JPWO2010047369A1 - Treatment for diabetic nephropathy - Google Patents

Abstract

General formula (I) [wherein R1 represents lower alkyl optionally having substituent (s), etc., R2 and R3 are the same or different and each represents a hydrogen atom, and R4 and R5 are the same or Differently, it represents a hydrogen atom or the like, Q1-Q2-Q3 represents CH = CH-CH = CH, etc., Y represents a single bond or the like, Z1-Z2 represents C = CR13 (wherein R13 represents A represents a group selected from the group consisting of the following formulas (b1) to (b6) (wherein R18 represents a lower alkyl which may have a substituent). A therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure, etc., comprising the tricyclic compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

  The present invention relates to a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

  Diabetic nephropathy is a major cause of introduction of dialysis, and the life prognosis of diabetic patients who have reached dialysis therapy is poor. Therefore, treatment that prevents the development of diabetic nephropathy and suppresses its development is important. Nephropathy in diabetes is caused by the appearance of albuminuria (early nephropathy). If not treated, albuminuria increases by 10 to 20% annually, and proteinuria becomes positive after 10 to 15 years (apparent) Nephropathy). When the stage progresses to the stage of overt nephropathy, more than half of cases are thought to fall into end stage renal failure within 10 years (Scientific-based Diabetes Practice Guidelines, Japan Diabetes Society, 2007).

  As the onset mechanism of diabetic nephropathy, abnormal renal hemodynamics, abnormal glomerular metabolism, formation of glycation end products, etc. are important. Especially in diabetes, imported arterioles are dilated compared to glomerular export arterioles and glomerular hypertension is observed, and the pressure load due to glomerular hypertension reduces the function of mesangial cells, the appearance of albuminuria and glomerulosclerosis (Experimental Biology and Medicine 2008; 233: 4-11).

Strict blood glucose and blood pressure control is important for the suppression of the progression of such diabetic nephropathy.
In early nephropathy, blood glucose and blood pressure control is thought to suppress the development of diabetic nephropathy. In addition, blood pressure management with antihypertensive drugs may be useful in treatment in the stage of overt nephropathy, especially blood pressure control with ACE inhibitors and angiotensin II receptor antagonists suppresses progression to overt nephropathy It is considered to be.

  Angiotensin II receptor antagonists specifically inhibit the angiotensin II type 1 (AT1) receptor on the cell membrane surface. Angiotensin II receptor antagonist dilates glomerular export arterioles, lowers glomerular hypertension, and inhibits the action of angiotensin II, which causes glomerular fibrosis and hypertrophy, leading to the development and progression of glomerular sclerosis It is thought to suppress.

  Peroxisome proliferator activated receptor (PPAR) gamma agonists improve hyperglycemia in type 2 diabetic patients by improving insulin resistance. Blood glucose control is important for the suppression of the onset and progression of diabetic nephropathy, and PPARγ agonists are thought to correct hyperglycemia and suppress the onset and progression of diabetic nephropathy. PPARγ agonists have lipid lowering action, antioxidant action, anti-inflammatory action and blood pressure lowering action in addition to the insulin resistance improving action, and these actions also contribute to the urinary albumin lowering action. (Kidney Int. 2001; 60: 14-30).

  Chronic heart failure is “a condition in which the heart's pumping function is reduced due to chronic myocardial injury, and it is impossible to pump blood volume to meet the oxygen demand of peripheral major organs in an absolute or relative manner. It is defined as “a pathological condition that caused congestion in the system and impaired life function” (Chronic Heart Failure Treatment Guidelines (revised 2005)). Basic diseases of heart failure are classified into those based on mechanical disorders such as valvular disease and hypertension, myocardial disorders such as ischemic heart disease and dilated cardiomyopathy, and transmission disorders such as atrial fibrillation. In heart failure, the renin-angiotensin system activated by a decrease in renal blood flow due to decreased cardiac output and an increase in sympathetic nerve activity via baroreceptor reflex is thought to play a central role in pathogenesis Yes.

  An angiotensin II receptor antagonist specifically inhibits the angiotensin II type 1 (AT1) receptor on the cell membrane surface and suppresses the activation of the renin-angiotensin system. Suppressing renin-angiotensin system activation in heart failure is an increase in cardiac output due to a decrease in afterload accompanying a decrease in peripheral vascular resistance, a diuretic effect due to an increase in renal blood flow and a suppression of renal Na reabsorption, and a sympathetic nerve It is thought to bring about an improvement effect on hemodynamics such as reduction of pulmonary congestion due to reduction of preload such as reduction of circulating plasma volume, venous return volume, left ventricular end-diastolic volume, etc. by suppressing activation enhancement. Angiotensin II has been reported to induce cardiovascular remodeling such as cardiomyocyte hypertrophy, increase in extracellular matrix, and proliferation of vascular smooth muscle and fibroblasts. Angiotensin II receptor antagonists have been reported to inhibit the action of these angiotensin II, suppress cardiac hypertrophy and cardiovascular remodeling, which are the previous stages of heart failure, and improve the pathology of heart failure (circulation ( Circulation) 2006; 114: 2850-70).

PPARγ agonist has lipid lowering action, antioxidant action, anti-inflammatory action, blood pressure lowering action in addition to insulin resistance improving action, left ventricular diastolic dysfunction in diabetic model rats, left ventricle after myocardial infarction Remodeling, reported to suppress cardiac hypertrophy due to pressure load (J Cardiovasc Pharmacol. 2001; 38: 868-74, Circulation 2002; 106: 3126- 32, Circulation 2002; 105: 1240-46).
A drug containing a compound used in the present invention as an active ingredient and having PPARγ agonist activity, preferably further an angiotensin II receptor antagonistic activity is known (see Patent Document 1).

