JPWO2013161980A1 - Cyclohexanediamide derivative and pharmaceutical use thereof - Google Patents

Abstract

The object of the present invention is to provide a compound exhibiting sEH inhibitory activity, and to provide a medicament that exhibits therapeutic and preventive effects on chronic kidney disease and pulmonary hypertension based on the sEH inhibitory action. The present invention provides a cyclohexanediamide derivative represented by the following chemical formula. [Selection figure] None

Description

  The present invention relates to a cyclohexanediamide derivative and a pharmaceutical use thereof.

  As the number of patients with kidney disease increases, the number of dialysis patients continues to increase all over the world, and the number has increased more than 10 times over the past 30 years. Under such circumstances, a new disease concept called chronic kidney disease was proposed in 2002 (Non-patent Document 1). Chronic kidney disease is a major concept that includes a state of renal function that does not lead to renal failure to the end stage of renal failure. Is proposed because it has been found that the risk of progression to renal failure is high if left untreated.

  When patients with chronic kidney disease progress to end-stage renal failure, they cannot survive without artificial dialysis or kidney transplantation, thus significantly reducing the patient's quality of life. Furthermore, patients with chronic kidney disease often have cardiovascular disease, which further increases the risk of death. For this reason, early treatment of chronic kidney disease is extremely important, and is considered to have great significance from the viewpoint of suppressing the concurrent occurrence of cardiovascular diseases.

  However, since there is currently no effective therapeutic agent for chronic kidney disease, patients with chronic kidney disease are prescribed angiotensin-based antihypertensive agents such as angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. By performing blood pressure management, it is usual that treatment to stop the progression and progression of chronic kidney disease and cardiovascular disease is performed (Non-patent Document 2).

  On the other hand, pulmonary hypertension is a general term for pathological conditions in which an increase in pulmonary arterial pressure is observed, and it is known that exercise tolerance is remarkably reduced, most of which is progressive and has a poor prognosis. In healthy individuals, pulmonary arterial pressure is maintained lower than systemic blood pressure, but in patients with pulmonary hypertension, mean pulmonary arterial pressure is 25 mmHg or more at rest (30 mmHg or more during exercise), and this state persists for a long time. Right ventricular hypertrophy and right heart failure are induced, and in the worst case, death.

  As one of the causes of pulmonary hypertension is considered to involve pulmonary vasospasm, short-term treatment of pulmonary hypertension such as prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase inhibitors Drugs that exhibit pulmonary vasodilatory effects have been used (Non-patent Document 3).

  In recent years, epoxyeicosatrienoic acids (hereinafter referred to as EETs), one of endothelial cell-derived hyperpolarizing factors, have an antihypertensive action and a protective action on vascular endothelium. It has been reported to show an organ protecting action (Non-patent Documents 4 and 5). EETs are metabolized to dihydroxyeicosatrienoic acids (hereinafter referred to as DHETs) by soluble epoxide hydrolase (hereinafter referred to as sEH), but are soluble epoxide hydrolase inhibitors (hereinafter referred to as s). Inhibitors) have been shown to increase the amount of EETs and to exert a blood pressure increase suppression and vascular endothelial protection action (Non-Patent Documents 6 to 8 and Patent Document 1).

  However, it has been reported that even sEH inhibitors have no therapeutic effect on spontaneous hypertensive rat models (Non-Patent Documents 9 to 11).

  On the other hand, compounds showing sEH inhibitory activity and useful for the treatment of chronic kidney disease and pulmonary hypertension have been reported (Patent Documents 1 and 2 and Non-Patent Document 8). It does not have a cyclohexanediamide structure.

  In addition, as compounds having a cyclohexanediamide structure, O6-alkylguanine derivatives (Patent Document 3) and aminomethylcyclohexaneamine derivatives (Patent Document 4) have been reported. Regarding the relationship between these derivatives and sEH inhibitory activity Is not disclosed at all.

International Publication No. 2007/106525 JP 2011-16742 A International Publication No. 2010/034931 International Publication No. 2009/146539

NKF-K / DOQI, American Journal of Kidney Disease, 2001, volume 37 (suppl. 1), p. S182-S238 Akihiko Iino et al., “CKD Medical Guide 2009”, edited by Japanese Society of Nephrology, 2009, p58-68 Toru Sato, Latest Medicine, 2010, 65, No. 8, p. 1698-1702 Lee et al., The Journal of the Federation of American Society for Exploratory Biology, 2010, Vol. 24, p. 3770-3781 Dhanasekaran et al., AJP-Heart and Circuit Physiology, 2006, Vol. 291, H517-H531. Spector et al., Progress in Lipid Research, 2004, Vol. 43, p. 55-90 Larsen et al., Trends in Pharmacological Science, 2006, 28, No. 1, p. 32-38 Imig et al., Pharmaceuticals, 2009, Volume 2, p. 217-227 Shen et al., Bioorganic and Medicinal Chemistry Letters, 2009, Vol. 19, p. 3398-3404 Shen et al., Journal of Medicinal Chemistry, 2009, Vol. 52, p. 5009-5012 Shen et al., Bioorganic and Medicinal Chemistry Letters, 2009, Vol. 19, p. 5314-5320

  However, in the treatment of chronic kidney disease, blood pressure management with angiotensin antihypertensive drugs alone is not sufficient to prevent the progression of chronic kidney disease, and the use of angiotensin antihypertensive drugs increases the risk of side effects such as cough. May be accompanied. In addition, treatment and prevention methods for pulmonary hypertension have not been established yet, and drugs used for the treatment of pulmonary hypertension frequently cause side effects such as headache and flushing. There is a risk. Among them, prostacyclin derivatives not only have a short half-life, but also have inadequate efficacy even when continuously administered, and there are concerns about the risks associated with side effects such as hepatotoxicity when endothelin receptor antagonists are reached. Yes.

  In addition, chronic kidney disease and pulmonary hypertension can seriously reduce the patient's quality of life and are serious diseases with a risk of death. Creation is strongly desired.

  The cause is unknown, but even if it is a compound showing sEH inhibitory activity, it does not always show a therapeutic effect on hypertension (Non-Patent Documents 10 to 12). Thus, it is not easy to find an sEH inhibitor exhibiting a therapeutic effect. However, if sEH is inhibited and EETs decomposition is strongly suppressed to find a compound exhibiting an inhibitory action against a decrease in renal function and an increase in pulmonary artery pressure associated with the progression of the disease state, sEH is not overexpressed. I came to think that it can be a highly safe medicine that does not affect the organization.

  Therefore, an object of the present invention is to provide a compound exhibiting sEH inhibitory activity, and to provide a medicament that exhibits therapeutic and preventive effects on chronic kidney disease and pulmonary hypertension based on the sEH inhibitory action.

  As a result of intensive studies to solve the above problems, the present inventors have shown that a novel cyclohexanediamide derivative exhibits sEH inhibitory activity, and an excellent therapeutic effect on chronic kidney disease and pulmonary hypertension based on its mechanism of action. The present invention was completed.

［式中、Ｒ^１は、水酸基、シアノ基、炭素数１〜６のアルキル基若しくはアルキルオキシ基、炭素数３〜６のシクロアルキル基、炭素数２〜７のアルキルオキシアルキル基、炭素数４〜７のシクロアルキルアルキル基（該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、−ＳＲ^６、−Ｓ（＝Ｏ）Ｒ^６又は−Ｓ（＝Ｏ）_２Ｒ^６で置換されていてもよい）、フェニルオキシ基（該フェニルオキシ基は、ベンゼン環の１〜３個の水素原子が、それぞれ独立して、炭素数１〜６のアルキルオキシ基で置換されていてもよい）、−Ｎ（Ｈ）Ｃ（＝Ｏ）Ｒ^７、−Ｎ（Ｈ）Ｓ（＝Ｏ）_２Ｒ^７、−Ｃ（＝Ｏ）Ｎ（Ｈ）Ｒ^７又は−Ｃ（＝Ｏ）ＯＲ^７を表し、Ｒ^２及びＲ^３は、それぞれ独立して、水素原子（ただし、Ｒ^２及びＲ^３は、同時に水素原子を表すことはない）、炭素数１〜６のアルキル基又は炭素数２〜７のアルキルオキシアルキル基（該アルキル基及び該アルキルオキシアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい）を表すか、一緒になって−（ＣＨ_２）_ｌ−を表すか、又は、さらにＲ^１と一緒になってアダマンチル基を表してもよく、Ｒ^４及びＲ^５は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基又は炭素数１〜６のアルキル基若しくはアルキルオキシ基（該アルキル基及び該アルキルオキシ基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子で置換されていてもよい）を表し、Ｒ^６は、炭素数１〜６のアルキル基を表し、Ｒ^７は、炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、炭素数２〜７のアルキルオキシアルキル基又は炭素数４〜７のシクロアルキルアルキル基（該アルキル基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい）を表し、ｌは、２〜５の整数を表す。］That is, the present invention provides a cyclohexanediamide derivative represented by the following general formula (I).

