukuba No. 229 (72) Inventor Eiko Hirasaki 1-14-2 Ninomiya, Tsukuba City, Ibaraki Prefecture Bonur Tsukuba No. 311

Claims (1)

[Claims] 1. A Maillard reaction inhibitor containing, as an active ingredient, an amidinoheterocyclic derivative represented by the following general formula (I) (Formula 1) or a pharmaceutically acceptable salt thereof. [Chemical 1] (The symbols in the formulas have the following meanings. R ¹ : hydrogen atom, lower alkyl group or phenyl group. R ² : hydrogen atom, lower alkyl group, phenyl group, amino group, lower alkoxy group, carboxy group, or lower group. An alkoxycarbonyl group, X: a nitrogen atom or a group represented by the formula —CR ³ ═, R ³ : a hydrogen atom, a lower alkyl group, a phenyl group, a halogen atom or a lower alkanoyl group.