JP2012136459A - N-hydroxyethyl-carbamate derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a renin inhibitor and represented by formula (1), or to provide a pharmaceutically acceptable salt of the compound.SOLUTION: The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is provided. In formula (1), Ris a 1C-4C alkoxycarbonyl group substituted with formula (a), a group represented by formula (b), or the like; Ris methyl or the like; Rand Rare each independently the same as or different from each other, being H, a compound group represented by 1C-4C alkyl (wherein, the 1C-4C alkyl is optionally substituted with amino or the like) or a pharmaceutically acceptable salt of the 1C-4C alkyl, or the like; and Ris 1C-6C alkyl ( wherein, the alkyl is optionally substituted with 1-3 fluorine atom(s)).

Description

  The present invention relates to N-hydroxyethyl-carbamate derivatives useful as pharmaceuticals. Furthermore, the present invention relates to a therapeutic agent for hypertension comprising an N-hydroxyethyl-carbamate derivative effective as a renin inhibitor as an active ingredient.

A renin inhibitor is a drug that directly inhibits renin located in the most upstream of the renin-angiotensin (RA) system, which plays an important role in the onset and progression of cardiovascular diseases such as hypertension, congestive heart failure, and kidney damage. Therefore, it is highly expected to be useful as a therapeutic drug for cardiovascular diseases.
In fact, the following structural formula is a renin inhibitor developed in recent years:

で表されるアリスキレン（特許文献１）は、高血圧患者を対象とした臨床試験において、血漿レニン活性を顕著に抑制し、他のＲＡ系抑制薬に匹敵する優れた降圧効果を示すことが確認されている（非特許文献１〜３）。また前述の背景から、レニン阻害薬は優れた降圧作用だけでなく、より優れた腎心血管の保護作用も期待されている。一般的にＲＡ系抑制薬の腎心血管の保護作用は、用量依存的に増強すると言われており、レニン阻害薬においてもより高用量を服薬できる安全性に優れた薬剤であることが求められている。

It has been confirmed that aliskiren (Patent Document 1) represented by the formula significantly suppresses plasma renin activity and exhibits an excellent antihypertensive effect comparable to other RA-based inhibitors in a clinical trial targeting hypertensive patients. (Non-Patent Documents 1 to 3). In addition, from the above-mentioned background, renin inhibitors are expected not only to have an excellent antihypertensive effect, but also to have an excellent renal cardiovascular protective effect. In general, it is said that RA cardiovascular protective action of RA inhibitors is dose-dependently enhanced, and renin inhibitors are required to be safe drugs that can be used at higher doses. ing.

As a group of compounds substituted with nitrogen atoms in the structure of aliskiren, the following formula

で表わされる化合物（式中、Ｃ）Ｘは‐Ａｌｋ‐Ｃ(Ｏ)‐ＮＲ^５Ｒ^４、ここにおいてＡｌｋはＣ_１−８アルキレン、およびＲ^４はテトラヒドロピラニルＣ_０−４アルキル、ＴはＲ^１、Ｒ^１は置換されているアリール、Ｒ^２及びＲ^３は独立して水素原子等、Ｒ^５は水素原子等、Ｑは水素原子等、Ｚは水素原子等である。）が知られている（特許文献２）。しかし、後述する式（１）で表される化合物は、特許文献２に開示されている化合物と構造が異なる。

In which C) X is —Alk—C (O) —NR ⁵ R ⁴ , where Alk is C _1-8 alkylene, and R ⁴ is tetrahydropyranyl C _0-4 alkyl, T is R ¹ and R ¹ are substituted aryl, R ² and R ³ are independently a hydrogen atom, R ⁵ is a hydrogen atom, Q is a hydrogen atom, and Z is a hydrogen atom. ) Is known (Patent Document 2). However, the compound represented by the formula (1) described later is different in structure from the compound disclosed in Patent Document 2.

Japanese Patent No. 3340322 European Patent Application No. 1911762

Hypertension 42 (6): p.1137-43, (2003) Circulation 111 (8): p.1012-8, (2005) J Hypertens. 24 (Suppl 4): S82.Abstract P4.269, (2006)

  In clinical trials, aliskiren has been observed to have gastrointestinal disorders such as diarrhea as dose-dependent side effects in clinical trials. It is difficult to strengthen. It also has the effect of inducing inflammation when administered subcutaneously. One cause of gastrointestinal disorders such as aliskiren's diarrhea is considered to be an inflammation-inducing action in parts that are considered to be in direct contact (for example, the digestive tract of the oral cavity, gastrointestinal tract, etc. that are likely to be exposed at high concentrations). It is done. The problem to be solved by the present invention is to provide a novel compound in which the above-mentioned problems of aliskiren are solved.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have unexpectedly found that the following compound having a specific substituent on the secondary amine at the 5-position of aliskiren or a pharmaceutically acceptable salt thereof (hereinafter referred to as necessary). Accordingly, the present invention is sometimes abbreviated as a compound of the present invention.) It has been found that side effects such as effects and symptoms derived from inflammation-inducing action can be reduced, and the present invention has been completed.

That is, the present invention is as follows.
Item 1: A compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

［式中、Ｒ^１は、
１：Ｃ_１−６アルキル基（該基は、
（ａ）アミノ、
（ｂ）ヒドロキシ、または
（ｃ）下記式：

[Wherein R ¹ is
1: C _1-6 alkyl group (the group is
(A) amino,
(B) hydroxy, or (c) the following formula:

で表される基（ここにおいて、Ｒ^２は、
（ｉ）Ｃ_１−４アルキル基（該基は、Ｃ_１−４アルコキシで置換されてもよい。）、
（ｉｉ）Ｃ_３−６シクロアルキル基、または
（ｉｉｉ）Ｃ_６−１０アリール基（該基は、Ｃ_１−４アルコキシで置換されてもよい。）である。）で置換されている。）、
２：Ｃ_１−４アルキルカルボニル基（該基は、
（ａ）アミノ、または
（ｂ）ヒドロキシで置換されてもよい。）、
３：Ｃ_１−４アルコキシカルボニル基（該基は、下記式：

(Wherein R ² is a group represented by
(I) a C _1-4 alkyl group (this group may be substituted with C _1-4 alkoxy),
(Ii) a C _3-6 cycloalkyl group, or (iii) a C _6-10 aryl group, which group may be substituted with C _1-4 alkoxy. ). ),
2: C _1-4 alkylcarbonyl group (the group is
It may be substituted with (a) amino, or (b) hydroxy. ),
3: C _1-4 alkoxycarbonyl group (the group has the following formula:

で表される基（ここにおいて、Ｒ^２は、前掲と同義である。）で置換されている。）、または
４：下記式：

(Wherein R ² has the same meaning as described above). ) Or 4:

で表される基（ここにおいて、Ｒ^３およびＲ^４は、各々独立して、同一または異なって、
（ａ）水素原子、
（ｂ）Ｃ_１−４アルキル基（該基は、
Ｃ_１−４アルコキシ、
Ｃ_３−６シクロアルキル（該基は、Ｃ_１−４アルコキシで置換されてもよい。）、 ５員もしくは６員の飽和へテロ環、または
５員もしくは６員の飽和へテロ環オキシで置換されてもよい。）、
（ｃ）Ｃ_３−１０シクロアルキル基（該基は、
１〜２個のフッ素原子、または
Ｃ_１−４アルコキシで置換されてもよい。）、
（ｄ）Ｃ_６−１０アリール基（該基は、
ハロゲン原子、または
Ｃ_６−１０アリール（該アリールは、ハロゲン原子またはＣ_１−４アルコキシで置換されてもよい。）で置換されてもよい。）、
（ｅ）５員もしくは６員の飽和へテロ環基、または
（ｆ）５員〜１０員の単環式もしくは多環式のヘテロアリール基（該基は、
Ｃ_１−４アルキル、または
Ｃ_１−４アルコキシで置換されてもよい。）であり、
Ｒ^５は、
１：Ｃ_１−６アルキル基（該基は、
（ａ）１〜３個のフッ素原子、
（ｂ）ヒドロキシ、
（ｃ）Ｃ_１−４アルコキシ、
（ｄ）カルボキシ、
（ｅ）Ｃ₆₋₁₀アリール、
（ｆ）５員もしくは６員の飽和へテロ環、
（ｇ）Ｃ_３−６シクロアルキル、
（ｈ）Ｃ_１−４アルコキシカルボニル、
（ｉ）Ｃ_１−４アルコキシカルボニルアミノ、
（ｊ）アミノ、
（ｋ）モノ−もしくはジ−（Ｃ_１−６アルキル）アミノ、
（ｌ）５員〜７員の環状アミン、
（ｍ）アミノカルボニル、または
（ｎ）５員〜７員の環状アミノカルボニルで置換されてもよい。）、
２：Ｃ_３−１０シクロアルキル基（該基は、ヒドロキシで置換されてもよい。）、
３：Ｃ_６−１０アリール基（該基は、
（ａ）ハロゲン原子、
（ｂ）Ｃ_１−４アルキル、
（ｃ）Ｃ_３−６シクロアルキルＣ_１−４アルキル、
（ｄ）シアノ、
（ｅ）Ｃ_１−４アルコキシ、または
（ｆ）Ｃ_１−４アルキルカルボニルオキシから選択される同種または異種の１〜３個の基で置換されていてもよい。）、
４：Ｃ_１−４アルキルカルボニル基（該基は、
（ａ）ヒドロキシ、または
（ｂ）Ｃ_３−６シクロアルキルで置換されてもよい。）、
５：５員〜１０員の単環式もしくは多環式ヘテロアリール基、
６：５員もしくは６員の飽和へテロ環基（該基は、Ｃ_１−４アルコキシで置換されてもよいＣ_１−４アルキルで置換されてもよい。）、
７：Ｃ_１−６アルコキシ基（該基は、Ｃ_３−６シクロアルキルで置換されてもよい。）、
８：Ｃ_３−６シクロアルキルオキシ基（該基は、Ｃ_１−４アルコキシで置換されてもよい。）、または
９：５員もしくは６員の飽和ヘテロ環オキシ基である。）である。］

