JP2004315500A - Skeletal muscle protective agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new medicine useful as a skeletal muscle protective agent. <P>SOLUTION: This skeletal muscle protective agent contains a compound having squalene synthase inhibitory activity, or its salt or its prodrug. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a compound having a squalene synthase inhibitory activity or a salt thereof, or a skeletal muscle protective agent comprising a prodrug thereof, and the like.

Skeletal muscle is an important muscle that attaches to bone and participates in body movements, but has various factors such as ischemia, exertion, excessive exercise, trauma (bruise, skeletal muscle bleeding, electric shock), burns, Necrosis or melting of skeletal muscle is caused by malignant hyperthermia, malignant syndrome, metabolic myopathy, inflammatory myopathy, muscular dystrophy, infection, poisoning, metabolic abnormalities, and hyperthermia. In addition, for example, drug-induced myalgia caused by an HMG-CoA reductase inhibitor, cyclosporine, fibrate-based drug, or the like occurs, and in severe cases, rhabdomyolysis occurs. In such a case, the drug which is considered to be the cause of administration is stopped, rest is maintained, and sufficient fluid replacement is performed. There is no effective treatment for muscle lesions, and treatment of complications and underlying diseases is central.
On the other hand, compounds having a squalene synthase inhibitory activity are useful as prophylactic and therapeutic agents for hyperlipidemia and arteriosclerosis, triglyceride lowering agents, lipid lowering agents, high-density lipoprotein-cholesterol increasing agents, antifungal agents and the like. Although it is known (Patent Literatures 1 to 5), there is only a report (Non-Patent Literature 1) that cytotoxicity is less likely to occur as compared to HMG-CoA reductase inhibitors as an effect on skeletal muscle. There have been no reports of a protective effect on skeletal muscle both in vitro and in vivo. It is also known that compounds having squalene synthase inhibitory activity increase ubiquinone (Patent Document 6), but it has been revealed that the myotoxicity of HMG-CoA reductase inhibitors is independent of ubiquinone. (Non-Patent Document 2).

JP-A-6-239843 JP-A-8-157369 JP-A-9-136880 JP 2002-080468 A JP-A-2002-205956 WO 03/002147 pamphlet Oliver P. Flint et al, "Toxicology and Applied Pharmacology", 1997, Vol. 145, p. 91-98 William H. Schaefer et al, "Toxicology and Applied Pharmacology", August 13, 2003, doi: 10.1016 / j.taap.

  Drugs that can protect skeletal muscle from various factors, especially the cytotoxicity of HMG-CoA reductase inhibitors, have not been known so far, and the development of new clinically useful drugs is currently awaited. It is.

  The present inventors have conducted intensive studies in view of the above circumstances, and unexpectedly found, for the first time, that a compound having a squalene synthase inhibitory activity is clinically useful as a drug for protecting skeletal muscle. Thus, the present invention has been completed.

〔式中、Ｒ_１は水素原子または置換されていてもよい炭化水素基を、Ｒ_２およびＲ_３は同一または異なって水素原子，置換されていてもよい炭化水素基あるいは置換されていてもよい複素環基を、Ｘ'はエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基あるいは脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基から構成される基を、環Ａは置換されていてもよいベンゼン環または置換されていてもよい複素環を、環Ｊ'は環構成原子として３個以下のヘテロ原子を含有する７または８員の複素環を、環Ｊ'はＲ_１，Ｒ_２，Ｒ_３及びＸ'以外にさらに置換基を有していてもよい〕で表される化合物である前記（１）記載の剤；
（７）スクアレン合成酵素阻害作用を有する化合物が、式

〔式中、Ｒ_１は水素原子または置換されていてもよい炭化水素基を、Ｒ_２およびＲ_３は同一または異なって水素原子，置換されていてもよい炭化水素基あるいは置換されていてもよい複素環基を、Ｘ_１は結合手または２価の原子鎖を、Ｙはエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基または脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基を、環Ｂは置換されていてもよいベンゼン環を示す〕で表される化合物である前記（１）記載の剤；
（８）スクアレン合成酵素阻害作用を有する化合物が、式

〔式中、Ｒ_ｂは置換されていてもよい水酸基で置換されていてもよい低級アルキル基を、Ｘ_ｂは置換されていてもよいカルバモイル基又は脱プロトン化しうる水素原子を有する置換されていてもよい複素環基を、Ｒ_１ｂは低級アルキル基を、Ｗはハロゲン原子を示す。〕で表される化合物である前記（１）記載の剤；
（９）Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシから選ばれた１ないし３個の置換基を有していてもよいＣ_１−６アルキルである前記（８）記載の剤；
（１０）Ｒ_１ｂがメチルである前記（８）記載の剤；
（１１）Ｗが塩素原子である前記（８）記載の剤；
（１２）Ｘ_ｂが式

〔式中、Ｒ_２b及びＲ_３bはそれぞれ水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基又はアシル基であるか、あるいはＲ_２b及びＲ_３bは隣接する窒素原子と一緒になって、窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし３個環構成原子として含んでいてもよい置換されていてもよい５または６員含窒素複素環を形成していてもよい〕で表される基である前記（８）記載の剤；
（１３）Ｘ_ｂが式

〔式中、Ｒ"は水素原子又はＣ_１−４アルキルを示す〕で表される基である前記（８）記載の剤；
（１４）スクアレン合成酵素阻害作用を有する化合物が、式

〔式中、Ｒ^１ｃは置換基を有していてもよい１−カルボキシエチル基、置換基を有していてもよいカルボキシ−Ｃ_３−６直鎖アルキル基、置換基を有していてもよいＣ_３−６直鎖アルキル−スルホニル基、置換基を有していてもよい（カルボキシ−Ｃ_５−７シクロアルキル）−Ｃ_１−３アルキル基、または 式 −Ｘ^１ｃ−Ｘ^２ｃ−Ａｒ−Ｘ^３ｃ−Ｘ^４ｃ−ＣＯＯＨ（式中、Ｘ^１ｃおよびＸ^４ｃはそれぞれ結合手または置換基を有していてもよいＣ_１−４アルキレン基を示し、Ｘ^２ｃおよびＸ^３ｃはそれぞれ結合手、−Ｏ−または−Ｓ−を示し、Ａｒは置換基を有していてもよい２価の芳香環基を示す。但し、Ｘ^１ｃが結合手のとき、Ｘ^２ｃは結合手を示し、Ｘ^４ｃが結合手のとき、Ｘ^３ｃは結合手を示す）で表される基を示し、Ｒ^２ｃはアルカノイルオキシ基および／または水酸基で置換されていてもよいＣ_３−６アルキル基を、Ｒ^３ｃは低級アルキル基を、Ｗはハロゲン原子を示す（但し、Ｒ^１ｃが置換基を有する１−カルボキシエチル基、置換基を有するカルボキシ−Ｃ_３−６直鎖アルキル基、４−カルボキシシクロヘキシルメチル基または４−カルボキシメチルフェニル基のとき、Ｒ^２ｃはアルカノイルオキシ基および／または水酸基を有するＣ_３−６アルキル基を示す）〕で表される化合物である前記（１）記載の剤；
（１５）Ｒ^２ｃが水酸基、アセトキシ、プロピオニルオキシ、ｔ−ブトキシカルボニルオキシおよびパルミトイルオキシから選ばれた１ないし３個の置換基を有していてもよいＣ_３−６アルキル基である前記（１４）記載の剤；
（１６）Ｒ^３ｃがメチル基である前記（１４）記載の剤；
（１７）Ｗが塩素原子である前記（１４）記載の剤；
（１８）３位がＲ−配位で５位がＳ−配位である前記（１４）記載の剤；
（１９）スクアレン合成酵素阻害作用を有する化合物が、Ｎ−〔〔（３Ｒ,５Ｓ）−１−（３−アセトキシ−２,２−ジメチルプロピル）−７−クロロ−５−（２,３−ジメトキシフェニル）−２−オキソ−１,２,３,５−テトラヒドロ−４,１−ベンゾオキサゼピン−３−イル〕アセチル〕ピペリジン−４−酢酸またはＮ−〔〔（３Ｒ,５Ｓ）−７−クロロ−５−（２,３−ジメトキシフェニル）−１−（３−ヒドロキシ−２,２−ジメチルプロピル）−２−オキソ−１,２,３,５−テトラヒドロ−４,１−ベンゾオキサゼピン−３−イル〕アセチル〕ピペリジン−４−酢酸である前記（１）記載の剤；
（２０）筋細胞内ゲラニルゲラニル化代謝物の減少抑制作用を有する化合物またはその塩、またはそのプロドラッグを含有してなる骨格筋保護剤；
（２１）哺乳動物に有効量のスクアレン合成酵素阻害作用を有する化合物またはその塩、またはそのプロドラッグを投与することを特徴とする骨格筋保護方法；
（２２）哺乳動物に有効量の筋細胞内ゲラニルゲラニル化代謝物の減少抑制作用を有する化合物またはその塩、またはそのプロドラッグを投与することを特徴とする骨格筋保護方法；
（２３）骨格筋保護剤の製造のためのスクアレン合成酵素阻害作用を有する化合物またはその塩、またはそのプロドラッグの使用；
（２４）骨格筋保護剤の製造のための筋細胞内ゲラニルゲラニル化代謝物の減少抑制作用を有する化合物またはその塩、またはそのプロドラッグの使用；
などに関する。 That is, the present invention
(1) a skeletal muscle protective agent comprising a compound having a squalene synthase inhibitory activity or a salt thereof, or a prodrug thereof;
(2) the agent according to (1), which is a skeletal muscle protective agent that protects skeletal muscle from cell damage;
(3) the agent according to the above (1), which is a skeletal muscle protective agent that protects skeletal muscle from cytotoxicity possessed by other drugs;
(4) the agent according to the above (3), wherein the other agent is an HMG-CoA reductase inhibitor;
(5) The agent according to the above (1), which is a prophylactic or therapeutic agent for myalgia or rhabdomyolysis;
(6) The compound having squalene synthase inhibitory activity is represented by the formula

[In the formula, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X 'is a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, an amino group which may be substituted, or a hydrogen atom which can be deprotonated. A ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, and ring J ′ is 3 Or a 7- or 8-membered heterocycle containing not more than one heteroatom, and the ring J ′ may further have a substituent other than R ₁ , R ₂ , R ₃ and X ′. According to the above (1), ;
(7) The compound having squalene synthase inhibitory activity is represented by the formula

[In the formula, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X ₁ represents a bond or a divalent atom chain; Y represents a carboxyl group which may be esterified; a carbamoyl group which may be substituted; a hydroxyl group which may be substituted; And the optionally substituted heterocyclic residue having an optionally substituted amino group or a deprotonatable hydrogen atom, and ring B represents an optionally substituted benzene ring. ) Described agents;
(8) The compound having a squalene synthase inhibitory activity is represented by the formula

Wherein R _b represents a lower alkyl group which may be substituted with an optionally substituted hydroxyl group, and X _b represents a carbamoyl group which may be substituted or a substituted group having a deprotonatable hydrogen atom. A heterocyclic group, R _1b represents a lower alkyl group, and W represents a halogen atom. The agent according to the above (1), which is a compound represented by the formula:
(9) Even when R _b has one to three substituents selected from a hydroxyl group, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy. The agent according to the above (8), which is a good C _1-6 alkyl;
(10) the agent according to the above (8), wherein R _1b is methyl;
(11) the agent according to the above (8), wherein W is a chlorine atom;
(12) _Xb is a formula

[Wherein, R _2b and R _3b are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group, or R _2b and R _3b are adjacent nitrogen atoms. Together with the atom, forms a 5- or 6-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted; The agent according to the above (8), which is a group represented by the formula:
(13) _Xb is a formula

Wherein R ″ represents a hydrogen atom or C _1-4 alkyl;
(14) The compound having a squalene synthase inhibitory activity is represented by the formula

[In the formula, R ^1c represents a 1-carboxyethyl group which may have a substituent, a carboxy-C _3-6 linear alkyl group which may have a substituent, or a group which has a substituent. good _{C 3-6} linear alkyl - sulfonyl group, which may have a substituent (carboxy _{-C 5-7 cycloalkyl) -C 1-3} alkyl group, or a group of the formula -X ^1c -X ^2c, -Ar- X ^3c -X ^4c -COOH (wherein, X ^1c and X ^4c each represent a bond or a C _1-4 alkylene group which may have a substituent, X ^2c and X ^3c each represent a bond,- O- or -S-, and Ar represents a divalent aromatic ring group which may have a substituent, provided that when X ^1c is a bond, X ^2c is a bond and X ^4c is when bonds, X ^3c represents a group represented by a bond) The R ^2c is alkanoyloxy group and / or hydroxyl group optionally substituted C _3-6 also be an alkyl group, an R ^3c is a lower alkyl group, W is a (but, R ^1c substituent a halogen atom 1 A carboxyethyl group, a substituted carboxy-C _3-6 linear alkyl group, a 4-carboxycyclohexylmethyl group or a 4-carboxymethylphenyl group, R ^2c represents an alkanoyloxy group and / or a C ₃ group having a hydroxyl group; _-6 represents an alkyl group)]], the agent according to the above (1),
(15) The above-mentioned (14) wherein R ^2c is a C _3-6 alkyl group _optionally having 1 to 3 substituents selected from a hydroxyl group, acetoxy, propionyloxy, t-butoxycarbonyloxy and palmitoyloxy. ) Described agents;
(16) the agent according to the above (14), wherein R ^3c is a methyl group;
(17) the agent according to the above (14), wherein W is a chlorine atom;
(18) The agent according to the above (14), wherein the 3-position is R-coordination and the 5-position is S-coordination;
(19) The compound having a squalene synthase inhibitory action is N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxy). Phenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid or N-[[(3R, 5S) -7- Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-yl] acetyl] piperidine-4-acetic acid;
(20) a skeletal muscle protective agent comprising a compound having a geranylgeranylated metabolite reduction inhibitory activity in a muscle cell or a salt thereof, or a prodrug thereof;
(21) a method for protecting skeletal muscle, which comprises administering to a mammal an effective amount of a compound having a squalene synthase inhibitory activity, a salt thereof, or a prodrug thereof;
(22) a method for protecting skeletal muscle, which comprises administering to a mammal an effective amount of a compound having an inhibitory effect on reduction of geranylgeranylated metabolites in muscle cells, a salt thereof, or a prodrug thereof;
(23) Use of a compound having a squalene synthase inhibitory activity or a salt thereof, or a prodrug thereof for the production of a skeletal muscle protective agent;
(24) Use of a compound having an inhibitory effect on reduction of geranylgeranylated metabolite in muscle cells or a salt thereof, or a prodrug thereof for the production of a skeletal muscle protective agent;
And so on.

〔式中、Ｒ_１は水素原子または置換されていてもよい炭化水素基を、Ｒ_２およびＲ_３は同一または異なって水素原子，置換されていてもよい炭化水素基あるいは置換されていてもよい複素環基を、Ｘ'はエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基あるいは脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基から構成される置換基を、環Ａは置換されていてもよいベンゼン環または置換されていてもよい複素環を、環Ｊ'は環構成原子として３個以下のヘテロ原子を含有する７ないし８員の複素環を、環Ｊ'はＲ_１，Ｒ_２，Ｒ_３及びＸ'以外にさらに置換基を有していてもよい〕で表される化合物；あるいは、式

〔式中、Ｒ_１は水素原子または置換されていてもよい炭化水素基を、Ｒ_２およびＲ_３は同一または異なって水素原子，置換されていてもよい炭化水素基あるいは置換されていてもよい複素環基を、Ｘ_１は結合手または２価の原子鎖を、Ｙはエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基または脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基を、環Ｂは置換されていてもよいベンゼン環を示す〕で表される化合物；などが好ましく用いられる。
他のスクアレン合成酵素阻害薬としては、A-104109（アボットラボラトリーズ)、

F-10863-A(Zaragozic acid D3, 三共)、
ER-28448、ER-27856(ER-28448 prodrug)とキヌクリジン誘導体〔quinuclidine derivatives〕(エーザイ)、

RPR-107393およびRPR-101821(アベンティス)、

チアジアゾール誘導体〔thiadiazole derivatives〕(ノボノルディスク)、

イソプロピルアミン誘導体〔isopropylamine derivatives〕(山之内製薬)、

イソキヌクリジン誘導体〔isoquinuclidine derivatives〕(寿製薬)、

マロン酸誘導体〔malonic acid derivatives〕(日本化薬)、

プロピオニル誘導体〔propionyl derivatives〕(第一製薬)

などが挙げられ、これらのスクアレン合成酵素阻害薬も本発明の剤に用いることができる。 As the `` compound having a squalene synthase inhibitory action '' used in the present invention, any compound having a squalene synthase inhibitory action may be used.For example, squalestatins (for example, U.S. Pat. No. 5430055, U.S. Pat.No. 5,409,950, U.S. Pat.No. 5,369,125, JP-A-7-173166, JP-A-9-124655, JP-A-9-227566 Annual Review of Microbiology, Vol. 49, pp. 607-639, 1995, Journal of Medicinal Chemistry, Vol. 38, pp. 3502-3513, 1995, Journal of Medicinal Chemistry, Vol. 39, 207-216, 1996, Journal of Medicinal Chemistry, Vol. 39, pp. 1413-1422 , 1996)), phosphoric acid compounds and carboxylic acid compounds of the substrate analog (e.g., U.S. Pat.No. 5,374,628, U.S. Pat.No. 5,441,946, U.S. Pat. Chemistry, Vol. 38, pp. 2596-2605, 1995, Arzniemittel-Forschung Drug Research, Vol. 46, 759-762, 1996, Journal of Medicinal Chemistry, Vol. 31, 1869-1871, 1988, Journal of Medicinal Chemistry, Vol. 39, 657-660, 1996, Journal of Medicinal Chemistry, Vol .39, 661-664, 1996, etc.), carboxylic acid derivatives (e.g., WO9740006, WO9633159, WO9521834, WO9748701, EP 645377, EP 645378, EP 814080, EP Patent No. 790235, JP-A-7-173120, JP-A-10-316634, JP-A-10-298134, JP-A-10-298177, JP-A-10-316617, JP-A-9-136680, WO2000-00458 No., WO2001-98282, WO98-29380, Bioorganic Medicinal Chemistry Letters, Vol. 5, 1989-1994, 1995, Bioorganic Medicinal Chemistry Letters, Vol. 6, 463-466, 1996, Journal of Medicinal Chemistry , Vol. 40, p. 2123-2125, 1997), amine compounds such as quinuclidine derivatives (e.g., U.S. Patent No. 5,389,912, U.S. Patent No. 5,49,918, U.S. Patent No. 5,395,846, U.S. Patent No. 545 No. 1596, JP-A-8-134067, JP-A-2000-169474, JP-A-10-152453, JP-A-2000-502716, WO9403541, WO9405660, WO9535295, WO9626938, WO9531458, WO9500146, WO9725043 And WO9812170), and those similar to Zaragozic acids and the like.

