JP2001131088A - Therapeutic agent for syndrome x - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic and/or a therapeutic agent for syndrome X, etc. SOLUTION: Anti-TXA2 compound is used as the prophylactic and/or the therapeutic agent for syndrome X. The anti-TXA2 compound can become a prophylactic/therapeutic agent for insulin-resistant diabetes alone and a prophylactic/therapeutic agent for hyperlipemia. Since further the anti-TXA2 compound stabilizes arteriosclerotic nest, the anti-TXA2 can become a prophylactic/therapeutic agent for arteriosclerosis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for preventing and / or treating Syndrome X syndrome, a stabilizer for atherosclerotic lesions, an agent for improving insulin resistance, and an agent for preventing and / or treating hyperlipidemia.

[0002]

BACKGROUND OF THE INVENTION Diabetes, hypertension and hyperlipidemia are risk factors for atherosclerosis and subsequent cardiovascular accidents. A state in which these diseases are combined in the same individual is called Syndrome X syndrome, and it is known that the risk of cardiovascular accidents increases dramatically.

However, in the case of Syndrome X syndrome, it is necessary to use a combination of a therapeutic agent for diabetes, a therapeutic agent for hyperlipidemia, and a therapeutic agent for hypertension. The combined use of such drugs requires adjustment of the respective doses according to the patient's condition, and furthermore, the side effects must be taken into consideration, and the burden on the doctor is great. The burden of having to take drugs is also great. Therefore, a single compound having a preventive or therapeutic effect on Syndrome X syndrome, that is, a drug containing a single compound having a plurality of pharmacological effects simultaneously is desired.

[0004]

An object of the present invention is to provide a drug capable of preventing or treating Syndrome X syndrome. Another object of the present invention is to provide a preventive and / or therapeutic agent for diabetes (particularly diabetes due to insulin resistance), hyperlipidemia, or hypertension. Further, another object of the present invention is to provide an atherosclerotic lesion stabilizing agent to enable prevention and / or treatment of arteriosclerosis.

[0005]

SUMMARY OF THE INVENTION The present invention relates to a preventive and / or therapeutic agent for syndrome X syndrome comprising an anti-TXA2 compound.

[0006] In a preferred embodiment, the anti-TX
The A2 compound is a compound having a TXA2 receptor antagonism.

[0007] The present invention also relates to an atherosclerotic lesion stabilizer comprising an anti-TXA2 compound.

In a preferred embodiment, the anti-TX
The A2 compound is a compound having a TXA2 receptor antagonism.

Further, the present invention relates to an insulin sensitizer comprising an anti-TXA2 compound.

In a preferred embodiment, the anti-TX
The A2 compound is a compound having a TXA2 receptor antagonism.

[0011] The present invention also relates to a preventive and / or therapeutic agent for hyperlipidemia comprising an anti-TXA2 compound.

In a preferred embodiment, the anti-TX
The A2 compound is a compound having a TXA2 receptor antagonism.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION An anti-TXA2 compound is used as an agent for treating / preventing syndrome X syndrome of the present invention. In the present invention, the anti-TXA2 compound is a compound having a TXA2 synthesis inhibitory activity, a compound having a TXA2 receptor antagonism, a compound having a TXA2 antagonism, or a compound having an effect of blocking signal transmission from the TXA2 receptor. Or say.

TXA2 (thromboxane A2) is a metabolite of arachidonic acid mainly produced from platelets and the like, and induces platelet aggregation and contracts vascular smooth muscle. Therefore, TXA2 is important as a chemical mediator causing thrombosis, ischemic heart disease, and cerebrovascular disorder. In addition, TXA2 is involved in the onset or exacerbation of bronchial asthma and bronchitis because it contracts the smooth muscle of the trachea and bronchi. Therefore, substances that inhibit the production of TXA2 and drugs that antagonize the TXA2 receptor are recognized to be effective in treating the above diseases.