International Publication No. 2008/096829 Pamphlet

  An object of the present invention is to provide a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to the following (1) to (26).
(1) Formula (I)

<In the formula, R ¹ has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent. Represents an optionally substituted lower alkylsulfanyl,
R ² and R ³ are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (I)

Is a group selected from the group consisting of the following formulas (a1) to (a20):

[Wherein, R ¹ has the same meaning as defined above, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R ⁹ and R ^0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - ^CONR 11 ^{R 12 (wherein, R 11} and ^{R 12} are the same Or, differently, it has a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl, or optionally substituted. Each of R ¹¹ and R ¹² together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent. An aryl which may be substituted, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, R ⁸ represents a hydrogen atom or a substituent Represents lower alkyl optionally having
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ¹ -Q ² -Q ³ represents CH═CH—CH═CH, S—CH═CH, or CH═CH—S;
Y represents a single _{bond, CH 2, CH 2 CH 2} , CH = CH, O, S, CH 2 O, OCH 2, CH 2 S, or SCH _2,
Z ¹ -Z ² represents C═CR ¹³ (wherein R ¹³ represents a hydrogen atom or a lower alkyl optionally having a substituent), CH—CR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ is the same or different and represents a hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ¹⁶ R ¹⁷ (wherein R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom; Or represents a lower alkyl optionally having a substituent),
A represents a group selected from the group consisting of the following formulas (b1) to (b6).

(Wherein R ¹⁸ represents lower alkyl optionally having substituent (s) or aryl optionally having substituents)>
A therapeutic and / or prophylactic agent for diabetic nephropathy comprising a tricyclic compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.
(2) The tricyclic compound represented by the formula (I) is represented by the formula (IA)

<In the formula, R ^1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent. Represents an optionally substituted lower alkylsulfanyl,
R ^2A and R ^3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (IA)

Is a group selected from the group consisting of the following formulas (A1) to (A20):

[Wherein, R ^1A has the same meaning as described above, and R ^6A and R ^7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted. Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ^9A R ^10A (wherein R ^9A and R ^10A are the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, It represents a lower alkanoyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent or an aralkyl which may have a substituent. ^{R 9A} and ^{R 10A} are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen ^{atom), - CONR} 11A ^{R 12A (wherein, R 11A} and R ^12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted. Represents an aralkyl which may have a group, or R ^11A and R ^12A together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic group which may have a substituent) An aryl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, or an aliphatic heterocycle which may have a substituent Represents a cyclic group R ^8A represents a lower alkyl which may have a hydrogen atom or a substituent]
R ^4A and R ^5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ^1A -Q ^2A -Q ^3A represents CH = CH-CH = CH, S-CH = CH or CH = CH-S,,
Y ^A represents a single bond, CH ₂ , CH ₂ CH ₂ , CH═CH, O, S, CH ₂ O, OCH ₂ , CH ₂ S, or SCH ₂ ,
Z ^1A -Z ^2A represents C═CR ^13A (wherein R ^13A represents a hydrogen atom or a lower alkyl which may have a substituent), CH—CR ^14A R ^15A (wherein R ^14A and R ^15A represents the same or different hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ^16A R ^17A (wherein R ^16A and R ^17A are the same or different and represent a hydrogen atom or Represents a lower alkyl optionally having substituent (s),
(I) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA represents a lower alkyl which may have a substituent), CH—CR ^14A R ^15AA (wherein R ^14A represents R ^15AA represents lower alkyl which may have a substituent, or N-CR ^16AA R ^17A (wherein R ^16AA is lower alkyl which may have a substituent, R ^17A is as defined above)
A ^A represents a group selected from the group consisting of the following formulas (B1) to (B6),

(In the formula, R ^18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
(Ii) Z ^1A -Z ^2A is ^{C═CR 13AB} (wherein R ^13AB represents a hydrogen atom), CH—CR ^14AB R ^15AB (wherein R ^14AB and R ^15AB both represent a hydrogen atom), or When N-CR ^16AB R ^17AB (wherein R ^16AB and R ^17AB both represent a hydrogen atom)
A ^A represents a group selected from the group consisting of the following formulas (B3) to (B6).

(Wherein R ^18A has the same ^meaning as above)>
The therapeutic and / or prophylactic agent for diabetic nephropathy according to (1), which is a tricyclic compound represented by the formula:
(3) Group in formula (IA)

Is a group selected from the group consisting of the aforementioned formulas (A1) to (A20), The therapeutic and / or prophylactic agent for diabetic nephropathy according to (2).
(4) in formula (IA)

Are represented by the following formulas (A4), (A9), (A11) and (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for diabetic nephropathy according to (2), which is a group selected from the group consisting of:
(5) in formula (IA)

Is represented by the following formula (A4)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
(2) The therapeutic and / or prophylactic agent for diabetic nephropathy according to (2).
(6) In formula (IA)

Is represented by the following formula (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
(2) The therapeutic and / or prophylactic agent for diabetic nephropathy according to (2).
(7) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA is as defined above), CH—CHR ^15AA (wherein R ^15AA is as defined above), or N—CR The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of (2) to (6), which is ^16AA R ^17A (wherein R ^16AA and R ^17A are as ^defined above, respectively).
(8) A ^A is the following formula (B3)

The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of (2) to (7).
(9) The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of (2) to (8), wherein Q ^1A -Q ^2A -Q ^3A is CH═CH—CH═CH.
(10) The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of (2) to (9), wherein Y ^A is CH ₂ CH ₂ or CH ₂ O.
(11) A method for preventing and / or treating diabetic nephropathy, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to any one of (1) to (10).
(12) Use of the compound or pharmaceutically acceptable salt according to any one of (1) to (10) for the manufacture of a preventive and / or therapeutic agent for diabetic nephropathy.
(13) An agent comprising the compound or pharmaceutically acceptable salt according to any one of (1) to (10) for use in the prevention and / or treatment of diabetic nephropathy.
(14) Formula (I)

<In the formula, R ¹ has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent. Represents an optionally substituted lower alkylsulfanyl,
R ² and R ³ are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (I)

Is a group selected from the group consisting of the following formulas (a1) to (a20):

[Wherein, R ¹ has the same meaning as defined above, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R ⁹ and R ^0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - ^CONR 11 ^{R 12 (wherein, R 11} and ^{R 12} are the same Or, differently, it has a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl, or optionally substituted. Each of R ¹¹ and R ¹² together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent. An aryl which may be substituted, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, R ⁸ represents a hydrogen atom or a substituent Represents lower alkyl optionally having
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ¹ -Q ² -Q ³ represents CH═CH—CH═CH, S—CH═CH, or CH═CH—S;
Y represents a single _{bond, CH 2, CH 2 CH 2} , CH = CH, O, S, CH 2 O, OCH 2, CH 2 S, or SCH _2,
Z ¹ -Z ² represents C═CR ¹³ (wherein R ¹³ represents a hydrogen atom or a lower alkyl optionally having a substituent), CH—CR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ is the same or different and represents a hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ¹⁶ R ¹⁷ (wherein R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom; Or represents a lower alkyl optionally having a substituent),
A represents a group selected from the group consisting of the following formulas (b1) to (b6).

