JPH03261772A - Thiazolidine compound and glycation inhibitor containing the same - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (n is 2-4). EXAMPLE:2(RS)-5,5-Dimethyl-D-galacto-(1',2',3',4',5'-pentahydroxypentyl) thiazohidine-4-(S)-carboxylic acid. USE:A glycation-inhibiting agent. Useful for treating arterial sclerosis accompanied with diabetic cataract or aging, etc. The compound of formula I has an extremely strong glycation-inhibiting activity and a little adverse action. PREPARATION:An aldose of formula II and penicillamine of formula III are heated and refluxed in the presence of a base (e.g. pyridine) in a solvent such as methanol for 1-10 hours to provide the compound of formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a thiapridine compound represented by the following general formula (1) HO-CH2-(CH) (except when -CHO is galactose or arabinose). .

2.-Mechanism (I) H (wherein, n represents an integer of 2 to 4).
represents an integer from 2 to 4) and a glycation inhibitor useful as a therapeutic agent for diabetic cataracts, arteriosclerosis, etc., containing the same as an active ingredient.

[Conventional technology]

The non-enzymatic and non-specific binding reaction between amino groups and sugars has long been described by L. C. Maillard in 1nvi.
It has been suggested that this phenomenon can occur not only in vitro but also in vivo [Maillard, L.
,C,.

Compt, Rend, Sac, Biol, 7
2, 599 (1912)).

However, although the technology that utilizes this reaction has rapidly developed in the food chemistry field, it has not been studied in the medical field, and it takes a long time for this reaction to attract attention in the hemoglobin fraction17). HbA, c
was found to be increased in diabetic patients3.
The ahbar report is the first.

[Rahbar, S., Cl1n, Chim, Ac.
ta, 22. 296 (1968)].

On the other hand, a non-enzymatic bonding reaction between amino groups in proteins and sugars (
Maillard reaction) is a non-enzymatic glycosylation (n
on-er + zymatic glycosylati
The reaction in which glucose binds to proteins is called glucosylation.
(on), but recently the Chemical Terminology Committee has redefined all of these as glycation.
It is proposed that they be collectively called.

In the Maillard reaction, the aldehyde group of a reducing sugar is dehydrated and condensed with the free amino group of a protein, resulting in the formation of almidine.
It begins with the formation of a Schiff base called ne). This aluminum zine is unstable in aqueous solution and gradually becomes amad! J (Amador i) Rearrangement occurs and changes to an Amador rearrangement product (Amador compound) which is Ketoamine.

Among these reactions, the reaction up to the formation of a Shipp base is reversible, but the Amatoli rearrangement is almost irreversible, so the Amatoli compound is relatively stable. The reaction up to this point is called the early stage of glycation. On the other hand, the subsequent reaction is in the late stage.
ge), and although the mechanism is still not completely elucidated, it produces various deoxydines,
Furthermore, it reacts with the amino group of another protein to form a polymer. The polymer thus formed is a fluorescent browning product, which is used in advanced glycosylation end products (
advanced glycosylation en
It is called AGE protein (abbreviated as AGE protein), and is considered to be a factor in diabetic cataracts and aging-related arteriosclerosis, and has been extensively studied.

Against the above background, glycation inhibitors have attracted attention in recent years, and many studies have been conducted to develop them. For example, Brownlee et al. found that aminoguanidine suppresses the reaction of Amatoli rearrangement compounds and subsequent reactions in glycation proceeding from albumin and glucose, and also suppresses the production of AGB protein in the arterial wall of diabetic rats (Brownlae, M.
, et al., 232.1629 (1986
) ] is reported. Also, JP-A-62-1421
No. 14 discloses a composition for suppressing the formation of glycation end products, which is comprised of a compound having an active nitrogen-containing group capable of reacting with the active carbonyl group of the Amatoli rearrangement product. Furthermore, Ouchida et al. have reported that hydrazine derivatives have Maillard inhibitory effects (
(Japanese Patent Application Laid-Open No. 64-56614).

[Problem to be solved by the invention]

However, most of the conventional glycation inhibitors are hydrazine derivatives, but compounds with a hydrazine group, such as aminoguanidine, contain not only amatri rearrangement compounds but also all active carbonyl groups. There is a drawback that there is a risk of interfering with the homeostasis of the living body because it may react with other compounds.

Therefore, it has been desired to develop a compound that does not inhibit the homeostasis of living organisms and has a strong glycation inhibiting effect.

[Means for Solving the Problems] Under these circumstances, the inventors have conducted extensive research to solve the above problems, and have found that the thiazolidine compound represented by the general formula (I) has an extremely strong glycation inhibiting effect. The present invention has been completed based on the discovery that the present invention has the same characteristics as that of a human, and has few side effects.

That is, the present invention provides a tiapridine compound represented by the general formula (I) and a glycation inhibitor containing the same as an active ingredient.

The thiazolidine compound of the present invention is a compound represented by the above general formula (I), where n represents an integer of 2 to 4.

However, the compound in formula (I) in which H HD-CH2-(C)I) and -CHO are represented by galactose or arabinose is a known compound.

