JPS62234085A - Remedy for diabetic complication comprising thiazolidine derivative as active ingredient - Google Patents

Abstract

PURPOSE:A remedy for diabetic complication having improved inhibitory action on aldose reductase, promoting action on prostaglandin I2 synthesis, inhibitory action on 5-lipoxygenase and low toxicity, comprising a thiazolidine derivative shown by a specific structural formula as an active ingredient. CONSTITUTION:The aimed remedy comprising a thiazolidine derivative shown by formula [R<1> is H or 1-8C alkyl; R<2> is H or 1-5C alkyl; R<3> is H, 1-4C aliphatic acyl, heteroatm-containing 5- or 6-membered heterocyclic acyl, etc.; R<4> is 1-8C alkyl or 1-4C alkoxy; R<5> is H, 1-5C alkyl, etc.,; W is methylene, carbonyl, group shown by formula II or formula III (R<6> is H, 1-4C alkyl, aralkyl, etc.); U is methylene or U and R<1> are optionally bonded to form double bond when W is carbonyl; U and W are optionally bonded to show double bond; n is 1-3] and a pharmaceutically acceptable salt thereof as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for diabetic complications, which contains a thiazolinone derivative represented by the following general formula +1 as all active ingredients.

Conventionally, sulfonylurea-based oral antidiabetic agents have the effect of completely lowering blood sugar levels, but they have not been effective in alleviating various chronic symptoms associated with diabetes, such as diabetic cataracts, diabetic retinopathy, and diabetic neuropathy. It is recognized that it is difficult to protect or prevent it.

Due to the above-mentioned circumstances, research has been carried out in various places for many years on effective therapeutic agents for these intractable diseases.
There are no examples of complete success yet.

Aldose reductase is an enzyme that reduces aldoses in humans and other animals, such as glucose, to lactose, and all corresponding polyols, such as sorbitol, to lactitol. It is feared that lactosemia may accumulate in the crystalline lens, peripheral nerves, kidneys, etc., and as a result, the above-mentioned complications may be induced (Science, 182.1146 (1973)).

Jap, J., Ophthalmo L., 20, 3
99 (1976) and Mezabolism, 28
, 456 (1979)).

Furthermore, abnormalities in arachidonic acid metabolism in diabetic conditions have recently attracted attention, and the role of prostacyclin (PGI) in the onset and prevention process of diabetic angiopathy has attracted attention. That is, PC) I2 synthetic foot measurements were carried out using arterial segments, vein segments, aortas, etc. of various insulin-dependent diabetic humans and animals, and the amount of PC-PG-2 synthesized in insulin-dependent circulatory urinary disease was determined. It has been confirmed that there is a decline in
LifeSci, 23, 351 (1978), La
ncet, 1.325 (1979).

N., Engl., J., Med., 300, 36
6 (1979), Thromb, Haemos
T.

42.334 (1979), Biochem, Me
d, 23.231 (1980).

Prostaglandins, 24, 35 (1
982)).

'1) Hydrobaroxide produced by lipoxygenase has an inhibitory effect on PGI2 production in the vascular wall.
As a result, it causes vascular damage (J, Biol,
Chem, 254.2191 (1979)].

Therefore, compound il+ has lipoxygenase inhibitory effect ft
It is thought to have a stronger protective effect against vascular disorders.

The present inventors conducted a wide range of compound searches with respect to aldose reductase inhibitory activity, 4-xygenase inhibitory activity 2, and PGI2 production increasing activity, with the aim of preventing or treating the chronic complications of diabetes mentioned above. As a result, thiazolinone derivatives (Il has an aldose reductase inhibitory effect, 5
-Lipoxygenase inhibition 2 and PGI. The present invention was completed by discovering that it has a production-increasing effect and is extremely toxic to humans.

