JPH08157369A - Triglyceride lowering agent - Google Patents

Abstract

PURPOSE: To obtain the subject lowering agent, containing a condensed ring compound represented by a specific formula and useful for preventing and treating hyperlipemia, above all, preventing and treating hypertriglyceridemia according to a new mode of action. CONSTITUTION: This lowering agent contains a compound of the formula [R<1> is H or a (substituted)hydrocarbon; R<2> and R<3> are each H, a (substituted) hydrocarbon or a (substituted)heterocyclic ring; X' is a (esterified)carboxyl, a (substituted)carbamoyl, a (substituted)OH, a (substituted)amino or a (substituted)heterocyclic ring having H which can be deprotonated; ring A is a (substituted)benzene ring or a (substituted)heterocyclic ring; ring J' is a 7- to an 8-membered heterocyclic ring containing <=3 hetero-atoms as ring constituent atoms], preferably (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid or its pharmaceutically permissible salt (preferably an Na salt).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a triglyceride lowering agent useful for preventing or treating hypertriglyceridemia or hyperlipidemia.

[0002]

2. Description of the Related Art An abnormal increase in serum lipid concentration is called hyperlipidemia or hyperlipemia. Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipids (lecithin,
Sphingomyelin, etc.), triglycerides (triglycerides), free fatty acids, other sterols, etc., but especially clinically problematic are cholesterol,
Increase in triglyceride (COMMON DISEASE SERIE
S No.19 Hyperlipidemia edited by Haruo Nakamura. Therefore, proper control of blood lipid levels is extremely important for the prevention or treatment of various diseases associated with arteriosclerosis such as ischemic heart disease and cerebral infarction.
Hypertriglyceridemia is also considered to be associated with pancreatic disorders.

Drugs that lower blood cholesterol levels include those that trap bile acids such as cholestyramine (Colestipol) and inhibit their absorption (eg, US Pat. No. 4027009) and melinamide (US Pat. No. 4027009). Melinamide) (French Patent No. 147656)
No. 9) and the like that inhibit acylcoenzyme A cholesterol acyltransferase (ACAT) to suppress intestinal absorption of cholesterol, as well as drugs that suppress cholesterol biosynthesis are drawing attention. As a cholesterol biosynthesis inhibitor, Lovastatin which inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in particular (Lovastatin) (US Pat. No. 423)
1938), Simvastatin (US Pat. No. 4,444,784), Pravastatin (Pravasta).
tin) (US Pat. No. 4,346,227) and the like are used for medicines. However, inhibition of HMG-CoA reductase also inhibits biosynthesis of other components necessary for the living body such as ubiquinone, dolichol and heme A, in addition to cholesterol biosynthesis, and side effects caused by them are concerned. Has been done. Further, as the triglyceride lowering agent, fibric acid compounds such as clofibrate (British Patent No. 860303), fenofibrate (German Patent No. 2250327), etc. have been used for pharmaceuticals,
Concomitant use with statins is contraindicated due to liver toxicity.

Hyperlipidemia is hyperlipoproteinemia.
Also called roteinemia), it is classified into 6 types (WHO classification) in terms of lipoproteins as follows. Type I: hypercairomicronemia showing an increase in cairomicrons, type IIa: high LD showing an increase in low-density lipoprotein (LDL)
L hyperemia (hypercholesterolemia), type IIb: combined hyperlipidemia showing an increase in LDL and very low density lipoprotein (VLDL), type III: presence of β very low density lipoprotein (βVLDL) Abnormal β-lipoproteinemia, type IV: endogenous hypertriglyceridemia showing an increase in VLDL, type V: mixed hyperlipidemia showing an increase in VLDL and chylomicron.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a triglyceride lowering agent useful for preventing or treating hyperlipidemia, in particular, a triglyceride lowering agent for preventing / treating hypertriglycerideemia by a new mechanism of action.

[0006]

As a result of intensive studies in view of the above circumstances, the present inventors have found that a specific fused ring compound has an unexpectedly excellent triglyceride lowering action, and It came to completion. That is, the present invention provides (1) formula (I)

[Chemical 7] [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ and R ₃ are the same or different and are hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocycle. X'is a carboxyl group which may be esterified, a carbamoyl group which may be substituted,
The ring A is substituted with a substituent composed of an optionally substituted hydroxyl group, an optionally substituted amino group, or an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom. An optionally benzene ring or an optionally substituted heterocycle, ring J ′ is a 7- to 8-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms, and ring J ′ is R ₁ , R ₂ , R ₃ and X ′ may further have a substituent] or a pharmacologically acceptable salt thereof, especially (2) where R ₁ is a fat A triglyceride-lowering agent according to (1) above, which is a group acyclic hydrocarbon group;

Formula (3) (I ')

Embedded image [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ and R ₃ are the same or different and are hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocycle. A group, X ₁ is a bond or a divalent atom chain, Y is a carboxyl group which may be esterified,
Ring B is substituted with an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group, or an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom. An optionally present benzene ring] or a pharmacologically acceptable salt thereof, and the triglyceride-lowering agent according to (1) above, and (4) hyperlipidemia, especially high triglyceride. The present invention relates to the triglyceride lowering agent according to the above (1), (2) or (3), which is used for preventing or treating blood sugar.

In formulas (I) and (I ′), the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ₁ is an aliphatic chain (acyclic) hydrocarbon group, Examples thereof include an alicyclic hydrocarbon 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 such as an alkyl group, an alkenyl group and an alkynyl group. Of these, a branched alkyl group is preferable. 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 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl,
_Examples thereof include C _1-7 alkyl such as n-heptyl, and among them, C _3-5 alkyl such as n-propyl, isopropyl, isobutyl and neopentyl are 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, 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-
Examples thereof include C _2-6 alkenyl such as hexenyl and 5-hexenyl. Among them, vinyl, allyl, isopropenyl,
2-methylallyl, 2-methyl-1-propenyl, 2-
Methyl-2-propenyl, 3-methyl-2-butenyl and the like are particularly preferable. 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-
Examples thereof include C _2-6 alkynyl such as hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, and among them, ethynyl, 1-propynyl, 2-propynyl and the like are particularly preferable.

