JPH049375A - Thiourea derivative and age generation inhibitor - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> and R<2> form halogen together with C in bonded benzene ring or benzene ring substitutable with alkyl, etc.; R<3> is halogen, alkyl or OH, etc.; or, R<1> and R<2> are oxo together with C in bonded benzene ring or cyclopentene or cyclohexen substituted with OH; R<3> is H, halogen or thiol, etc.; etc.]. EXAMPLE:1-benzoyl-3-[4-(8-oxo-5,6,7,8-tetrahydro-2-naphthyl)-2-thiazol yl]-2-thiourea. USE:Used as an AGE generation inhibitor or a preventive and a remedy of diabetic complication or arterial sclerosis. PREPARATION:An aminothiazole derivative expressed by formula II or salt of the derivative is reacted with an isothiocyanate derivative expressed by formula III in a solvent (e.g. dioxane) or without solvent at 0-150 deg.C to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to thiourea derivatives or salts thereof and pharmaceuticals containing them, particularly AGE production inhibitors.

Conventional technology In recent years, non-enzymatic glycosylation (nonenzymatic glycosylation) has been recognized as causing various physiological disorders associated with diabetes and arteriosclerosis.
Glycosylation of proteins by ymatic glycosylation is attracting attention. In other words, glucose in the blood is non-enzymatically bonded to the amine 7 group of proteins through a Nff base through a simple chemical reaction, and then a relatively stable ketoamine conductor (1-amino/1-deoxyfructose) is formed through Amatoli rearrangement. formation of protein, which causes changes in protein structure and function. This Amatoli rearrangement product further undergoes a dehydration reaction within several months to several years, resulting in A G E (
advanced glycosylation en
d products) and converted into glucose derivatives irreversibly. AGE emits yellowish-brown fluorescence and has the property of binding to nearby proteins to form crosslinks. Proteins cross-linked by AGE are thought to cause damage in various tissues. In diabetes, non-enzymatic saccharification of this protein increases in proportion to the rise in blood sugar, and this is thought to be one of the causes of diabetic complications [A, Cerami
) et al., Metabolism IJetabolism), vol. 28 (Suppl. 1), p. 431, 1979. v
M Monier et al., New England Journal of Medicine.
ngland Journal of Med ic
1ne), vol. 314, p. 403, 1986].

This process is also thought to be a cause of aging. for example,
Senile cataracts are associated with AGE conversion of crystallin, a protein in the eye's lens. Furthermore, the formation of AGEs is also associated with atherosclerotic lesions. It has been confirmed that AGH is also involved in the thickening of the basement membrane of small blood vessels associated with aging and the thickening of the renal glomerular basement membrane that causes a decline in kidney function. 1M BrBnlee et al., Science, vol. 232. 1629 pages,
In 1986, M. Brownlee et al. reported that aminoguanidine suppresses the transition from Amatoli rearrangement products to AGEs [M. Brownlee et al.
ee) et al., Science, vol. 232,
p. 1629, 1986. It is attracting attention as a medicine to prevent diseases associated with aging.

Problems to be Solved by the Invention However, the action of the above-mentioned aminoguanidine is not necessarily sufficient, and a practically satisfactory AGE production inhibitor has not yet been found.

An object of the present invention is to provide compounds that have an AGE production inhibiting effect and are useful as preventive and therapeutic agents for diabetic complications and arteriosclerosis, and pharmaceuticals containing them.

The present inventors conducted extensive research on compounds useful for preventing the above-mentioned diseases by inhibiting AGE production, and found that the following thiourea derivatives of the present invention have a strong AGE production inhibiting effect. The present invention was completed by discovering that the present invention has the following properties.