By the way, it is known that in diabetes, TXA2 production is increased, the balance with PGI ₂ (prostaglandin I ₂ ) is lost, and vascular complications due to excessive aggregation of platelets are likely to occur. Therefore, anti-TXA2 compounds are said to be effective for diabetic vascular complications and diabetic neuropathy. Insulin plays a very important role in the development of diabetes. The target organ for insulin is muscle,
In the liver and adipose tissue, among them, in muscle and adipose tissue, insulin acts to keep blood glucose constant by enhancing the uptake of sugar into cells. Intake of sugar into cells of this insulin cannot be enhanced,
A state in which the ability to lower the blood glucose level is reduced is called insulin resistance. By improving the insulin resistance, reduction in blood glucose level, improvement in HbA1c, and prevention and treatment of diabetic complications are expected. However, although it has been known that the anti-TXA2 compound is effective for diabetic vascular complications and neuropathy, it has not been known until now that insulin resistance is improved, that is, the blood sugar level is reduced. .

The present inventors have found for the first time that anti-TXA2 compounds can ameliorate the symptoms of insulin resistance. That is, they have found for the first time that an anti-TXA2 compound is used for treatment and prevention of insulin-resistant diabetes, and have completed the present invention.

[0017] Hyperlipidemia is a major risk factor for arteriosclerosis. In hyperlipidemia, LDL cholesterol shows a high level, and macrophages that phagocytose this LDL cholesterol are called foamed macrophages, which cause inflammation in the intima of blood vessels and play a major role in atherosclerotic lesion formation. It is known to fulfill. However, it has never been known that an anti-TXA2 compound lowers serum cholesterol level or serum triglyceride (effect on hyperlipidemia). According to the present invention, it has been shown for the first time that an anti-TXA2 compound has a preventive / therapeutic effect for hyperlipidemia.

On the other hand, as a composition for preventing or treating arteriosclerosis, a TXA2 antagonist is used, for example, as disclosed in JP-A-2-229112 and European Patent Publication No. 2
No. 34708, JP-A-5-70453, and the like. However, the mechanisms of arteriosclerosis prevention and treatment represented by these publications are TXA2 and PGI.
₂ to change the balance. That is, T
XA2 has a platelet aggregation action and a vasoconstriction action, whereas PGI ₂ has diametrically opposite actions of a platelet aggregation suppression action and a vasodilation action. Therefore, it suppresses the action of TXA2 and relatively regulates the PGI ₂ activity. To suppress the enhancement of platelet deposition on arteriosclerotic lesions and to treat and prevent thrombosis. However, the efficacy of a TXA2 antagonist on arteriosclerosis based on development from such a viewpoint has not been confirmed in in vivo studies,
It has not yet been put to practical use as an agent for preventing and treating arteriosclerosis. Thus, the fact is that a TXA2 antagonist has not yet been developed as a therapeutic agent for arteriosclerosis.

In the process from arteriosclerosis to cardiovascular accident, the stability of atherosclerotic lesions (hereinafter referred to as plaques) plays a particularly important role. Unstable plaques have a thin fibrous cap and are rich in lipids and are prone to rupture. When ruptured, the plaque contents flow with the bloodstream and attach to small blood vessels, forming thrombi, causing cardiovascular accidents such as myocardial infarction and angina. It is known that unstable plaques are formed when the proportion of macrophages in the plaque-forming cell group increases. This is thought to be due to the inclusion of cholesterol in the macrophages and the digestion of the fibrous cap by the proteolytic enzymes released by the macrophages, resulting in a thin and brittle cap. Therefore, an agent that reduces the composition ratio of macrophages in plaques can be expected to have an effect of inducing stable plaque formation with a thick fibrous cap and low lipid content and preventing the occurrence of cardiovascular accidents.

The present inventors have found for the first time that an anti-TXA2 compound can reduce the composition ratio of macrophages in plaque, and have completed the present invention.
As described above, it has been pointed out that TXA2 having a platelet aggregation effect is involved in the onset and progression of arteriosclerosis. However, for the formation of vulnerable plaques rich in macrophages, TXA
Although the role of No. 2 was not clear, the present invention has clarified this and found that the generation of vulnerable plaque is suppressed by the anti-TXA2 compound.

