JPH07179429A - Condensed ring compound and its use - Google Patents

Abstract

PURPOSE:To obtain a new condensed ring compound which is useful in the prophylaxis and therapy for hypercholesterolemia and coronary ayteriosclerosis because it has excellent inhibitory action against squalene synthase. CONSTITUTION:A compound of formula I [R1 is H, a (substituted) hydrocarbon group; R2' isa a (substituted) phenyl, a (substituted) aromatic heterocyclic group; X' is an (esterified) carboxyl, a (substituted) carbamoyl, a (substituted) OH, a (substituted) NH2, a (substituted) heterocyclic ring residue bearing H atoms which may be deprotonated; ring A is a (substituted) benzene ring, a (substituted) aromatic heterocyclic ring; ring J1 is a 7-membered ring bearing 3 or less hetero atoms; D is C, N; Z1 is C, N, S(O)p (p is 0 to 2), O; K is C, N; ring J1 may bear substituents in addition to R1, R2' and X'], for example, 3,5-trans-7- chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-ben zothiazepine-3- acetic acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a fused ring compound or a salt thereof, and a squalene synthase inhibitor containing these as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Hypercholesterolemia is known as the three major risk factors for ischemic heart disease as well as hypertension and smoking. Proper control of blood cholesterol levels is important for preventing or treating this ischemic heart disease. Besides, it is extremely important for the prevention or treatment of coronary atherosclerosis. Drugs that lower blood cholesterol levels include cholestyramine (Choles
tyramine), colestipol and the like that trap bile acids and inhibit their absorption (for example, disclosed in US Pat. No. 4,027,090), melinamide (Melinamide)
(Disclosed in French Patent No. 1476569), such as acyl coenzyme A cholesterol acyl transferase (ACA).
In addition to those that inhibit T) to suppress intestinal absorption of cholesterol, drugs that suppress cholesterol biosynthesis have attracted attention. As a cholesterol biosynthesis inhibitor,
In particular, Lovastatin (disclosed in US Pat. No. 4,231,938), which inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Simvastatin (US Pat. No. 4).
No. 444784), pravastatin (Pravastati
n) (disclosed in US Pat. No. 4,346,227) and the like are used for medicine. 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. Squalene synthase is an enzyme involved in the essential steps of the new cholesterol biosynthetic pathway. This enzyme is an enzyme that catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.

On the other hand, inhibiting squalene synthase
Compounds expected to inhibit cholesterol biosynthesis
As for, Journal of Medicinal Chemistry, Vol. 5
1, No. 10, pp. 1869-1871, 1988,
Japanese Patent Laid-Open Nos. 1-213288 and 2-10108
No. 8, JP-A-2-235820, JP-A-2-
No. 235821, Japanese Patent Laid-Open No. 3-20226,
Japanese Patent Laid-Open No. 3-68591 and Japanese Patent Laid-Open No. 3-148288
Publication and US Patent No. 5,019,390, US Patent No.
5,135,935, WO9215579, WO93
No. 09115. Also, squalene synthesis
Compounds that exhibit antifungal activity by inhibiting
Variously known (JP-A-4-279589, EP
-475706, EP-494622, E
P-503520, etc.). 2-oxo-2,3,
Induction of 4,5-tetrahydro-1H- [1] -benzazepine
Regarding conductors, J. Med. Chem.,14, 849 (197
1), Chem. Pharm. Bull.,38, 3331 (1990),
J. Chem. Soc. PERKIN TRANS.1., 353
(1991), J. Med. Chem.,14, 40 (1971)
It is shown. 2-oxo-1,2,3,5-tetrohi
For doro-4,1-benzothiazepine derivatives, see J.
 Prakt. Chem.,36, 5 (1967), Arch. Pharm.,
300, 299 (1967), U.S. Pat. No. 3,463,774.
It is shown.

2,3-Dihydro-2-oxo-1H- in which the 3-position is an alkyl group substituted with an ester, a carboxylic acid or carbamoyl, and the 5-position is substituted with an aryl group.
1,4-benzodiazepine derivatives are described in J. Heterocycl.
hem., 27 , 631 (1990), JP-A-63-2466.
66, Bull. Chim. Farm., 113 , 642 (19).
74), J. Chem. Soc., Chem. Commun., (1973),
721, J. Org. Chem., 38, 3502 (1973),
Takeda Research Institute., 29 , 134 (1970). 2-oxo-2,3,5,6-tetrahydro-1H
For the -4,1-benzoxazocine derivative, Che
m. Pharm. Bull., 34 (1), 140 (1986). For 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-dione derivatives, see “Hetroc,” edited by R. Ian Fryer.
yclic Compounds "(1991) (John Wiley & Sons. In
c.) Many examples are shown on pages 289 to 313.
Regarding the 2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepine derivative, JP-B-45-111
No. 48 is shown. 2-oxo-1,2,4,5-
Regarding the tetrahydro-3H-1,3-benzodiazepine derivative, J. Chem. Soc., Perkin Trans. 1 (1
2), 1331 (1976), French Patent 252883.
8 is shown.

[0005]

Ubiquinone, dolichol, heme A, etc. are known to be biosynthesized from farnesyl pyrophosphate on the cholesterol biosynthetic pathway, and therefore, in order to eliminate side effects due to these defects. It is desirable to inhibit the enzyme system after farnesyl pyrophosphate, especially squalene synthase, in the cholesterol biosynthetic pathway.

[0006]

As a result of intensive studies in view of the above circumstances, the present inventors have found that a fused ring compound has an excellent squalene synthase inhibitory action, and completed the present invention. It was That is, the present invention provides (1) Formula (I)

[Chemical 11] [Wherein, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ 'is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group, and X'is an ester. An optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group,
The substituent composed of an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation, a ring A is an optionally substituted benzene ring or an optionally substituted Optionally aromatic heterocycle, ring J ₁ is a 7-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms, D is C or N, and Z ₁ is C, N, S (O ) _q (q is 0, 1 or 2) or O, K is C or N, and the ring J ₁ is R ₁ , R ₂ ', X'.
Besides, it may further have a substituent. However, ring A
And the condensed ring consisting of ring J ₁ and 2-oxo-1,2,3,3
5-tetrahydro-4,1-benzoxazepine ring, 2
-Oxo- (2,3-dihydro or 2,3,4,5
-Tetrahydro) -1H-1,4-benzodiazepine ring and 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine ring] or a salt thereof. , (2) Formula (I ')

[Chemical 12] [Wherein, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ 'is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group, and X'is an ester. An optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group,
The substituent composed of an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation, a ring A is an optionally substituted benzene ring or an optionally substituted Optionally aromatic heterocycle, ring J ₂ is a 7-membered heterocycle, Z ₂ is S (O) _q (q is 0,
1 or 2), C or O, and K is C or N
, G represents O or S. Provided that the condensed ring consisting of ring A and ring J ₂ is a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring] or a salt thereof. The above (1)
The described compound or a salt thereof,

Formula (3) (I ″)

[Chemical 13] [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aroma. In the group heterocyclic 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 hydrogen which can be deprotonated. A substituent is composed of an optionally substituted heterocyclic residue having an atom, ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocycle, and ring J ′ is a ring. A 7- to 8-membered heterocycle containing 3 or less heteroatoms as constituent atoms, D represents C or N, and ring J ′ further has a substituent in addition to R ₁ , R ₂ and X ′. May be. Provided that the condensed ring consisting of ring A and ring J ′ is a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring] or a salt thereof. A squalene synthase inhibitor containing
And (4) Formula (I ''')

[Chemical 14] [In the formula, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aroma. Group heterocyclic group, X 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, or a substituted group An optionally substituted heterocyclic residue having an amino group or a deprotonizable hydrogen atom, ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocycle,
Z ₃ is = N -, - N (R 7) - (R 7 is hydrogen, an alkyl group or an acyl _{group), - S (O) q} - (q is 0, 1 or 2), - CH ₂ -or -O-, and G represents O or S. The broken line portion indicates a double bond when Z ₃ is = N-, and a single bond when Z ₃ is other than = N-. However, Z ₃ is −
When O- and ring A is a benzene ring which may be substituted, G is S], or a squalene synthase inhibitor according to the above (3), which comprises a salt thereof. To do.

The present invention further provides a process for producing a novel compound represented by the formula (I) or a salt thereof. In formulas (I), (I ′), (I ″) and (I ′ ″), the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ₁ is an aliphatic chain. Examples thereof include a formula hydrocarbon group, 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 linear or molecular chain aliphatic hydrocarbon groups such as an alkyl group, an alkenyl group and an alkynyl group. Of these, an 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, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl , C _1-7 alkyl such as n-heptyl,
Among them, n-propyl, isopropyl, isobutyl,
C _3-5 alkyl such as 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, 3-butenyl, 2-ethyl-1
-Butenyl, 2-methyl-2-butenyl, 3-methyl-
2-butenyl, 1-pentenyl, 2-pentenyl, 3-
Examples include C _2-6 alkenyl such as pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, and among them, vinyl and 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
C ₂ such as -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. _-6 alkynyl, among which ethynyl, 1-propynyl, 2
-Propinyl and the like are particularly preferred.

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-
1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like can be mentioned. Examples of the cycloalkadienyl group include 2,4-cyclopentadiene-1-yl and 2,4-
Examples thereof include cyclohexadiene-1-yl and 2,5-cyclohexadiene-1-yl. Examples of the aryl group of the hydrocarbon group include a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, and among them, phenyl and 1-naphthyl. , 2-naphthyl and the like are particularly preferable.

The substituent of the "optionally substituted hydrocarbon group" represented by R ₁ is 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 the substitutable position with any of these substituents.
Five (preferably 1 to 3) may be substituted. Examples of the aryl group which may be substituted include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. The aryl substituent which may be substituted has 1 to 1 carbon atoms.
Three 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 may be substituted with 1 to 2 of these optional substituents. As the cycloalkyl group of the optionally substituted cycloalkyl group,
Examples thereof include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the substituent of the optionally substituted cycloalkyl group and the number of substitutions thereof include the same kind and number 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 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 is an aromatic heterocyclic group having at least one hetero atom of oxygen, sulfur and nitrogen as an atom (ring atom) constituting the ring system, Examples thereof include saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), but aromatic heterocyclic groups are preferable. The aromatic heterocyclic group is an 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 aromatic condensed complex Cyclic group (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, phenoxalinyl. , 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), but furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl and the like are preferable. Examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl,
Examples include oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Examples of the substituent of the optionally substituted heterocyclic group include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.) and the like. The optionally substituted amino group, the optionally substituted hydroxyl group,
And the substituent in the optionally substituted thiol group includes, for example, lower (C _1-3 ) alkyl (eg, methyl,
Ethyl, propyl, etc.) and the like. 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 may be an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.). Further, R ₁ has 1 carbon atom which may have a substituent.
~ 6 acyl groups (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 formulas (I), (I '), (I'') and (I'''), as a substituent of the "optionally substituted phenyl group" represented by R ₂ or R ₂ '. Is halogen (eg, fluorine, chlorine, bromine, iodine, etc.), optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted hydroxyl group, nitro, cyano, etc. It may be substituted with 1 to 3 (preferably 1 to 2) of the same 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, but especially methyl and ethyl. Is 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.), aryl group (eg phenyl, 1-naphthyl, 2-
And aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. In addition, these substituents are
Substituents adjacent to each other may form a ring, for example,

[Chemical 15] And the ring may be substituted with a lower (C _1-3 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and the like.

The aromatic heterocyclic group of the "optionally substituted aromatic heterocyclic group" represented by R ₂ or R ₂ 'is
The aromatic heterocyclic group detailed in R ₁ may be mentioned,
Of these, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl and the like are preferable. As the substituent of the aromatic heterocyclic group,
Examples thereof include alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.). In formulas (I ″) and (I ′ ″), the alkyl group of the “optionally substituted alkyl group” represented by R ₂ has 1 to 6 carbon atoms.
Individual lower alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), preferably methyl, ethyl. And C _1-4 alkyl groups such as propyl, isopropyl, butyl, t-butyl and the like.
The substituent of the optionally substituted lower alkyl group is halogen (eg, fluorine, chlorine, bromine, iodine), a lower alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy). , Butoxy, t-butoxy, etc.) and the like. Among the above, R ₂ or R ₂ ′ is preferably an optionally substituted phenyl group, more preferably a substituted phenyl group, particularly preferably a phenyl group substituted with halogen, lower alkoxy or the like.

In formulas (I), (I ') and (I''),
The “substituent composed of an optionally esterified carboxyl group” represented by X ′ is a substituent having an optionally esterified carboxyl group and an optionally esterified carboxyl group. Groups. 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. “Substituent composed of an optionally substituted hydroxyl group” represented by X ′
Include a substituent having an optionally substituted hydroxyl group and 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. The “substituent composed of an optionally substituted amino group” represented by X ′ is
Examples of the substituent include an optionally substituted amino group and an optionally substituted amino group. Examples of the optionally substituted amino group include those similar to the optionally substituted amino group defined in Y below. The “substituent having a deprotonable hydrogen atom and composed of an optionally substituted heterocyclic residue” represented by X ′ has a deprotonable hydrogen atom and may be substituted. Examples of the substituent include a heterocyclic residue and an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom. 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 16] [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,

[Chemical 17] In represented by those can be mentioned, wherein, m, n represents 0, 1, 2 or 3 independently, E represents a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfone, -N (R ₃₎
-, - NHCO -, - CON (R 5) - or -NHC
Represents ONH-. Here, R ₄ and R ₅ represent hydrogen, an optionally substituted lower alkyl group, an optionally substituted aralkyl group, or an optionally substituted phenyl group.
R ₃ represents hydrogen, a lower alkyl group, an aralkyl group or an acyl group. The alkyl group of the “optionally substituted lower alkyl group” represented by R ₄ and R ₅ 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).
As the substituent of the optionally substituted lower alkyl group, an aromatic heterocyclic group (eg, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), and optionally substituted amino Group, a hydroxyl group which may be substituted, a thiol group which may be substituted, a carboxyl group which may be esterified, a halogen atom (eg, fluorine, chlorine, bromine,
(Iodine) and the like. Examples of the substituent in the optionally 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. Examples of the optionally esterified carboxyl group include methoxycarbonyl,
Examples thereof include ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-naphthoxycarbonyl and the like, with preference given to methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

The aralkyl group of the "optionally substituted aralkyl group" represented by R ₄ and R ₅ is benzyl,
Naphthylmethyl, phenylpropyl, phenylbutyl and the like can be mentioned. As the substituent of the optionally substituted aralkyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy group), a hydroxyl group , Amino groups, carboxyl groups, sulfhydryl groups and the like. Examples of the substituent of the “optionally substituted phenyl group” represented by R ₄ and R ₅ 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, the “lower alkyl group” and “aralkyl group” represented by R ₃ include a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, butyl, tert-group).
Butyl), and aralkyl groups having 7 to 15 carbon atoms (eg, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc.).

The "acyl group" represented by R ₃ includes a lower alkanoyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), a lower alkenoyl group (eg, acryloyl, methacryloyl). , Crotonoyl, isocrotonoyl, etc.), cycloalkanecarbonyl group (eg, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, etc.), lower alkanesulfonyl group (eg, mesyl, ethanesulfonyl, propanesulfonyl etc.) , Aroyl groups (eg, benzoyl, p-toluoyl, 1-naphthoyl, 2-naphthoyl, etc.), aryl lower alkanoyl groups (eg, phenylacetyl, phenylpropionyl, hydrid) Atoropoiru, phenyl butyryl), aryl lower alkenoyl groups (e.g., cinnamoyl, etc. Atoropoiru), arene sulfonyl group (e.g.,
(Benzenesulfonyl, p-toluenesulfonyl group, etc.)
And so on. Further, X may be a carbon chain containing a double bond or -LC (OH)-(L represents a bond or a linear or branched alkylene chain). The "carbon chain containing a double bond" preferably includes one having 1 to 7 carbon atoms, more preferably 1 to 4 carbon atoms forming a straight chain portion, and having a side chain. You may have. The double bond in the carbon chain is contained in either or both of the straight chain portion and the branched chain portion, and preferably, the double bond is included in the straight chain portion. The number of double bonds contained in the carbon chain is not particularly limited as far 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 double-bonded to substitutable carbon atoms on the rings of J ₁ , J ₂ and 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, for example, methylene, ethylene, trimethylene, Examples of the divalent group include tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene, and methyltrimethylene.
Preferred are those having 1 to 3 carbon atoms such as methylene, ethylene, trimethylene and propylene.

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

[Chemical 18] [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 (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-
Butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.), aryloxycarbonyl (eg, phenoxycarbonyl, 1-naphthoxycarbonyl, benzyloxycarbonyl, etc.) and the like can be mentioned. 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.),
An optionally substituted aryl group (eg, phenyl, 1-
Naphthyl, 2-naphthyl, etc.), an optionally substituted aralkyl group (eg, benzyl, phenethyl, etc.) and the like can be mentioned, and these substituents may be the same or different or substituted with two. The substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl is lower (C _1-5 ).
Carboxyl group which may be esterified with alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, neopentyl), aromatic heterocyclic group (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. 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,
Methyl, ethyl, propyl, isopropyl, butyl, t-
Examples thereof include a carboxyl group which may be esterified with butyl). 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 can be mentioned.

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, t-butyl, etc.), A C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substituted aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.),
Examples thereof include optionally substituted aralkyl groups (eg, benzyl, phenethyl, etc.). 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,
Methyl, ethyl, propyl, isopropyl, butyl, t-
Examples thereof include a carboxyl group which may be esterified with butyl). Examples of the substituent of the “optionally substituted amino group” represented by Y 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.), optionally substituted aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted aralkyl group (Eg, benzyl, phenethyl, etc.) 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, (Methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.)
And a carboxyl group which may be esterified. Further, substituents on two nitrogen atoms may be combined with nitrogen atoms to form a cyclic amino group, and examples of such cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl and piperidino. , Morpholino, 1-
Examples thereof include piperazinyl.

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 And a 7-membered (preferably 5-membered) monocyclic heterocyclic residue (preferably nitrogen-containing heterocyclic residue). For example, tetrazol-5-yl or formula

[Chemical 19] [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. Examples of the optionally substituted lower alkyl group include methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl 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 or an alkyl group substituted with an optionally substituted heterocyclic residue having a deprotonizable hydrogen atom. Groups are preferred. In the formulas (I) and (I ′), examples of the aromatic heterocycle represented by ring A include the aromatic heterocyclic groups detailed in R _1.

[Chemical 20] What is represented by is preferable.

The substituents of the "optionally substituted benzene ring" and "optionally substituted aromatic heterocycle" represented by ring A include halogen (eg, fluorine, chlorine,
(Bromine, iodine), a lower alkyl group having 1 to 4 carbon atoms which may be substituted (eg, methyl, ethyl, propyl, butyl, tert-butyl, etc.), which may be substituted having 1 to 4 carbon atoms Examples include good lower alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), nitro groups, 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 optionally substituted lower alkyl group or the optionally substituted lower alkoxy group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), etc. Three
It may be replaced individually. As ring A, 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-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms" represented by ring J ₁ is, for example, O, S (O) _q.
(Q represents 0, 1 or 2) and a 7-membered saturated or unsaturated heterocycle containing at least one of N. However, the number of hetero atoms in the atoms (ring-constituting atoms) forming the ring of the heterocycle is 3 or less. Also,
In addition to the groups represented by R ₁ , R ₂ ′ and X ′, the ring J ₁ may further have 1 or 2 substituents at substitutable positions. As the substituent, when the substituent is bonded to a nitrogen atom on the ring J ₁ (when Z ₁ is N), an alkyl group (eg,
C _1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc., acyl group (eg, formyl, acetyl, propionyl, butyroyl etc.) C _1-4 acyl group) and the like. The alkyl group or acyl group further has a halogen atom (eg,
1 to 5 of them may be substituted with fluorine, chlorine, bromine, iodine). When the substituent is bonded to the carbon atom on the ring J ₁ , 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 ₁ , in addition to the groups represented by R ₁ , R ₂ ′ and X ′, those substituted with oxo or thioxo at a substitutable position are preferable. D as a ring-constituting atom of ring J ₁
Of these, C is preferable. As K as a ring-constituting atom of the ring J ₁ , C is preferable.

The fused ring consisting of ring A and ring J ₁ is
For example

[Chemical 21] And so on. As the formula (I), those represented by the formula (I ′) are preferable. In the formula (I ′), the “7-membered heterocycle” represented by ring J ₂ is, for example, O, S (O) _q
(Q represents 0, 1 or 2) and a 7-membered saturated heterocycle containing at least one of N. Ring J ₂
Z ₂ as a ring-constituting atom of is preferably S
(O) _q (q is 0, 1 or 2). Further, C is preferable as K as a ring-constituting atom of the ring J ₂ . In the formula (I ′), G is more preferably O.