Structure of the Invention The therapeutic agent for diabetic complications of the present invention (-1, general formula [wherein R1 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms] represents an alkyl group, R3 is a hydrogen atom, and has 1 to 4 carbon atoms.
aliphatic acyl group, an aromatic east acyl group which may have a substituent, or t represents a five- or six-membered heterocyclic acyl group containing nitrogen, oxygen, or sulfur atoms, and ptJ represents a carbon number of 1 to 1. 8
The alkyl group represents an alkoxy group having 1 to 4 carbon atoms, R5 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, W represents a methylene group, Carzanyl group, formula CH-OH group, formula; c
=N-oa6 group (wherein R6 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which may have a carboxy group or a lower alkoxycarnyl group as a substituent, and a substituent) an aralkyl group, an aliphatic acyl group having 1 to 4 carbon atoms, an aromatic acyl group which may have an fL substituent, or a 5- or 6-membered heterocyclic acyl group containing nitrogen, oxygen, or cypress atoms; A double bond may be formed with sword 1 indicating (shown in the figure) or U described below, and U indicates a double bond together with 711 indicating a methylene group or W, but
W is a chalconyl group or a formula; c=N-oa6 group (in the formula, R6 has the same meaning as described above) tl- may also form a double bond with R1, n is 1 Indicates an integer between 3 and 3. ] It contains a thiazolinone derivative represented by and its pharmacologically acceptable filler active ingredient.

In the general formula FII, where R1 represents an alkyl group, t>, R1 is methyl, ethyl, propyl, isopropyl, butyl, inobutyl, tert-butyl, pentyl, impentyl, neopentyl, 2-methylbutyl, 1-ethyl. Propyl, hexyl, inohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1.1-tumethylbutyl,
1,3-trimethylbutyl, 2-ethylbutyl, 1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl, 1,1-noethylzolopyl,
4.4-trimethylpentyl, octyl, 1-)fheptyl, 2-ethylbutylmata are straight-chain or branched chains of 5,5-trimethylhexyl having 1 to 8 carbon atoms. can give.

When R2 represents an alkyl group, R2 is methyl, ethyl, propyl, isozolobyl, butyl, isobutyl,
Straight chain or branched carbon atoms having 1 to 5 carbon atoms such as pentyl or impentyl are included.

When R3 represents an aliphatic acyl group, R5 has 1 to 4 carbon atoms such as formyl, acetyl, propionyl, butyryl, or impetyl; when R3 represents an aromatic acyl group, R' is benzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl, 4-aminobenzoyl, 3-tmethylaminobenzoyl, 2-methoxybenzoyl, 3,4-nochlorobenzoyl, 3.5-no tart-butyl-4-
When an aromatic acyl group such as hydroxybenzoyl or 1-naphthoyl is mentioned, and a heterocyclic acyl group is indicated,
Examples of R5 include cycloacyl groups such as 2-furoyl, 3-thenoyl, 3-pyridinecarbonyl, and 4-bilinonecarbonyl.

When R4 represents an alkyl group, R4 is methyl, ethyl, propyl, inpropyl, butyl, inobutyl,
tart-butyl, pentyl, impentyl, neo(methyl, tert-hentyl, hexyl, 1,1-trimethylbutyl, 1,3-trimethylbutyl, heptyl, 1,1
-noethylpropyl, octyl, 1-methylheptyl,
Examples include linear or branched carbon atoms having 1 to 8 carbon atoms such as 2-ethylhexyl or 1,1,3.3-tetramethylbutyl, and when R represents an alkoxy group.
Examples of J include those having 1 to 4 carbon atoms, such as +2 methoxy, ethoxy, propoxy, inpropoxy, butoxy, and e+esoptoxy.

When R5 represents an alkyl group, R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples of pentyl include linear or branched carbon atoms such as impentyl, and when representing an alkoxy group, R5 is methoxy, ethoxy, propoxy, impropoxy, butoxy. Alternatively, those having 1 to 4 carbon atoms such as isobutoxy can be mentioned.

W is a methylene group, a carbinyl group, a CH-O
H group or the formula c=u-ah6 group [in the formula, R6 is a hydrogen atom; methyl, ethyl, propyl, inpropyl, butyl,
A linear or branched alkyl group having 1 to 4 carbon atoms such as isobutyl or tert-butyl (the alkyl group is a carboxy group, methoxycarbonyl, ethoxycarbonyl, impropoxycarbonyl, phthoxycarbonyl) lower alkoxycarbonyl group such as
It does not work even if it has it as a ta group. ); Aralkyl group such as benol, p-methylbenzyl: E (5K
Aliphatic acyl group and aromatic acyl group having the same meanings as K-Keru and 9 indicate a multicyclic acyl group. ], but it can also be used to form a double alloy with U, which will be described later.

U II usually represents a methylene group, but may also represent a double pharyngeal group together with W, and generally W is a carbonyl group, formula ';C=
When representing an N-OR6 group (in the formula, R6 has the same meaning as defined above), U may represent a double bond together with R1.