That is, the present inventors have surprisingly found that an anti-TXA2 compound has an insulin ameliorating action, a hyperlipidemia, an insulin resistance model animal, a hyperlipidemia model animal or an arteriosclerosis model animal. The present invention has been found to have an improving effect and a plaque stabilizing effect, thereby completing the present invention.

[0022] In the hypertension, although production of TXA2 renal arteries or the pulmonary artery is enhanced, anti TXA2 compound reduces the production of TXA2, or by antagonizing, the balance between the action and PGI ₂ acts TXA2 It is known to normalize and relax vascular smooth muscle.
It is also known that administration of a compound having a TXA2 antagonistic activity from an early stage to spontaneously hypertensive rats (SHR), which is known as a model animal for essential hypertension, suppresses the onset of hypertension due to SHR. (Euro
pean Journal of Pharmacol
ogy 1985, 109, 135). Therefore, it has been known that a compound having a TXA2 antagonistic effect is effective for hypertension.

Therefore, the anti-TXA2 compound has been found to have an antihyperlipidemic effect and an insulin resistance improving effect in addition to the known antihypertensive effect, and is useful as a preventive or therapeutic agent for syndrome X syndrome. It was shown that. Furthermore, against arteriosclerosis, the anti-TXA2 compounds reduce the proportion of macrophages in the plaque, and are beneficial for stabilizing the plaque and thus reducing cardiovascular accidents.

Examples of the compound having an effect of inhibiting the synthesis of TXA2 include (E) -3- (4-1H-imidazol-1-ylmethyl) phenyl) -2-propenoic acid (OK
Y046), 4,5-dihydro-2- (1H-imidazol-1-ylmethyl) -benzo (b) thiophen-6-
Carboxylic acid sodium salt (CS-518), 4-hydroxy (5- (1H-imidazol-1-yl) -2-methylphenyl) methyl-3,5-dimethylbenzoic acid monosodium salt (Y20811), (E)- α-[(4-methoxy-2,5-dimethyl-3,6-dioxo-1,4
-Cyclohexadien-1-yl) methylene] -3-pyridineheptanoic acid (E-6700), (E) -7-phenyl-7- (3-pyridinyl) -6-heptenoic acid (CV
-4151), 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoic acid (E5510), 5,7
-Dimethyl-2- (methylamino) -4- (3-pyridinylmethyl) -6-benzothiazolol (E-304
0), (E) -3- [4- (1H-Imidazol-1-ylmethyl) phenyl] -2-propenyl-methyl-1,
4-Dro-2,6-dimethyl-4- (3-nitrophenyl) 3,5-pyridinedicarboxylate (F-040
1), [1R- [1α, 2β (1E, 3S *), 3
α]]-6-[[2- (3-Cyclohexyl-3-hydroxy-1-propenyl) -3-hydroxy-5-oxocyclopentyl] thio] hexanoic acid methyl ester (TEI-5178), 4-bromo-6 -[3- (4-
Chlorophenyl) propoxy] -5-[(3-pyridinylmethyl) amino] -3 (2H) -pyridazinone monohydrochloride (NM702) and the like.