(Wherein R ¹⁸ represents lower alkyl optionally having substituent (s) or aryl optionally having substituents)>
A therapeutic and / or prophylactic agent for heart failure comprising a tricyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:
(15) The tricyclic compound represented by the formula (I) is represented by the formula (IA)

<In the formula, R ^1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent. Represents an optionally substituted lower alkylsulfanyl,
R ^2A and R ^3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (IA)

Is a group selected from the group consisting of the following formulas (A1) to (A20):

[Wherein, R ^1A has the same meaning as described above, and R ^6A and R ^7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted. Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ^9A R ^10A (wherein R ^9A and R ^10A are the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, It represents a lower alkanoyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent or an aralkyl which may have a substituent. ^{R 9A} and ^{R 10A} are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen ^{atom), - CONR} 11A ^{R 12A (wherein, R 11A} and R ^12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted. Represents an aralkyl which may have a group, or R ^11A and R ^12A together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic group which may have a substituent) An aryl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, or an aliphatic heterocycle which may have a substituent Represents a ring group R ^8A represents a lower alkyl which may have a hydrogen atom or a substituent]
R ^4A and R ^5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ^1A -Q ^2A -Q ^3A represents CH = CH-CH = CH, S-CH = CH or CH = CH-S,,
Y ^A represents a single bond, CH ₂ , CH ₂ CH ₂ , CH═CH, O, S, CH ₂ O, OCH ₂ , CH ₂ S, or SCH ₂ ,
Z ^1A -Z ^2A represents C═CR ^13A (wherein R ^13A represents a hydrogen atom or a lower alkyl which may have a substituent), CH—CR ^14A R ^15A (wherein R ^14A and R ^15A represents the same or different hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ^16A R ^17A (wherein R ^16A and R ^17A are the same or different and represent a hydrogen atom or Represents a lower alkyl optionally having substituent (s),
(I) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA represents a lower alkyl which may have a substituent), CH—CR ^14A R ^15AA (wherein R ^14A represents R ^15AA represents lower alkyl which may have a substituent, or N-CR ^16AA R ^17A (wherein R ^16AA is lower alkyl which may have a substituent, R ^17A is as defined above)
A ^A represents a group selected from the group consisting of the following formulas (B1) to (B6),

(In the formula, R ^18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
(Ii) Z ^1A -Z ^2A is ^{C═CR 13AB} (wherein R ^13AB represents a hydrogen atom), CH—CR ^14AB R ^15AB (wherein R ^14AB and R ^15AB both represent a hydrogen atom), or When N-CR ^16AB R ^17AB (wherein R ^16AB and R ^17AB both represent a hydrogen atom)
A ^A represents a group selected from the group consisting of the following formulas (B3) to (B6).

(Wherein R ^18A has the same ^meaning as above)>
The therapeutic and / or prophylactic agent for heart failure according to (14), which is a tricyclic compound represented by the formula:
(16) Group in formula (IA)

The therapeutic and / or preventive agent for heart failure according to (15), wherein is a group selected from the group consisting of the formulas (A1) to (A20).
(17) In the formula (IA)

Are represented by the following formulas (A4), (A9), (A11) and (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for heart failure according to (15), which is a group selected from the group consisting of:
(18) in formula (IA)

Is represented by the following formula (A4)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or preventive agent for heart failure according to (15), which is a group represented by:
(19) In formula (IA)

Is represented by the following formula (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or preventive agent for heart failure according to (15), which is a group represented by:
(20) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA is as defined above), CH—CHR ^15AA (wherein R ^15AA is as defined above), or N—CR The therapeutic and / or prophylactic agent for heart failure according to any one of (15) to (19), which is ^16AA R ^17A (wherein R ^16AA and R ^17A are as ^defined above).
(21) A ^A is the following formula (B3)

The therapeutic and / or prophylactic agent for heart failure according to any one of (15) to (20).
(22) The therapeutic and / or preventive agent for heart failure according to any one of (15) to (21), wherein Q ^1A -Q ^2A -Q ^3A is CH═CH—CH═CH.
(23) The therapeutic and / or prophylactic agent for heart failure according to any one of (15) to (22), wherein Y ^A is CH ₂ CH ₂ or CH ₂ O.
(24) A method for preventing and / or treating heart failure, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to any one of (14) to (23).
(25) Use of the compound or pharmaceutically acceptable salt according to any one of (14) to (23) for the manufacture of an agent for preventing and / or treating heart failure.
(26) An agent comprising the compound or pharmaceutically acceptable salt according to any one of (14) to (23) for use in the prevention and / or treatment of heart failure.