That is, the present invention relates to a compound of the general formula [wherein (i) R' and R1, together with the two carbon atoms of the Hensen ring to which they are bonded, are optionally substituted with a halogen atom, an alkyl group, an alkokene group, or a hydroxyl group] form a ring, and R3 is a haloken atom, an alkyl group, a hydroxyl group, a thiol group, or the formula R'CO○- (in the formula, R
4 represents an alkyl group) or (i
i) R' and R2 together with the two carbon atoms of the benzene ring to which they are bonded form a cyclopentene or cyclohexene substituted with an oxo group or a hydroxyl group, and R3 is a hydrogen atom or a halogen atom, an alkyl group, a hydroxyl group, a thiol group, or represents a group represented by the formula R'CO○- (in the formula, R4 represents an alkyl group), or (iii) R' is a hydrogen atom, and R1 and R3 are each a hydrogen atom or a halogen atom, an alkyl group, Hydroxyl group, thiol group, or formula
A thiourea derivative represented by a group represented by R'C00- (in the formula, R4 represents an alkyl group) (hereinafter sometimes abbreviated as thiourea derivative (1)) or a salt thereof. The present invention relates to an AGE production inhibitor. Formula (1)
Among the compounds represented by () and (r+), the compounds defined by (r+) are compounds that have not been described in any literature.

The alkyl group represented by R", R3, and R' is preferably a linear, monobranched, or cyclic one having 1 to 10 carbon atoms,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl,
Examples include pentyl, impentyl, hexyl, heavenly, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentinobecyclohexyl, and the like. Among these, those having 1 to 6 carbon atoms are particularly preferred.

Examples of the halogen atom represented by R'' and R3 include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred.

Cyclopentene and 7-chlorohexene substituted with an oxo group or a hydroxyl group formed together with the two carbon atoms of the Hensen ring to which R1 and R'' are bonded are, for example, in the formula, where R3 is on the phenyl ring, relative to the bonding site of the carbonyl group. , the 0-position, the 2m-position, and the p-position.

In addition, the alkyl group as a substituent on the benzene ring formed by R1, R1 together with the two carbon atoms of the Hensen ring to which they are bonded may be an alkyl group as described above for R1, R3, R', or a halogen atom. As, R”, R'
Haloken atoms as described above for each are preferred. Similarly, as an alkoxy group as a substituent, R
1, R3t Regarding R4, alcoquine having a linear, monobranched, or cyclic alkyl group having 1 to 10 carbon atoms (e.g., methquine, ethoxy, propoxy, isopropoxy, cyclopropoquine, butoxy, imbutoxy, 5e
e-butoxy, tert-butoxy, cyclobutoxy,
bentoquine/, isopentoquine, neopentoxy, cyclopentoxy, hexyloxy, cyclohexyloxy,
Hexyloxy, cycloheptyloxy, octyloxy, nonyloxy, decyloxy, etc.) are preferred. Note that these substituents may be substituted at any position on the benzene ring formed together with the two carbon atoms of the benzene ring to which R' and R2 are bonded.

Examples of the salt of compound (I) include pharmaceutically acceptable acid salts for the thiazole ring such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, maleic acid, and fumaric acid, or -NHC.
Examples include alkali metal salts such as sodium and potassium of the 3NH group.

The above compound (r) or a salt thereof can be produced, for example, as follows.

Method A [wherein R', R1, R' are the above (i l (ii)
, has the same meaning as (iii). That is, compound (■) or a salt thereof can be obtained by heating the ami/thiazole derivative (It) or its salt and the isothiocyanate derivative (III) in a solvent or without a solvent. Here, examples of the salt of (II) include acid salts (hydrochloride, sulfate, acetate, etc.) of an amino group or a basic group (dialkylamino group) of R1. Examples of such solvents include ethers such as dioxane, tetrahydrofuran, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and quinolene, ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, and dichloromethane. , 1.2-dichloroethane, 1.1,
Examples include 2.2-tetrachloroethane, acetone, and a mixed solvent thereof. The reaction temperature is approximately 1°C to approximately 1°C.
50°C1, preferably about 10°C to 100°C, and the reaction time is usually 0.1 to 50 hours, preferably 0.5 to 100°C.
It is 20 hours.

In the first method, by treating a compound in which R2 or R3 is an acetoxyl group with an acid in alcohol, R1 or R3 is
A compound in which 3 is a hydroxyl group is produced.