Wherein R ³ and R ⁴ are each independently the same or different,
(A) a hydrogen atom,
(B) a C _1-4 alkyl group (the group is
C _1-4 alkoxy,
C _3-6 cycloalkyl (the group may be substituted with C _1-4 alkoxy), 5- or 6-membered saturated heterocyclic, or 5- or 6-membered saturated heterocyclic oxy May be. ),
(C) a C _3-10 cycloalkyl group (the group is
It may be substituted with 1 to 2 fluorine atoms or C _1-4 alkoxy. ),
(D) a C _6-10 aryl group (the group is
It may be substituted with a halogen atom, or C _6-10 aryl (the aryl may be substituted with a halogen atom or C _1-4 alkoxy). ),
(E) a 5- or 6-membered saturated heterocyclic group, or (f) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group is
C _1-4 alkyl, or C _1-4 alkoxy may be substituted. ) And
R ⁵ is
1: C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) hydroxy,
(C) C _1-4 alkoxy,
(D) carboxy,
(E) C _6-10 aryl,
(F) a 5- or 6-membered saturated heterocycle,
(G) C _3-6 cycloalkyl,
(H) C _1-4 alkoxycarbonyl,
(I) C _1-4 alkoxycarbonylamino,
(J) amino,
(K) mono- or di- (C _1-6 alkyl) amino,
(L) a 5- to 7-membered cyclic amine,
(M) aminocarbonyl, or (n) 5-7 membered cyclic aminocarbonyl may be substituted. ),
2: C _3-10 cycloalkyl group (the group may be substituted with hydroxy),
3: C _6-10 aryl group (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with 1 to 3 groups of the same or different types selected from C _1-4 alkylcarbonyloxy. ),
4: C _1-4 alkylcarbonyl group (the group is
It may be substituted with (a) hydroxy, or (b) C _3-6 cycloalkyl. ),
5: 5- to 10-membered monocyclic or polycyclic heteroaryl group,
6: 5-membered or 6-membered saturated heterocyclic group (the group may be substituted with C _1-4 alkyl which may be substituted with C _1-4 alkoxy);
7: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
8: A C _3-6 cycloalkyloxy group (the group may be substituted with C _1-4 alkoxy), or a 9: 5-membered or 6-membered saturated heterocyclic oxy group. ). ]

Item 2: The compound represented by the formula (1) is

で表される化合物（Ｒ^１は、項１と同じである。）である、項１に記載の化合物、またはその薬学上許容される塩。

The compound of claim | item 1, or its pharmacologically acceptable salt which is a compound represented by these (R < ¹ > is the same as the claim | item 1.).

Item 3: R ¹ is a C _1-4 alkoxycarbonyl group (the group has the following formula:

（Ｒ^２は、前掲と同じである。）で置換されている。）である、項１または項２に記載の化合物、またはその薬学上許容される塩。

(R ² is the same as described above). The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof.

Item 4: R ¹ is represented by the following formula:

（Ｒ^２は、前掲と同じである。）で表される基である、項３に記載の化合物、またはその薬学上許容される塩。

Item 4. The compound according to Item 3, or a pharmaceutically acceptable salt thereof, wherein R ² is the same as defined above.

Item 5: The compound according to Item 4, or a pharmaceutically acceptable salt thereof, wherein R ² is a methyl group.

Item 6: R ¹ is represented by the following formula:

で表される基（ここにおいて、Ｒ^３およびＲ^４は、各々独立して、同一または異なって、水素原子、またはＣ_１−４アルキル基であり、
Ｒ^５は、
１：Ｃ_１−４アルキル基（該基は、
（ａ）アミノ、
（ｂ）ヒドロキシ、
（ｃ）Ｃ_１−４アルコキシ、
（ｄ）カルボキシ、
（ｅ）Ｃ_１−４アルコキシカルボニル、または
（ｆ）Ｃ_1-4アルコキシカルボニルアミノで置換されていてもよい。）、
２：Ｃ_３−１０シクロアルキル基、
３：Ｃ_１−４アルキルカルボニル基、
４：Ｃ_６−１０アリール基（該基は、
（ａ）ハロゲン、
（ｂ）Ｃ_１−４アルキル、
（ｃ）Ｃ_３−６シクロアルキルＣ_１−４アルキル、
（ｄ）シアノ、
（ｅ）Ｃ_１−４アルコキシ、または
（ｆ）Ｃ_１−４アルキルカルボニルオキシから選択される同種または異種の１〜３個の基で置換されていてもよい。）、
５：５員〜１０員の単環式もしくは多環式ヘテロアリール基、
６：５員もしくは６員の飽和へテロ環基、
７：Ｃ_１−６アルコキシ基（該基は、Ｃ_３−６シクロアルキルで置換されていてもよい。）、
８：Ｃ_３−６シクロアルキルオキシ基、または
９：５員もしくは６員の飽和ヘテロ環オキシ基である。）である、項１に記載の化合物、またはその薬学上許容される塩。

(Wherein R ³ and R ⁴ are each independently the same or different and each represents a hydrogen atom or a C _1-4 alkyl group;
R ⁵ is
1: C _1-4 alkyl group (the group is
(A) amino,
(B) hydroxy,
(C) C _1-4 alkoxy,
(D) carboxy,
(E) C _1-4 alkoxycarbonyl, or (f) C _1-4 alkoxycarbonylamino may be substituted. ),
2: C _3-10 cycloalkyl group,
3: C _1-4 alkylcarbonyl group,
4: C _6-10 aryl group (the group is
(A) halogen,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with 1 to 3 groups of the same or different types selected from C _1-4 alkylcarbonyloxy. ),
5: 5- to 10-membered monocyclic or polycyclic heteroaryl group,
6: 5-membered or 6-membered saturated heterocyclic group,
7: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
8: C _3-6 cycloalkyloxy group, or 9: 5-membered or 6-membered saturated heterocyclic oxy group. Or a pharmaceutically acceptable salt thereof.

Item 7: The compound according to Item 6, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, and R ⁴ is a methyl group.

Item 8: R ⁵ is
1: C _1-4 alkyl group,
2: C _3-6 cycloalkyl group,
3: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
4: C _3-6 cycloalkyloxy group,
5: 5-membered or 6-membered saturated heterocyclic oxy group,
6: C _6-10 aryl (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with one or two groups selected from the same or different groups selected from C _1-4 alkylcarbonyloxy. Or the compound according to Item 6 or 7, or a pharmaceutically acceptable salt thereof, which is a 7: 5- to 10-membered monocyclic or polycyclic heteroaryl group.

Item 9: R ⁵ is
1: C _1-4 alkyl group, or 2: C _1-6 alkoxy group, or 3: C _6-10 aryl (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
It may be substituted with 1 or 2 groups of the same or different types selected from (d) cyano, or (e) C _1-4 alkoxy. Or a pharmaceutically acceptable salt thereof, which is a 4: 5-membered to 10-membered monocyclic or polycyclic heteroaryl group.

Item 10: A compound represented by formula (2), or a pharmaceutically acceptable salt thereof.