  The present invention provides a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

FIG. 1 (left) shows the amount of protein excreted in urine 12 weeks after administration of Compound 95 in Zucker Fatty rats. FIG. 1 (right) shows the amount of urinary albumin excreted 12 weeks after administration of Compound 95 in Zucker Fatty rats. The unit of the vertical axis in FIG. 1 represents mg / kg / day. Each column in FIG. 1 represents the results in the Lean group, the Control group, and the compound 95 (10 mg / kg) administration group from the left (refer to the meanings of the Lean group and the Control group later). ***: P <0.001 [Student ’s t-test against Control group]. FIG. 2 shows the amount of protein excreted in urine 12 weeks after administration of Compound 95 in Zucker diabetic Fatty rats. The unit of the vertical axis in FIG. 2 represents mg / kg / day. The columns in FIG. 2 represent the results in the Lean group, the Control group, and the compound 95 (10 mg / kg) administration group from the left (see below for the meanings of the Lean group and the Control group). ***: P <0.001 [Student ’s t-test against Control group]. FIG. 3 shows the relative weight of the heart 8 weeks after administration of Compound 95 in stroke-prone spontaneously hypertensive rats (SHRSP). The unit of the vertical axis in FIG. 3 represents g / 100 gB.W. The columns in FIG. 3 represent the results in the WKY group, the Control group, and the compound 95 (10 mg / kg) administration group from the left (see below for the meanings of the WKY group and the Control group). ***: P <0.001 [Student ’s t-test against Control group]. ###: P <0.001 [Student ’s t-test against WKY group]. FIG. 4 shows the relative weight of the heart 8 weeks after administration of Compound 95 in salt-loaded Dahl-S (salt-sensitive hypertensive) rats. The unit of the vertical axis in FIG. 4 represents g / 100 gB.W. The columns in FIG. 4 represent the results in the Normal group, the Control group, and the compound 95 (10 mg / kg) administration group from the left (see below for the meanings represented by the Normal group and the Control group). ***: P <0.001 [Student ’s t-test against Control group]. ###: P <0.001 [Student ’s t-test for normal group comparison]

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of general formulas (I) and (IA):
Lower alkyl and lower alkyl, lower alkylsulfanyl, lower alkanoyloxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylcarbamoyl and lower alkyl moiety of di-lower alkylcarbamoyl include, for example, linear or branched alkyl having 1 to 10 carbon atoms. More specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like can be mentioned. The two lower alkyl moieties of the di-lower alkylcarbamoyl may be the same or different.

Examples of the lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like. Is given.
Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

  Examples of aralkyl include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl, naphthyl. Examples thereof include methyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the like.

Examples of aryl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, azulenyl, anthryl and the like.
Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic group part of the aliphatic heterocyclic carbonyl include, for example, a 5-membered or 6-membered monocyclic fatty acid containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. An aromatic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. More specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl 5,6-dihydro-2H-pyranyl, oxazolidinyl, mole Lino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl Benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolyl Nyl, dihydrobenzodioxanyl and the like.

  As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed. A bicyclic or tricyclic fused ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl Lil, benzotriazolyl, oxazolopyridyl pyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc. naphthyridinyl and the like.

  Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3 to 8 membered rings and containing at least one nitrogen atom ( The condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, Folino, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzoimidazolidinyl, benzimidazolyl, dihydroindazolyl , Indazolyl, benzotriazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl and the like.

Halogen means each atom of fluorine, chlorine, bromine and iodine.
Lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkoxy optionally having substituent, lower alkylsulfanyl optionally having substituent, substituted Lower alkanoyloxy which may have a group, lower alkanoyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, lower alkylcarbamoyl which may have a substituent, and Examples of the substituent in the di-lower alkylcarbamoyl which may have a substituent are the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl, C _3-8 cycloalkyl having 1 to 3 substituents. , Aliphatic heterocyclic group, aromatic heterocyclic group, C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryl Ruoxy, C _7-16 aralkyloxy, C _2-11 alkanoyloxy, C _7-15 aroyloxy, C _1-10 alkylsulfanyl, —NR ^X R ^Y (wherein R ^X and R ^Y are the same or different, hydrogen Atom, C _1-10 alkyl, C _3-8 cycloalkyl, C _6-14 aryl, aromatic heterocyclic group, C _7-16 aralkyl, C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxy Carbonyl or C _7-16 aralkyloxycarbonyl), C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl, C _6-14 aryloxycarbonyl, C _1-10 alkylcarbamoyl, diC _{1 And} a substituent selected from the group consisting of _-10 alkylcarbamoyl and the like.

The substituents in the aryl which may have a substituent, the aralkyl which may have a substituent, and the aromatic heterocyclic group which may have a substituent may be the same or different. ~ 3, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl, C _1-10 alkyl, trifluoromethyl, C _3-8 cycloalkyl, C _6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group , C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryloxy, C _7-16 aralkyloxy, C _2-11 alkanoyloxy, C _7-15 aroyloxy, C _1-10 alkylsulfanyl, —NR during ^X R ^Y (wherein, ^{R X} and ^{R Y} are the same or different, a hydrogen _{atom, C 1-10 alkyl, C 3-8} cycloalkyl Represents _{C 6-14} aryl, an aromatic heterocyclic _{group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10} alkoxycarbonyl, or _{C 7-16} aralkyloxycarbonyl), C Substituents selected from the group consisting of _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl, C _6-14 aryloxycarbonyl, C _1-10 alkylcarbamoyl, di-C _1-10 alkylcarbamoyl, etc. can give.

Cycloalkyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, aliphatic heterocyclic carbonyl which may have a substituent and may have a substituent Examples of the substituent in the nitrogen-containing heterocyclic group formed together with a good adjacent nitrogen atom are the same or different, for example, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carbamoyl having 1 to 3 substituents. , C _1-10 alkyl, trifluoromethyl, C _3-8 cycloalkyl, C _6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryloxy, C _7-16 aralkyloxy, C _2-11 alkanoyloxy, C _7-15 aroyloxy, C _1-10 alkylsulfanyl, —N R ^X R ^Y (wherein R ^X and R ^Y are the same or different and each represents a hydrogen atom, C _1-10 alkyl, C _3-8 cycloalkyl, C _6-14 aryl, aromatic heterocyclic group, C _{7- 16} aralkyl, C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl or C _7-16 aralkyloxycarbonyl), C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxy Examples thereof include a substituent selected from the group consisting of carbonyl, C _6-14 aryloxycarbonyl, C _1-10 alkylcarbamoyl, diC _1-10 alkylcarbamoyl and the like.

C _1-10 alkyl as shown here and C _1-10 alkoxy, C _2-11 alkanoyloxy, C _1-10 alkylsulfanyl, C _2-11 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylcarbamoyl and Examples of the C _1-10 alkyl moiety of diC _1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl. The two C _1-10 alkyls in the diC _1-10 alkylcarbamoyl may be the same or different.