Examples of the alicyclic hydrocarbon group of the hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl group, cycloalkenyl group and cycloalkadienyl group. The cycloalkyl group is preferably a cycloalkyl group having a carbon number of 3 to 9, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like, and among them, C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
_{A 3-6} cycloalkyl group is preferred. Examples of the cycloalkenyl group include 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2-cyclohexene-
Examples thereof include C _5-6 cycloalkenyl groups such as 1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl. Examples of the cycloalkadienyl group include 2,4-cyclopentadiene-1-yl and 2,4-cyclohexadiene-1-
Yl, 2,5-cyclohexadiene C _5-6 diene-1-yl
Examples thereof include a cycloalkadienyl group. Examples of the aryl group of the hydrocarbon group include monocyclic or condensed polycyclic aromatic hydrocarbon groups having 6 to 16 carbon atoms, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. However, C _6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.

As the substituent of the "optionally substituted hydrocarbon group" represented by R ₁ , an optionally substituted aryl group, an optionally substituted cycloalkyl group or a cycloalkenyl group, and a substituted Optionally substituted heterocyclic group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine, iodine), oxo, etc. 1 to 5 (preferably 1 to 3) of the hydrocarbon groups may be substituted at positions substitutable with these optional substituents. Examples of the aryl group which may be substituted include C _6-16 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl, and acenaphthylenyl, and among them, phenyl, 1-naphthyl, 2-
C _6-10 aryl groups such as naphthyl are preferred. The aryl substituent which may be substituted has 1 to 1 carbon atoms.
3 alkoxy groups (eg, methoxy, ethoxy, propoxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine, iodine), alkyl groups having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.), etc. And the aryl group may be substituted with 1 to 2 of these optional substituents. The cycloalkyl group of the optionally substituted cycloalkyl group includes C _3-7 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Examples thereof include a cycloalkyl group. The substituent of the optionally substituted cycloalkyl group and the number of substitutions thereof are,
The same kind and number as the substituent in the optionally substituted aryl group can be mentioned. As the cycloalkenyl group of the optionally substituted cycloalkenyl group,
Examples thereof include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Examples of the substituents of the optionally substituted cycloalkenyl group and the number of substitutions thereof include the same kind and number as the substituents in the optionally substituted aryl group. The heterocyclic group of the optionally substituted heterocyclic group, as an atom (ring atom) constituting the ring system,
At least one of oxygen, sulfur and nitrogen, preferably 1 to
Examples thereof include an aromatic heterocyclic group having 4 heteroatoms and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), preferably an aromatic heterocyclic group. As the aromatic heterocyclic group, a 5- or 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, flazanil, 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 5 to 6 members Aromatic condensed heterocyclic group having 2 to 3 condensed rings (eg, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, 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, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, Pyrazolo [1,5- a ]
Pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,
2,4-triazolo [4,3- a ] pyridyl, 1,2,
4-triazolo [4,3- b ] pyridazinyl and the like), but among them, 5- or 6-membered aromatic monocyclic heterocyclic groups such as furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, and pyrimidinyl are preferable. Examples of the non-aromatic heterocyclic group include 4- to 8-membered non-aromatic heterocyclic groups such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl. To be The optionally substituted heterocyclic group is 1 to 4, preferably 1
To 2 substituents may be included, and as such a substituent, an alkyl group having 1 to 3 carbon atoms (eg, methyl,
Ethyl, propyl, etc.) and the like. Examples of the substituent in the optionally substituted amino group (including an amino group, a mono- or di-substituted amino group), the optionally substituted hydroxyl group, and the optionally substituted thiol group include Lower (C _1-3 ) alkyl (eg, methyl, ethyl, propyl, etc.) and the like can be mentioned. Further, 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 is further an alkyl group having 1 to 3 carbon atoms ( Example,
Methyl, ethyl, propyl, etc.) Furthermore, as described above, R ₁ may have an oxo group as a substituent, and R ₁ also includes such a carboxylate acyl group which is an oxo-substituted hydrocarbon group. As such an example, for example, an acyl group having 1 to 6 carbon atoms which may have a substituent (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, bromine).

In the formulas (I) and (I '), the "optionally substituted hydrocarbon group" represented by R ₂ and R ₃ is "an optionally substituted hydrocarbon group represented by R _1. And the groups described as ". However, the following may be used as the alkyl group, the aryl group and the substituents thereof. 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.), preferably C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. The optionally substituted alkyl group may have 1 to 4 substituents, and examples of such a substituent include halogen (eg, fluorine, chlorine, bromine, iodine), and 1 to 4 carbon atoms.
Lower alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.)
Etc. "Aryl group which may be substituted"
Examples of the monocyclic or condensed polycyclic aromatic hydrocarbon group include, for example, phenyl, naphthyl, anthryl,
Examples thereof include phenanthryl and acenaphthylenyl, with phenyl being particularly preferred. The substituent of the "optionally substituted aryl group" includes halogen (eg, fluorine, chlorine, bromine, iodine, etc.), optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted And the like, and may be substituted with 1 to 3 (preferably 1 to 2) of the same or different substituents. Examples of the lower alkyl include methyl, ethyl, n-propyl,
Examples thereof include alkyl groups having 1 to 4 carbon atoms such as isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, with methyl and ethyl being particularly preferred. The lower alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, se.
Examples thereof include alkoxy groups having 1 to 4 carbon atoms such as c-butoxy and tert-butoxy, with methoxy and ethoxy being particularly preferred. Examples of the substituent of the optionally substituted lower alkyl group or the optionally substituted lower alkoxy group include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and 1 at any position. ~ 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, t-
Butyl etc.), C _3-6 cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _6-10 aryl group (eg phenyl, 1-naphthyl, 2-naphthyl etc.), C _7-12 aralkyl group (Eg, benzyl, phenethyl, etc.) and the like. In addition, these substituents may form a ring by adjacent substituents, and the aryl group of the “optionally substituted aryl group” represented by R ₂ or R ₃ is a phenyl group. For example,

[Chemical 9] May be used, and such a group may be substituted with 1 to 4 lower (C _1-3 ) alkyl groups (eg, methyl, ethyl, propyl, isopropyl, etc.) and the like. Good.

The heterocyclic group of the "optionally substituted heterocyclic group" represented by R ₂ and R ₃ is a substituent of the "optionally substituted hydrocarbon group" represented by R _1. Examples thereof include the heterocyclic groups described in detail in connection with the above-mentioned "optionally substituted heterocyclic group". Among them, furyl,
Thienyl, indolyl, isoindolyl, pyrazinyl,
Particularly preferred are 5- to 6-membered aromatic monocyclic heterocycles such as pyridyl, pyrimidyl and imidazolyl. Examples of the substituent of the heterocyclic group include alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.), and may have 1 to 4 of these substituents. Among the above, R ₂ and R ₃ are preferably an optionally substituted phenyl group, more preferably a substituted phenyl group,
Particularly, a phenyl group substituted with 1 to 3, preferably 1 to 2 halogen (s) such as chlorine and bromine and lower (C _1-3 ) alkoxy is preferable. Further, one of R ₂ and R ₃ is preferably hydrogen.