[Wherein, R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, and 4 carbon atoms. To 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group and the cycloalkylalkyl group each have 1 to 3 hydrogen atoms, An atom, a hydroxyl group, a cyano group, —SR ⁶ , optionally substituted with —S (═O) R ⁶ or —S (═O) ₂ R ⁶ ), a phenyloxy group (the phenyloxy group is a benzene ring) 1 to 3 hydrogen atoms may be independently substituted with an alkyloxy group having 1 to 6 carbon atoms), —N (H) C (═O) R ⁷ , —N (H ) S (= O) ₂ R ⁷ , —C (═O) N (H) R ⁷ or —C (═O) OR ⁷ , wherein R ² and R ³ are each independently a hydrogen atom (provided that R ² and R ³ are simultaneously hydrogen An alkyl group having 1 to 6 carbon atoms or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group are each independently composed of 1 to 3 hydrogen atoms). And may be substituted with a halogen atom, a hydroxyl group or a cyano group), together with — (CH ₂ ) ₁ —, or with R ¹ to form an adamantyl group. R ⁴ and R ⁵ may each independently represent a hydrogen atom, a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each 1 ~ 3 hydrogen atoms, it Each independently may be substituted with a halogen atom), R ⁶ represents an alkyl group having 1 to 6 carbon atoms, R ⁷ represents an alkyl group having 1 to 6 carbon atoms, 3 carbon atoms A cycloalkyl group having 6 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms may be each independently substituted with a halogen atom, a hydroxyl group or a cyano group), and l represents an integer of 2 to 5. ]

Cyclohexane diamide derivative of the above, ^{R 2} and ^{R 3} are each independently, represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or, together - _{(CH 2) l} - represents, R ⁵ is preferably a substituent at the 2-position on the benzene ring.

  In this case, it is excellent in that a stronger sEH inhibitory activity can be expected.

In the cyclohexanediamide derivative, R ¹ is an alkyl group having 1 to 6 carbon atoms or —N (H) C (═O) R ⁷ , and R ⁴ is a halogen atom, a cyano group, or 1 carbon atom. a 6 alkyl or alkyloxy group, R ⁵ is more preferably a halogen atom or an alkyl group or an alkyloxy group having 1 to 6 carbon atoms.

  In this case, stronger sEH inhibitory activity can be expected, and in addition, since pharmacokinetics are also excellent, a more excellent therapeutic effect in chronic kidney disease and pulmonary hypertension can be expected.

  Moreover, this invention provides the sEH inhibitor which contains said cyclohexane diamide derivative as an active ingredient.

  Furthermore, this invention provides the pharmaceutical which contains said cyclohexane diamide derivative as an active ingredient. This medicament is particularly preferably a therapeutic or prophylactic agent for chronic kidney disease or pulmonary hypertension.

  Since the cyclohexanediamide derivative of the present invention has a strong sEH inhibitory activity, it can exert a high therapeutic effect or preventive effect on chronic kidney disease and pulmonary hypertension based on its action mechanism, and has side effects according to the patient's symptoms. A reduced prescription can be selected.

It is a figure which shows the effect | action of Example compound 1 and 2 with respect to a serum creatinine (sCre) value in a rat anti-glomerular basement membrane antiserum (anti-GBM antiserum) administration nephritis model.

［式中、Ｒ^１は、水酸基、シアノ基、炭素数１〜６のアルキル基若しくはアルキルオキシ基、炭素数３〜６のシクロアルキル基、炭素数２〜７のアルキルオキシアルキル基、炭素数４〜７のシクロアルキルアルキル基（該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、−ＳＲ^６、−Ｓ（＝Ｏ）Ｒ^６又は−Ｓ（＝Ｏ）_２Ｒ^６で置換されていてもよい）、フェニルオキシ基（該フェニルオキシ基は、ベンゼン環の１〜３個の水素原子が、それぞれ独立して、炭素数１〜６のアルキルオキシ基で置換されていてもよい）、−Ｎ（Ｈ）Ｃ（＝Ｏ）Ｒ^７、−Ｎ（Ｈ）Ｓ（＝Ｏ）_２Ｒ^７、−Ｃ（＝Ｏ）Ｎ（Ｈ）Ｒ^７又は−Ｃ（＝Ｏ）ＯＲ^７を表し、Ｒ^２及びＲ^３は、それぞれ独立して、水素原子（ただし、Ｒ^２及びＲ^３は、同時に水素原子を表すことはない）、炭素数１〜６のアルキル基又は炭素数２〜７のアルキルオキシアルキル基（該アルキル基及び該アルキルオキシアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい）を表すか、一緒になって−（ＣＨ_２）_ｌ−を表すか、又は、さらにＲ^１と一緒になってアダマンチル基を表してもよく、Ｒ^４及びＲ^５は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基又は炭素数１〜６のアルキル基若しくはアルキルオキシ基（該アルキル基及び該アルキルオキシ基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子で置換されていてもよい）を表し、Ｒ^６は、炭素数１〜６のアルキル基を表し、Ｒ^７は、炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、炭素数２〜７のアルキルオキシアルキル基又は炭素数４〜７のシクロアルキルアルキル基（該アルキル基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい）を表し、ｌは、２〜５の整数を表す。］The cyclohexanediamide derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein, R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, and 4 carbon atoms. To 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group and the cycloalkylalkyl group each have 1 to 3 hydrogen atoms, An atom, a hydroxyl group, a cyano group, —SR ⁶ , optionally substituted with —S (═O) R ⁶ or —S (═O) ₂ R ⁶ ), a phenyloxy group (the phenyloxy group is a benzene ring) 1 to 3 hydrogen atoms may be independently substituted with an alkyloxy group having 1 to 6 carbon atoms), —N (H) C (═O) R ⁷ , —N (H ) S (= O) ₂ R ⁷ , —C (═O) N (H) R ⁷ or —C (═O) OR ⁷ , wherein R ² and R ³ are each independently a hydrogen atom (provided that R ² and R ³ are simultaneously hydrogen An alkyl group having 1 to 6 carbon atoms or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group are each independently composed of 1 to 3 hydrogen atoms). And may be substituted with a halogen atom, a hydroxyl group or a cyano group), together with — (CH ₂ ) ₁ —, or with R ¹ to form an adamantyl group. R ⁴ and R ⁵ may each independently represent a hydrogen atom, a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each 1 ~ 3 hydrogen atoms, it Each independently may be substituted with a halogen atom), R ⁶ represents an alkyl group having 1 to 6 carbon atoms, R ⁷ represents an alkyl group having 1 to 6 carbon atoms, 3 carbon atoms A cycloalkyl group having 6 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms may be each independently substituted with a halogen atom, a hydroxyl group or a cyano group), and l represents an integer of 2 to 5. ]

  "C1-C6 alkyl group" means a straight chain having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, such as a methyl group, Ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-2-propyl group (tert-butyl group), 2-methyl-1-propyl group, 2,2 -A dimethyl- 1-propyl group, 1-pentyl group, 2-pentyl group, or 3-pentyl group is mentioned.

  The “C 1-6 alkyloxy group” means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom. For example, a methoxy group, an ethoxy group, a 1-propyloxy group, 2 -A propyloxy group, 1-butyloxy group, or 2-butyloxy group is mentioned.

  “C3-C6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

  “C2-C7 alkyloxyalkyl group” means a group having 2 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with an alkyloxy group. For example, methoxymethyl Group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, propoxymethyl group or isopropoxymethyl group.

  The “cycloalkyl group having 4 to 7 carbon atoms” means a group having 4 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group. For example, cyclopropyl Examples thereof include a methyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the above-mentioned cyclohexanediamide derivative, in general formula (I), R ¹ is preferably a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or —N (H) C (═O) R ^7. It is more preferably an alkyl group of ˜6 or —N (H) C (═O) R ⁷ , and further preferably a methyl group or a propionamidyl group. In this case, in the alkyl group having 1 to 6 carbon atoms, 1 to 3 hydrogen atoms are each independently a halogen atom, a hydroxyl group, a cyano group, —SR ⁶ , —S (═O) R ⁶ or —S. (═O) ₂ R ⁶ may be substituted.

R ² and R ³ are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or preferably taken together are — (CH ₂ ) ₁ —, and each independently More preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or together, — (CH ₂ ) ₂ — or — (CH ₂ ) ₃ —. More preferably, they are an atom, a methyl group, or a 2-propyl group.

R ⁴ is preferably a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, and more preferably a halogen atom or a cyano group.

R ⁵ is preferably a substituent at the 2-position on the benzene ring. R ⁵ is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, more preferably a halogen atom or an alkyloxy group having 1 to 6 carbon atoms, and a trifluoromethoxy group. More preferably.

R ⁶ is preferably a methyl group.

R ⁷ is preferably a methyl group or an ethyl group.

  l is preferably 2 or 3.

  The cyclohexanediamide derivative represented by the above general formula (I) (hereinafter, cyclohexanediamide derivative (I)) includes a compound having an asymmetric carbon atom. In this case, optical isomers and diastereomers are present, but the cyclohexanediamide derivative (I) includes not only a single isomer but also a racemate and a diastereomeric mixture.

  The starting materials and reagents used for the production of the cyclohexanediamide derivative (I) may be commercially available products or may be synthesized by known methods.