Examples of solvents include alcohols such as methanol and ethanol, alcohols and ethers (tetrahydrofuran, dioxane, etc.), N,N-dimethylformamide,
A mixed solvent such as dimethyl sulfoxide is used. acid(
The amount of hydrochloric acid, sulfuric acid, etc. used is usually in large excess, and the reaction temperature is -20°C to 1000°C, preferably 00°C to 80°C.
It is. The reaction time is usually 0.1 to 10 hours, preferably 0.2 to 5 hours.

The thiourea derivative (1) thus obtained can be isolated and purified by known separation and purification means, such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, and chromatography.

The aminothiazole derivative (II) used in the above production method is, for example, manufactured by Chemical Abstracts (Ch
chemical Abstracts), 53 volumes,
14089e (1959); Chemical Abstracts, Vol. 105, 221003s (1986), European Journal of Medicinal Chemistry (
European Journal of Medicine
inal Chemistry) volume 16, page 355 (
1981); New Experimental Chemistry Course Vol. It can be produced by the method described in Chemistry Course, Volume 14, Synthesis and Reaction of Organic Compounds [IV] J (1976), or a method analogous thereto.

Thiourea derivative (1) or its salt has an excellent AGE production inhibiting effect and is therefore used as a medicine for humans and livestock, and is used to treat and prevent various diseases caused by the transfer of proteins to AGE. It is safely used as an AGE production inhibitor.

The thiourea derivative (1) or a salt thereof can be prepared into capsules, tablets, powders, etc., alone or in combination with other active ingredients, by adding auxiliary agents such as neutralizing agents, stabilizers, and dispersants according to conventional methods. It can be used in formulations such as solutions, suspensions or elixirs. They can be administered parenterally (eg rectally) or orally.

The thiourea derivative (1) or a salt thereof can be used in combination with binders such as syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone, etc., fillers such as lactose, sugars, corn starch, calcium phosphate, sorbitol, glycine, etc., and lubricants such as After suitably mixing with magnesium stearate, talc, polyethylene glycol, silica, a disintegrant such as potato starch, or a wetting agent such as sodium lauryl sulfate, it is prepared as a tablet, capsule, powder, or powder for oral administration according to a conventional method. etc. can be done.

Tablets, powders, etc. can also be coated with a film by a method known per se. Oral formulations may be used as liquid formulations such as aqueous or oily suspensions, solutions, emulsions, 70 knobs, elixirs, and the like.

A preparation for rectal administration containing a thiourea derivative (I) or a salt thereof is prepared by mixing a waste base, an additive, and a thiourea derivative (r) or a salt thereof in accordance with a conventional method, and preparing, for example, an oily solid waste agent. , a semi-solid ointment-like waste agent, and a capsule waste agent by filling a liquid composition into soft capsules. The thiourea derivative (1) or its salt is usually selected from a range of approximately 0.5 to 50% by weight based on the entire formulation, but is not limited thereto. In the present invention, other nonionic surfactants, such as polyoxyethylene fatty acid ester, polyoxy Ethylene higher alcohol ethernato'E: May be used in combination, or an anionic surfactant may be added.

Furthermore, various salts or stabilizers may be blended or added in order to increase the solubility or stability of the thiourea derivative (■) or its salt. In addition, dispersants, preservatives, etc. can be added if necessary from a pharmaceutical standpoint.

Further, components such as known antioxidants, preservatives, lubricants, thickeners, or flavoring agents may be mixed into these preparations in accordance with conventional methods. Furthermore, other active ingredients may be mixed with the formulation to produce a formulation that exhibits the desired AGE production inhibiting effect.

Thiourea derivative (1) or a salt thereof can be used as an AGE production inhibitor for the treatment and prevention of diabetic complications, senile cataracts, atherosclerosis, renal glomerular basement membrane thickening, etc. in humans and mammals. Can be used. The daily dosage of thiourea derivative (I) or a salt thereof may vary depending on the patient's condition, body weight, method of administration, etc.;
) or a salt thereof) is about 0.05 to 80 mg, preferably about 0.1 to 101 g, and is suitably administered by rectal administration in 2 to 4 doses per day. It is appropriate to administer the active ingredient (thiourea derivative (1) or its salt) in an amount of about 0.5 to 100 mg, preferably about 10 to 50 mg, per kg of body weight for an adult, divided into 1 to 3 doses.