In the formula (I), the "substituent composed of an optionally esterified carboxyl group" represented by X'is an optionally esterified carboxyl group and an optionally esterified carboxyl group. Substituents having a good carboxyl group may be mentioned. Examples of the optionally esterified carboxyl group include the same groups as those of the optionally esterified carboxyl group defined in Y below. Examples of the “substituent composed of an optionally substituted carbamoyl group” represented by X ′ include an optionally substituted carbamoyl group and a substituent having an optionally substituted carbamoyl group. To be Examples of the optionally substituted carbamoyl group include the same groups as those of the optionally substituted carbamoyl group defined by Y below. Examples of the “substituent composed of an optionally substituted hydroxyl group” represented by X ′ include an optionally substituted hydroxyl group and a substituent having an optionally substituted hydroxyl group. Examples of the optionally substituted hydroxyl group include the same ones as the optionally substituted hydroxyl group defined by Y below. Examples of the “substituent composed of an optionally substituted amino group” represented by X ′ include an optionally substituted amino group and a substituent having an optionally substituted amino group. To be Examples of the optionally substituted amino group include those similar to the optionally substituted amino group defined in Y below. The "substituent having a deprotonizable hydrogen atom and optionally substituted heterocyclic residue" represented by X'has a deprotonable hydrogen atom (that is, has an active proton) And a substituent having an optionally substituted heterocyclic residue and an optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation. Examples of the optionally substituted heterocyclic residue include the same as those of the optionally substituted heterocyclic residue having a deprotonizable hydrogen atom defined in Y below. . X ′ is, for example, formula (a)

[Chemical 10] [In the formula, X is a bond or a divalent or trivalent atomic chain, and Y is an optionally esterified carboxyl group,
An optionally substituted heterocyclic residue having an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or a deprotonatable hydrogen atom, the broken line portion is Groups having a single bond or a double bond].

In the formula (a), the "divalent atom chain" represented by X preferably has 1 to 7 atoms, more preferably 1 to 4 atoms constituting the straight chain portion. Any valent chain may be used, and it may have a side chain. For example,

Embedded imageIn the formula, m and n are independently
Represents 0, 1, 2 or 3, and E is a bond or oxygen source
Child, sulfur atom, sulfoxide, sulfone, -N (R_Five)
-, -NHCO-, -CON (R₆) -Or-NHC
Represents ONH-. Where R_FourAnd R₆Is hydrogen, replaced
Optionally lower alkyl group, optionally substituted alkyl group
The aralkyl group and the phenyl group which may be substituted are shown.
Also, R_FiveIs hydrogen, a lower alkyl group, an aralkyl group or
Indicates an acyl group. R_FourAnd R₆"Replaced
The lower alkyl group which may be, is, for example, carbon.
Number 1 to 6 linear or branched lower alkyl group
(Example: methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, n-pen
Chill, isopentyl, neopentyl, etc.).
The number of the optionally substituted lower alkyl group is preferably 1 to 4.
It may have 1 to 2 substituents.
As the substituent, an aromatic heterocyclic group (eg, furyl, thieny)
Red, indolyl, isoindolyl, pyrazinyl, pyridi
R, pyrimidyl, imidazolyl, etc. N, O, S hetero
5-6 membered aromatic heterocycle containing 1-4 atoms), substituted
Optionally an amino group, an optionally substituted hydroxyl group,
Optionally substituted thiol group, esterified
Optionally a carboxyl group, a halogen atom (eg, fluorine,
Chlorine, bromine, iodine) and the like. The replaced
Optionally an amino group (amino group or mono- or di-substituted
Mino group), an optionally substituted hydroxyl group, and a substituted
The thiol group which may have a substituent is lower
(C _1-3) Alkyl (eg methyl, ethyl, propyl
And others). Optionally esterified
Examples of the carboxyl group include methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, phenoxy
Sicarbonyl, 1-naphthoxycarbonyl, etc. C_2-5A
Lucoxycarbonyl and C_7-11Aryloxycarboni
However, methoxycarbonyl and ether are preferred.
Toxoxycarbonyl and propoxycarbonyl.

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

R_FiveThe "acyl group" represented by
Grade (C_1-6) Alkanoyl groups (eg formyl, acetyl)
Le, propionyl, butyryl, isobutyryl, valery
, Isovaleryl, pivaloyl, hexanoyl, etc.),
Lower (C_3-7) Alkenoyl groups (eg acryloyl,
Tacryloyl, crotonoyl, isocrotonoyl
DO), C _4-7Cycloalkanecarbonyl group (eg, cyclo
Propane carbonyl group, cyclobutane carbonyl group,
Clopentanecarbonyl group, cyclohexanecarbonyl
Group), lower (C_1-4) Alkanesulfonyl group (eg,
Mesyl, ethanesulfonyl, propanesulfonyl, etc.
DO), C_7-14Aroyl groups (eg, benzoyl, p-toluo)
Ill, 1-naphthoyl, 2-naphthoyl, etc.), C_6-10
Aryl lower (C_2-4) Alkanoyl groups (eg phenyl
Acetyl, phenylpropionyl, hydroatropoi
, Phenylbutyryl, etc.), C_6-10Aryl lower (C
_3-5) Alkenoyl groups (eg, cinnamoyl, atropoi
, Etc., C_6-10Arenesulfonyl groups (eg benzene
Sulfonyl, p-toluenesulfonyl group, etc.)
You can Further, X contains a double bond.
Carbon chain or -L-CH (OH)-(L is a bond or
It may be a chain or branched alkylene chain).
The "carbon chain containing a double bond" is preferably
Has 1 to 7 carbon atoms constituting the straight chain portion, and more preferably
It preferably has 1 to 4 and has a side chain.
May be. The double bond in the carbon chain is a straight chain portion
Or contained in either or both of the branched chains
However, those included in the straight chain portion are preferred.
Can be Also, the number of double bonds contained in the carbon chain is possible
It is not particularly limited as long as possible, but 1 to 2 is preferable.