[Wherein, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X 'is a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, an amino group which may be substituted, or a hydrogen atom which can be deprotonated. Wherein ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, and ring J 'is a ring-constituting atom. A 7- to 8-membered heterocyclic ring containing 3 or less heteroatoms, and the ring J ′ may further have a substituent other than R ₁ , R ₂ , R ₃ and X ′. Compound; or formula

[Wherein, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X ₁ represents a bond or a divalent atom chain; Y represents a carboxyl group which may be esterified; a carbamoyl group which may be substituted; a hydroxyl group which may be substituted; Or an optionally substituted heterocyclic residue having an optionally substituted amino group or a deprotonatable hydrogen atom, and ring B represents an optionally substituted benzene ring]. Can be
Other squalene synthase inhibitors include A-104109 (Abbott Laboratories),

F-10863-A (Zaragozic acid D3, Sankyo),
ER-28448, ER-27856 (ER-28448 prodrug) and quinuclidine derivatives (Eisai),

RPR-107393 and RPR-101821 (Aventis),

Thiadiazole derivatives (Novo Nordisk),

Isopropylamine derivatives (Yamanouchi Pharmaceutical),

Isoquinuclidine derivatives (Kotobuki Pharmaceutical),

Malonic acid derivatives (Nippon Kayaku),

Propionyl derivatives (Daiichi Pharmaceutical)

And the like, and these squalene synthase inhibitors can also be used in the agent of the present invention.

The “compound having a squalene synthase inhibitory action” used in the present invention can also be used in the form of a salt, a prodrug or the like.
The “salt” of the compound having a squalene synthase inhibitory activity used in the present invention is preferably a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt. Such salts include, for example, inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, For example, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and the like are used. Furthermore, when the “compound having a squalene synthase inhibitory action” used in the present invention has an acidic group such as a carboxylic acid, the “compound having a squalene synthase inhibitory action” is, for example, an inorganic base (for example, A salt may be formed with an alkali metal or alkaline earth metal such as sodium, potassium, calcium, and magnesium, or ammonia, or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine).
The "prodrug" of the compound having a squalene synthase inhibitory activity or a salt thereof (hereinafter, may be referred to as an SSI compound) used in the present invention is an SSI compound obtained by a reaction with an enzyme or gastric acid under physiological conditions in a living body. A compound which is converted to an SSI compound by enzymatically oxidizing, reducing, or hydrolyzing, or a compound which is converted to an SSI compound by being hydrolyzed by gastric acid or the like. As a prodrug of the SSI compound, a compound in which the amino group of the SSI compound is acylated, alkylated, or phosphorylated (for example, the amino group of the SSI compound is eicanosylated, alanylated, pentylaminocarbonylated, (5-methyl- 2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.), and the hydroxyl group of the SSI compound is acyl , Alkylated, phosphorylated, and borated compounds (for example, compounds in which the hydroxyl group of an SSI compound is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated) Etc.) or the carbohydrate of SSI compound Compounds in which the sil group is esterified or amidated (for example, the carboxyl group of the SSI compound is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxy Ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like. . These compounds can be produced from the SSI compound by a method known per se.
In addition, the prodrug of the SSI compound may be one that changes to an SSI compound under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163 to 198. .
Further, the SSI compound may be a hydrate.
If an optically active form of the SSI compound is required, it can be obtained, for example, using optically active starting materials or by resolving the racemic form of the compound using conventional methods. In addition, the SSI compound may have an asymmetric carbon in the molecule, but when two kinds of stereoisomers of R-coordination or S-coordination exist, each of them or a mixture thereof is included in the present invention. It is.

In the formulas (I) and (Ia), examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ₁ include an aliphatic chain (acyclic) hydrocarbon group and an alicyclic hydrocarbon group. Examples thereof include a hydrogen group and an aryl group, and among them, an aliphatic chain hydrocarbon group is preferable.
Examples of the aliphatic chain hydrocarbon group of the hydrocarbon group include a linear or branched aliphatic hydrocarbon group, for example, an alkyl group, an alkenyl group, and an alkynyl group. Of these, a branched alkyl group is preferred. Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, include _{C 1-7} alkyl such as n- heptyl, inter alia, n- C _3-5 alkyl such as propyl, isopropyl, isobutyl and neopentyl is preferable, and isobutyl and neopentyl are particularly preferable. Examples of the alkenyl group include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1 - hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, include _{C 2-6} alkenyl 5-hexenyl, among others, vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl , 2-methyl-2-propenyl, 3-methyl-2-butenyl and the like are particularly preferred. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, include _{C 2-6} alkynyl 5-hexynyl and the like, among others ethynyl, 1-propynyl, 2-propynyl and the like are particularly preferred.
Examples of the alicyclic hydrocarbon group of the hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group. As the cycloalkyl group, a cycloalkyl group having 3 to 9 carbon atoms is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Among them, cyclopropyl, cyclobutyl, cyclopentyl And a C _3-6 cycloalkyl group such as cyclohexyl. Examples of the cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, And C _5-6 cycloalkenyl groups such as -cyclopenten-1-yl. The cycloalkadienyl group includes, for example, C _5-6 cycloalkane of 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl And a dienyl group.
Examples of the aryl group of the hydrocarbon group include monocyclic or condensed polycyclic aromatic hydrocarbon groups having 6 to 16 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl and the like. However, a C _6-10 aryl group such as phenyl, 1-naphthyl and 2-naphthyl is particularly preferred.

Examples of the substituent of the “optionally substituted hydrocarbon group” for R ₁ include an optionally substituted aryl group, an optionally substituted cycloalkyl group, and an optionally substituted cycloalkenyl group An optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, a halogen (eg, fluorine, chlorine, bromine, iodine), Oxo and the like, and the hydrocarbon group may be substituted with 1 to 5 (preferably 1 to 3) at positions that can be substituted with any of these substituents. Examples of the aryl group of the optionally substituted aryl group include C _6-16 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, and among them, phenyl, 1-naphthyl and 2-naphthyl A C _6-10 aryl group is preferred. Examples of the substituent of the optionally substituted aryl include an alkoxy group having 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine), Examples thereof include 1 to 3 alkyl groups (eg, methyl, ethyl, propyl, etc.), and the aryl group may be substituted with one or two of these optional substituents. Examples of the cycloalkyl group cycloalkyl group which may optionally be said substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like C _3-7 cycloalkyl groups cycloheptyl, and the like. Examples of the substituent of the optionally substituted cycloalkyl group and the number of the substituent include the same types and numbers as the substituents of the optionally substituted aryl group. Examples of the cycloalkenyl group of the optionally substituted cycloalkenyl group include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Examples of the substituent of the optionally substituted cycloalkenyl group and the number of the substituents include the same types and numbers as the substituents of the optionally substituted aryl group. The heterocyclic group of the optionally substituted heterocyclic group has, as atoms (ring atoms) constituting a ring system, at least one, preferably 1 to 4 heteroatoms of oxygen, sulfur and nitrogen. Examples thereof include an aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), and an aromatic heterocyclic group is preferable. As the aromatic heterocyclic group, a 5- to 6-membered aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl) 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl , 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and an aromatic condensed heterocyclic group having 2-3 condensed 5- to 6-membered rings (eg: benzofuranyl, isobenzofuranyl Benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazoly Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl , Pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolozinyl, pyrrazolinyl [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidi , 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like, among which furyl, thienyl, indolyl, isoindolyl, A 5- to 6-membered aromatic monocyclic heterocyclic group such as pyrazinyl, pyridyl and pyrimidinyl is preferred. Examples of the non-aromatic heterocyclic group include 4- to 8-membered non-aromatic heterocyclic groups such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. Can be The optionally substituted heterocyclic group may have 1 to 4, preferably 1 to 2 substituents. Examples of such a substituent include an alkyl group having 1 to 3 carbon atoms ( Examples: methyl, ethyl, propyl, etc.). Examples of the substituent on the optionally substituted amino group (including an amino group, a mono- or di-substituted amino group), an optionally substituted hydroxyl group, and an optionally substituted thiol group include: And lower (C _1-3 ) alkyl (eg, methyl, ethyl, propyl, etc.). When the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ₁ is an alicyclic hydrocarbon group or an aryl group, the substituent further includes an alkyl group having 1 to 3 carbon atoms ( For example, methyl, ethyl, propyl, etc.).
Further, as described above, R ₁ may have an oxo group and a substituent, and R ₁ also includes such an oxo-substituted hydrocarbon carboxylic acid acyl group. Such examples include, for example, an optionally substituted acyl group having 1 to 6 carbon atoms (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, dimethylacetyl, trimethylacetyl) Etc.). The acyl group may have 1 to 5 substituents at substitutable positions, and examples of the substituent include halogen (eg, fluorine, chlorine, and bromine).

で示されるものが用いられていてもよく、さらにこの様な基は低級（Ｃ_１−３）アルキル基（例、メチル、エチル、プロピル、イソプロピル等）などで１〜４個置換されていてもよい。 In the formulas (I) and (Ia), the “optionally substituted hydrocarbon group” represented by R ₂ and R ₃ is referred to as the “optionally substituted hydrocarbon group” represented by R _1. Group. However, the following may be used as the alkyl group, the aryl group, and their substituents. That is, as the alkyl group of the “optionally substituted alkyl group”, a lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , Pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), and preferably a _C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like. The alkyl group which may be substituted may have 1 to 4 substituents, and examples of such a substituent include halogen (eg, fluorine, chlorine, bromine, iodine), and lower alkyl having 1 to 4 carbon atoms. And alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.).
The `` optionally substituted aryl group '' includes a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Particularly preferred. Examples of the substituent of the “optionally substituted aryl group” include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl which may be substituted, lower alkoxy which may be substituted, And nitro, cyano, etc., which may be substituted with 1 to 3 (preferably 1 to 2) identical or different substituents. Examples of the lower alkyl include an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Is preferred. Examples of the lower alkoxy include alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and methoxy and ethoxy are particularly preferred. preferable. Examples of the substituent of the lower alkyl group which may be substituted or the lower alkoxy group which may be substituted include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.). Up to 5 may be substituted. Examples of the substituent in the optionally substituted hydroxyl group include a lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C _3-6 cycloalkyl group (Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), C _7-12 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. Can be In addition, these substituents may form a ring with adjacent substituents, and when the aryl group of the “optionally substituted aryl group” represented by R ₂ or R ₃ is a phenyl group For example,

Embedded image may be used, and 1 to 4 such groups may be further substituted with a lower (C _1-3 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.). Good.

Examples of the heterocyclic group of the “optionally substituted heterocyclic group” represented by R ₂ and R ₃ include the “heterocyclic group that may be substituted” represented by R _1. Heterocyclic groups which are described in detail in connection with "optionally substituted heterocyclic group", include 5 to 6 members such as furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl and the like. Aromatic monocyclic heterocycles are particularly preferred. Examples of the substituent of the heterocyclic group include alkyl having 1 to 3 carbons (eg, methyl, ethyl, propyl, etc.) and may have 1 to 4 of these substituents.
Among the above, as R ₂ and R ₃ , an optionally substituted phenyl group is preferable, and more preferably, a substituted phenyl group, particularly halogen such as chlorine and bromine, and lower (C _1-3 ) alkoxy And the like, a phenyl group substituted with 1 to 3, preferably 1 to 2 is preferred. Further, one of R ₂ and R ₃ is preferably hydrogen.

〔式中、Ｘは結合手または２価もしくは３価の原子鎖を、Ｙはエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基または脱プロトン化しうる水素原子を有する、置換されていてもよい複素環残基を、破線部分は単結合または二重結合を示す〕で表される基が挙げられる。 In the formula (I), the “group composed of a carboxyl group which may be esterified” represented by X ′ includes a carboxyl group which may be esterified and a carboxyl group which may be esterified. The group which it has is mentioned. Examples of the optionally esterified carboxyl group include the same as those exemplified for the optionally esterified carboxyl group defined by Y below.
Examples of the “group composed of an optionally substituted carbamoyl group” represented by X ′ include an optionally substituted carbamoyl group and a group having an optionally substituted carbamoyl group. Examples of the optionally substituted carbamoyl group include those similar to the examples of the optionally substituted carbamoyl group defined by Y below.
Examples of the “group composed of an optionally substituted hydroxyl group” represented by X ′ include an optionally substituted hydroxyl group and a group having an optionally substituted hydroxyl group. Examples of the optionally substituted hydroxyl group include the same as those exemplified for the optionally substituted hydroxyl group defined by Y below.
Examples of the “group comprising an optionally substituted amino group” represented by X ′ include an optionally substituted amino group and a group having an optionally substituted amino group. Examples of the optionally substituted amino group include the same as those exemplified for the optionally substituted amino group defined by Y below.
Examples of the “group comprising an optionally substituted heterocyclic residue having a deprotonatable hydrogen atom” represented by X ′ include a deprotonatable hydrogen atom (ie, having an active proton), Examples include an optionally substituted heterocyclic residue and a group having an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated. Examples of the optionally substituted heterocyclic residue include those similar to the optionally substituted heterocyclic residue having a deprotonatable hydrogen atom defined by Y below. .
X ′ is, for example, the formula (a)

[Wherein X represents a bond or a divalent or trivalent atom chain, and Y represents a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, An optionally substituted heterocyclic residue having an optionally substituted amino group or a deprotonatable hydrogen atom, and the dashed line portion represents a single bond or a double bond].

で表わされるものが挙げられ、式中、ｍ、ｎは独立して０、１、２又は３を表わし、Ｅは結合手または酸素原子、イオウ原子、スルホキシド、スルホン、−Ｎ(Ｒ_５)−、−ＮＨＣＯ−、−ＣＯＮ(Ｒ_６)−あるいは−ＮＨＣＯＮＨ−を表わす。ここでＲ_４及びＲ_６は水素原子、置換されていてもよい低級アルキル基、置換されていてもよいアラルキル基、置換されていてもよいフェニル基を示す。また、Ｒ_５は水素原子、低級アルキル基、アラルキル基又はアシル基を示す。
Ｒ_４及びＲ_６で示される「置換されていてもよい低級アルキル基」のアルキル基としては、炭素数１〜６個の直鎖もしくは分枝状の低級アルキル基（例：メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、イソペンチル、ネオペンチル等）が挙げられる。該置換されていてもよい低級アルキル基は１〜４個好ましくは１〜２個の置換基をもっていてもよく、これらの置換基としては、芳香族複素環基（例、フリル、チエニル、インドリル、イソインドリル、ピラジニル、ピリジル、ピリミジル、イミダゾリルなどＮ、Ｏ、Ｓのヘテロ原子を１〜４個含む５〜６員芳香族複素環）、置換されていてもよいアミノ基、置換されていてもよい水酸基、置換されていてもよいチオール基、エステル化されていてもよいカルボキシル基、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素）などが挙げられる。該置換されていてもよいアミノ基（アミノ基又はモノ−又はジ置換アミノ基）、置換されていてもよい水酸基、及び置換されていてもよいチオール基における置換基としては、低級（Ｃ_１−３）アルキル（例、メチル、エチル、プロピルなど）などが挙げられる。該エステル化されていてもよいカルボキシル基としては、例えばメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、フェノキシカルボニル、１−ナフトキシカルボニルなどＣ_２−５アルコキシカルボニル及びＣ_７−１１アリールオキシカルボニルが挙げられるが、好ましくはメトキシカルボニル、エトキシカルボニル、プロポキシカルボニルである。 In the formula (a), the “divalent atomic chain” represented by X is preferably a divalent chain having 1 to 7, more preferably 1 to 4, atoms constituting a linear portion. If it is, any may be sufficient and it may have a side chain.
For example,

Wherein m and n each independently represent 0, 1, 2 or 3, and E represents a bond or an oxygen atom, a sulfur atom, a sulfoxide, a sulfone, -N (R ₅ )- _{, -NHCO -, - CON (R} 6) - or represents a -NHCONH-. Here, R ₄ and R ₆ represent a hydrogen atom, a lower alkyl group which may be substituted, an aralkyl group which may be substituted, and a phenyl group which may be substituted. R ₅ represents a hydrogen atom, a lower alkyl group, an aralkyl group or an acyl group.
As the alkyl group of the “optionally substituted lower alkyl group” represented by R ₄ and R ₆ , a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n -Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and the like). The lower alkyl group which may be substituted may have 1 to 4, preferably 1 to 2 substituents, and these substituents include an aromatic heterocyclic group (eg, furyl, thienyl, indolyl, 5- or 6-membered aromatic heterocycle containing 1-4 N, O and S heteroatoms such as isoindolyl, pyrazinyl, pyridyl, pyrimidyl and imidazolyl), an optionally substituted amino group and an optionally substituted hydroxyl group And a thiol group which may be substituted, a carboxyl group which may be esterified, and a halogen atom (eg, fluorine, chlorine, bromine and iodine). Substituents in the optionally substituted amino group (amino group or mono- or di-substituted amino group), an optionally substituted hydroxyl group, and an optionally substituted thiol group include lower (C _{1- 3} ) Alkyl (eg, methyl, ethyl, propyl, etc.) and the like. Examples of the carboxyl group which may be esterified include, for example, C _2-5 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-naphthoxycarbonyl and C _7-11 aryloxycarbonyl. And preferably methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

Examples of the aralkyl group of the “optionally substituted aralkyl group” represented by R ₄ and R ₆ include C ₇ -C ₁₅ aralkyl groups such as benzyl, naphthylmethyl, phenylpropyl and phenylbutyl. The optionally substituted aralkyl group may have 1 to 4, preferably 1 to 2 substituents, and examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine) And an alkoxy group having 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy group), a hydroxyl group, an amino group, a carboxyl group, a sulfhydryl group and the like.
Examples of the substituent of the “phenyl group which may be substituted” represented by R ₄ and R ₆ include a halogen atom (eg, fluorine, chlorine, bromine, iodine), C _1-3 alkoxy (eg, methoxy, ethoxy, Propoxy), C _1-3 alkyl (eg, methyl, ethyl, propyl) and the like.
However, R ₄ may be different for each methylene chain.
The “lower alkyl group” and “aralkyl group” represented by R ₅ include a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, butyl, tert-butyl, etc.), a carbon number of 7 And up to 15 aralkyl groups (eg, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc.).