Examples of the compound having a TXA2 receptor antagonistic action include 4- [2- (benzenesulfamide)
Ethyl] phenoxyacetic acid (BM13177), 4- [2-
(4-chlorobenzenesulfonamido) ethyl] phenylacetic acid (BMI3505), [1S- [1α, 2α
(Z), 3α (1E, 3S *, 4R *), 4α]]-7
-[3- (3-hydroxy-4-phenyl-1-pentenyl) -7-oxabicyclo [2.2.1] hept-2
-Yl] -5-heptenoic acid (SQ29548), [1S
-[1α, 2α (Z), 3α, 4α]]-7- [3-
[[[[(1-Oxoheptyl) amino] acetyl] amino]
Methyl] -7-oxabicyclo [2.2.1] hept-2
-Yl] -5-heptenoic acid (SQ30741), [1S-
[1α, 2α (Z), 3α, 4α]]-6-[[[3- [2-
(Phenylamino) carbonyl] hydrazono] methyl]-
7-oxabicyclo [2.2.1] hept-2-yl]-
4-hexenoic acid (SQ33261), [1S- [1α, 2
α (Z), 3α, 4α]]-6-[[[[[[3- (4-Chlorophenyl) amino] carbonyl] hydrazono] methyl] -7
-Oxabicyclo [2.2.1] hept-2-yl] -4
-Hexenoic acid (SQ33552), [1S- [1α, 2α
(Z), 3α, 4α]]-2-[[3- [4-[[4- (cyclohexylbutyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept- 2-
Yl] methyl] benzenepropionic acid (SQ3396
1), (±) -zeta- (2,4,5-trimethyl-
3,6-dioxo-1,4-cyclohexadiene-1-
Yl) -benzeneheptanoic acid (AA-2414),
[(±)-[1α, 2α (Z), 3β, 4α]]-7- [3
-[(Phenylsulfonyl) amino] bicyclo [2.2.
1] Hept-2-yl] -5-heptenoic acid (S145),
[1R- [1α, 2α (Z), 3β, 4α]]-7- [3-
[[Phenylsulfonyl] amino] bicyclo [2.2.1] hept-2-yl] -5-heptenoic acid calcium salt (S1
452), 3-[[(4-fluorophenyl) sulfonyl] amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propionic acid (BAYu3405),
3- (4-(((4-chlorophenyl) sulfonyl) amino) butyl) -6- (1-methylethyl) -1-azulenesulfonic acid (KT2-962), 6- (2S, 4
R) -1- (4-Chlorophenylsulfonyl) -4-
(4-chlorophenylsulfonylamino) -pyrrolidin-2-yl- (Z) -5-hexenoic acid (FR1068
81), (E) -11- (2- (5,6-dimethyl-1)
-Benzimidazolyl) ethylidine) -6,11-dihydrodibenz (b, e) oxepin-2-carboxylic acid sodium salt (KW3635), [1R- [1α (Z),
2β, 3β, 5α]]-7- [5-([1,1′-biphenyl] -4-ylmethoxy) -3-hydroxy-2-
(1-Piperidinyl) cyclopentyl] -4-heptenoic acid (GR32191), 2-((((4-chlorophenyl) sulfonyl) amino) methyl) -2,3-dihydro-1H-indene-5-acetic acid monosodium salt ( Z33
5), (E) -5-[[[pyridinyl [3- (trifluoromethyl) phenyl] methylene] amino] oxy] pentanoic acid (R68070), 5 (Z) -7- [2,2-dimethyl-4 -Phenyl-1,3-dioxan-cis-5-yl] heptenoic acid (ICI159999), 5 (Z) -7
-[(2,4,5-cis) -4- (2-hydroxyphenyl) -2-trifluoromethyl-1,3-dioxan-5-yl] heptenoic acid (ICI 185282), 4
(Z) -6-[(2,4,5-cis) 2- (2-chlorophenyl) -4- (2-hydroxyphenyl) 1,3-
Dioxan-5-yl] hexenoic acid (ICI 19260)
5), 7- [2α, 4α- (dimethylmethano) -6β-
(2-cyclopentyl-2β-hydroxyacetamido) -1α-cyclohexyl] -5 (Z) -heptenoic acid (ONO3708), (−) 6,8-difluoro-9-
p-Methylsulfonylbenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L67059)
6), 3- [1- (4-chlorobenzyl-5-fluoro-3-methylindol-2-yl] -2,2-dimethylpropionic acid (L655240), N, N′-bis [7- (3 -Chlorobenzeneaminosulfonyl) -1,
2,3,4-tetrahydro-isoquinol-yl] disulfonylimide (SKF88046), [1α (Z),
2β, 5α]-(+)-7- [5-[[(1,1′-biphenyl) -4-yl] methoxy] -2- (4-morpholinyl) -3-oxocyclopentyl] -4-heptenoic acid (AH23848), (Z, 2-endo-3-oxo) -7- (3-acetyl-2-bicyclo [2.2.
1] Heptyl-5-hepta-3Z-enoic acid-4-phenylthiosemicarbazone (EP092), [(+)-1S
− (1α, 2α, 3α, 4α)]-2-[[3- [4 [(n
-Pentylamino) carbonyl] -2-oxazolyl]-
7-oxabicyclo [2.2.1] hept-2-yl] methyl] benzenepropanoic acid (BMS-180291),
2- (4,5-bis (4-methoxyphenyl) -2-thiazolyl) -1H-pyrrole-1-acetic acid ethyl ester (KBT-3022), 5-n-hexyloxy-3-
(2- (1H-imidazol-1-yl) ethyl) -indoline-1-propionic acid (KY063).