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

Among the above, X'is represented by the formula (b)

[Chemical 12] [Wherein X ₁ is a bond or a divalent atom chain, Y is a carboxyl group which may be esterified, a carbamoyl group which may be substituted, a hydroxyl group which may be substituted, a substituted Represents an optionally substituted heterocyclic residue having an amino group or a hydrogen atom capable of deprotonation]. In formula (b), X ₁
Examples of the divalent atomic chain represented by are the same as the divalent atomic chain defined in X above. In the formulas (a) and (b), the “divalent atom chain” represented by X or X ₁ preferably has 1 to 10 carbon atoms constituting the straight chain portion.
There are 7 (more preferably 1 to 4) linear or branched alkylene chains. 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, those having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene and propylene. In formulas (a) and (b), the “optionally esterified carboxyl group” represented by Y is a lower alkoxycarbonyl having 2 to 7 carbon atoms (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.), C _7-14 aryloxycarbonyl ( Examples include phenoxycarbonyl, 1-naphthoxycarbonyl), C _8-12 aralkyloxycarbonyl (eg, benzyloxycarbonyl etc.) and the like. Of these, a carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferred.

The substituent of the "optionally substituted carbamoyl group" represented by Y is an 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.),
And optionally substituted C _6-14 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted C _7-11 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. These substituents may be the same or different and may be substituted by one or two. The substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl includes a lower (C _1-5 ) alkyl (eg, methyl, ethyl, propyl , Isopropyl, butyl, t-butyl, pentyl, isopentyl, neopentyl), a carboxyl group which may be esterified with 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, and these substituents may be the same or different and may be substituted 1 to 3. The substituent of the optionally substituted aryl group and the optionally substituted aralkyl group is a halogen atom (eg, fluorine,
Examples thereof include chlorine, bromine, iodine) and a carboxyl group which may be esterified with a lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.). Further, in the optionally substituted carbamoyl group, the substituents on two nitrogen atoms may combine with the nitrogen atom to form a cyclic amino group, and examples of such a cyclic amino group include Is 1
-Azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like.

The substituent of the "optionally substituted hydroxyl group" represented by Y is, for example, lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), substituted An _optionally substituted C _7-11 aralkyl group (eg,
Benzyl, phenethyl, etc.) and the like. The substituent of the optionally substituted aryl group and the optionally substituted aralkyl group is a halogen atom (eg,
Fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl,
(Butyl, t-butyl, etc.) and the like, which may be esterified with a carboxyl group. The “optionally substituted amino group” for Y includes mono-substituted and di-substituted amino groups, and examples of these substituents include lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl). , Isopropyl, butyl, t-butyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.), an optionally substituted C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted C _7-11
Aralkyl groups (eg, benzyl, phenethyl, etc.) and the like can be mentioned. Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include
Carboxyl optionally esterified with halogen atom (eg, fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.) And the like, which may have 1 to 4 and preferably 1 to 2 of these substituents. Further, the substituents on two nitrogen atoms may be combined with the nitrogen atom to form a cyclic amino group, and examples of such a cyclic amino group include 1-azetidinyl, 1
-Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like.

The heterocyclic residue of the “optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation” represented by Y includes at least one of N, S and O 5 To 7-membered (preferably 5-membered) monocyclic heterocyclic residues (preferably nitrogen-containing heterocyclic residues), which have a hydrogen atom capable of forming a proton upon elimination. Is good. For example, tetrazol-5-yl or formula

[Chemical 13] [In the Formula, i is -O- or -S-, j is> C = O,>
C = S or> S (O) ₂ ] (in particular, 2,5-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 is preferable) and the like. The heterocyclic residue may be protected by an optionally substituted lower alkyl group (preferably C _1-4 alkyl) or an acyl group. The lower alkyl group which may be the substituent, C _1-3 alkyl, nitro, optionally substituted by C _1-3 alkoxy phenyl optionally substituted or C _1-3 alkoxy C _{1- 4} alkyl (methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-
Methoxybenzyl, p-nitrobenzyl, etc.) and the like. Examples of the acyl group include lower (C _2-5 ) alkanoyl and benzoyl. Among the above, as X ′, an alkyl group substituted with an optionally esterified carboxyl group, an alkyl group substituted with an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom An alkyl group substituted with a group or an optionally substituted carbamoyl group is preferable. In the formula (I), examples of the heterocyclic ring represented by ring A include the heterocyclic groups described in detail in relation to the substituent of the hydrocarbon group represented by R _1.

Embedded image What is represented by is preferable.

The substituents of the "optionally substituted benzene ring" and "optionally substituted heterocycle" represented by ring A include halogen (eg, fluorine, chlorine, bromine, iodine), carbon number. 1 to 4 optionally substituted lower alkyl groups (eg, methyl, ethyl, propyl, butyl, te,
rt-butyl etc.), an optionally substituted lower alkoxy group having 1 to 4 carbon atoms (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc.), a hydroxyl group, a nitro group, cyano and the like. Can be mentioned. Ring A may have 1 to 3, preferably 1 to 2 of these substituents. Further, these substituents may form a ring with adjacent substituents. The substituent of the optionally substituted lower alkyl group or the optionally substituted lower alkoxy group is a halogen atom (eg, fluorine,
(Chlorine, bromine, iodine), etc.
Three may be substituted. As ring A, those substituted with methoxy or chlorine atom are preferable, and those substituted with chlorine atom are particularly preferable. In the formula (I ′), the substituent of the “optionally substituted benzene ring” represented by ring B is halogen (eg, fluorine, chlorine, bromine, iodine), substituted with 1 to 4 carbon atoms. Optionally lower alkyl groups (eg, methyl, ethyl, propyl, butyl, te
rt-butyl etc.), an optionally substituted lower alkoxy group having 1 to 4 carbon atoms (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc.), a hydroxyl group, a nitro group, cyano and the like. Can be mentioned. Ring B may have 1 to 3, preferably 1 to 2 of these substituents. Further, these substituents may form a ring with adjacent substituents. The substituent of the optionally substituted lower alkyl group or the optionally substituted lower alkoxy group is a halogen atom (eg, fluorine,
(Chlorine, bromine, iodine), etc.
Three may be substituted. As ring B, those substituted with methoxy or chlorine atom are preferable, and those substituted with chlorine atom are particularly preferable.