Furthermore, the thiourea derivative (I) or its salt has excellent distribution in the body, has virtually no side effects, and can be used to improve protein A
It is an ideal AGE production inhibitor that exhibits excellent therapeutic and preventive effects against diseases caused by GE transition.

(Action) The thiourea derivative (I) or its salt exhibits an excellent inhibitory effect on the production of denatured substances of glycated proteins (A GE ).

Experimental example Advanced Glycosylation
The production of Encf products (AGE) and its measurement are reported by Brownlee et al. [Science, Vol. 232,
1629, 1986, according to J. That is, 0.
5M-phosphate buffer (p) r7.4. ), bovine serum albumin (frac/gnV, Wako Pure Chemical Industries, Ltd., 20%), D-glucose (100mM) and sodium azide (3+n
M) was dissolved and used as a reaction solution (control). The specimen was dissolved in dimethyl sulfonate and added to the reaction solution at a concentration of 1++M or Q, 5sM. These solutions were incubated at 37°C for 7 days. Before and after incubation, the solution was diluted with phosphate buffer and the excitation wavelength was 370rr.
m, fluorescence was measured at a fluorescence wavelength of 440ni (RF-510
(type fluorometer, Shimadzu Corporation), and using the amount of change (ΔF), the production rate (%) was calculated according to the following formula. Note that a reaction solution containing no D-glucose was used as a blind test.

Table 1 Compound AGE generation rate The measurement results according to this method are shown in Table 1.

The above results indicate that AGE is produced when compound (I) or its salt is added to the reaction solution, or AGE is produced when compound (I) or its salt is not added.
Production rate = 100%), therefore, the compound (
It can be seen that 1) or a salt thereof has an excellent AGE production inhibiting effect.

Effects of the Invention The thiourea derivative (1) of the present invention or its salt has an excellent effect of suppressing or inhibiting ACE production, as is clear from the above experimental examples. Provided are new AGE production inhibitors useful for the prevention and treatment of diseases caused by.

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

Note that all melting points were measured by the hot plate method and are uncorrected.

In the following description, Me represents a methyl group, Et represents an ethyl group, iPr represents an isopropyl group, and tBu represents a tert-
Ac represents a butyl group, and Ac represents an acetyl group.

Example 1 A mixture of 2-amino-4-(8-oxo-5,6,78-tetrahydro-2-naphthyl)thiazole (2,00 g), benzoyl inthiocyanate (1,60 g) and acetone (200 d) The mixture was heated under reflux for 3 hours and then cooled. The precipitated crystals were filtered and recrystallized from dichloromethane-methanol to give 1-benzoyl-3-[4-(8-oxo-5,6,7,8-tetrahydro-2-naphthyl)-
2-thiazolyl]-2-thiourea (2.05 g, yield 61%) was obtained as colorless needles. m, p, 233 2
34°C0Cff1IH17N30. Calculated value as S: C, 61, 89, H, 4, 20; N, 1
0.31° Analysis value C, 62,07, H, 4,07;
N, 10.2g.

Examples 2-12 The compounds shown in Table 2 were obtained in the same manner as in Example 1.

Example 13 Ammonium thionate (4.19 g) in acetone (
4-chlorobenzoyl chloride (9,
62 g) was added, heated on a water bath for 1 minute, and then stirred at room temperature for 1 hour. Then, 2-amino-4-(4-isopropylphenyl)thiazole (10.0 g) was added and the mixture was heated under reflux for 4 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and washed with water and ethanol. Recrystallized from dichloromethane-ethanol to give 1-(4-chlorobenzoyl)-
Colorless needle crystals of 3[4-(4-isopropylphenyl)-2-thiazolyl]-2-thiourea (11.2 g, yield 59%) were obtained. tp, 210-211'C0C,
, H,, Calculated value as CQN 30S2: C, 57, 75, H 4, 36; N, 10
．． 10° analysis value: C, 57, 61, H, 4, 32;
N, 10.03° Examples 14 to 22 The compounds shown in Table 3 were obtained in the same manner as in Example 13.

