WO1996022086A1

WO1996022086A1 - MEDICINE CONTAINING β-OXO-β-BENZENEPROPANE-THIOAMIDE DERIVATIVE

Info

Publication number: WO1996022086A1
Application number: PCT/JP1996/000046
Authority: WO
Inventors: Hideki Bessho; Youichi Abe; Toshiaki Tamaki; Shoji Kimura; Yasuharu Aki; Masayoshi MITSUKA; Mieko Nagae; Asami Seino; Akihiro Narimatsu; Yuji Abe
Original assignee: Mitsubishi Chemical Corporation
Priority date: 1995-01-17
Filing date: 1996-01-16
Publication date: 1996-07-25

Abstract

A medicine containing a β-oxo-β-benzenepropane-thioamide derivative represented by general formula (I) as the active ingredient and being useful in the treatment and prevention of kidney diseases, diseases caused by the proliferation of smooth muscle fibers and heart diseases, wherein R?1 and R2¿ represent each independently C¿1-6? alkyl, or R?1 and R2¿ bind to each other to form C¿2-5? alkylene; R?3 and R4¿ represent each independently hydrogen, halogeno, C¿1-6? alkyl, C1-6 alkoxy, trifluoromethyl, cyano, nitro, C2-6 dialkylamino or imidazolyl optionally having one or more substituents selected from C1-6 alkyl, C1-6 alkoxy and halogeno.

Description

Specification

Pharmaceuticals containing / S-oxo-S-benzenepropane amide derivative

The present invention comprises a β-oxo-β-benzenepropane amide derivative as an active ingredient, and comprises a renal disease; a disease caused by proliferation of smooth muscle cells; and a heart disease such as angina pectoris, myocardial infarction and heart failure. The present invention relates to a medicament useful for preventing and / or treating a disease. Background art

Blood vessels have a layered structure composed of an intima composed of vascular endothelial cells, a media composed of vascular smooth muscle cells and fibroblasts, and an outer membrane. In healthy adults, blood pressure is maintained by the contraction and relaxation functions of vascular smooth muscle cells, and the blood flow supplied to all organs such as the brain, heart, and digestive organs is regulated. Recently, pathological conditions in the vascular wall have been shown to cause excessive proliferation of vascular smooth muscle cells in response to vascular damage (N. Engl. J. Med. 314, 488-500, 1986). This overgrowth narrows the lumen of the blood vessel and, in some cases, obstructs the blood vessel and interferes with the distribution of blood to the area under control.

Hyperproliferation of vascular smooth muscle cells can be based on internal damage or on external damage. When based on internal damage, for example, it progresses to atherosclerosis, renal hypertension, pulmonary hypertension, vasculitis and diabetic retinopathy. For the prevention and treatment of arteriosclerosis, drugs such as lipid-lowering agents and hypotensive agents have been conventionally used. However, these drugs merely reduce the risk factors for arteriosclerosis and do not affect the cause of the disease itself.

Hyperproliferation of vascular smooth muscle cells due to external injury can be due to wounding and surgery. Surgery that may cause hyperproliferation of vascular smooth muscle cells includes, for example, percutaneous angioplasty using balloon or laser; percutaneous angioplasty using a stent; artectomy, rotaplator Percutaneous angioplasty using a technique called new device; vascular graft surgery including vascular bypass surgery and artificial vascular graft surgery Surgery; an invasive diagnostic method involving internal incision of a blood vessel such as an arterial catheter test; and organ transplantation of the kidney, liver, lung and heart. For example, restenosis occurs approximately 3 to 6 months after percutaneous coronary angioplasty for patients with coronary stenosis, and the incidence is 30 to 40% when using a balloon (J. Am. Coll. Cardiol., 12, pp. 616-623, 1988), 40% by laser (Am. J. Cardiol., 70, pp. 1533-1539, 1992; J. Interventional Cardiol., 5, 15-23, 1992), using a stent 20 to 30¾ (Circulation, 86, pp. 1836-1844, 1992), and 20 to 30 による (at International J. Cardiol., 35, pp. 143-146, 1992; J. Am. Coll. Cardiol., 21, p. 15-25, 1993), and 37¾ (by modern medical care, 25, pp. 2733-2737, 1993). It has been reported that anastomotic stenosis occurs in coronary artery transplantation 15-20%> (Circulation, 88, pp. 93-98, 1993).

In these surgeries, heparin is used to prevent stenosis or occlusion of thrombotic blood vessels during and after surgery (Circulation, 78, pp. 654-660, 1988). However, it has been reported that heparin inhibits the proliferation of vascular smooth muscle cells in normal subjects, but has no effect on the proliferation of vascular smooth muscle cells in patients with restenosis (Lancet, 341, pp. 341-342, 1993). In fact, it has been shown that heparin administration cannot prevent the proliferation of vascular smooth muscle cells that are clinically diagnosed as restenosis (Am. Heart J., 117, pp. 777-782). , 1989).

For these reasons, the search for causative therapeutic agents, such as agents having the effect of suppressing intimal hyperplasia of blood vessels and proliferation of vascular smooth muscle based on internal and external damages, has been advanced. Drugs have been proposed (JP-A-58-65224, JP-A-58-172317, JP-A-2-84402, JP-A-3-83923, JP-A-4-99775, JP-A-4-230630). JP-A-5-194226, JP-A-6-9688, and JP-A-6-157332). However, no promising drugs have yet been found.

On the other hand, in renal diseases such as glomerulonephritis, diabetic nephropathy, sclerosis, and nephrotic syndrome, it is known that the disorder progresses due to an increase in glomerular pressure, and drugs that reduce glomerular pressure are It has been reported to inhibit the worsening of disability (Brunner, EP et al., Kidney Int., 36, pp. 969-977, 1989; and Anderson, S. et al., Kidney Int., 36, pp. 526-536, 1989). Antihypertensive drugs such as calcium antagonists Some believe that it is useful for treatment and prevention, but calcium antagonists mainly act in a relaxant manner on imported arteries to increase renal blood flow, but at the same time increase glomerular filtration rate Therefore, the glomerular pressure does not decrease (Naunyn-Schmiedeberg's Arch. Pharmacol., 336, 572, 1987). Therefore, there is a need for the development of a therapeutic agent for 肾 disease, which has the effect of increasing renal blood flow and lowering glomerular pressure without increasing glomerular filtration rate.

Heart diseases such as angina, myocardial infarction, and heart failure are among the three major adult diseases along with stroke and cancer, and the number of patients is increasing year by year as the population ages. For these heart diseases, drugs have been developed mainly for the purpose of improving symptoms. For example, nitrates, 3-blockers, calcium antagonists, etc., are used to treat angina, and perokinase (UK), properokinase (proUK), and tissue plasminogen are used to treat myocardial infarction. Activator-1 (t-PA) is used. In the treatment of heart failure, digitalis (cardiac glycoside), diuretics, angiotensin converting enzyme inhibitors, calcium antagonists, α-blockers, nitric acid and other vasodilators are used clinically. I have.