Further, as the formula (I '),

[Chemical formula 22] [Wherein R ₁ , X ′, rings A, Z ₂ and G have the same meanings as described above. Ring B represents a phenyl group having a substituent. However,
When Z ₂ is O and the ring A is a benzene ring which may be substituted, G represents S].

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

The fused ring consisting of ring A and ring J'is
For example

[Chemical formula 23] And so on. As D as a ring-constituting atom of ring J ′, C is preferable. As the formula (I ″), those represented by the formula (I ′ ″) are preferable. Z ₃ is preferably S (O) _q (q is 0, 1 or 2). More preferably, G is O. In the 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, etc.), and 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.

The present compound will be specifically disclosed below.
3,5-cis-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-chloro-5
-(2-Chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-chloro-5 -(2-chlorophenyl) -1-
Propyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-chloro-5- (2-chlorophenyl) -1- Isobutyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3
-Acetic acid methyl ester, 3,5-trans-7-chloro-5- (2-methoxyphenyl) -2-oxo-1-
Propyl-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester,

3,5-trans-7-chloro-5- (2
-Methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-chloro-5- ( 2-Methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester, 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3
-Acetic acid, 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2
-Methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5
-(2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,

(3R) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1-isobutyl-2-
Oxo-1H-1,4-benzodiazepine-3-acetic acid
Methyl ester, (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, (3S) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester, (3S ) -7-Chloro-5- (2-chlorophenyl) -2,3-dihydro-1-isobutyl-2
-Oxo-1H-1,4-benzodiazepine-3-acetic acid,

N- [3,5-trans-7-chloro-5
-(2-Chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl] glycine methyl ester, N- [3,5-trans- 7-chloro-5- (2-
Chlorophenyl) -1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl] glycine, 3,5-trans-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 ethyl ester, 7-chloro-5- (2-chlorophenyl) -1-isobutyl-2- Oxo-2,3,4,5-
Tetrahydro-1H- [1] -benzazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-thioxo- 4,1-benzoxazepine-3-acetic acid ethyl ester,

3,5-trans-7-chloro-5- (2
-Chlorophenyl) -1-neopentyl-1,2,3,3
5-tetrahydro-2-thioxo-4,1-benzoxazepine-3-acetic acid, 7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,
3,5-Tetrahydro-4,1-thieno [2,3-e]
Oxazepine-3-acetic acid ethyl ester, 3,5-trans-7-chloro-5- (2-chlorophenyl) -1
-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-
3-acetic acid, 3,5-trans-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 ethyl ester,
3,5-cis-7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester,

3,5-trans-7-chloro-5- (2
-Methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid, 3,5-cis-7-chloro -5- (2-Methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-3-
Acetic acid, 3,5-trans-7-chloro-1-isobutyl-5- (2-methoxyphenyl) -2-oxo-1,
2,3,5-Tetrahydro-4,1-thieno [2,3-
e] Oxazepine-3-acetic acid ethyl ester, 3,5
-Cis-7-chloro-1-isobutyl-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-
3-Acetic acid ethyl ester, 3,5-trans-7-chloro-1-isobutyl-5- (2-methoxyphenyl)
-2-oxo-1,2,3,5-tetrahydro-4,1
-Thieno [2,3-e] oxazepine-3-acetic acid,

3,5-cis-7-chloro-1-isobutyl-5- (2-methoxyphenyl) -2-oxo-1,
2,3,5-Tetrahydro-4,1-thieno [2,3-
e] Oxazepine-3-acetic acid, 3,5-trans-7-
Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7 -Chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5-
(2,4-dimethoxyphenyl) -1-isobutyl-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,

3,5-trans-7-chloro-5- (3
-Hydroxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (4-hydroxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3
-Acetic acid, 3,5-trans-7-chloro-5- (3-hydroxy-2-methoxyphenyl) -1-isobutyl-
2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetic acid, 3,5-trans-7-
Chloro-5- (4-hydroxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetic acid,
3,5-trans-7-chloro-5- (3-ethoxy-
2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid,

3,5-trans-7-chloro-5- (4
-Ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,
1-benzothiazepine-3-acetic acid, 3,5-trans-
7-chloro-5- (3-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetic acid,
3,5-trans-7-chloro-5- (4-ethoxy-
2-Methoxyphenyl) -1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5
-(2-chloro-3-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2-chloro-4-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,3
5-tetrahydro-4,1-benzothiazepine-3-acetic acid,

3,5-trans-7-chloro-5- (2
-Chloro-3-methoxyphenyl) -1-isobutyl-
2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetic acid, 3,5-trans-7-
Chloro-5- (2-chloro-4-methoxyphenyl)-
1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5
-Trans-7-chloro-5- (2-chloro-3-hydroxyphenyl) -1-neopentyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5-
(2-Chloro-4-hydroxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2-chloro-3-hydroxyphenyl) -1-isobutyl-2-oxo-1,2,3,3
5-tetrahydro-4,1-benzothiazepine-3-acetic acid, 3,5-trans-7-chloro-5- (2-chloro-4-hydroxyphenyl) -1-isobutyl-2-oxo-1,2 , 3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, and the like.

The salts of the compounds (I), (I '), (I'') and (I''') include, for example, hydrochloride, hydrobromide,
Inorganic salts such as sulfates, nitrates, phosphates, such as acetate,
Tartrate, citrate, fumarate, maleate,
Organic acid salts such as toluene sulfonate and methane sulfonate, for example, sodium salt, potassium salt, calcium salt,
Examples thereof include metal salts such as aluminum salts, and pharmacologically acceptable salts such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, quinine salts, cinchonine salts, and other base salts. The production method of the compound of the present invention is described below. Formula (Ia)

[Chemical formula 24] [Wherein Y'represents an optionally esterified carboxyl group defined in Y, and other symbols have the same meanings as above], the compound represented by the following method can be produced. You can

(Method A)

[Chemical 25]

(Method B)

[Chemical formula 26] [In the formula, R ₆ represents the alkyl moiety of the esterified carboxyl group defined by Y ′, and Q represents halogen. Other symbols have the same meanings as above]. From formula (II) in (method A) to formula (Ia-1), formula (I) in (method B)
The production of the formula (Ia-3) from I ′) can be carried out, for example, with an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, a hydrocarbon solvent such as benzene, toluene, hexane or heptane, methanol, ethanol, propanol or butanol. Alcohol solvent, acetone, dimethylformamide, dimethylsulfoxide, acetic acid solvent, if necessary, acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
It can be carried out in the presence of phosphoric acid, methanesulfonic acid, toluenesulfonic acid). The amount of the compound represented by the formula (III) is usually 1 to 10 mol, preferably 1 to 1 mol, relative to 1 mol of the compound represented by the formula (II) or the formula (II ′).
Use about 2 molar amount. The reaction temperature is 0 to 200 ° C, preferably about 50 to 100 ° C. The reaction time is usually 1 to
It is 24 hours, preferably about 1 to 3 hours.

The method for producing the formula (Ia-2) from the formula (Ia-4) in the (Method B) is, for example, diethyl ether,
An ether solvent such as tetrahydrofuran or dioxane,
In a hydrocarbon solvent such as benzene, toluene, hexane, heptane, etc., in a dimethylformamide, dimethylsulfoxide solvent, if necessary, a base (for example, sodium hydride,
Lithium hydride etc.). The compound represented by the formula (V) is used usually in an amount of 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound represented by the formula (Ia-4). Reaction temperature is 0-200
C., preferably about 20 to 100.degree. The reaction time is 1 to 24 hours, preferably about 1 to 5 hours.

The production method from Formula (Ia-1) to Formula (Ia-2) in (Method A) and Formula (Ia-3) to Formula (Ia-4) in (Method B) is, for example, water or Ether-based solvents such as diethyl ether, tetrahydrofuran, dioxane, hydrocarbon-based solvents such as benzene, toluene, hexane, heptane, methanol, ethanol, propanol, etc.
Alcohol-based solvent such as butanol, acetone, dimethylformamide solvent, if necessary a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, Barium hydroxide, etc.)
Can be performed in the presence of. For 1 mol of the compound represented by the formula (Ia-1) or the formula (Ia-3),
The compound represented by V) is generally used in an amount of 1-10 mol, preferably 1-2 mol. Reaction temperature is 0-100
C., preferably about 20 to 50.degree. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours.

The method of producing the formula (Ia-2) from the formula (Ia-2) in the (Method B) is, for example, water or an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, benzene, toluene, hexane or heptane. Hydrocarbon solvents such as, methanol, ethanol, propanol,
Alcohol solvent such as butanol, acetone, dimethylformamide solvent, if necessary a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, (For example, barium hydroxide). Reaction temperature is 0-100
C., preferably about 20 to 50.degree. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours. Formula (Ib)

[Chemical 27] The compound represented by the formula [wherein the symbols have the same meanings as defined above] can be produced by the following method.

(Method C)

[Chemical 28]

(Method D)

[Chemical 29] [In the formula, P represents an amine protecting group such as a carbobenzyloxy group and a t-butyloxycarbonyl group. Other symbols have the same meanings as above].

Formula (VI) in (Method C) and (Method D)
To the formula (VIII) or the formula (VI ′) to the formula (VIII ′) include, for example, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as benzene, toluene, hexane and heptane. , A halogen-based solvent such as dichloromethane or chloroform, a condensing agent such as diethyl cyanophosphate or dicyclohexylcarbodiimide in acetonitrile or dimethylformamide, and if necessary, a base (eg, triethylamine, 4-
It can be carried out in the presence of dimethylaminopyridine, N-methylpiperidine, etc.). Formula (VI) or Formula (VI ')
The amount of the compound represented by the formula (VII) is usually 1 to 5 mol, and preferably 1 to 1 mol of the compound represented by
Use about 1.5 molar amount. The reaction temperature is 0 to 100 ° C, preferably about 20 to 50 ° C. Reaction time is 1-24
The time is preferably about 2 to 5 hours. In this case, the condensing agent is usually used in an amount of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound represented by the formula (VI) or the formula (VI ′).

From the formula (VIII) in the (method C) to the formula (Ib
-1) or formula (VIII ') in (method D) to formula (Ib
-3), for example, diethyl ether, tetrahydrofuran, an ether solvent such as dioxane, a hydrocarbon solvent such as benzene, toluene, hexane, heptane, an alcohol solvent such as methanol, ethanol, propanol, butanol, In a halogen-based solvent such as acetone, dimethylformamide, acetonitrile solvent, dichloromethane, chloroform, etc., by a method known per se, for example, when P is a carbobenzyloxy group, P is t reduced by catalytic reduction using palladium, platinum or the like as a catalyst. In the case of a butoxycarbonyl group, a compound obtained by dissolving or suspending in an acid (for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid) to remove the amine protecting group P is treated with, for example, diethyl ether,
In an ether solvent such as tetrahydrofuran or dioxane, a hydrocarbon solvent such as benzene, toluene, hexane or heptane, an alcohol solvent such as methanol, ethanol, propanol or butanol, a dimethylformamide or acetonitrile solvent, if necessary, an acid (for example, hydrochloric acid, It can be performed in the presence of bromic acid, acetic acid, propionic acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, etc.).
The reaction temperature is 0 to 100 ° C, preferably about 30 to 70 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 10
It's about time.

In the (Method D), the production method from the formula (Ib-3) to the formula (Ib-1) is the same as in the (Method B) in the production method of the compound represented by the above formula (Ia). It can be produced by a method similar to the production method from Ia-4) to formula (Ia-2). Further, in the (method C), the formula (Ib-1) to the formula (Ib-2) and in the (method D), the formula (Ib-1)
To the formula (Ib-2) are represented by the formula (Ia- in the method B) in the process for producing the compound represented by the formula (Ia).
It can be produced by a method similar to the production method from 2) to formula (Ia-1). Expression (Ic)

[Chemical 30] The compound represented by the formula [wherein the symbols have the same meanings as defined above] can be produced by the following method.

[0049]

[Chemical 31] [Wherein the symbols have the same meanings as described above] J. Med. Chem., 27 , 1508 (1984), J. Med. C
hem., 14 , 851 (1971), the compound represented by the formula (IX) obtained by synthesizing the compound represented by the formula (IX) is a compound represented by the formula (Ia). From the formula (Ia-4) to the formula (Ia-) in (Method B) in the production method.
It can be manufactured by the same method as the manufacturing method in 2). The compound represented by the formula (Ic-1) can be produced from the compound represented by the formula (X) by, for example, an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, or a hydrocarbon solvent such as benzene, toluene, hexane or heptane. , Dimethylformamide, dimethylsulfoxide solvent in the presence of sodium hydride, lithium hydride, lithium diisopropylamide and the like. The amount of the compound represented by the formula (XI) is usually 1 to 5 mol, preferably 1 to 1 mol, relative to 1 mol of the compound represented by the formula (X).
Use about 2 molar amount. The reaction temperature is -78 ° to 50 ° C, preferably -78 ° to 0 ° C, and the reaction time is generally 1 to 24 hours, preferably 3 to 10 hours. Formula (Ic-1)
The compound represented by the formula (Ic-2) can be produced from the compound represented by the same manner as in the production of the formula (Ia) from the formula (Ia-2) to the formula (Ia-1) in the method (B). It can be manufactured. Expression (Id)

[Chemical 32] The compound represented by the formula [wherein the symbols have the same meanings as defined above] can be produced by the following method.

(Method E)

[Chemical 33]

(Method F)

[Chemical 34]

(Method G)

[Chemical 35] [In the formula, each symbol has the same meaning as above]. From the formulas (VI ′) to (XIII) and the formula (XIV) in the above (Method E)
To (XV), or formulas (VI) to (XVI) in (Method F),
Formulas (II) to (XVII) can be carried out by utilizing an acylation reaction known per se. For the acylation reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, halogen solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, hydrocarbon solvents such as benzene, toluene, hexane and heptane, dimethylformamide. , In a solvent such as dimethylsulfoxide, if necessary, water and a base (for example, an organic base such as 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, It can be carried out in the presence of sodium hydride, potassium hydride, etc.). Formula (VI '), (X
IV), (VI) and 1 mol of the compound represented by (II),
The acid chloride and methanesulfonic acid chloride represented by formula (XII) and 4-chloroformylbutyric acid ester are usually 1
It is used in an amount of about 10 to 10 mol, preferably about 1 to 3 mol. The reaction temperature is −50 to 100 ° C., preferably 0 to
It is about 50 ° C. The reaction time is usually 1 to 48 hours, preferably 5 to 10 hours.

From the formulas (XIII) to (X
III '), Formula (VI') to (VI) in (Method F), Formula (II ')
From (II) to (II), for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, hydrocarbon solvents such as benzene, toluene, hexane, heptane, alcohol solvents such as methanol, ethanol, propanol, acetone, It can be carried out in a dimethylformamide solvent, if necessary, in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). The compound represented by the formula (V) is usually 1 to 10 mol, preferably 1 to 2 mol per 1 mol of the compound represented by the formulas (XIII), (VI ′) and (II ′). Used to a degree. The reaction temperature is 0 to 100 ° C, preferably 20 to 5
It is about 0 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours. Also, from the formula (XV) in (Method E) to (Id-1), from the formula (VI ') in (Method F)
(II '), (XVI) to (XVII) carbonyl group reduction reaction, protic solvent (methanol, ethanol, propanol, butanol, etc.) or aprotic solvent (eg, ethyl ether, tetrahydrofuran, dioxane, etc.) ) In the solvent of metal hydrogen complex compound (for example, lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, etc.). Such a metal-hydrogen complex compound has the formula (X
V), (VI ') and (XVI) are generally used in an amount of 0.3 to 5 mols, preferably 0.5 to 2 mols, per mol of the compound. The reaction temperature is −20 to 100 ° C.
It is preferably about 20 to 50 ° C.

From formulas (XVII) in (Method F) to (Id-2)
The cyclization reaction into, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, hydrocarbon solvents such as benzene, toluene, hexane, heptane, alcohol solvents such as methanol, ethanol, propanol, butanol, acetone, It can be carried out in a solvent such as dimethylformamide, if necessary, in the presence of a base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). These bases are generally used in an amount of 1-5 mol, preferably 1-2 mol, per 1 mol of the compound represented by the formula (XVII). The reaction temperature is -20 to 100 ° C, preferably about 20 to 100 ° C. The reaction time is usually 1 to 20 hours, preferably 2
~ 5 hours. From (XIII ') in (Method E)
The reaction to (XIV) is carried out in an alcohol represented by the formula (IV ′), if necessary, in the presence of an inorganic acid such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or an organic acid such as toluenesulfonic acid or methanesulfonic acid. The reaction can be carried out at a reaction temperature of -20 to 100, preferably about 20 to 50 ° C. The reaction time is usually 10 to 100 hours, preferably 10 to 48 hours.

(Id-1) to (Id-4) in (Method E),
The reaction from (Id-2) to (Id-4) in Method F is described by the formula (Ia)
From (Ia-2) to (Ia-1) in (Method B) when synthesizing
Can be manufactured by a method similar to that for manufacturing. The compounds represented by (Id-3) and (Id-5) in (Method G) can be produced according to known methods. Expression (Id ')

[Chemical 36] [Wherein the symbols have the same meanings as described above] is a compound represented by the formula (Ik ′) described below.

[Chemical 37] It can be produced by oxidizing a compound represented by the formula [wherein the symbols have the same meanings as defined above]. At that time, any solvent may be used as long as it does not interfere with the reaction.
It can be manufactured by using chromic acid or nickel peroxide. At that time, the oxidizing agent is used in an amount of 0.5 to 20 molar equivalents, preferably 1 to 3 molar equivalents, and the reaction temperature is 0 to 100 relative to 1 mol of the compound represented by the formula (Ik ′).
C., preferably about 15 to 50.degree. The reaction time is 0.5 to 5 hours, preferably about 1 to 2 hours.

Formula (Ie)

[Chemical 38] The compound represented by the formula [wherein the symbols have the same meaning as defined above] can be produced by the following method.

[Chemical Formula 39] [Wherein the symbols have the same meanings as defined above] Production of formula (VI) or formula (XXII) into formula (XXIII)
For example, in an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, a hydrocarbon solvent such as benzene, toluene, hexane, heptane, an alcohol solvent such as methanol, ethanol, propanol and butanol, a solvent such as dimethylformamide and dimethyl sulfoxide, Compound 1 represented by formula (VI) or formula (XXII)
The compound represented by the formula (XXIV) is usually 1 to mol.
It is used in an amount of 10 mol, preferably about 1 to 2 mol. The reaction temperature is 0 to 200 ° C, preferably about 50 to 100 ° C. The reaction time is 1 to 48 hours, preferably 10 to 24 hours
It's about time.

Production from the formula (XXIII) to the formula (Ie) is carried out in a solvent which does not interfere with usual reactions, for example, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as benzene, toluene, hexane and heptane. In a solvent, an alcohol solvent such as methanol, ethanol, propanol, butanol, etc., or a solvent such as dimethylformamide, dimethylsulfoxide, etc., with respect to 1 mol of the compound represented by the formula (XXIII), triphosgene, 1,1′-
A carbonylating agent such as carbonyldiimidazole or 4-nitrophenyl chloroformate is usually used in an amount of 1-10 mol, preferably 1-2 mol. Reaction temperature is 0
To 200 ° C, preferably about 50 to 100 ° C. The reaction time is 0.5 to 24 hours, preferably about 1 to 5 hours. Expression (If)

[Chemical 40] The compound represented by the formula [wherein the symbols have the same meaning as defined above] can be produced by the following method.

[0058]

[Chemical 41] [In the formula, symbols have the same meaning as above]

The process for producing the compound represented by the formula (XXVII) from the compound represented by the formula (XXV) and the formula (XXVI) is carried out by using dimethylformamide as a solvent in the presence of sodium hydride, lithium hydride, alkyllithium and the like. 1 to 5 molar equivalents of the compound represented by the formula (XXVI), preferably 1 to 1.5 moles, relative to 1 mol of the compound represented by the formula (XXV) in an ether solvent such as ethyl ether, tetrahydrofuran and dioxane. Equivalent amount is used, and the reaction temperature is -78 to 100.
C, preferably about -20 to 30C. The reaction time is 0.1 to 5 hours, preferably 0.5 to 2 hours. The compound represented by the formula (XXVII) to the formula (XXVIII) can be produced, for example, by using a solvent such as a protic solvent (methanol, ethanol, propanol, butanol) or an aprotic solvent (eg ethyl ether, tetrahydrofuran, dioxane). It can be produced by treating with a metal-hydrogen complex compound (for example, lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, lithium borohydride, etc.).
Such a metal-hydrogen complex compound is usually 0.3 to 5 mole equivalent based on 1 mole of the compound represented by the formula (XXVII),
Preferably about 0.5 to 2 molar equivalents are used. The reaction temperature is -20 to 100 ° C, preferably 0 to 20 ° C. The reaction time is usually 0.5 to 10 hours, preferably 1 to
5 hours.