Example 23 4-acetoxybenzoic acid (1,OOg) in THF (10
d) After adding DMF (1 drop) to the solution, oxalyl chloride (775 mg) was added and stirred at room temperature for 1 hour. After changing the solvent to acetone (lM), ammonium thionanate (510 mg) was added to acetone (lM).
The solution was added, heated on a water bath for 1 minute, and then stirred at room temperature for 10 minutes. Then 2-amino-4-(5,6,7,
8-tetrahydro-2-naphthyl)thiazole (1,2
Add 7g> of acetone (10d) solution and heat to 55-60°C.
I stirred it for 3 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and washed with water and ethanol. Recrystallized from dichloromethaneethanol to give 1-(4-acetoxybenzoyl)-3-14-C5,6,7,8-tetrahydro-
2-naphthyl)-2-thiazolyl]2-thiourea(
1.33 g (yield: 53%) of pale yellow prism crystals were obtained.

m, p, 212-213°C0 Examples 24-39 The compounds shown in Table 4 were obtained in the same manner as in Example 23.

Example 40 1-(4-acetoxyhendiyl)-3-[4(5,6
,7,8-tetrahydro-2-naphthyl)2-thiazolyl]-2-thiourea (5,85 g) and f3NHC (1
The mixture of -MeOH (8C1,) was stirred at room temperature for 1 hour and then at 60°C for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried, and purified through silica gel column chromatography, and the obtained crystals were recrystallized from dichloromethaneethanol to give 1-(4-hydrobovodibenzoyl)-3-[4-(5,6,7,8-
Tetrahydro-2-naphthyl)-2-thiazolyl]-2
-thiourea (2.08 g, yield 39%) was obtained as a colorless prism product. m, p, 212-213°C0C,,
H, 1lN30. Calculated value as S: C, 61,59; H, 4,68; N,
10.26° Analysis value: C, 61, 65; H, 4,
69; N, 10.27° Examples 41-43 The compounds shown in Table 5 were obtained in the same manner as in Example 40.

Table 2 Table 3 Table 4 Table 5

Claims (2)

[Claims] (1) General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, (i) R^1 and R^2 are the two carbon atoms of the benzene ring to which they are bonded, as well as a halogen atom, an alkyl group,
It forms a benzene ring which may be substituted with an alkoxy group or a hydroxyl group, and R^3 is a halogen atom, an alkyl group, a hydroxyl group, a thiol group, or the formula R^4COO- (in the formula, R
^4 indicates an alkyl group) or (
ii) R^1 and R^2 together with the two carbon atoms of the benzene ring to which they are bonded form a cyclopentene or cyclohexene substituted with an oxo group or a hydroxyl group, and R^3 is a hydrogen atom or a halogen atom, an alkyl group, or a hydroxyl group. , a thiol group, or a group represented by the formula R^4COO- (in the formula, R^4 represents an alkyl group), or (iii) R
^1 is a hydrogen atom, and R^2 and R^3 are each a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group, a thiol group, or a formula R^4COO- (wherein R^4 represents an alkyl group). AGE characterized by containing a thiourea derivative or a salt thereof represented by
production inhibitor. (2) General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, (i) R^1 and R^2 are the two carbon atoms of the benzene ring to which they are bonded, as well as a halogen atom, an alkyl group,
Forms a benzene ring which may be substituted with an alkoxy group or a hydroxyl group, R^3 is a halogen atom, an alkyl group, a hydroxyl group, a thiol group, or has the formula R^4COO- (wherein R^4 represents an alkyl group) ), or (ii) R^1 and R^2 together with the two carbon atoms of the benzene ring to which they are bonded form a cyclopentene or cyclohexene substituted with an oxo group or a hydroxyl group, and R^
3 is a hydrogen atom or a halogen atom, an alkyl group, a hydroxyl group,
A thiol group, or a group of the formula R^4COO- (wherein R^4
represents a group represented by (represents an alkyl group)] or a salt thereof.