The “acyl group” represented by R ₅ includes a lower (C _1-6 ) alkanoyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower (C _3-7 ) ) Alkenoyl groups (eg, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, etc.), C _4-7 cycloalkanecarbonyl groups (eg, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, etc.), lower (C _1-4 ) Alkanesulfonyl group (eg, mesyl, ethanesulfonyl, propanesulfonyl, etc.), C _7-14 aroyl group (eg, benzoyl, p-toluoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-10 aryl lower (C _-4) alkanoyl group (e.g., phenylacetyl, phenylpropionyl, hydro atto Ropo yl, phenyl _{butyryl), C 6-10} aryl lower _{(C 3-5)} alkenoyl (e.g., cinnamoyl, etc. Atoropoiru), _{C 6 -10} arene sulfonyl group (eg, benzenesulfonyl, p-toluenesulfonyl group and the like).
Further, X may be a carbon chain containing a double bond or -L-CH (OH)-(L represents a bond or a linear or branched alkylene chain). Examples of the “carbon chain containing a double bond” include those having 1 to 7 carbon atoms, more preferably 1 to 4 carbon atoms constituting a straight chain portion. You may have. The double bond in the carbon chain is contained in either one or both of the straight-chain portion and the branched-chain portion, and preferably includes those contained in the straight-chain portion. The number of double bonds contained in the carbon chain is not particularly limited as much as possible, but is preferably 1 to 2.

Examples of the carbon chain containing the double bond include methine, vinylene, propenylene, butenylene, butadienylene, methylpropenylene, ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene, propylbutenylene, methylbutadienylene , Ethyl butadienylene, propyl butadienylene, pentenylene, hexenylene, heptenylene, pentadienylene, hexadienylene, heptadienylene and the like, and preferably, methine, vinylene, propenylene, butenylene and butadienylene. Here, when the carbon chain is trivalent, the carbon chain is connected to a substitutable carbon atom on the ring of the ring J ′ by a double bond.
Examples of the “linear or branched alkylene chain” represented by L include a linear or branched alkylene chain having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, Examples include divalent groups such as tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene, and methyltrimethylene. Examples thereof include those having 1 to 3 carbon atoms such as trimethylene and propylene.

〔式中、Ｘ_１は結合手または２価の原子鎖を、Ｙはエステル化されていてもよいカルボキシル基，置換されていてもよいカルバモイル基，置換されていてもよい水酸基，置換されていてもよいアミノ基または脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基を示す〕で表される基が好ましい。
式（b）中、Ｘ_１で示される２価の原子鎖としては、前記Ｘで定義された２価の原子鎖と同様なものが挙げられる。
式（a）および（b）中、ＸまたはＸ_１で示される「２価の原子鎖」としては、好ましくは、直鎖部分を構成する炭素数が１〜７個（より好ましくは１〜４個）である直鎖状あるいは分枝鎖状のアルキレン鎖が挙げられる。該アルキレン鎖としては、例えば、メチレン，エチレン，トリメチレン，テトラメチレン，ペンタメチレン，ヘキサメチレン，ヘプタメチレン，プロピレン，エチルメチレン，エチルエチレン，プロピルエチレン，ブチルエチレン，メチルテトラメチレン，メチルトリメチレンなどの２価基が挙げられるが、好ましくは、メチレン，エチレン，トリメチレン，プロピレンなどの炭素数１〜４個のものが挙げられる。
式（a）および（b）において、Ｙで示される「エステル化されていてもよいカルボキシル基」としては、炭素数２−７の低級アルコキシカルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、tert−ブトキシカルボニル、sec−ブトキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ネオペンチルオキシカルボニルなど）、Ｃ_７−１４アリールオキシカルボニル（例、フェノキシカルボニル、１−ナフトキシカルボニル）、Ｃ_８−１２アラルキルオキシカルボニル（例、ベンジルオキシカルボニルなど）などが挙げられる。なかでもカルボキシル基、メトキシカルボニル、エトキシカルボニルが好ましい。 Among the above, as X ′, the formula (b)

[In the formula, X ₁ represents a bond or a divalent atom chain, and Y represents a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, Or a substituted or unsubstituted heterocyclic residue having a hydrogen atom capable of being deprotonated.].
In the formula (b), examples of the divalent atom chain represented by X ₁ include the same as the divalent atom chain defined for X.
In the formulas (a) and (b), the “divalent atomic chain” represented by X or X ₁ preferably has 1 to 7 carbon atoms (more preferably 1 to 4 carbon atoms) constituting a straight chain portion. And a linear or branched alkylene chain. Examples of the alkylene chain include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene, and methyltrimethylene. Examples thereof include a valent group, and preferably include a group having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, and propylene.
In the formulas (a) and (b), the “optionally esterified carboxyl group” represented by Y includes lower alkoxycarbonyl having 2 to 7 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc., C _7-14 aryloxycarbonyl (eg, phenoxycarbonyl, 1-naphthoxycarbonyl) ), C _8-12 aralkyloxycarbonyl (eg, benzyloxycarbonyl, etc.) and the like. Among them, a carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferred.

As the substituent of the “optionally substituted carbamoyl group” for Y, the optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl) , Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), optionally substituted C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), substituted C _6-14 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), and optionally substituted C _7-11 aralkyl group (eg, benzyl, phenethyl, etc.). May be the same or different and may be substituted one or two times. As the substituent for the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl, lower (C _1-5 ) alkyl (eg, methyl, ethyl, propyl) , Isopropyl, butyl, tert-butyl, pentyl, isopentyl, neopentyl), a carboxyl group which may be esterified with a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms (eg, furyl, thienyl, Indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group, hydroxyl group, phenyl group and the like. These substituents may be the same or different and may be substituted with 1 to 3 substituent (s). Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), a lower (C _1-4 ) alkyl group (eg, And carboxyl groups which may be esterified with methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. Further, in the optionally substituted carbamoyl group, a substituent on two nitrogen atoms may be combined with a nitrogen atom to form a cyclic amino group. Examples of such a cyclic amino group Includes 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like. Further, the cyclic amino group may further have a substituent.

Examples of the substituent of the “optionally substituted hydroxyl group” represented by Y include lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C _{3- 6} cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted And a good C _7-11 aralkyl group (eg, benzyl, phenethyl and the like) and the like. Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), a lower (C _1-4 ) alkyl group (eg, And carboxyl groups which may be esterified with methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.
The “optionally substituted amino group” for Y includes mono- and di-substituted amino groups, and examples of these substituents include lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl) , Isopropyl, butyl, tert-butyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), and optionally substituted C _6-10 aryl group (eg, phenyl, 1 -Naphthyl, 2-naphthyl, etc.) and optionally substituted _C7-11 aralkyl groups (eg, benzyl, phenethyl and the like). Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine) and a lower (C _1-4 ) alkyl group (eg, And carboxyl groups which may be esterified with methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. These substituents may have 1 to 4, preferably 1 to 2 substituents. . Further, a substituent on two nitrogen atoms may form a cyclic amino group together with the nitrogen atom. Examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino , Morpholino, 1-piperazinyl and the like. Further, the cyclic amino group may further have a substituent.

〔式中、ｉは−Ｏ−または−Ｓ−を、ｊは＞Ｃ＝Ｏ，＞Ｃ＝Ｓまたは＞Ｓ(Ｏ)_２を示す〕で表される基（なかでも、２，５−ジヒドロ−５−オキソ−１，２，４−オキサジアゾール−３−イル，２，５−ジヒドロ−５−チオキソ−１，２，４−オキサジアゾール−３−イル，２，５−ジヒドロ−５−オキソ−１，２，４−チアジアゾール−３−イルが好ましい）などが挙げられる。
上記複素環残基は、置換されていてもよい低級アルキル基（好ましくはＣ_１−４アルキル）またはアシル基などで保護されていてもよい。該置換されていてもよい低級アルキル基としては、Ｃ_１−３アルキル，ニトロ，Ｃ_１−３アルコキシで置換されていてもよいフェニル又はＣ_１−３アルコキシで置換されていてもよいＣ_１−４アルキル（例、メチル，トリフェニルメチル，メトキシメチル，エトキシメチル，ｐ−メトキシベンジル，ｐ−ニトロベンジルなど）などが挙げられる。該アシル基としては、低級（Ｃ_２−５）アルカノイル，ベンゾイルなどが挙げられる。
上記した中でも、Ｘ'としては、エステル化されていてもよいカルボキシル基で置換されているアルキル基、脱プロトン化しうる水素原子を有する置換されていてもよい複素環残基で置換されているアルキル基または置換されていてもよいカルバモイル基で置換されているアルキル基が好ましい。 The heterocyclic residue of the “optionally substituted heterocyclic residue having a deprotonatable hydrogen atom” represented by Y is a 5- to 7-membered member containing at least one of N, S and O (Preferably a 5-membered) monocyclic heterocyclic residue (preferably a nitrogen-containing heterocyclic residue), which preferably has a hydrogen atom capable of forming a proton upon elimination. For example, tetrazol-5-yl or a formula

[Wherein i represents -O- or -S-, j represents> C = O,> C = S or> S (O) ₂ ] (among which 2,5,5-dihydro -5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5 -Oxo-1,2,4-thiadiazol-3-yl) and the like.
The above heterocyclic residue may be protected with an optionally substituted lower alkyl group (preferably _C1-4 alkyl) or an acyl group. The lower alkyl group which may be substituted includes phenyl which may be substituted with C _1-3 alkyl, nitro, C _1-3 alkoxy or C _1- which may be substituted with C _1-3 alkoxy. _4- alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) and the like. Examples of the acyl group include lower ( _C2-5 ) alkanoyl, benzoyl and the like.
Among the above, as X ′, an alkyl group substituted with a carboxyl group which may be esterified, an alkyl substituted with a heterocyclic group which may be substituted and having a hydrogen atom which can be deprotonated, An alkyl group substituted with a group or an optionally substituted carbamoyl group is preferred.

で表されるものが好ましい。
環Ａで示される「置換されていてもよいベンゼン環」および「置換されていてもよい複素環」の置換基としては、ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、炭素数１〜４個の置換されていてもよい低級アルキル基（例、メチル、エチル、プロピル、ブチル、tert−ブチル等）、炭素数１〜４個の置換されていてもよい低級アルコキシ基（例：メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、tert−ブトキシ等）、水酸基、ニトロ基、シアノなどが挙げられる。環Ａはこれらの置換基を１〜３個、好ましくは１〜２個有していてもよい。また、これらの置換基は、隣接する置換基同志で環を形成してもよい。該置換されていてもよい低級アルキル基又は置換されていてもよい低級アルコキシ基の置換基としては、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素）等が挙げられ、任意の位置に１〜３個置換されていてもよい。環Ａとしてはメトキシもしくは塩素原子で置換されたものが好ましく、特に塩素原子で置換されたものが好ましい。
式（Ia）において、環Ｂで示される「置換されていてもよいベンゼン環」の置換基としては、ハロゲン（例、フッ素，塩素，臭素，ヨウ素）、炭素数１〜４個の置換されていてもよい低級アルキル基（例、メチル、エチル、プロピル、ブチル、tert−ブチル等）、炭素数１〜４個の置換されていてもよい低級アルコキシ基（例：メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、tert−ブトキシ等）、水酸基、ニトロ基、シアノなどが挙げられる。環Ｂはこれらの置換基を１〜３個、好ましくは１〜２個有していてもよい。また、これらの置換基は、隣接する置換基同志で環を形成してもよい。該置換されていてもよい低級アルキル基又は置換されていてもよい低級アルコキシ基の置換基としては、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素）等が挙げられ、任意の位置に１〜３個置換されていてもよい。環Ｂとしてはメトキシもしくは塩素原子で置換されたものが好ましく、特に塩素原子で置換されたものが好ましい。 In the formula (I), examples of the heterocyclic ring represented by ring A include the heterocyclic groups described in detail in connection with the substituent of the hydrocarbon group represented by R _1.

Is preferably represented by
Examples of the substituent of the “optionally substituted benzene ring” and the “optionally substituted heterocyclic ring” represented by ring A include halogen (eg, fluorine, chlorine, bromine, iodine), carbon number 1-4. Optionally substituted lower alkyl groups (eg, methyl, ethyl, propyl, butyl, tert-butyl, etc.), and optionally substituted lower alkoxy groups having 1 to 4 carbon atoms (eg, methoxy, ethoxy) , Propoxy, isopropoxy, butoxy, tert-butoxy, etc.), hydroxyl, nitro, cyano and the like. Ring A may have 1 to 3, preferably 1 to 2 of these substituents. Further, these substituents may form a ring with adjacent substituents. Examples of the substituent of the lower alkyl group which may be substituted or the lower alkoxy group which may be substituted include a halogen atom (eg, fluorine, chlorine, bromine, iodine) and the like. Three may be substituted. Ring A is preferably substituted by methoxy or chlorine atom, and particularly preferably substituted by chlorine atom.
In the formula (Ia), examples of the substituent of the “optionally substituted benzene ring” represented by ring B include a halogen (eg, fluorine, chlorine, bromine, iodine) and a substituted carbon atom having 1 to 4 carbon atoms. Lower alkyl groups (eg, methyl, ethyl, propyl, butyl, tert-butyl, etc.) and lower alkoxy groups having 1 to 4 carbon atoms which may be substituted (eg, methoxy, ethoxy, propoxy, isopropoxy) , Butoxy, tert-butoxy, etc.), hydroxyl, nitro, cyano and the like. Ring B may have 1-3, preferably 1-2, of these substituents. Further, these substituents may form a ring with adjacent substituents. Examples of the substituent of the lower alkyl group which may be substituted or the lower alkoxy group which may be substituted include a halogen atom (eg, fluorine, chlorine, bromine, iodine) and the like. Three may be substituted. Ring B is preferably substituted with methoxy or a chlorine atom, particularly preferably substituted with a chlorine atom.

In the formula (I), examples of the heterocycle in the “7- or 8-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms” represented by ring J ′ include, for example, O, S (O) q ( q represents 0, 1 or 2) and 7 or 8 membered saturated or unsaturated heterocyclic ring containing at least one of N. However, the number of hetero atoms in the atoms (ring-constituting atoms) constituting the ring of the heterocyclic ring is three or less.
The ring J ′ may have, in addition to the groups represented by R ₁ , R ₂ , R ₃ , and X ′, _one or _two rings at positions where a substituent can be further substituted. As the substituent, when the substituent is bonded to a nitrogen atom on ring J ′, an alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl) , isopentyl, a _{C 1-6} alkyl neopentyl, etc.), an acyl group (eg formyl, acetyl, propionyl, _{C 1-4} acyl group such as butyroyl), and the like. The alkyl group or the acyl group may be further substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine). When the substituent is bonded to a carbon atom on ring J ′, examples of the substituent include oxo, thioxo, an optionally substituted hydroxyl group, and an optionally substituted amino group. The optionally substituted hydroxyl group and the optionally substituted amino group are the same as the “optionally substituted hydroxyl group” and the “optionally substituted amino group” defined for Y. Is mentioned.
The ring J ′ is preferably a ring in which oxo or thioxo is substituted at a substitutable position, in addition to the groups represented by R ₁ , R ₂ , R ₃ and X ′.

などが挙げられる。 As a condensed ring consisting of ring A and ring J ′, for example,

And the like.

〔式中、Ｒ_１，Ｒ_２，Ｒ_３，Ｘ'，環Ａは前記と同意義を示す。環Ｊ_１は７員の複素環を、Ｚ_１は−Ｎ(Ｒ_７)−（Ｒ_７は水素原子，アルキル基またはアシル基を示す），−Ｓ(Ｏ)ｑ−（ｑは０，１または２を示す），−ＣＨ_２−または−Ｏ−を、ＫはＣまたはＮを、ＧはＯまたはＳを示す。〕で表わされるものが好ましい。 Formula (I) includes formula (I ′)

[Wherein, R ₁ , R ₂ , R ₃ , X ′ and ring A have the same meaning as described above. A heterocyclic ring _{J 1} is 7-membered, _{Z 1} is -N _{(R 7)} - (indicating the _{R 7} is a hydrogen atom, an alkyl group or an acyl group), - S (O) q- (q is 0, 1 Or 2), —CH ₂ — or —O—, K represents C or N, and G represents O or S. ] Are preferred.