Item 11: A compound represented by formula (3), or a pharmaceutically acceptable salt thereof.

Item 12: A pharmaceutical composition comprising the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 13: A renin inhibitor comprising the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 14: A therapeutic agent for a disease caused by renin inhibition comprising the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 15: Use of the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof in the treatment and / or prevention of a disease caused by renin inhibition.

Item 16: Use of the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof in the treatment and / or prevention of hypertension.

Item 17: A disease caused by renin inhibition, which comprises administering an effective amount of the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. Treatment methods.

Item 18: A pharmaceutical comprising a combination of the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof and a drug selected from the following drug group (A):
The drug group (A) is an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue, GLP-1, a GLP-1 analog, a protein tyrosine phosphatase inhibitor, β3 agonist, DPPIV inhibition Agent, aldose reductase inhibitor, neurotrophic factor, PKC inhibitor, AGE inhibitor, active oxygen scavenger, cerebral vasodilator, HMG-CoA reductase inhibitor, squalene synthetase inhibitor, ACAT inhibitor, angiotensin conversion Enzyme inhibitor, Angiotensin II antagonist, Calcium antagonist, ACE / NEP inhibitor, β blocker, α blocker, αβ blocker, central anti-obesity agent, pancreatic lipase inhibitor, peptidic appetite suppressant, cholecyst Kinin agonist, xanthine derivative, thiazide preparation, anti-aldosterone preparation, charcoal Anhydrase inhibitors, chlorbenzenesulfonamide formulation, azosemide, isosorbide, ethacrynic acid, a group consisting of piretanide, bumetanide, and furosemide.

  Hereinafter, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is collectively referred to as “the compound of the present invention” as necessary.

  The compound of the present invention has excellent renin inhibitory activity and is useful as a therapeutic agent for hypertension.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the notation “C _1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms. Further, in the present specification, a substituent that does not particularly indicate the term “which may be substituted” or “substituted” means an “unsubstituted” substituent. For example, “C _1-6 alkyl” means “unsubstituted”.

  In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted. The number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C _1-6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, " _C1-4 alkyl group" etc. are mentioned. Specific examples of “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“C _3-10 cycloalkyl group” means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms. For example, preferably, “C _3-6 cycloalkyl group” and the like can be mentioned. Specific examples of “C _3-10 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl and the like.

“C _6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferably, and the like "C ₆ aryl group" (phenyl). Specific examples of “C _6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

  Examples of the “heteroaryl group” include a 5-membered to 10-membered monocyclic or polycyclic group, and the group includes the same or different heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It is different and includes one or more (for example, 1 to 4). Preferable examples include a 5-membered or 6-membered monocyclic group, and the like includes one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples of the “heteroaryl group” include, for example, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzthiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridadyl, quinolyl , Isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo [1,2-a] pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl or isoquinolinolyl.

_{"C 1-6} alkoxy group" is synonymous with _{"C 1-6} alkyl group", _{"C 1-6} alkyl" moiety is the same as defined in the _{"C 1-6} alkyl". Preferably, " _C1-4 alkoxy group" etc. are mentioned. Specific examples of “C _1-4 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

_{"C 3-6} cycloalkyl" moiety of the _{"C 3-6} cycloalkyl group" is the same as the _{"C 3-6} cycloalkyl". Specific examples include cyclopropyloxy and the like.

“C _3-6 cycloalkyl C _1-4 alkyl” means a group in which the above “C _3-6 cycloalkyl” is bonded to “C _1-4 alkyl”. Specific examples include cyclopropylmethyl and the like.

The “C _1-4 alkylcarbonyl group” means a group in which the “C _1-4 alkyl group” is bonded to a carbonyl group. Specific examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, 2-propylcarbonyl, tert-butylcarbonyl, and the like.

“C _1-4 alkoxycarbonyl group” means a group in which the “C _1-4 alkoxy group” is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.

The “C _1-4 alkoxycarbonylamino group” means a group obtained by substituting one amino group with the above “C _1-4 alkoxycarbonyl group”. Specific examples include methoxycarbonylamino, ethoxycarbonylamino and the like. “C _1-4 alkyl” may be substituted with 1 to 3 fluorine atoms.

  Examples of the “saturated heterocyclic group” include a 5-membered or 6-membered saturated heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. Specifically, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo Examples include oxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl and the like. In the group, the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as a pyrrolidino group.

  The “saturated heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. For example, a bicyclic 11- or 12-membered “saturated heterocycle” in which the 5-membered or 6-membered “saturated heterocyclic group” and the 6-membered aromatic hydrocarbon or 6-membered unsaturated heterocycle are condensed. Is mentioned. Examples of the 6-membered aromatic hydrocarbon include benzene. Examples of the 6-membered unsaturated heterocycle include pyridine, pyrimidine, pyridazine and the like. Specifically, dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrololidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl , Decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.

  The “saturated heterocycle” part of the “saturated heterocyclic oxy group” is the same as the above “saturated heterocycle group”. Specific examples include pyranyloxy and pyrrolidinyloxy.

“5- to 7-membered cyclic amino” means a 5- to 7-membered cyclic amino group. A group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino oxide, piperazino, 2-pyrrolidone-1-yl and the like. The ring may be substituted with, for example, a halogen atom, C _1-4 alkyl, or C ₆ aryl which may be substituted with C _1-4 alkoxy.

“5- to 7-membered cyclic amino” of “5- to 7-membered cyclic aminocarbonyl” means the above-mentioned “
The same as “5- to 7-membered cyclic amino”.

The compound of the present invention can also be exemplified as a compound in which “R ¹ ” is replaced by the partial structures of P1 to P181 described later.

Although the manufacturing method of the compound represented by Formula (1) in this invention is demonstrated with an example below, this invention is not limited to this from the first. In the present specification, the following abbreviations may be used for the sake of simplicity.
Boc: tert-butoxycarbonyl group Cbz: benzyloxycarbonyl group Me: methyl group Ac: acetyl group Me: methyl group Et: ethyl group i-Pr: isopropyl group Bz: benzoyl group TFA: trifluoroacetic acid NMM: N-methylmorpholine

  The compound represented by the formula (1) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method. The compound represented by formula (1) can be synthesized by appropriately selecting and combining the methods shown below according to the type of the starting material.

Manufacturing method 1
Among the compounds represented by formula (1), the compound represented by formula (1-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein, A is the same as described above, and R ³ , R ⁴ , and R ⁵ have the same meanings as described in item 1 above]. ]

1) Step 1
Compound (1-3) can be produced by reacting compound (1-1) with compound (1-2) in the presence of a base in an inert solvent. Examples of the base include triethylamine, N-methylmorpholine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] nona. And organic bases such as -5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, and picoline. Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane, aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or halogenated hydrocarbon solvents such as chloroform, dichloromethane or dichloroethane. And a mixed solvent thereof may be used. The reaction temperature is selected from the range of about −20 ° C. to about 40 ° C.
Compound (1-2) can be produced by using a method described in literature or the like. For example, it can be produced by a method of reacting the corresponding ketone and aldehyde with triphosgene (Tetrahedron Letters 30, 2033 (1989), Tetrahedron Letters 42, 7751 (2001), etc.).

2) Step 2
Compound (1-5) can be produced by reacting compound (1-3) with compound (1-4) in the presence of silver carbonate in an inert solvent. Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane, aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or halogenated hydrocarbon solvents such as chloroform, dichloromethane or dichloroethane. And a mixed solvent thereof may be used. The reaction temperature is selected from the range of about 20 ° C to about 80 ° C.

Manufacturing method 2
Among the compounds represented by the formula (1), the compound represented by the formula (2-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, A, R ³ and R ⁴ are as defined above, and R ¹⁰¹ is a C _1-6 alkyl group which may be substituted with C _3-6 cycloalkyl, C _1-4 alkoxy. An optionally substituted C _3-6 cycloalkyl group, or a 5- or 6-membered saturated heterocyclic group. ]

1) Step 1
Compound (2-2) can be produced by continuously carrying out the following reactions (i. To ii.) From compound (1-2) in an inert solvent. Examples of the inert solvent include ether solvents such as diethyl ether, dioxane, and tetrahydrofuran.
i. In the presence of pyridine, the compound (1-2) is reacted with the compound (2-1). The reaction temperature is selected from the range of about −10 ° C. to about 30 ° C.
ii. i. The reaction mixture is filtered, the filtrate is concentrated, toluene is added to the resulting concentrate, and sodium iodide and tetrabutylammonium bromide are added to the resulting solution for reaction. The reaction temperature is selected from the range of about 80 ° C to about 150 ° C.
2) Step 2
Compound (2-3) can be produced by reacting carbon dioxide gas and compound (2-2) with compound (1-1) in the presence of an inorganic base in an inert solvent. Examples of the inorganic base include cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or potassium carbonate. Examples of the inert solvent include dimethylformamide. The reaction temperature is selected from the range of about 0 ° C to about 40 ° C.