Compounds which simultaneously exhibit TXA2 synthesis inhibitory activity and TXA2 receptor antagonistic activity include, for example, [2S
-[2α, (Z), 4β]]-6- [4-[[(4-chlorophenyl) sulfonyl] amino] -1 (3-pyridinylmethyl) -2-pyrrolidinyl] -5-hexenoic acid (KDI792) and the like. No.

As the anti-TXA2 compound, compounds having the same effect may be used alone or in combination of two or more. Compounds having different effects may be used alone or in combination of two or more.

The dosage form of the anti-TXA2 compound is oral,
It can be parenteral or topical. The dose of the anti-TXA2 compound cannot be determined unconditionally because it depends on the patient's condition, age, weight, administration route, sex, drug to be administered, and the like. In the case of an adult, it is usually preferable to administer 1 to 500 mg / day, preferably 10 to 200 mg / day once or several times a day, but it is needless to say that the dose may vary depending on the various factors described above. .

The dosage form of the anti-TXA2 compound is not particularly limited. The dosage form is appropriately determined depending on the physical properties and administration form of the anti-TXA2 compound. For example, for oral administration, tablets, capsules, granules, fine granules, powders, liquids,
It may be in the form of a syrup or the like. In the case of a preparation for parenteral administration, it may be in the form of injections, drops, suppositories and the like. For topical administration, cataplasms, creams,
It may be in the form of an ointment, a spray or the like.

As the additives, liquids or solvents, and bases used for preparing the above-mentioned various dosage forms of the anti-TXA2 compound, substances generally used by those skilled in the art for the above-mentioned various dosage forms are used.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0032]

EXAMPLES (Example 1) The blood glucose level lowering effect of an anti-TXA2 compound was examined using a mouse known as an insulin resistance model animal. 6 week old C57BL / 6
The blood glucose level of ob / ob mice was measured and 1 after randomization.
The animals were divided into groups of 6 animals. TXA2 receptor antagonist [1S-
[1α, 2α (Z), 3α (1E, 3S *, 4R *),
4α]]-7- [3- (3-hydroxy-4-phenyl-1-pentenyl) -7-oxabicyclo [2.2.
1] Hept-2-yl] -5-heptenoic acid (SQ295
48: hereinafter referred to as compound A) or (±) -1α,
2α (Z), 3β, 4α))-7- (3-((phenylsulfonyl) amino) bicyclo (2.2.1) hept-2-yl) -5-heptenoic acid (S145: hereinafter referred to as compound B) ) For 1 day or 2 days for 3 weeks
Once orally. Blood was collected from the tail vein, and the blood glucose level was measured using a glucose analyzer (GL-101, manufactured by Mitsubishi Chemical Corporation). The blood glucose lowering rate was determined from the following equation.

[0033]

(Equation 1)

Table 1 shows the results.

[0035]

[Table 1]

The results show that the anti-TXA2 compound improves blood glucose in a model animal known as insulin resistance.

Example 2 Spontaneously Obese Rats (Zuc
ker, fa, fa) was used to examine the anti-hyperlipidemic effect of the anti-TXA2 compound. Compound A (10 mg / Kg), a TXA2 receptor antagonist, was orally administered once a day to spontaneously obese rats (5 rats per group). After 4 weeks and 6 weeks, the serum cholesterol and serum triglyceride concentrations were measured, and the serum cholesterol lowering rate and the serum triglyceride lowering rate were determined by the following formulas. Table 2 shows the results.