〔式中、Ｒ_１，Ｒ_２，Ｒ_３，Ｘ_１，Ｙ，環Ａは前記と同意義を示す。Ｚ_２はＳ(Ｏ)ｑ（ｑは０，１または２を示す）またはＯを示す〕で表わされるものが好ましい。 In the above formula (I ′), the alkyl group represented by R ₇ is a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and the like, and may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine).
Examples of the acyl group represented by R ₇ include a C _1-4 acyl group (eg, formyl, acetyl, propionyl, butyroyl, etc.), and a halogen atom (eg, fluorine, chlorine, bromine, iodine) and the like. May be substituted.
In the formula (I ′), as Z ₁ , S (O) q (q represents 0, 1 or 2) and O are preferable. K is preferably C and G is preferably O.
Formula (I ′) is more preferably formula (I ″)

[Wherein, R ₁ , R ₂ , R ₃ , X ₁ , Y and ring A have the same meaning as described above. Z ₂ is preferably S (O) q (q represents 0, 1 or 2) or O].

で表される化合物が好ましい。
式（Ia）としては、式（Ia'）

〔式中、Ｒ_１，環Ｂは前記と同意義を示す。Ｑは水素または金属イオンを、環Ｃは置換されていてもよいフェニル基を示す〕で表されるものであってもよい。式中、７員環の面に対して、３位と５位の置換基が逆方向を向いているトランスを示し、（Ｒ）はＲ−配置を示す。
上記式（Ia'）において、Ｑで示される金属イオンとしては、ナトリウムイオン，カリウムイオン，カルシウムイオン，アルミニウムイオンなどが挙げられるが、なかでもナトリウムイオン，カリウムイオンが好ましい。
環Ｃで示される「置換されていてもよいフェニル基」の置換基としては、前記Ｒ_２およびＲ_３で定義された「置換されていてもよい炭化水素基」の例として述べた「置換されていてもよいアリール基」の置換基としてあげたものと同様なものが挙げられる。 The compound represented by the formula (I) includes the compound represented by the formula (Ia)

The compound represented by is preferred.
As the formula (Ia), the formula (Ia ′)

[Wherein, R ₁ and ring B are as defined above. Q represents hydrogen or a metal ion, and ring C represents an optionally substituted phenyl group]. In the formula, a trans in which the substituents at the 3- and 5-positions face in the opposite direction to the surface of the 7-membered ring is shown, and (R) shows an R-configuration.
In the above formula (Ia '), examples of the metal ion represented by Q include a sodium ion, a potassium ion, a calcium ion, and an aluminum ion, and among them, a sodium ion and a potassium ion are preferable.
Examples of the substituent of the “optionally substituted phenyl group” represented by ring C include the “substituted or substituted phenyl group” described as an example of the “optionally substituted hydrocarbon group” defined for R ₂ and R ₃ above. And the same as the substituents for the "optionally substituted aryl group".

  Examples of the salt of the compound represented by the formula (I) include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, such as acetate, tartrate, citrate and fumarate , Maleic acid salts, toluenesulfonic acid salts, organic acid salts such as methanesulfonic acid salts, such as sodium salts, potassium salts, calcium salts, metal salts such as aluminum salts, such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, And pharmacologically acceptable salts such as salts of bases such as quinine salts and cinchonine salts. Particularly, a sodium salt is preferable.

Specific examples of the compound represented by the formula (I) are as follows.
(3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-cyano-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-cyano-5- (2,4-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,

(3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,

(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid,
(3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-cyano-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,

(3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-cyano-5- (2,4-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,

(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,
(3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid ,

(3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid,
(3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid,

(3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,
(3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid,
(3R) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-acetic acid,

(3R, 5S) -7-chloro-5- (2-chlorophenyl) -2,3,4,5-tetrahydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-acetic acid,
N-[[(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3- Yl] -acetyl] glycine,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -3-dimethylaminocarbonylmethyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine ,
7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H- [1] -benzazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepine-3-acetic acid,
(3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine- 3-acetic acid,

(3R, 5S) -7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine -3-acetic acid,
(3R, 5S) -7-chloro-1-isobutyl-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine -3-acetic acid,
(3R, 5S) -7-chloro-5- (3-hydroxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (4-hydroxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (3-hydroxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (4-hydroxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,

(3R, 5S) -7-chloro-5- (3-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (3-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-3-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,

(3R, 5S) -7-Chloro-5- (2-chloro-4-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-3-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-4-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-3-hydroxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-4-hydroxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-chloro-5- (2-chloro-3-hydroxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid,
(3R, 5S) -7-Chloro-5- (2-chloro-4-hydroxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3 -Acetic acid, and salts thereof.

  The compound represented by the above general formula (I) and a salt thereof [hereinafter sometimes simply referred to as the compound (I) including the salt. ] Are disclosed in, for example, EPA 567,026, WO 95/21834 (Japanese Patent Application No. 6-15531), EPA 645377 (Japanese Patent Application No. 6-229159), and EPA 645378 (Japanese Patent Application No. 6-229160). Can be manufactured according to the disclosure of

で表される化合物が好ましい。
式（Ib）で表わされる化合物としては、
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシから選ばれた１ないし３個の置換基を有していてもよいＣ_１−６アルキルである化合物；
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシから選ばれた１ないし３個の置換基を有していてもよい分枝状のＣ_３−６アルキルである化合物；
Ｒ_ｂが２,２−ジメチル−３−ヒドロキシプロピル、３−ヒドロキシ−２−ヒドロキシメチル−２−メチルプロピル、３−アセトキシ−２,２−ジメチルプロピル、３−アセトキシ−２−ヒドロキシメチル−２−メチルプロピル又は３−アセトキシ−２−アセトキシメチル−２−メチルプロピルである化合物；
Ｒ_１ｂがメチルである化合物；
Ｗが塩素原子である化合物；
Ｘ_ｂが式

〔式中、Ｒ_２ｂ及びＲ_３ｂはそれぞれ水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基又はアシル基であるか、あるいはＲ_２ｂ及びＲ_３ｂは隣接する窒素原子と一緒になって窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし３個環構成原子として含んでいてもよい置換されていてもよい５または６員含窒素複素環を形成する〕で表される基である化合物；
Ｘ_ｂで表される基において、
Ｒ_２ｂが水素原子又はＣ_１−７アルキル基を示し、
Ｒ_３ｂが
（1）（a）Ｃ_１−７アルキル、（b）Ｃ_３−７シクロアルキル、（c）Ｃ_２−６アルケニル、（d）Ｃ_６−１０アリール及び（e）Ｃ_６−１０アリール−Ｃ_１−４アルキルから選ばれる炭化水素基〔ここで（a）Ｃ_１−７アルキル、（b）Ｃ_３−７シクロアルキル及び（c）Ｃ_２−６アルケニルはそれぞれ
（i）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（ii）Ｃ_１−６アルキル又はＣ_２−７アルカノイルオキシ−Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、
（iii）スルホン酸基、
（iv）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基、
（v）Ｃ_１−３アルキルでアルキル化されていてもよい水酸基、
（vi）Ｃ_１−３アルキルでアルキル化されていてもよいスルフヒドリル基、
（vii）カルバモイル基、
（viii）水酸基、塩素原子、フッ素原子、アミノスルホニル及びＣ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基より選ばれる１ないし５個の置換基で置換されていてもよいフェニル基、
（ix）Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基、
（x）ピペリジン，ピロリジン，モルホリン，チオモルホリン，ピペラジン，４−メチルピペラジン，４−ベンジルピペラジン，４−フェニルピペラジン，１,２,３,４−テトラヒドロイソキノリン又はフタルイミドから導かれるＣ_１−３アルキル、ベンジル又はフェニルで置換されていてもよい環状アミノ基及び
（xi)ピリジン，イミダゾール，インドール又はテトラゾ−ルから導かれる芳香族５〜６員複素環基
より選ばれる１ないし４個の置換基を有していてもよく、
（d）Ｃ_６−１０アリール及び（e）Ｃ_６−１０アリール−Ｃ_１−４アルキルはそれぞれ
（i）Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（ii）Ｃ_１−６アルキル又はＣ_２−７アルカノイルオキシ−Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、
（iii）スルホン酸基、
（iv）Ｃ_１−４アルキルスルホニル、Ｃ_６−１０アリールスルホニル又はＣ_６−１０アリール−Ｃ_１−４アルキルスルホニル基、
（v）Ｃ_１−６アルキル又はＣ_６−１０アリ−ル−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基、
（vi）Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、スルホン酸基、Ｃ_１−４アルキルスルホニル、Ｃ_６−１０アリールスルホニル又はＣ_６−１０アリール−Ｃ_１−４アルキルスルホニル基、Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基で置換されていてもよいＣ_１−３アルキル基及び
（vii）ハロゲン
より選ばれる1ないし4個の置換基を有していてもよい〕、
（2）テトラゾリル，４,５−ジヒドロ−５−オキソ−１,２,４−オキサジアゾリル，４,５−ジヒドロ−５−チオキソ−１,２,４−オキサジアゾリル，２,３−ジヒドロ−３−オキソ−１,２,４−オキサジアゾリル，２,３−ジヒドロ−３−チオキソ−１,２,４−オキサジアゾリル，３,５−ジオキソ−１,２,４−オキサジアゾリジニル，４,５−ジヒドロ−５−オキソ−イソオキサゾリル，４,５−ジヒドロ−５−チオキソ−イソオキサゾリル，２,３−ジヒドロ−２−オキソ−１,３,４−オキサジアゾリル，２,３−ジヒドロ−３−オキソ−１,２,４−テトラゾリル又は２,３−ジヒドロ−３−チオキソ−１,２,４−テトラゾリル基、又は
（3）（i）１又は２個のハロゲンで置換されていてもよいＣ_２−７アルカノイル基、及び（ii）Ｃ_１−３アルキル、Ｃ_１−３アルコキシ及びハロゲンから選ばれる１ないし４個の置換基で置換されていてもよいＣ_６−１０アリールスルホニル基、Ｃ_１−４アルキルスルホニル基又はＣ_６−１０アリール−Ｃ_１−４アルキルスルホニル基
から選ばれるアシル基を示すか、
又はＲ_２ｂ及びＲ_３ｂは隣接の窒素原子と一緒になってピペリジン、ピペラジン、ピロリジン、２−オキソピペラジン、２,６−ジオキソピペラジン、モルホリン又はチオモルホリンより導かれる５員又は６員環〔ここで、５員又は６員環は
（A）Ｃ_１−３アルキル又はＣ_２−７アルカノイルで置換されていてもよい水酸基、
（B）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（C）Ｃ_１−６アルキル又はＣ_２−７アルカノイルオキシ−Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、
（D）スルホン酸基、
（E）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基、
（F）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、Ｃ_１−６アルキル又はＣ_２−７アルカノイルオキシ−Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、スルホン酸基、Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基、Ｃ_１−３アルキル又はＣ_２−７アルカノイルで置換されていてもよい水酸基、Ｃ_１−３アルキルでアルキル化されていてもよいスルフヒドリル基、カルバモイル基、及び水酸基、ハロゲン、アミノスルホニル及びＣ_１−３アルキルで置換されていてもよいアミノ基より選ばれた１ないし５個の置換基で置換されていてもよいフェニル、Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基又はテトラゾリルで置換されていてもよいＣ_１−６アルキル及びＣ_２−５アルケニル、
（G）Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基、
（H）ピペリジン、ピロリジン、モルホリン、チオモルホリン、４−メチルピペラジン、４−ベンジルピペラジン、又は４−フェニルピペラジンから導かれる環状アミノ基、
（I）シアノ基、
（J）カルバモイル基、
（K）オキソ基、
（L）テトラゾリル又は２,５−ジヒドロ−５−オキソ−１,２,４−オキサジアゾリル基、
（M）Ｃ_６−１０アリールスルホニル、Ｃ_１−４アルキルスルホニル又はＣ_６−１０アリール−Ｃ_１−４アルキルスルホニルで置換されていてもよいカルバモイル基、
（N）Ｃ_１−３アルキルでアルキル化されていてもよいスルフヒドリル基、
及び
（O）水酸基、ハロゲン、アミノスルホニル及びＣ_１−３アルキルで置換されていてもよいアミノ基から選ばれる１ないし５個の置換基で置換されていてもよいフェニル基
より選ばれる1ないし4個の置換基を有していてもよい〕を形成する化合物；
Ｘ_ｂで表される基において、
Ｒ_２ｂ及びＲ_３ｂは隣接するカルバモイル基の窒素原子と一緒になってピペリジン、ピペラジン、ピロリジン、２−オキソピペラジン又は２,６−ジオキソピペラジンより導かれる５員又は６員環を形成し、その５員又は６員環はそれぞれ
（i）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（ii）Ｃ_１−６アルキル又はＣ_２−７アルカノイル−Ｃ_１−６アルキルでモノ又はジ−置換されていてもよいリン酸基、
（iii）スルホン酸基、
（iv）Ｃ_１−６アルキル又はＣ_６−１０アリール−Ｃ_１−４アルキルで置換されていてもよいスルホンアミド基、
（v）Ｃ_１−３でアルキル化されていてもよい水酸基、
（vi）Ｃ_１−３アルキルでアルキル化されていてもよいスルフヒドリル基、
（vii）カルバモイル基、
（viii）水酸基、ハロゲン、アミノスルホニル及びＣ_１−３アルキルで置換されていてもよいアミノ基より選ばれた１ないし５個の置換基で置換されていてもよいフェニル基、
（ix）Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基、
及び
（x）テトラゾリル基
から選ばれる１〜２個の置換基を有していてもよいＣ_１−６アルキル基で置換されていてもよい環である化合物；
Ｘ_ｂで表される基において、
Ｒ_２ｂが水素原子又はＣ_１−７アルキル、Ｒ_３ｂがＣ_１−４アルキルスルホニルである化合物；
Ｘ_ｂで表される複素環基がテトラゾリル、４,５−ジヒドロ−５−オキソ−１,２,４−オキサジアゾリル、４,５−ジヒドロ−５−チオキソ−１,２,４−オキサジアゾリル、２,３−ジヒドロ−３−オキソ−１,２,４−オキサジアゾリル、２,３−ジヒドロ−３−チオキソ−１,２,４−オキサジアゾリル、３,５−ジオキソ−１,２,４−オキサジアゾリジニル、４,５−ジヒドロ−５−オキソ−イソオキサゾリル、４,５−ジヒドロ−５−チオキソ−イソオキサゾリル、２,３−ジヒドロ−２−オキソ−１,３,４−オキサジアゾリル、２,３−ジヒドロ−３−オキソ−１,２,４−テトラゾリル又は２,３−ジヒドロ−３−チオキソ−１,２,４−テトラゾリルである化合物；
Ｒ_１ｂがメチル、
Ｗが塩素原子、
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔｅｒｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシより選ばれる１個ないし３個の置換基で置換された分枝状のＣ_３−６アルキル、
Ｘ_ｂが式

〔式中、Ｒ_２ｂ'は水素原子又はＣ_１−７アルキルを示し、Ｒ_３ｂ'はＣ_１−４アルキルを示す。〕で表される基である化合物；
Ｒ_１ｂがメチル、
Ｗが塩素原子、
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔｅｒｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシより選ばれる１個ないし３個の置換基で置換された分枝状のＣ_３−６アルキル、
Ｘ_ｂが式

〔式中、Ｒ_ｂ'は水素原子又はＣ_１−７アルキルを示し、ｎは１ないし５の整数を示す。〕で表される基である化合物；
Ｒ_１ｂがメチル、
Ｗが塩素原子、
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔｅｒｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシより選ばれる１個ないし３個の置換基で置換された分枝状のＣ_３−６アルキル、
Ｘ_ｂが式