In formula (I), the heterocycle in the "7- to 8-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms" represented by ring J'is, for example, O,
7 to 8-membered saturated or unsaturated heterocycles containing at least one of S (O) _q (q represents 0, 1 or 2) and N are mentioned. However, the number of hetero atoms in the atoms (ring-constituting atoms) forming the ring of the heterocycle is 3 or less. In addition to the groups represented by R ₁ , R ₂ , R ₃ and X ′, the ring J ′ may further have 1 to 2 substituents at substitutable positions. Examples of the substituent include an alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, when the substituent is bonded to a nitrogen atom on the ring J ′. , isopentyl, a C _1-6 alkyl neopentyl, etc.), an acyl group (e.g., formyl, acetyl, propionyl, C _1-4 acyl group such as butyroyl), and the like. The alkyl group or acyl group may be further substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine). In addition, when the substituent is bonded to a carbon atom on the ring J ′, the substituent includes oxo, thioxo, an optionally substituted hydroxyl group, an optionally substituted amino group and the like. The optionally substituted hydroxyl group and optionally substituted amino group are the same as the above-mentioned "optionally substituted hydroxyl group" and "optionally substituted amino group" defined in Y. Is mentioned. As the ring J ′, in addition to the groups represented by R ₁ , R ₂ , R ₃ and X ′, those having oxo or thioxo substituted at the substitutable position are preferable.

As the condensed ring consisting of ring A and ring J ',
For example

[Chemical 15] And the like.

As the formula (I), the formula (Ia)

Embedded image [In the formula, R ₁ , R ₂ , R ₃ , X ′ and ring A have the same meanings as described above. Ring J ₁ is a 7-membered heterocycle, Z ₁ is —N (R ₇ ) — (R ₇ represents hydrogen, 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. ]
Those represented by are preferred.

In the above formula (Ia), 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, etc.), which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine) and the like. 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), etc. It may be replaced individually. Formula (Ia)
In the above, Z ₁ is preferably S (O) _q (q represents 0, 1 or 2) and O. C is preferable as K and O is preferable as G. As the formula (Ia), more preferably,
Formula (Ib)

[Chemical 17] [In the formula, R ₁ , R ₂ , R ₃ , X ₁ , Y and ring A have the same meanings as described above. Z ₂ is preferably S (O) _q (q represents 0, 1 or 2) or O].

As the formula (I), those represented by the above formula (I ') are particularly preferable. The formula (I ′) is more preferably the formula (I ″)

Embedded image [In the formula, R ₁ and ring B have the same meanings as described above. Q represents hydrogen or a metal ion, and ring C represents an optionally substituted phenyl group]. In the formula, a trans is shown in which the substituents at the 3- and 5-positions face in the opposite directions with respect to the plane of the 7-membered ring, and (R) represents the R-configuration. In the above formula (I ″), the metal ion represented by Q is
Examples thereof include sodium ion, potassium ion, calcium ion, aluminum ion, etc. Among them, sodium ion and potassium ion are preferable. As the substituent of the “optionally substituted phenyl group” represented by ring C, the “substituted” described in the examples of the “optionally substituted hydrocarbon group” defined for R ₂ and R ₃ above. The same as those mentioned as the substituent of the "optionally substituted aryl group" can be mentioned.

The salts of the compounds represented by the formulas (I), (Ia), (Ib), (I ') and (I'') include, for example, hydrochlorides, hydrobromides, sulfates, nitrates, Inorganic salts such as phosphates, such as acetates, tartrates, citrates, fumarates, maleates, toluene sulfonates, methane sulfonates, etc. organic salts such as sodium salts, potassium salts, calcium Salts, metal salts such as aluminum salts, such as triethylamine salts, guanidine salts, ammonium salts,
Examples thereof include pharmacologically acceptable salts such as base salts such as hydrazine salt, quinine salt and cinchonine salt. The sodium salt is particularly preferable. When the present compound is specifically exemplified below,

(3R, 5S) -7-cyano-5- (2,3
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, 5
S) -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, 5
S) -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
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, (3
R, 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, 5
S) -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- (2,2
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, (3
R, 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- (2,2
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
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- (2,2
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, 5
S) -7-Cyano-5- (2-chlorophenyl) -1-
Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid, (3
R, 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-1,2,3,3
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-acetyl] glycine, (3R, 5
S) -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 [2,2
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 [2,2
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, (3
R, 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, (3
R, 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-
Examples thereof include benzothiazepine-3-acetic acid and salts thereof.

The compounds represented by the above general formulas (I), (Ia), (Ib), (I ') and (I'') and salts thereof [hereinafter referred to as
Compounds (I), (Ia), (I
b), (I ') and (I ") may be abbreviated.]
Is, for example, EPA 567026, WO 95/218.
34 (Japanese Patent Application No. 6-15531), EPA 645377
(Japanese Patent Application No. 6-229159), EPA645378.
(Japanese Patent Application No. 6-229160) and the like, and it can be manufactured according to the disclosure of these publications.

Compounds (I), (Ia), (I in the present invention
b), (I ') and (I'') have low toxicity, are safe, and have a triglyceride-lowering effect, therefore, mammals (eg,
It is useful for preventing or treating hyperlipidemia such as hypertriglyceridemia in mice, rats, rabbits, dogs, cats, cows, pigs, monkeys, humans, etc., and renal diseases such as nephritis and nephropathy, arteriosclerosis. , Ischemic disease, myocardial infarction, angina, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, cerebral infarction, thrombosis, diabetes (for example, type based on insulin resistance), pancreatic disorder, percutaneous coronary artery It is useful for preventing or treating restenosis after plastic surgery (PTCA). Compounds (I), (Ia), (Ib), (I ')
Since (I '') has a triglyceride lowering effect, it is advantageously used for treating or preventing hyperlipidemia associated with an increase in triglyceride, for example, hypertriglyceridemia.

Considering the triglyceride lowering action and cholesterol lowering action of the compound of formula (I) and their biological properties, hyperlipidemia, particularly hypertriglycerideemia, hyperlipoproteinemia and hypercholesterolemia and It is particularly suitable for the treatment and prevention of atherosclerotic vascular lesions resulting therefrom and their sequelae such as coronary artery disease, cerebral ischemia, intermittent claudication, gangrene and the like.
In the treatment of these disorders, the compounds of general formula (I) may be used therapeutically alone or in combination with other pharmaceutical ingredients including other lipid-lowering or cholesterol-lowering drugs, In this case, these compounds are preferably administered as an oral preparation, and may be optionally administered as a rectal preparation in the form of suppositories. Possible combination components in this case are, for example, fibrates [eg, clofibrate, benzafibrate, gemfiprozil, etc.], nicotinic acid, its derivatives and analogues [eg, acipimox and probucol], bile acid-binding resins. [Eg, cholestyramine, colestipol, etc.], compounds that inhibit cholesterol absorption [eg, sitosterol, neomycin, etc.], compounds that inhibit cholesterol biosynthesis [eg, HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, etc.] , Squalene epoxidase inhibitors [eg N
B-598 and related compounds]. Further possible combination components are oxidosqualene-lanosterol cyclases, such as decalin derivatives, azadecalin derivatives and indane derivatives.