The C _3-8 cycloalkyl and C _3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
Examples of the aryl portion of C _6-14 aryl and C _6-14 aryloxy, C _7-15 aroyl, C _7-15 aroyloxy and C _6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples. The

The _{C 7-16} aralkyl moiety of the C _7-16 aralkyl and _{C 7-16} aralkyloxy and _{C 7-16} aralkyloxycarbonyl, for example groups mentioned for illustrative said aralkyl is exemplified.
Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen include the groups exemplified in the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen.

  As the compounds (I) and (IA), the compounds described in the above (1) to (20) are more preferable. More specifically, the compounds represented by the general formula (IA-A) or (IA-B),

(In the formula, D represents CH or N, R ^1X represents C _1-6 alkyl, C _3-8 cycloalkyl or C _1-6 alkoxy, and R ^6X represents a hydrogen atom, halogen, trifluoromethyl, or C 1 _{Represents 1-6} alkyl, R ^7X represents a hydrogen atom, halogen, or C _1-6 alkyl, Y ^X represents CH ₂ CH ₂ , CH ₂ O, or OCH ₂ , and R ^13X represents a hydrogen atom or C _{1 -6} alkyl, ^{a X} represents the following formula (b2) or (b3).

) Is preferred,
Formula (IA-C) or (IA-D),

^{(Wherein, D, R 1X, R 6X} , R 7X, Y X, R 13X and ^{A X} each have the same meanings as defined above)
The compound represented by these is more preferable.
Even more preferably, in each group of compounds (IA-A), (IA-B), (IA-C), and (IA-D),
D is CH or N;
R ^1X is preferably, for example, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, and more preferably ethyl, propyl, cyclopropyl, ethoxy and the like.
R ^6X is, for example, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl and the like, more preferably a hydrogen atom, chlorine atom, methyl and the like, and even more preferably a chlorine atom and methyl.
R ^7X is, for example, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, or isopropyl, and more preferably a hydrogen atom or methyl.
Y ^X is more preferably, for example, CH ₂ CH ₂ or CH ₂ O.
As R ^13X , for example, C _1-6 alkyl is preferable, methyl, ethyl, propyl and the like are more preferable, and methyl is more preferable.
A ^X, for example the formula (b3) are preferable.

  Pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Pharmaceutically acceptable acid addition salts of compounds (I) and (IA) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalic acid Organic salts such as salts, maleates, fumarate, citrates, benzoates, methanesulfonates, and the like. Examples of pharmaceutically acceptable metal salts include sodium salts and potassium salts. Alkaline earth metal salts such as alkali salts, magnesium salts, calcium salts, aluminum salts, zinc salts and the like. Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium. Examples of pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and pharmaceutically acceptable amino acid addition salts. Is, for example lysine, glycine, phenylalanine, aspartic acid, addition salts, such as glutamic acid.

The pharmaceutically acceptable salts of compounds (I) and (IA) may exist in the form of adducts with water or various solvents, and these adducts are also present in the diabetic nephropathy of the present invention. Or it can be used for therapeutic and / or prophylactic agents such as heart failure.
Diabetic nephropathy refers to diabetic nephropathy in renal failure such as nephrosis, early nephropathy, overt nephropathy or end stage renal failure.

Heart failure means heart failure selected from left heart failure, right heart failure, acute heart failure or chronic heart failure. Specific diseases that cause heart failure include cardiomyopathy, valvular disease, ischemic heart disease, hypertensive heart disease, atrial fibrillation, pulmonary heart, congenital heart disease, pericardial disease, myocarditis, etc. However, it is not limited to these.
Among compounds (I) and (IA), there may exist stereoisomers such as geometric isomers and optical isomers, tautomers, etc., but diabetic nephropathy or heart failure of the present invention, etc. All possible isomers and mixtures thereof can be used for the therapeutic and / or prophylactic agent.

Next, the manufacturing method of the compound used by this invention is demonstrated. Compound (I) or a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method described in WO2008 / 096829. Although the specific example of the compound used for this invention at Table 1-Table 34 is shown, the range of the compound used for this invention is not limited to them.
When it is desired to obtain the salts of compounds (I) and (IA), the compounds (I) and (IA) may be purified as they are when they are obtained in the salt form. (I) and (IA) may be isolated or purified by dissolving or suspending them in a suitable solvent and adding an acid or base to form a salt.

  In the table, the example number, reference example number and compound number are the example number, reference example number and compound number in WO2008 / 096829.

Next, the pharmacological action of typical compound (I) will be specifically described with reference to test examples.
Test Example 1 Action on Diabetic Nephropathy First, in order to examine the inhibitory effect of the onset of diabetic nephropathy, male Zucker Fatty (Crlj: ZUC-Lepr ^{fa) with} hyperinsulinemia, impaired glucose tolerance and obesity was studied. ^: genotype Lepr ^fa / Lepr ^fa ) Rats were used. In addition, male Zucker Lean as a control normal rats were used ^{(Crlj:: ZUC-Lepr fa} Lepr fa / + or + / +) rats. Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL. Eight-week-old Zucker Fatty rats were orally administered Compound 95 (10 mg / kg) or vehicle (0.5% MC, control group) once a day for 12 weeks in a volume of 5 mL / kg. Zucker Lean rats were administered vehicle (0.5% MC, Lean group). Twelve weeks after the start of administration, urine was collected for 24 hours using a metabolic cage, and urinary protein excretion and urinary albumin excretion were measured as indicators of renal damage. The results are shown in FIG.

The control group showed increased urinary protein excretion and urinary albumin excretion compared to the Lean group. In Zucker Fatty rats, Compound 95 (10 mg / kg) significantly suppressed increases in urinary protein excretion and urinary albumin excretion. From the above results, it was revealed that Compound 95 suppresses the onset of diabetic nephropathy in Zucker Fatty rats.
Furthermore, in order to investigate the therapeutic effect on diabetic nephropathy, male Zucker diabetic Fatty (ZDF, ZDF / CrlCrlj-Lepr ^fa ) rats of 11 weeks of age already presenting with diabetic nephropathy were used in the test. In addition, male Lean (ZDF / CrlCrlj-? / +) Rats were used as control normal rats. Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL. Eleven week old ZDF rats were orally administered Compound 95 (10 mg / kg) or vehicle (0.5% MC, control group) once a day for 12 weeks in a volume of 5 mL / kg. Solan (0.5% MC, Lean group) was similarly administered to 11-week-old Lean rats. Twelve weeks after the start of administration, urine was collected for 24 hours using a metabolic cage, and urinary protein excretion was measured as an indicator of renal damage. The results are shown in FIG.