Since the above-mentioned existing drugs have excellent pharmacological effects in their respective application fields, in recent years, it has been recommended to use different drugs taking advantage of the characteristics of each drug according to the type and symptoms of heart disease. I have. However, for example, the calcium antagonist diltiazem (Di ltiazem: 3- (Acetyloxy) -5- [2-(, dimethylamino) -ethyl] -2,3-dihydro-2- ( 4-methoxyphenyl)-1, 5-benzothiazepin _4 (5H)-one) Ester) has an inhibitory effect on HK and cannot be applied to heart failure. Also, it is not easy for a cardiologist to make an accurate diagnosis in an emergency and to make an appropriate selection from existing treatments according to the disease. Therefore, there is a need for the development of a therapeutic agent for heart diseases that can be applied to heart diseases such as angina pectoris, myocardial infarction, and heart failure without distinction. JP-A-5-246980 discloses that the following formula:

(Wherein, R ¹ and R ² each independently represent a hydrogen atom, or an alkyl group or a cycloalkyl group of C ₃ -C ₆ for ~, or R ¹ and R ² together such connexion - (- ₆ of represents a Arukire emissions group. R "represents a hydrogen atom, an alkyl group or a cycloalkyl group of C ₃ -C ₆ for ~, or R ⁴ represents an alkyl group or - a cycloalkyl group of C ₆ a -, or R ³ and R ⁴ together represent a C _{2 to} C _r alkylene group, X ¹ , X and X ³ each independently represent a hydrogen atom, a halogen atom, an alkyl group of (^ to ^, c ₃ A cycloalkyl group of

(^ - (^ alkoxy group, Application Benefits Furuoromechiru group, Shiano group, nitro group, dialkyl amino groups c ₂ to c _12, a sulfamoyl group, or a nitrogen as a good diplomatic atoms which may have a substituent Represents a 5- or 6-membered heterocyclic group containing atoms, provided that R ¹ represents a hydrogen atom, R ² represents an n-propyl group, R ³ represents a hydrogen atom, R ⁴ represents a methyl group, and X ¹ , ( ^Except when X ² and Χ ^{並びに} represent a hydrogen atom, and R ¹ represents a hydrogen atom, R ² , R ³ , and R ^{4 all} represent a methyl group, and X ¹ , X ^2, and ^ represent a hydrogen atom) ^ -Oxo-β-benzenepropane amide derivative represented by the formula:

This publication states that the S-oxo-β-benzenepropane thioamide derivative represented by the above general formula has a potassium channel opening action, a vasodilator action, a bronchodilator action, a gastrointestinal smooth muscle relaxation action, etc. It is taught that its pharmacological action is useful for treating hypertension, asthma, irritable bowel syndrome and enteritis. Specifically, a compound of R ¹ = H; R ² = Me; R ³ = Me; R ⁴ = Me; X 4-cyano; X ² = H; X ³ = H (No. 224), R ^ H R ² = e; R ³ = Me; R ⁴ = Me; X ¹ = 4- (l-imidazolyl); X ² = H; a compound of X ³ = H (No. 226), R ^ H; R ^{^{2 = Me; R 3 = Me}} ; R 4 = Me; ( preparative ^{Imidazoriru); X 2 = H; X} 3 = compound of H (No.

265), R ^ H; R 2 = e; R u and ^{_{_{R 4 = -CH 0 CH 0 CH}}} 0 -; 4- (1- I ^{imidazolyl); X 2 = H; X} 3 = compound of H (No. 356); and RH; R Me; R ³ and ^{_{_{R 4 = - CH 2 CH 2}}} CH 2 -; X 1 - (2- methylcarbamoyl-1-b ^{imidazolyl); X 2 = H; X} 3 = compound of H (No. 357) discloses a drug dose (IC _{3 ()} ) that inhibits 20 mil force rheumatoid contraction by 30% using rat thoracic artery. In addition, in the same publication, the above-mentioned compound of No. 224, compound of No. 226, compound of No. 265, R ^ H; R ² = Me; R ³ = Me; R ⁴ = Me; X ¹ = 2 -(l—T midazolyl); a compound of X ² = H; X ³ = H (No. 302), R ^ H; R ² = Me; R ³ and R ⁴ =-CH ₂ CH ₂ _; X ¹ = 4- (l-imidazolyl); Χ ^Δ = Η; Χ ³ = Η (No. 342), No. 356, and No. 357 compounds reduce blood pressure in spontaneously hypertensive rats Is disclosed. However, this publication does not suggest or teach the effects of the above compounds on the kidney; the effects on the proliferation of vascular smooth muscle cells; and the usefulness in the treatment and prevention of heart disease. Disclosure of the invention

An object of the present invention is to provide a medicament useful for treating and preventing or preventing renal disease. More specifically, it rapidly reduces intraglomerular pressure based on a new mechanism of action that is different from conventional therapeutic agents for renal disease, and reduces glomerulitis, diabetic nephropathy, renal sclerosis, and nephrotic syndrome. (4) An object of the present invention is to provide a medicament capable of preventing the occurrence of a disease beforehand or effectively treating a renal disease as described above. From another viewpoint, an object of the present invention is to provide a method for preventing renal disease, which can rapidly increase blood flow without increasing the amount of glomerular filtration, and can suppress the occurrence and progression of renal damage. Or to provide a therapeutic agent.

Another object of the present invention is to provide a medicament useful for treating and preventing or preventing arteriosclerosis and aortic aneurysm, and for preventing arterial stenosis after angioplasty. More specifically, it suppresses the excessive proliferation of vascular smooth muscle cells based on a new mechanism of action different from conventional drugs, and prevents the occurrence of arteriosclerosis, aortic aneurysm, etc., and cures them. It is an object of the present invention to provide a medicament which enables a therapeutic treatment or the prevention of arterial stenosis after angioplasty.

Still another object of the present invention is to provide a medicament which can treat and prevent or prevent heart diseases such as angina, myocardial infarction, and heart failure. More specifically, it has pharmacological actions such as coronary vasodilator action, coronary spasm remission action, ischemic myocardial protection action, inotropic action, angina pectoris, myocardial infarction (acute myocardial infarction, chronic myocardial infarction), heart failure, etc. It is an object of the present invention to provide a medicament capable of preventing the occurrence of heart diseases in advance or enabling treatment of these heart diseases. . The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a specific / 3_oxo_3-benzenebenzenepropane thioamide derivative known to have a potassium channel opening action has a blood flow rate Has the effect of increasing urinary volume and urinary excretion of urine by increasing urine output without increasing glomerular filtration rate. I found something. In addition, the present inventors have concluded that the above-mentioned compound has an inhibitory action on the proliferation of vascular smooth muscle cells; It has a favorable pharmacological action on the heart, does not suppress cardiac function unlike conventional calcium antagonists, and has found that its action on coronary and ischemic myocardium is excellent in selectivity. The present invention has been completed based on these findings.