In addition, the compounds of general formula (I) are suitable for the treatment of diseases associated with hyperchylomicronemia, eg acute pancreatitis. Regarding the mechanism of pancreatitis, chylomicrons cause microembolism in pancreatic capillaries, or pancreatic lipase decomposes triglyceride to increase free fatty acids generated due to hyperchylomicronemia, which strongly stimulates the local area. It is also said to occur. Therefore, the compound of formula (I) of the present invention has a triglyceride lowering action and thus can be used for the treatment of pancreatitis, and can be used alone or in combination with known therapeutic methods for the treatment of pancreatitis. For the treatment of this disease, the compounds of formula (I) can be administered orally or topically, or they can be used alone or in combination with known active compounds. Possible combination components in this case include, for example, aprotinin (trasylol), gabexate mesylate (FOWOY FOY), nafamostat mesilate (fusan), citicoline (nicoline), ulinastatin (miracled), etc. for anti-enzymatic therapy. . Anticholinergics, non-narcotic analgesics, and narcotics are also used for the purpose of pain relief. A further notable application of the compounds of general formula (I) is secondary hyperlipidemia. These include diabetes, hypothyroidism, nephrotic syndrome or chronic renal failure, which cause hyperlipidemia, but in many cases hyperlipidemia exacerbates these diseases,
It is said to form a so-called vicious circle. Given the hypolipidemic effect, the compounds of general formula (I) are also suitable for the treatment and prevention of the progression of these diseases, in which case they can be administered alone or in combination with the medicaments mentioned below.

Antidiabetic: Kinedac, Benfil,
Humarine, Euglucon, Glymicron, Daonyl, Novolin, Monotard, Insulins, Glucobai, Dimerin, Rustinone, Basilcon, Deamelin S, Isudirins; Hypothyroid drug: Dry thyroid (threoid),
Levothyroxine sodium (Tyrazine S), liothyronidine sodium (thyronine, thyromine); Nephrotic syndrome therapeutic agents: Prednisolone (predonin), prednisolone sodium succinate (predonin), usually used as the first-line steroid therapy. Methylprednisolone sodium succinate (Sol medrol), betamethasone (Linderone), etc. are used. In addition, antiplatelet drugs such as dipyridamole (versantine) and dilazep hydrochloride (comelian) are used for anticoagulant therapy. Drugs for treating chronic renal failure: diuretics [eg, furosemide (lasix), bumetanide (rennetron), azosemide (diaart)] ] In combination with antihypertensive agents (eg, ACE inhibitors, (enalapril maleate (renibase)) and Ca antagonists (manninhyron), α receptor blockers, etc., they can be preferably used by oral administration.

A further possible use of the compounds of the general formula (I) according to the invention is in the inhibition of thrombus formation. The blood triglyceride level is positively correlated with the factor VII involved in blood coagulation, and ω
Since triglyceride is lowered and coagulation is suppressed by ingestion of -3 fatty acid, it is considered that hyperTGemia promotes thrombus formation. Moreover, since VLDL in hyperlipidemic patients strongly increased plasminogen activator inhibitor secretion from vascular endothelial cells than in normolipidemic patients, it is considered that triglyceride (TG) reduces fibrinolytic activity. To be Therefore, considering the TG-lowering effect, the compounds of general formula (I) are suitable for the prevention and treatment of thrombus formation. In that case, they may be used alone or in combination with the known therapeutic agents described below, preferably by oral administration. Anti-thrombosis drug: anticoagulant [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin)], thrombolytic drug [eg, urokinase], antiplatelet drug [eg, aspirin, sulfinpyrazolo (anthuran), Dipyridamole (Persanthin), Ticlopidine (Panaldine), Cilostazol (Pletal)] Compound (I) is injected orally or parenterally,
It can be used by infusion, inhalation method, rectal injection, or topical administration, or as it is, or a pharmaceutical composition preparation (for example, powder, granules, tablets, pills, capsules, injections, syrups, emulsions, Elixirs, suspensions, solutions, etc.). That is, at least one compound of the present invention alone or a pharmaceutically acceptable carrier (adjuvant, excipient,
It can be used as a mixture with excipients and / or diluents).

The pharmaceutical composition can be formulated according to a conventional method. Such a preparation can be usually produced by mixing / kneading the active ingredient with additives such as a excipient, a diluent and a carrier. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution and the like. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. A suppository for rectal administration is a drug and a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract and melt in the rectum. It can be manufactured by mixing with a substance that emits.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills and capsules described above. Formulations in such dosage forms comprise the active ingredient compound and at least one additive, for example sucrose,
Lactose, lactose, mannitol (D
-Mannitol), maltitol, dextran, starches (eg, corn starch), microcrystalline cellulose, agar, alginates, chitins, chitosans, pectins, tragacanth gums, gum arabic, gelatins,
It can be produced by mixing and / or kneading with collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms can also, as usual, contain further additives such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, Antioxidants such as α-tocopherol and cysteine, disintegrants (eg, croscarmellose sodium), binders (eg, hydroxypropyl cellulose),
Examples thereof include thickeners, buffering agents, sweetening agents, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsion preparations, syrup preparations, elixir preparations, suspension preparations, solution preparations and the like, which are inert diluents commonly used in the art, such as water and, if necessary, It may contain additives. These oral liquid preparations can be produced by a conventional method such as mixing an active ingredient compound with an inert diluent, and optionally other additives. In the case of an orally administered drug, it usually depends on the dosage form, but is usually 0.01 to 99 W%, preferably 0.1.
1-90 W% It is usually preferable to add 0.5-50 W% of the active ingredient compound of the present invention.