Specific examples of such compounds of the present invention include 2(R3)-5
, 5-dimethyl-D-galacto-(1', 2', 3',
4',5'-pentahydroxypentyl)thiazolidine-4(S)-carboxylic acid (compound 1), 2 (R3
)-5,5-dimethyl-D-manno (1', 2', 3
',4'5'-pentahydroxypentyl)thiazolidine-4(s)-carboxylic acid (compound 2), 2
(R3)-5,5-dimethyl-D-gluco-(1',
2', 3'4'5'-pentahydroxypentyl)
Thiazolidine-4(S)-carboxylic acid (compound 3),
2 (RS)-5゜5-dimethyl-D-arabino-(1
'2'3',4'-tetrahydroxybutyl)thiazoliso:'4 (S)-jyibphonic acid (compound 4), 2 (RS)-5,5-dimethyl-L-arabino-(1'2', 3',4'-tetrahydroxybutyl)thiazolidine-4(S)-carboxylic acid (compound 5),
2(R3)-5,5-dimethyl-D-lyxo-(1'2
',3',4'-tetrahydroxybutyl)thiazolidine-4(S)-carboxylic acid (compound 6),2(RS)-
5,5-dimethyl-D-ribo-(1'2',3',4〆-tetrahydroxybutyl)thiazolidine-4(S)-
Carboxylic acid compound 7>, 2(RS)-5,5-dimethyl-D-xylo-<1'2',3',4'-tetrahydroxybutyl)thiazolidine-4(S)-carboxylic acid (
Compound 8), 2(R5)-5,5-dimethyl-L-xylo-(1'2',3',4'-tetrahydroxybutyl)thiazolidine-4(S)-carboxylic acid (Compound 9),
2(R3)-5,5-dimethyl-D-malto-(3'-
α-D-glucopyranosyl 1', 2', 3'4', 5
'-pentahydroxypentyl)thiazolidine-4(S
)-carboxylic acid (compound 10), (R5)-5,5-dimethyl-〇-galacto (1'2', 3', 4', 5'
-pentahydroxypentyl)thiazolidine-4(R
S)-carboxylic acid (compound 11), (R8)-5,5
-dimethyl-D-arabino-(1', 2', 3', 4'
~tetrahydrobutyl)thiazolidine-4(RS)-
Carboxylic acid (compound 12), (R5)-5,5-dimethyl-〇-glucose (1', 2', 3', 4', 5'
-pentahydroxypentyl)tiapridine-4 (R3
)-carboxylic acid (compound 13), (RS) -5,5
-dimethyl-D-xylo-(1', 2', 3', 4'
-tetrahydroxybutyl)thiazolidine-4 (R3
)-carboxylic acid (compound 14), (RS)-5,5-
Examples include dimethyl-D-ribo-(1',2-/,3/,4/-tetrahydroxybutyl)thiazolidine-4(RS)-carvone WIl (compound 15).

The thiazolidine compound (I) of the present invention can be prepared by adding penicillamine (II) to aldose (II), for example, according to the following reaction formula.
It is produced by reacting I).

1'E (III) (I) (wherein, n has the same meaning as above) aldose (■
) and penicillamine (■) is carried out by heating under reflux for 1 to 10 hours in a solvent such as methanol or ethanol in the presence of a base such as pyridine or potassium carbonate. When this reaction solution is cooled, the compound (1) of the present invention is precipitated as crystals.

[Effect]

Representative compounds of the present invention were tested for their Maillard reaction inhibitory effects.

(Test method) Bovine serum albumin (BSA) 6%, 200mM glucose, 3mM sodium azide and test drug 20mM at pH
7.4 phosphate buffer (dissolved in 1.4 ml and heated at 37°C)
Incubated with 7 days and 14 days of this solution
The fluorescence intensity was measured, and the glycation inhibiting effect was confirmed from the difference in intensity from the control group.

The results are shown below.

(Results) As shown in the table below, the compound of Example 2.11 showed an inhibitory tendency, and the compound of Example 13 showed a significant inhibitory effect.

(In the table, the control (-) indicates the group to which neither glucose nor the test drug was added, and the control (+) indicates the group to which 200 d glucose was added and no test drug was added).

The compound (1) of the present invention can be administered as a glycation inhibitor as it is, but if necessary, it may be mixed with other usual pharmacologically acceptable carriers, excipients, diluents, etc. to give the desired effect. It can be formulated into a dosage form and administered orally or parenterally. There is no particular limit to the amount of the compound (I) of the present invention in such pharmaceutical formulations, but - 1 to 10
The weight process is about 0% by weight. There is also no particular limitation on the dose, but it is preferably 1 to 500 μ/day.

[Effects of the Invention] The tiapridine compound of the present invention has a strong glycation inhibiting effect and has few side effects, so it can be used as a glycation inhibitor for treating diabetic cataracts, arteriosclerosis associated with aging, etc. It is useful as a.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Aldose 10 mmo1, penicillamine 10 mmoj!
and 10 mmoj of pyridine! was dissolved in 50 methanol and heated under reflux for 2 hours. After cooling the reaction solution, it was left in a -3°C freezer overnight. The precipitate was filtered and recrystallized to obtain pure compounds 1 to 15 of the present invention. The yields and melting points of Compounds 1 to 15 are shown in Table 1, and the results of elemental analysis, mass spectrum, infrared absorption spectrum, optical rotation, and nuclear magnetic resonance spectrum ('H-NMR) are shown in Table 2.
In addition, the results of nuclear magnetic resonance spectrum (C-NMR) are shown in Table 3.

Table 1 Margin below

Claims (1)

[Claims] 1. General formula (I ′) ▲ Numerical formula, chemical formula, table, etc. ▼ (I ′) (In the formula, n represents an integer from 2 to 4. However, ▲ Numerical formula, chemical formula, table, etc. Thiazolidine compounds represented by (excluding cases where ▼ is galactose or arabinose). 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n represents an integer from 2 to 4) It is characterized by containing a thiazolidine compound as an active ingredient. glycation inhibitor.