That is, the present invention provides the following formula (I):

(Wherein, R ¹ and R ² each independently represent a CΊc ₆ alkyl group, or are linked to each other to represent a C _{2 to} C ₅ alkylene group, and R ³ and R ⁴ each independently represent a hydrogen atom atom, a halogen atom, (^ - (^ alkyl group; triflate Ruo Russia methyl; Xia amino group; a nitro group; dialkyl § of ~ c ₆ amino group; ~ alkoxy group or ~ alkyl group, to c ₆ Represents an imidazolyl group optionally having one or more substituents selected from an alkoxy group and a halogen atom.) YS-oxo-3-benzenepropane amide derivative represented by the formula: Provide a preventive and therapeutic agent for diseases; a preventive and therapeutic agent for diseases caused by proliferation of smooth muscle cells; and a preventive and therapeutic agent for heart disease, comprising a salt, a hydrate or a solvate thereof as an active ingredient.肾 Disease prevention · Use of the above compound for the manufacture of a prophylactic / therapeutic agent for a disease caused by proliferation of smooth muscle cells, and a prophylactic / therapeutic agent for a heart disease is also provided as one embodiment of the present invention. , R ³ is (^ ~ (: ₆ alkyl groups, (^ ~ (; ₆ alkoxy Shi group and each prophylactic or therapeutic agent of the is one or more substituents which may I Midazo Lil group which may have a selected from a halogen atom; R ⁴ or the agent for preventing or treating the hydrogen atom; R Each of the above-mentioned prophylactic and therapeutic agents wherein ¹ and R ² are linked to form a trimethylene group; each of the above prophylactic and therapeutic agents wherein R ³ is bonded to the carbonyl group in a para-position to the carbonyl group; Each of the above prophylactic and therapeutic agents wherein R ³ is a 1-imidazolyl group.

In another aspect of the present invention, there is provided a method comprising a step of administering an effective amount of each of the above-mentioned medicaments to a mammal (preferably a human), comprising renal disease, arteriosclerosis, and large cerebral aneurysm. A method of preventing and / or treating a disease selected from the group consisting of arterial stenosis after angioplasty and heart disease; a method of reducing glomerular internal pressure without substantially changing the glomerular filtration rate; A method for inhibiting coronary blood flow without inhibiting cardiac function; a method for increasing coronary blood flow; a method for relieving coronary spasm; a method for protecting ischemic myocardium; How to improve myocardial contractile dysfunction; How to increase myocardial contractility; How to relieve coronary spasm without suppressing cardiac function; How to protect ischemic myocardium without suppressing cardiac function; Suppress How to improve local contractile dysfunction of the myocardium without is provided.

Further, as a drug containing the compound of the above formula U) as an active ingredient, a renal protective agent; a dilator of glomerular imported and exported arterioles; a vascular protective agent; Is selected from the group consisting of angina pectoris, myocardial infarction, and heart failure; the above-mentioned agents for preventing and treating heart disease; agents for increasing coronary blood flow; agents for protecting ischemic myocardium; An agent for increasing coronary blood flow without suppression of function; an agent for protecting ischemic myocardium; and an agent for improving local myocardial contraction insufficiency are provided. In another embodiment, use of the compound of the above formula (1) for the production of these medicaments is provided. Is provided. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing that the medicament of the present invention suppresses a decrease in ATP content in reperfused myocardium. BEST MODE FOR CARRYING OUT THE INVENTION

The prophylactic / therapeutic agent of the present invention is represented by the formula (I): δ-oxo-β-benze It is characterized in that an active ingredient is a propanepanamide derivative, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. In the above definition, (^-(^ alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group, etc. Examples of the C ₂ -C ₅ alkylene group include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, etc. Examples of the halogen atom include a fluorine atom and a chlorine atom. , A bromine atom or an iodine atom may be used. (Examples of the alkoxy group of ^ to (: ₆ include, for example, a methoxy group, an ethoxyquin group, an n-propoxy group, an isopropoxy group, an n-butoxy group, Examples thereof include an n-pentyloxy group, an n-hexyloxy group, etc. Examples of the dialkylamino group of c _{2 to} c ₆ include, for example, a dimethylamino group, a methylethylamino group, and a getyla group. Examples include a mino group and a dipropylamino group. The imidazolyl group can be bonded to the phenyl group at any position.

As a pharmaceutically acceptable salt of the compound represented by the formula (I), an acid addition salt and the like can be used. For example, mineral salts such as hydrochloride, sulfate and phosphate, and acetates Organic acid salts such as malonate, fumarate, maleate, methanesulfonate, and paratoluenesulfonate can be used as acid addition salts. Any hydrate or solvate thereof may be used as an active ingredient of the medicament of the present invention, in addition to a salt or a compound in a free form. Solvents that can form solvates with the above compounds include, for example, methanol, ethanol, isopropanol, acetate, ethyl acetate, methylene chloride, and the like. It is preferable to use an ethanol solvate that is a solvate. Further, the compound represented by the formula (I) may have one or two or more asymmetric carbon atoms depending on the types of R ¹ and R ^2. The isomers, arbitrary mixtures thereof, racemates which are equal mixtures of optical isomers, arbitrary distereoisomers based on two or more asymmetric centers, or arbitrary mixtures thereof, are all the pharmaceuticals of the present invention. It can be used as an effective component of

The compound included in the general formula (1) is a known compound disclosed in Japanese Patent Application Laid-Open No. 5-246980 (EP548680) itself, or is easily prepared by the method described in the same. And can be easily obtained by those skilled in the art. It is a compound that can be used. Among the compounds included in the above general formula, a compound in which R ¹ and R ² are linked to form a trimethylene group; R ³ is one or more selected from an alkyl group of, an alkoxy group of, and a halogen atom A compound which is an imidazolyl group which may have a substituent or a 1-imidazolyl group; a compound wherein R ³ is bonded to the carbonyl group in a para-position to the carbonyl group; or R ⁴ is a hydrogen atom Certain compounds are preferred compounds. Preferred compounds as the active ingredient of the medicament of the present invention are illustrated below, but the active ingredients of the medicament of the present invention are not limited to the following compounds. table 1

, 2 _D 3

Compound No. R ¹ R

1 H Me H H

2 H Me 4-F H

3 H Me 4-0Me H

4 H Me 2- (l— a midazolinole) H

5 H Me 3- (1- midazolyl) H

6 H Me 4- (1-Midazolinore) H

7 H Me 4-(1-midazolyl) 3-C1

8 H Et 4-(1-imidazolyl) H

9 H -Pr 4-(1-imidazolyl) H

10 H n-Pr 4- (1-imidazolyl) H

1 1 H Hex H H

12 Me Me 4— Me H Me Me 4-OMe H

Me e 4-F H

Me Me 4-Br H

Me Me 4- CI H

Me Me 4-CN H

Me Me 4-CF ₃ H

Me Me 4-(1-Dimi Dazolyl) H

Me Me 4- (2- Me-timi dazolyl) H

Me Me 4-(2-Et-1-dimidazolyl) H

Me Me 4- (2- i-Pr-toy mi dazolyl) H

Me Me 4-(2-n- Pr-1-imi dazolyl) H

Me Me 4- (2-1 small imidazolyl) H

Me Me 4-(2- OMe-1-imi dazolyl) H

Me Me 4- (2-C1-1-Midazolyl) H

Me Me 4- (4- Me- tomi dazolyl) H

Me Me 4- (5-Me)