The dose for a particular patient depends on age, weight,
These factors and other factors are taken into consideration depending on the general health condition, sex, diet, administration time, administration method, excretion rate, drug combination, and the degree of the medical condition being treated by the patient at that time or other factors. Compounds (I), (Ia) of the present invention,
The triglyceride lowering agent containing (Ib), (I ') and (I'') has low toxicity and can be used safely.
The daily dose depends on the patient's condition, weight, type of compound,
Depending on the route of administration, for example, prevention of hyperlipidemia
When used as a therapeutic agent, the daily dose for an adult (as a body weight of about 60 kg) is about 1 to 500 mg, preferably about 10 to 200 mg as an active ingredient in the case of an oral agent, and effective in the case of a parenteral agent. About 0.1-100m as a component
g, preferably about 1 to 50 mg, usually about 1 to 20 mg, with no toxicity observed in this range.

[0049]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Examples, but the present invention is not limited thereto. In addition, it is used in the following formulation examples and test examples (3
R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-Tetrahydro-4,1-benzoxazepine-
3-acetic acid (hereinafter sometimes referred to as compound A '), its sodium salt (hereinafter sometimes referred to as compound A), (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) ) -1-Neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (hereinafter sometimes referred to as compound B ′), its sodium salt (hereinafter sometimes referred to as compound B), (3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (hereinafter sometimes referred to as compound C ′), its sodium salt (hereinafter sometimes referred to as compound C), (3R , 5S) -7-Chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetic acid (hereinafter sometimes referred to as compound D '), its sodium salt (hereinafter compound D)
(Sometimes referred to as), EPA567026 and W above.
For example, compound A produced according to the method described in O95 / 21834 (Japanese Patent Application No. 6-15531) is EPA5 described above.
Compound 12 obtained by hydrolyzing Compound 11 obtained according to Example 2 described in 67026 according to Example 74
Was subjected to optical resolution according to Example 2 described in WO95 / 21834 (Japanese Patent Application No. 6-15531), and was further converted to a sodium salt according to Example 5 to produce the compound. Compounds A ', B, B', C, C ', D and D'were similarly prepared.

Formulation Example A hyperlipidemic agent containing the compounds (I), (Ia), (Ib), (I ′) and (I ″) or a salt thereof as an active ingredient in the present invention is, for example, It can be manufactured by the following formulation. 1. Capsule (1) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine -3-Acetic acid sodium salt (Compound A) 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and 1 of (4) After mixing / 2, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine- 3-Acetic acid sodium salt (Compound A) 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) ) 2/3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets.

3. Injectable (1) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine -3-Acetic acid sodium salt (Compound A) 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg Dissolve (1), (2), (3) in distilled water for injection to a total volume of 2 ml. , Enclose in ampoule. All steps are performed aseptically. 4. Capsule (1) (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine -3-Acetic acid sodium salt (Compound B) 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and 1 of (4) After mixing / 2, granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

5. Tablet (1) (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine- 3-Acetic acid sodium salt (Compound B) 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) ) 2/3 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 6. Injectable (1) (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-Acetic acid sodium salt (Compound B) 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg Dissolve (1), (2), (3) in distilled water for injection to a total volume of 2 ml. , Enclose in ampoule. All steps are performed aseptically.

7. Capsule (1) (3R, 5S) -7-Chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 -Benzoxazepine-3-acetic acid sodium salt (Compound D) 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and After mixing 1/2 of (4), granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 8. Tablet (1) (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-acetic acid sodium salt (Compound D) 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), ( 3), 2/3 of (4) and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets.

9. Injection (1) (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 -Benzoxazepine-3-acetic acid sodium salt (Compound D) 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) was injected to a total volume of 2 ml. Dissolve in distilled water for use and seal in an ampoule. All steps are performed aseptically. 10. Capsule (1) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine -3-Acetic acid (Compound A ') 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and 1 / of (4) Mix 2 and then granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

11. Tablet (1) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine- 3-Acetic acid (Compound A ') 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2/3 of 1 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 12. Capsule (1) (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine -3-Acetic acid (compound B ') 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1 /) of (1), (2) and (3) and (4) Mix 2 and then granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

13. Tablet (1) (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benz oxazepine- 3-Acetic acid (Compound B ') 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), (4) 2/3 of 1 and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 14. Capsule (1) (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 -Benzoxazepine-3-acetic acid (Compound D ') 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and ( Mix 1/2 of 4) and granulate. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

15. Tablet (1) (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-acetic acid (Compound D ') 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3) ), 2/3 of (4) and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets.

16. Tablets A mixture consisting of 175 g of Compound A, 175 g of D-mannitol, 118.65 g of corn starch and 105 g of croscarmellose sodium according to the following composition:
After thoroughly mixing with a vertical granulator (FM-VG-10 type, manufactured by Paulex), the mixture was kneaded with an aqueous solution in which 19.25 g of hydroxypropyl cellulose was dissolved (kneading condition: 400 rpm, 10 minutes). The white kneaded product was dried for 30 minutes at a blast temperature of 60 ° C. using a fluid dryer (FD-3S, manufactured by Paulex Co., Ltd.), and then 1.5 mmφ was used using a power mill (P-3 type, manufactured by Showa Kagaku Kikai Kosakusho). It was sieved with a punching screen to give granules. This granule 525.14
g, croscarmellose sodium 31 g and magnesium stearate 1.86 g were added, and a mixer (TM-
15 type, manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 5 minutes to give granules for tableting. 180m of the granules with a tablet machine (Correct 19K, Kikusui Seisakusho) using a 8.0 mmφ flat corner punch
Tablets were made at g and pressure of 0.7 ton / cm ² to obtain 2,350 tablets. Compound A 50 mg D-mannitol 50 mg Corn starch 33.9 mg Croscarmellose sodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mg 180.0 mg in total (per tablet)

Test Example The biological activity of the compounds (I), (Ia), (Ib), (I ′) and (I ″) or salts thereof according to the present invention will be described with reference to Test Examples. Test Example 1 (plasma lipid lowering action in marmosets) [Method] Male common marmosets (19-68 months old, obtained from Japan EDM Co., Ltd.) (3R, 5S)
-7-chloro-5- (2,3-dimethoxyphenyl)-
1-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid sodium salt (Compound A), (3R, 5S) -7-chloro-5- ( 2,4-Dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-Benzoxazepine-3-acetic acid sodium salt (Compound B) and (3R, 5S) -7-chloro-5-
An aqueous solution of (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid sodium salt (Compound C) was placed on a stomach tube for 4 days. Was administered. Blood was collected from the femoral vein under non-fasting conditions, and total cholesterol, HDL (high density lipoprotein) -cholesterol, and triglyceride in plasma were measured by an enzymatic method using a kit (Wako Pure Chemical Industries, Ltd.). In addition, non-HDL-cholesterol was calculated by subtracting HDL-cholesterol from total cholesterol.