〔式中、Ｒ"は水素原子又はＣ_１−４アルキルを示す〕で表される基である化合物；
Ｒ_１ｂがメチル、
Ｗが塩素原子、
Ｒ_ｂが水酸基，アセチルオキシ，プロピオニルオキシ，ｔｅｒｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシより選ばれる１個ないし３個の置換基で置換された分枝状のＣ_３−６アルキル、
Ｘ_ｂがテトラゾリルである化合物；
Ｒ_ｂが１個又は２個の水酸基で置換されていてもよい低級アルキル、
Ｘ_ｂが
（1）（a）Ｃ_１−７アルキル、（b）Ｃ_３−７シクロアルキル、（c）Ｃ_２−６アルケニル、（d）Ｃ_６−１０アリール及び（e）Ｃ_７−１４アリールアルキルから選ばれる炭化水素基〔ここで（a）Ｃ_１−７アルキル、（b）Ｃ_３−７シクロアルキル、（c）Ｃ_２−６アルケニルはそれぞれ
（i）Ｃ_１−６アルキル又はＣ_７−１０アリールアルキルでエステル化されていてもよいカルボキシル基、
（ii）リン酸基、
（iii）スルホン酸基、
（iv）Ｃ_１−６アルキル又はＣ_７−１０アリールアルキルで置換されていてもよいスルホンアミド基、
（v）Ｃ_１−３アルキルでアルキル化されていてもよい水酸基、
（vi）Ｃ_１−３アルキルでアルキル化されていてもよいスルフヒドリル基、
（vii）カルバモイル基、
（viii）水酸基、塩素原子、フッ素原子、アミノスルホニル及びＣ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基より選ばれる置換基で置換されていてもよいフェニル基、
（ix）Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基、
及び
（x）ピペリジン，ピロリジン，モルホリン，チオモルホリン，ピペラジン，４−メチルピペラジン，４−ベンジルピペラジン又は４−フェニルピペラジンから導かれるＣ_１−３アルキル、ベンジル又はフェニルで置換されていてもよい環状アミノ基及び
（xi)ピリジン，イミダゾール，インドール又はテトラゾ−ルから導かれる芳香族５〜６員複素環基
より選ばれる１ないし４個の置換を有していてもよく、
（d）Ｃ_６−１０アリール及び（e）Ｃ_７−１４アリールアルキルはそれぞれ
（i）Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（ii）リン酸基、
（iii）スルホン酸基、
（iv）Ｃ_１−６アルキル又はＣ_７−１０アリールアルキルで置換されていてもよいスルホンアミド基、
（v）Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、リン酸基、スルホン酸基、Ｃ_１−６アルキル又はＣ_７−１０アリールアルキルで置換されていてもよいスルホンアミド基で置換されていてもよいＣ_１−３アルキル基
又は
（vi）ハロゲン原子
より選ばれる1ないし4個の置換基を有していてもよい〕で置換されていてもよいカルバモイル基、
（2）テトラゾリル，４,５−ジヒドロ−５−オキソ−１,２,４−オキサジアゾリル，４,５−ジヒドロ−５−チオキソ−１,２,４−オキサジアゾリル，２,３−ジヒドロ−３−オキソ−１,２,４−オキサジアゾリル，２,３−ジヒドロ−３−チオキソ−１,２,４−オキサジアゾリル，３,５−ジオキソ−１,２,４−オキサジアゾリジニル，４,５−ジヒドロ−５−オキソ−イソオキサゾリル，４,５−ジヒドロ−５−チオキソ−イソオキサゾリル，２,３−ジヒドロ−２−オキソ−１,３,４−オキサジアゾリル，２,３−ジヒドロ−３−オキソ−１,２,４−テトラゾリル又は２,３−ジヒドロ−３−チオキソ−１,２,４−テトラゾリル基、
（3）（i）１又は２個のハロゲンで置換されていてもよいＣ_２−７アルカノイル基、及び（ii）Ｃ_１−３アルキル、Ｃ_１−３アルコキシ及びハロゲンから選ばれる１ないし４個の置換基で置換されていてもよいＣ_６−１０アリールスルホニル基、Ｃ_１−４アルキルスルホニル基又はＣ_７−１４アリールアルキルスルホニル基から選ばれるアシル基で置換されていてもよいカルバモイル、
又は
（4）ピペリジン、ピペラジン、ピロリジン、２−オキソピペラジン、２,６−ジオキソピペラジン、モルホリン及びチオモルホリンより導かれる環状アミノカルボニル基
〔ここで環状アミノカルボニル基は
（A）水酸基、
（B）Ｃ_１−４アルキルでエステル化されていてもよいカルボキシル基、
（C）リン酸基、
（D）スルホン酸基、
（E）Ｃ_１−６アルキル又はＣ_７−１０アリールアルキルで置換されていてもよいスルホンアミド基、
（F）上記（A）、（B）、（C）、（D）又は（E）で置換されていてもよいＣ_１−３アルキル又はＣ_２−５アルケニル、
（G）Ｃ_１−３アルキルでモノ又はジ−置換されていてもよいアミノ基、
（H）ピペリジン、ピロリジン、モルホリン、チオモルホリン、４−メチルピペラジン、４−ベンジルピペラジン又は４−フェニルピペラジンから導かれる環状アミノ基、
（I）シアノ基、
（J）カルバモイル基、
（K）オキソ、
（L）Ｃ_１−３アルコキシ、
（M）テトラゾリル又は２,５−ジヒドロ−５−オキソ−１,２,４−オキサジアゾリルから導かれる複素環基及び
（N）Ｃ_６−１０アリールスルホニル、Ｃ_１−４アルキルスルホニル又はＣ_７−１４アリールアルキルスルホニルで置換されていてもよいカルバモイル基より選ばれる1ないし4個の置換基を有していてもよい〕である化合物；
Ｒ_ｂが２，２−ジメチル−３−ヒドロキシプロピル基である化合物；などが好ましい。
前記式中、Ｒ_ｂで示される低級アルキル基としては、メチル，エチル，ｎ−プロピル，イソプロピル，ｎ−ブチル，イソブチル，ｎ−ペンチル，イソペンチル，ネオペンチル，ヘキシル等Ｃ_１−６アルキルが挙げられる。なかでも、Ｃ_３−６アルキル基が好ましく、Ｃ_４−５アルキル基がより好ましい。とりわけイソブチル，ネオペンチル等の分枝状Ｃ_４−５アルキル基が好ましい。
Ｒ_ｂで示される低級アルキルの置換基としては例えば炭素数Ｃ_２−２０アルカノイル又はＣ_１−７アルキルで置換されていてもよい水酸基などが挙げられる。このような置換基としては例えば水酸基，アセチルオキシ，プロピオニルオキシ，ｔｅｒｔ−ブトキシカルボニルオキシ，パルミトイルオキシ，ジメチルアミノアセチルオキシ及び２−アミノプロピオニルオキシ等が挙げられる。
このような置換基は置換可能な位置に１〜３個置換していてもよい。
さらに、Ｒ_ｂで示される置換されていてもよい低級アルキルとしては例えば、２,２−ジメチル−３−ヒドロキシプロピル，３−ヒドロキシ−２−ヒドロキシメチル−２−メチルプロピル，３−アセトキシ−２,２−ジメチルプロピル，３−アセトキシ−２−ヒドロキシメチル−２−メチル−プロピル及び３−アセトキシ−２−アセトキシメチル−２−メチルプロピル等が挙げられる。
Ｘ_ｂで示される置換されていてもよいカルバモイル基は式

で表される基のようなものが挙げられる。 The compound represented by the formula (I) includes the compound represented by the formula (Ib)

The compound represented by is preferred.
As the compound represented by the formula (Ib),
R _b is hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, to 1 selected from dimethylamino acetyloxy and 2-amino-propionyloxy may have three substituents C ₁ A compound which is _-6 alkyl;
A branch in which R _b may have 1 to 3 substituents selected from a hydroxyl group, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; A C _3-6 alkyl in the form of:
_Rb is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2- A compound which is methylpropyl or 3-acetoxy-2-acetoxymethyl-2-methylpropyl;
A compound wherein R _1b is methyl;
Compounds wherein W is a chlorine atom;
X _b is the formula

[Wherein, R _2b and R _3b are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group, or R _2b and R _3b are adjacent nitrogen atoms. Together with the atom, a 5- or 6-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted may be substituted. A compound represented by the formula:
In the group represented by _Xb ,
R _2b represents a hydrogen atom or a C _1-7 alkyl group,
R _3b is (1) (a) C _1-7 alkyl, (b) C _3-7 cycloalkyl, (c) C _2-6 alkenyl, (d) C _6-10 aryl and (e) C _6-10 A hydrocarbon group selected from aryl-C _1-4 alkyl [where (a) C _1-7 alkyl, (b) C _3-7 cycloalkyl and (c) C _2-6 alkenyl are each (i) C _{1 A} carboxyl group which may be esterified with _-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(Ii) a phosphate group optionally mono- or di-substituted with C _1-6 alkyl or C _2-7 alkanoyloxy-C _1-6 alkyl,
(Iii) sulfonic acid group,
(Iv) a sulfonamide group optionally substituted with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(V) a hydroxyl group which may be alkylated with C _1-3 alkyl,
(Vi) a sulfhydryl group optionally alkylated with C _1-3 alkyl,
(Vii) a carbamoyl group,
(Viii) phenyl optionally substituted with 1 to 5 substituents selected from hydroxyl, chlorine, fluorine, aminosulfonyl and amino optionally mono- or di-substituted by _C1-3alkyl. Group,
(Ix) an amino group optionally mono- or di-substituted with C _1-3 alkyl,
(X) C _1-3 alkyl derived from piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline or phthalimide; A cyclic amino group optionally substituted with benzyl or phenyl and (xi) 1 to 4 substituents selected from aromatic 5- to 6-membered heterocyclic groups derived from pyridine, imidazole, indole or tetrazole; May be
(D) C _6-10 aryl and (e) C _6-10 aryl-C _1-4 alkyl are each (i) a carboxyl group which may be esterified with C _1-4 alkyl;
(Ii) a phosphate group optionally mono- or di-substituted with C _1-6 alkyl or C _2-7 alkanoyloxy-C _1-6 alkyl,
(Iii) sulfonic acid group,
(Iv) C _1-4 alkylsulfonyl, C _6-10 arylsulfonyl or C _6-10 aryl-C _1-4 alkylsulfonyl group,
(V) a sulfonamide group optionally substituted with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(Vi) a carboxyl group which may be esterified with C _1-4 alkyl, a phosphoric acid group which may be mono- or di-substituted with C _1-6 alkyl, a sulfonic group, a C _1-4 alkylsulfonyl, Substituted with a C _6-10 arylsulfonyl or C _6-10 aryl-C _1-4 alkylsulfonyl group, a sulfonamide group _optionally substituted with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl Which may have 1 to 4 substituents selected from C _1-3 alkyl groups and (vii) halogen.
(2) tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo -1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro- 5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2, 4-tetrazolyl or 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl group, or (3) (i) a C _2-7 alkanoyl group optionally substituted with one or two halogens, And (ii) C _1-3 alkyl, C C _6-10 arylsulfonyl group, C _1-4 alkylsulfonyl group or C _6-10 aryl-C _1-4 alkyl optionally substituted with 1 to 4 substituents selected from _1-3 alkoxy and halogen Indicates an acyl group selected from a sulfonyl group,
Or R _2b and R _3b are a 5- or 6-membered ring derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine, 2,6-dioxopiperazine, morpholine or thiomorpholine together with an adjacent nitrogen atom [here Wherein the 5- or 6-membered ring is (A) a hydroxyl group which may be substituted with C _1-3 alkyl or C _2-7 alkanoyl,
(B) a carboxyl group which may be esterified with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(C) a phosphate group which may be mono- or di-substituted with C _1-6 alkyl or C _2-7 alkanoyloxy-C _1-6 alkyl,
(D) sulfonic acid group,
(E) a sulfonamide group optionally substituted with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(F) a carboxyl group which may be esterified with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl, C _1-6 alkyl or C _2-7 alkanoyloxy-C _1-6 alkyl. A mono- or di-substituted phosphoric acid group, a sulfonic acid group, a C _1-6 alkyl or a C _6-10 aryl-C _1-4 alkyl _optionally substituted with a sulfonamide group, C _1-3 A hydroxyl group optionally substituted with alkyl or C _2-7 alkanoyl, a sulfhydryl group optionally substituted with C _1-3 alkyl, a carbamoyl group, and a hydroxyl group, halogen, aminosulfonyl and C _1-3 alkyl is 1 selected from an amino group optionally to 5 phenyl which may be substituted with a substituent, a mono- or di-by C _1-3 alkyl - substituted Which may be substituted with also an amino group or tetrazolyl optionally C _1-6 alkyl and C _2-5 alkenyl,
(G) an amino group optionally mono- or di-substituted with C _1-3 alkyl,
(H) a cyclic amino group derived from piperidine, pyrrolidine, morpholine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine, or 4-phenylpiperazine,
(I) a cyano group,
(J) a carbamoyl group,
(K) an oxo group,
(L) tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl group,
(M) a carbamoyl group optionally substituted with C _6-10 arylsulfonyl, C _1-4 alkylsulfonyl or C _6-10 aryl-C _1-4 alkylsulfonyl;
(N) a sulfhydryl group optionally alkylated with C _1-3 alkyl,
And (O) a phenyl group optionally substituted with 1 to 5 substituents selected from a hydroxyl group, a halogen, an aminosulfonyl and an amino group optionally substituted with a _C1-3 alkyl. Which may have one or more substituents].
In the group represented by _Xb ,
R _2b and R _3b together with the nitrogen atom of the adjacent carbamoyl group form a 5- or 6-membered ring derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine or 2,6-dioxopiperazine, The 5- or 6-membered ring is (i) a carboxyl group which may be esterified with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl, respectively.
(Ii) a phosphate group optionally mono- or di-substituted with C _1-6 alkyl or C _2-7 alkanoyl-C _1-6 alkyl,
(Iii) sulfonic acid group,
(Iv) a sulfonamide group optionally substituted with C _1-6 alkyl or C _6-10 aryl-C _1-4 alkyl,
(V) a hydroxyl group which may be alkylated at C _1-3 ,
(Vi) a sulfhydryl group optionally alkylated with C _1-3 alkyl,
(Vii) a carbamoyl group,
(Viii) a phenyl group optionally substituted with 1 to 5 substituents selected from a hydroxyl group, halogen, aminosulfonyl and an amino group optionally substituted with _C1-3 alkyl,
(Ix) an amino group optionally mono- or di-substituted with C _1-3 alkyl,
And (x) a compound which is a ring which may be substituted by a C _1-6 alkyl group which may have 1 to 2 substituents selected from a tetrazolyl group;
In the group represented by _Xb ,
A compound wherein R _2b is a hydrogen atom or C _1-7 alkyl, and R _3b is C _1-4 alkylsulfonyl;
The heterocyclic group represented by _Xb is tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3 A compound which is -oxo-1,2,4-tetrazolyl or 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl;
R _1b is methyl,
W is a chlorine atom,
A branched C in which _Rb is substituted with one to three substituents selected from a hydroxyl group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; _3-6 alkyl,
X _b is the formula

[In the formula, R _{2b ′} represents a hydrogen atom or C _1-7 alkyl, and R _{3b ′} represents C _1-4 alkyl. A compound represented by the formula:
R _1b is methyl,
W is a chlorine atom,
A branched C in which _Rb is substituted with one to three substituents selected from a hydroxyl group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; _3-6 alkyl,
X _b is the formula

[In the formula, R _b ′ represents a hydrogen atom or C _1-7 alkyl, and n represents an integer of 1 to 5. A compound represented by the formula:
R _1b is methyl,
W is a chlorine atom,
A branched C in which _Rb is substituted with one to three substituents selected from a hydroxyl group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; _3-6 alkyl,
X _b is the formula

[Wherein R ″ represents a hydrogen atom or C _1-4 alkyl].
R _1b is methyl,
W is a chlorine atom,
A branched C in which _Rb is substituted with one to three substituents selected from a hydroxyl group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; _3-6 alkyl,
A compound wherein X _b is tetrazolyl;
R _b is lower alkyl optionally substituted with one or two hydroxyl groups,
X _b is (1) (a) C _1-7 alkyl, (b) C _3-7 cycloalkyl, (c) C _2-6 alkenyl, (d) C _6-10 aryl and (e) C _7-14 A hydrocarbon group selected from arylalkyl [where (a) C _1-7 alkyl, (b) C _3-7 cycloalkyl, and (c) C _2-6 alkenyl are (i) C _1-6 alkyl or C _A carboxyl group which may be esterified with a _7-10 arylalkyl,
(Ii) a phosphate group,
(Iii) sulfonic acid group,
(Iv) a sulfonamide group optionally substituted with C _1-6 alkyl or C _7-10 arylalkyl;
(V) a hydroxyl group which may be alkylated with C _1-3 alkyl,
(Vi) a sulfhydryl group optionally alkylated with C _1-3 alkyl,
(Vii) a carbamoyl group,
(Viii) a phenyl group which may be substituted with a substituent selected from a hydroxyl group, a chlorine atom, a fluorine atom, an aminosulfonyl and an amino group which may be mono- or di-substituted with C _1-3 alkyl;
(Ix) an amino group optionally mono- or di-substituted with C _1-3 alkyl,
And (x) a cyclic amino optionally substituted with C _1-3 alkyl, benzyl or phenyl derived from piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine or 4-phenylpiperazine. A group and (xi) 1 to 4 substituents selected from aromatic 5- to 6-membered heterocyclic groups derived from pyridine, imidazole, indole or tetrazole;
(D) C _6-10 aryl and (e) C _7-14 arylalkyl are each (i) a carboxyl group which may be esterified with C _1-4 alkyl,
(Ii) a phosphate group,
(Iii) sulfonic acid group,
(Iv) a sulfonamide group optionally substituted with C _1-6 alkyl or C _7-10 arylalkyl;
(V) a carboxyl group, a phosphoric acid group, a sulfonic acid group, which may be esterified with C _1-4 alkyl, a sulfonamide group which may be substituted with C _1-6 alkyl or C _7-10 arylalkyl. A C _1-3 alkyl group which may be substituted or (vi) may have 1 to 4 substituents selected from a halogen atom].
(2) tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo -1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro- 5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2, 4-tetrazolyl or 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl group,
(3) (i) a _C2-7 alkanoyl group optionally substituted by one or two halogens, and (ii) one to four selected from _C1-3 alkyl, _C1-3 alkoxy and halogen A carbamoyl which may be substituted with an acyl group selected from a C _6-10 arylsulfonyl group, a C _1-4 alkylsulfonyl group or a C _7-14 arylalkylsulfonyl group which may be substituted with a substituent of
Or (4) a cyclic aminocarbonyl group derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine, 2,6-dioxopiperazine, morpholine and thiomorpholine [where the cyclic aminocarbonyl group is (A) a hydroxyl group,
(B) a carboxyl group which may be esterified with C _1-4 alkyl,
(C) a phosphate group,
(D) sulfonic acid group,
(E) a sulfonamide group optionally substituted with C _1-6 alkyl or C _7-10 arylalkyl,
(F) C _1-3 alkyl or C _2-5 alkenyl _optionally substituted with (A), (B), (C), (D) or (E),
(G) an amino group optionally mono- or di-substituted with C _1-3 alkyl,
(H) a cyclic amino group derived from piperidine, pyrrolidine, morpholine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine or 4-phenylpiperazine,
(I) a cyano group,
(J) a carbamoyl group,
(K) oxo,
(L) _C1-3 alkoxy,
(M) a heterocyclic group derived from tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl and (N) C _6-10 arylsulfonyl, C _1-4 alkylsulfonyl or C _7-14 Arylalkylsulfonyl, which may have 1 to 4 substituents selected from carbamoyl groups which may be substituted].
A compound wherein R _b is a 2,2-dimethyl-3-hydroxypropyl group; and the like.
In the above formula, examples of the lower alkyl group represented by R _b include C _1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl. Among them, a C _3-6 alkyl group is preferred, and a C _4-5 alkyl group is more preferred. Particularly, a branched C _4-5 alkyl group such as isobutyl and neopentyl is preferred.
Examples of the substituent of the lower alkyl represented by R _b include a hydroxyl group which may be substituted with C _2-20 alkanoyl or C _1-7 alkyl. Examples of such a substituent include a hydroxyl group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy.
One to three such substituents may be substituted at substitutable positions.
Examples of the optionally substituted lower alkyl represented by R _b include, for example, 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2, 2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methyl-propyl, 3-acetoxy-2-acetoxymethyl-2-methylpropyl and the like.
The optionally substituted carbamoyl group represented by _Xb is represented by the formula

And the like.