The compound of formula (XXIX) can be produced by oxidizing the compound of formula (XXVIII). As the solvent used at that time,
Any compound may be used as long as it does not interfere with the reaction, and can be produced, for example, by using dimethylsulfoxide and oxalyl chloride or (sulfur trioxide) pyridine complex in a solvent such as dioxane, tetrahydrofuran, dichloromethane, dichloroethane, chloroform. At that time, the oxidizing agent is 0.5 to 20 molar equivalents, preferably 1 to 3 molar equivalents, and the reaction time is -78 ° to 50 ° C, preferably -78 °, relative to 1 mol of the compound represented by the formula (XXVIII). ~ 20
It is about ℃. The reaction time is 0.1 to 10 hours, preferably 0.2 to 2 hours. If necessary, a base (for example, 4-dimethylaminopyridine, triethylamine,
(Triethylenediamine, tetramethylethylenediamine, etc.). The compound represented by the formula (XXX) can be produced by subjecting the compound represented by the formula (XXIX) and the compound represented by the formula (XXXV) to a reductive amination reaction. For example, in an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, a hydrocarbon solvent such as benzene, toluene, hexane and heptane, an alcohol solvent such as methanol, ethanol and propanol, a metal hydrogen complex compound (for example, sodium borohydride, Lithium aluminum hydride,
In the presence of sodium cyanoborohydride, etc.)
X) is 0.5 to 10 molar equivalents of the compound of the formula (XXXV), preferably 0.5 to 1 mole of the compound of the formula (XXXV).
1.5 molar equivalents, the metal complex compound is 0.3 to 5 molar equivalents,
Preferably about 0.5 to 1.5 molar equivalents are used. The reaction temperature is 0 to 100 ° C, preferably about 30 to 60 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 1
It is about 0 hours.

The compound represented by the formula (XXXI) has the formula (XXI
It can be produced by reacting the compound represented by X) with trifluoroacetic anhydride or trifluoroacetic acid chloride. Ether solvents such as diethyl ether, tetrahydrofuran, dioxane, hydrocarbon solvents such as benzene, toluene, hexane, heptane, dichloromethane,
In a halogen-based solvent such as dichloroethane or chloroform, or a solvent such as dimethylformamide, 0.5 to 3 molar equivalents of trifluoroacetic anhydride or trifluoroacetic acid chloride, preferably 1 to 1 mol of the compound represented by the formula (XXX) are used. Two
The molar equivalent and the reaction temperature are 0 to 100 ° C., preferably 20 to
It is about 50 ° C. The reaction time is 5 minutes to 5 hours, preferably about 0.1 to 1 hour. If necessary, this production should be carried out in the presence of a base (for example, an organic base such as 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.). You can The method for producing the compound represented by the formula (XXXII) is as follows. The compound represented by the formula (XXXI) is prepared by using an alcohol solvent such as methanol, ethanol, propanol or butanol, dimethylformamide, acetonitrile,
It can be produced by catalytic hydrogen reduction using a palladium / carbon catalyst in a solvent such as ethyl acetate. Hydrogen pressure is 1 to 100 atm, preferably 1 to 10
Atmospheric pressure and reaction temperature are 0 to 200 ° C., preferably 20 to 50
It is about ℃.

The compound represented by the formula (XXXIII) has the formula (XX
It can be produced by subjecting the compound represented by XII) to a nitrogen-carbon bond reaction between a halogenated hydrocarbon group or a reductive amination reaction between an aldehyde or a ketone group. The production conditions are the same as the method for producing the compound represented by the formula (Ia) from the formula (Ia-4) to the formula (Ia-2) in (Method B), or the formula (If)
From the formula (XXIX) to the formula (XXIX) in the process for producing the compound represented by
It can be manufactured by a method similar to the manufacturing method for X).
The production of the formula (XXXIV) is carried out by using hydrochloric acid, alcoholic solvent such as methanol, ethanol, propanol, butanol, etc., ether solvent such as tetrahydrofuran, dioxane, etc.
It can be produced by hydrolyzing the formula (XXXIII) in the presence of an acid such as sulfuric acid or phosphoric acid. Reaction temperature is 0 to 1
00 ° C, preferably 30-70 ° C, reaction time 1-48
The time is preferably about 10 to 20 hours. Expression (XXXI
The method for producing the compound represented by the formula (If-1) from V) is the same as the method for producing the compound represented by the formula (Ie) from the formula (XXIII) to the formula (Ie-1). Can be manufactured in. Further, the production method of the compound represented by the formula (If-1) to the formula (If-2) is the same as the production method of the compound represented by the formula (Ia). It can be produced by the same method as the production method for Ia-1).

Formula (Ig)

[Chemical 42] The compound represented by the formula [wherein the symbols have the same meaning as defined above] can be produced by the following method.

[Chemical 43] [Wherein the symbols have the same meanings as described above] The compound represented by the formula (XXXVI) is a compound represented by the formula (Ia-4) A method similar to the production method for Ia-2), or the formula (If)
From the formula (XXIX) to the formula (XXIX) in the process for producing the compound represented by
It can be produced by a reductive amination method similar to the production method for X).

The production method of the formula (XXXVII) is as follows. It can be produced by reacting malonyl dichloride in a solvent such as water. Malonyl dichloride is used in an amount of 1 to 10 molar equivalents, preferably 1 to 2 relative to 1 mol of the compound represented by the formula (XXXVI).
About molar equivalent. The reaction temperature is -20 to 100 ° C, preferably 0 to 70 ° C, and the reaction time is 0.5 to 24 hours, preferably 1 to 3 hours. The production method of the formula (Ig-1) is the compound of the formula (XXXVII) and the formula (XXXVII).
It can be produced by reacting the compound represented by I) in the presence of, for example, sodium hydride, alkyllithium and the like. For example, dimethylformamide, acetonitrile, diethyl ether, tetrahydrofuran,
In a solvent such as dioxane, the compound represented by the formula (XXXVIII) was added to 1 mol of the compound represented by the formula (XXXVII) in an amount of 0.
5 to 5 molar equivalents, preferably 1 to 2 molar equivalents are used, and sodium hydride and alkyllithium are used in 0.5 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents. The reaction temperature is −20 to 100 ° C., preferably 0 to 30 ° C., and the reaction time is 0.5 to 24 hours, preferably about 1 to 3 hours.

Of the compounds of formula (I '), those of formula (Ih)

[Chemical 44] The compound represented by the formula [wherein the symbols have the same meaning as defined above] can be produced by the following method.

[Chemical formula 45] The compound represented by the formula (XXXIX) can be produced by subjecting the compound represented by the formula (XXVIII) to hydrogen and a palladium catalyst, hydrazine and a Raney nickel catalyst, and the like. Examples of the solvent include alcohol solvents such as methanol, ethanol and propanol, ethyl acetate,
It can be produced by using tetrahydrofuran, dimethylformamide, or acetonitrile.

Expression (XXXX), Expression (XXXXI), Expression (Ih−
1) and the compound of formula (Ih-2)
The compound (d) can be produced by the same method as the production method (method G). Among the compounds of formula (I ′), formula (Ii)

[Chemical formula 46] [Wherein the symbols have the same meanings as defined above] are represented by the formula (Ij)

[Chemical 47] [Wherein the symbols have the same meanings as described above], a compound represented by the following formula is reacted with diphenylphosphoryl azide in the presence of a base in a solvent, and then the obtained product is treated with an acid in the solvent. It can be manufactured. The solvent used in the reaction of the compound represented by the formula (Ij) and diphenylphosphoryl azide may be any solvent as long as it does not interfere with the reaction, and examples thereof include dimethylformamide and dichloromethane,
Examples thereof include halogen-based solvents such as dichloroethane and chloroform, ether-based solvents such as diethyl ether, tetrahydrofuran and dioxane. Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, and the like. Compound 1 represented by formula (Ij)
Diphenylphosphoryl azide is used in an amount of 1 to 10 molar equivalents, preferably 1.5 to 3 molar equivalents, based on moles. The reaction temperature is -20 to 50 ° C, preferably 0 to 20 ° C. The reaction time is 0.5 to 5 hours, preferably about 1 to 2 hours. When the product obtained by the above reaction is treated with an acid, the solvent used includes water, dioxane, dimethylformamide and the like. Examples of the acid used include sulfuric acid, hydrochloric acid, nitric acid and hydrobromic acid. Mineral acids may be mentioned. The reaction temperature is 20 to 200 ° C, preferably 50 to
The reaction time is about 0.5 to 5 hours, preferably about 1 to 2 hours.

Of the compounds of formula (I '), those of formula (Ik)

[Chemical 48] [Wherein the symbols have the same meanings as defined above] are represented by the formula (Im)

[Chemical 49] [In the formula, m'represents 0, 1 or 2, and other symbols have the same meanings as described above], and can be produced by subjecting the compound to a reduction reaction. For example, in a solvent of a protic solvent (methanol, ethanol, propanol, butanol, etc.) or an aprotic solvent (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), a metal hydrogen complex compound (eg, lithium aluminum hydride, aluminum hydride) It can be produced by treating with sodium, sodium borohydride, etc.). Such a metal-hydrogen complex compound is usually 0.3 to 5 molar equivalents relative to 1 mol of the compound represented by the formula (Im),
Preferably about 0.5 to 2 molar equivalents are used. The reaction temperature is -20 to 100 ° C, preferably 0 to 20 ° C. The reaction time is usually 0.5 to 10 hours, preferably about 1 to 3 hours.

Further, the compound represented by the formula (Ik) has the formula (Ik)
It can also be produced by converting the amine moiety of the compound represented by i) to a hydroxyl group. For example, formula (Ii)
It can be produced by adding sodium nitrite to a compound represented by the following in the presence of an acid in a solvent and then treating the obtained diazo compound in the presence of a base in the solvent. The diazotization can be performed, for example, by adding 0.5 mol of sodium nitrite to 1 mol of the compound represented by the formula (Ii) in a solvent such as water or hydrous dioxane or hydrous dimethylformamide.
~ 3 molar equivalents, preferably 1-1.5 molar equivalents are used.
Any acid may be used as long as it does not interfere with the reaction,
For example, acetic acid and sulfuric acid are mainly used. Reaction temperature is -2
0-20 ° C, preferably 0-5 ° C, reaction time 5-60
Minutes, preferably about 10 to 30 minutes.

Formula (XXXXII) as a synthetic intermediate

[Chemical 50] [In the formula, Q ′ represents halogen (chlorine, bromine, iodine), and other symbols have the same meanings as described above. ] The compound represented by the formula (Ii) is the same as the method used for producing the compound represented by the formula (Ik) from the compound represented by the formula (Ii).
The compound represented by i) can be produced by diazotizing with sodium nitrite in hydrochloric acid, hydrobromic acid or hydroiodic acid and then heating. Reaction temperature is 20-2
00 ° C., preferably 50 to 100 ° C., reaction time 5 minutes to
It is about 2 hours, preferably about 15 to 30 minutes.

Expression (In)

[Chemical 51] [In the formula, Y "is an esterified carboxyl group, optionally substituted carbamoyl group, hydroxyl group, hydrogen, halogen (chlorine, bromine, iodine) in the above-defined Y.
And other symbols have the same meanings as described above. ] Is a compound of the formula (Ij) and a compound of the formula (XXXXIII)

[0071]

[Chemical 52] [In the formula, symbols have the same meanings as described above. ] It can manufacture by condensing with the compound shown by these. The compound represented by formula (Ij) and the compound represented by formula (XXXXIII) can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. As the solvent to be used, hydrocarbon solvents such as benzene, toluene, hexane, heptane, halogen solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, ether solvents such as ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide. Etc. As the base, triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, etc. are used. As the condensing agent,
Examples of the condensing agent used for peptide synthesis include dicyclohexylcarbodiimide, diethyl cyanophosphate, and 1-ethyl-3- (3-dimethylaminopropyl).
Carbodiimide etc. are mentioned. The compound represented by the formula (XXXXIII) is used in an amount of 0.5 to 2 molar equivalents, preferably 1 to 1.2 molar equivalents, and the condensing agent is used in an amount of 0.5 to 5 molar, based on 1 mole of the compound represented by the formula (Ij). An equivalent amount, preferably 1 to 2 molar equivalents, is used. The reaction time is 0 to 100 ° C, preferably 2
The reaction time is 0 to 50 ° C. and the reaction time is 0.5 to 24 hours, preferably about 1 to 5 hours.

Formula (Io)

[Chemical 53] [In the formula, symbols have the same meanings as described above. The compound represented by the formula] is obtained by reacting the compound represented by the formula (Ij) with diphenylphosphoryl azide in a solvent in the presence of a base, and then obtaining the obtained product in a solvent, the compound represented by the formula (XXXXIII). It can be produced by reacting with. Expression (I
The solvent used in the reaction of the compound represented by j) with diphenylphosphoryl azide may be any solvent as long as it does not interfere with the reaction. The ether solvents of Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, and the like. Compound 1 represented by formula (Ij)
The diphenylphosphoryl azide is used in an amount of 1 to 10 molar equivalents, preferably 1.5 to 3 molar equivalents, based on moles. The reaction temperature is −20 to 50 ° C., preferably 0 to 20 ° C., and the reaction time is 0.5 to 5 hours, preferably 1 to 2 hours.

The product thus obtained and the formula (XXXX
Examples of the solvent used in the reaction with the compound represented by III) include halogen solvents such as dichloromethane, dichloroethane and chloroform, ether solvents such as ether, tetrahydrofuran and dioxane, acetonitrile and dimethylformamide. A base is used if necessary. Examples of the base include organic bases such as triethylamine, 4-dimethylaminopyridine, triethylenediamine and tetramethylethylenediamine. The compound represented by the formula (XXXXIII) is 0.5 to 3 molar equivalents relative to 1 mol of the compound represented by the formula (Ij),
Preferably 1 to 1.5 molar equivalents are used. The reaction temperature is 0 to 150 ° C., preferably 30 to 100 ° C., and the reaction time is 0.5 to 24 hours, preferably about 1 to 3 hours. Expression (Ip)

[Chemical 54] [In the formula, symbols have the same meanings as described above. ] The compound represented by the following is the compound represented by the formula (Ii) and (XXXXIV)

[Chemical 55] [In the formula, symbols have the same meanings as described above. ] It can manufacture by condensing with the compound shown by these. This reaction can be carried out in exactly the same manner as in the production method of the compound represented by the formula (In).

Formula (Iq)

[Chemical 56] [Wherein E'represents an oxygen atom or -NH- in E defined above, and other symbols have the same meanings as described above] are represented by the formula (Ii), the formula (Ik) With the compound shown by (XXXXV)

[Chemical 57] It can be produced by reacting each of the compounds represented by the formula [wherein the symbols are as defined above]. Inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, and potassium carbonate; organic bases such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, and tetramethylethylenediamine. , In the presence of a base such as sodium hydride, an alcohol solvent such as methanol, ethanol, propanol and butanol, an ether solvent such as diethyl ether, tetrahydrofuran and dioxane, a solvent such as dimethylformamide, the formula (XXXXV)
The compound represented by is reacted. Formula (Ii) or Formula (Ik)
The compound represented by the formula (XXXXV) is used in an amount of 0.5 to 1.5 molar equivalents relative to 1 mol of the compound represented by the formula (Ii)
Alternatively, with respect to 1 mol of the compound represented by the formula (Ik), the base used is 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents,
The reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
The reaction time is 0.5 to 24 hours, preferably about 1 to 3 hours.

Formula (Ir)

[Chemical 58] [In the formula, symbols have the same meanings as described above. And a compound represented by the formula (XXXXII) and a compound represented by the formula (XXXXVI)

[Chemical 59] [In the formula, symbols have the same meanings as described above. ] It can manufacture by making it react with the compound shown by these. The solvent used is an aprotic solvent such as ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, etc., and if necessary, an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, etc. , 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, and other organic bases, sodium hydride, cesium fluoride, and the like may be used. The compound represented by the formula (XXXXVI) is used in an amount of 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to 1 mole of the compound represented by the formula (XXXXII). The reaction temperature is 0 to 200 ° C., preferably 20
~ 100 ° C, reaction time is 10 minutes to 5 hours, preferably 3
It is about 0 minutes to 2 hours.

Expression (Is)

[Chemical 60] [In the formula, symbols have the same meanings as described above. ] The compound represented by the formula has the formula (It)

[Chemical formula 61] [In the formula, Y ′ ″ represents an esterified carboxyl group of Y defined above, and other symbols have the same meanings as described above. ] The compound shown by these can be manufactured by hydrolyzing. That is, the compound represented by the formula (It) is treated with an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) in a solvent such as water, methanol, ethanol, propanol, butanol, etc. Or in the presence of sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or in the presence of a mineral acid (for example, nitric acid, hydrochloric acid, hydrobromic acid, iodo acid, sulfuric acid, etc.) or trifluoroacetic acid 10 to 150
C., preferably 10 to 50.degree. C. Although the reaction time depends on the reaction temperature, it is generally 1 to 24 hours, preferably 2 to 10 hours.

Formula (Iu)

[Chemical formula 62] [In the formula, Y "" represents an optionally substituted carbamoyl group in Y defined above, and other symbols have the same meanings as described above.]

[Chemical formula 63] [Wherein the symbols have the same meanings as defined above] and a condensation reaction between the substituent of the "optionally substituted carbamoyl group" defined by Y "" and an amine having the same substituent. It can be manufactured by attaching to. The reaction can be performed under the same conditions as those for producing the compound represented by the formula (In).

Formula (Iw)

[Chemical 64] [Wherein, R ₈ represents a substituent of “optionally substituted hydroxyl group” defined by Y, and other symbols have the same meanings as above], and a compound represented by the formula (Ix)

[Chemical 65] [Wherein the symbols are as defined above] and a compound of the formula (XXXXVII) HO-R ₈ (XXXXVII) [wherein the symbols are as defined above] are represented by the formula (Iq) It can be produced by a method similar to that for producing a compound.

Formula (Iy)

[Chemical formula 66] [Wherein, R ₉ represents an optionally substituted amino group defined by Y, and other symbols have the same meanings as those defined above] are represented by the formula (XXXXVIII) HR ₉ (XXXXVIII) Where the symbols are the same as those defined above] and the compound represented by the formula (Ix) can be produced by the same method as in the production of the compound represented by the formula (Iq). Formula (Iz)

[Chemical formula 67] [Wherein the symbols have the same meanings as defined above] are represented by the formula (Iα)

[Chemical 68] [Wherein the symbols have the same meanings as defined above], for example, diethyl ether, tetrahydrofuran,
Ethereal solvents such as dioxane, benzene, toluene,
In a hydrocarbon solvent such as hexane or heptane, a halogen solvent such as dichloromethane or chloroform, a solvent such as acetonitrile or dimethylformamide, metachloroperbenzoic acid is usually used in an amount of 1 to 5 mol per 1 mol of the compound represented by the formula (Iα). Amount, preferably about 1 to 1.5 molar amount. The reaction temperature is 0 to 100 ° C, preferably about 0 to 30 ° C. The reaction time is 1 to 10 hours, preferably 1 to 2
It's about time.

Formula (Iβ)

[Chemical 69] [Wherein the symbols are as defined above],
A compound represented by the formula (Iz) or the compound represented by the formula (Iα) can be used as a starting material to produce a compound represented by the formula (Iα) by a method similar to the method for producing the compound represented by the formula (Iz). . Formula (Iγ)

[Chemical 70] [Wherein the symbols are as defined above],
Formula (Iδ)

[Chemical 71] [Wherein the symbols have the same meanings as above], for example, an alcohol solvent such as water, methanol, ethanol, propanol, an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, It can be produced by using a reducing agent such as sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride in a hydrocarbon solvent such as hexane or heptane or a halogen solvent such as dichloromethane or chloroform. The reducing agent is used in an amount of 0.2 to 5 molar equivalents, preferably 0.3 to 1 molar equivalents, relative to 1 mol of the compound represented by the formula (Iδ). Reaction temperature is 0-10
The temperature is 0 ° C, preferably about 20 to 50 ° C. The reaction time is 0.5 to 10 hours, preferably about 1 to 3 hours.