Production method 3
Among the compounds represented by formula (1), the compound represented by formula (3-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein, A is the same as described above, and R ¹⁰² represents a C _1-4 alkyl group which may be substituted with amino or hydroxy, or a group represented by the following formula:

で表される基（ここにおいて、Ｒ^２は、前掲と同義である。）で置換されているＣ_１−４アルコキシ基を表し、Ｘ^１は、塩素原子、水酸基もしくはp-ニトロフェノキシ基を表す。］

Represents a C _1-4 alkoxy group substituted with a group represented by the formula (wherein R ² has the same meaning as described above), and X ¹ represents a chlorine atom, a hydroxyl group or a p-nitrophenoxy group. . ]

1) Step 1
Compound (3-2) can be produced from compound (1-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .

Manufacturing method 4
Among the compounds represented by the formula (1), the compound represented by the formula (4-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, A is the same as described above, and R ² has the same meaning as described in the above item 1.] ]

1) Step 1
Compound (4-2) can be produced by reacting compound (4-1) with nitrophenyl chloroformate in the presence of a base in an inert solvent. Examples of the base include triethylamine, N-methylmorpholine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] nona. And organic bases such as -5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, and picoline. Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane, aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or halogenated hydrocarbon solvents such as chloroform, dichloromethane or dichloroethane. And a mixed solvent thereof may be used. The reaction temperature is selected from the range of about −20 ° C. to about 40 ° C.
Compound (4-1) can be produced by a method described in literature (for example, Tetrahedron Letters 43, 1161 (2002)).

2) Step 2
Compound (4-3) can be produced by reacting compound (1-1) with compound (4-2) in the presence of an additive and a base in an inert solvent. Examples of the base include triethylamine, N-methylmorpholine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] nona. And organic bases such as -5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, and picoline. Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane, aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or halogenated hydrocarbon solvents such as chloroform, dichloromethane or dichloroethane. And a mixed solvent thereof may be used. Examples of the additive include dimethylaminopyridine. The reaction temperature is selected from the range of about −10 ° C. to about 40 ° C.

  In each of the above production steps, when the raw material compound of each reaction has a reaction active group such as a hydroxyl group, an amino group or a carboxyl group, these groups other than the site to be reacted are preliminarily added as necessary. The compound of interest can be obtained by protecting with an appropriate protecting group and removing the protecting group after each reaction or several reactions. As a protecting group for protecting a hydroxyl group, an amino group, a carboxyl group, etc., a usual protecting group used in the field of organic synthetic chemistry may be used, and introduction and removal of such a protecting group can be carried out according to ordinary methods. (For example, the method described in Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)).

  For example, examples of the hydroxyl protecting group include a tert-butyldimethylsilyl group, a methoxymethyl group, and a tetrahydropyranyl group. Examples of the amino group protecting group include a tert-butyloxycarbonyl group and a benzyloxycarbonyl group. It is done. Such a hydroxyl-protecting group can be removed by reacting in a solvent such as hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran or the like in the presence of an acid such as a base, sulfuric acid or acetic acid. In the case of a tert-butyldimethylsilyl group, for example, the reaction can be performed in a solvent such as tetrahydrofuran in the presence of tetrabutylammonium fluoride. In the case of a tert-butyloxycarbonyl group, the amino protecting group is removed in the presence of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as hydrous tetrahydrofuran, methylene chloride, chloroform or hydrous methanol. In the case of a benzyloxycarbonyl group, for example, it can be carried out by reacting in a solvent such as acetic acid in the presence of an acid such as hydrobromic acid.

Examples of the form of protection when protecting the carboxyl group include tert-butyl ester, ortho ester, acid amide and the like. In the case of tert-butyl ester, such removal of the protecting group is carried out by reacting in a water-containing solvent in the presence of hydrochloric acid, for example. In the case of ortho ester, water-containing methanol, water-containing tetrahydrofuran, water-containing 1 In the case of acid amide, for example, in the presence of an acid such as hydrochloric acid or sulfuric acid, water is treated with an acid in a solvent such as 1,2-dimethoxyethane and subsequently with an alkali such as sodium hydroxide. The reaction can be carried out in a solvent such as hydrous methanol or hydrous tetrahydrofuran.
Manufacturing method 5
Among the compounds represented by the formula (1), the compound represented by the formula (5-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein, A, R ³ and R ⁵ are as defined above. ^{However, R 30} is a hydrogen atom, M is the following formula:

である。ここにおいて、Ｒ^６およびＲ^７は、各々独立して、水素原子、Ｃ_１−６アルキルカルボニルオキシ基、Ｃ_３−６シクロアルキルカルボニルオキシ基、置換されていてもよいＣ_６−１０アリールカルボニルオキシ基、５員〜１０員の単環式もしくは多環式ヘテロアリールカルボニルオキシ基、飽和ヘテロ環カルボニルオキシ基、置換されていてもよいＣ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_１−６アルコキシ基、置換されていてもよいＣ_３−６シクロアルコキシ基、置換されていてもよいＣ_６−１０アリール基、置換されていてもよいＣ_６−１０アリールオキシ基、置換されていてもよい５員〜１０員の単環式もしくは多環式ヘテロアリールオキシ基、Ｃ_１−６アルキルアミノカルボニルオキシ基、Ｃ_３−６シクロアルキルアミノカルボニルオキシ基、置換されていてもよいアミノ基、置換されていてもよい５員〜１０員の単環式もしくは多環式ヘテロアリール基、ヒドロキシ基、またはスルホンアミド基であるか、あるいはＲ^６およびＲ^７は、それらが結合している原子と一緒になって、Ｃ_３−６シクロアルキル環、飽和ヘテロ環、Ｃ_５−１０シクロアルケニル環、Ｃ_６−１０アリール環、または５員〜１０員の単環式もしくは多環式ヘテロアリール環を形成してもよく；
Ｒ^８は、水素原子、ハロゲン原子、またはＣ_１−６アルキル基であり；
ｍは、１、２、３、または４である。］

It is. Here, R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkylcarbonyloxy group, a C _3-6 cycloalkylcarbonyloxy group, or an optionally substituted C _6-10 arylcarbonyloxy group. Group, 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyloxy group, saturated heterocyclic carbonyloxy group, optionally substituted C _1-6 alkyl group, optionally substituted C _{3- 6} cycloalkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted C _3-6 cycloalkoxy group, optionally substituted C _6-10 aryl group, optionally substituted good C _6-10 aryloxy group, a monocyclic or polycyclic heteroaryloxy group having 5-membered to 10-membered optionally substituted, C _1-6 alkylamino Ruboniruokishi group, C _3-6 cycloalkyl amino carbonyl group, an optionally substituted amino group, a monocyclic or polycyclic heteroaryl group 10-membered substituted 5 may membered, hydroxy group, Or a sulfonamido group, or R ⁶ and R ⁷ together with the atoms to which they are attached, a C _3-6 cycloalkyl ring, a saturated heterocycle, a C _5-10 cycloalkenyl ring, C May form a _6-10 aryl ring, or a 5-10 membered monocyclic or polycyclic heteroaryl ring;
R ⁸ is a hydrogen atom, a halogen atom, or a C _1-6 alkyl group;
m is 1, 2, 3, or 4. ]