As the “optionally substituted hydrocarbon” for R _2b and R _3b , an _optionally substituted C _1-7 linear or branched alkyl group (for example, methyl, ethyl, n-propyl) , Isopropyl, n-butyl, isobutyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, neopentyl, hexyl, heptyl), an optionally substituted C _3-7 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, etc.) ), straight-chain or branched alkenyl group optionally C _2-6 substituted (e.g. For example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1 -Butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl , 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.), an optionally substituted C _6-10 aryl group (eg, phenyl, naphthyl group) and an optionally substituted C _7-14 arylalkyl group ( For example, benzyl, phenethyl, naphthylmethyl) and the like.

The “optionally substituted C _1-7 linear or branched alkyl group, an optionally substituted C _3-7 cycloalkyl group, and a C _2-6 linear or branched alkenyl group. Examples of the substituent for the “group” include a C _1-6 alkyl group or a C _6-10 aryl-C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl, benzyl, etc.) A carboxyl group which may be esterified with C _1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.) or acetyloxymethyl , pivaloyloxymethyl C _2-7 alkanoyloxy -C _1-6 alkyl mono- or di-such as a methyl group - optionally substituted phosphoric acid , A sulfonic acid _group, an alkyl group or a _{C 6-10} aryl _{-C 1-4} alkyl _{C 1-6} (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, benzyl, etc.) optionally substituted with A sulfonamide group, a hydroxyl group which may be alkylated with a C _1-3 alkyl group (eg, methyl, ethyl, propyl, etc.) and a sulfhydryl group, a carbamoyl group, 1 to 5 substituents [for example, a hydroxyl group chlorine, fluorine, aminosulfonyl group, an alkyl group of C _1-3 (e.g., methyl, ethyl, propyl, etc.) optionally substituted phenyl group is also an amino group] be substituted by, C _1-3 An amino group which may be mono- or di-substituted with an alkyl group (e.g., methyl, ethyl, propyl, etc.) and a cyclic amino group (e.g., piperi Emissions, pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline, _{C 1-3} alkyl derived from cyclic amines phthalimide , A 5- or 6-membered cyclic amino group which may be substituted with benzyl, phenyl and the like, and which may further contain an oxygen atom and a sulfur atom as ring-constituting atoms) and a hetero atom selected from N, O and S An aromatic 5- to 6-membered heterocyclic ring containing 1 to 4 (for example, pyridine, imidazole, indole, tetrazole and the like) can be mentioned.

Further, a C _6-10 aryl group and a C _6-10 aryl-C ₁ as substituents of an _optionally substituted amino group forming a carbamoyl group of the “optionally substituted carbamoyl group” represented by _Xb the substituent _-4 alkyl _group, an alkyl group of _{C 1-4} (e.g., methyl, ethyl, propyl, tert- butyl group, etc.) esterified carboxyl group which may _{be, C 1-6} alkyl (e.g. , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl) or a _C2-7 alkanoyloxy-C such as a pivaloyloxymethyl group or an acetyloxymethyl group. mono- or di at _1-6 alkyl group - optionally substituted phosphoric acid group, a sulfonic acid group, C _1-4 alkylsulfamoyl _{Alkylsulfonyl, C 6-10} arylsulfonyl or _{C 6-10} aryl _{-C 1-4 alkylsulfonyl,} alkyl or _{C 6-10} Ali _{C 1-6} - Le _{-C 1-4} alkyl group (e.g., methyl, ethyl , Propyl, isopropyl, butyl, tert-butyl, benzyl, etc.), a sulfonamide group optionally substituted with a carboxyl group optionally esterified with a _C1-4 alkyl group, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, n- pentyl, isopentyl, neopentyl, by _{C 2-7} alkanoyloxy _{-C 1-6} alkyl group such as an alkyl group or a pivaloyloxymethyl group _{C 1-6} hexyl, etc. mono- or di-optionally substituted phosphoric acid group, a sulfonic acid group and _{C 1-6 alkyl, C 6-10} ant - -C _1-4 alkyl substituted by good C _1-3 substituted in good sulfonamide group optionally alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), halogen (e.g., fluorine, chlorine) And the like.
The "hydrocarbon group" may have 1 to 5 substituents at substitutable positions.

The “optionally substituted heterocyclic group” represented by R _2b and R _3b may have 1 to 2 (preferably 1) substituents such as an oxo group and a thioxo group, and Heterocyclic groups having a deprotonatable hydrogen atom are preferred. Such a heterocyclic group is preferably a 5- to 6-membered heterocyclic group containing 1 to 4, preferably 2 to 3, hetero atoms selected from S, O and N. Specifically, tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3- Oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro -5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2 , 4-tetrazolyl and 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl. Particularly, a tetrazolyl group is preferable.

The “acyl group” represented by R _2b and R _3b has a carboxylic acid acyl group derived from a carboxylic acid (for example, a C _2-7 carboxylic acid acyl group such as acetyl, propionyl, butyryl, benzoyl) and a substituent. to have a good _{C 6-10} arylsulfonyl be _{group, C 1-4} alkylsulfonyl group and a _{C 6-10} ant - Le _{-C 1-4} alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, phenylsulfonyl, naphthylsulfonyl , Phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl, naphthylethylsulfonyl, etc.). Examples of the substituent of the aryl, alkyl- and arylalkylsulfonyl groups include C ₁ -C ₃ alkyl (eg, methyl, ethyl, propyl, etc.), C _1-3 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), halogen ( Examples thereof include chlorine, fluorine, and bromine), which may be substituted at 1 to 4, preferably 1 to 2 substitutable positions.
The above carboxylic acid acyl group may have one or two halogens (eg, chlorine, fluorine, bromine) as substituents.

R _2b and R _3b are cyclic amino groups which may be substituted with a C _1-3 alkyl or C _2-7 alkanoyl formed together with a nitrogen atom of an adjacent carbamoyl, for example, piperazine, piperidine , Pyrrolidine, piperazin-2-one, piperazine-2,6-dione, morpholine, thiomorpholine and the like, further comprising 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen Examples thereof include a group derived from a 5- or 6-membered cyclic amine which may be contained as a ring-constituting atom. These cyclic amino groups may have 1 to 4, preferably 1 to 2 substituents. Examples of the substituent include a hydroxyl group which may be substituted with C _1-3 alkyl or C _2-7 alkanoyl, a C _1-4 alkyl group (for example, methyl, ethyl, propyl, tert-butyl group and the like) or C Carboxyl group, C _1-6 alkyl or C _2-7 alkanoyloxy-C _1-6 alkyl group which may be esterified with _7-10 arylalkyl (for example, acetyloxymethyl group, pivaloyloxymethyl group) A phosphoric acid group, a sulfonic acid group and a C _1-6 alkyl group or a C _6-10 aryl-C _1-4 alkyl group which may be mono- or di-substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, good sulfonamido group optionally substituted with benzyl or the like), _{"C 1-6} alkyl or _{C 6-10} ant - le - _1-4 alkyl esterified carboxyl group which may _{be, C 1-6} alkyl or _{C 2-7} alkanoyloxy _{-C 1-6} alkyl group (e.g., acetyloxy methyl group, a pivaloyloxymethyl group) A phosphoric acid group, a sulfonic acid group which may be mono- or di-substituted, a sulfonamide group optionally substituted with a C _1-6 alkyl or a C _6-10 aryl-C _1-4 alkyl, _A hydroxyl group optionally substituted with _1-3 alkyl or C _2-7 alkanoyl, a sulfhydryl group optionally substituted with C _1-3 alkyl, a carbamoyl group, and 1 to 5 substituents (for example, a hydroxyl group, halogen, aminosulfonyl, C _1-3 phenyl optionally substituted by alkyl, such as an amino group which may be substituted with), C _1-3 alkyl Mono- or di - substituted by an amino group optionally or tetrazolyl "which may be C _1-6 alkyl and C _2-5 alkenyl substituted with alkyl groups of C _1-3 (e.g., methyl, ethyl, propyl, etc. )), A C ₁ group such as an amino group or a cyclic amino group which may be mono- or di-substituted (for example, piperidine, pyrrolidine, morpholine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, etc.) -C ₃ alkyl, benzyl, may be substituted by phenyl, further nitrogen atom, a sulfur atom, group derived selected heteroatoms from which may contain 5- or 6-membered cyclic amine from an oxygen atom), cyano group, a carbamoyl group, oxo _{group, C 1-3} alkoxy (e.g., methoxy, ethoxy, ethylenedioxy, etc.), the Heterocyclic group which may be substituted with an oxo group or a thioxo group having a hydrogen atom capable of being deprotonated (for example, tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl) etc.), C _6-10 arylsulfonyl exemplified as the substituent of "optionally substituted carbamoyl group" optionally substituted amino group forming carbamoyl of represented by X, C _6-10 ant - Le _-C1-4 alkylsulfonyl and _C1-4 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, phenyl, sulfonyl, benzylsulfonyl, etc.), _C1-3 A sulfhydryl group or one that may be alkylated with alkyl 5 substituents (e.g., hydroxyl, halogen, amino, etc. alkylsulfonyl and C _1-3 alkyl optionally substituted with amino group) carbamoyl groups substituted with phenyl optionally substituted with the like.

等が挙げられる。
Ｒ_２ｂ’及びＲ_ｂ’としては水素原子及びＣ_１−７アルキル等が挙げられる。とりわけ水素原子が好ましい。
Ｒ_２ｂ，Ｒ_２ｂ'及びＲ_ｂ'で表されるＣ_１−７アルキルとしては前記の「炭化水素基」のＣ_１−７アルキルと同様のものが挙げられる。
Ｒ”としては水素原子及びＣ_１−４アルキル等が挙げられる。とりわけ水素原子が好ましい。
Ｒ_３ｂ'及びＲ"で表されるＣ_１−４アルキルとしては例えばメチル、エチル、プロピル、イソプロピル、ｎ−ブチル、ｔｅｒｔ−ブチル等が挙げられる。 Examples of the optionally substituted carbamoyl group represented by _Xb include, for example,

And the like.
_{Examples of} R _{2b ′} and R _{b ′} include a hydrogen atom and C _1-7 alkyl. Particularly, a hydrogen atom is preferable.
R _2b, as the _{C 1-7} alkyl represented by _{R 2b 'and R b'} are the same as those of the _{C 1-7} alkyl of "hydrocarbon group" of the.
Examples of R "include a hydrogen atom and _C1-4 alkyl. A hydrogen atom is particularly preferred.
Examples of the C _1-4 alkyl represented by R _{3b ′} and R ″ include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and the like.

Examples of the optionally substituted heterocyclic group having a deprotonatable hydrogen atom represented by _Xb include a nitrogen-containing (preferably containing 1 to 4 nitrogen atoms) having a Bronsted acid-active proton. It is preferably a membered heterocyclic ring, and preferably contains 1 to 4, preferably 2 to 3, nitrogen, sulfur and oxygen atoms. These substituents include an oxo group, a thioxo group and the like, and may have one or two, particularly one, of these substituents. Examples of the "optionally substituted heterocyclic group having a deprotonatable hydrogen atom" represented by X include X such as tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl. And the like as the "optionally substituted heterocyclic group" as a substituent of the "optionally substituted carbamoyl group".
_Examples of the “lower alkyl group” represented by R _1b include C ₁ -C ₆ alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, and hexyl. Particularly, a C ₁ -C ₃ alkyl group is preferable. As R _1b , a methyl group is particularly preferred from the aspect of pharmacological activity.
The “halogen atom” represented by W includes chlorine, fluorine, bromine and iodine atoms. Particularly, a chlorine atom is preferable.

Examples of the salt of the compound represented by the formula (Ib) include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, such as acetate, tartrate, citrate and fumaric acid. Organic salts such as salts, maleates, toluenesulfonates, and methanesulfonates, for example, metal salts such as sodium, potassium, calcium, and aluminum salts, for example, triethylamine, guanidine, ammonium, and hydrazine salts And pharmaceutically acceptable salts such as salts of bases such as quinine salt and cinchonine salt.
Hydrates and non-hydrates of the compound represented by the formula (Ib) are also included in the present invention.
The compound represented by the formula (Ib) or a salt thereof has asymmetric carbons at the 3- and 5-positions, but the substituents at the 3- and 5-positions are opposite to the surface of the 7-membered ring. In particular, a trans isomer, which is an isomer, is preferable, and an absolute configuration at the 3-position and an absolute configuration at the 5-position of the S-configuration are particularly preferable.

The following are specifically preferred as the compound represented by the formula (Ib) or a salt thereof.
N-methanesulfonyl-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide,
N-methanesulfonyl-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -2-oxo-1 , 2,3,5-Tetrahydro-4,1-benzoxazepin-3-yl] acetamide,
N- [2- (pyrrolidin-1-yl) ethyl]-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2 -Methylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide,
N- [2- (pyrrolidin-1-yl) ethyl]-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl ) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide;

N-methanesulfonyl-[(3R, 5S) -1- [3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide,
N-methanesulfonyl-[(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1 , 2,3,5-Tetrahydro-4,1-benzoxazepin-3-yl] acetamide,
N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid,
N-[[(3R, 5S) -1- (3-hydroxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid,
N-[[(3R, 5S) -1- (2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro- 4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid,
N-[[(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2 , 3,5-Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid,
N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid ethyl ester,
N-[[(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2 , 3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid ethyl ester,

(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -1,2,3,5-tetrahydro-3- [1H (Or 3H) -tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one,
(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -1,2,3,5-tetrahydro-3 -[1H (or 3H) -tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one,
(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl-7-chloro-5- (2,3-dimethoxyphenyl) -1,2,3,5-tetrahydro-3- [1H ( Or 3H) -tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one;
(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -1,2,3,5-tetrahydro-3 -[1H (or 3H) -tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one,
N- [2- (pyrrolidin-1-yl) ethyl]-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3 , 5-Tetrahydro-4,1-benzoxazepin-3-yl] acetamide; and the like

  The compound represented by the formula (Ib) or a salt thereof is described, for example, in EPA 567 026, WO 95/21834 (PCT application based on Japanese Patent Application No. 6-15531), EPA 645377 (application based on Japanese Patent Application No. 6-229159), It can be produced according to a method disclosed in Japanese Patent Application Publication Nos. EPA 645378 (application based on Japanese Patent Application No. 6-229160) and WO9710224, or a method analogous thereto.

で表される化合物が好ましい。
式（Ic）で表わされる化合物としては、
Ｒ^１ｃが３−カルボキシプロピル基、１−カルボキシエチル基、それぞれ置換基を有していてもよいＣ_３−６直鎖アルキル−スルホニル基、（カルボキシ−Ｃ_５−７シクロアルキル）−Ｃ_１−３アルキル基、（カルボキシフリル）−アルキル基、カルボキシ−Ｃ_６−１０アリール基、（カルボキシ−Ｃ_２−３アルキル）−Ｃ_６−１０アリール基または（カルボキシ−Ｃ_１−３アルキル）−Ｃ_７−１４アラルキル基である化合物；
Ｒ^１ｃが置換基を有していてもよい（カルボキシ−Ｃ_１−４アルキル）−Ｃ_６−１０アリール基である化合物；
Ｒ^１ｃが置換基を有していてもよい（カルボキシ−Ｃ_２−３アルキル）−Ｃ_６−１０アリール基である化合物；
Ｒ^１ｃが置換基を有していてもよい（カルボキシ−Ｃ_２−3アルキル）−フェニル基である化合物；
Ｒ^１ｃが置換基を有していてもよい（カルボキシフリル）−アルキル基である化合物；
Ｒ^２ｃがアルカノイルオキシ基および／または水酸基を有するＣ_３−６アルキル基である化合物；
Ｒ^２ｃが水酸基、アセトキシ、プロピオニルオキシ、ｔｅｒｔ−ブトキシカルボニルオキシおよびパルミトイルオキシから選ばれた１ないし３個の置換基を有していてもよいＣ_３−６アルキル基である化合物；
Ｒ^２ｃが２，２−ジメチルプロピル、３−ヒドロキシ−２，２−ジメチルプロピルまたは３−アセトキシ−２，２−ジメチルプロピルである化合物；
Ｒ^３ｃがメチル基である化合物；
Ｗが塩素原子である化合物；
３位がＲ−配位で５位がＳ−配位である化合物；などが好ましい。 The compound represented by the formula (I) includes the compound represented by the formula (Ic)

The compound represented by is preferred.
As the compound represented by the formula (Ic),
R ^1c is a 3-carboxypropyl group, a 1-carboxyethyl group, a C _3-6 linear alkyl-sulfonyl group optionally having a substituent, (carboxy-C _{5-7cycloalkyl} ) -C _{1- 3} alkyl group, (carboxyfuryl) -alkyl group, carboxy-C _6-10 aryl group, (carboxy-C _2-3 alkyl) -C _6-10 aryl group or (carboxy-C _1-3 alkyl) -C _{7 A} compound which is a _-14 aralkyl group;
A compound wherein R ^1c is an ^optionally substituted (carboxy-C _1-4 alkyl) -C _6-10 aryl group;
A compound wherein R ^1c is an ^optionally substituted (carboxy-C _2-3 alkyl) -C _6-10 aryl group;
A compound in which R ^1c is an ^optionally substituted (carboxy-C _2-3 alkyl) -phenyl group;
A compound in which R ^1c is an ^optionally substituted (carboxyfuryl) -alkyl group;
A compound wherein R ^2c is a C _3-6 alkyl group having an alkanoyloxy group and / or a hydroxyl group;
A compound wherein R ^2c is a C _3-6 alkyl group _optionally having 1 to 3 substituents selected from a hydroxyl group, acetoxy, propionyloxy, tert-butoxycarbonyloxy and palmitoyloxy;
A compound wherein R ^2c is 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl or 3-acetoxy-2,2-dimethylpropyl;
A compound wherein R ^3c is a methyl group;
Compounds wherein W is a chlorine atom;
A compound in which the 3-position is R-coordination and the 5-position is S-coordination;