Formula (Iθ)

[Chemical 72] [Wherein the symbols are as defined above],
Formula (Iπ)

[Chemical formula 73] [Wherein the symbols have the same meanings as defined above], for example, an alcohol solvent such as methanol, ethanol or propanol, an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, benzene,
It can be produced by reacting Lawesson's reagent or phosphorus pentasulfide in a hydrocarbon solvent such as toluene, hexane or heptane, a halogen solvent such as dichloromethane or chloroform, or a solvent such as hexamethylphosphoric triamide or dimethyl sulfoxide. it can. The Lawesson's reagent or phosphorus pentasulfide to be used is used in an amount of 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the compound represented by the formula (Iπ), and the reaction temperature is 0 to 150 ° C, preferably 50.
The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.

Formula (Iλ)

[Chemical 74] [Wherein the symbols are as defined above] a compound represented by the formula (i?) Compound represented by the formula _{(XXXXIX) R 7 -Q '(} XXXXIX) wherein the symbols are as defined above] It can be produced by reacting with the compound shown. The production method can be performed under the same conditions as the production methods of (XIII) of (Method E) and (VI) and (II) of (Method F) in the compound represented by the formula (Id).

In the present invention, the general formulas (I), (I '),
The compounds represented by (I ″) and (I ′ ″) have a squalene synthase inhibitory action or an antifungal action, but among the compounds used in the present invention, other compounds of the cholesterol biosynthetic pathway Some also inhibit enzymes. In any case, the compounds represented by the general formulas (I), (I ′), (I ″) and (I ′ ″) suppress cholesterol biosynthesis,
Mammals (eg mouse, rat, rabbit, dog, cat,
It is useful for preventing or treating hypercholesterolemia and coronary atherosclerosis of cattle, pigs, humans, etc.) and for preventing or treating fungal infections. When administering such a compound to humans, the administration method may be either oral or parenteral. The composition for oral administration includes solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrup. Agents, emulsions, suspensions and the like. Such a composition can be produced by a method known per se and contains a carrier or an excipient that is usually used in the field of formulation. For example, carriers or excipients for tablets include lactose, starch, sucrose,
Examples thereof include magnesium stearate.

The composition for parenteral administration includes, for example, injections, suppositories, etc. The injections are subcutaneous injections,
It includes dosage forms such as intradermal injection and intramuscular injection. Such an injection is prepared by a method known per se, that is, by suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid which is usually used for an injection. Examples of the aqueous solution for injection include physiological saline solution, isotonic solution and the like, and may be used in combination with an appropriate suspending agent such as sodium carboxymethyl cellulose, nonionic surfactant and the like, if necessary. Examples of the oily liquid include sesame oil and soybean oil, and as the solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. The prepared injection solution is usually filled in a suitable ampoule. The compounds represented by the general formulas (I), (I ′), (I ″) and (I ′ ″) or salts thereof have low toxicity and can be safely used. Varies depending on the patient's condition, weight, type of compound, administration route, etc. For example, when used as a therapeutic agent for hypercholesterolemia, the daily dose for adults is
About 1 to 500 mg, preferably about 10 to 200 mg,
No toxicity is seen in this range. Formula (I),
The compounds represented by (I ′), (I ″) and (I ′ ″) are mammals (eg, humans) as squalene synthase inhibitors.
, The effective daily dose for adults is
In the case of oral administration, about 1 to 500 mg, preferably about 10
It is 200 mg, and in the case of parenteral administration (eg, injection, suppository, etc.), it is about 0.1-100 mg, preferably about 1-50 mg.

Further, the compounds represented by the general formulas (I), (I '), (I'') and (I''') have a wide range of antibacterial activity as determined by the broth or agar dilution method. Indicates. The compounds represented by the general formulas (I), (I ′), (I ″) and (I ′ ″), when administered to a mammal (eg, human, etc.) for the purpose of fungal treatment, The effective daily dose for an adult is about 0.1 to 100 mg, preferably about 1 to 50 mg for oral administration, and about 0.1 for parenteral administration (eg, injection, suppository, etc.). 1-100 mg, preferably about 1-5
0 mg may be mentioned. In the present specification, when an abbreviation is used for an amino acid or the like, IUPAC-IUBCommision on
It is based on the abbreviations by Biochemical Nomenclature or the abbreviations commonly used in this field, and examples thereof are: Trp: tryptophan, Ser: serine, Asp: aspartic acid, Glu: glutamic acid, Gly: glycine, Leu:
Leucine, Ala: Alanine, Me: Methyl, Et: Ethyl, P
h: Phenyl. When an amino acid may have an optical isomer, the L-form is shown unless otherwise specified.

EXAMPLES The present invention will be described in more detail by showing Examples, Formulation Examples, and Test Examples, but it goes without saying that the present invention is not limited to these. In the following description, when X ′ and R ₂ or R ₂ ′ is bonded to a saturated carbon, a stereoisomer may be obtained depending on the kind of the compound. Here, with respect to the plane of the ring J ₁ , J ₂ or J ′,
An isomer in which X ′ and R ₂ or R ₂ ′ face the same direction is cis, and an isomer in which the opposite direction faces is cis.

Example 1 3,5-trans-7-chloro-5- (2-chlorophenyl) -2-oxo-1,2,3,5-tetrahydro-4,
1-benzothiazepine-3-acetic acid methyl ester

[Chemical 75] 2-amino-5-chloro-α- (2-chlorophenyl)
Benzyl alcohol (6g) and thiomalic acid (3.42
g) was dissolved in a mixed solvent of concentrated hydrochloric acid (60 ml) and acetic acid (60 ml), and the mixture was stirred at 100 ° C. for 3 hours. Cool the reaction,
100 ml of 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with dichloromethane containing 10% (V / V) of tetrahydrofuran. The extract was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was dissolved in xylene containing 3% (V / V) dimethylformamide, and the final solution was heated under reflux. The solvent was distilled off, and the residue was methanol (50 ml) and concentrated sulfuric acid (0.5 ml).
Was added and the mixture was heated under reflux for 3 hours. The solvent was evaporated, the residue was dissolved in dichloromethane, washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was recrystallized from a mixed solvent of dichloromethane / petroleum ether to obtain 5.6 g of colorless crystals having a melting point of 200-205 ° C. Elemental analysis _{C 18 H 15 Cl 2 NO 3} S · 0.3H calcd ₂ O C53.82 H3.91 N3.49 Found C53.78 H4.04 N3.22

Example 2 3,5-cis-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 76] 5-chloro-α- (2-chlorophenyl) -2- (neopentylamino) benzyl alcohol (6.5 g) and thiomalic acid (2.85 g) were treated as in Example 1,
The obtained residue was recrystallized from a mixed solvent of dichloromethane / petroleum ether to give colorless crystals 2.3 having a melting point of 153-156 ° C.
1 g was obtained. Calcd C59.23 H5.40 N3.00 S6.87 experimental values as elemental analysis _{C 23 H 25 Cl 2 NO 3} S C58.99 H5.32 N2.76 S6.80

Example 3 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 77] The residue obtained by concentrating the mother liquor from which the cis isomer was removed by recrystallization in Example 2 was dissolved in methanol (30 ml), potassium carbonate (0.87 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent, hexane: acetic acid ethyl ester = 3: 1).
(V / V)), and the obtained solid is dichloromethane /
Recrystallization from petroleum ether gave 2.73 g of colorless crystals having a melting point of 133-136 ° C. Calcd C59.23 H5.40 N3.00 S6.87 experimental values as elemental analysis _{C 23 H 25 Cl 2 NO 3} S C59.36 H5.30 N2.84 S6.86

Example 4 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine- 3-acetic acid methyl ester

[Chemical 78] 3,5-trans-7-chloro-5- (2-chlorophenyl) -2-oxo-1,2, obtained in Example 1
3,5-tetrahydro-4,1-benzothiazepine-3-
A solution of acetic acid methyl ester (0.5 g) in dimethylformamide (5 ml) was cooled to 0 ° C, sodium hydride (36 mg) was added, and the mixture was stirred at 0 ° C for 5 min. 1-Brominated propane (0.19 g) was added to this solution, and the mixture was stirred at room temperature for 3 hours. Water was added, the mixture was extracted with dichloromethane, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate = 3: 1 (V / V)) to obtain 0.56 g of a colorless oily compound. IR ν _max (neat) cm ⁻¹ : 1740, 1670. ¹ H-NMR (CDCl ₃ ) δ: 0.978 (3H, t, J = 7.6Hz), 1.
563-1.881 (2H, m), 2.445 (1H, dd, J = 4.0,17.0Hz), 3.170
(1H, dd, J = 10.6,17.0Hz), 3.477 (1H, ddd, J = 5.2,10.2,13.
6Hz), 3.673 (3H, s), 3.720 (1H, dd, J = 4.0,10.6Hz), 4.21
5 (1H, ddd, J = 6.0,10.4,13.6Hz), 6.023 (1H.s), 6.633 (1
H, d, J = 2.2Hz), 7.214-7.477,7.766-7.798 (6H, m)

Example 5 The following compound was obtained by the same operation as in Example 4.

[Table 1]

Example 6 7-Chloro-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 79] 2-Amino-5-chloro-α- (2-methoxyphenyl) benzyl alcohol (1 g) and thiomalic acid (0.
The same procedure as in Example 1 was carried out using 60 g) to obtain 1.34 g of a pale yellow amorphous solid. IRν _max (KBr) cm ^-1 : 1740, 1680. ¹ H-NMR (CDCl ₃ ) δ: 2.394-2.535 (1H, m), 3.03
1-3.187 (1H, m), 3.674,3.691 (6H, each s), 3.792-3.925
(1H, m), 5.512,6.237 (1H,), 6.744-7.783 (7H, m)

Example 7 3,5-trans-7-chloro-5- (2-methoxyphenyl) -2-oxo-1-propyl-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetic acid
Methyl ester

[Chemical 80] 7-chloro-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1 obtained in Example 6
-Benzothiazepine-3-acetic acid methyl ester (0.
5g) and by the same procedure as in Example 4, melting point 81-
0.17 g of colorless crystals at 107 ° C. were obtained. Elemental analysis _{C 22 H 24 ClNO 4 S ·} 0.3H calcd ₂ O C60.14 H5.64 N3.19 Found C59.97 H5.81 N3.01

Example 8 5-chloro-α- (2-methoxyphenyl) -2- (neopentylamino) benzyl alcohol or 2-isobutylamino-5-chloro-α- (2-methoxyphenyl) benzyl alcohol was used. The following compounds were obtained by the same operations as in Example 2 and Example 3.

[Table 2]

Example 9 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid

[Chemical 81] 3,5-trans-7-chloro-5-obtained in Example 3
(2-Chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.15 g) and potassium carbonate (0.07 g) To water (2 ml) and methanol (4
(ml) mixed solvent and heated to reflux at 60 ° C. for 2 hours.
Water (50 ml) was added, the solution was acidified with 1N hydrochloric acid, and then extracted with dichloromethane. The extract was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from dichloromethane / petroleum ether to give colorless crystals having a melting point of 269-271 ° C.
12 g was obtained. Calcd C58.41 H5.12 N3.10 S7.09 experimental values as elemental analysis _{C 22 H 23 Cl 2 NO 3} S C58.39 H5.19 N2.84 S6.78

Example 10 The following compounds were synthesized by the same operation as in Example 9.

[Table 3]

Example 11 (3R) -7-chloro-5- (2-chlorophenyl)-
2,3-Dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester

[Chemical formula 82] (1) (3R) -3-benzyloxycarbonylamino-
3- [N- [4-chloro-2 (2-chlorobenzoyl)
Phenyl] carbamoyl] propionic acid methyl ester N-benzyloxycarbonyl-D-aspartic acid
β-methyl ester (4.3 g) was added to dichloromethane (5
0 ml) and cooled to 0 ° C. N-Methylmorpholine (1.6 g) and isobutyl chloroformate (2.2 g) were added thereto, and the mixture was stirred at room temperature for 10 minutes. 2-amino-2 ', 5-dichlorobenzophenone (4.
A solution of 1 g) in dichloromethane (20 ml) was added, and the mixture was heated under reflux for 20 minutes. The reaction solution was stirred at room temperature for 2 days, dichloromethane (100 ml) was added, and a 10% aqueous citric acid solution was added.
The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was mixed with hexane / acetic acid ethyl ester (3: 1 (V /
V)) was recrystallized to obtain 3.73 g of pale yellow crystals having a melting point of 160-162 ° C.

(2) (3R) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H
1,4-benzodiazepine-3-acetic acid methyl ester (1) The compound (3.76 g) obtained in methanol (60 m
l) 10% Pd / carbon (0.5g) and concentrated hydrochloric acid (0.5
9 ml) was added and catalytic reduction was carried out at room temperature and atmospheric pressure. The catalyst was removed, the solvent was distilled off, the residue was dissolved in a mixed solvent of dichloromethane; tetrahydrofuran = 9: 1 (100 ml),
The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in dimethylformamide (20 ml), acetic acid (1 ml) was added thereto, and the mixture was heated with stirring at 60 ° C. for 2 hours. Ethyl acetate (50 ml) was added to the reaction mixture, which was washed with 5% aqueous potassium hydrogen sulfate solution, saturated sodium hydrogen carbonate and saturated brine, the solvent was distilled off, and the residue was recrystallized from ethyl ether to give a melting point of 168-. 170 ° C colorless crystals 2.9
7 g was obtained. Elemental analysis _{C 18 H 14 Cl 2 N 2} O 3 · 0.75H calcd ₂ O C55.33 H4.00 N7.17 Found C54.92 H3.60 N7.21

Example 12 (3R) -1-isobutyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H
-1,4-benzodiazepine-3-acetic acid methyl ester

[Chemical 83] The (3R) -7-chloro-5- (2 obtained in Example 11
-Chlorophenyl) -2,3-dihydro-2-oxo-
1H-1,4-Benzodiazepine-3-acetic acid methyl ester (0.5 g) and isobutyl bromide (0.23 g) were used to carry out the same procedure as in Example 4 to obtain a colorless oily compound.
3 g was obtained. IR ν _max (neat) cm ⁻¹ : 1740, 1680, 1600. ¹ H-NMR (CDCl ₃ ) δ: 0.795 (3H, d, J = 6.4Hz), 0.
882 (3H, d, J = 6.6Hz), 1.759 (1H, m), 3.220 (1H, dd, J = 7.0,
16.8Hz), 3.438 (1H, dd, J = 7.4,16.8Hz), 3.528 (1H, qd, J =
4.8,14.2Hz), 3.723 (3H, s), 4.167 (1H, t, J = 7.1Hz), 4.3
32 (1H, dd, J = 10.0,14.2Hz), 7.078 (1H, d, J = 2.4Hz), 7.37
1-7.532 (6H, m)

Example 13 (3R) -1-isobutyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H
-1,4-benzodiazepine-3-acetic acid

[Chemical 84] (3R) -1-isobutyl-7-obtained in Example 12
Chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3
-Acetic acid methyl ester (0.23 g) from Example 9
By the same operation as above, 0.11 g of colorless crystals having a melting point of 175-178 ° C. was obtained. Elemental analysis _{C 21 H 20 Cl 2 N 2} O 3 · 0.2H calcd ₂ O C59.65 H4.86 N6.62 Found C59.65 H4.96 N6.62

Example 14 (3R, 5S) -1-isobutyl-7-chloro-5-
(2-Chlorophenyl) -2,3,4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-
Acetic acid

[Chemical 85] (3R) -1-isobutyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-obtained in Example 13
2-oxo-1H-1,4-benzodiazepine-3-acetic acid (30 mg) was dissolved in a mixed solvent (0.7 ml) of methanol; water = 6: 1, and sodium borohydride (10 mg) was added.
mg) was added. After stirring the reaction solution for 2 hours at room temperature, dichloromethane (50 ml) and water (50 ml) were added. After acidifying the aqueous layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed and the residue was recrystallized from dichloromethane / petroleum ether, mp 184-188
17 mg of colorless crystals at 0 ° C. were obtained. Elemental analysis _{C 21 H 22 Cl 2 N 2} O 3 · H 2 O Calculated C57.41 H5.50 N6.38 Found C57.56 H5.16 N6.40

Example 15 (3S) -7-chloro-5- (2-chlorophenyl)-
2,3-Dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester

[Chemical 86] N-benzyloxycarbonyl-L-aspartic acid
An amorphous solid was obtained by the same operation as in Example 11 using β-methyl ester. IRν _max (KBr) cm ^-1 : 1740, 1690, 1610. ¹ H-NMR (CDCl ₃ ) δ: 3.218 (1H, dd, J = 6.8,17.0H
z), 3.447 (1H, dd, J = 7.4,17.0Hz), 3.756 (3H, s), 4.234
(1H, t, J = 7.1Hz), 7.069-7.130,7.353-7.486 (7H, m)

Example 16 (3S) -1-isobutyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H
-1,4-benzodiazepine-3-acetic acid methyl ester

[Chemical 87] (3S) -7-chloro-5- (2 obtained in Example 15
-Chlorophenyl) -2,3-dihydro-2-oxo-
Using 1H-1,4-benzodiazepine-3-acetic acid methyl ester and by the same procedure as in Example 4, a pale yellow oily compound was obtained. IR ν _max (neat) cm ⁻¹ : 1740, 1680, 1610. ¹ H-NMR (CDCl ₃ ) δ: 0.794 (3H, d, J = 6.6Hz), 0.
881 (3H, d, J = 6.8Hz), 1.728 (1H, m), 3.219 (1H, dd, J = 7.0,
16.8Hz), 3.437 (1H, dd, J = 7.4,16.8Hz), 3.528 (1H, qd, J =
4.4,14.2Hz), 3.723 (3H, s) ,. 4.166 (1H, t, J = 7.1Hz), 4.
332 (1H, dd, J = 10.0,14.2Hz), 7.077 (1H, d, J = 2.4Hz), 7.3
70-7.530 (6H, m)

Example 17 (3S) -7-chloro-5- (2-chlorophenyl)-
2,3-dihydro-1-isobutyl-2-oxo-1H
-1,4-benzodiazepine-3-acetic acid

[Chemical 88] (3S) -1-isobutyl-7-obtained in Example 16
Chloro-5- (2-chlorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3
By the same operation as in Example 9 using acetic acid methyl ester, a colorless solid having a melting point of 171 to 179 ° C. was obtained. Elemental analysis value Calculated value as C ₂₁ H ₂₀ Cl ₂ N ₂ O ₃ C60.15 H4.81 N6.68 Experimental value C60.41 H4.89 N6.85

Example 18 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester S-oxide

[Chemical 89] 3,5-trans-7-chloro-5 obtained in Example 3
To a solution of-(2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (1 g) in dichloromethane (10 ml), Metachloroperbenzoic acid (0.37 g) was added, and the mixture was stirred at room temperature for 10 minutes. Dichloromethane (50 ml) was added to the reaction solution, washed with saturated sodium hydrogen carbonate, and the aqueous layer was further extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Dichloromethane residue
Recrystallization from hexane gave 0.59 g of colorless crystals having a melting point of 166-169 ° C. Elemental analysis _{C 23 H 25 Cl 2 NO 4} S · 1.7H calcd ₂ O C53.85 H5.58 N2.73 Found C53.70 H5.27 N2.36

Example 19 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid S-oxide

[Chemical 90] 3,5-trans-7-chloro-obtained in Example 18
5- (2-chlorophenyl) -1-neopentyl-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester S-oxide (0.5 g) was treated in the same manner as in Example 9 to give mp 230
0.38 g of colorless crystals at -235 ° C was obtained. Elemental analysis value
Calculated as C ₂₂ H ₂₃ Cl ₂ NO ₄ S C56.41 H4.95 N2.99 Experimental value C56.36 H5.04 N3.04

Example 20 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester S-dioxide

[Chemical Formula 91] 3,5-trans-7-chloro-5 obtained in Example 3
-(2-Chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.3 g) in dichloromethane (10 ml) solution To the mixture, metachloroperbenzoic acid (0.25 g) was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, the same operation as in Example 18 gave 1.01 g of colorless crystals having a melting point of 218 to 224 ° C. Calculated elemental analysis _{C 23 H 25 Cl 2 NO 5} S C46.14 H5.06 N2.81 Found C46.22 H5.16 N2.69

Example 21 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid S-dioxide

[Chemical Formula 92] 3,5-trans-7-chloro-5 obtained in Example 9
-(2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (0.3 g) was added to Example 18 and Example 2.
By the same operation as for 0, 0.14 g of colorless crystals having a melting point of 245-249 ° C. was obtained. Elemental analysis _{C 22 H 23 Cl 2 NO 5} S · 0.2H calcd ₂ O C54.15 H4.83 N2.87 Found C54.08 H4.83 N2.65