Me Me 4- (4, δ-di-Cl-l-dimidazolyl) H

Me Me 4-(1- imi dazolyl) 3-F

Me Me 4-C1-) 3-C1

Me Me 4- (1- imi dazolyl) 3-Br

Me Me 4-(1- I Midazolyl) 3-1

Me Me 4- (1-dimidazolyl) 3-CN

Me Me 4- (1- imi dazolyl) 3- Me

Me Me 4- (1- Dimi dazolyl) 3-Et

Me Me 4- (1- imi dazolyl) 3-i-Pr

Me Me 4-(1-Dimi dazolyl) 3-n-Pr

Me Me 4-(1-i midazolyl) 3-OMe

Me Me 4- (1-Dimi dazolyl) 3-ΟΕΐ

Me Me 4- (1-dimidazolyl) 3-O-iPr

r 71 Me Me 3- (l-mi dazolyl) 4-OPr

72 Me Me 3-C1- imi dazolyl) 4-CF ₃

73 Me Me 2-C1-

74 Me Me 2- (2-Me-Toy Mi Dazolyl) H

75 Me Me 2-(2-Et 10 mi dazolyl) H

76 Me Me 2- (2-i-Pr-1-imidazolyl) H

77 Me Me 2- (2-n- Pr-mi-dazolyl) H

78 Me Me 2- (2-1-Timi dazolyl) H

79 Me Me 2- (2-OMe-1-imidazolyl) H

80 Me Me 2- (2-CH-Midazolyl) H

81 Me Me 2- (4-Me-timi dazolyl) H

82 Me Me 2- (5-Me-toymi dazolyl) H

83 Me Me 2-(4,5-di-Cl-l-imidazolyl) H

84 Me Me 2- (1-imidazolyl) 3-F

85 Me Me 2- (1-Dimidazolyl) 3-CI

86 Me Me 2- (1-dimidazolyl) 3-Br

87 Me Me 2- (1-dimidazolyl) 3-1

88 Me Me 2- (1-dimidazolyl) 3-CN

89 Me Me 2- (1-dimidazolyl) 3-Me

90 Me Me 2- (1- i Midazolyl) 3-Et

91 Me Me 2- (1-imidazolyl) 3-i-Pr

92 Me Me 2-(1-dimidazolyl) 3-n-Pr

93 Me Me 2- (1-dimidazolyl) 3-O e

94 Me Me 2-C1-Imidazolyl) 3-OEt

95 Me Me 2- (1-dimidazolyl) 3-O-iPr

96 Me Me 2- (1-dimidazolyl) 3-OPr

97 Me Me 2- (1- I Mi Dazoriru) 3- CF ₃

98 Me Me Otte OMe

99 Et Et 4- (1-i midazolyl) H 100 Et Et 4-(1-imi dazolyl) 3-F

101 Hex Hex 4-(1-imi dazolyl) H

102 (1 Me Hex 4-(1-imi dazolyl) H

103 4-(1-Dimi dazolyl) H

104 3-(1-Dimi dazolyl) H

105 2-(1-imi dazolyl) H

106-CH ^ H CH-HH

108-CH CH CH-4- -C1 H

109-CH ^ CH ^ CH ^-4- -Br H

110-CH ^ CH ^ CH ^-4- -I H

111-CH ^ CH ^ CH ^-4- -Me H

116 llr> V «H Il 4- (1--imi dazolyl) H

117 Cilri H 4- (2- -Me-1-i midazolyl) H

118 HrjChrjCll-4- (2-Et-l-imidazolyl) H

119 4- (2- -i-Pr- 1-dazolyl) H

120 "HfjChrjChf)" 4- (2- -n-Pr-1--midazolyl) H

121 4- (2- -I-1-imi dazolyl) H

122 Hrj-I 4- (2-OMe-1-imi dazolyl) H

123 'H Hrj-1- (2- -C1-1-imidazolyl) H

124 4- (2- ■ Me-1-iimidazolyl) H

125 One 4- (4- -Me-1-ymidazolyl) H

126 Hf> Hc Hi) -1- 4- (5-Me-1-imidazolyl) H

127 4- (4, 5-di-Cl-l-imidazolyl) H

128 4- (1-Dimidazolyl) 3-F

129-CH CH CH ^-4- (1-imidazolyl) 3-C1

130-CH ^ CH CH-4- (1-imidazolyl) 3-Br

131-CH CHgCH-4-(1-imidazolyl) 3-1

132 4- (1-imidazolyl) 3-CN

133 4-(1-Dimi dazolyl) 3-Me

134 4- (1-imidazolyl)

3- Et

135 One CH9 then one Ho 4- (1-imidazolyl) 3- i-Pr

136-CllgClIg-4-(1-imidazolyl) 3-n-Pr

137 4-(1-Midazolyl) 3-OMe

138 4-(1-imidazolyl) 3-OEt

139 4-(1-Dimi Dazolyl)

3-0-i-

140-CilgCil Cll-4- (1-Dimidazolyl) 3-OPr

141-Cll Cll Cilg-4- (1-imidazolyl) 3-CF ₃

143-CiigCn Cii-3-C1 H

144 One Hr> One Re 3-CN H

145-Cxi Cn Cn-3- Me H

147 3- (1-imidazolyl) H

148 3- (2-Me-Timi dazolyl)

H

149 -shi ii Cn Cxi-3- (2-Eth-trimidazolyl) H

150 3-(2-i-Pr-H midazolyl)