In the above formula, R ^1c is a 1-carboxyethyl group which may have a substituent, a carboxy-C _3-6 linear alkyl group which may have a substituent, or a group which has a substituent. good _{C 3-6} linear alkyl - sulfonyl group, which may have a substituent (carboxy _{-C 5-7 cycloalkyl) -C 1-3} alkyl group, or a group of the formula -X ^1c -X ^2c, -Ar- X ^3c -X ^4c -COOH (wherein, X ^1c and X ^4c each represent a bond or a C _1-4 alkylene group which may have a substituent, X ^2c and X ^3c each represent a bond,- O— or —S—, and Ar represents a divalent aromatic ring group which may have a substituent, provided that when X ^1c is a bond, X ^2c is a bond and X ^4c is when bonds, a group represented by X ^3c represents a bond) shows .
The _{C 3-6} linear alkyl group in the optionally carboxy _{-C 3-6} straight-chain alkyl group which may have a substituent group represented by R ^1c, n- propyl, n- butyl, n- pentyl, n- Hexyl. Of these, n-propyl and n-butyl are preferred, and n-propyl is more preferred.
It may have a substituent group represented by R ^1c _{C 3-6} linear alkyl - as a _{C 3-6} straight-chain alkyl group in the sulfonyl group, n- propyl, n- butyl, n- pentyl, n- Hexyl. Of these, n-propyl and n-butyl are preferred, and n-propyl is more preferred.
^Examples of the C _5-7 cycloalkyl group in the (carboxy-C _5-7 cycloalkyl) -C _1-3 alkyl group which may have a substituent represented by R ^1c include cyclopentyl, cyclohexyl, and cycloheptyl. Can be Of these, cyclopentyl and cyclohexyl are preferred, and cyclohexyl is more preferred.
The _{C 1-3} alkyl group in the substituent may have a (carboxy _{-C 5-7 cycloalkyl) -C 1-3} alkyl group represented by R ^1c, methyl, ethyl, n- propyl, isopropyl Is mentioned. Of these, methyl and ethyl are preferred, and methyl is more preferred.
In the group represented by the formula —X ^1c —X ^2c —Ar—X ^3c —X ^4c —COOH as R ^1c , “optionally substituted C _1-4 represented by X ^1c and X ^4c As the “C _1-4 alkylene group” in the “alkylene group”, for example, methylene, dimethylene, trimethylene, tetramethylene and the like can be mentioned, and a C _1-3 alkylene group is preferable, and among them, a linear alkylene group is preferably used. Can be
Examples of the “divalent aromatic ring group” in the “optionally substituted bivalent aromatic ring group” represented by Ar include, for example, a divalent aromatic hydrocarbon group and a divalent aromatic heterocyclic group. And a ring group.
Here, the divalent aromatic hydrocarbon group includes, for example, a group formed by removing one hydrogen atom from a C _6-10 aryl group (eg, phenyl, naphthyl, etc.). As a valent aromatic hydrocarbon group, phenylene is preferably used.
Examples of the divalent aromatic heterocyclic group include, as atoms (ring atoms) constituting a ring system, 1 to 3 (preferably 1 to 2) hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. And a group formed by removing one hydrogen atom from an aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of the same.
Here, as the aromatic heterocyclic group, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 5- to 6-membered aromatic monocyclic heterocyclic groups (preferably furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl and the like) such as pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and for example, benzofuranyl, isobenzofuranyl, benzo [B] thienyl, indolyl, isoindolyl, 1 H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, fenoxathiinyl, thianthrenyl, phenatrilinyl, phenatronilonyl, phenatronilonyl, phenatronilonyl, phenatronilonyl, phenatronilonyl 2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyrid 8- to 12-membered members such as dazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl An aromatic condensed heterocyclic group (preferably, a heterocyclic ring in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring or the 5- or 6-membered aromatic monocyclic heterocyclic group described above; Heterocycle in which two identical or different heterocycles are condensed, more preferably the above-mentioned heterocycle in which a 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring) and the like.

May have a "substituent represented by and Ar; represented by X ^1c and X ^4c" C _1-4 alkylene group "of the" optionally C _1-4 alkylene group which may have a substituent " Examples of the substituent that the “divalent aromatic ring group” in the “divalent aromatic ring group” may have include (i) a C _1-6 alkyl group or a C _6-10 aryl-C _1-4. A carboxyl group which may be esterified with an alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl, benzyl, etc.), (ii) a C _1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.) or acetoxymethyl, pivaloyloxymethyl group Mono- or di-by C _2-7 alkanoyloxy _{-C 1-6} alkyl - optionally substituted phosphate group, (iii) a sulfonic acid group, _(iv) alkyl or _{C 6-10} aryl _{C 1-6} A sulfonamide group which may be substituted with a _-C1-4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, etc.), (v) a _C1-3 alkyl group (e.g., , Methyl, ethyl, propyl, etc.), a hydroxyl group and a sulfhydryl group, (vi) a carbamoyl group, (vii) 1 to 5 substituents [for example, a hydroxyl group, chlorine, fluorine, aminosulfonyl group, alkyl C _1-3 (e.g., methyl, ethyl, propyl, etc.) may be substituted with also an amino group] be substituted with, via an O or S Bound which may be a phenyl group Te, _(viii) alkyl of _{C 1-3} (e.g., methyl, ethyl, propyl, etc.) mono - or di - amino group which may be substituted, (ix) _{C 1 -3} alkyl (e.g., methyl, ethyl, etc.), benzyl, 1 to 3 optionally substituted cyclic amino group such as phenyl (e.g., piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, 4 A nitrogen atom such as a cyclic amino group derived from a cyclic amine such as benzylpiperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline or phthalimide (excluding one hydrogen atom), an oxygen atom, a sulfur atom, A 5- or 6-membered cyclic amino group which may contain an atom as a ring-constituting atom), (x) 1 to 4 heteroatoms selected from N, O and S. A 5- or 6-membered aromatic heterocyclic group (for example, pyridyl, imidazolyl, indolyl, tetrazolyl, etc.), (xi) a halogen atom (eg, chlorine, fluorine, bromine, iodine, etc.) ), _{(xii) C 1-4 alkoxy, C 1-4} alkylthio group, carboxyl and each substituted group optionally substituted _{C 1-4} alkyl group selected from phenyl (e.g., methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, etc.), a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.) or a C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio) , isopropylthio, butylthio, tert- butylthio, _etc.), (xiii) _{C 5- 7} cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), (xiv) C _1-7 alkanoyloxy (eg, formyloxy, acetoxy, propionyloxy, butyryloxy, t-butoxycarbonyloxy, isobutyryloxy, valeryloxy) , Pivaloyloxy, etc.). Such a substituent may be present at 1 to 6, preferably 1 to 3 at a substitutable position. Also, two substituents may combine to form C _3-6 alkylene, C _3-6 alkyleneoxy, C _3-6 alkylenedioxy and the like. substituents, are attached form a C ₄ alkylene, it will form the tetrahydronaphthalene group.
Specific examples of the group represented by the formula ^{-X 1c -X 2c -Ar-X 3c} -X 4c -COOH as R ^1c is, which may have a substituent (carboxy - heteroaryl) -C _{1 -4} alkyl group (preferably _optionally substituted (carboxy-furyl) -C _1-4 alkyl group), optionally substituted (carboxy-C _6-10 aryl)- A C _1-4 alkyl group, a carboxy-heteroaryl group _optionally having a substituent, a carboxy-C _6-10 aryl group _optionally having a substituent, _optionally having a substituent ( A carboxy-C _1-4 alkyl) -heteroaryl group, an optionally substituted (carboxy-C _1-4 alkyl) -C _6-10 aryl group [preferably, a (carboxy-C _2-3 alkyl) ) _{-C 6- 0} aryl group], which may have a substituent (carboxy _{-C 1-4} alkyl) - heteroaryl _{-C 1-4} alkyl group which may have a substituent (carboxy _{-C 1-4} Alkyl) -C _7-14 aralkyl group (preferably, optionally having a substituent (carboxy-C _1-3 alkyl) -C _7-14 aralkyl group), and optionally having a substituent ( (Carboxy-C _1-4 alkoxy) -C _6-10 aryl group, optionally substituted (carboxy-C _1-4 alkoxy) -C _6-10 aryl-C _1-4 alkyl group, substituent (Carboxy-C _1-4 alkyl) -C _6-10 aryloxy-C _1-4 alkyl group, which may have a substituent (carboxy-C _6-10 aryloxy) -C _1-4 alkyl Group, which may have a substituent (carboxy -C _1-4 alkylthio) - such heteroaryl groups.
Here, examples of the heteroaryl include those similar to the aforementioned “aromatic heterocyclic group”, and the heteroaryl is the same as the substituent that the aforementioned “aromatic heterocyclic group” may have. May have various substituents. As the C _6-10 aryl include phenyl, naphthyl, azulenyl, and phenyl is preferably used, the C _6-10 aryl, and the "aromatic heterocyclic group" may have substituent It may have the same substituent as the group.
Examples of the alkyl group in the (carboxyfuryl) -C _1-4 alkyl group which may have a substituent represented by R ¹ include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1, Examples thereof include a C _1-4 linear or branched alkyl group such as 1-dimethylethyl. Among these, a _C1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl and n-butyl is preferable, and methyl, ethyl and n-propyl are more preferable. Examples of the carboxyfuryl group include 3-carboxy-2-furyl, 4-carboxy-2-furyl, 2-carboxy-3-furyl, 2-carboxy-5-furyl and the like. Of these, 3-carboxy-2-furyl and 4-carboxy-2-furyl are preferred, and 3-carboxy-2-furyl is more preferred.
The _{C 2-3} alkyl in which may have a substituent (carboxy _{-C 2-3 alkyl) -C 6-10} aryl group represented by R ^1c, ethyl, n- propyl, isopropyl and the like, Ethyl, n-propyl is preferred. _{Examples of the} C _6-10 aryl group include phenyl, naphthyl and azulenyl, and phenyl is preferred.
In the (carboxy-C _1-3 alkyl) -C _7-14 aralkyl group which may have a substituent represented by R ^1c , the C _1-3 alkyl group is methyl, ethyl, n-propyl, isopropyl. And methyl and ethyl are preferred, and ethyl is particularly preferred. As the C _7-14 aralkyl group (C _6-10 aryl-C _1-4 alkyl group), phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl , (1-naphthyl) methyl, (2-naphthyl) methyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3- (1-naphthyl) propyl , 4- (1-naphthyl) butyl, 4- (2-naphthyl) butyl, and phenylmethyl, 1-phenylethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl, ( (1-Naphthyl) ethyl and (2-naphthyl) ethyl are preferred, and phenylmethyl and 2-phenylethyl are particularly preferred.
When each of the groups represented by R ^1c has a substituent, examples of the substituent include “a divalent aromatic ring group” in “a divalent aromatic ring group which may have a substituent” represented by Ar. The same substituents as the substituents which may be present are mentioned, and such a substituent may be present at 1 to 6, preferably 1 to 3 at a substitutable position. In each group represented by R ^1c , the carboxyl moiety is preferably unsubstituted, but any moiety other than carboxyl may have a substitutable substituent at a substitutable position.
As R ^1c , a 3-carboxypropyl group, a 1-carboxyethyl group, a C _3-6 linear alkyl-sulfonyl group each optionally having a substituent, (carboxy-C _5-7 cycloalkyl) -C _1-3 alkyl group, (carboxyfuryl) -alkyl group, carboxy-C _6-10 aryl group, (carboxy-C _1-4 alkyl) -C _6-10 aryl group [preferably, (carboxy-C _2-3 Alkyl) -C _6-10 aryl group], (carboxy-C _1-3 alkyl) -C _7-14 aralkyl group and the like, and may have a substituent (carboxy-C _1-4 alkyl)-. C _6-10 aryl group is preferable, more preferably may have a substituent (carboxy _{-C 2-3 alkyl) -C 6-10} aryl group, especially, Which may have a substituent (carboxy -C _2-3 alkyl) - phenyl group is preferred.

Represented by R ^2c, as the _{C 3-6} alkyl group in good _{C 3-6} alkyl group optionally substituted with alkanoyloxy group or a hydroxy group e.g., n- propyl, isopropyl, 1,1-dimethylethyl, n- Butyl, isobutyl, n-pentyl, 2,2-dimethylpropyl, isopentyl, n-hexyl, isohexyl and the like. Of these, isopropyl, 1,1-dimethylethyl, n-butyl, isobutyl, 2,2-dimethylpropyl and isohexyl are preferred, and 2,2-dimethylpropyl is particularly preferred.
Examples of the alkanoyloxy group in the C _3-6 alkyl group optionally substituted with an alkanoyloxy group or a hydroxyl group represented by R ^2c include formyloxy, acetoxy, propionyloxy, butyryloxy, tert-butoxycarbonyloxy, and isobutyi. Riruokishi, valeryloxy, pivaloyloxy, lauryloxy, palmitoyloxy, (preferably, a C _1-7 alkanoyloxy group) C _1-20 alkanoyloxy groups such as stearoyloxy and the like. Of these, acetoxy, propionyloxy, tert-butoxycarbonyloxy, and palmitoyloxy are preferred, and acetoxy is particularly preferred. One to three alkanoyloxy groups or hydroxyl groups may be substituted at substitutable positions.
Preferred examples of the C _3-6 alkyl group optionally substituted with an alkanoyloxy group or a hydroxyl group represented by R ^2c include 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl, and 3-hydroxypropyl. -2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2-acetoxymethyl-2-methylpropyl and the like Is mentioned. Of these, 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-acetoxy-2,2-dimethylpropyl are particularly preferred.
Further, as R ^2c , a C _3-6 alkyl group having an alkanoyloxy group and / or a hydroxyl group is preferable.

^Examples of the lower alkyl group represented by R ^3c include a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, and hexyl. Particularly, a _C1-3 alkyl group is preferable. As R ^3c , a methyl group is particularly preferred from the aspect of pharmacological activity.
Examples of the halogen atom represented by W include chlorine, fluorine, bromine and iodine atoms. Particularly, a chlorine atom is preferable.

The compound represented by the formula (Ic) is included in the present invention whether it is a free form or a pharmacologically acceptable salt. As such salts, when the compound represented by the formula (Ic) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc) , Iron, transition metals such as copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N′-dibenzylethylenediamine, Salts with basic amino acids such as arginine, lysine and ornithine).
When the compound represented by the formula (Ic) of the present invention has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid) Acid acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., aspartic acid, glutamic acid, etc. May form a salt with

  The compound represented by the formula (Ic) or a salt thereof has an asymmetric carbon at the 3-position and the 5-position, but may be a mixture of stereoisomers, or the isomers can be separated by known means. . Trans isomers, which are isomers in which the substituents at the 3- and 5-positions are oriented in opposite directions with respect to the surface of the 7-membered ring, are particularly preferred, where the absolute configuration at the 3-position is R and the absolute configuration at 5-position is S An arrangement is preferred. It may also be a racemate or an optically active form. The optically active substance can be separated from the racemate by a known optical resolution means.

As the compound represented by the formula (Ic) of the present invention or a salt thereof, specifically, the following are preferred.
N-propanesulfonyl-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide or a salt thereof (2R) -2-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxy) Phenyl) -1- (2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] aminopropionic acid or a salt thereof 3- [3-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-1,2,3,5 -Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] aminophen Nil] propionic acid or its salt 4-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] aminobutanoic acid or its salt trans-4-[[(3R, 5S) -1- (3-acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] -Aminomethyl-1-cyclohexanecarboxylic acid or its salt trans-4-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2 -Dimethylpropyl) -2-oxo-1,2,3,5-te Trahydro-4,1-benzoxazepin-3-yl] acetyl] -aminomethyl-1-cyclohexanecarboxylic acid or a salt thereof 3- [3-[[[(3R, 5S) -1- (3-acetoxy) -2,2-Dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl ] Acetyl] amino] -4-fluorophenyl] propionic acid or its salt 3- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3 -Hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] -4-methylphenyl] propionic acid ,Also And its salt 3- [3-[[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2- Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] -4-methylphenyl] propionic acid or its salt 3- [3-[[[( 3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4 , 1-benzoxazepin-3-yl] acetyl] aminomethyl] phenyl] propionic acid or its salt 3- [3-[[[(3R, 5S) -1- (3-acetoxy-2,2- Dimethylpropyl) -7-chloro-5- (2, -Dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] aminomethyl] phenyl] propionic acid or its salt 3- [3- [[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5 -Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] -4-methoxyphenyl] propionic acid or its salt 2- [2-[[((3R, 5S) -7-chloro- 5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -Yl] acetyl] amino] ethyl] furan-3-carboxylic acid or The salt 3- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo- 1,2,3,5-tetrahydro-4,1-benzoxazen-3-yl] acetyl] amino] -4-fluorophenyl] propionic acid or its salt 3- [3-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzo Oxazepin-3-yl] acetyl] aminophenyl] propionic acid or its salt 4- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-] (3-Hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-i ] Acetyl] amino] -4-methoxyphenyl] butanoic acid or its salt 5- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3 -Hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] -4-methoxyphenyl] pentanoic acid Or a salt thereof 5- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-] Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] -4-fluorophenyl] pentanoic acid or a salt thereof.

The compound represented by the above formula (Ic) or a salt thereof is described in, for example, EPA 567 026, WO 95/21834 (international application based on Japanese Patent Application No. 6-15531), EPA 645377 (application based on Japanese Patent Application No. 6-229159), It can be produced according to a method disclosed in gazettes such as EPA 645378 (application based on Japanese Patent Application No. 6-229160), WO 01/98282 (international application based on Japanese Patent Application No. 2000-190253), or a method analogous thereto.
As the raw material compound of the compound represented by the formula (I) of the present invention, the same salt as described above is used, but is not particularly limited as long as the reaction is not hindered.