Example 22 N- [3,5-trans-1-neopentyl-7-chloro-5- (2-chlorophenyl) -2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetyl] glycine methyl ester

[Chemical formula 93] 3,5-trans-7-chloro-5-obtained in Example 9
(2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (0.1 g) and glycine methyl ester hydrochloride (31 mg) It was dissolved in dichloromethane (2 ml), diethyl cyanophosphate (54 mg) and triethylamine (49 mg) were added at 0 ° C, and the mixture was stirred at room temperature for 30 min.
Dichloromethane (50 ml) was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane / petroleum ether to give a melting point of 188-1.
99 mg of colorless crystals at 89 ° C. were obtained. Elemental analysis value Calculated value as C ₂₅ H ₂₈ Cl ₂ N ₂ O ₄ S C57.36 H5.39 N5.35 Experimental value C57.36 H5.39 N5.19

Example 23 N- [3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetyl] glycine

[Chemical 94] The compound (50 mg) obtained in Example 22 was hydrolyzed in the same manner as in Example 9 to obtain 35 mg of colorless crystals having a melting point of 229-230 ° C. Elemental analysis _{C 24 H 26 Cl 2 N 2} O 4 S · 0.3H calcd ₂ O C55.99 H5.21 N5.44 Found C55.98 H5.09 N5.29

Example 24 3,5-trans-7-chloro-5- (2-chlorophenyl) -3-dimethylaminocarbonylmethyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4 , 1-benzothiazepine

[Chemical 95] 3,5-trans-7-chloro-5-obtained in Example 9
(2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (1 g) and dimethylamine hydrochloride (0.
Dichlorocyanophosphate (375 mg) and triethylamine (558 m) in a solution of 2 g) in dichloromethane (20 ml).
g) was added and stirred at room temperature for 30 minutes. Dichloromethane (100 ml) was added to the reaction solution, which was washed with 5% hydrochloric acid, saturated sodium hydrogen carbonate and saturated saline, and the solvent was evaporated. The residue was recrystallized from dichloromethane / petroleum ether, melting point 1
0.98 g of colorless crystals at 90-193 ° C. were obtained. Elemental analysis value Calculated value as C ₂₄ H ₂₈ Cl ₂ N ₂ O ₂ S C60.12 H5.89 N5.84 Experimental value C59.99 H5.88 N5.92

Example 25 7-Chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H
-[1] -Benzazepine-3-acetic acid ethyl ester

[Chemical 96] J. Med. Chem., 27 , 1508 (1984), J. Med. C
The following intermediates were synthesized according to the method of hem., 14 , 851 (1971). (1) 3- (Ethoxycarbonyl) -4- (2-chlorophenyl) -4-phenyl-3-butenoic acid Oil compound IRν _max (neat) cm ⁻¹ : 1730, 1715, 1705. (2) 4- (2 -Chlorophenyl) -4-phenylbutyric acid
Ethyl ester oily compound ^{_{IRν max (neat) cm -1:}} 1730. 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.1Hz), 2.2
-2.5 (4H, m), 4.10 (2H, q, J = 7.1Hz), 4.45-4.6 (1H, m), 7.
0-7.4 (9H, m)

(3) 4- (2-chlorophenyl) -4-phenylbutyric acid Melting point 133-135 ° C. Elemental analysis value Calculated value as C ₁₆ H ₁₅ ClO ₂ C69.95 H5.50 Experimental value C70.10 H5.42 ( 4) 4- (2-chlorophenyl) -1-tetralone oily compound IRν _max (neat) cm ⁻¹ : 1685. ¹ H-NMR (CDCl ₃ ) δ: 2.2-2.5 (2H, m), 2.6-2.8
(2H, m), 4.85 (1H, t, J = 5.9Hz), 6.7-7.5 (7H, m), 8.05-8.
2 (1H, m) (5) 4- (2-chlorophenyl) -1-tetralone oxime Melting point 114-115 ° C. (6) 5- (2-chlorophenyl) -2,3,4,5-tetrahydro-1H- [ 1] -Benzazepin-2-one Melting point 226-227 ° C. Elemental analysis value Calculated value as C ₁₆ H ₁₄ ClNO C 70.72 H 5.19 N 5.15 Experimental value C 70.94 H 5.20 N 5.20

(7) 5- (2-chlorophenyl) -1-isobutyl-2,3,4,5-tetrahydro-1H- [1]
-Benzazepin-2-one 5- (2-chlorophenyl) -2,3,4,5-tetrahydro-1H- [1] -benzazepin-2-one (2.
To a solution of 8 g) and isobutyl bromide (2.24 ml) in dimethylformamide (20 ml) was added sodium hydride (0.82 g, 60% content) at 0 ° C. The mixture was stirred at room temperature for 4 hours, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 2.98 g of colorless crystals having a melting point of 139-140 ° C. Elemental analysis C ₂₀ H ₂₂ Calculated ClNO C73.27 H6.76 N4.27 Found C73.08 H6.69 N4.36 (8) 7- chloro-5- (2-chlorophenyl) -1-isobutyl - 2,3,4,5-Tetrahydro-1H- [1]
-Benzazepin-2-one 5- (2-chlorophenyl) -1-isobutyl-2,3,
A solution of 4,5-tetrahydro-1H- [1] -benzazepin-2-one (2.7 g) and N-chlorosuccinimide (1.65 g) in dimethylformamide (10 ml) was heated with stirring at 70 ° C. for 7 hours. Acetic acid ethyl ester (100 ml) was added, washed with dilute hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was recrystallized from hexane / acetic acid ethyl ester to give 2.39 g of colorless crystals having a melting point of 152-154 ° C.

(9) 7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H- [1] -benzazepine-3-acetic acid ethyl ester dried Isopropylamine (0.25 ml) was added to tetrahydrofuran (5 ml), and the mixture was cooled to -15 ° C. A hexane solution of 1.58 M n-butyllithium (1.
14 ml) was added and the mixture was stirred at -15 ° C for 45 minutes. There, 7-chloro-5 dissolved in tetrahydrofuran (5 ml)
-(2-Chlorophenyl) -2,3,4,5-tetrahydro-1H- [1] -benzazepin-2-one (0.5
g) was added and the mixture was stirred at 0 ° C. for 15 minutes. The reaction solution is -78
Cooled to ℃, iodoacetic acid ethyl ester (0.25 ml)
Was added, and the mixture was stirred at -78 ° C for 15 minutes and 0 ° C for 1 hour.
1N Hydrochloric acid (50 ml) was added, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 0.1 g of an oily compound. IRν _max (neat) cm ⁻¹ : 1730, 1660. ¹ H-NMR (CDCl ₃ ) δ: 0.5-1.15 (6H, m), 1.15-1.
4 (3H, m), 1.7-3.1 (5H, m), 3.1-3.9 (2H, m), 4.0-4.2 (2H,
m), 4.4-4.8 (1H, m), 6.4-7.6 (7H, m) SIMS (m / z): 449 (MH ⁺ ).

Example 26 7-Chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H-
[1] -Benzazepine-3-acetic acid

[Chemical 97] The compound (90 mg) obtained in Example 25 was treated in the same manner as in Example 9 to obtain 50 mg of colorless crystals having a melting point of 165-171 ° C. Calcd C62.86 H5.51 N3.33 Found as elemental analysis _{C 22 H 23 Cl 2 NO 3} C62.77 H5.61 N3.29

Example 27 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepine -3-
Acetic acid ethyl ester

[Chemical 98] 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.0 g) and Lawesson's reagent (1.
A solution of 3 g) in toluene (15 ml) was heated to reflux for 8 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.68 g of yellow crystals having a melting point of 200-201 ° C. Elemental analysis value Calculated value as C ₂₄ H ₂₇ Cl ₂ NO ₃ S C60.00 H5.66 N2.92 Experimental value C60.10 H5.78 N2.65

Example 28 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepine -3-
Acetic acid

[Chemical 99] The compound (0.4 g) obtained in Example 27 was treated in the same manner as in Example 9 to obtain 0.1 g of yellow crystals having a melting point of 248 to 249 ° C. Calculated elemental analysis _{C 22 H 23 Cl 2 NO 3} S C58.41 H5.12 N3.10 Found C58.48 H5.33 N3.01

Example 29 3,5-trans-7-chloro-5- (2-chlorophenyl) -1,2,3,5-tetrahydro-2-thioxo-
4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 100] 3,5-trans-7-chloro-5 obtained in Example 1
-(2-chlorophenyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid ethyl ester (1.0 g) was treated in the same manner as in Example 27 to give yellow crystals 0.95 having a melting point of 194-197 ° C.
g was obtained. Calcd C52.43 H3.67 N3.40 Found as elemental analysis _{C 18 H 15 Cl 2 NO 2} S 2 C52.41 H3.53 N3.10

Example 30 7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,
1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester

[Chemical 101] (1) 5-chloro-3- (2-chlorobenzoyl) -2-
Neopentylaminothiophene 2-amino-5-chloro-3- (2-chlorobenzoyl) thiophene (10.89 g) was added to methanol (200
ml) and acetic acid (100 ml) mixed with pivalaldehyde (8.69 ml) and molecular sieve 3
A (0.5 g) was added, and the mixture was stirred at 60 ° C. for 2 hours. A solution of sodium cyanoborohydride (2.51 g) in methanol (10 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated, the residue was dissolved in acetic acid ethyl ester, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, evaporated to remove the solvent, and purified by silica gel column chromatography. Then, 4.85 g of pale yellow crystals having a melting point of 74-76 ° C. were obtained. Calcd C56.14 H5.01 N4.09 Found as elemental analysis _{C 16 H 17 Cl 2 NOS C56.18} H5.17 N3.89

(2) 3- [N- [5-chloro-3- (2-
Chlorobenzoyl) -2-thienyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester 5-chloro-3- (2-chlorobenzoyl) -2-neopentylaminothiophene (4.85 g) and triethylamine (5.92 ml) And a small amount of a solution of dimethylaminopyridine in dimethylformamide (60 ml) was added dropwise with a solution of dimethylformamide (20 ml) in fumaric acid monoethyl ester chloride (4.60 g). The reaction solution was stirred at room temperature overnight, poured into water, and then extracted with ethyl acetate. The extract was washed with 1 molar aqueous potassium hydrogen sulfate solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was separated and purified by silica gel column chromatography, and the obtained compound was recrystallized from hexane / acetic acid ethyl ester to give 4.3 g of colorless crystals with a melting point of 79-81 ° C. Elemental analysis _{C 22 H 23 Cl 2 NO 4} S · 0.5H calcd ₂ O C55.35 H5.07 N2.93 Found C55.25 H4.83 N3.00

(3) 3- [N- [5-chloro-3- (α-
Hydroxy-2-chlorobenzyl) -2-thienyl]-
N-neopentylcarbamoyl] acrylic acid ethyl ester 3- [N- [5-chloro-3- (2-chlorobenzoyl) -2-thienyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester (2.37 g) Cesium trichloride heptahydrate (2.98 g) in methanol (1
00 ml) solution at room temperature with sodium borohydride (30 ml)
3 mg) was added slowly. After stirring for 20 minutes at room temperature, acetone was added and the solvent was distilled off. To the residue were added 1 mol of potassium hydrogensulfate and ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give an amorphous solid (2.47 g).
Got ¹ H-NMR (CDCl ₃ ) δ: 0.91,1.00 (9H), 1.20-1.3
5 (3H, m), 2.50-2.59 (1H, m), 2.90-4.28 (4H, m), 5.95,6.
05 (total 1H), 6.52-7.60 (7H, m)

(4) 7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester 3- [N- [5-chloro-3- (α-hydroxy-2-
Chlorobenzyl) -2-thienyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester (2.37)
g) in ethanol (50 ml), potassium carbonate (7
(00 mg) was added, and the mixture was stirred at room temperature for 8 hours. It was poured into water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography to obtain a pale yellow oily compound (1.73 g). ¹ H-NMR (CDCl ₃ ) δ: 0.99,1.02 (9H, each s),
1.26,1.28 (3H, each t), 2.60-3.09 (3H, m), 4.08-4.25 (2
H, m), 4.38,4.57 (1H, each d), 4.67,4.92 (1H, eachdd),
5.87,6.42 (1H, each s), 6.06,6.51 (1H, each s), 7.20-
7.66 (4H, m)

Example 31 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-thieno [2,3-e] benzoxazepine-3-acetic acid

[Chemical 102] The compound (1.64 g) obtained in Example 30 was dissolved in a mixed solvent of methanol (30 ml) and tetrahydrofuran (30 ml), potassium carbonate was added, and the mixture was heated and stirred at 60 ° C. for 2 hours. The reaction solution was acidified with 1N hydrochloric acid, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was separated and purified by silica gel column chromatography.
The obtained solid was recrystallized from hexane / acetic acid ethyl ester to obtain 68 mg of colorless crystals having a melting point of 202-204 ° C. Elemental analysis value Calculated value as C ₂₀ H ₂₁ Cl ₂ NO ₄ S C54.30 H4.78 N3.17 Experimental value C54.20 H4.62 N3.16

Example 32 3,5-trans-7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,
5-Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester and 3,5-cis-
7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-thieno [2,3-e] oxazepine-3-acetic acid
Ethyl ester

[Chemical 103] It was produced in the same manner as in Example 30. (1) 5-chloro-3- (2-methoxybenzoyl) -2
-Neopentylaminothiophene, melting point 117-118
℃ Elemental analysis value Calculated value as C ₁₇ H ₂₀ ClNO ₂ S C60.43 H5.97 N4.15 Experimental value C60.15 H5.92 N4.10

(2) 3- [N- [5-chloro-3- (2-
Methoxybenzoyl) -2-thienyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester Oil compound ¹ H-NMR (CDCl ₃ ) δ: 0.96 (9H, s), 1.26 (3H, t, J
= 7.2Hz), 3.57 (1H, d, J = 13.7Hz), 3.73 (3H, s), 3.74 (1H,
d, J = 13.7Hz), 4.18 (2H, q, J = 7.2Hz), 6.75 (1H, s), 6.81 (1
H, d, J = 15.3Hz), 6.90-7.04 (2H, m), 7.12 (1H, d, J = 15.3H
z), 7.31-7.51 (2H, m) (3) 3- [N- [5-chloro-3- (α-hydroxy-
2-Methoxybenzyl) -2-thienyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester Oil compound ¹ H-NMR (CDCl ₃ ) δ: 0.91, 1.00
(9H, each), 1.24, 1.28 (3
H, each t), 2.80-2.91, 3.32.
(1H), 3.74, 3.82 (3H, each
s), 4.06-4.27 (3H, m), 5.8
1,5.93 (1H, each d), 6.40-
7.34 (7H, m)

(4) 3,5-trans-7-chloro-5
-(2-Methoxyphenyl) -1-neopentyl-2-
Oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester mp 148-150 ° C. Elemental analysis C ₂₃ H ₂₈ ClNO Calculated ₅ S C59 .28 H6.06 N3.01 experimental value C59.17 H5.95 N2.90 3,5-cis-7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2, 3,5-
Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester ¹ H-NMR (CDCl ₃ ) δ: 0.97 (9H, s), 1.26 (3H, t, J
= 7.1Hz), 2.81 (1H, dd, J = 8.1,17.0Hz), 2.96 (1H, d, J = 14.
2Hz), 3.01 (1H, dd, J = 5.8,17.0Hz), 3.89 (3H, s), 4.10-4.
23 (2H, m), 4.54 (1H, d, J = 14.2Hz), 4.90 (1H, dd, J = 5.8,8.
1Hz), 6.42 (1H, s), 6.56 (1H, s), 6.88-6.97 (2H, m), 7.2
2-7.32 (1H, m), 7.35-7.41 (1H, m)

Example 33 3,5-trans-7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,
5-Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid

[Chemical 104] The ethyl ester of the trans form obtained in Example 32 (0.5
1 g) and by the same operation as in Example 31, melting point 2
0.18 g of colorless crystals at 20-222 ° C was obtained. Elemental analysis value Calculated value as C ₂₁ H ₂₄ ClNO ₅ S C57.59 H5.52 N3.20 Experimental value C57.54 H5.58 N3.18

Example 34 3,5-cis-7-chloro-5- (2-methoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid

[Chemical 105] The cis-form ethyl ester obtained in Example 32 (0.28
g) and by the same procedure as in Example 31, melting point 18
0.16 g of colorless crystals at 9-191 ° C. were obtained. Elemental analysis value Calculated value as C ₂₁ H ₂₄ ClNO ₅ S C57.59 H5.52 N3.20 Experimental value C57.36 H5.42 N3.11

Example 35 3,5-trans-7-chloro-1-isobutyl-5-
(2-Methoxyphenyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester and 3,5-cis-7
-Chloro-1-isobutyl-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1
-Thieno [2,3-e] oxazepine-3-acetic acid ethyl ester

[Chemical formula 106] It was produced in the same manner as in Example 30. (1) 5-Chloro-2-isobutylamino-3- (2-methoxybenzoyl) thiophene mp 83-84 ° C. Elemental analysis C ₁₆ H ₁₈ ClNO Calculated ₂ S C59.34 H5.60 N4.33 Found C59.41 H5.63 N4.30

(2) 3- [N- [5-chloro-3- (2-
Methoxybenzoyl) -2-thienyl] -N-isobutylcarbamoyl] acrylic acid ethyl ester Oil compound ¹ H-NMR (CDCl ₃ ) δ: 0.92 (6H, br), 1.28 (3H, t,
J = 7.1Hz), 1.89-2.12 (1H, m), 3.12-3.27 (1H, m), 3.75 (3
H, s), 3.80-4.00 (1H, m), 4.20 (2H, q, J = 7.1Hz), 6.76-7.
54 (7H, m) (3) 3- [N- [5-chloro-3- (α-hydroxy-
2-Methoxybenzyl) -2-thienyl] -N-isobutylcarbamoyl] acrylic acid ethyl ester Oil compound ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.00 (6H, m), 1.19-
1.32 (3H, m), 1.88-2.16 (1H, m), 2.69-3.24 (2H, m), 3.7
4,3.79 (3H, each s), 3.87-4.26 (3H, m), 5.80-5.99 (1H,
m), 6.49-7.64 (7H, m)

(4) 3,5-trans-7-chloro-1-
Isobutyl-5- (2-methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,
3-e] oxazepine-3-acetic acid ethyl ester mp 126 - 128 ° C. Elemental analysis C ₂₂ H ₂₆ ClNO ₅ Calculated S C58.46 H5.80 N3.10 Found C58.23 H5.72 N3.03 3 , 5-cis-7-chloro-1-isobutyl-5- (2
-Methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid ethyl ester oil compound ¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6Hz), 1.2
7 (3H, t, J = 7.1Hz), 2.05-2.24 (1H, m), 2.81 (1H, dd, J = 8.
1,17.0Hz), 3.00 (1H, dd, J = 5.6,17.0Hz), 3,09 (1H, dd, J =
5.3,14.1Hz), 3.88 (3H, s), 4.17 (2H, q, J = 7.1Hz), 4.31
(1H, dd, J = 9.3,14.1Hz), 4.89 (1H, dd, J = 5.6,8.1Hz), 6.4
1 (1H, s), 6.48 (1H, s), 6.86-6.96 (2H, m), 7.20-7.34 (2
H, m)

Example 36 3,5-trans-7-chloro-1-isobutyl-5-
(2-Methoxyphenyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid

[Chemical formula 107] Ester in trans form obtained in Example 35 (0.68 g)
Using the same procedure as in Example 31, melting point 183-1
0.22 g of colorless crystals at 85 ° C. were obtained. Calcd C56.67 H5.23 N3.30 Found as elemental analysis _{C 20 H 22 ClNO 5 S C56.40} H5.18 N3.29

Example 37 3,5-cis-7-chloro-1-isobutyl-5- (2
-Methoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepine-3-acetic acid

[Chemical 108] Using the cis-ester (0.59 g) obtained in Example 35 and in the same manner as in Example 31, 0.27 g of a colorless solid having a melting point of 144-146 ° C. was obtained. Calcd C56.67 H5.23 N3.30 Found as elemental analysis _{C 20 H 22 ClNO 5 S C56.94} H5.24 N3.58

Example 38 3,5-trans-7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid methyl ester

[Chemical 109] 5-chloro-α- (2,3-dimethoxyphenyl) -2
-(Neopentylamino) benzyl alcohol (1.0
g) and thiomalic acid (0.41 g) were treated in the same manner as in Example 1 to obtain 0.38 g of colorless crystals having a melting point of 193-196 ° C. Elemental analysis _{C 25 H 30 ClNO 5 S ·} 0.3H calcd ₂ O C60.36 H6.20 N2.86 Found C60.43 H6.21 N2.75