H

151-ul Cii Cn-3-(2-ΙΊ-Pr-1-dimidazolyl) H

152 3-(2-1-1- i midazolyl) H

153 3- (2-OMe-l- imi dazolyl) H

154 レ Hr> H H ure H9 -1- (2-C1-1-imidazolyl) H

155 レ Ho H Hf> レ H H woo 3-(2-Me-1-i midazolyl) H

156 3- (4-Me-trimi dazolyl) H

157 レ Ho Ho Ho H Hr 1 3-(5-Me-Timimidazolyl) H O 9/22

158-CH CHgCI ^-3-(4, 5-di- -C1-1- imidazolyl) H

159-CH CHgCH-3-(Timi dazolyl) 4-F

160 3-(Timi dazolyl) 4-C1

161-CH CHgCi ^-3--(1-imidazolyl) 4-Br

162-CH ^ CH CH-3--(1-imidazolyl) 4-1

163-Ci ^ Cl ^ CH-3--(1-imidazolyl) 4-CN

164 レレ C Il Cil 3- 3--

165 ure Hure IigCxi I 3--(1-imidazolyl) 4-Et

166 3--(1-imidazolyl) 4-i-Pr

167-Cil Cil Cil-3--(1-imidazolyl) 4-n-Pr

168-CngCil Cll-3--(1-imidazolyl) 4-OMe

169-Cll CilgCll-3--(1-imidazolyl) 4-OEt

170 ^_ CH H> Cn2 ~ 3--(1-imidazolyl) 4-0-i-Pr

171 3- -α-Midazolyl) 4-OPr

172 3- ■ (1-imidazolyl) 4-CF ₃

173 3- • CF ₃ 4-CI

174 4- (2-diimidazolyl) H

175 2- (1-imidazolyl) H

176 2- (2-Me-l-imidazolyl) H

177 2- (2-Et

-l-i mi dazolyl) H

178 One Cng and H H 2- (2-i-Pr-1 -imidazolyl) H

179 H H9 H HrjCHrj-1- (2-n-Pr-1-i-midazolyl) H

180 Cll then il) Hrj 1 2-(2-1-1-imidazolyl) H

m-ure H-ure H9-le Hrj-1 2- (2-OMe-l-dimidazolyl) H

182 One-piece H-ure 2- (2-C1-1-dimidazolyl) H

183 レ Hf Hi) レ 2- 2- (4-Me-l--midazolyl) H

184 レ Ho Ho Ho 一 1 2- (5-Me-l-5- midazolyl) H

185 H H ₀ HQ Η Η 2-(4, 5-di-Cl-l-midazolyl) H

186 Ii Cii then H. One 2- (1-dimidazolyl). 3-F 187-CH ^ CH ^ CH ^-2-(1-dimidazolyl) 3-C1

188-CH ^ CH CH-2- (1-imidazolyl) 3-Br

189 2- (1-imidazolyl) 3-1

190-CH CH CH-2- (1-imidazolyl) 3-CN

191 2- (1-imidazolyl) 3-Me

192 2- (1-imidazolyl) 3-Εΐ

193 2- (1-imidazolyl) 3-i-Pr

194 2- (1-imidazolyl) 3-n-Pr

195-Cii Cn C-2-C1-imidazolyl) 3-OMe

196-Cxi CilgCil-2- (1-imidazolyl) 3-ΟΕΐ

197 2- (1-imidazolyl) 3-0-i-Pr

198 2-C1-imidazolyl) 3-OPr

199 2-(1-Dimi Dazolyl)

3- F3

200 One dore Hure Ii One 2-CN 3-CF ₃

201 1 Cllr) H 1 3-N0 ₂ 4-O e

203 -CHrjChrjCil-3-OPr H

204 One Cll Re Hrj One 3-CN 4-CN

205 One Shi H Hhr Two-OMe 4-OMe

206 H H

207 ーレレレ Hrj 一 4-F H

208-(CH ₂₎ 4-4- (1-imidazolyl) H

209 H H

- ^(CH 2) 5—

21 Me Me 3- (2-1- 1- imi dazolyl) 4-OMe

211 Me Me 3- (2-Me-Timi midazolyl) 4-OMe

212 4- (2-Br-toy midazolyl) H

213 Me Me 3- (2-OMe-l- imi dazolyl) 4-OMe

214 Me Me 3- (2-1 small dazolyl) 4-Et

215 Me Me 3- (2-Me-toymi dazolyl) 4-Et 216-CH ₂ CH ₂ CH ₂ -4- (1-imidazolyl) 2-OMe For example, among the compounds exemplified in Table 1 above, the compound of No. 52 (R ¹ and R ² = -CH ₃ ; R ³ = 3- (2-Il-imidazolyl); R ⁴ = H), the compound of No. 73 (R ¹ and R ² =-; R ³ = 2- (1-imidazolyl); R ⁴ = H), No. 116 compound (R ¹ and R ² = -CH ₂ CH ₂ CH _2- ; R ³ = 4- (1-imidazolyl); R ⁴ = H), No. 119 compound (R ¹ and R ² =-CH ₂ CH ₂ CH _2- ; R ° = 4- (2-i-Pr -1-imidazolyl); R ⁴ = H), compound of No. 121 (R ¹ and R ² = -CH ₂ CH ₂ CH _2- ; R ³ = 4- (2-1-1-imidazolyl); R ⁴ = H), compound of No. 138 (R ¹ and R ² = -CH ₂ CH ₂ CH _{^{2 -; R 3 = 4- (}} l- I ^{imidazolyl); R 4 = 3 - OEt} ) compounds such as are preferred have compound as an active ingredient of the medicament of the present invention. As a particularly preferred compound, the compound of No. 116 exemplified in Table 1 above can be exemplified, and this compound is specifically shown as a compound of No. 356 in Table 1 of JP-A-5-246980. Example 1 describes the manufacturing method in detail.

Without wishing to be bound by any particular theory, the /?-Oxo-β-benzenepropane amide derivative described above relaxes both the imported and exported arterioles before and after the glomeruli of the kidney. This has the effect of rapidly increasing the blood flow of the kidney without increasing the glomerular filtration rate. Therefore, the medicament of the present invention has a protective effect on the kidney, and is useful for the prevention and treatment of renal diseases such as glomerulonephritis, diabetic nephropathy, renal sclerosis, and nephrotic syndrome. However, the medicament of the present invention is not limited to these diseases, and can be used for the prevention and / or treatment of any disease that requires kidney protection.

Further, the above-mentioned ^ -oxo-β-benzenepropane amide derivative has an action of suppressing excessive proliferation of smooth muscle cells, particularly vascular smooth muscle cells. Therefore, the medicament of the present invention is useful for various diseases caused by proliferation of smooth muscle cells, for example, arteriosclerosis such as coronary arteriosclerosis, cerebral arteriosclerosis, arteriosclerosis, arteriosclerosis obliterans, aortic aneurysm, and more. It is useful as a prophylactic and / or therapeutic agent for the prevention and disease of vascular hypertrophy or stenosis which occurs after percutaneous angioplasty, vascular transplantation, internal arterial incision, organ transplantation and the like. From another viewpoint, the medicament of the present invention has a protective effect on blood vessels, and prevents or develops arteriosclerosis, aortic aneurysm, or arterial stenosis after angioplasty. It also has the effect of reducing or completely relieving these diseases. However, the medicament of the present invention requires prevention and treatment of arteriosclerosis as one disease, and protection of blood vessels such as hypertension, diabetes, and hyperlipidemia, which may be accompanied by arteriosclerosis. It may be used to prevent or treat any kind of disease.

Furthermore, the above-mentioned oxo-β-benzenepropane amide derivative has an effect of increasing coronary blood flow and relieving coronary spasm, and thus is useful for the prevention and treatment of angina pectoris, and has a protective effect on ischemic myocardium. It is useful in the prevention and treatment of myocardial infarction such as acute myocardial infarction and chronic myocardial infarction. It is also useful for prevention and treatment. In particular, the medicament of the present invention has the above-mentioned pharmacological action on the heart, and is characterized by being applicable to the prevention and treatment of a wide range of heart diseases such as angina pectoris, myocardial infarction, and heart failure. Further, unlike the conventional calcium antagonists, the medicament of the present invention does not decrease cardiac contractility, and has a feature of high selectivity to coronary vessels. Therefore, the medicament of the present invention is not limited to the above-mentioned heart diseases such as angina pectoris, myocardial infarction, and heart failure, and prevents heart diseases requiring protection of cardiac tissues, coronary vessels, and cardiac functions. And can be used for treatment.