“Skeletal muscle protection” in the present invention refers to various factors such as ischemia, exertion, excessive exercise, trauma (bruise, skeletal muscle hemorrhage, electric shock), burn, malignant hyperthermia, malignant syndrome, and metabolic myopathy. , Inflammatory myopathy, muscular dystrophy, infection, poisoning, metabolic abnormalities, hyperthermia, etc., causing skeletal muscle necrosis or melting, or to show a therapeutic or preventive effect, more specifically, (A skeletal muscle protection effect based on suppression of cell damage caused by these). It also includes the therapeutic or preventive effects on myalgia due to cytotoxicity of other drugs (eg, HMG-CoA reductase inhibitors, cyclosporins, fibrate drugs, etc.) and rhabdomyolysis in severe cases.
In particular, the agent of the present invention shows an excellent therapeutic or preventive effect on myalgia caused by an HMG-CoA reductase inhibitor, and also on severe rhabdomyolysis, Suppresses the induced decrease in geranylgeranylated metabolites (eg, geranylgeranyl pyrophosphate, geranylgeraniol, geranylgeranylated protein, etc.) in muscle cells. Here, examples of HMG-CoA reductase inhibitors include atorvastatin, lovastatin, simvastatin, pravastatin, rosuvastatin, itavastatin, fluvastatin, cerivastatin, pitavastatin and the like.
The agent of the present invention has an excellent skeletal muscle protective effect, and is low in toxicity and safe (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.). In terms of point, it is more excellent as a medicine). Therefore, the agent of the present invention can be used in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.), for example, for the prevention and treatment of rhabdomyolysis, It can be used safely as a prophylactic / therapeutic agent for myoglobinuria associated with rhabdomyolysis, a prophylactic / therapeutic agent for myalgia, and the like.
In the agent of the present invention, the active ingredient, a compound having a squalene synthase inhibitory activity or a salt thereof, or a prodrug thereof (hereinafter, also referred to as an SSI compound or a prodrug thereof) may be in an original state. Carriers, usually excipients (eg, calcium carbonate, kaolin, sodium bicarbonate, lactose, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binders (eg, dextrins, rubbers) , Alcoholized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrants (eg, carboxymethylcellulose calcium, croscarmellose sodium, crospopidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc.), lubricant For example, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, tar dye, caramel, iron sesquioxide, titanium oxide, riboflavins, etc.), flavoring agents (eg, sweets, flavors) Etc.), stabilizers (eg, sodium sulfite, etc.), preservatives (eg, parabens, sorbic acid, etc.), and the like. The agent of the present invention including the above-mentioned preparation suitably contains an SSI compound or a prodrug thereof in an amount effective for treating and preventing a disease. The content of the SSI compound or its prodrug in the preparation of the present invention is usually 0.1 to 100% by weight of the whole preparation. The preparation used in the present invention may contain other pharmaceutical ingredients other than the SSI compound or its prodrug as an active ingredient, and these ingredients are not particularly limited as long as the object of the present invention is achieved. It can be used in an appropriate mixing ratio. Specific examples of dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, fine granules, powders, syrups, emulsions, suspensions, injections, and sustained-release formulations. Injections, inhalants, ointments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).

Specifically, a tablet is produced by adding an excipient, a binder, a disintegrant or other appropriate additives and mixing the SSI compound or a prodrug thereof as they are, and mixing them by an appropriate method. After forming the granules, a lubricant etc. is added and compression-molded, or the SSI compound or its prodrug is mixed as it is, or excipients, binders, disintegrants or other appropriate additives are added and mixed evenly. It can also be produced by directly compression-molding the product, or by directly compressing the granules prepared beforehand as they are, or after adding an appropriate additive and mixing them evenly, followed by compression molding. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. Further, the agent can be coated with an appropriate coating agent. Injectable preparations are prepared by dissolving, suspending or emulsifying a certain amount of the SSI compound or a prodrug thereof in water for injection, physiological saline, Ringer's solution, etc. in the case of aqueous solvents, and usually in vegetable oils, etc. in the case of non-aqueous solvents. Or a fixed amount of the SSI compound or a predetermined amount of the prodrug thereof, and sealed in a container for injection to produce.
As the carrier for oral preparations, for example, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added.
Further, the preparation of the present invention can also be used as a sustained release preparation. The sustained-release preparation can be prepared, for example, by microcapsules (eg, microsphere microparticles) produced by a method of drying in water (o / w method, w / o / w method, etc.), a phase separation method, a spray drying method or a method analogous thereto. (Capsules, microparticles, etc.) can be administered as it is, or can be formulated and administered in various dosage forms using the microcapsules or the spherical, needle-like, pellet-like, film-like, or cream-like pharmaceutical composition as a raw material. Examples of the dosage form include parenteral preparations (for example, injections or implants for intramuscular, subcutaneous, organ, etc .; transmucosal preparations for nasal cavity, rectum, uterus, etc.), oral preparations (for example, hard capsules, Soft capsules, granules, powders, suspensions, etc.).
When the sustained-release preparation is an injection, a microcapsule is used as a dispersant (for example, a surfactant such as Tween 80 or HCO-60; a polysaccharide such as carboxymethyl cellulose, sodium alginate, or sodium hyaluronate; protamine sulfate; Together with preservatives (eg, methyl paraben, propyl paraben, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), local anesthetics (eg, xylocaine hydrochloride, chlorobutanol, etc.), etc. Aqueous suspensions or dispersions with vegetable oils (eg, sesame oil, corn oil, etc.) or mixtures thereof with phospholipids (eg, lecithin) or medium chain fatty acid triglycerides (eg, Miglyol 812, etc.) Sustained-release injections are used as oily suspensions.
When the sustained-release preparation is a microcapsule, the average particle size is about 0.1 to about 300 μm, preferably about 1 to about 150 μm, and more preferably about 2 to about 100 μm.
Examples of the method for making the microcapsules into a sterile preparation include a method of sterilizing the whole production process, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.

The dose of the agent of the present invention varies depending on the route of administration, symptoms, age and weight of the patient, and the like. For example, when orally administered to an adult patient as a skeletal muscle protective agent, the amount of SSI compound is 1 to 1 per day. It is desirable to administer 400 mg / day, preferably 6 to 120 mg / day in one or several divided doses. The administration route may be oral or parenteral.
The dosage of the sustained-release preparation as an example of the agent of the present invention may vary depending on the administration route, symptoms, age or body weight of the patient, and the duration of release, etc. The concentration is not particularly limited as long as the concentration is maintained in the body, and the number of administrations can be appropriately selected depending on the situation, such as once a day to three days, or once a week to three months.

  When the skeletal muscle protective agent of the present invention is used to protect skeletal muscle from cytotoxicity of an HMG-CoA reductase inhibitor, the dosage forms of the SSI compound and the HMG-CoA reductase inhibitor used in the present invention are particularly There is no limitation, and at the time of administration, the SSI compound and the HMG-CoA reductase inhibitor may be combined. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing an SSI compound and an HMG-CoA reductase inhibitor, (2) SSI compound and HMG-CoA reductase inhibition Simultaneous administration of the two preparations obtained by separately formulating the drug and the same administration route, (3) the two preparations obtained by separately formulating the SSI compound and the HMG-CoA reductase inhibitor Administration at the same administration route with a time difference, (4) Simultaneous administration of two formulations obtained by separately formulating the SSI compound and the HMG-CoA reductase inhibitor by different administration routes, (5) Administration of two formulations obtained by separately formulating an SSI compound and an HMG-CoA reductase inhibitor at different time points by different administration routes (for example, SSI compound → HMG-CoA reductase inhibitor) Administration incidentally, or in the reverse order) and the like. The dose of the HMG-CoA reductase inhibitor can be appropriately selected based on the clinically used dose. The mixing ratio of the SSI compound and the HMG-CoA reductase inhibitor 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 SSI compound may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the HMG-CoA reductase inhibitor.

  The agent of the present invention has an excellent skeletal muscle protective action, for example, an excellent preventive / therapeutic effect against myalgia and rhabdomyolysis caused by other drugs such as HMG-CoA reductase inhibitors. Is shown.

Hereinafter, experimental results showing the pharmacological effect of the agent of the present invention will be described.
Test compound 1:
N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3, 5-Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid Test compound 1 is a compound described as Example 36 in JP-A-2002-080468. It can be synthesized by the method described in the publication.
Test compound 2:
3- [3-[[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] amino] phenyl] propionic acid Test compound 2 was described as Example 36 in JP-A-9-136880. It is a compound and can be synthesized by the method described in the publication. Further, it is shown in Experimental Example 1 of the publication that Test Compound 2 has a squalene synthase inhibitory action.
Test compound 3:
N-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3, 5-Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid Test compound 3 is a compound described as compound number 13-1 in JP-A-9-136880. Can be synthesized by the method described in the publication. In addition, it is shown in Experimental Example 1 of the publication that the test compound 3 has a squalene synthase inhibitory action.

Data represent Mean±SE (N=4).
*P<0.025 vs. コントロール（one-tailed Williams' test）

表１の結果から、ＳＳＩ化合物は骨格筋中のゲラニルゲラニオール濃度を増加させることが分かる。 Test example 1
Method of increasing geranylgeraniol (GGOH) in soleus muscle:
Six-week-old male SD rats (four rats per group) were injected with vehicle or test compound 1 or 2 at a volume of 10 mL / kg to give 40 or 200 mg / kg once a day for 14 days by intragastric probe. Gavage was administered by gavage. The animals were sacrificed under ether anesthesia the morning after 14 administrations. The soleus muscle was immediately collected, frozen on dry ice, and stored at -80 ° C. At a later date, phosphatase was added to the muscle homogenate to dephosphorylate, and then the concentration of geranylgeraniol (sum of geranylgeranyl pyrophosphate and geranylgeraniol) in the muscle was quantified using LC / MS / MS (Table 1).
result:
Table 1

Data represent Mean ± SE (N = 4).
* P <0.025 vs. control (one-tailed Williams' test)

The results in Table 1 show that the SSI compound increases the concentration of geranylgeraniol in skeletal muscle.

各データは平均±標準誤差(N=3)を示す。
♯P<0.025 vs グループ１（one-tailed Williams' test）
*P<0.01 vs グループ３（Student's t test）
$P<0.01 vs グループ５（Student's t test）

表２の結果から、ＳＳＩ化合物により増加するゲラニルゲラニオールの生体内での活性体であるゲラニルゲラニルピロリン酸は優れた骨格筋細胞毒性軽減作用を有することが分かる。 Test example 2
Effect of adding geranylgeranyl pyrophosphate (GGPP) on the cytotoxicity of HMG-CoA reductase inhibitors:
Sixth generation human normal skeletal muscle cells (Bio Whittaker) were cultured on a 96-well plate in SkGM medium (Bio Whittaker) and confluent into groups 1-6 shown in Table 1 After 3 days from the simultaneous addition of the drugs in Treatment 1 and Treatment 2, the intracellular ATP content was measured using an ATP Lite-M kit (Packard), and the number of viable cells was measured (Table 2).
result:
Table 2

Each data represents the mean ± standard error (N = 3).
♯P <0.025 vs group 1 (one-tailed Williams' test)
* P <0.01 vs group 3 (Student's t test)
$ P <0.01 vs group 5 (Student's t test)

The results in Table 2 show that geranylgeranyl pyrophosphate, which is an in vivo active form of geranylgeraniol increased by the SSI compound, has an excellent skeletal muscle cytotoxicity-reducing effect.

各データは平均±標準誤差(N=3)を示す。
#P<0.025 vs グループ１（one-tailed Williams' test）
*P<0.05 vs グループ３（Student's t test） Test example 3
Effect of test compound 3 addition on cytotoxicity of HMG-CoA reductase inhibitor (1)
Method:
Sixth generation human normal skeletal muscle cells (Bio Whittaker) were cultured in a 96-well plate in SkGM medium (Bio Whittaker), and after confluence, grouped into groups 1-4 shown in Table 3 After 3 days from the simultaneous addition of the drugs in Treatment 1 and Treatment 2, the intracellular ATP content was measured using an ATP Lite-M kit (Packard), and the number of viable cells was measured (Table 3).
result:
Table 3

Each data represents the mean ± standard error (N = 3).
#P <0.025 vs group 1 (one-tailed Williams' test)
* P <0.05 vs group 3 (Student's t test)

各データは平均±標準誤差(N=3)を示す。
♯P<0.025 vs グループ１（one-tailed Williams' test）
**P<0.01 vs グループ３（Student's t test）
*P<0.05 vs グループ５（Student's t test）

表３および４の結果から、ＳＳＩ化合物は優れた骨格筋細胞毒性軽減作用を有することが分かる。 Test example 4
Effect of test compound 3 addition on cytotoxicity of HMG-CoA reductase inhibitor (2)
Method:
The 6th generation human normal skeletal muscle cells (Bio Whittaker) were cultured on a 96-well plate in SkGM medium (Bio Whittaker) and confluent into groups 1-6 shown in Table 4 One day after the addition of the drug in treatment 1, the medium was completely removed, and the drug in treatment 2 was added. Three days later, the intracellular ATP content was measured using an ATP Lite-M kit (Packard), and The number was measured (Table 4).
result:
Table 4

Each data represents the mean ± standard error (N = 3).
♯P <0.025 vs group 1 (one-tailed Williams' test)
** P <0.01 vs group 3 (Student's t test)
* P <0.05 vs group 5 (Student's t test)

The results in Tables 3 and 4 show that the SSI compound has an excellent skeletal muscle cytotoxicity-reducing action.

Formulation Example The skeletal muscle protective agent of the present invention can be produced, for example, by the following formulation.
In addition, in the following prescription, as components (additives) other than the active ingredient, products listed in the Japanese Pharmacopoeia, non-Japanese Pharmacopoeia drug standards or drug excipient standards can be used.
1. Capsule (1) N-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1 , 2,3,5-Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid
10mg
(2) Lactose 90mg
(3) Microcrystalline cellulose 70mg
(4) Magnesium stearate 10mg
180mg per capsule
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.
2. Tablet (1) N-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid
10mg
(2) Lactose 35mg
(3) Corn starch 150mg
(4) Microcrystalline cellulose 30mg
(5) Magnesium stearate 5mg
One tablet 230mg
After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
3. Injection (1) N-[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1 , 2,3,5-Tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid
10mg
(2) Inosit 100mg
(3) 20 mg of benzyl alcohol
130mg per ampoule
(1), (2), and (3) are dissolved in distilled water for injection so that the total volume is 2 ml, and sealed in an ampoule. All steps are performed under aseptic conditions.

The agent of the present invention has an excellent skeletal muscle protective action, for example, an excellent preventive / therapeutic effect against myalgia and rhabdomyolysis caused by other drugs such as HMG-CoA reductase inhibitors. Is shown.

Claims (19)

A skeletal muscle protective agent comprising a compound having a squalene synthase inhibitory activity, a salt thereof, or a prodrug thereof. The agent according to claim 1, which is a skeletal muscle protective agent that protects skeletal muscle from cell damage. The agent according to claim 1, which is a skeletal muscle protective agent that protects skeletal muscle from the cytotoxicity of other agents. The agent according to claim 3, wherein the other agent is an HMG-CoA reductase inhibitor. The agent according to claim 1, which is an agent for preventing or treating myalgia or rhabdomyolysis. A compound having a squalene synthase inhibitory action is represented by the formula

[In the formula, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X 'is a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, an amino group which may be substituted or a hydrogen atom which can be deprotonated. A ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, and ring J ′ is 3 Or a 7- or 8-membered heterocycle containing not more than one heteroatom, and the ring J ′ may further have a substituent other than R ₁ , R ₂ , R ₃ and X ′. The agent according to claim 1, which is A compound having a squalene synthase inhibitory action is represented by the formula

[Wherein, R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and are a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. X ₁ represents a bond or a divalent atom chain; Y represents a carboxyl group which may be esterified; a carbamoyl group which may be substituted; a hydroxyl group which may be substituted; And an optionally substituted heterocyclic residue having an optionally substituted amino group or a deprotonatable hydrogen atom, and ring B represents an optionally substituted benzene ring]. The described agent. A compound having a squalene synthase inhibitory action is represented by the formula

Wherein R _b represents a lower alkyl group which may be substituted with an optionally substituted hydroxyl group, and X _b represents a carbamoyl group which may be substituted or a substituted group having a deprotonatable hydrogen atom. A heterocyclic group, R _1b represents a lower alkyl group, and W represents a halogen atom. The agent according to claim 1, which is a compound represented by the formula: R _b is hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, to 1 selected from dimethylamino acetyloxy and 2-amino-propionyloxy may have three substituents C ₁ The agent according to claim 8, which is _-6 alkyl. The agent according to claim 8, wherein R _1b is methyl. 9. The agent according to claim 8, wherein W is a chlorine atom. X _b is the formula

[Wherein, R _2b and R _3b are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group, or R _2b and R _3b are adjacent nitrogen atoms. Together with the atom, forms a 5- or 6-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted; The group according to claim 8, which is a group represented by the formula: X _b is the formula

9. The agent according to claim 8, which is a group represented by the formula: wherein R "represents a hydrogen atom or _C1-4 alkyl. A compound having a squalene synthase inhibitory activity is N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl)- 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid or N-[[(3R, 5S) -7-chloro-5 -(2,3-Dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- 2. The agent according to claim 1, which is [yl] acetyl] piperidine-4-acetic acid. A skeletal muscle protective agent comprising a compound having an inhibitory effect on reduction of geranylgeranylated metabolites in muscle cells, a salt thereof, or a prodrug thereof. A method for protecting skeletal muscle, comprising administering to a mammal an effective amount of a compound having a squalene synthase inhibitory activity, a salt thereof, or a prodrug thereof. A method for protecting skeletal muscle, comprising administering to a mammal an effective amount of a compound having an inhibitory effect on reduction of geranylgeranylated metabolites in muscle cells, a salt thereof, or a prodrug thereof. Use of a compound having a squalene synthase inhibitory activity, a salt thereof, or a prodrug thereof for the production of a skeletal muscle protective agent. Use of a compound having a geranylgeranylated metabolite reduction inhibitory activity in muscle cells, a salt thereof, or a prodrug thereof for the production of a skeletal muscle protective agent.