Example 39 3,5-trans-7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid

[Chemical 110] 3,5-trans-7-chloro-5-obtained in Example 38
(2,3-Dimethoxyphenyl) -1-neopentyl-
2-Oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (10 g) was treated as in Example 9 to give colorless crystals, mp 263-277 ° C. 7 g was obtained. Elemental analysis value Calculated value as C ₂₄ H ₂₈ ClNO ₅ S C60.31 H5.91 N2.93 Experimental value C60.03 H5.86 N2.84

Example 40 N-[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetyl] -L-leucine methyl ester and N-[(3S, 5R) -7-chloro-5- (2,3-
Dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl] -L-leucine methyl ester

[Chemical 111] 3,5-trans-7-chloro-5-obtained in Example 39
(2,3-Dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (7.1 g) and L-leucine
Methyl ester (2.7 g) was added to dichloromethane (150
ml) and add to it diethyl cyanophosphate (3.6
g) and triethylamine (3.3 g) were added, and the mixture was stirred at room temperature for 3 hours.
Stir for 0 minutes. The solution was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (developing solvent).
Hexane: acetic acid ethyl ester = (4: 1 → 3: 1V /
V)) is separated and purified, and N-[(3
R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzothiazepine-3-acetyl] -L-leucine methyl ester, melting point 12
Obtained as 4.13 g of colorless crystals at 1-123 ° C. [Α] ^{_{D 22 -235.2 ° (c = 0.39}} , MeOH) 1 H-NMR (CDCl 3) δ: 0.932 (6H, t, J = 6.2Hz), 0.
989 (9H, s), 1.49-1.67 (3H, m), 2.322 (1H, dd, J = 3.2,14.2
Hz), 2.97 (1H, dd, J = 10.6,14.2Hz), 3.187 (1H, d, J = 14.0H
z), 3.696 (3H, s), 3.715 (3H, s), 3.779 (1H, dd, J = 3.2,1
0.6Hz), 3.889 (3H, s), 4.420 (1H, d, J = 14.0Hz), 4.47-4.
59 (1H, m), 6.05-6.10 (1H, br), 6.270 (1H, s), 6.814-7.4
00 (6H, m) N-[(3S, 5R) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-from the second fraction Tetrahydro-4,
1-Benzothiazepine-3-acetyl] -L-leucine methyl ester was obtained as an amorphous solid, 4.15 g. [Α] _D ²² + 178.6 ° (c = 0.47, MeOH) ¹ H-NMR (CDCl ₃ ) δ: 0.89-0.92 (6H, m), 0.996
(9H, s), 1.51-1.66 (3H, m), 2.323 (1H, dd, J = 4.2,14.4H
z), 2.990 (1H, dd, J = 10.2,14.4Hz), 3.226 (1H, d, J = 13.8H
z), 3.69-3.78 (7H, m), 3.890 (3H, s), 4.44-4.54 (2H, m),
6.281 (1H, s), 6.37-6.41 (1H, br), 6.801-7.396 (6H, m)

Example 41 (3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzo Thiazepine-3
-Acetic acid methyl ester

[Chemical 112] N-[(3R, 5S) -7-chloro-obtained in Example 40
5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetyl] -L-leucine methyl ester (4.13 g) in methanol (100 ml)
Concentrated hydrochloric acid (50 ml) was added to the solution and the mixture was heated under reflux for 24 hours.
After extraction with dichloromethane, drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester =
It was separated and purified at 3: 1 V / V). The obtained solid was recrystallized from a mixed solvent of dichloromethane-petroleum ether to obtain 2.87 g of colorless crystals having a melting point of 170-171 ° C.

Example 42 (3S, 5R) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzo Thiazepine-3
-Acetic acid methyl ester

[Chemical 113] N-[(3S, 5R) -7-chloro-obtained in Example 40
5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetyl] -L-leucine methyl ester (4.15 g) was treated as in Example 41 to give 2.70 g of colorless crystals with a melting point of 168-170 ° C.

Example 43 (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzo Thiazepine-3
-Acetic acid

[Chemical 114] (3R, 5S) -7-chloro-5-obtained in Example 41
(2,3-Dimethoxyphenyl) -1-neopentyl-
1,2,3,5-Tetrahydro-2-oxo-4,1-benzothiazepine-3-acetic acid methyl ester (2.6g)
Was treated in the same manner as in Example 9 to obtain 1.98 g of colorless crystals having a melting point of 263-271 ° C. [Α] ^{_{D 22 -303.5 ° (c = 0.92}} , MeOH) Elemental analysis C Calculated as _{24 H 28 ClNO 5 S C60.31 H5.90} N2.93 Found C60.09 H6.08 N2 .99

Example 44 (3S, 5R) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzo Thiazepine-3
-Acetic acid

[Chemical 115] (3S, 5R) -7-chloro-5-obtained in Example 42
(2,3-Dimethoxyphenyl) -1-neopentyl-
1,2,3,5-Tetrahydro-2-oxo-4,1-benzothiazepine-3-acetic acid methyl ester (2.5 g)
Was treated in the same manner as in Example 9 to obtain 1.88 g of colorless crystals having a melting point of 261-270 ° C. [Α] _D ²² + 290.2 ° (c = 0.61, MeOH) Elemental analysis value Calculated value as C ₂₄ H ₂₈ ClNO ₅ S C60.31 H5.90 N2.93 Experimental value C60.13 H5.89 N2. 97

Example 45 3,5-trans-7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid methyl ester

[Chemical formula 116] 5-chloro-α- (2,4-dimethoxyphenyl) -2
-(Neopentylamino) benzyl alcohol (38.
9 g) and thiomalic acid (16.1 g) were treated as in Example 1 to give 32.5 g of colorless crystals, mp 190-191 ° C.
Got Elemental analysis value Calculated value as C ₂₅ H ₃₀ ClNO ₅ S C 61.03 H 6.15 N 2.85 Experimental value C 60.95 H 6.12 N 2.75

Example 46 3,5-trans-7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid

[Chemical 117] 3,5-trans-7-chloro-5-obtained in Example 45
(2,4-dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (27 g) was treated as in Example 9 to give colorless crystals, mp 157-160 ° C. 6 g was obtained. Elemental analysis value Calculated value as C ₂₄ H ₂₈ ClNO ₅ S C60.31 H5.91 N2.93 Experimental value C60.57 H5.83 N2.66

Example 47 N-[(3S, 5R) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetyl] -L-alanine tert-butyl ester and N-[(3R, 5S) -7-chloro-5- (2,
4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetyl] -L-alanine tert-butyl ester

[Chemical 118] 3,5-trans-7-chloro-5-obtained in Example 46
(2,4-dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (15 g) and L-alanine tert-butyl ester hydrochloride (6.0 g) were treated as in Example 40. Treated with N-[(3S, 5
R) -7-Chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetyl] -L-alanine tert-butyl ester was obtained as an amorphous solid, 6.31 g. ¹ H-NMR (CDCl ₃ ) δ: 0.975 (9H, s), 1.322 (3H,
d, J = 7.0Hz), 1.463 (9H, s), 2.300 (1H, dd, J = 3.8,14.6H
z), 2.993 (1H, dd, J = 10.0,14.6Hz), 3.205 (1H, d, J = 13.8H
z), 3.663 (3H, s), 3.713 (1H, dd, J = 3.8,10.0Hz), 3.858
(3H, s), 4.358 (1H, q, J = 7.0Hz), 4.472 (1H, d, J = 13.8Hz),
6.243 (1H, s), 6.471 (1H, d, J = 2.4Hz), 6.606 (1H, dd, J =
2.4,8.4Hz), 6.836 (1H, d, J = 1.8Hz), 7.264 (2H, m), 7.62
4 (1H, d, J = 8.6Hz) From the second fraction N-[(3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2 , 3,5-tetrahydro-4,
1-Benzothiazepine-3-acetyl] -L-alanine tert-butyl ester was obtained as an amorphous solid, 7.91 g. ¹ H-NMR (CDCl ₃ ) δ: 0.968 (9H, s), 1.338 (3H,
d, J = 7.0Hz), 1.440 (9H, s), 2.332 (1H, dd, J = 3.6,15.2H
z), 2.937 (1H, dd, J = 10.4,15.2Hz), 3.186 (1H, d, J = 13.8H
z), 3.660 (3H, s), 3.781 (1H, dd, J = 3.6,10.4Hz), 4.369
(1H, q, J = 7.0Hz), 4.447 (1H, d, J = 13.8Hz), 6.240 (1H, s),
6.470 (1H, d, J = 2.4Hz), 6.603 (1H, dd, J = 2.4,8.6Hz), 6.
841 (1H, s), 7.264 (2H, m), 7.629 (1H, d, J = 8.6Hz)

Example 48 (3S, 5R) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid methyl ester

[Chemical formula 119] N-[(3S, 5R) -7-chloro-obtained in Example 47
5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetyl] -L-alanine tert-butyl ester (6.31 g) was treated as in Example 41 to give 4.0 g of colorless crystals, mp 187-188 ° C.

Example 49 (3S, 5R) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid methyl ester

[Chemical 120] N-[(3R, 5S) -7-chloro-obtained in Example 47
5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzothiazepine-3-acetyl] -L-alanine tert-butyl ester (7.91 g) was treated as in Example 41 to give 3.89 g of colorless crystals, mp 188-190 ° C.

Example 50 (3S, 5R) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid

[Chemical 121] (3S, 5R) -7-chloro-5-obtained in Example 48
(2,4-dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (3.5 g)
Was treated in the same manner as in Example 9 to obtain 3.22 g of colorless crystals having a melting point of 147-151 ° C. [Α] _D ²² + 255.9 ° (c = 0.35, MeOH) Elemental analysis value Calculated value as C ₂₄ H ₂₈ ClNO ₅ S C60.31 H5.91 N2.93 Experimental value C60.58 H5.82 N2.8. 79

Example 51 (3S, 5R) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid

[Chemical formula 122] (3R, 5S) -7-chloro-5-obtained in Example 49
(2,4-dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (3.37
g) was treated as in Example 9, melting point 148-152 ° C.
To obtain 3.28 g of colorless crystals of. [Α] ^{_{D 22 -252.3 ° (c = 0.47}} , MeOH) Elemental analysis C Calculated as _{24 H 28 ClNO 5 S C60.31 H5.91} N2.93 Found C60.32 H5.83 N2 .87

Example 52 7-Chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,4,5-tetrahydro-3
H-1,3-benzodiazepine-3-acetic acid methyl ester

[Chemical 123] (1) α- (5-chloro-2-nitrophenyl) -2-chlorophenylacetic acid methyl ester sodium hydride (3.4 g), 2-chlorophenylacetic acid methyl ester (28.3 g) and 4-chloro-1,
A solution of 2-dinitrobenzene (27g) in dimethylformamide (100ml) was stirred at 0 ° C for 1 hour. The reaction mixture was added to dilute hydrochloric acid (300 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The remaining oil was subjected to silica gel column chromatography (developing solvent hexane:
Acetic acid ethyl ester = 10: 1 V / V)
Recrystallization from hexane gave a melting point of 96-97.
26.3 g of yellow crystals having a temperature of ℃ were obtained. Elemental analysis value Calculated value as C ₁₅ H ₁₁ Cl ₂ NO ₄ C52.96 H3.26 N4.12 Experimental value C53.04 H3.34 N4.06

(2) 2- (2-Nitro-5-chlorophenyl) -2- (2-chlorophenyl) ethanol α- (5-chloro-2-nitrophenyl) -2-chlorophenylacetic acid methyl ester (26.3 g) And lithium borohydride (2 g) in tetrahydrofuran (200
The mixture was stirred at room temperature for 4 hours. Add this mixture to 20
% Aqueous acetic acid solution (50 ml) and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography to obtain oily compound 1
1.0 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.90 (1H, br), 4.15-4.33
(2H, m), 5.270 (1H, t, J = 6.2Hz), 7.20-7.40 (6H, m), 7.86
7 (1H, d, J = 8.4Hz) (3) α- (5-chloro-2-nitrophenyl) -2-chlorophenylacetaldehyde Dimethylsulfoxide (6.7 ml) in dichloromethane (30 ml) was mixed with oxalyl chloride (6 ml). 0.2 ml) in dichloromethane (300 ml) was added at -78 ° C, and the mixture was further stirred at -78 ° C for 10 minutes. 2- (2-nitro-5-chlorophenyl) -2- (2-
A solution of chlorophenyl) ethanol (11.04 g) in dichloromethane (100 ml) was added, and the mixture was further added at -78 ° C for 15
Stir for minutes. Triethylamine (37 ml) was added and the temperature was 0 ° C.
After raising the temperature until it becomes saturated aqueous ammonium chloride solution (12
4 ml) was added. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The remaining oily compound is separated and purified by silica gel column chromatography (developing solvent
Hexane: acetic acid ethyl ester = 3: 1 V / V) to obtain 9.15 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 6.299 (1H, s), 6.836 (1H,
d, J = 2.2Hz), 7.14-7.65 (5H, m), 8.096 (1H, d, J = 8.8Hz),
9.887 (1H, s)

(4) N- [2- (2-chlorophenyl)-
2- (2-Nitro-5-chlorophenyl) ethyl] glycine methyl ester α- (5-chloro-2-nitrophenyl) -2-chlorophenylacetaldehyde (1.68 g) in methanol (15 ml) was added to glycine methyl ester hydrochloride. Salt (0.69 g) and sodium acetate (0.45 g) were added, and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.35 g) was added thereto, and hydrogen chloride was added for 5 minutes. The mixture was stirred at 50 ° C. for 3 hours, 1N aqueous sodium hydroxide solution (50 ml) was added, and the mixture was extracted with dichloromethane. After washing with water, the solvent was distilled off, and the remaining oily substance was subjected to silica gel column chromatography (developing solvent).
Hexane: acetic acid ethyl ester = 3: 1 V / V) was separated and purified to obtain 1.1 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 3.200 (1H, dd, J = 6.8,12.2H
z), 3.366 (1H, dd, J = 7.6,12.2Hz), 3.482 (2H, s), 3.731
(3H, s), 5.255 (1H, t, J = 7.2Hz), 7.22-7.44 (6H, m), 7.846
(1H, d, J = 8.6Hz) (5) N- [2- (2-chlorophenyl) -2- (2-nitro-5-chlorophenyl) ethyl] -N- (trifluoroacetyl) glycine methyl ester N- [2- (2-Chlorophenyl) -2- (2-nitro-5-chlorophenyl) ethyl] glycine Methyl ester (4.9 g) and pyridine (3.0 g) in dichloromethane (50 ml) was added to anhydrous trifluoroacetic acid ( 2.9
7 g) was added and the mixture was stirred for 10 minutes at room temperature. The solution was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 5: 1V / V) to obtain 5.95 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 3.786 (3H, s), 4.138 (1H, d
d, J = 7.0,14.0Hz), 4.215 (2H, s), 4.434 (1H, dd, J = 8.8,1
4.0Hz), 5.473 (1H, dd, J = 7.0,8.8Hz), 7.27-7.52 (6H, m),
7.874 (1H, d, J = 8.4Hz)

(6) N- [2- (2-amino-5-chlorophenyl) -2- (2-chlorophenyl) ethyl] -N
-(Trifluoroacetyl) glycine methyl ester N- [2- (2-chlorophenyl) -2- (2-nitro-5-chlorophenyl) ethyl] -N- (trifluoroacetyl) glycine methyl ester (1 g) ethyl acetate 10% Pd / carbon catalyst (100 mg) was added to the ester (20 ml) solution, and catalytic reduction was carried out at room temperature and atmospheric pressure.
After the reaction was completed, the catalyst was removed and the solvent was distilled off. The residue was subjected to silica gel column chromatography (developing solvent hexane:
Acetic acid ethyl ester = 4: 1 V / V) was separated and purified to obtain 0.39 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 3.705 (1/4 × 3 H, s), 3.742
(3/4 × 3H, s), 3.473-4.247 (4H, m), 4.72-4.80 (1/4 × 1H,
m), 4.874 (3/4 × 1H, dd, J = 5.8,9.4Hz), 6.57-6.63 (1H,
m), 7.05-7.44 (6H, m) (7) N- [2- (5-chloro-2-neopentylaminophenyl) -2- (2-chlorophenyl) ethyl] -N
-Trifluoroacetylglycine methyl ester N- [2- (2-amino-5-chlorophenyl) -2-
(2-Chlorophenyl) ethyl] -N- (trifluoroacetyl) glycine methyl ester (0.39 g) in methanol (5 ml) was added acetic acid (0.05 ml) and pivalaldehyde (78 mg) at room temperature for 30 minutes. It was stirred. Sodium cyanoborohydride (57 mg) was added and the mixture was stirred at room temperature for 1 hr, then dichloromethane (50 ml) was added. The solution was washed with a 1N aqueous sodium hydroxide solution and then with water, the solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 5: 1V / V). Thus, 0.27 g of an oily compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.851 (9H, s), 2.65-2.83
(2H, m), 3.316 (1/4 × 1H, d, J = 17.4Hz), 3.51-3.60 (1H,
m), 3.702 (1/4 × 3H, s), 3.748 (3/4 × 3H, s), 3.873 (1H, d
d, J = 9.8,13.4Hz), 4.055 (3/4 × 1H, d, J = 17.8Hz), 4.274
(1H, dd, J = 5.8,13.4Hz), 4.72-4.86 (1H, m), 6.53-6.60 (1
H, m), 7.11-7.40 (6H, m)

(8) N- [2- (5-chloro-2-neopentylaminophenyl) -2- (2-chlorophenyl)
Ethyl] glycine methyl ester N- [2- (5-chloro-2-neopentylaminophenyl) -2- (2-chlorophenyl) ethyl] -N-trifluoroacetylglycine methyl ester (0.2
g) in methanol (3 ml), concentrated hydrochloric acid (0.6 ml)
Was added and the mixture was heated under reflux for 24 hours. After adding 1N aqueous sodium hydroxide solution (8 ml), the mixture was extracted with dichloromethane.
The extract was washed with water and the solvent was distilled off to obtain 72 mg of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 0.823 (9H, s), 2.659 (1H,
d, J = 11.2Hz), 2.769 (1H, d, J = 11.2Hz), 3.029 (1H, dd, J =
5.2,11.8Hz), 3.279 (1H, dd, J = 8.4,11.8Hz), 3.427 (1H,
d, J = 17.6Hz), 3.528 (1H, d, J = 17.6Hz), 3.741 (3H, s), 4.
563 (1H, dd, J = 5.2,8.4Hz), 6.538 (1H, d, J = 8.8Hz), 6.99-
7.42 (6H, m) (9) 7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepine-3-acetic acid Methyl ester N- [2- (5-chloro-2-neopentylaminophenyl) -2- (2-chlorophenyl) ethyl] glycine methyl ester (0.47 g) and triethylamine (0.21 g) in toluene (5 ml) solution Triphosgene (0.14 g) was added to and the mixture was heated with stirring at 70 ° C. for 5 minutes. Dichloromethane (50 ml) was added to the reaction solution, washed with 1N hydrochloric acid and water, the solvent was distilled off, and the residue was recrystallized from hexane to give colorless crystals having a melting point of 142-148 ° C.
30 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.940 (9H, s), 3.492 (1H,
d, J = 14.4Hz), 3.639 (1H, d, J = 17.2Hz), 3.715 (3H, s), 3.
876 (2H, d, J = 8.6Hz), 4.038 (1H, d, J = 17.2Hz), 4.308 (1H,
d, J = 14.4Hz), 5.317 (1H, t, J = 8.6Hz), 6.645 (1H, d, J = 1.8
Hz), 7.14-7.50 (6H, m)

Example 53 7-Chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,4,5-tetrahydro-3
H-1,3-benzodiazepine-3-acetic acid

[Chemical formula 124] 7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,4,5-tetrahydro-3
H-1,3-benzodiazepine-3-acetic acid methyl ester (0.30 g) was treated as in Example 9 with a melting point of 2
0.21 g of colorless crystals having a temperature of 28-231 ° C. was obtained. Calcd C60.70 H5.56 N6.43 Found as elemental analysis _{C 22 H 24 Cl 2 N 2} O 3 C60.37 H5.49 N6.15

Example 54 3,6-trans-8-chloro-6- (2-chlorophenyl) -1-neopentyl-2-oxo-2,3,5,6
-Tetrahydro-1H-4,1-benzoxazocine-
3-acetic acid methyl ester