[式中、Ｒ^１’は、水酸基、シアノ基、炭素数１〜６のアルキル基若しくはアルキルオキシ基、炭素数３〜６のシクロアルキル基、炭素数２〜７のアルキルオキシアルキル基、炭素数４〜７のシクロアルキルアルキル基（該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、１〜３個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、−ＳＲ^６、−Ｓ（＝Ｏ）−Ｒ^６又は−Ｓ（＝Ｏ）_２Ｒ^６で置換されていてもよい）、−Ｎ（Ｈ）Ｃ（＝Ｏ）Ｒ^７、−Ｃ（＝Ｏ）Ｎ（Ｈ）Ｒ^７又は−Ｃ（＝Ｏ）ＯＲ^７を表す。Ｒ^２〜Ｒ^７は、上記定義に同じ。]The cyclohexanediamide derivative (Ia) can be produced, for example, by a condensation reaction of an amine derivative (II) and a carboxylic acid derivative (III) in the presence of a base and a condensing agent, as shown in Scheme 1 below.

[Wherein, R ^{1 ′} represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, and a carbon number 4 to 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group each independently have 1 to 3 hydrogen atoms, halogen atom, a hydroxyl group, a cyano ^group, -SR 6, optionally substituted with -S (= O) -R ⁶ or ^{_{-S (= O) 2 R 6}} ), - N (H) C (= O) R ⁷ , —C (═O) N (H) R ⁷ or —C (═O) OR ⁷ is represented. R ^{2 to} R ⁷ are the same as defined above. ]

  Examples of the condensing agent used in the condensation reaction include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [ Bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (hereinafter, HATU), and HATU is preferred. 1-10 equivalent is preferable with respect to amine derivative (II), and, as for the equivalent of this condensing agent, 1-3 equivalent is more preferable.

  Examples of the solvent used in the condensation reaction include N, N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dichloromethane, chloroform, diethyl ether, or dimethyl ether, with DMF or THF being preferred, and DMF being More preferred.

  Examples of the base used in the condensation reaction include organic bases such as diisopropylethylamine (hereinafter DIPEA), triethylamine (hereinafter TEA), pyridine or N-methylmorpholine, or organic acid salts such as potassium carbonate, sodium carbonate or sodium bicarbonate. DIPEA or TEA is preferable. 1-100 equivalent is preferable with respect to amine derivative (II), and, as for the equivalent of this base, 1-10 equivalent is more preferable.

  The equivalent amount of the carboxylic acid derivative (III) used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.1 to 10 equivalents, and even more preferably 0.8 to 2 equivalents with respect to the amine derivative (II). .

  The reaction temperature of the condensation reaction is preferably −50 to 100 ° C., more preferably 0 to 50 ° C., and further preferably 0 to 30 ° C. The reaction time for the condensation reaction is preferably 1 minute to 48 hours, more preferably 1 minute to 24 hours, and even more preferably 10 minutes to 24 hours.

  The concentration of the amine derivative (II) at the start of the condensation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more preferably 0.1 to 10M.

[式中、Ｒ^２〜Ｒ^５及びＲ^７は、上記定義に同じ。]The cyclohexanediamide derivative (Ib) in which R ¹ is —N (H) C (═O) R ⁷ is prepared by reacting an amine derivative (IV) and an acid in the presence of a base as shown in the following scheme 2, for example. It can be produced by a condensation reaction with a chloride derivative (V) or a condensation reaction between an amine derivative (IV) and a carboxylic acid derivative (VI) in the presence of a base and a condensing agent.

[Wherein R ^{2 to} R ⁵ and R ⁷ are the same as defined above. ]

  Examples of the solvent used for the condensation reaction with the acid chloride derivative (V) include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, or 1,2-dimethoxyethane. 1,2-dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.

  The equivalent of the acid chloride (V) used for the condensation reaction with the acid chloride derivative (V) is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the amine derivative (IV). 5 equivalents are more preferred.

  Examples of the base used for the condensation reaction with the acid chloride derivative (V) include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred. 1-100 equivalent is preferable with respect to amine derivative (IV), and, as for the equivalent of this base, 1-10 equivalent is more preferable.

  The reaction temperature of the condensation reaction with the acid chloride derivative (V) is preferably -50 to 100 ° C, more preferably -20 to 60 ° C, and further preferably 0 to 40 ° C. The reaction time for the condensation reaction with acid chloride (V) is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.

  The concentration at the start of the reaction of the amine derivative (IV) in the condensation reaction with the acid chloride derivative (V) is preferably from 0.01 to 100M, more preferably from 0.01 to 10M, still more preferably from 0.1 to 10M.

  On the other hand, the condensation reaction of the amine derivative (IV) and the carboxylic acid derivative (VI) can be performed under the same conditions as in Scheme 1.

[式中、Ｒ^２〜Ｒ^５及びＲ^７は、上記定義に同じ。]The cyclohexanediamide derivative (Ic) in which R ¹ is —N (H) S (═O) ₂ R ⁷ can be synthesized with, for example, an amine derivative (IV) in the presence of a base as shown in Scheme 3 below. It can be produced by a sulfonamidation reaction with a sulfonic acid chloride derivative (VII).

[Wherein R ^{2 to} R ⁵ and R ⁷ are the same as defined above. ]

  Examples of the solvent used in the sulfonamidation reaction include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, or 1,2-dimethoxyethane, but dichloromethane, 1,2-dichloroethane, Acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.

  The equivalent of the sulfonic acid chloride derivative (VII) used for the sulfonamidation reaction is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and further preferably 1 to 1.5 equivalents with respect to the amine derivative (IV). preferable.

  Examples of the base used for the sulfonamidation reaction include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred. 1-100 equivalent is preferable with respect to amine derivative (IV), and, as for the equivalent of this base, 1-10 equivalent is more preferable.

  The reaction temperature of the sulfonamidation reaction is preferably -50 to 50 ° C, more preferably -30 to 30 ° C, and further preferably -20 to 20 ° C. The reaction time of the sulfonamidation reaction is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 8 hours.

  The concentration at the start of the reaction of the amine derivative (IV) in the sulfonamidation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.

[式中、Ｒ^２〜Ｒ^５は、上記定義に同じであり、Ｒ^８は、保護基を表す。]The amine derivative (IV), which is the starting material in the above-mentioned schemes 2 and 3, is, for example, after the condensation reaction between the amine derivative (II) and the carboxylic acid derivative (VIII) in the presence of a base, as shown in the following scheme 4. Can be produced by a deprotection reaction to remove the protecting group.

[Wherein, R ^{2 to} R ⁵ are the same as defined above, and R ⁸ represents a protecting group. ]

  The condensation reaction of the amine derivative (II) and the carboxylic acid derivative (VIII) can be performed under the same conditions as in Scheme 1.

  The deprotection reaction following the condensation reaction can be performed, for example, by a known method described in Protective Groups in Organic Synthesis 3rd edition (Green et al., 1999, John Wiley & Sons, Inc.). For example, when the protecting group is a tert-butoxycarbonyl group, the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid (hereinafter, TFA).

  As the carboxylic acid derivative (VIII) in Scheme 4 above, a commercially available product may be used as it is, or it may be produced by a known method.

[式中、Ｒ^４、Ｒ^５及びＲ^８は、上記定義に同じ。]The amine derivative (II) which is a starting material in the above-mentioned schemes 1 and 4 is, for example, as shown in the following scheme 5 in the presence of a base and a condensing agent, between a benzylamine derivative (IX) and a cyclohexane derivative (X). After the condensation reaction, it can be produced by a deprotection reaction to remove the protecting group.

[Wherein R ⁴ , R ⁵ and R ⁸ are the same as defined above. ]

  The condensation reaction of the benzylamine derivative (IX) and the cyclohexane derivative (X) can be performed under the same conditions as in Scheme 1.

  The deprotection reaction can be performed under the same conditions as in the method described in Scheme 4.

  The condensation reaction of Scheme 5 can also be carried out in the presence of a base by converting the cyclohexane derivative (X) to an acid chloride.

  Examples of the reagent for converting the cyclohexane derivative (X) to acid chloride include oxalyl chloride and thionyl chloride, with oxalyl chloride being preferred. 1-10 equivalent is preferable with respect to a cyclohexane derivative (X), and, as for the equivalent of this reagent, 1-1.5 equivalent is more preferable.

  Examples of the solvent used for converting the cyclohexane derivative (X) to the acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, DMF, and mixed solvents thereof. , Dichloromethane, THF or DMF, or a mixed solvent thereof is preferable, and a mixed solvent of dichloromethane and DMF or a mixed solvent of THF and DMF is more preferable. As a ratio of the mixed solvent, for example, in the case of a mixed solvent of dichloromethane and DMF, dichloromethane: DMF = 1 to 1000: 1 is preferable, and 1 to 100: 1 is more preferable.

  The reaction temperature for converting the cyclohexane derivative (X) to acid chloride is preferably −50 to 100 ° C., preferably −30 to 30 ° C., and more preferably −20 to 0 ° C. The reaction time for converting the cyclohexane derivative (X) to acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 2 hours.

  The concentration of the cyclohexane derivative (X) at the start of the reaction when the cyclohexane derivative (X) is converted to acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 3M. preferable.

  As the benzylamine derivative (IX) in the above scheme 5, a commercially available product may be used as it is, or it may be produced by a known method.

[式中、Ｒ^２〜Ｒ^５及びＲ^７は、上記定義に同じ。]The cyclohexanediamide derivative (Ib) can also be produced, for example, by a condensation reaction between a benzylamine derivative (IX) and a carboxylic acid derivative (XI) in the presence of a base and a condensing agent, as shown in Scheme 6 below. it can.