Japanese Patent Application Laid-Open No. 5-246980 discloses that the compound, which is an active ingredient of the present invention, has a potassium channel opening action and has a vasodilatory action, a bronchodilatory action, a gastrointestinal tract smooth muscle relaxation action, and the like. It has been shown that pharmacological effects can be expected.However, it has been specifically described that it has a protective effect on the kidney, has a vascular smooth muscle cell proliferation inhibitory effect, and has an effect on coronary blood vessels and cardiac function. Not. Also, as shown in the following examples, the action of the medicament of the present invention on the heart is not based solely on the force channel opening action.

The above-mentioned compound, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, which is an active ingredient of the medicament of the present invention, may be administered to a patient as a medicament itself. It is preferable that a pharmaceutical composition containing one or more of these active ingredients is produced and administered to a patient. Examples of such a pharmaceutical composition include tablets, capsules, pongee granules, powders, pills, troches, sublinguals, and liquid preparations for oral administration, or injections, suppositories, ointments, and patches. Preparations for parenteral administration such as Can be exemplified.

Tablets or capsules for oral administration are usually presented as unit dosages, such as binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding a usual pharmaceutical carrier. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrroli. A disintegrating agent such as don, starch derivative, or sodium starch glycolate; a lubricant such as magnesium stearate; a wetting agent such as sodium lauryl sulfate may be used.

Liquid preparations for oral administration include, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs, as well as dry preparations which can be re-dissolved in water or a suitable vehicle before use. . Such solutions may contain conventional additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyxethyl cellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat. Agents, emulsifiers such as lecithin, sorbitan monoolate, gum arabic, armando oil, rectified coconut oil, oily esters (eg glycerin esters), propylene glycol, ethyl alcohol (including edible oils Non-aqueous media, preservatives such as methyl, ethyl or propyl esters of P-hydroxybenzoic acid, or sorbic acid, and, if necessary, conventional flavoring or coloring agents. it can.

Preparations for oral administration can be manufactured by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation. Formulations for parenteral administration are generally provided as liquid unit dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solutions for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtrating and filling suitable vials or ampoules and sealing. To enhance stability, the composition may be filled into vials after freezing and the water removed under vacuum. Parenteral suspensions are manufactured in substantially the same manner as parenteral solutions, but the active ingredient must be suspended in a vehicle and sterilized with etylene oxide. Can be more suitably produced. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.

The dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the patient's symptoms, weight, age, sex, etc. In this case, about 0.01 mg to l, 000 mg can be administered orally per day per adult. It is advisable to administer such a dosage in one or several divided doses per day. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1: Effect of the drug of the present invention on the kidney

(1) After the dog was anesthetized with pentobarbital, the renal artery was exposed by laparotomy and denervation was performed. The renal blood flow was measured using an electromagnetic blood flow meter, and the glomerular filtration rate was measured by the creatinine clearance method. Systemic blood pressure was measured from the femoral artery via a catheter inserted into the aorta. Urine was collected from a catheter inserted into the ureter. As the active ingredient of the medicament of the present invention, the compounds of No. 116 exemplified in Table 1 above (R ¹ and R ² = -CH ₀ CH ₀ CH _0- ; R ³ = 4- (trimidazolyl); Using R ⁴ = H: 4- (trimidazolyl) -N-methyl-β-oxo-α, a-trimethylenebenzenepropane amide, the drug was continuously infused into the 内 artery (ira).

By continuous administration of the medicament of the present invention (30 zg / kg min. Ira), renal blood flow was rapidly increased (45 °), and remained almost constant during continuous infusion. On the other hand, glomerular filtration rate did not show any change, and almost no change was observed in systemic blood pressure. Table 2 shows the effects of the medicament of the present invention on blood flow and glomerular filtration rate. Table 2 Renal blood flow glomerular filtration rate

(ml g 'inin) (ml' min) Before administration 2.68 ± 0.31 0.72 ± 0.04

After drug administration 3.89 Sat 0.29 0.73 ± 0.06

(2) The effect on glomerular filtration coefficient (kf value) was examined. Pretreatment with acetylcholine (ACh) 4 g kg'min. I.r.a. was performed to maximize both the import and export arterioles. ACh treatment increased renal blood flow 2.1-fold, and no further increase was observed even after administration of the drug of the present invention at 30 ^ g kg min. I. R. A. At this time, there was no change in glomerular filtration rate, and there was almost no change in systemic blood pressure. Table 3 shows the effect of the medicament of the present invention on renal blood flow and glomerular filtration rate when pretreated with ACh. From these results, it is clear that the medicament of the present invention reduces the glomerular pressure without affecting the glomerular coefficient, and is useful for the treatment and prevention of renal disorders. Table 3 Blood flow glomerular filtration rate

(, ml / gmin), ml, 'g'min) Before administration 2.96 Sat 0.33 0.77 Sat 0.05

After ACh treatment 6.31 Sat 0.59 0.82 ± 0.05

ACh treatment + drug 6.83 Sat 0.46 0.81 ± 0.06 Example 2: Effect of the drug of the present invention on vascular smooth muscle proliferation

(1) Inhibition of rat aortic smooth muscle cell proliferation (in vitro)

Rat aortic smooth muscle cells prepared by the enzyme dispersion method (Berk, BC, et al., Hypertension, 13, 305-314, 1989) were inoculated into a 96-well culture plate in the presence of 10¾ FCS / DMEM ( 2.5 xlO ³ 100 ^ l 'ell). On the next day, the medium was replaced with 2% FCS DMEM containing various portability drugs, and the cells were further cultured for 3 days. On the last day, add 5 mg ml of MTT solution 10 \ to the medium, incubate for 4 hours, wash the medium, add 0.04 N HC1 100 1 isopropanol and measure the absorbance at 590 nm to determine the cell number. It was measured

(MTT method). As the active ingredient of the medicament of the present invention, the compounds of No. 116 exemplified in Table 1 above (R ¹ and R ² = -CH ₂ CH ₂ C1L-; R ³ = 4- (1-imidazolyl); R ⁴ = H: 4- (1-imidazolyl)-

N- methyl β- Okiso - shed, - had use the Application Benefits methylene benzenepropanoic Nono ⁰ Nchioami de).

The drug of the present invention (0.64-400 mg) inhibited the proliferation of cultured smooth muscle cells by serum in a dose-dependent manner. Lemakalim: (-)-6-Cyano_3, 4-dihydro-2,2-dimethyl-trans-4- (2-oxo-l-pyrrolidyl) -2H-benzo [b] pyran-3- ol) had no significant effect on the proliferation of smooth muscle cells. Table 4 shows the effect of each drug on vascular smooth muscle proliferation. Table 4 Reagent concentration (^ M) Number of cells (¾) Drug of the present invention 0.64 103

3.2 50

16 20

Remacarim 0.64 105

3.2 96

16 92 (2) Inhibition of vascular smooth muscle cell proliferation in a carotid artery ballooning model (in vivo) Ballooning of the left carotid artery of a rat was performed with a balloon catheter, and 5-bromo-2'-deoxyperidine was implanted by an osmotic pump implanted under the back of the rat. (BrdU, 5-Bromo-2'-deoxyuridine) was administered for 5 days. Alternatively, a solvent (5 ml of gum arabic solution, 5 ml kg) was continuously administered once a day from 3 days before the execution of ballooning. The fifth carotid artery was removed from Ballooning and sliced specimens were prepared. After BrdU in the tissue specimen was stained with an anti-BrdU antibody, the number of BrdU-incorporated cells (BrdU-positive cells) was counted. The average number of BrdU-positive cells in the vehicle-treated group was 103.0 per tissue specimen. On the other hand, in the group to which the drug of the present invention (10 mg / kg) was administered, it was 61.8, which was lower than that in the group to which the solvent was administered. Five ) . Table 5 Reagents Average per tissue specimen