Examples of the substituent of “optionally substituted” in the definitions of formulas (5-6) and (5-7) include (a) halogen atom; (b) cyano group; (c) C _3-6. A cycloalkyl group (the group may be substituted with a halogen atom, a hydroxyl group or C _1-4 alkoxy); (d) a hydroxyl group; (e) a C _1-4 alkoxy group (a fluorine atom, C _1-4 alkoxy); Or may be substituted with C _3-6 cycloalkyl); (f) C _3-6 cycloalkyloxy group; (g) C ₆ aryloxy group (the group is a halogen atom, cyano and C _1-4). May be substituted with the same or different groups selected from the group consisting of alkoxy)); (h) benzyloxy group; (i) formyl group; (j) C _1-4 alkylcarbonyl group; (k) C _3-6 cycloalkylcarbonyl (L) phenylcarbonyl group; (m) benzylcarbonyl group; (n) formylcarbonyloxy group; (o) C _1-4 alkylcarbonyloxy group (such as methylcarbonyloxy); (p) C _3-6 cyclo (Q) carboxyl group; (r) C _1-4 alkoxycarbonyl group; (s) C _3-6 cycloalkoxycarbonyl group, (t) amino group; (u) alkylcarbonyloxy group (cyclopropylcarbonyloxy and the like); Mono-substituted amino group (the group is (u1) C _1-6 alkyl, (u2) C _3-6 cycloalkyl, (u3) C _3-6 cycloalkyl C _1-4 alkyl group, (u4) benzyl, _{(u5) C 3-6} cycloalkyl _{C 1-4} alkoxycarbonyl (cyclopropyl methoxycarbonyl, etc.), _{(u6) C 1-4} Arukiruka Boniru, _{(u7) C 3-6} cycloalkylcarbonyl, (u8) heterocyclic _{C 1-4} alkyl into saturated (pyranylmethyl, etc.), (u9) heterocyclic carbonyl to saturated (pyranyl carbonyl, etc.), (u10) to saturated Substituted with terocyclic oxycarbonyl (such as pyranyloxycarbonyl), (u11) saturated heterocyclic C _1-4 alkylcarbonyl (such as pyranylmethylcarbonyl), or (u12) C _1-4 alkylsulfonyl (such as methylsulfonyl) (V) a di-substituted amino group (the group is substituted with two same or different groups selected from the above (u1) to (u12)); (w) A 5- to 7-membered cyclic amino group; (x) an optionally substituted aminocarbonyl group; (y) an optionally substituted aminocarbonyloxy group; or (z) a saturated heterocyclic group. The ring, for _{example, C 1-4} alkoxy which may be substituted with _{C 1-4 alkyl, C 1-4} alkoxy, or _{C 1-4} may be substituted with an alkyl carbonyl amino. ) And the like. Note that the substituent list is not limited to these.

  The “optionally substituted amino group” means an amino group, a mono- or di-substituted amino group, and a 5- to 7-membered cyclic amino group.

  The “optionally substituted aminocarbonyl group” means that “optionally substituted amino” is bonded to carbonyl. The “optionally substituted aminocarbonyl” part of the “optionally substituted aminocarbonyloxy group” has the same meaning as the above “optionally substituted aminocarbonyl group”.

1) Step 1
Compound (5-1) can be produced by utilizing a known production method (for example, Synthesis 1990, 12, 1159. etc.).
Compound (5-2) can be produced by reacting compound (5-1) with sulfuryl chloride in a suitable inert solvent. The reaction temperature ranges from about −78 ° C. to the boiling point of the solvent used, and is preferably −10 ° C. to 25 ° C. The reaction time is 10 minutes to 5 days. The amount of sulfuryl chloride used is 0.1 to 100 equivalents, preferably 0.8 to 2 equivalents, relative to the equivalent of compound (5-1).
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, and tert-butyl. Examples thereof include ether solvents such as methyl ether and cyclopentyl methyl ether, and mixed solvents thereof. Preferably, toluene, tetrahydrofuran, chloroform, or dichloromethane is used.
Compound (5-2) is isolated or used in the next step 2 without being isolated.

2) Step 2
Compound (5-4) can be produced by reacting compound (5-2) with compound (5-3) in a suitable inert solvent, if necessary, in the presence of a suitable base. The reaction temperature ranges from about −78 ° C. to the boiling point of the solvent used, and is preferably −10 ° C. to 25 ° C. The reaction time is 10 minutes to 5 days. The amount of the base used is 0 to 10 equivalents, preferably 0.8 to 5 equivalents, relative to the equivalents of compound (5-1) or compound (5-2).
Examples of the base used include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, cesium carbonate, sodium carbonate, Inorganic bases such as sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium amide, and organometallic reagents such as n-butyllithium. Preferred is pyridine or N-methylmorpholine. Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, and tert-butyl. Examples thereof include ether solvents such as methyl ether and cyclopentyl methyl ether, and mixed solvents thereof. Preferably, toluene, tetrahydrofuran, chloroform, or dichloromethane is used.

3) Step 3
Compound (5-5) can be produced by reacting compound (1-1) and compound (5-4) in a suitable inert solvent, if necessary, in the presence of a suitable base. . The reaction temperature ranges from about −78 ° C. to the boiling point of the solvent used, and is preferably −10 ° C. to 25 ° C. The reaction time is 10 minutes to 5 days.
Specific examples of the base used when used include, for example, organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium hydroxide, sodium hydroxide, hydrogenation Inorganic bases such as sodium, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis And organometallic reagents such as (trimethylsilyl) amide, lithium amide, and n-butyllithium. Preferably 4-dimethylpyridine is mentioned. The amount of the base used is 0.1 to 10 equivalents, preferably 0.2 to 2 equivalents, relative to the equivalent of compound (1-1). Specific examples of the inert solvent include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane. And an aprotic polar solvent such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof. Preferably, tetrahydrofuran is used.

  The compounds represented by the formula (1) include those having an optically active center, and therefore, these can be obtained as a racemate or in an optically active form when an optically active starting material is used. it can. If necessary, the racemates obtained can be physically or chemically resolved into their optical enantiomers by known methods. Preferably, diastereomers are formed from the racemate by a reaction using an optical resolution agent. Different forms of diastereomers can be resolved by known methods such as fractional crystallization.

  The compound of the present invention can be converted into a salt by mixing with a pharmaceutically acceptable base compound or acid compound in a solvent such as water, methanol, ethanol, acetone or the like. Examples of pharmaceutically acceptable salts include inorganic salts such as sodium salt, potassium salt, calcium salt and magnesium salt, inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, bromic acid and nitric acid, or ammonia, methylamine, cyclohexane and the like. Organic bases such as propylamine, diethylamine, morpholine, N-methylmorpholine, tert-butylamine, glycine, phenylalanine, cyclohexylamine, dicyclohexylamine, benzylamine, brucine, phenylethylamine, ethanolamine, N-methylglucamine, triethanolamine Salt or fumaric acid, oxalic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, tosylic acid, trifluoromethanesulfonic acid, benzoic acid, adipic acid, ascorbic acid, aspartic acid, boric acid, butyric acid , Camphorsulfonic acid, cyclopentane sulfonic acid, dodecyl sulfate, lactic acid, nicotinic acid, organic acid salts such as salicylic acid and malic acid.

  The compound of the present invention can be applied to the treatment of various diseases because of its inhibitory effect on renin. The compounds described herein are useful as therapeutic agents for hypertension. These compounds are also useful for the management of acute and chronic congestive heart failure. These compounds are used in primary and secondary pulmonary hypertension, primary and secondary aldosteronemia, renovascular hypertension, primary and secondary renal diseases (eg glomerulonephritis, IgA nephropathy, Diabetic nephropathy, hypertensive nephropathy (nephrosis syndrome, nephrotic syndrome, renal failure, etc.), left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina , Myocardial infarction, cardiomyopathy, stroke, restenosis after revascularization, diabetic retinopathy, treatment of cognitive impairment (eg Alzheimer's disease, cerebrovascular dementia, etc.) and vascular disorders (eg migraine, Raynaud's disease) Etc.) or expected to be useful for minimal suppression or prevention of the atherosclerotic process. It is also useful for treating diseases associated with high intraocular pressure (eg glaucoma). In addition, it is effective in improving the therapeutic effect for these diseases.

  The compounds of the present invention, when used therapeutically, are used as pharmaceutical compositions as oral or parenteral (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of compositions for parenteral administration include, for example, injections. Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.

  The dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but the compound of the present invention or a pharmaceutically acceptable salt thereof is usually used for adults (body weight 50 kg). The salt is administered at a dose of 0.1 to 1000 mg / day, preferably 1 to 300 mg / day once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks.

  The compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug). Can be used in combination. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, CC-555, YM-440, KRP-297, S-011, etc.), α-glucosidase inhibitors ( Examples, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc. No Phonylurea; repaglinide, senagrinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogues (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitors (eg, vanadic acid) Etc.), β3 agonists (eg, GW-427353B, N-5984, etc.), DPPIV inhibitors (eg, sitagliptin, vildagliptin, saxagliptin, SYR-322, etc.).