[Chemical 125] (1) 2- (2-amino-5-chlorophenyl) -2-
(2-Chlorophenyl) ethanol A solution of 2- (2-nitro-5-chlorophenyl) -2- (2-chlorophenyl) ethanol (7.0 g) obtained in Example 52- (2) in ethanol (70 ml) was added to hydrazine. A hydrate (3.4 g) and Raney nickel (0.1 g) were added, and the mixture was stirred at room temperature for 30 minutes. The catalyst was removed, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester = 2: 1V).
/ V) to separate and purify to obtain 4.44 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 4.107 (2H, d, J = 6.6Hz), 4.
587 (1H, t, J = 6.6Hz), 6.597 (1H, d, J = 8.4Hz), 7.01-7.43
(6H, m) (2) 2- (5-chloro-2-neopentylaminophenyl) -2- (2-chlorophenyl) ethanol 2- (2-amino-5-chlorophenyl) -2- (2-
To a solution of chlorophenyl) ethanol (4.44 g) in methanol (50 ml) was added acetic acid (1.4 ml) and pivalaldehyde (2.0 g), and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (1.5 g) was added to the solution, and the mixture was stirred at room temperature for 1 hr. Then, the same treatment as in Example 52- (7) was carried out to obtain 5.5 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 0.813 (9H, s), 2.654 (1H,
d, J = 11.4Hz), 2.766 (1H, d, J = 11.4Hz), 4.11-4.15 (2H,
m), 4.590 (1H, t, J = 6.3Hz), 6.549 (1H, d, J = 8.6Hz), 7.01
-7.44 (6H, m)

(3) 3- [N- [2- [1- (2-chlorophenyl) -2-hydroxyethyl] -4-chlorophenyl] -N-neopentylcarbamoyl] acrylic acid
Ethyl ester 2- (5-chloro-2-neopentylaminophenyl)
-2- (2-chlorophenyl) ethanol (5.5 g)
And sodium hydrogen carbonate (1.7 g) were added to dichloromethane (30 ml), and fumaric acid monoethyl ester chloride (2.6 g) was added, followed by stirring at room temperature for 1 hour. Dichloromethane (100 ml) was added, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 5: 1V / V) to obtain 6.9 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 0.679 (1/2 × 9 H, s), 0.941
(1/2 × 9H, s), 1.210 (1/2 × 3H, t, J = 7.2Hz), 1.249 (1/2 ×
3H, t, J = 7.2Hz), 2.300 (1/2 × 1H, d, J = 13.8Hz), 2.879 (1 /
2 × 1H, d, J = 13.4Hz), 3.96-4.29 (4H, 1/2 × 1H, m), 4.60-
4.67 (1H, m), 4.821 (1/2 × 1H, t, J = 7.0Hz), 5.863 (1/2 × 1
H, d, J = 15.2Hz), 6.167 (1/2 × 1H, d, J = 15.2Hz), 6.69-7.8
1 (8H, m) (4) 8-chloro-6- (2-chlorophenyl) -1-neopentyl-2-oxo-2,3,5,6-tetrahydro-1H-4,1-benzoxazocine-3 -Acetic acid ethyl ester 3- [N- [2- [1- (2-chlorophenyl) -2-
Hydroxyethyl] -4-chlorophenyl] -N-neopentylcarbamoyl] acrylic acid ethyl ester (6.8 g), 18-crown-6 (3.78 g) and potassium carbonate were added to dichloromethane (70 ml) at room temperature for 3 days. It was stirred. The insoluble matter was filtered off, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent).
Hexane: acetic acid ethyl ester = 5: 1 V / V) was separated and purified to obtain 1.64 g of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.028 (9H, s), 1.227 (3H,
t, J = 7.2Hz), 2.740 (1H, dd, J = 6.6,17.2Hz), 2.974 (1H, d
d, J = 7.8,17.2Hz), 3.716 (1H, d, J = 13.4Hz), 3.94-4.14 (5
H, m), 4.417 (1H, dd, J = 1.4,11.4Hz), 4.671 (1H, dd, J = 1.
4,8.8Hz), 7.014 (1H, d, J = 2.2Hz), 7.23-7.43 (6H, m)

Example 55 3,6-trans-8-chloro-6- (2-chlorophenyl) -1-neopentyl-2-oxo-2,3,5,6
-Tetrahydro-1H-4,1-benzoxazocine-
3-acetic acid

[Chemical formula 126] 3,6-trans-8-chloro-6-obtained in Example 54
(2-Chlorophenyl) -1-neopentyl-2-oxo-2,3,5,6-tetrahydro-1H-4,1-benzoxazocine-3-acetic acid ethyl ester (1.2 g)
Was treated in the same manner as in Example 9 to obtain 0.23 g of colorless crystals having a melting point of 127-133 ° C. Elemental analysis _{C 23 H 25 Cl 2 NO 4} · H 2 O Calculated C58.98 H5.81 N2.99 Found C58.82 H5.43 N2.97

Example 56 7-Chloro-5- (2-chlorophenyl) -1-neopentyl-1,2-dihydro-2-oxo-3H-1,3,
4-benzotriazepine-3-acetic acid ethyl ester

[Chemical 127] (1) 5-chloro-2-neopentylaminophenyl 2
-Chlorophenyl thioketone 2-amino-2 ', 5-dichlorobenzophenone (10
To a solution of g) in methanol (50 ml) was added pivalaldehyde (3.24 g) and acetic acid (5 ml), and the mixture was stirred at 0 ° C for 30 minutes. Sodium cyanoborohydride (3.1 g) was added to this solution and the mixture was heated with stirring at 60 ° C. for 24 hours, then the solution was concentrated and dichloromethane (100 ml) was added. After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 20: 1 V / V) to obtain 6.3 g of a yellow solid. . This compound (0.5
g) in toluene (5 ml) solution, Lawson's reagent (Lawess
on's reagent) (0.3 g) was added, and the mixture was heated under reflux for 2 hours. Acetic acid ethyl ester (50 ml) was added, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 0.54 g of a red oily compound.

(2) 2-neopentylamino-2 ', 5-
Dichlorobenzophenone ethoxycarbonylmethylhydrazone 5-chloro-2-neopentylaminophenyl 2-chlorophenyl Thioketone (0.54 g) in ethanol (7 ml) was added with hydrazinoacetic acid ethyl ester hydrochloride (0.11 g), and at 70 ° C day and night. Heated and stirred. Dichloromethane (50 ml) was added to the reaction solution, which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 15: 1V / V) to obtain 0.16 g of an oily substance. ¹ H-NMR (CDCl ₃ ) δ: 0.950 (9H, s), 1.273 (3H,
t, J = 7.2Hz), 2.964 (2H, d, J = 5.8Hz), 4.04-4.27 (4H, m),
5.969 (1H, t, J = 5.8Hz), 6.681 (1H, d, J = 9.0Hz), 6.879 (1
H, d, J = 2.6Hz), 7.15-7.50 (5H, m) (3) 7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2-dihydro-2-oxo-3H-1 ,
3,4-benzotriazepine-3-acetic acid ethyl ester 2-neopentylamino-2 ', 5-dichlorobenzophenone ethoxycarbonylmethylhydrazone (0.1
6 g) of triethylamine (90 mg) in toluene (2 m
l) Triphosgene (54 mg) was added to the solution, and the temperature was 70 ° C.
The mixture was heated and stirred for 1 hour. Acetic acid ethyl ester (50 ml)
Was added, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester = 3: 1).
(V / V) to separate and purify to obtain 0.16 g of an oily compound. ¹ H-NMR (CDCl ₃ ) δ: 0.883 (9H, s), 1.238 (3H,
t, J = 7.0Hz), 3.376 (1H, d, J = 14.0Hz), 4.184 (2H, q, J = 7.0
Hz), 4.319 (1H, d, J = 16.8Hz), 4.363 (1H, d, J = 14.0Hz),
4.484 (1H, d, J = 16.8Hz), 6.857 (1H, d, J = 2.6Hz), 7.20-7.
50 (6H, m)

Example 57 7-Chloro-5- (2-chlorophenyl) -1-neopentyl-1,2-dihydro-2-oxo-3H-1,3,
4-benzotriazepine-3-acetic acid

[Chemical 128] 7-Chloro-5- (2-chlorophenyl) -1-neopentyl-1,2-dihydro-2-oxo-3H-1,3,4-benzotriazepine-3-acetic acid obtained in Example 56
To a solution of ethyl ester (0.16 g) in ethanol (3 ml) was added 1N aqueous sodium hydroxide solution (0.3 ml), and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was added to the reaction solution, and the solution was acidified with 1N hydrochloric acid, and then the solution was concentrated. Dichloromethane (50 ml) was added, the mixture was washed with water, the solvent was evaporated, and the residue was recrystallized from dichloromethane-petroleum ether to give 91 mg of colorless crystals with a melting point of 181-183 ° C. Calcd C58.07 H4.87 N9.67 Found as elemental analysis _{C 21 H 21 Cl 2 N 3} O 3 C57.90 H5.13 N9.46

Example 58 3,5-trans-7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-3- (tetrazol-5-yl) methyl-1,2,3,5- Tetrahydro-4,
1-benzothiazepin-2-one

[Chemical formula 129] (1) 3- [3,5-trans-7-chloro-5- (2,4
-Dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetylamino] propionitrile 3,5-trans obtained in Example 46 -7-Chloro-5
(2,4-dimethoxyphenyl) -1-neopentyl-
To a solution of 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (1 g) and 3-aminopropionitrile (150 mg) in dichloromethane (10 ml), diethyl cyanophosphate was added. (340 mg) and triethylamine (320 mg) were added, and the mixture was stirred at room temperature for 10 minutes. Dichloromethane (100 mg) was added to the solution, washed with a 1N aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from hexane to obtain 1.07 g of colorless crystals having a melting point of 83-103 ° C. Elemental analysis value Calculated value as C ₂₇ H ₃₂ ClN ₃ O ₄ S C61.18 H6.08 N7.93 Experimental value C61.41 H6.11 N7.84

(2) 3,5-trans-7-chloro-3-
[1- (2-cyanoethyl) tetrazol-5-yl]
Methyl-5- (2,4-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one 3- [3,5-trans-7-chloro -5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzothiazepine-3-acetylamino] propionitrile (0.1 g)
A solution of triphenylphosphine (99 mg), diethylazodicarboxylate (66 mg) and trimethylsilyl azide (44 mg) in tetrahydrofuran (2 ml) was stirred at room temperature for 24 hours. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester = 1: 1 V / V) to obtain 59 mg of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 0.938 (9H, s), 2.96-3.16
(4H, m), 3.17-3.52 (1H, m), 3.667 (3H, s), 3.867 (3H, s),
3.92-3.99 (1H, m), 4.16-4.28 (1H, m), 4.73-4.81 (2H,
m), 6.290 (1H, s), 6.49-7.65 (6H, m) (3) 3,5-trans-7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-3- (tetrazole -5-yl) methyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one 3,5-trans-7-chloro-3- [1- (2-cyanoethyl) tetrazole- 5-yl] methyl-5-
(2,4-dimethoxyphenyl) -1-neopentyl-
1,2,3,5-Tetrahydro-4,1-benzothiazepin-2-one (59 mg) was dissolved in a mixed solvent of methanol (1 mg) and tetrahydrofuran (1 mg), and 1N aqueous sodium hydroxide solution (0. 11 ml) was added and the mixture was stirred at room temperature for 6 hours. Water (50 ml) was added to the reaction solution to make it acidic and then extracted with dichloromethane. The extract was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane-hexane to give 26 mg of colorless crystals having a melting point of 168-173 ° C.
Got Calculated elemental analysis _{C 24 H 28 ClN 5 O 3} S C57.42 H5.62 N13.95 Found C57.28 H5.22 N13.84

Example 59 (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-3- (tetrazol-5-yl) methyl-1,2,3,5- Tetrahydro-4,
1-benzothiazepin-2-one

[Chemical 130] (3R, 5S) -7-chloro-5-obtained in Example 43
(2,3-Dimethoxyphenyl) -1-neopentyl-
Obtained by the same treatment as in Example 58 using 1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetic acid. (1) 3-[(3R, 5S) -7-chloro-5- (2,3)
-Dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetylamino] propionitrile ¹ H-NMR (CDCl ₃ ) δ: 0.991 (9H, s), 2.336 (1H, d
d, J = 3.8,14.8Hz), 2.54-2.63 (2H, m), 2.938 (1H, dd, J = 1
0.6,14.8Hz), 3.217 (1H, d, J = 13.6Hz), 3.39-3.50 (2H,
m), 3.720 (3H, s), 3.778 (1H, dd, J = 3.8,10.6Hz), 3.892
(3H, s), 4.455 (1H, d, J = 13.6Hz), 6.279 (1H, s), 6.60-6.
66 (1H, br), 6.821 (1H, d, J = 1.8Hz), 6.981 (1H, dd, J = 1.4,
8.0Hz), 7.16-7.39 (4H, m) (2) (3R, 5S) -7-chloro-3- [1- (2-cyanoethyl) tetrazol-5-yl] methyl-5-
(2,3-Dimethoxyphenyl) -1-neopentyl-
1,2,3,5-Tetrahydro-4,1-benzothiazepin-2-one ¹ H-NMR (CDCl ₃ ) δ: 0.962 (9H, s), 2.97-3.17
(4H, m), 3.473 (1H, dd, J = 10.6,14.6Hz), 3.729 (3H, s),
3.902 (3H, s), 4.020 (1H, dd, J = 3.6,10.6Hz), 4.306 (1H,
d, J = 14.0Hz), 4.74-4.81 (2H, m), 6.333 (1H, s), 6.84-7.
77 (6H, m) (3) (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-3- (tetrazol-5-yl) methyl-1,2,3 , 5-Tetrahydro-4,1-benzothiazepin-2-one Melting point 139-144 ° C. Elemental analysis value C ₂₄ H ₂₈ ClN ₅ O ₃ S Calculated value C57.42 H5.62 N13.95 Experimental value C57.55 H5.76 N13.78

Example 60 (3R, 5S) -7-chloro-5- (2-chlorophenyl) -3- (2-hydroxyethyl) -1-neopentyl-1,2,3,5-tetrahydro-4,1 -Benzoxazepine

[Chemical 131] (3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetic acid (2 g) and lithium aluminum hydride (0.4 g) were added to tetrahydrofuran (20 mg), and the mixture was heated under reflux for 6 hours. Water was added to remove insoluble matter by filtration, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 2: 1V / V) to give 1.65 g of an amorphous solid. Got ¹ H-NMR (CDCl ₃ ) δ: 0.963 (9H, s), 1.69-1.83
(2H, m), 2.45 (1H, br), 2.563 (1H, d, J = 14.6Hz), 3.090 (1
H, d, J = 10.6Hz), 3.72-3.84 (4H, m), 3.96-4.14 (1H, m),
6.344 (1H, d, J = 2.4Hz), 6.596 (1H, s), 7.05-7.71 (6H, m)

Example 61 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-3- (tetrazole-5-
Il) methylaminocarbonylmethyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzothiazepine

[Chemical 132] 3,5-trans-7-chloro-5-obtained in Example 9
(2-chlorophenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (0.2 g) and aminoacetonitrile sulfate (0.12 g) Diethyl cyanophosphate (0.12 g) and triethylamine (0.14 ml) were added to the dimethylformamide solution in (1) and the mixture was stirred at 0 ° C. for 40 minutes. Ice water was added to the reaction solution, which was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was recrystallized from hexane to give 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-3- (cyanomethylaminocarbonylmethyl) having a melting point of 233-234 ° C. 0.19 g of 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine was obtained. To a solution of this compound (0.2 g) in toluene (2 ml), trimethylsilyl azide (50 mg) and dibutyltin (IV) oxide (33 mg) were added, and the mixture was heated with stirring at 110 to 120 ° C for 24 hours. After concentration, ethyl ether (20
ml) was added and the mixture was washed with a dilute aqueous sodium hydroxide solution, the aqueous layer was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from dichloromethane-hexane to give colorless crystals having a melting point of 264 to 265 ° C.
g was obtained. Elemental analysis _{C 24 H 26 Cl 2 N 6} O 2 · 0.8H calcd ₂ O C53.31 H5.00 N15.54 Found C53.58 H5.14 N15.33

Example 62 7-Chloro-5- (2-chlorophenyl) -2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-ethyl acetate ester

[Chemical 133] (1) 2 ', 5-dichloro-2-neopentylaminodiphenylamine 2-amino-2', 5-dichlorodiphenylamine (2.35 g) in ethanol (50 ml) was dissolved in pivalaldehyde (1.21 ml), acetic acid ( 0.67g),
After stirring at room temperature for 1 hour, sodium cyanoborohydride (0.97 g) was added, and the final liquid was stirred. The reaction solution was concentrated, ethyl acetate (100 ml) was added, washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue is separated and purified by silica gel column chromatography (developing solvent hexane: toluene = 5: 1V / V),
1.7 g of an oily compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.89 (9H, s), 2.86 (2H, d, J
= 5.2Hz), 4.08 (1H, br), 5.66 (1H, br), 6.5-6.85 (3H, m),
7.0-7.2 (3H, m), 7.34 (1H, dd, J = 8.0,1.6Hz)

(2) 7-chloro-5- (2-chlorophenyl) -2,4-dioxo-1-neopentyl-2,3,4,
5-Tetrahydro-1H-1,5-benzodiazepine 2 ', 5-dichloro-2-neopentylaminodiphenylamine (3.7g) in tetrahydrofuran (25ml)
A solution of malonyl dichloride (1.33 ml) in tetrahydrofuran (5 ml) was added dropwise to the solution at 0 ° C., and the mixture was stirred at room temperature for 1 hr and then at 60 ° C. for 2 hr. The reaction solution was concentrated, ethyl acetate (100 ml) was added, and after washing with water,
It was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 2: 1V / V) to obtain 1.20 g of colorless crystals having a melting point of 245-246 ° C. Calcd C61.39 H5.15 N7.16 Found as elemental analysis _{C 20 H 20 Cl 2 N 2} O 2 C61.10 H5.04 N6.99 (3) 7- chloro-5- (2-chlorophenyl) -2,4
-Dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid
Ethyl ester 7-chloro-5- (2-chlorophenyl) -2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.3 g) and ethyl chloroacetate A solution of the ester (0.11 ml) in dimethylformamide (2 ml) was added with sodium hydride (containing 6
0%, 40 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Further, sodium hydride (40 mg × 3) and chloroacetic acid ethyl ester (0.11 ml) were added, and the mixture was stirred for 3 hours, then ethyl acetate (50 ml) was added and the mixture was washed with water.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester =
4: 1 V / V) to separate and purify to obtain 0.25 g of colorless crystals having a melting point of 152-153 ° C. Elemental analysis value Calculated value as C ₂₄ H ₂₆ Cl ₂ N ₂ O ₄ C60.38 H5.49 N5.87 Experimental value C60.22 H5.61 N6.05

Example 63 7-Chloro-5- (2-chlorophenyl) -2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid

[Chemical 134] 7-chloro-5- (2-chlorophenyl) -2,4-dioxo-1-neopentyl-2,3,4, obtained in Example 62
5-Tetrahydro-1H-1,5-benzodiazepine-
3-Acetic acid ethyl ester (0.2g) was treated as in Example 57 to give 0.1 colorless crystals, mp 282-285 ° C.
8 g was obtained. Calcd C58.81 H4.94 N6.23 Found as elemental analysis _{C 22 H 22 Cl 2 N 2} O 4 C58.71 H5.15 N6.21

Example 64 (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid sodium salt

[Chemical 135] (3R, 5S) -7-chloro-5-obtained in Example 51
(2,4-dimethoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid (1.275 g) was dissolved in methanol (50 ml), and 1N aqueous sodium hydroxide solution (2.57 ml) was added. Was added and concentrated, the residue was washed with ethyl acetate, and 1.23 g of colorless crystals having a melting point of 300 ° C. or higher.
Got [Α] _D ²⁴ -267.7 ° (c = 0.64, MeOH) Elemental analysis value C ₂₄ H ₂₇ ClNO ₅ SNa · 0.7H ₂ O Calculated value C56.24 H5.58 N2.73 Experimental value C56 .16 H5.80 N2.81