At 11 weeks of age, a significant increase in urinary protein excretion was observed in the control group compared to the Lean group. In ZDF rats, Compound 95 (10 mg / kg) significantly suppressed the increase in urinary protein excretion. From the above results, it was revealed that Compound 95 suppresses the development of diabetic nephropathy in ZDF rats.
From the results of the above test, it was considered that Compound (I) or a pharmaceutically acceptable salt is useful for the treatment and / or prevention of diabetic nephropathy and the like.
Test Example 2 Stroke-prone spontaneously hypertensive spontaneously hypertensive rats (SHRSP) were used in an action test for heart disease . Wistar Kyoto rats (WKY) were used as control normal rats (n = 6). Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL. Compound 95 (10 mg / kg) or vehicle (0.5% MC, control group) was orally administered to 14-week-old male SHRSP once a day for 8 weeks in a volume of 5 mL / kg (each n = 8). Solvents (0.5% MC, WKY group) were administered to WKY rats. Eight weeks after the start of administration, the animals were dissected under anesthesia and the heart weight was measured. The results are shown in FIG. A significant increase in relative heart weight (heart weight relative to body weight of 100 g) was observed in the Control group compared to the WKY group. In SHRSP, Compound 95 exhibited an antihypertensive action and significantly suppressed an increase in cardiac hypertrophy compared to the control group. From the above results, it was revealed that Compound 95 suppresses cardiac hypertrophy in SHRSP.

From the results of the above tests, it was considered that Compound (I) or a pharmaceutically acceptable salt is useful for the treatment and / or prevention of heart failure and the like.
Test Example 3 Salt-sensitive hypertensive (Dahl-S) rats were used in an action test for heart disease . Compound 95 was suspended in 0.5% methylcellulose (MC) and prepared to a concentration of 2 mg / mL. 6-week-old male Dahl-S rats were loaded with a diet containing 8% sodium chloride, and after 2 weeks, compound 95 (10 mg / kg) or vehicle (0.5% MC, control group) was added at 5 mL / kg. The dose was orally administered once a day for 8 weeks (n = 8 each). As a normal group, Dahl-S rats were similarly loaded with a normal diet (n = 5). Eight weeks after the start of administration, the animals were dissected under anesthesia and the heart weight was measured. The results are shown in FIG. In the Control group, 2 out of 8 cases died. On the other hand, there were no deaths in the compound 95 administration group. In the control group, a significant increase in relative heart weight (heart weight relative to body weight of 100 g) was observed compared to the normal group. In the salt-loaded Dahl-S rat, Compound 95 exhibited an antihypertensive effect and significantly suppressed the increase in cardiac hypertrophy as compared to the control group. From the above results, it was clarified that Compound 95 has a life-prolonging effect and suppresses cardiac hypertrophy in Dahl-S rats.

From the results of the above tests, it was considered that Compound (I) or a pharmaceutically acceptable salt is useful for the treatment and / or prevention of heart failure and the like.
Compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof can be administered alone as they are, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.

  The pharmaceutical preparation according to the present invention comprises compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof alone or as an active ingredient for any other therapeutic and / or prophylactic agent as active ingredients. It can contain as a mixture of these. These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). Manufactured by any method.

As the administration route, it is desirable to use one that is most effective for use as a therapeutic and / or prophylactic agent, and examples thereof include oral administration and parenteral administration such as intravenous administration.
For example, tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.

For example, an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
The dose and frequency of administration of compound (I) and compound (IA) or a pharmaceutically acceptable salt thereof are the dosage form, patient age, body weight, nature or severity of symptoms to be treated and / or prevented, etc. Usually, in the case of oral administration, the dose is 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, once to several times a day. In the case of parenteral administration such as intravenous administration, usually 0.001 to 1000 mg, preferably 0.01 to 100 mg, is administered once a day to several times per adult. However, the dose and the number of doses vary depending on the various conditions described above.

  EXAMPLES 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.

Production Example 1: Tablet A tablet having the following composition is prepared by a conventional method. Compound 29, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
Formulation Compound 29 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

Formulation Example 2: Injection An injection having the following composition is prepared by a conventional method. Compound 29, 1 g is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formulation Compound 29 2 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

Production Example 3: Tablets Tablets having the following composition are prepared by a conventional method. Compound 95, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate is added and mixed, and tableting is performed with a tableting machine having a 8 mm diameter punch to obtain tablets (containing 20 mg of active ingredient per tablet).
Formulation Compound 95 20 mg
Lactose 143.4 mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
200 mg

Formulation Example 4: Injection An injection having the following composition is prepared by a conventional method. Compound 95, 1 g is added to and mixed with distilled water for injection, and further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7. Then, the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formula Compound 95 2 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

  The present invention can provide a therapeutic and / or prophylactic agent for diabetic nephropathy or heart failure containing, for example, a tricyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Claims (26)

Formula (I)

<In the formula, R ¹ has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent. Represents an optionally substituted lower alkylsulfanyl,
R ² and R ³ are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (I)

Is a group selected from the group consisting of the following formulas (a1) to (a20):

[Wherein, R ¹ has the same meaning as defined above, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R ⁹ and R ^0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - ^CONR 11 ^{R 12 (wherein, R 11} and ^{R 12} are the same Or, differently, it has a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl, or optionally substituted. Each of R ¹¹ and R ¹² together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent. An aryl which may be substituted, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, R ⁸ represents a hydrogen atom or a substituent Represents lower alkyl optionally having
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ¹ -Q ² -Q ³ represents CH═CH—CH═CH, S—CH═CH, or CH═CH—S;
Y represents a single _{bond, CH 2, CH 2 CH 2} , CH = CH, O, S, CH 2 O, OCH 2, CH 2 S, or SCH _2,
Z ¹ -Z ² represents C═CR ¹³ (wherein R ¹³ represents a hydrogen atom or a lower alkyl optionally having a substituent), CH—CR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ is the same or different and represents a hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ¹⁶ R ¹⁷ (wherein R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom; Or represents a lower alkyl optionally having a substituent),
A represents a group selected from the group consisting of the following formulas (b1) to (b6).