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, SK-860, CT-112, etc.), neurotrophic factors (eg, NGF, NT -3, BDNF, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), reactive oxygen scavengers (eg, ALT766) Examples, thioctic acid, etc.) and cerebral vasodilators (eg, thioprid, mexiletine, etc.). Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Can be mentioned. Antihypertensive agents include angiotensin-converting enzyme inhibitors (eg, captopril, enalapril fumarate, alacepril, delapril hydrochloride, lizinopril, imidapril hydrochloride, benazepril hydrochloride, cilazapril, temocapril hydrochloride, trandolapril, fosinopril sodium Salt, moexipril hydrochloride, perindopril, quinapril hydrochloride, ramipril, spirapril, zofenapril calcium salt), angiotensin II antagonist (eg, olmesartan medoxomil, candesartan cilexetil, losartan, eprosartan mesylate, valsantan, telmisartan, irbesartan, irbesartan , Tasosartan, Azilsartan Medoxomil (TAK-491), Azilsartan (TAK-536), Fimasartan, Pratosartan, etc.), calcium antagonist (E.g., nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine besylate, alanidipine, azelnidipine, valnidipine hydrochloride, benidipine hydrochloride, cilnidipine, clevidipine, diltiazem hydrochloride, efonidipine hydrochloride ethanol adduct, Felodipine, isradipine, rasidipine, lercanidipine hydrochloride, levamlodipine, nifedipine, verapamil, etc.), ACE / NEP inhibitors (eg, omapatrilate, fasiditol, etc.), β-blockers (eg, atenolol, bisoprolol, betaxolol, metoprolol, etc.), α blockers (eg, urapidil, terazosin, doxazosin, bunazosin, etc.), αβ blockers (eg, amosulalol, arotinolol, labetalol, carvedilol, etc.) It is.

  Examples of anti-obesity agents include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like. Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluthiazide. , Polythiazide, methiclotiazide, bendroflumethiazide, chlorothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, eplerenone, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, , Chlorthalidone, mefluside, indapamide, metolazone, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.

The combination drug is preferably a drug selected from the following drug group (A):
The drug group (A) is an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue, GLP-1, a GLP-1 analog, a protein tyrosine phosphatase inhibitor, β3 agonist, DPPIV inhibition Agent, aldose reductase inhibitor, neurotrophic factor, PKC inhibitor, AGE inhibitor, active oxygen scavenger, cerebral vasodilator, HMG-CoA reductase inhibitor, squalene synthetase inhibitor, ACAT inhibitor, angiotensin conversion Enzyme inhibitor, Angiotensin II antagonist, Calcium antagonist, ACE / NEP inhibitor, β blocker, α blocker, αβ blocker, central anti-obesity agent, pancreatic lipase inhibitor, peptidic appetite suppressant, cholecyst Kinin agonist, xanthine derivative, thiazide preparation, anti-aldosterone preparation, charcoal Anhydrase inhibitors, chlorbenzenesulfonamide formulation, azosemide, isosorbide, ethacrynic acid, a group consisting of piretanide, bumetanide, and furosemide.

  More preferable drug group (A) is an angiotensin converting enzyme inhibitor, angiotensin II antagonist, calcium antagonist, ACE / NEP inhibitor, β blocker, α blocker, αβ blocker, thiazide preparation, and antialdosterone formulation A group consisting of

  More preferably, it is a group consisting of an angiotensin II antagonist, a calcium antagonist, and a thiazide preparation.

  The above concomitant drugs may be used in combination of at least one, preferably 1 to 4, more preferably 1 to 2, more preferably 1 kind in an appropriate ratio.

  When the compound of the present invention is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. Note that abbreviations may be used to simplify the description, but these abbreviations have the same meanings as described above.

Reference example 1
4- (Bromomethyl) -5-methyl-1,3-dioxol-2-one

４，５−ジメチル−１，３−ジオキソール−２−オン (65g, 570mmol)を四塩化炭素 (2860 ml)に溶かし、Ｎ−ブロモスクシンイミド（103.5g, 純度98%, 1.0eq）、２，２−アゾビスイソブチロニトリル (0.93g、0.01eq)を加えて70℃に昇温して2時間加熱撹拌した。反応溶液を室温に冷却して、減圧下で溶媒を約半分留去した。浮遊物をろ過し、冷蔵庫で終夜放置した。再度溶媒を減圧留去し、得られた残渣を減圧蒸留（92〜94℃／0.3〜0.375mmHg）することで参考例１の化合物 (73.3g、66%)の黄色オイルを得た。
R_f = 0.35 (ヘキサン:酢酸エチル = 3:1).

4,5-Dimethyl-1,3-dioxol-2-one (65 g, 570 mmol) was dissolved in carbon tetrachloride (2860 ml), and N-bromosuccinimide (103.5 g, purity 98%, 1.0 eq), 2,2 -Azobisisobutyronitrile (0.93 g, 0.01 eq) was added, the temperature was raised to 70 ° C, and the mixture was heated and stirred for 2 hours. The reaction solution was cooled to room temperature, and about half of the solvent was distilled off under reduced pressure. The floating material was filtered and left in the refrigerator overnight. The solvent was distilled off again under reduced pressure, and the obtained residue was distilled under reduced pressure (92 to 94 ° C./0.3 to 0.375 mmHg) to obtain a yellow oil of the compound of Reference Example 1 (73.3 g, 66%).
R _f = 0.35 (hexane: ethyl acetate = 3: 1).

Reference example 2
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl formate

The compound of Reference Example 1 (91.10 g, 438 mmol) was dissolved in acetonitrile (500 ml), formic acid (29 ml, 1.75 eq) was added, cooled to 0 ° C., and triethylamine (97 ml, 1.6 eq) was slowly added dropwise. . After 30 minutes, the temperature was raised to room temperature and stirred for 2 hours. Water (500 nl) was added to the reaction solution, and the mixture was extracted with ethyl acetate (1000 ml). The extract was washed with saturated brine (300 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound of Reference Example 2 (66.74 g, 96%).
R _f = 0.42 (hexane: ethyl acetate = 3: 1).

Reference example 3
4- (Hydroxymethyl) -5-methyl-1,3-dioxol-2-one

The compound of Reference Example 2 (66.74 g, 438 mmol) was dissolved in methanol (500 ml) and water (150 ml), concentrated hydrochloric acid (9.17 ml, 0.25 eq) was added dropwise, and the mixture was stirred at room temperature for 4 hours. Water (200 ml) was added to the reaction solution, methanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with saturated brine (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1 to 1/1) to obtain the compound of Reference Example 3 (29.76 g, 54%).
R _f = 0.26 (hexane: ethyl acetate = 1: 1).

Reference example 4
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-nitrophenyl carbonate

Dissolve the compound of Reference Example 3 (29.76 g, 228 mmol) in dichloromethane (300 ml), cool to 0 ° C., add pyridine (30 ml, 1.6 eq), and p-nitrophenyl chloroformate (46.1 g, 1.0 eq). ) In dichloromethane (200 ml) was added dropwise. After 1 hour, the mixture was warmed to room temperature and stirred for 16 hours. To the reaction solution was added 1N hydrochloric acid (100 ml) and water (100 ml), and the mixture was extracted with chloroform (500 ml). The organic layer was washed with saturated brine (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained white solid was suspended in 2-propanol (500 ml), heated to 70 ° C. and stirred for 2 hours. The precipitated white solid was collected by filtration, washed with 2-propanol (200 ml) and diisopropyl ether (200 ml), and sufficiently dried under reduced pressure to obtain the compound of Reference Example 4 (56.28 g, 83%).
1H NMR (400 MHz, d ₆ -DMSO) δ8.37 (ddd, J = 9.2, 3.3, 2.2 Hz, 2H), 7.63 (ddd, J = 9.2, 3.3, 2.1 Hz, 2H), 5.23 (s, 2H ), 2.23 (s, 3H).

Reference Example 5
O- (1-Chloroethyl) S-cyclohexyl carbonothioate

N-methylmorpholine (14.9 g) was added dropwise over 10 minutes to a solution of 1-chloroethyl chloroformate (20 g, 140 mmol) and cyclohexanethiol (12.2 g, 105 mmol) in toluene (100 g) under ice cooling. After stirring at the same temperature for 1 hour and a half, the mixture was warmed to room temperature and further stirred for 3 hours. Water (81 ml) was added to the reaction solution and extracted. The organic layer was washed with 5% aqueous sodium bicarbonate (100 ml) and water (100 ml) and then concentrated under reduced pressure to obtain the compound of Reference Example 5 (36.5 g, 93%).
1H NMR (300 MHz, CDCl ₃ ) δ.6.60 (q, J = 6.0 Hz, 1H), 3.48-3.36 (m, 1H), 2.11-1.95 (m, 2H), 1.82 (d, J = 6.0 Hz, 3H), 1.85-1.22 (m, 8H).