The compound 'F'II of the present invention represented by the general formula (Il)
J can be made into a pharmacologically acceptable non-toxic salt according to a conventional method, and examples of such salts include alkaline metal salts such as attrium salt and potassium salt, or alkaline earth salts such as calcium salt. Examples include metal salts, lysine salts, basic amino acid salts such as arginine salts, etc. When the target compound (I) has a basic group, it can be made into a nontoxic acid addition salt; Examples of salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, succinate, maleate, fumarate, malate, glutamate, as/? Examples include organic acid salts such as laginate, Az+-sulfonate, and methanesulfonate.

In addition, in the compound represented by the general formula (1) in the present invention, each stereoisomer based on the asymmetric carbon atom at the 4th position of the chroman ring and the 5th position of the thiazolinone ring, and the 4th position of the chroman ring has the formula>cH- oH group, the stereoisomer based on its asymmetric carbon atom, 7 HCHHCHCH3-C
H2-18C2H3tt tt n
,, p tt9 1So-C4H9p
tt p,, tt
ttlo C3H1, tt tt
tt ,, tt //11
CHH// ter t-C4Hg H〃〃15
CHCH3" CH3 3CH5-Co-u 19 tt tt C and 〃〃〃〃20
tt C'HHCH3CH3-CH-ttH Compound E'71 R'R2R3R' R
5W n23 CHCHHCH3CH3″C
'1 compound R2R3R' R5n30
CH3I CH3CH3131n n
tt tt 232 Ht'
ter t<aHq Htt compound λI
R2R5pa p, 5 233 CH,
CH,HCH3CH,134//H//1ar
t-C4H9H1142608 and patent application 1986-4
This compound is described in the specification of the No. 2609 application along with its agricultural method.

Effects of the Invention The compound represented by the general formula ([) of the present invention, when used in pharmacological and toxicity tests, exhibits excellent aldose reductase inhibitory activity, prostaglanone engineering synthesis promoting activity, and 5-lipoxygenase inhibitory effect. However, these tests are specifically explained below.

The method of Hayman et al. (S-Hayman and J
, H., Kinoshita J., Biol., Ch.
240, 877 (1965)), we prepared the aldose reductase of bovine crystal locus! Var
The method of ma et al. (S, D, Varma and J,
H. Kinoshita.

Biochem, Pharmac, 25, 25
05 (1976)], the total aldose reductase activity of the test compound was determined. The results are shown in Table 2. In Table 2, the inhibition of aluminum reductase at 10-5 Mvc is shown. (Hereinafter, compounds are indicated by compound numbers in Table 1.) Table 2 Aldose reductase inhibitory activity 155.1 15 59.6 20 67.6 23 55.5 25 41.3 ? , Q 44.9 Test Example 2 Effect of promoting prostaglanone 2 production in the arteries The method of Pace-Asciak et al. (PrOGZag12
Ll:1dlns+15+1005(1978)
Test 1 The amount of PGI 2 produced in the anastomosis was investigated using descending aortic rings of 14- to 16-week-old rats according to the modified method of (2009).

i.e., aortic ring and test compound '1i in 0.1 M) IJ salt hydrochloric acid condensate solution with pH 7.6 at 30 °C, 10
After brain incubation for j minutes, 1 + (IJC) arachidonic acid was added (0.16 μCi, 16 μM) and incubated for an additional 30 minutes. The reaction stopped when all of the hydrochloric acid was added. The produced 7'CPOI2 is converted into stable 6-kedoprostaglanson F1 (f) under these conditions and extracted with ethyl acetate. :
Acetic acid:isooctane:X=11:2:5:10, Kie
Fractionation was performed using selgel 6t1F) f. The 6-keto prostaglanone F1a fraction on the silica gel thin layer was identified using a two-dimensional Lannoactezo scanner, and then its radioactivity was quantified. The amount of PGI2 produced was calculated as the radioactivity of 6-kedozolostaglandin F1a per dry weight of arterial ring, and the control (no compound added) was set as 100, and it was expressed as a relative head. the result? Shown in Table 3.

Table 3 Control 100 1 (20 μf/mg) 17023 (20 μm
Town A 172 11 (20μf/mj) 150*100 for control
and expressed as a relative value.