[Wherein R ^{2 to} R ⁵ and R ⁷ are the same as defined above. ]

  The condensation reaction of the benzylamine derivative (IX) and the carboxylic acid derivative (XI) can be performed under the same conditions as in Scheme 1.

[式中、Ｒ^２、Ｒ^３及びＲ^７は、上記定義に同じであり、Ｒ^９は、保護基を表す。]The carboxylic acid derivative (XI), which is the starting material in Scheme 6 above, is, for example, a condensation reaction between an amine derivative (XII) and an acid chloride derivative (V) in the presence of a base, as shown in Scheme 7 below, or In the presence of a base and a condensing agent, after the condensation reaction of the amine derivative (XII) and the carboxylic acid derivative (VI), it can be produced by a deprotection reaction to remove the protecting group.

[Wherein R ² , R ³ and R ⁷ are the same as defined above, and R ⁹ represents a protecting group. ]

  The condensation reaction between the amine derivative (XII) and the acid chloride derivative (V), or the condensation reaction between the amine derivative (XII) and the carboxylic acid derivative (VI) can be performed under the same conditions as in Scheme 2.

  The deprotection reaction following the condensation reaction can be performed, for example, by a known method described in Protective Groups in Organic Synthesis 3rd edition (Green et al., 1999, John Wiley & Sons, Inc.). For example, when the protecting group is a methyl group, the protecting group can be removed by treatment with a strong base such as sodium hydroxide.

[式中、Ｒ^２、Ｒ^３、Ｒ^８及びＲ^９は、上記定義に同じ。]The amine derivative (XII) which is the starting material in the above-mentioned scheme 7 is a condensation reaction between an amine derivative (XIII) and a carboxylic acid derivative (VIII) in the presence of a base and a condensing agent, for example, as shown in the following scheme 8. Then, it can manufacture by the deprotection reaction which removes a protecting group.

[Wherein R ² , R ³ , R ⁸ and R ⁹ are the same as defined above. ]

  The condensation reaction of the amine derivative (XIII) and the carboxylic acid derivative (VIII) can be performed under the same conditions as in Scheme 1.

  The deprotection reaction can be performed under the same conditions as in the method described in Scheme 4.

  The cyclohexanediamide derivative (I) obtained as described above, or the intermediate, raw material compound or reagent used in the production of the cyclohexanediamide derivative (I) is extracted, distilled, or chromatographed as necessary. Alternatively, it may be isolated and purified by a method such as recrystallization.

  In addition, the medicament, sEH inhibitor and the therapeutic and prophylactic agent for chronic kidney disease or pulmonary hypertension of the present invention are characterized by containing cyclohexanediamide derivative (I) as an active ingredient.

  Since the above cyclohexanediamide derivative (I) exhibits a potent sEH inhibitory activity, it can be used as a pharmaceutical and an sEH inhibitor, and is particularly a chronic disease that is caused by a decrease in the amount of EETs present due to excessive sEH. It is preferably used as a therapeutic or prophylactic agent for kidney disease and pulmonary hypertension.

  “SEH” is an important metabolic enzyme in vivo that catalyzes the hydrolysis of the substrate epoxide and converts it to the corresponding diol. The best known substrate of sEH is EETs, one of endothelial cell-derived hyperpolarizing factors, which metabolizes EETs into DHETs and inactivates them. EETs have a blood pressure increase inhibitory effect and a vascular endothelial protective effect, and are known to show an organ protective effect in kidney and lung diseases (The Journal of the Federation of American Society for Experimental Biology, 2010). 24, P.3770-3781 and AJP-Heart and Circuit Physiology, 2006, Vol.291, H517-H531).

  “SEH inhibitory activity” means an activity that inhibits the action of sEH. Therefore, the sEH inhibitory activity includes the activity of inhibiting the enzymatic reaction of sEH to catalyze the hydrolysis of EETs, which is one of sEH substrates.

  The “sEH inhibitor” means a compound showing sEH inhibitory activity or a composition containing the compound as an active ingredient.

  The sEH inhibitory activity is, for example, that human sEH and its substrate EETs are reacted in the presence of an sEH inhibitor, and the amount of DHETs produced is compared with the amount of DHETs produced in the absence of the sEH inhibitor. Can be measured. In addition, a commercially available measurement kit (Soluable Epoxy Hydroinhibitor Screening Assay Kit; Cayman) is used, or is described in a known literature (Analytical Biochemistry, 2005, Vol. 343, p. 66-75, etc.). The sEH inhibitory activity of the sEH inhibitor can be measured.

  In addition, in the presence and absence of an sEH inhibitor, racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate was used as a substrate for sEH, and 4-nitrophenolate anion was used. Measure the appearance or use cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate as a substrate for sEH and use 6-methoxy-2-naphthaldehyde. The sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the appearance.

The term “chronic kidney disease” means a disease defined by The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K / DOQI). That is, (1) a disease having a renal disorder defined by a structural or functional abnormality of the kidney for 3 months or more, regardless of the presence or absence of a glomerular filtration rate (GFR), or (2) It means a disease whose glomerular filtration rate is less than 60 mL / min / 1.73 m ² for 3 months or more regardless of the presence or absence of kidney damage.

  “Pulmonary hypertension” is a condition in which an increase in pulmonary arterial pressure in which blood is sent from the heart to the lung is observed, the mean pulmonary artery pressure in a resting position is 25 mmHg or more, or pulmonary disease, sleep apnea syndrome and In alveolar hypoventilation syndrome, it means that the mean pulmonary artery pressure is at least 20 mmHg at rest (more than 30 mmHg at exercise) (digest version of pulmonary hypertension treatment guideline (2006 revision), P2-P3.) .

  The therapeutic effect of cyclohexanediamide derivative (I) on chronic kidney disease can be evaluated using an animal model that has artificially induced chronic kidney disease. As such an animal model, for example, an anti-glomerular basement membrane antiserum (anti-GBM antiserum) administration nephritis model (Kidney International, 2003, Vol. 64, p.1241-1252, etc.) using a mouse or a rat, etc. ) Or 5/6 nephrectomy (Journal of the American Society of Nephrology, 2002, Vol. 13, p. 2909-2915, etc.). Abnormalities in kidney function can be confirmed by measuring serum creatinine levels.

  The therapeutic effect of cyclohexanediamide derivative (I) on pulmonary hypertension can be evaluated using an animal model that artificially induces pulmonary hypertension. As such an animal model, for example, monocrotaline administration pulmonary hypertension model using rats (Journal of Pharmaceutical Sciences, 2009, Vol. 111, p. 235-243) can be mentioned. An increase in pulmonary artery pressure can be confirmed by measuring right ventricular systolic pressure. The right ventricular hypertrophy and pulmonary hypertrophy associated with pulmonary hypertension were measured by measuring the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) and lung weight ratio (lung weight / body weight), respectively. This can be confirmed.

  When the cyclohexanediamide derivative (I) is used as a medicine, a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human as it is or as a pharmaceutical composition in an appropriate dosage form. ) Can be administered orally or parenterally (for example, transdermal administration, intravenous administration, rectal administration, inhalation administration, nasal administration or ophthalmic administration).

  Examples of the dosage form for administration to mammals include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions or suppositories, or known continuous forms. A formulation is mentioned. These dosage forms can be produced by a known method and contain a carrier generally used in the pharmaceutical field. Examples of such carriers include excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, or soothing agents in liquid preparations. Moreover, you may use additives, such as a tonicity agent, a buffering agent, antiseptic | preservative, an antioxidant, a coloring agent, a sweetener, an adsorbent, or a wetting agent, as needed.

  Examples of the excipient include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.

  Examples of the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, or sodium carboxymethylcellulose.

  Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropylcellulose.

  Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.

  Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.

  Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.

  Examples of soothing agents include benzyl alcohol.

  Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol or D-mannitol.

  Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate or citrate.

  Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

  Examples of the antioxidant include sulfite and ascorbic acid.

  The medicine preferably contains the cyclohexanediamide derivative (I) in an amount of 0.001 to 99% by weight, and more preferably 0.01 to 99% by weight. The effective dose and frequency of administration of the cyclohexanediamide derivative (I) vary depending on the administration form, patient age, body weight, or the nature or severity of the symptoms to be treated, but usually 1 to 1000 mg per day is preferable. 1-300 mg can be administered once or divided into several times.

  The above medicines may be administered alone, but may be combined with other drugs or used in combination with other drugs in order to supplement or enhance the preventive or therapeutic effect of the disease or reduce the dose. Can also be used.

  Examples of other drugs that can be combined or used together (hereinafter referred to as combination drugs) include, for example, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a hypotensive agent, a therapeutic agent for pulmonary hypertension, an anti-obesity agent, A diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, or a cachexia improving agent is mentioned.

  When using the above medicines in combination with a concomitant drug, the administration time of the above medicine and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, with a time difference. May be administered. The concomitant drug may be a low molecular compound, a polymer such as a protein, polypeptide or antibody, or a vaccine. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the above medicine and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination of the above medicine and concomitant drug, and the like. For example, when the administration subject is a human, the concomitant drug may be used at a compounding ratio of 0.01 to 99.99 with respect to the cyclohexanediamide derivative (I).