Reference Example 6
1-{[(Cyclohexylsulfanyl) carbonyl] oxy} ethyl 2-methylpropanoate

To a toluene (28 g) solution of the compound of Reference Example 5 (28 g, 107 mmol) and isobutyric acid (14.19 g, 161 mmol) under ice-cooling, a mixture of N, N-diisopropylethylamine (20.8 g, 161 mmol) was added. Added dropwise over a period of minutes. The mixture was heated at 75 ° C. and stirred for 10 hours. To the reaction solution, toluene (50 ml) and water (72 ml) were added for extraction. The organic layer was washed with 5% aqueous NaHCO ₃ solution (72 ml × 2) and water (72 ml × 2). The organic layer was concentrated under reduced pressure to obtain the compound of Reference Example 6 (26 g, 88%).
1H NMR (300 MHz, CDCl ₃ ) δ. 6.92 (q, J = 6.0 Hz, 1H), 3.43-3.22 (m, 1H), 2.62-2.49 (m, 1H), 2.09-1.92 (m, 2H), 1.82-1.68 (m, 2H), 1.65-1.07 (m, 15H).

Reference Example 7
(3S, 4S) -1-Hydroxy-2,5-dioxopyrrolidine-3,4-diyl dibenzoate

  Acetic anhydride (100 g, 980 mmol) was added to dibenzoyl-L-tartaric acid (50 g, 140 mmol) at room temperature, and then stirred at 80 ° C. for 2 hours. The mixture was allowed to cool to room temperature with stirring, and further stirred under ice cooling. The precipitated solid was filtered to obtain (3S, 4S) -2,5-dioxotetrahydrofuran-3,4-diyl dibenzoate (44.1 g, 93%).

The obtained (3S, 4S) -2,5-dioxotetrahydrofuran-3,4-diyldibenzoate (44 g, 129 mmol) in tetrahydrofuran (220 g) solution under ice-cooling, 50% hydroxyamine aqueous solution (10.3 g, 155 mmol) was added dropwise over 10 minutes. Thereafter, the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was extracted with 0.5N aqueous hydrochloric acid (220 ml) and ethyl acetate (440 ml). The organic layer was washed with saturated brine (300 ml) and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure. Toluene (132 ml) was added to the obtained residue, and the mixture was stirred at 80 ° C. for 4 hours. Thereafter, the mixture was cooled with ice cooling while stirring and stirred for 2 hours. The precipitated solid was collected by filtration to obtain the compound of Reference Example 7 (42.8 g, 93%).
1H NMR (400 MHz, CDCl ₃ ) δ: 8.09-8.06 (m, 4H), 7.67-7.62 (m, 2H), 7.62-7.46 (m, 4H), 5.86 (s, 2H).

Reference Example 8
(3S, 4S) -1-[({(1R) -1-[(2-Methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate

  Under a nitrogen atmosphere, sulfuryl chloride (7.4 g, 54.7 mmol) was added dropwise to a tetrahydrofuran (20 g) solution of the compound of Reference Example 6 (10 g, 36.5 mmol) at −5 ° C. over 15 minutes, followed by stirring for 1 hour. Under the same temperature, a solution of the compound of Reference Example 3 (10.4 g, 29.2 mmol) in tetrahydrofuran (17 ml) was added, and N-methylmorpholine (7.4 g, 72.9 mmol) was slowly added dropwise over 30 minutes. After stirring at the same temperature for 2 hours, the reaction mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with water (100 ml) and saturated brine (100 ml) and then dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. Heptane (100 ml) was added to the resulting residue, stirred, and then collected by filtration to obtain (3S, 4S) -1-[({1-[(2-methylpropanoyl) oxy] ethoxy} as a diastereomeric mixture. Carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate (14.4 g) was obtained.

Ethyl acetate (49 ml) was added to the obtained diastereomer mixture (14.4 g), heated at 50 ° C. to dissolve, heptane (24.5 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After returning to room temperature and stirring for 3 hours, the precipitated solid (3.6 g) was collected by filtration. Ethyl acetate (25 ml) was added to the obtained solid (3.6 g) and dissolved at 50 ° C., heptane (16.5 ml) was added, and the mixture was stirred at the same temperature for 1 hr. After returning to room temperature, the mixture was stirred for 2 hours, and the precipitated solid was collected by filtration to obtain the compound of Reference Example 8 (2.6 g, 98.9% de).
1-{(Chlorocarbonyl) oxy} ethyl 2-methylpropanoate
1H NMR (300 MHz, CDCl ₃ ) δ: 6.88-6.78 (m, 1H), 2.68-2.53 (m, 1H), 1.58 (d, J = 5.5 Hz, 3H), 1.23-1.12 (m, 6H).
(3S, 4S) -1-[({(1R) -1-[(2-Methylpropanoyl) oxy] ethoxy} carbonyl) oxy] -2,5-dioxopyrrolidine-3,4-diyl dibenzoate
1H NMR (400 MHz, CDCl ₃ ) δ: 8.12-8.07 (m, 4H), 7.68-7.60 (m, 2H), 7.52-7.45 (m, 4H), 6.89 (q, J = 5.4 Hz, 1H), 6.01 (brs, 2H), 2.61 (qq, J = 7.0, 7.0 Hz, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.20 (dd, J = 7.0, 7.0 Hz, 6H).
CHIRALPAK® IC (0.46 cmI.D. x 25 cmL), moving bed: n-hexane / methylene chloride = 60/40, flow rate: 1.0 mL / min, temperature: 40 ° C., wavelength: 254 nm
RT 17.855 min.

Example 1
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl {(3S, 5S, 6S, 8S) -8-[(3-amino-2,2-dimethyl-3-oxopropyl) Carbamoyl] -6-hydroxy-3- [4-methoxy-3- (3-methoxypropoxy) benzyl] -2,9-dimethyldecan-5-yl} carbamate

Under a nitrogen atmosphere, a suspension of aliskiren fumarate (1.22 g, 1 mmol) in tetrahydrofuran (1.7 ml) at room temperature, triethylamine (253 mg, 2.5 mmol), 4-dimethylaminopyridine (98 mg, 0.8 mmol), (5 -Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-nitrophenyl carbonate (531 mg, 1.8 mmol) was added sequentially. After stirring for 1 day, the reaction solution was concentrated. The obtained residue was purified by silica gel chromatography to obtain the compound of Example 1 (600 mg, 84%).
1H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.38 (m, 1H), 7.14 (brs, 1H), 6.96 (d, J = 9.6 Hz, 1H), 6.89-6.76 (m, 2H), 6.73 (s, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.95 (d, J = 14.2 Hz, 1H), 4.85 (d, J = 14.2 Hz, 1H), 4.44 (d, J = 5.9 Hz , 1H), 3.97 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H), 3.55-3.40 (m, 3H), 3.31-3.19 (m, 5H), 3.15-3.07 (m, 1H), 2.62-2.53 (m, 1H), 2.35-2.28 (m, 2H), 2.15 (s, 3H), 1.99-1.89 (m, 2H), 1.74-1.05 (m, 8H), 1.04 (s, 6H), 0.91-0.65 (m, 12H).

Example 2
(1R) -1-[({(3S, 5S, 6S, 8S) -8-[(3-Amino-2,2-dimethyl-3-oxopropyl) carbamoyl] -6-hydroxy-3- [4- Methoxy-3- (3-methoxypropoxy) benzyl] -2,9-dimethyldecan-5-yl} carbamoyl) oxy] ethyl 2-methylpropanoate

Under a nitrogen atmosphere, the compound of Reference Example 8 (253 mg, 2.5 mmol) was sequentially added to a solution of aliskiren fumarate (300 mg, 0.246 mmol) in tetrahydrofuran (1.5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction solution was concentrated, the resulting residue was purified by silica gel chromatography to obtain the compound of Example 2 (274 mg, 53%).
1H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.36 (m, 1H), 7.14 (brs, 1H), 6.98 (d, J = 9.9 Hz, 1H), 6.89-6.74 (m, 2H), 6.73 -6.64 (m, 2H), 6.59 (d, J = 9.0 Hz, 1H), 4.40 (d, J = 6.0 Hz, 1H), 3.92 (t, J = 6.3 Hz, 2H), 3.70 (s, 3H) , 3.57-3.40 (m, 3H), 3.39-3.15 (m, 5H), 3.13-3.03 (m, 1H), 2.58-2.44 (m, 1H), 2.28-2.15 (m, 2H), 1.98-1.86 ( m, 2H), 1.70-1.20 (m, 9H), 1.12-0.92 (m, 14H), 0.88-0.65 (m, 12H).