5barra and Karnovsk Y method (J, Bi
ol, Chem・234゜1355 (1959) J
[Accordingly, peritoneal polymorphonuclear leukocytes from male guinea pigs with IL4oo to 5oo2 were prepared, and after ultrasound treatment, 10.
The inhibitory activity of the test compound was determined using the 000xP supernatant fraction as an enzyme preparation.

In other words, the reaction for measuring 5-lipoxygenase activity is 2
mM CaCZ2.1mM Glutathione, 2mMAT
P~l-(+40 arachidonic acid (0,16 μCi,
16 μm, 4), with test compound and enzyme, 50
m! , 4 phosphate support', "MJ (pt'17.4)
IIP procedure;'t:, Pretreatment of E* compound 1 and 9 was carried out at 30°C for 5 minutes, and then 30 minutes after addition of arachidonic acid.
It was heated at ℃ for 30 minutes. Thereafter, 0.2N citric acid was added to stop the reaction, and the reaction product was extracted with ethyl acetate. The extract was concentrated under a stream of total nitrogen and fractionated using silica gel thin layer chromatography (noethyl ether: petroleum ether: acetic acid = 85:15:0.1). 5-hydroxyeicosatetraenoic acid (5-hydroxyeicosatetraenoic acid) on a thin layer of silica gel
After identifying the 5-HgTE) fraction using a two-dimensional radioactive scanner, the total radioactivity was quantified and the 50% inhibitory concentration (
IC5o)? Calculated. As a result, the IC5okl of test compound (1) was 0.043 ttM.

Test Example 4 Acute snow test compound ``j!:'' was orally administered to ddY mice (male) and observed for 5 days, and the results shown in Table 4 were obtained.

(j t'iF Table As a result of pharmacological tests on cattle and above, the thiazolinone derivative of the present invention (
I) is used as a therapeutic agent for various chronic complications associated with diabetes, such as diabetic resident cataract; microangiopathy such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy; and various diseases caused by diabetes. It is useful for the prevention and treatment of arteriosclerotic vascular disorders; congenital cataracts associated with lactosemia.

The dosage forms include oral and parenteral administration, and in the case of oral administration, it can be administered, for example, in the form of tablets, pills, granules, powders, capsules, and syrups. In the case of parenteral administration, it can be used, for example, as an injection (intravenously, intramuscularly, subcutaneously), a drop, a suppository, an external preparation, or a patch. For administration to the ocular mucosa, eye drops and eye ointment are preferable. .

The dosage of the active ingredient according to the present invention varies depending on the desired therapeutic effect, administration method, treatment period, age, body weight, symptoms, and dosage form, but is 50 rli to 50 rli per day for adults. can be administered orally or parenterally. In addition, in the case of ocular mucosal administration, a 0.1 to 10-thickness agent is preferable.

The active ingredient of the present invention can be prepared in a conventional manner using excipients, lubricants, binders, flavoring agents, solubilizing agents, clouding agents,
Coating aids and other additives commonly used in the field of formulation technology can be used as appropriate.

Next, a more specific explanation will be given using a formulation example t.

Formulation example Oral capsule Compound 1100η

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and R^2 represents a hydrogen atom or a carbon number Represents 1 to 5 alkyl groups, R^3 is a hydrogen atom, and has 1 carbon number
to 4 aliphatic acyl groups, aromatic acyl groups that may have substituents, or five- or six-membered heterocyclic acyl groups containing nitrogen, oxygen, and sulfur atoms, and R^4 has 1 carbon number.
It represents an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, R^5 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and W is Methylene group, carbonyl group, formula>CH-OH group, formula>C=N-OR^6 group (in the formula, R^6 is a hydrogen atom,
An alkyl group having 1 to 4 carbon atoms which may have a carboxyl group or a lower alkoxycarbonyl group as a substituent, an aralkyl group having 1 to 4 carbon atoms which may have a substituent, and an aliphatic acyl group having 1 to 4 carbon atoms. , represents an aromatic acyl group which may have a substituent or a five- or six-membered heterocyclic acyl group containing nitrogen, oxygen, or sulfur atoms. ) or may form a double bond together with U described below, and U represents a methylene group or a double bond together with W, but when W is a carbonyl group or the formula>C=N-OR^6 Group (
In the formula, R^6 has the same meaning as described above. ) may form a double bond together with R^1, and n represents an integer of 1 to 3. ] A therapeutic agent for diabetic complications comprising a thiazolidine derivative represented by the following and a pharmacologically acceptable salt thereof as an active ingredient.