  Examples of diabetes therapeutic agents include animal insulin preparations extracted from bovine or porcine pancreas, human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast, insulin zinc, protamine insulin zinc, insulin fragments or derivatives, etc. Insulin preparations, insulin resistance improving agents such as pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, α-glucosidase inhibitors such as voglibose, acarbose, miglitol or emiglitate, biguanides such as phenformin, metformin or buformin, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole Insulin secretion promoters such as repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, amylin agonists such as pramlintide, phosphotyrosine phosphatase inhibitors such as vanadic acid, DPP-IV inhibitors such as sitagliptin, vildagliptin and alogliptin, exenatide, liraglutide, etc. GLP-1-like agonists, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists or SGLUT inhibitors.

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat or fidarestat, neurotrophic factors such as NGF, NT-3 or BDNF, neurotrophic factors Examples include production / secretion promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thioprid or mexiletine.

  Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanttle, cerivastatin, and itavastatin, bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate , Clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonifibrate, fibrate compounds such as simfibrate or theofibrate, squalene synthase inhibitors, ACAT inhibitors such as avasimib or eflucimate , Anion exchange resins such as cholestyramine, niobium such as probucol, nicomol or niceritrol Chin acid drugs or ethyl icosapentate, plant sterols such as soysterol or gamma oryzanol.

  Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors such as captopril, enalapril or delapril, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan or tasosartan and other angiotensin II antagonists, manidipine, nifedipine, nicardipine, Calcium antagonists such as amlodipine or efonidipine, potassium channel openers such as lebuchromacalim, clonidine or aliskiren.

  Examples of therapeutic agents for pulmonary hypertension include endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, and macitentan, PDE-5 inhibitors such as sildenafil, tadalafil, and vardenafil, beraprost, iloprost, epoprostenol, and treprostinil. Examples include prostacyclin preparations, PEI2 agonists selexipag or kinase inhibitors such as fasudil, imatinib, sorafenib or bafetinib.

  Anti-obesity agents include, for example, central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, β3 agonists, leptin or CNTF (ciliary neurotrophic factor) or cholecystokinin agonists such as lynchtripto.

  Examples of the diuretic include xanthine derivatives such as sodium theobromide salicylate or calcium theobromide, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide. , Antialdosterone preparations such as spironolactone or triamterene, carbonic anhydrase inhibitors such as acetazolamide, chlorobenzenesulfonamide preparations such as chlorthalidone, mefluside or indapamide, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide or furosemide.

  Examples of chemotherapeutic agents include alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as methotrexate or 5-fluorouracil, anticancer antibiotics such as mitomycin or adriamycin, plants such as vincristine, vindesine or taxol. Derived anticancer agents, cisplatin, oxaloplatin, carboplatin, etopoxide and the like.

  Examples of the immunotherapeutic agent include muramyl dipeptide derivatives, picibanil, lentinan, schizophyllan, krestin, interferon, interleukin (IL), granulocyte colony stimulating factor or erythropoietin.

  Examples of the antithrombotic agent include heparin such as heparin sodium, heparin calcium or dalteparin sodium, warfarin such as warfarin potassium, antithrombin agent such as argatroban, thrombolytic agent such as urokinase, tisokinase, alteplase, nateplase, monteplase or pamiteplase. And platelet aggregation inhibitors such as ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium or sarpogrelate hydrochloride.

  Examples of cachexia improvers include, for example, cyclooxygenase inhibitors such as indomethacin or diclofenac, progesterone derivatives such as megesterol acetate, carbohydrate steroids such as dexamethasone, metoclopramide drugs, tetrahydrocannabinol drugs or fats such as eicosapentaenoic acid Examples include antibodies to TNF-α, LIF, IL-6, or oncostatin M, which are metabolism-improving agents, growth hormones, IGF-1, or cachexia-inducing factors.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Purification by silica gel column chromatography was performed using a “HI-FLASH” column (manufactured by Yamazen Co.) or Purif-α2 (manufactured by Shoko Scientific Co., Ltd.) unless otherwise specified.

(Example 1)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzaldehyde (hereinafter referred to as Reference Example Compound 1):
To a THF (0.40 L) solution of 4-bromo-1-iodo-2- (trifluoromethoxy) benzene (25 g, 68 mmol) at −78 ° C., an n-butyllithium hexane solution (1.6 N, 86 mL, 0.14 mol) was added dropwise over 1.5 hours. After stirring at −78 ° C. for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise to the reaction solution over 10 minutes. After stirring at −78 ° C. for 2 hours, an aqueous citric acid solution (0.25 M, 0.25 L, 63 mmol) was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16 g (87%) of Reference Example Compound 1.

[Step 2]
Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanol (hereinafter referred to as Reference Example Compound 2):
At −10 ° C., sodium borohydride (2.4 g, 63 mmol) was added to a methanol (0.23 L) solution of Reference Example Compound 1 (16 g, 59 mmol). After stirring at −10 ° C. for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction solution. The reaction solution was concentrated under reduced pressure, water was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 1 → 1: 1) to give Reference Example Compound 2 Of 15 g (91%).

[Step 3]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate (hereinafter referred to as Reference Example Compound 3):
Methanesulfonyl chloride (0.63 mL, 8.1 mmol) was added to a solution of Reference Example Compound 2 (0.63 mL, 7.4 mmol) and TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) at room temperature. . After stirring at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.6 g (quantitative) of Reference Example Compound 3.

[Step 4]
Synthesis of 2- (4-bromo-2- (trifluoromethoxy) benzyl) isoindoline-1,3-dione (hereinafter referred to as Reference Example Compound 4):
Under ice-cooling, potassium phthalimide (2.1 g, 11 mmol) was added to a DMF (20 mL) solution of Reference Example compound 3 (2.6 g, 7.4 mmol). After stirring overnight at room temperature, water was added. The resulting solid was collected by filtration, washed with water, and dried to obtain 2.7 g (91%) of Reference Example Compound 4.

[Step 5]
Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine (hereinafter referred to as Reference Example Compound 5):
Hydrazine monohydrate (0.98 g, 19 mmol) was added to a methanol (40 mL) solution of Reference Example compound 4 (2.6 g, 6.5 mmol) at room temperature. After stirring at 60 ° C. for 2 hours, the mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.5 g (85%) of Reference Example Compound 5.

[Step 6]
Synthesis of tert-butyl (cis-4-((4-bromo-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamate (hereinafter referred to as Reference Example Compound 6):
At room temperature, cis-4-((tert-butoxycarbonyl) amino) cyclohexanecarboxylic acid (0.27 g, 1.1 mmol), Reference Example Compound 5 (0.30 g, 1.1 mmol) and DIPEA (0.48 mL, 2 .7 mmol) in DMF (3.0 mL) was added HATU (0.41 g, 1.1 mmol). After stirring at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 40: 60) to obtain 0.37 g (68%) of Reference Example Compound 6.

[Step 7]
Synthesis of tert-butyl (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamate (hereinafter referred to as Reference Example Compound 7):
Under 150 degrees, reference compound 6 (0.050 g, 0.10 mmol), tetrakis (triphenylphosphine) palladium (0.035 g, 0.030 mmol) and zinc cyanide (0.018 g, 0.15 mmol) 1- The methyl-2-pyrrolidone (1.0 mL) solution was stirred for 1 hour in a microwave reactor (MONOWAVE 300; manufactured by Anton Paar). Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → 30: 70) to obtain 0.015 g (34%) of Reference Example Compound 7.

[Step 8]
Synthesis of cis-4-amino-N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 8):
TFA (6.4 mL, 83 mmol) was added to a dichloromethane (40 mL) solution of Reference Example compound 7 (1.8 g, 4.2 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.3 g (93%) of Reference Example Compound 8.

[Step 9]
Synthesis of methyl (S) -3-methyl-2-propionamidobutanoate (hereinafter referred to as Reference Example Compound 9):
Propionyl chloride (7.8 mL, 89 mmol) was added to a solution of L-valine methyl ester hydrochloride (10 g, 60 mmol) and pyridine (17 mL, 210 mmol) in dichloromethane (100 mL) under ice cooling. After stirring for 3 hours under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 12 g (quantitative) of Reference Example Compound 9.

[Step 10]
Synthesis of (S) -3-methyl-2-propionamidobutanoic acid (hereinafter referred to as Reference Example Compound 10):
A 1N aqueous sodium hydroxide solution (90 mL, 90 mmol) was added to a methanol (100 mL) solution of Reference Example Compound 9 (11 g, 60 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction solution was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.5 g (82%) of Reference Example Compound 10.

[Step 11]
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 1) :
To a DMF (20 mL) solution of Reference Example Compound 8 (0.70 g, 2.1 mmol), Reference Example Compound 10 (0.34 g, 2.0 mmol) and DIPEA (0.85 mL, 4.9 mmol) at room temperature, HATU (0.97 g, 2.5 mmol) was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.63 g (65%) of Example Compound 1.

(Example 2)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-pivalamidocyclohexanecarboxamide (hereinafter, Example Compound 2):
Under ice cooling, pivaloyl chloride (0.070 mL, 0.57 mmol) was added to a solution of Reference Example Compound 8 (0.15 g, 0.44 mmol) and pyridine (0.11 mL, 1.3 mmol) in dichloromethane (5.0 mL). ) Was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 10: 90) to obtain 0.13 g (68%) of Example Compound 2.