(Wherein R ¹⁸ represents lower alkyl optionally having substituent (s) or aryl optionally having substituents)>
A therapeutic and / or prophylactic agent for diabetic nephropathy comprising a tricyclic compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient. A tricyclic compound represented by the formula (I) is represented by the formula (IA)

<In the formula, R ^1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent. Represents an optionally substituted lower alkylsulfanyl,
R ^2A and R ^3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (IA)

Is a group selected from the group consisting of the following formulas (A1) to (A20):

[Wherein, R ^1A has the same meaning as described above, and R ^6A and R ^7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted. Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ^9A R ^10A (wherein R ^9A and R ^10A are the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, It represents a lower alkanoyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent or an aralkyl which may have a substituent. ^{R 9A} and ^{R 10A} are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen ^{atom), - CONR} 11A ^{R 12A (wherein, R 11A} and R ^12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted. Represents an aralkyl which may have a group, or R ^11A and R ^12A together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic group which may have a substituent) An aryl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, or an aliphatic heterocycle which may have a substituent Represents a cyclic group R ^8A represents a lower alkyl which may have a hydrogen atom or a substituent]
R ^4A and R ^5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ^1A -Q ^2A -Q ^3A represents CH = CH-CH = CH, S-CH = CH or CH = CH-S,,
Y ^A represents a single bond, CH ₂ , CH ₂ CH ₂ , CH═CH, O, S, CH ₂ O, OCH ₂ , CH ₂ S, or SCH ₂ ,
Z ^1A -Z ^2A represents C═CR ^13A (wherein R ^13A represents a hydrogen atom or a lower alkyl which may have a substituent), CH—CR ^14A R ^15A (wherein R ^14A and R ^15A represents the same or different hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ^16A R ^17A (wherein R ^16A and R ^17A are the same or different and represent a hydrogen atom or Represents a lower alkyl optionally having substituent (s),
(I) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA represents a lower alkyl which may have a substituent), CH—CR ^14A R ^15AA (wherein R ^14A represents R ^15AA represents a lower alkyl which may have a substituent, or N-CR ^16AA R ^17A (wherein R ^16AA represents a lower alkyl which may have a substituent, R ^17A is as defined above)
A ^A represents a group selected from the group consisting of the following formulas (B1) to (B6),

(In the formula, R ^18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
(Ii) Z ^1A -Z ^2A is ^{C═CR 13AB} (wherein R ^13AB represents a hydrogen atom), CH—CR ^14AB R ^15AB (wherein R ^14AB and R ^15AB both represent a hydrogen atom), or When N-CR ^16AB R ^17AB (wherein R ^16AB and R ^17AB both represent a hydrogen atom)
A ^A represents a group selected from the group consisting of the following formulas (B3) to (B6).

(Wherein R ^18A has the same ^meaning as above)>
The therapeutic and / or prophylactic agent for diabetic nephropathy according to claim 1, which is a tricyclic compound represented by the formula: Group in formula (IA)

The therapeutic and / or prophylactic agent for diabetic nephropathy according to claim 2, wherein is a group selected from the group consisting of the formulas (A1) to (A20). In formula (IA)

Are represented by the following formulas (A4), (A9), (A11) and (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for diabetic nephropathy according to claim 2, which is a group selected from the group consisting of: In formula (IA)

Is represented by the following formula (A4)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for diabetic nephropathy according to claim 2, which is a group represented by the formula: In formula (IA)

Is represented by the following formula (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for diabetic nephropathy according to claim 2, which is a group represented by the formula: Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA is as defined above), CH—CHR ^15AA (wherein R ^15AA is as defined above), or N—CR ^16AA R ^17A ( ^Wherein R ^16AA and R ^17A have the same ^{meanings as defined} above, respectively). The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of claims 2 to 6. A ^A is the following formula (B3)

The therapeutic and / or prophylactic agent for diabetic nephropathy according to any one of claims 2 to 7. Treatment and / or preventive agent for diabetic nephropathy according to any one of claims 2~8 Q ^1A -Q ^2A -Q ^3A is CH = CH-CH = CH. Y ^A treatment and / or preventive agent for diabetic nephropathy according to any one of claims 2 to 9 is _CH 2 CH ₂ or CH ₂ O.   A method for preventing and / or treating diabetic nephropathy, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 1.   Use of the compound or pharmaceutically acceptable salt according to any one of claims 1 to 10 for the manufacture of a preventive and / or therapeutic agent for diabetic nephropathy.   The agent containing the compound or pharmaceutically acceptable salt in any one of Claims 1-10 for using for the prevention and / or treatment of diabetic nephropathy. Formula (I)

<In the formula, R ¹ has a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a lower alkoxy which may have a substituent, or a substituent. Represents an optionally substituted lower alkylsulfanyl,
R ² and R ³ are the same or different and are each a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (I)

Is a group selected from the group consisting of the following formulas (a1) to (a20):

[Wherein, R ¹ has the same meaning as defined above, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, optionally substituted] Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, or represents aralkyl which may have an optionally substituted lower alkoxycarbonyl or a substituent, or R ⁹ and R ^0, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom), - ^CONR 11 ^{R 12 (wherein, R 11} and ^{R 12} are the same Or, differently, it has a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl, or optionally substituted. Each of R ¹¹ and R ¹² together with the adjacent nitrogen atom forms a nitrogen-containing heterocyclic group which may have a substituent), and has a substituent. An aryl which may be substituted, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, R ⁸ represents a hydrogen atom or a substituent Represents lower alkyl optionally having
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ¹ -Q ² -Q ³ represents CH═CH—CH═CH, S—CH═CH, or CH═CH—S;
Y represents a single _{bond, CH 2, CH 2 CH 2} , CH = CH, O, S, CH 2 O, OCH 2, CH 2 S, or SCH _2,
Z ¹ -Z ² represents C═CR ¹³ (wherein R ¹³ represents a hydrogen atom or a lower alkyl optionally having a substituent), CH—CR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ is the same or different and represents a hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ¹⁶ R ¹⁷ (wherein R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom; Or represents a lower alkyl optionally having a substituent),
A represents a group selected from the group consisting of the following formulas (b1) to (b6).