Number of BrdU-positive cells Vehicle-administered group ( _n = 7) 103.0

Drug administration group of the present invention (n = 5) 61.8

Example 3: Effect of the drug of the present invention on the heart

(1) As the active ingredient of the medicament of the present invention, the compound of No. 116 exemplified in Table 1 above (R ¹ and R ² = -CH ² CH ₀ CH.-; R ³ = 4- (trimidazolyl); The following tests were performed using R ⁴ = H: 4- (trimidazolyl) -N-methyl-^-oxo-a, a-trimethylenebenzenepropanethioamide. Control drugs include Nicorandil (N- [2- (Nitrooxy) ethyl] -3-pyridinecarboxamide), which has a potassium channel opening action and increases cGMP and is used clinically in the treatment of angina pectoris. Lemakalim (Lemakalim: (-) _ 6-Cyano-3,4-dihydro-2,2 1: 3- -dimethyl-trans-4- (2-oxo-l-pyrrolidyl) -2H-benzo [b] pyran-3-ol), and a potent drug antagonist, clinically used in the treatment of hypertension and angina pectoris The used two Fujipin was used.

(2) Increased coronary blood flow

The male and female mongrel dogs were thoracotomized under pentobarbital anesthesia, the left circumflex branch of the left coronary artery was removed, and the coronary blood flow was measured using an electromagnetic flowmeter. The test drug was administered intravenously. As a result, the medicament of the present invention (0.01 to 1 mg kg) increased coronary blood flow in a concentration-dependent manner by intravenous administration. Compared with the dose that increases coronary blood flow by 50 冠 (ED _{C ()} ), the medicament of the present invention (ED _{C ()} : 210 g / kg) is different from nicorandil (ED _5Q : 420 kg) used as a control. It was twice as powerful.

In addition, glibenclamide (clibenclamide: N- [4-(^-(2-raethoxy-5-chlorobenzamide) ethyl) benzosulfonyl] -N'-cyclohexylurea), which is known as a calcium channel blocker, is used. An inhibitory experiment on the effect of increasing the coronary blood flow by the medicament of the present invention and nicorandil was conducted. It is suggested that the action suppressed by glibenclamide is based on the potassium channel opening action (see, for example, Biochera. Biophys. Res. Commun., 146, 21-25, 1987). As a result, the action of nicorandil was inhibited by 88.4 ベン by glibenclamide, but the action of the medicament of the present invention was inhibited only by 69.6¾. This result suggests that the effect of the medicament of the present invention on increasing coronary blood flow is not based on the opening effect of a single potassium channel.

(3) Remission of crown spasm

The heart of a male rat (Sprague-Dawley strain) was excised and a force aura was introduced into the aorta. The blood was perfused with Crepes-Henseleit solution in a Langendorff manner at a constant pressure of 60 bandg Hg, and the coronary blood flow was measured using an electromagnetic blood flow meter. Coronary spasm was induced by administering 30 pmole of Endothelin-1 from the aortic power neura. Five minutes after the administration of Endothelin-1, when the decrease in coronary perfusion was stabilized, the test drug was administered from the aortic force neuron. The degree of recovery of coronary perfusion was calculated and defined as the effect of relieving spasm. As a result, the drug of the present invention (3 to 1,000 nmole) restored the coronary blood flow decreased by endothelin-1 in a concentration-dependent manner by intracoronary injection. Perfusion rate was restored to the level prior to endothelin-1 administration (relieving coronary spasm) by the concentration of the drug (ED _{1 Q ()} ). In comparison, the drug of the present invention (ED1 _{() ()} : 180 nmole) was 2.7 times stronger than nicorandil ( _ED1QQ : 480 nmole). In addition, in the same manner as described above, an experiment for inhibiting the action of relieving coronary spasm using glibenclamide of potassium channel-blocker showed that the action of the drug of the present invention was inhibited by only 26%. This result clearly shows that the coronary spasm relieving action of the drug of the present invention is not substantially based on the opening action of the power channel.

(4) Protective effect on ischemic myocardium

The heart of a male rat (Sprague-Dawley strain) was excised and a force aura was inserted into the aorta. Perfusion was performed at constant pressure of 60 mmHg in the Langensdorf method using Cleps-Henseleit solution, and the double product (LVDP x HR) was calculated from the left ventricular pressure (LVDP) and heart rate (HR). After switching to the perfusate containing the test drug, the aortic force neura was blocked 5 minutes later and a 20-minute ischemia was induced. Thereafter, reperfusion was performed for 30 minutes using a perfusion solution containing no test drug. The degree of recovery of the double product after reperfusion was calculated assuming that the double product before the test drug treatment was 100%.

In control experiments, the recovery of the double product 30 minutes after reperfusion was 22.8. On average. The medicament (0.3 to 10 / iM) of the present invention restored the double product after reperfusion in a concentration-dependent manner. When compared with the concentration of the drug that restores cardiac function by 60% (ED _6Q ), the drug of the present invention (ED _6Q : _1.25 M) is about 40 times more potent than nicorandil (ED _6Q : 47 M). Was. Neither drug showed any cardiosuppressive effect in the above concentration range. In addition, the effect of the medicament of the present invention on the energy metabolism of reperfused myocardium was determined by the method of Lamprech, W. and Trautschold, I., Methods of Enzymatic Analysis, edited by HU Bergmeyer, Academic Press (New York), 2101. As a result, the medicament of the present invention suppressed a decrease in myocardial ATP content. The results are shown in Figure 1.

(5) Improving myocardial stunning (local contractile dysfunction)

The male and female hybrid dogs were opened under pentobarbital anesthesia and the left anterior descending coronary artery (LAD) was removed. A pair of ultrasonic crystal probes were inserted into the endocardial layer in the LAD region to measure segment shortening and used as an index of local contraction function. The LAD was occluded for minutes and then reperfused for 120 minutes. Test drug is 15 minutes before ischemia It was continuously infused intravenously until the end of the experiment or administered 30 minutes after reperfusion. As a result, the medicament of the present invention (1 to 10 g kg min) recovered the segment 'shorting after reperfusion in a dose-dependent manner with little effect on blood pressure. The dose (ED _5Q ) to restore 50% of local wall motion «SS) was 0.9 kg min. Remacarim (0.1, 0.3 / ig kg min), which was used as a positive control, also restored the segmentation's shot after reperfusion in a dose-dependent manner, but at the same time significantly reduced blood pressure. Nifedipine (l / g kg min) reduced blood pressure, but had a weaker effect on segment 'shots (ineffective at l / g kg min). Table 6 shows the results. Table 6 Reagents and concentrations Segments Mean blood pressure change