(Example 3)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methyl-2- (methylsulfonamide) propanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of ethyl 2-methyl-2- (methylsulfonamide) propanoate (hereinafter referred to as Reference Example Compound 11):
Methanesulfonyl chloride (1.9 mL, 25 mmol) was added to a dichloromethane solution of ethyl 2-amino-2-methylpropanoate hydrochloride (4.0 g, 24 mmol) and DIPEA (13 mL, 72 mmol) under ice cooling. After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 → 1: 1) to obtain 4.3 g (86%) of Reference Example Compound 11.

[Step 2]
Synthesis of 2-methyl-2- (methylsulfonamido) propanoic acid (hereinafter referred to as Reference Example Compound 12):
A sodium hydroxide aqueous solution (1N, 29 mL, 29 mmol) was added to a methanol (35 mL) solution of Reference Example Compound 11 (4.0 g, 19 mmol) at room temperature. After stirring at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in 1N hydrochloric acid and then extracted with a chloroform: methanol mixed solvent (10: 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 2.5 g (72%) of Reference Example Compound 12.

[Step 3]
of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methyl-2- (methylsulfonamide) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 3) Synthesis:
Under ice-cooling, oxalyl chloride (0.037 mL, 0.43 mmol) was added to a solution of Reference Example Compound 12 (0.074 g, 0.41 mmol) and DMF (1 mL) in dichloromethane (5 mL). After stirring at room temperature for 30 minutes, the reaction solution was added to a dichloromethane (10 mL) solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and DIPEA (0.015 mL, 0.88 mmol) under ice cooling. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.11 g (75%) of Example Compound 3.

Example 4
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2- (methylsulfonamido) butanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((S) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 13):
Reference Example Compound 8 (0.10 g, 0.29 mmol), ((S) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid at room temperature HATU (0.14 g, 0.36 mmol) was added to a DMF (10 mL) solution of (0.10 g, 0.28 mmol) and DIPEA (0.12 mL, 0.70 mmol) After stirring overnight at room temperature, Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.16 g (84%) of Reference Example Compound 13.

[Step 2]
Synthesis of cis-4-((S) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 14) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 13 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.072 g (69%) of Reference Example Compound 14.

[Step 3]
cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2- (methylsulfonamido) butanamide) cyclohexanecarboxamide (hereinafter referred to as Example compound) 4) Synthesis:
Under ice cooling, a solution of Reference Compound 14 (0.035 g, 0.077 mmol) and pyridine (0.019 mL, 0.23 mmol) in dichloromethane (2.0 mL) was added to methanesulfonyl chloride (0.0072 mL, 0.092 mmol). Was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0042 g (10%) of Example Compound 4.

(Example 5)
cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 5) Synthesis of:
Under ice cooling, propionyl chloride (0.0080 mL, 0.092 mmol) was added to a solution of Reference Example Compound 14 (0.035 g, 0.077 mmol) and pyridine (0.019 mL, 0.23 mmol) in dichloromethane (2.0 mL). added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0052 g (13%) of Example Compound 5.

(Example 6)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((R) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 15):
Reference Example Compound 8 (0.50 g, 1.3 mmol), ((R) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid at room temperature HATU (0.65 g, 1.7 mmol) was added to a DMF (10 mL) solution of (0.47 g, 1.3 mmol) and DIPEA (0.90 mL, 5.2 mmol) After stirring overnight at room temperature, Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.55 g (61%) of Reference Example Compound 15.

[Step 2]
Synthesis of cis-4-((R) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 16) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 15 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.10 g (94%) of Reference Example Compound 16.

[Step 3]
cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 6) Synthesis of:
Under ice-cooling, propionyl chloride (0.011 mL, 0.13 mmol) was added to a solution of Reference Compound 16 (0.050 g, 0.11 mmol) and pyridine (0.027 mL, 0.33 mmol) in dichloromethane (2.0 mL). added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0068 g (12%) of Example Compound 6.

(Example 7)
Synthesis of N- (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) adamantane-1-carboxamide (hereinafter Example Compound 7):
Under ice-cooling, a solution of reference compound 8 (0.10 g, 0.29 mmol) and TEA (0.20 mL, 1.5 mmol) in dichloromethane (2.0 mL) was added to adamantane-1-carbonyl chloride (0.064 g, 0 .32 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude product was washed with a saturated aqueous sodium hydrogen carbonate solution and then recrystallized with ethanol-water to obtain 0.11 g (72%) of Example Compound 7.

(Example 8)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1- (trifluoromethyl) cyclopropanecarboxamide) cyclohexanecarboxamide (hereinafter, Example Compound 8):
DMF of Reference Example Compound 8 (0.10 g, 0.29 mmol), 1- (trifluoromethyl) cyclopropanecarboxylic acid (0.045 g, 0.29 mmol) and DIPEA (0.12 mL, 0.70 mmol) at room temperature To the (1.0 mL) solution was added HATU (0.13 g, 0.35 mmol). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and recrystallized from hexane-ethyl acetate to obtain 0.10 g (Example Compound 8) ( 72%).

Example 9
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1-propionamidocyclobutanecarboxamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of tert-butyl (1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamoyl) cyclobutyl) carbamate (hereinafter Reference Example Compound 17):
At room temperature, Reference Compound 8 (0.30 g, 0.88 mmol), 1-((tert-butoxycarbonyl) amino) cyclobutanecarboxylic acid (0.18 g, 0.84 mmol) and DIPEA (0.37 mL, 2.1 mmol) ) In DMF (10 mL) was added HATU (0.41 g, 1.1 mmol). After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 40: 60 → ethyl acetate only) to obtain 0.50 g (quantitative) of Reference Example Compound 17.

[Step 2]
Synthesis of cis-4- (1-aminocyclobutanecarboxamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 18):
TFA (1.4 mL, 19 mmol) was added to a dichloromethane (15 mL) solution of Reference Example compound 17 (0.050 g, 0.93 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.41 g (quantitative) of Reference Example Compound 18.

[Step 3]
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1-propionamidecyclobutanecarboxamide) cyclohexanecarboxamide (hereinafter, Example Compound 9):
Under ice cooling, propionyl chloride (0.048 mL, 0.55 mmol) was added to a solution of Reference Compound 18 (0.20 g, 0.46 mmol) and DIPEA (0.24 mL, 1.4 mmol) in dichloromethane (5.0 mL). added. After stirring for 3 hours under ice cooling, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.19 g (85%) of Example Compound 9.

(Example 10)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-hydroxy-2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 10):
DMF (1) of Reference Example Compound 8 (0.10 g, 0.29 mmol), 2-hydroxy-2-methylpropanoic acid (0.031 g, 0.29 mmol) and DIPEA (0.12 mL, 0.70 mmol) at room temperature. .0 mL) solution was added HATU (0.13 g, 0.35 mmol). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only → ethyl acetate: methanol = 90: 10), and 0.040 g of Example Compound 10 ( 32%).

(Example 11)
3-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,2-dimethyl-3-oxopropanoate (hereinafter, Example Compound 11) Synthesis of:
Reference Example Compound 8 (0.50 g, 1.5 mmol), 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (0.26 g, 1.6 mmol) and DIPEA (0.61 mL, 3.5 mmol) at room temperature. ) In DMF (3.0 mL) was added HATU (0.67 g, 1.8 mmol). After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.65 g (91%) of Example Compound 11.

(Example 12)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methoxy-2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 12):
DMF (1) of Reference Example Compound 8 (0.10 g, 0.29 mmol), 2-methoxy-2-methylpropanoic acid (0.038 g, 0.32 mmol) and DIPEA (0.12 mL, 0.70 mmol) at room temperature. .0 mL) solution was added HATU (0.13 g, 0.35 mmol). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.063 g (49%) of Example Compound 12.

(Example 13)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2- (4-methoxyphenoxy) -2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 13) :
At room temperature, Reference Compound 8 (0.080 g, 0.23 mmol), 2- (4-methoxyphenoxy) -2-methylpropanoic acid (0.054 g, 0.26 mmol) and DIPEA (0.098 mL, 0.56 mmol) ) In DMF (1.0 mL) was added HATU (0.11 g, 0.28 mmol). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and then recrystallized from hexane-ethyl acetate to obtain 0.080 g of Example Compound 13. (64%) was obtained.

(Example 14)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (3-hydroxy-2,2-dimethylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 14):
Under ice cooling, lithium tetrahydroborate (0.080 g, 3.7 mmol) was added to a THF (5.0 mL) solution of Example Compound 11 (0.59 g, 1.2 mmol). After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10) to obtain 0.35 g (64%) of Example Compound 14.

(Example 15)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylthio) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 15):
Reference Example Compound 8 (0.30 g, 0.89 mmol), 2,2-dimethyl-3- (methylthio) propanoic acid (0.14 g, 0.97 mmol) and DIPEA (0.37 mL, 2.1 mmol) at room temperature HATU (0.40 g, 1.1 mmol) was added to a solution of DMF (1.0 mL). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.31 g (75%) of Example Compound 15.

(Example 16)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylsulfinyl) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 16):
3-Chloroperbenzoic acid (70%, 0.055 g, 0.22 mmol) was added to a solution of Example Compound 15 (0.10 g, 0.21 mmol) in dichloromethane (1.0 mL) under ice cooling. After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent: ethyl acetate only → ethyl acetate: methanol = 90: 10), and Example Compound 16 Of 0.097 g (94%) was obtained.