Test Example 1: In Vitro Renin Inhibitory Effect Measurement Test 4.2 ng / mL of recombinant human renin in 0.1 M HEPES buffer pH 7.4 containing 0.1 M NaCl, 1 mM EDTA and 0.1 mg / mL BSA, test The compound was reacted at 37 ° C. for 1 hour. Arg-Glu (EDANS) -Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys (DABCYL) -Arg or DABCYL-γ-Abu-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-EDANS was added to a final concentration of 4 μM. An increase in fluorescence intensity at an excitation wavelength of 340 nm and a fluorescence wavelength of 500 nm was detected using a fluorescence plate reader, and a compound concentration that inhibited by 50% was calculated as an IC ₅₀ value from the enzyme inhibitory activity when a plurality of test compounds were added.

Test Example 2: Rat single subcutaneous administration irritation test CD system male rat subcutaneous abdomen is divided into 4 parts, 0.1 ml of the test compound is administered once in each place, 1 day and 3 days after administration The administration site was observed and inflammation-like changes were observed. The test compound was weighed and prepared by adding DMSO to a concentration of 2%.

Comparative Example 1: Bis [(2S, 4S, 5S, 7S) -5-amino-N- (2-carbamoyl-2-methylisopropyl) -4-hydroxy-2- (1-methylethyl) -7- [4 -Methoxy-3- (3-methoxypropoxy) benzyl] -8-methylnonanamide] monofumarate

When the compound of Comparative Example 1 was administered subcutaneously, strong inflammation was observed after 1 day, and a dark red color of the epidermis or a red nest of the subcutaneous tissue was observed. Further intense inflammation was observed even after 3 days. On the other hand, no abnormal findings were observed in the compounds of the present invention in which the nitrogen atom in the structure was substituted with a specific substituent. This is considered that the basicity of the amine moiety in the structure is one of the causes of the inflammation-inducing action, and by introducing a specific substituent on the nitrogen atom of the amine moiety, the basicity of the amine moiety is reduced, This is because inflammation was reduced.

  The compounds of the present invention are useful as therapeutic agents for hypertension. These compounds are also useful for the management of acute and chronic congestive heart failure. These compounds are primary and secondary pulmonary hypertension, primary and secondary aldosteronemia, renovascular hypertension, primary and secondary renal diseases such as glomerulonephritis, IgA nephropathy, Diabetic nephropathy, hypertensive nephropathy (neurosclerosis), nephrotic syndrome, renal failure, left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina, myocardium Infarct, cardiomyopathy, stroke, restenosis after revascularization, diabetic retinopathy, cognitive impairment, eg Alzheimer's disease, treatment of cerebrovascular dementia, and vascular disorders, eg migraine, Raynaud's disease, and atheromatous It is also expected to be useful for minimizing the arteriosclerosis process. It is also useful for the treatment of diseases associated with high intraocular pressure, such as glaucoma.

Claims (11)

A compound represented by formula (1), or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ is
1: C _1-6 alkyl group (the group is
(A) amino,
(B) hydroxy, or (c) the following formula:

(Wherein R ² is a group represented by
(I) a C _1-4 alkyl group (this group may be substituted with C _1-4 alkoxy),
(Ii) a C _3-6 cycloalkyl group, or (iii) a C _6-10 aryl group, which group may be substituted with C _1-4 alkoxy. ). ),
2: C _1-4 alkylcarbonyl group (the group is
It may be substituted with (a) amino, or (b) hydroxy. ),
3: C _1-4 alkoxycarbonyl group (the group has the following formula:

(Wherein R ² has the same meaning as described above). ) Or 4:

Wherein R ³ and R ⁴ are each independently the same or different,
(A) a hydrogen atom,
(B) a C _1-4 alkyl group (the group is
C _1-4 alkoxy,
C _3-6 cycloalkyl (the group may be substituted with C _1-4 alkoxy), 5- or 6-membered saturated heterocyclic, or 5- or 6-membered saturated heterocyclic oxy May be. ),
(C) a C _3-10 cycloalkyl group (the group is
It may be substituted with 1 to 2 fluorine atoms or C _1-4 alkoxy. ),
(D) a C _6-10 aryl group (the group is
It may be substituted with a halogen atom, or C _6-10 aryl (the aryl may be substituted with a halogen atom or C _1-4 alkoxy). ),
(E) a 5- or 6-membered saturated heterocyclic group, or (f) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group is C _1-4 alkyl, or C _{1 -4} alkoxy may be substituted).
R ⁵ is
1: C _1-6 alkyl group (the group is
(A) 1 to 3 fluorine atoms,
(B) hydroxy,
(C) C _1-4 alkoxy,
(D) carboxy,
(E) C _6-10 aryl,
(F) a 5- or 6-membered saturated heterocycle,
(G) C _3-6 cycloalkyl,
(H) C _1-4 alkoxycarbonyl,
(I) C _1-4 alkoxycarbonylamino,
(J) amino,
(K) mono- or di- (C _1-6 alkyl) amino,
(L) a 5- to 7-membered cyclic amine,
(M) aminocarbonyl, or (n) 5-7 membered cyclic aminocarbonyl may be substituted. ),
2: C _3-10 cycloalkyl group (the group may be substituted with hydroxy),
3: C _6-10 aryl group (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with 1 to 3 groups of the same or different types selected from C _1-4 alkylcarbonyloxy. ),
4: C _1-4 alkylcarbonyl group (the group is
It may be substituted with (a) hydroxy, or (b) C _3-6 cycloalkyl. ),
5: 5- to 10-membered monocyclic or polycyclic heteroaryl group,
6: 5-membered or 6-membered saturated heterocyclic group (the group may be substituted with C _1-4 alkyl which may be substituted with C _1-4 alkoxy);
7: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
8: A C _3-6 cycloalkyloxy group (the group may be substituted with C _1-4 alkoxy), or a 9: 5-membered or 6-membered saturated heterocyclic oxy group. ). ] The compound represented by formula (1) is

Compound represented by (R ¹ is the same as in claim 1.) The compound or a pharmaceutically acceptable salt thereof, as claimed in claim 1. R ¹ is a C _1-4 alkoxycarbonyl group (the group has the following formula:

(R ² is the same as described above). Or a pharmaceutically acceptable salt thereof. R ¹ is represented by the following formula:

The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R ² is the same as defined above. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R ² is a methyl group. R ¹ is represented by the following formula:

(Wherein R ³ and R ⁴ are each independently the same or different and each represents a hydrogen atom or a C _1-4 alkyl group;
R ⁵ is
1: C _1-4 alkyl group (the group is
(A) amino,
(B) hydroxy,
(C) C _1-4 alkoxy,
(D) carboxy,
(E) C _1-4 alkoxycarbonyl, or (f) C _1-4 alkoxycarbonylamino may be substituted. ),
2: C _3-10 cycloalkyl group,
3: C _1-4 alkylcarbonyl group,
4: C _6-10 aryl group (the group is
(A) halogen,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with 1 to 3 groups of the same or different types selected from C _1-4 alkylcarbonyloxy. ),
5: 5- to 10-membered monocyclic or polycyclic heteroaryl group,
6: 5-membered or 6-membered saturated heterocyclic group,
7: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
8: C _3-6 cycloalkyloxy group, or 9: 5-membered or 6-membered saturated heterocyclic oxy group. Or a pharmaceutically acceptable salt thereof. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, and R ⁴ is a methyl group. R ⁵ is
1: C _1-4 alkyl group,
2: C _3-6 cycloalkyl group,
3: C _1-6 alkoxy group (this group may be substituted with C _3-6 cycloalkyl),
4: C _3-6 cycloalkyloxy group,
5: 5-membered or 6-membered saturated heterocyclic oxy group,
6: C _6-10 aryl (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
(D) cyano,
(E) C _1-4 alkoxy, or (f) optionally substituted with one or two groups selected from the same or different groups selected from C _1-4 alkylcarbonyloxy. Or a 7: 5- to 10-membered monocyclic or polycyclic heteroaryl group, or a pharmaceutically acceptable salt thereof. R ⁵ is
1: C _1-4 alkyl group, or 2: C _1-6 alkoxy group, or 3: C _6-10 aryl (the group is
(A) a halogen atom,
(B) C _1-4 alkyl,
(C) C _3-6 cycloalkyl C _1-4 alkyl,
It may be substituted with 1 or 2 groups of the same or different types selected from (d) cyano, or (e) C _1-4 alkoxy. ), Or a 4: 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, or a pharmaceutically acceptable salt thereof. A compound represented by formula (2), or a pharmaceutically acceptable salt thereof.

A compound represented by formula (3), or a pharmaceutically acceptable salt thereof.