(Wherein R ¹⁸ represents lower alkyl optionally having substituent (s) or aryl optionally having substituents)>
A therapeutic and / or prophylactic agent for heart failure comprising a tricyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: A tricyclic compound represented by the formula (I) is represented by the formula (IA)

<In the formula, R ^1A has an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted lower alkoxy, or an optionally substituted substituent. Represents an optionally substituted lower alkylsulfanyl,
R ^2A and R ^3A are the same or different and each is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkanoyl. , Optionally substituted lower alkoxycarbonyl, optionally substituted lower alkyl carbamoyl, optionally substituted di-lower alkyl carbamoyl, or optionally substituted. Represents a good aliphatic heterocyclic carbonyl,
Or a group in formula (IA)

Is a group selected from the group consisting of the following formulas (A1) to (A20):

[Wherein, R ^1A has the same meaning as described above, and R ^6A and R ^7A are the same or different and each may have a hydrogen atom, halogen, nitro, cyano, formyl, oxo, hydroxy, or optionally substituted. Alkoxy, lower alkanoyloxy optionally having substituent, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkanoyl optionally having substituent , Optionally substituted lower alkoxycarbonyl, —NR ^9A R ^10A (wherein R ^9A and R ^10A are the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, It represents a lower alkanoyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent or an aralkyl which may have a substituent. ^{R 9A} and ^{R 10A} are, respectively to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen ^{atom), - CONR} 11A ^{R 12A (wherein, R 11A} and R ^12A may be the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxycarbonyl or substituted. Represents an aralkyl which may have a group, or R ^11A and R ^12A together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic group which may have a substituent) An aryl which may have a substituent, an aralkyl which may have a substituent, an aromatic heterocyclic group which may have a substituent, or an aliphatic heterocycle which may have a substituent Represents a ring group R ^8A represents a lower alkyl which may have a hydrogen atom or a substituent]
R ^4A and R ^5A are the same or different and each represents a hydrogen atom, halogen, hydroxy, lower alkoxy, or lower alkyl,
Q ^1A -Q ^2A -Q ^3A represents CH = CH-CH = CH, S-CH = CH or CH = CH-S,,
Y ^A represents a single bond, CH ₂ , CH ₂ CH ₂ , CH═CH, O, S, CH ₂ O, OCH ₂ , CH ₂ S, or SCH ₂ ,
Z ^1A -Z ^2A represents C═CR ^13A (wherein R ^13A represents a hydrogen atom or a lower alkyl which may have a substituent), CH—CR ^14A R ^15A (wherein R ^14A and R ^15A represents the same or different hydrogen atom or lower alkyl optionally having substituent (s), or N—CR ^16A R ^17A (wherein R ^16A and R ^17A are the same or different and represent a hydrogen atom or Represents a lower alkyl optionally having substituent (s),
(I) Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA represents a lower alkyl which may have a substituent), CH—CR ^14A R ^15AA (wherein R ^14A represents R ^15AA represents a lower alkyl which may have a substituent, or N-CR ^16AA R ^17A (wherein R ^16AA represents a lower alkyl which may have a substituent, R ^17A is as defined above)
A ^A represents a group selected from the group consisting of the following formulas (B1) to (B6),

(In the formula, R ^18A represents lower alkyl optionally having substituent (s) or aryl optionally having substituents).
(Ii) Z ^1A -Z ^2A is ^{C═CR 13AB} (wherein R ^13AB represents a hydrogen atom), CH—CR ^14AB R ^15AB (wherein R ^14AB and R ^15AB both represent a hydrogen atom), or When N-CR ^16AB R ^17AB (wherein R ^16AB and R ^17AB both represent a hydrogen atom)
A ^A represents a group selected from the group consisting of the following formulas (B3) to (B6).

(Wherein R ^18A has the same ^meaning as above)>
The therapeutic and / or prophylactic agent for heart failure according to claim 14, which is a tricyclic compound represented by the formula: Group in formula (IA)

The therapeutic and / or prophylactic agent for heart failure according to claim 15, wherein is a group selected from the group consisting of the formulas (A1) to (A20). In formula (IA)

Are represented by the following formulas (A4), (A9), (A11) and (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for heart failure according to claim 15, which is a group selected from the group consisting of: In formula (IA)

Is represented by the following formula (A4)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for heart failure according to claim 15, which is a group represented by the formula: In formula (IA)

Is represented by the following formula (A12)

(Wherein, R ^1A , R ^6A and R ^7A are as defined above)
The therapeutic and / or prophylactic agent for heart failure according to claim 15, which is a group represented by the formula: Z ^1A -Z ^2A is ^{C═CR 13AA} (wherein R ^13AA is as defined above), CH—CHR ^15AA (wherein R ^15AA is as defined above), or N—CR ^16AA R ^17A ( ^Wherein R ^16AA and R ^17A have the same ^{meanings as defined} above, respectively). The therapeutic and / or prophylactic agent for heart failure according to any one of claims 15 to 19. A ^A is the following formula (B3)

The therapeutic and / or prophylactic agent for heart failure according to any one of claims 15 to 20. Treatment and / or prophylactic agent for heart failure according to any one of claims 15~21 Q ^1A -Q ^2A -Q ^3A is CH = CH-CH = CH. The agent for treating and / or preventing heart failure according to any one of claims 15 to 22, wherein Y ^A is CH ₂ CH ₂ or CH ₂ O.   24. A method for preventing and / or treating heart failure, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to any one of claims 14 to 23.   Use of the compound or pharmaceutically acceptable salt according to any one of claims 14 to 23 for the manufacture of an agent for preventing and / or treating heart failure. An agent comprising the compound or pharmaceutically acceptable salt according to any one of claims 14 to 23 for use in the prevention and / or treatment of heart failure.

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