(Example 17)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylsulfonyl) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 17):
3-Chloroperbenzoic acid (70%, 0.13 g, 0.51 mmol) was added to a solution of Example Compound 15 (0.10 g, 0.21 mmol) in dichloromethane (1.0 mL) under ice cooling. After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (Amine Silica Gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10). The obtained product was recrystallized from hexane-ethyl acetate to obtain 0.091 g (85%) of Example Compound 17.

(Example 18)
Synthesis of cis-4- (3-cyano-2,2-dimethylpropanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter, Example Compound 18):
DMF of Reference Example Compound 8 (0.10 g, 0.29 mmol), 3-cyano-2,2-dimethylpropanoic acid (0.056 g, 0.44 mmol) and DIPEA (0.15 mL, 0.88 mmol) at room temperature To the (1.0 mL) solution was added HATU (0.17 g, 0.44 mmol). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.077 g (58%) of Example Compound 18.

(Example 19)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of methyl (R) -3-methyl-2-propionamidobutanoate (hereinafter referred to as Reference Example Compound 19):
Propionyl chloride (0.78 mL, 8.9 mmol) was added to a solution of D-valine methyl ester hydrochloride (1.0 g, 6.0 mmol) and pyridine (1.7 mL, 21 mmol) in dichloromethane (10 mL) under ice cooling. It was. After stirring for 3 hours under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 1.2 g (quantitative) of Reference Example Compound 19.

[Step 2]
Synthesis of (R) -3-methyl-2-propionamidobutanoic acid (hereinafter referred to as Reference Example Compound 20):
1N aqueous sodium hydroxide solution (8.0 mL, 8.0 mmol) was added to a solution of Reference Example Compound 19 (1.0 g, 5.3 mmol) in methanol (10 mL) at room temperature. After stirring at room temperature for 3 hours, the reaction solution was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.68 g (73%) of Reference Example Compound 20.

[Step 3]
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 19) :
At room temperature, HATU (15 mL) was added to a solution of Reference Example Compound 8 (0.30 g, 0.88 mmol), Reference Example Compound 20 (0.15 g, 0.84 mmol) and DIPEA (0.37 mL, 2.1 mmol) in DMF (15 mL). 0.41 g, 1.1 mmol) was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.31 g (75%) of Example Compound 19.

(Example 20)
Synthesis of cis-N- (4-Chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of cis-4-((S) -2- (tert-butoxycarbonyl) amino) -3-methylbutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 21):
At room temperature, cis-4-aminocyclohexanecarboxylic acid methyl hydrochloride (2.0 g, 10 mmol), (S) -2-((tert-butoxycarbonyl) amino) -3-methylbutanoic acid (2.2 g, 10 mmol) and HATU (5.1 g, 13 mmol) was added to a solution of DIPEA (7.0 mL, 40 mmol) in DMF (40 mL). After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 40: 60) to obtain 4.0 g (quantitative) of Reference Example Compound 21.

[Step 2]
Synthesis of methyl cis-4-((S) -2-amino-3-methylbutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 22):
TFA (16 mL, 210 mmol) was added to a dichloromethane (100 mL) solution of Reference Example compound 21 (3.7 g, 10 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.4 g (89%) of Reference Example Compound 22.

[Step 3]
Synthesis of methyl cis-4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 23):
Under ice cooling, propionyl chloride (0.87 mL, 10 mmol) was added to a solution of Reference Example Compound 22 (2.3 g, 9.1 mmol) and TEA (2.8 mL, 20 mmol) in dichloromethane (30 mL). After stirring for 3 hours under ice cooling, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 30: 70) to obtain 2.1 g (75%) of Reference Example Compound 23.

[Step 4]
Synthesis of cis-4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxylic acid (hereinafter referred to as Reference Example Compound 24):
A 1N aqueous sodium hydroxide solution (4.8 mL, 4.8 mmol) was added to a methanol (10 mL) solution of Reference Example Compound 23 (1.0 g, 3.2 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction solution was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.0 g (quantitative) of Reference Example Compound 24.

[Step 5]
Synthesis of cis-N- (4-chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 20):
At room temperature, MiniBlock (registered trademark) -XT (48-position; Mettler Toledo Bohdan) reaction tube was charged with DMF of Reference Example Compound 24 (0.010 g, 0.034 mmol) and HATU (0.017 g, 0.044 mmol). (0.50 mL) solution as well as DIPEA (0.015 mL, 0.084 mmol) in DMF (0.10 mL) was added. After stirring for 5 minutes at room temperature, a solution of 4-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was subjected to LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: 10 mM hydrogen carbonate. 0.0022 g (15%) of Example Compound 20 was obtained by performing (aqueous ammonium solution-acetonitrile).

For Example Compound 20, the LC retention time and [M + H] ⁺ or [M−H] ⁻ were measured using the analysis method described below. The analysis method is as follows: LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extend-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: A = acetonitrile B = 10 mM ammonium hydrogen carbonate aqueous solution, gradient: A / B = 5/95 → 80/20 (6 minutes), flow rate: 4 mL / min.

(Comparative Example 1)
(S) -N- (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) -2- (hydroxymethyl) pyrrolidine-1-carboxamide (hereinafter, Comparative Example Compound 1) Synthesis of:
Under ice-cooling, TEA (0.16 mL, 1.2 mmol) was added to a solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and triphosgene (30 mg, 0.35 mmol) in dichloromethane (3.0 mL). Was added. After stirring for 5 minutes under ice cooling, L-prolinol (0.030 g, 0.29 mmol) was added under ice cooling. After stirring at room temperature for 5 hours, methanol was added to the reaction solution, followed by concentration under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → ethyl acetate only) to obtain 0.12 g (83%) of Comparative Compound 1.

(Comparative Example 2)
Synthesis of cis-N- (5-chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Comparative Example Compound 2):
At room temperature, MiniBlock (registered trademark) -XT (48-position; Mettler Toledo Bohdan) reaction tube was charged with DMF of Reference Example Compound 24 (0.010 g, 0.034 mmol) and HATU (0.017 g, 0.044 mmol). (0.50 mL) solution as well as DIPEA (0.015 mL, 0.084 mmol) in DMF (0.10 mL) was added. After stirring for 5 minutes at room temperature, a solution of 5-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was subjected to LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: 10 mM hydrogen carbonate. 0.0039 g (26%) of Comparative Compound 2 was obtained by carrying out (aqueous ammonium solution-acetonitrile).

For Comparative Compound 2, the LC retention time and [M + H] ⁺ or [M−H] ⁻ were measured using the analysis method described below. The analysis method is as follows: LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extend-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: A = acetonitrile B = 10 mM ammonium hydrogen carbonate aqueous solution, gradient: A / B = 5/95 → 80/20 (6 minutes), flow rate: 4 mL / min.

  The physical property data of the compounds of the present invention listed in the above examples are shown in Table 1-1 to Table 1-3, the physical property data of the comparative compounds are shown in Table 2-1 to Table 2-2, and the reference examples. Physical property data are shown in Tables 3-1 to 3-3. In the table, N.I. D. Represents “no data”.

The solvent name in the 1H-NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (manufactured by JEOL). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple line), brs (wide), brd (wide double line), brt (wide triple line), dd (double double line), dt (double triple line), ddd (double double line) ) Or ddt (double double triple line). All solvents were commercially available. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology).

(Example 21)
Evaluation test of sEH inhibitory activity in vitro:
The sEH inhibitory activity of the cyclohexanediamide derivative (I) was evaluated using human sEH based on the method described in a publicly known document (Analytical Biochemistry, 2005, Vol. 343, p. 66-75).

Recombinant human sEH (final concentration 0.026 μg / mL; Cayman) together with the test compound in 25 mM Bis-Tris-HCl buffer (pH 7.0) containing 0.1 mg / mL BSA for 30 minutes at room temperature Incubated. Thereafter, cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate (final concentration 6.25 μmol / L; Cayman) was added as a fluorescent substrate, and further at room temperature for 20 minutes. After incubation, ZnSO ₄ (final concentration 0.2 mol / L) was added to stop the reaction, and the fluorescence intensity (Fusion α (Packard); Excitation: 330 nm, Emission: 485 nm) was measured.

The fluorescence intensity with no sEH added and no test compound added was defined as 0% sEH enzyme reaction rate, and the fluorescence intensity with sEH added and no test compound added was defined as 100% sEH enzyme reaction rate. Each sEH enzyme reaction rate was calculated and IC ₅₀ was determined. The results are shown in Table 4.

  As a result, Example Compounds 1 to 20 showed a very strong inhibitory activity against the enzymatic reaction of human sEH as compared with Comparative Compounds 1 and 2.

  Therefore, it was revealed that the cyclohexanediamide derivative (I) exhibits a very strong inhibitory activity on the enzyme reaction of human sEH.

(Example 22)
Evaluation of drug efficacy in a rat anti-glomerular basement membrane antiserum (anti-GBM antiserum) -administered nephritis model:
Rat anti-glomerular basement membrane antiserum (anti-GBM antiserum) -administered nephritis model (Proceedings of the National Academy of Sciences of United States of America, vol. 102, 77. In Example 2002, Vol. 449, pp. 167-176) was administered Example Compound 1 or 2, and the therapeutic effect of cyclohexanediamide derivative (I) on chronic kidney disease was evaluated.