[Results] The results are shown in [Table 1].

[Table 1] Plasma total cholesterol, non-HDL-cholesterol and triglycerides were significantly reduced depending on the dose of test compound.

Test Example 2 (Plasma lipid lowering action in Wistar fatty rats) [Method] Male Wistar fatty rats (30 weeks old, Ikeda,
H., Shino, A., Matsuo, T., Iwatsuka, H., And Suzuok
i, Z .: Diabetes, 30, 1045 (1981)), as a test compound, (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-
0.5 of 1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid sodium salt (Compound A)
% Methylcellulose solution was administered for 2 weeks using a stomach tube. Blood was collected from the orbital vein under non-fasting conditions, and total cholesterol and HDL-cholesterol in plasma were measured by an enzymatic method using a kit (Wako Pure Chemical Industries, Ltd.). Non-HD
L-cholesterol was calculated by subtracting HDL-cholesterol from total cholesterol. In addition, triglyceride was measured by an enzymatic method using a kit (Yatron Co., Ltd.).

[Results] The results are shown in [Table 2].

[Table 2] Plasma total cholesterol, non-HDL-cholesterol and triglyceride were significantly reduced depending on the dose of test compound.

[0063]

The effects of the compounds (I), (Ia), and
The triglyceride lowering agent containing (Ib), (I ') and (I'') has an excellent triglyceride lowering action, and therefore, it can be used in mammals (eg, mouse, rat, rabbit, dog,
It is useful for preventing or treating hyperlipidemia such as hypertriglyceridemia in cats, cattle, pigs, monkeys, humans, etc.).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/55 ACJ ACV // C07D 243/04 243/14 243/24 508 255/04 267/06 267/14 281/10 Z 403/04 223 243 413/04 223 243 257 171 317 413/14 319 417/04 223 243 257 271 317 319 491/048 7019-4C 498/04 108 116

Claims (29)

[Claims] (1) Formula (1) [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ and R ₃ are the same or different and are hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocycle. X'is a carboxyl group which may be esterified, a carbamoyl group which may be substituted,
The ring A is substituted with a substituent composed of an optionally substituted hydroxyl group, an optionally substituted amino group, or an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom. An optionally benzene ring or an optionally substituted heterocycle, ring J ′ is a 7- to 8-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms, and ring J ′ is R ₁ , R ₂ , R ₃ and X ′ may further have a substituent] or a pharmacologically acceptable salt thereof. 2. The triglyceride lowering agent according to claim 1, wherein R ₁ is an aliphatic acyclic hydrocarbon group. 3. The triglyceride reducing agent according to claim 2, wherein the aliphatic acyclic hydrocarbon group is a branched alkyl group. 4. The triglyceride lowering agent according to claim 1, wherein R ₂ or R ₃ is an optionally substituted phenyl group. 5. The triglyceride lowering agent according to claim 1, wherein X ′ is an alkyl group substituted with an optionally esterified carboxyl group. 6. The triglyceride reducing agent according to claim 1, wherein X ′ is an alkyl group substituted with an optionally substituted heterocyclic residue having a deprotonable hydrogen atom. 7. A heterocyclic residue is represented by: The triglyceride lowering agent according to claim 6, which is 8. The triglyceride lowering agent according to claim 1, wherein X ′ is an alkyl group substituted with an optionally substituted carbamoyl group. 9. The triglyceride lowering agent according to claim 8, wherein the optionally substituted carbamoyl group is a cyclic aminocarbonyl group. 10. An alkyl group having a linear carbon number of 1 to 4
The triglyceride lowering agent according to claim 5, which is an alkyl group of 11. A heterocycle represented by ring A is The triglyceride lowering agent according to claim 1, which is 12. The triglyceride lowering agent according to claim 1, wherein the substituent on ring J ′ is oxo or thioxo. 13. A condensed ring consisting of ring A and ring J ′ is represented by: The triglyceride lowering agent according to claim 1, which is 14. R ¹ and R ³ are each a hydrogen atom, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group. The triglyceride lowering agent described. 15. The formula: [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ and R ₃ are the same or different and are hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocycle. A group, X ₁ is a bond or a divalent atomic chain,
Y 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 protonated and which may be substituted. The triglyceride-lowering agent according to claim 1, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the ring B represents an optionally substituted benzene ring. 16. The triglyceride reducing agent according to claim 15, wherein R ₁ is an aliphatic acyclic hydrocarbon group. 17. The triglyceride lowering agent according to claim 16, wherein the aliphatic acyclic hydrocarbon group is a branched alkyl group. 18. The triglyceride lowering agent according to claim 15, wherein R ₂ or R ₃ is an optionally substituted phenyl group. 19. The triglyceride lowering agent according to claim 15, wherein X ₁ is a linear or branched alkylene chain. 20. The triglyceride lowering agent according to claim 19, wherein the alkylene chain is a linear alkylene chain having 1 to 4 carbon atoms. 21. The triglyceride lowering agent according to claim 15, wherein Y is an optionally esterified carboxyl group. 22. The triglyceride reducing agent according to claim 15, wherein Y is an optionally substituted heterocyclic residue having a hydrogen atom capable of being deprotonated. 23. A heterocyclic residue is represented by: The triglyceride lowering agent according to claim 22, which is 24. (3R, 5S) -7-chloro-5-
(2,3-Dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-
The triglyceride lowering agent according to claim 1, which comprises benzoxazepine-3-acetic acid or a pharmacologically acceptable salt thereof. 25. (3R, 5S) -7-chloro-5-
(2,4-Dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-
The triglyceride lowering agent according to claim 1, which comprises benzoxazepine-3-acetic acid or a pharmacologically acceptable salt thereof. 26. (3R, 5S) -7-Chloro-5- (4
-Ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,
The triglyceride lowering agent according to claim 1, which comprises 1-benzoxazepine-3-acetic acid or a pharmacologically acceptable salt thereof. 27. The triglyceride lowering agent according to claim 24, 25 or 26, wherein the pharmacologically acceptable salt is a sodium salt. 28. The triglyceride lowering agent according to claim 1, which is used for preventing or treating hyperlipidemia. 29. The triglyceride lowering agent according to claim 1, which is used for preventing or treating hypertriglyceridemia.