Shortening (¾) (¾) Control (n = 8)-1.8 ± 12.0-8 ± 2.9 Drug of the present invention kg min (n = 6) 52 ± 6.2-9 ± 2.3 "3" g kg min (n = 7) 65 ± 16.5 -11 ± 4.8

10 g kg min (n = 6) 106 ± 8.9-9 ± 9.4 Remacarim 0. lig "kg" min (n = 5) 46 ± 13.1 -25 ± 4.7

0.3 g kg min (n = 5) 81 ± 9.8 -45 ± 4.0 Diphepine 1 μg kg min (n = 6) 29 ± 25.2-31 ± 5.0

In addition, the medicament of the present invention (1 to 10 g / kg min) dose-dependently restored the reduced segment shortening even when administered 30 minutes after reperfusion. Table 7 shows the results. From these results, it is clear that the medicament of the present invention has an action of improving myocardial stunning (local contraction failure). Table 7 Pharmaceutical segmentation and seating of the present invention (¾)

1 g kg min 23 ± 9.4

3 u g kg min 45 ± 8.0

10 g kg min 62 ± 9.3

(6) Inotropic effect

Papillary muscles isolated from the right ventricle of the male guinea pig were suspended on a Magnus device, and the tension was measured using an FD big-box. The specimen was driven by 1 Hz electrical stimulation, and after the tension was stabilized, the test drug was cumulatively added to the nutrient solution. As a result, the medicament (0.01 to 100 M) of the present invention showed a positive inotropic effect in a concentration-dependent manner, and enhanced the myocardial contractile force. On the other hand, remacalime did not show a positive inotropic effect, and showed a negative inotropic effect at high concentrations. Table 8 shows the results.

Table 8 Reagents Vagueness (βΜ) Increase in tension (¾) Drug of the present invention 0.017

0.1 1 10

1 21

10 36

100 65

Remacarim 0.01 0

0.16

1 8

10-53

100 -100

Industrial applicability

The medicament of the present invention reduces glomerular pressure without increasing glomerular filtration rate while increasing renal blood flow, and thus is useful for prevention and / or treatment of various renal diseases. In addition, since it suppresses excessive proliferation of vascular smooth muscle cells, it is also useful for preventing and / or treating arteriosclerosis, cerebral aneurysm, and arterial stenosis after angioplasty. Furthermore, the medicament of the present invention has an effect of increasing coronary blood flow, an effect of relieving coronary spasm, an effect of protecting ischemic myocardium, an effect of improving myocardial stunning (local systolic insufficiency), and an effect of cardiotonia, and suppresses cardiac function It has high selectivity for coronary blood vessels, and is useful for the prevention and treatment of heart diseases such as angina pectoris, myocardial infarction and heart failure.

Claims

The scope of the claims

1. The following formula:

(Wherein, R ¹ and R ² each independently represent an alkyl group of ~ (: ₆ or linked together to represent an alkylene group of C _{2 to} Cr, and R ³ and R ⁴ each independently represent a hydrogen atom; Halogen atom; ~ (: an alkyl group of ₆ ; an alkoxy group of ~; a trifluoromethyl group; a cyano group; a nitro group; a dialkylamino group of c _{n to} c ₆ ; or an alkyl group of ~ (^, ~ c ₆ Represents an imidazolyl group optionally having one or more substituents selected from an alkoxy group and a halogen atom); S-oxo-^-benzenepropane amide derivative, a pharmaceutically acceptable derivative thereof. Prophylactic / therapeutic agents containing renal salts, hydrates or solvates thereof as active ingredients.

2. The following formula:

(Wherein, R ¹ and ^ each independently represent an alkyl group of (^ to (^ or an alkylene group linked to each other, and R and R ⁴ each independently represent a hydrogen atom; a halogen atom; An alkyl group of (^ to (: an alkoxy group of ₆ ; a trifluoromethyl group; a cyano group; a nitro group; a dialkylamino group of ~ c ₆ ; or an alkyl group of ~, an alkoxy group of ~ c ₆ and a halogen atom Or an imidazolyl group optionally having one or more substituents selected from the group consisting of: / 3 -oxo-^-benzenepropane thioamide, a pharmaceutically acceptable salt thereof, and a hydration thereof. Or solvate Prevention and treatment of diseases caused by proliferation of smooth muscle cells as active ingredients ₍

3. The following formula:

(Wherein, R ¹ and R ² each independently represent a C ₆ alkyl group or

1

Represents an alkylene group of c _{2 to} c ₅ ,, 3. and are each independently a hydrogen atom; a halogen atom; an alkyl group of (: ₆ ; an alkoxy group of); a trifluoromethyl group; a cyano group; DOO □ group; Jiarukiruami amino group of c ₂ to c _6; or (^ - (^ alkyl groups, one or more may have a substituent group b imidazolyl selected from alkoxy groups and halogen atoms to c ₆ / 3-oxo-^-benzenepropane amide derivative, its pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient .

4. Prevention of kidney disease 'The following formula for the manufacture of a therapeutic agent:

(Wherein, R ¹ and ^ each independently represent an alkyl group of (^ ~ or are linked to each other to represent a C ₂ -C _r alkylene group; R ³ and R ⁴ each independently represent a hydrogen atom; halogen atom; triflate Ruo Russia methyl; Xia amino group; a nitro group; dialkyl § amino groups c ₂ to c _6; ~ alkoxy group; an alkyl group ~ or ~ alkyl group, alkoxy group and Ha to c ₆ Represents an imidazolyl group which may have one or more substituents selected from a halogen atom), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Use of hydrates or solvates of

5. Prevention of diseases caused by proliferation of smooth muscle cells

(Wherein, R ¹ and! ^ Each independently represent an alkyl group of (^ ~ or are linked to each other to represent an alkylene group of ~ C ₅ ; R ³ and R ⁴ each independently represent a hydrogen atom; a halogen atom ; C ^ Cg alkoxy group; triflate Ruo Russia methyl; Xia amino group; a nitro group; C _n - (alkyl group ~: ₆ Jiarukiruami amino group; or-alkyl groups, and alkoxy groups to c ₆ Represents an imidazolyl group which may have one or more substituents selected from a halogen atom) /?-Oxo- / 3-benzenepropane amide derivative, a pharmaceutically acceptable salt thereof, Use of their hydrates or solvates.

6. Prevention of heart disease · The following formula for the manufacture of a therapeutic agent:

(Wherein, R ¹ and R ² each independently represent (^ to (: an alkyl group of ₆ or linked together to represent an alkylene group of C _{2 to} C ₅ , and R ³ and R ⁴ each independently represent hydrogen atom, a halogen atom, an alkyl group of ~; ~ ^ alkoxy groups; triflate Ruo Russia methyl; Xia amino group '; a nitro group; Jiarukiruami amino group of ~ c _6; or ~ alkyl group, a ~ c ₆ alkoxy And an imidazolyl group which may have one or more substituents selected from a group and a halogen atom). S-oxo-S-benzenepropane amide derivative, a pharmaceutically acceptable salt thereof, Use of hydrates or solvates of