  In the tail vein of rats (Wistar-Kyoto strain, male, 8 weeks old; Charles River Japan, Inc.), a method described in the literature (Proceedings of the National of Sciences of the United States of America, 102nd Amer 5th Amer. Vol. 7736-7741; European journal of pharmacology, 2002, vol. 449, p. 167-176), administered with rabbit anti-glomerular basement membrane antiserum (hereinafter referred to as anti-GBM antiserum). The group in which nephritis was induced was referred to as “nephritis induction group”. On the other hand, the group not administered with anti-GBM antiserum was designated as the “normal group”.

  Two weeks after administration of the anti-GBM antiserum, blood was collected from the tail vein or jugular vein of the rat, and serum creatinine (hereinafter referred to as sCre) was measured. sCre was measured using an enzymatic method.

  The sCre value (mean value ± standard error, n = 18) 2 weeks after administration of anti-GBM antiserum in the nephritis induction group was 0.47 ± 0.01 mg / dL. Compared to the sCre value in the normal group (0.27 ± 0.01 mg / dL (mean ± standard error, n = 3)), it was statistically significantly increased (t test, p <0.05) ). That is, in the nephritis induction group, it was shown that two weeks after administration of anti-GBM antiserum, a pathological condition of renal failure was exhibited.

  From the 2nd week after administration of anti-GBM antiserum to the end of the experiment, Example Compound 1 or 2 was suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 to rats in the nephritis-inducing group showing a pathological condition of renal failure. It became cloudy and was orally administered once a day at a dose of 3 mg / kg. The groups to which Example Compound 1 or 2 was administered were designated as “Example Compound 1 (3 mg / kg) administration group” or “Example Compound 2 (3 mg / kg) administration group”, respectively. In addition, as a comparative control, a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats in the nephritis induction group was designated as a “nephritis control group”. The normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80. In addition, sCre was measured by the same method as described above also 4 weeks after administration of anti-GBM antiserum.

  The measurement results of sCre values after 2 and 4 weeks after administration of anti-GBM antiserum are shown in FIG. The horizontal axis of the figure indicates the number of weeks after administration of anti-GBM antiserum, and the vertical axis indicates each measured value (mean value ± standard error, n = 6).

  In the nephritis control group, the sCre value at 2 and 4 weeks after administration of the anti-GBM antiserum was continuously high from 2 weeks after administration of the anti-GBM antiserum. Therefore, the nephritis control group was shown to exhibit chronic nephritis and renal failure.

  In addition, the sCre value in the Example Compound 1 (3 mg / kg) administration group and the Example Compound 2 (3 mg / kg) administration group 4 weeks after the anti-GBM antiserum administration was compared with the sCre value in the nephritis control group. , Each markedly low value (FIG. 1). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.

  From this result, it was revealed that cyclohexanediamide derivative (I) has a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.

(Example 23)
Evaluation of drug efficacy in rat monocrotaline-treated pulmonary hypertension model:
Example Compound 1 or 2 was administered to rat monocrotaline-administered pulmonary hypertension model (Journal of Pharmaceutical Sciences, 2009, Vol. 111, p. 235-243), and cyclohexanediamide derivative (I) against pulmonary hypertension The therapeutic effect was evaluated.

  A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 5 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal group”.

  Example Compound 1 (3 and 10 mg / kg) or Example Compound 2 (10 mg / kg) was orally administered once a day to rats in the pulmonary hypertension induction group for 24 days from the day of monocrotaline administration. Example compounds 1 and 2 were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80. Groups in which Example Compound 1 was administered at a dose of 3 or 10 mg / kg were referred to as “Example Compound 1 (3 mg / kg) administration group” or “Example Compound 1 (10 mg / kg) administration group”, respectively. . In addition, a group in which Example Compound 2 was administered at a dose of 10 mg / kg was designated as “Example Compound 2 Administration Group”. On the other hand, as a comparative control, a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”. A 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the normal group. Each group n = 10.

  The day after the final administration of the test compound, the right ventricular systolic pressure, systemic systolic blood pressure, and heart rate were measured. The right ventricular systolic pressure and systemic systolic blood pressure were measured using a blood pressure measurement amplifier (Nihon Koden Kogyo Co., Ltd.), and the heart rate was measured using an instantaneous heart rate monitor unit (Nihon Koden Kogyo Co., Ltd.). On the same day, the wet weights of the right ventricle, left ventricle and septum were measured to determine the right ventricular weight ratio (right ventricular weight / (septum weight + left ventricular weight)).

  The results are shown in Tables 5 and 6.

  The right ventricular systolic pressure (mean ± standard error, n = 10) of the pulmonary hypertension control group is 123 ± 5 mmHg, and the right ventricular systolic pressure (31 ± 2 mmHg (mean ± standard error, n = 10) of the normal group. Compared with 10)), the value was statistically significantly higher (Aspin-Welch t test, p <0.05), indicating that the patient had a pathological condition of pulmonary hypertension. In addition, the right ventricular systolic pressure in the group administered with Example Compound 1 (3 mg / kg) and the group administered with Example Compound 2 were statistically significant compared to the right ventricular systolic pressure in the pulmonary hypertension control group. It showed a low value (Dunnett's test, p <0.05) (Table 5). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect on the pathology of pulmonary hypertension.

  The right ventricular weight ratio (mean value ± standard error, n = 10) of the pulmonary hypertension control group is 0.54 ± 0.02, and the right ventricular weight ratio (0.27 ± 0.01 (mean value) of the normal group Compared with ± standard error, n = 10)), it is statistically significantly higher (Aspin-Welch t-test, p <0.05), indicating that the disease state of right ventricular hypertrophy is exhibited. It was done. In addition, the right ventricular weight ratio of the Example Compound 2 administration group was statistically significantly lower than the right ventricular weight ratio of the pulmonary hypertension control group (Dunnett's test, p <0). .05) (Table 6). Further, the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) administration group and the Example Compound 1 (10 mg / kg) administration group is lower than the right ventricular weight ratio of the pulmonary hypertension control group. (Table 6). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect also on the pathophysiology of right ventricular hypertrophy.

  On the other hand, the heart rate and systemic systolic blood pressure of the Example Compound 1 (3 mg / kg) administration group, the Example Compound 1 (10 mg / kg) administration group and the Example Compound 2 administration group were the same as those of the pulmonary hypertension control group. There was no significant difference in both heart rate and systemic systolic blood pressure (Dunnett's test, p <0.05).

  From this result, it was revealed that cyclohexanediamide derivative (I) has a therapeutic effect on pulmonary hypertension.

  The cyclohexanediamide derivative of the present invention exhibits potent sEH inhibitory activity, and can be used as a therapeutic or prophylactic agent for chronic kidney disease and pulmonary hypertension in the pharmaceutical field.

Claims (6)

A cyclohexanediamide derivative represented by the following general formula (I):

[Wherein, R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, and 4 carbon atoms. To 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group and the cycloalkylalkyl group each have 1 to 3 hydrogen atoms, An atom, a hydroxyl group, a cyano group, —SR ⁶ , optionally substituted with —S (═O) R ⁶ or —S (═O) ₂ R ⁶ ), a phenyloxy group (the phenyloxy group is a benzene ring) 1 to 3 hydrogen atoms may be independently substituted with an alkyloxy group having 1 to 6 carbon atoms), —N (H) C (═O) R ⁷ , —N (H ) S (= O) ₂ R ⁷ , Represents -C (= O) N (H ) R 7 or -C (= O) OR ^7,
R ² and R ³ are each independently a hydrogen atom (wherein R ² and R ³ do not represent a hydrogen atom at the same time), an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 2 to 7 carbon atoms. An oxyalkyl group (the alkyl group and the alkyloxyalkyl group each represent 1 to 3 hydrogen atoms each independently may be substituted with a halogen atom, a hydroxyl group or a cyano group), or together turned by - _{(CH 2) l} - or represents, or may represent adamantyl group further together with ^{R 1,}
R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group (the alkyl group and the alkyloxy group are each represented by 1 to 3 hydrogen atoms) Each atom may be independently substituted with a halogen atom)
R ⁶ represents an alkyl group having 1 to 6 carbon atoms,
R ⁷ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkyl group, The cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group each represent 1 to 3 hydrogen atoms, each of which may be independently substituted with a halogen atom, a hydroxyl group, or a cyano group.
l represents an integer of 2 to 5. ] R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH ₂ ) ₁ —;
The cyclohexanediamide derivative according to claim 1, wherein R ⁵ is a substituent at the 2-position on the benzene ring. R ¹ is an alkyl group having 1 to 6 carbon atoms or —N (H) C (═O) R ⁷ ;
R ⁴ is a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group,
The cyclohexanediamide derivative according to claim 2, wherein R ⁵ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxy group.   The pharmaceutical which contains the cyclohexane diamide derivative as described in any one of Claims 1-3 as an active ingredient.   The soluble epoxide hydrolase inhibitor which contains the cyclohexane diamide derivative as described in any one of Claims 1-3 as an active ingredient.   A therapeutic or prophylactic agent for chronic kidney disease or pulmonary hypertension, comprising the cyclohexanediamide derivative according to any one of claims 1 to 3 as an active ingredient.

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