[0038]

(Equation 2)

[0039]

[Table 2]

The results of Example 2 show that the anti-TXA2 activity in a model animal in which hyperlipidemia is known to occur spontaneously
Compounds have been shown to reduce serum cholesterol and serum triglycerides.

Example 3 Using C57BL / 6 mice, the effect of the anti-TXA2 compound on plaque stabilization was examined. This C57BL / 6 mouse is known to form atherosclerotic foci (plaque) when raised on a high cholesterol diet. 10 week old C57BL / 6 mice
The animals were divided into groups of 5 animals. As a control group, a normal diet or a high cholesterol diet (1.25% cholesterol, 15%
Fat), and the test substance administration group was given a TXA2 receptor antagonist compound A or compound B once or twice daily for 12 weeks in addition to a high cholesterol diet.
Oral administration. Twelve weeks later, the aorta was collected and stained with an anti-macrophage antibody (Mac-1) and a secondary antibody (HRPO-labeled rat anti-mouse IgG). HR
PO is horseradish peroxidase.
Table 3 shows the results.

[0042]

[Table 3]

The results of Example 3 qualitatively demonstrate that the anti-TXA2 compound reduces the composition ratio of macrophages in plaques in model animals known to form plaques when raised on a high cholesterol diet. Is shown. From this, by the anti-TXA2 compound,
It was suggested that plaque stability was provided.

Example 4 Japanese White Rabbits (10 weeks old, about 2.5 kg), which are known to form plaque when raised on a high cholesterol diet, were raised on a diet containing 0.5% cholesterol. . Perform grouping with 5 birds per group, TX
Compound B which is an A2 receptor antagonist (30 mg / kg)
Was orally administered twice a day for 10 weeks. Ten weeks later, the descending aorta was excised, the artery was incised in the longitudinal direction, and macrophages in the intimal lesion were stained with a RAM-11 antibody (anti-macrophage antibody), and computer image analysis was performed. The macrophage occupancy at the lesion site was determined based on the above.

[0045]

(Equation 3)

Table 4 shows the macrophage occupancy.

[0047]

[Table 4]

The results of Example 4 show that the anti-TXA2 compound reduces the proportion of macrophages in plaques in model animals known to form plaques when raised on a high cholesterol diet. Is shown in This suggested that the anti-TXA2 compound provided plaque stability.

[0049]

Industrial Applicability The anti-TXA2 compound can be a prophylactic / therapeutic agent for insulin-resistant diabetes and hyperlipidemia and stabilizes atherosclerotic foci (plaque), and therefore can be a prophylactic / therapeutic agent for arteriosclerosis. Was found. Therefore, it can be used as a preventive and / or therapeutic agent for syndrome X syndrome.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 43/00 111 A61P 43/00 111

Claims (8)

[Claims] 1. A preventive and / or therapeutic agent for syndrome X syndrome comprising an anti-TXA2 compound. 2. The preventive and / or therapeutic agent for syndrome X syndrome according to claim 1, wherein the anti-TXA2 compound is a compound having a TXA2 receptor antagonism. 3. An atherosclerotic lesion stabilizer comprising an anti-TXA2 compound. 4. The atherosclerotic lesion stabilizing agent according to claim 3, wherein the anti-TXA2 compound is a compound having a TXA2 receptor antagonism. 5. An insulin sensitizer comprising an anti-TXA2 compound. 6. The insulin sensitizer according to claim 5, wherein the anti-TXA2 compound is a compound having a TXA2 receptor antagonism. 7. A preventive and / or therapeutic agent for hyperlipidemia, comprising an anti-TXA2 compound. 8. The preventive and / or therapeutic agent for hyperlipidemia according to claim 7, wherein the anti-TXA2 compound is a compound having a TXA2 receptor antagonism.