Example 65 3,5-trans-7-chloro-5- (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 136] 3,5-trans-7-chloro-5 obtained in Example 1
-(2-chlorophenyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.5g) in dichloromethane (5m
l) Tetra n-butyl ammonium borohydride (0.96 g) was added to the solution, and the mixture was heated under reflux for 7 hours. The solvent was evaporated, 1N hydrochloric acid (8 ml) was added to the residue, and the mixture was heated under reflux for 10 min. The solution was neutralized with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 3: 1V / V) to give 0.13 g of a colorless oil. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.97 (1H, dd, J = 5.8,16.0H
z), 3.20 (1H, dd, J = 8.0,16.0Hz), 3.26 (1H, dd, J = 2.4,13.
4Hz), 3.35-3.42 (1H, m), 3.61 (1H, dd, J = 4.8,13.4Hz),
3.68 (3H, s), 5.96 (1H, s), 6.55 (1H, d, J = 2.2Hz), 6.83 (1
H, d, J = 8.2Hz), 7.03 (1H, dd, J = 2.4,8.2Hz), 7.28-7.56 (4
H, m)

Example 66 3,5-trans-7-chloro-5- (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester

[Chemical 137] (1) 5-chloro-2- (2,4-dimethoxybenzylamino) -α- (2-chlorophenyl) benzyl alcohol 2-amino-5-chloro-α- (2-chlorophenyl)
By the same procedure as in Example 30, 33 g of an oily compound was obtained from benzyl alcohol (20 g) and 2,4-dimethoxybenzaldehyde (12.5 g). ¹ H-NMR (CDCl ₃ ) δ: 3.75 (3H, s), 3.76 (3H, s),
4.23 (2H, s), 6.10 (1H, s), 6.35-6.44 (2H, m), 6.63 (1H,
d, J = 8.8Hz), 6.88 (1H, d, J = 2.6Hz), 7.03-7.12 (2H, m),
7.24-7.45 (4H, m) (2) 3- [N- [4-chloro-2- (2-chloro-α-
Hydroxybenzyl) phenyl] -N- (2,4-dimethoxybenzyl) carbamoylacrylic acid ethyl ester 5-chloro-2- (2,4-dimethoxybenzylamino) -α- (2-chlorophenyl) benzyl alcohol (33 g) Fumaric acid chloride monoethyl ester (12.
By the same procedure as in Example 30 from 8 g), 48.9 g of an oily compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.35 (3H, m), 3.46 (3
H, s), 3.78 (3H, s), 3.82,3.83 (2H, each s), 3.94-4.34
(2H, m), 4.64 (1/2 × 1H, d, J = 14.2Hz), 5.48 (1/2 × 1H, d, J
= 14.2Hz), 6.02-8.00 (12H, m)

(3) 3,5-trans-7-chloro-5-
(2-chlorophenyl) -1- (2,4-dimethoxybenzyl) -2-oxo-1,2,3,5-tetrahydro-
Ethanol (500) of the compound (48.9 g) obtained in 4,1-benzoxazepine-3-acetic acid ethyl ester (2)
(ml) solution, potassium carbonate (12.4 g) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and dichloromethane (200
ml) and washed with water. After drying over anhydrous sodium sulfate,
The solvent was distilled off, and the residue was recrystallized from a mixed solvent of dichloromethane-hexane to give colorless crystals having a melting point of 135-136 ° C.
4 g was obtained. (4) 3,5-trans-7-chloro-5- (2-chlorophenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester ( Compound (5 g) obtained in 3), potassium persulfate (10 g)
And dipotassium hydrogen phosphate (3.3 g) were added to a mixed solvent of acetonitrile (80 ml) and water (40 ml), and the mixture was heated under reflux for 2 hours. Water was added, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 3: 1V / V) to give 1.83 g of colorless crystals having a melting point of 132-137 ° C.
Got (5) 3,5-trans-7-chloro-5- (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (4) The compound (1.8 g) was treated in the same manner as in Example 65 to give a colorless oil (0.69 g). ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2Hz), 2.5
4 (1H, dd, J = 6.6,15.0Hz), 2.73 (1H, dd, J = 7.4,15.0Hz), 3.
29-3.22 (2H, m), 4.05 (2H, q, J = 7.2Hz), 4.20-4.32 (1H,
m), 6.33 (1H, s), 6.64 (1H, d, J = 2.4Hz), 6.72 (1H, d, J = 8.
4Hz), 7.04-7.43 (5H, m)

Example 67 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propyl-1,2,3,5-tetrahydro-
4,1-benzothiazepine-3-acetic acid methyl ester

[Chemical 138] 3,5-trans-7-chloro-obtained in Example 65
A solution of 5- (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.1 g) in methanol (2 ml) was treated with pyropionaldehyde (76 mg). Add acetic acid (24mg) and add 3
Stir for 0 minutes at room temperature. Sodium cyanoborohydride (25 mg) was added, the mixture was further stirred at room temperature for 1 hr, dichloromethane (50 ml) was added, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a colorless oil 0.13.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.4Hz), 1.4
6-1.63 (2H, m), 2.76-3.05 (5H, m), 3.24-3.46 (2H, m), 3.
68 (3H, s), 6.43 (1H, s), 6.53 (1H, d, J = 2.4Hz), 7.05-7.4
2 (5H, m), 7.73-7.77 (1H, m)

Example 68 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propyl-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetic acid ethyl ester

[Chemical 139] 3,5-trans-7-chloro-5-obtained in Example 66
(2-Chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.1 g) was treated in the same manner as in Example 67 to give a colorless oil (0. 06 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.2Hz), 1.1
9 (3H, t, J = 7.2Hz), 1.57-1.74 (2H, m), 2.53 (1H, dd, J = 5.
8,15.0Hz), 2.74 (1H, dd, J = 7.6,15.0Hz), 2.92-3.06 (2H,
m), 3.27-3.47 (2H, m), 4.10 (2H, dq, J = 1.4,7.2Hz), 4.17
-4.25 (1H, m), 6.39 (1H, d, J = 2.4Hz), 6.43 (1H, s), 6.90
(1H, d, J = 8.6Hz), 7.14 (1H, dd, J = 2.6,8.6Hz), 7.28-7.63
(4H, m)

Example 69 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propyl-1,2,3,5-tetrahydro-
4,1-benzothiazepine-3-acetic acid hydrochloride

[Chemical 140] 3,5-trans-7-chloro-5-obtained in Example 67
(2-chlorophenyl) -1-propyl-1,2,3,5
-Tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (0.13 g) in dioxane (1 ml)
6N Hydrochloric acid (1 ml) was added to the solution, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off, and the residue was recrystallized from ethanol-hexane to obtain 57 mg of colorless crystals having a melting point of 165-168 ° C. Elemental analysis value C ₂₀ H ₂₁ Cl ₂ NO ₂ S ・ HCl ・ 0.3H ₂ O
Calculated as C53.12 H5.04 N3.10 Experimental value C53.21 H5.03 N3.34

Example 70 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propyl-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetic acid

[Chemical 141] 3,5-trans-7-chloro-5-obtained in Example 68
(2-chlorophenyl) -1-propyl-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.15 g) was treated in the same manner as in Example 69 to obtain 50 mg of colorless crystals having a melting point of 105-112 ° C. Elemental analysis _{C 20 H 21 Cl 2 NO 3} · HCl · 0.6H calcd ₂ O C54.40 H5.30 N3.17 Found C54.33 H5.37 N3.31

Example 71 Methyl 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propionyl-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetate ester

[Chemical 142] 3,5-trans-7-chloro-5-obtained in Example 65
Sodium hydrogen carbonate (59 mg) was added to a dichloromethane (2 ml) solution of (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester (100 mg), and further. Propionyl chloride (60 mg) was added, and the mixture was stirred at room temperature for 2 hours. After adding dichloromethane (50 ml) and washing with water, the solvent was distilled off and recrystallized from ethyl ether-petroleum ether to give the melting point 191-.
90 mg of colorless crystals at 194 ° C. were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2Hz), 2.0
7-2.33 (2H, m), 2.83 (1H, dd, J = 7.6,16.8Hz), 3.02 (1H, d
d, J = 7.2,16.8Hz), 3.24 (1H, dd, J = 3.0,13.6Hz), 3.32-3.
44 (1H, m), 3.68 (3H, s), 4.85 (1H, dd, J = 5.0,13.6Hz), 6.
00 (1H, s), 6.60 (1H, d, J = 2.2Hz), 7.11-7.63 (6H, m)

Example 72 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propionyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid Ethyl ester

[Chemical 143] 3,5-trans-7-chloro-5-obtained in Example 66
By a procedure similar to that of Example 71, 70 mg of an oily substance was obtained from (2-chlorophenyl) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (100 mg). . ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.0Hz), 1.1
6 (3H, t, J = 7.4Hz), 2.14-2.52 (2H, m), 2.61 (1H, dd, J = 5.
4,15.4Hz), 2.88 (1H, dd, J = 9.2,15.4Hz), 3.25 (1H, dd, J =
3.2,13.6Hz), 3.85-4.16 (2H, m), 4.24-4.40 (1H, m), 4.5
6 (1H, dd, J = 6.0,13.6Hz), 6.29 (1H, s), 6.50 (1H, d, J = 2.2
Hz), 7.16-7.68 (6H, m)

Example 73 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propionyl-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid

[Chemical 144] 3,5-trans-7-chloro-5-obtained in Example 71
(2-chlorophenyl) -1-propionyl-1,2,
3,5-tetrahydro-4,1-benzothiazepine-3-
Acetic acid methyl ester (90 mg) in dioxane (2 ml)
2N Hydrochloric acid (1 ml) was added to the solution, and the mixture was heated under reflux for 2 hours. Dichloromethane (50 ml) was added, the solution was washed with water, the solvent was distilled off, and the residue was recrystallized from ethyl ether-hexane.
52 mg of colorless crystals having a melting point of 230-232 ° C. were obtained. Elemental analysis value Calculated value as C ₂₀ H ₁₉ Cl ₂ NO ₃ S C56.61 H4.51 N3.30 Experimental value C56.26 H4.65 N3.51

Example 74 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-propionyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid

[Chemical 145] 3,5-trans-7-chloro-5-obtained in Example 72
(2-chlorophenyl) -1-propionyl-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetic acid ethyl ester (70 mg) was treated in the same manner as in Example 73 to give 43 mg of colorless crystals having a melting point of 187-190 ° C.
Got Calcd C58.84 H4.69 N3.43 Found as elemental analysis _{C 20 H 19 Cl 2 NO 4} C58.75 H4.67 N3.59

Example 75 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid Tert-butyl ester

[Chemical 146] (1) 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetic acid tert-butyl ester 3,5-trans-7-chloro-5- (2-chlorophenyl) -2-oxo-1-neopentyl-1,2,3,5
Isobutene (1 ml) and concentrated sulfuric acid (0.05 ml) were added to a solution of tetrahydro-4,1-benzoxazepine-3-acetic acid (2 g) in dichloromethane (20 ml), and the mixture was left sealed for 24 hours. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent hexane: acetic acid ethyl ester = 5: 1).
(V / V) to separate and purify to obtain 1.67 g of colorless crystals having a melting point of 145-147 ° C. (2) 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-tert-butyl acetate In a dichloromethane solution of the compound (1 g) obtained from the ester (1), tetra-n-butylammonium borohydride (1.57
g) was added. Then, the same operation as in Example 65 was carried out to obtain 0.52 g of a colorless oily substance. ¹ H-NMR δ: 0.95 (9H, s), 1.44 (9H, s), 2.33 (1H, dd,
J = 5.0,15.4Hz), 2.55 (1H, dd, J = 7.8,15.4Hz), 2.56 (1H,
d, J = 13.2Hz), 3.09 (1H, dd, J = 1.8,11.2Hz), 3.63-3.78 (2
H, m), 4.12-4.26 (1H, m), 6.32 (1H, s), 6.59 (1H, s), 7.1
1-7.76 (6H, m)

Example 76 3,5-trans-7-chloro-5- (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid

[Chemical 147] 3,5-trans-7-chloro-5-obtained in Example 75
(2-chlorophenyl) -1-neopentyl-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-2N hydrochloric acid (1 ml) was added to a solution of acetic acid tert-butyl ester (0.5 g) in dioxane (5 ml), and the mixture was heated under reflux for 3 hours. After neutralization with 1N sodium hydroxide, dichloromethane (100 ml) was added and the mixture was washed with water. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent dichloromethane: methanol: water = 9: 1: 0.1V).
/ V) to separate and purify to obtain 85 mg of colorless crystals of an oily substance at 195 to 208 ° C. Elemental analysis _{C 22 H 25 Cl 2 NO 3} · 0.2H calcd ₂ O C62.04 H6.01 N3.29 Found C62.14 H6.01 N3.42

Method for measuring squalene synthase inhibitory activity The squalene synthase inhibitory activity was measured as follows using the enzyme solutions shown in Experimental Examples 1 and 2 described below.
That is, 5 μM [1 ⁻³ H] farnesyl pyrophosphate (specific activity 25 μCi / mole), 1 mM NADPH (reduced nicotinamide adenine dinucleotide phosphate), 5
A solution containing 50 mM of MgCl ₂ , 6 mM glutathione, 100 mM potassium phosphate buffer (pH 7.4) and a test drug (added as an aqueous solution or DMSO solution) (total volume: 50 μm)
To l), the enzyme solution (protein 0.8 μg) prepared in Experimental Example 1 and Experimental Example 2 was added and reacted at 37 ° C. for 45 minutes.
The reaction was stopped by adding 150 μl of a chloroform / methanol (1: 2) mixture, and then 50 μl of chloroform and 50 μl of 3N sodium hydroxide solution were added. 50 μl of a chloroform layer (lower layer) containing a reaction product containing squalene as a main component was mixed with 3 ml of a toluene liquid scintillator, and its radioactivity was measured by a liquid scintillation counter. The squalene synthase inhibitory activity was shown as the concentration (IC ₅₀ , molar concentration (M)) at which the radioactivity incorporated into the chloroform layer was inhibited by 50%.

Experimental Example 1 Preparation of rat enzyme Male SD rats (6 weeks old) were exsanguinated and killed, and then the liver was removed. After washing about 10 g of liver with ice-cold physiological saline,
15 ml ice-cold buffer [100 mM potassium phosphate (pH 7.
4), homogenized in 15 mM nicotinamide, 2 mM MgCl ₂ ], and centrifuged at 10,000 × g for 20 minutes (4 ° C.). The obtained supernatant was further centrifuged at 105,000 × g for 90 minutes (4 ° C.), and then the precipitate was collected on ice-cooled 100 ° C.
The cells were suspended in mM potassium phosphate buffer (pH 7.4) and then centrifuged again at 105,000 × g for 90 minutes (4 ° C.). The precipitate (microsome fraction) thus obtained was suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4) (protein concentration of about 40 mg / ml, measured by Pierce BCA protein assay kit). Was used as the enzyme solution.

Experimental Example 2 Preparation of human enzyme Human hepatoma cells HepG2 (about 1 × 10 ⁹ cells) obtained by culturing in Dulbecco's modified Eagle medium containing 10% fetal bovine serum (37 ° C., in the presence of 5% CO ₂ ). 10 ml ice-cold buffer [100 mM potassium phosphate buffer (pH 7.
4), 30 mM nicotinamide, 2.5 mM MgCl ₂ ], and then the cells were disrupted by ultrasonication (30 seconds, twice). A microsome fraction is obtained from the obtained sonicate by the same procedure as in Experimental Example 1. This is ice-cooled 10
It was suspended in 0 mM potassium phosphate buffer (pH 7.4) (protein concentration of about 4 mg / ml), and this was used as an enzyme solution. The results are shown in [Table 4].

[Table 4]

Formulation Example A squalene synthase inhibitor containing the fused ring compound represented by the formulas (I), (I ′), (I) and (I ′) of the present invention or a salt thereof as an active ingredient is For example, when used as a therapeutic agent for hypercholesterolemia, it can be produced by the following formulation. 1. Capsule (1) Compound obtained in Example 10-8 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) The whole amount and 1/2 of (4) are mixed and then granulated. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablet (1) Compound obtained in Example 10-8 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) and Total amount of (3) and 2/3 of (4) and 1 of (5)
After mixing / 2, granulate. The remaining (4) and
(5) is added to the granules and pressed into tablets.

3. Injection (1) Sodium salt of the compound obtained in Example 10-8 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2) and (3) so that the total amount is 2 ml. Dissolve in distilled water for injection and seal in an ampoule. All steps are performed aseptically. 4. Capsule (1) Compound obtained in Example 9 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), the total amount of (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.

5. Tablet (1) Compound obtained in Example 9 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) and (3) ) And 2/3 of (4) and 1 of (5)
After mixing / 2, granulate. The remaining (4) and
(5) is added to the granules and pressed into tablets. 6. Injection (1) Sodium salt of compound obtained in Example 9 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2) and (3) were injected to a total volume of 2 ml. Dissolve in distilled water for use and seal in an ampoule. All steps are performed aseptically.

[0188]

The squalene synthase inhibitor containing the fused ring compound of the present invention or a salt thereof as an active ingredient is useful for the treatment of hypercholesterolemia and the treatment of fungal infections.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location C07D 243/14 257/04 267/14 267/22 281/10 C 285/00 417/06 257 417 / 12 257 498/04 116 // C12N 9/99

Claims (27)

[Claims] 1. The formula: [Wherein, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ 'is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group, and X'is an ester. An optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group,
The substituent composed of an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation, a ring A is an optionally substituted benzene ring or an optionally substituted Optionally aromatic heterocycle, ring J ₁ is a 7-membered heterocycle containing 3 or less heteroatoms as ring-constituting atoms, D is C or N, and Z ₁ is C, N, S (O ) _q (q is 0, 1 or 2) or O, K is C or N, and the ring J ₁ is R ₁ , R ₂ ', X'.
Besides, it may further have a substituent. However, ring A
And the condensed ring consisting of ring J ₁ and 2-oxo-1,2,3,3
5-tetrahydro-4,1-benzoxazepine ring, 2
-Oxo- (2,3-dihydro or 2,3,4,5
-Tetrahydro) -1H-1,4-benzodiazepine ring and 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine ring] or a salt thereof. . 2. The formula: [Wherein, R ₁ is hydrogen or an optionally substituted hydrocarbon group, R ₂ 'is an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group, and X'is an ester. An optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group,
The substituent composed of an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom capable of deprotonation, a ring A is an optionally substituted benzene ring or an optionally substituted Optionally aromatic heterocycle, ring J ₂ is a 7-membered heterocycle, Z ₂ is S (O) _q (q is 0,
1 or 2), C or O, and K is C or N
, G represents O or S. Provided that the condensed ring consisting of ring A and ring J ₂ is a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring]. Or a salt thereof. 3. The compound according to claim 1, wherein R ₁ is an aliphatic chain hydrocarbon group, or a salt thereof. 4. The compound according to claim 3, wherein the aliphatic chain hydrocarbon group is an alkyl group, or a salt thereof. 5. The compound or salt thereof according to claim 1 or 2, wherein R ₂ 'is a substituted phenyl group. 6. The compound according to claim 1, wherein X ′ is an alkyl group substituted with an optionally esterified carboxyl group, or a salt thereof. 7. The compound according to claim 1 or 2, wherein X ′ is an alkyl group substituted with an optionally substituted heterocyclic residue having a deprotonable hydrogen atom. 8. A heterocyclic residue is represented by: The compound or salt thereof according to claim 7, which is: 9. The compound according to claim 6 or 7, wherein the alkyl group is a linear alkyl group having 1 to 4 carbon atoms, or a salt thereof. 10. An aromatic heterocycle represented by ring A is The compound or salt thereof according to claim 1 or 2, which is 11. The compound according to claim _{1, wherein} the substituent on ring J ₁ is oxo or thioxo, or a salt thereof. 12. A condensed ring consisting of ring A and ring J ₁ is The compound or salt thereof according to claim 1, which is 13. The compound or a salt thereof according to claim 2, wherein Z ₂ is S (O) _q (q represents 0, 1 or 2). 14. The compound according to claim 2, wherein K is C, or a salt thereof. 15. The formula: [Wherein R ₁ is hydrogen or an optionally substituted hydrocarbon group, and R ₂ is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic group] In the group heterocyclic 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 hydrogen which can be deprotonated. A substituent is composed of an optionally substituted heterocyclic residue having an atom, ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocycle, and ring J ′ is a ring. A 7- or 8-membered heterocyclic ring containing 3 or less heteroatoms as constituent atoms, D represents C or N, and ring J ′ further has a substituent in addition to R ₁ , R ₂ and X ′. May be. Provided that the condensed ring consisting of ring A and ring J ′ is a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring] or a salt thereof. A squalene synthase inhibitor comprising: 16. The squalene synthase inhibitor according to claim 15, wherein R ₁ is an aliphatic chain hydrocarbon group. 17. The squalene synthase inhibitor according to claim 16, wherein the aliphatic chain hydrocarbon group is an alkyl group. 18. The squalene synthase inhibitor according to claim 15, wherein R ₂ is a substituted phenyl group. 19. The X ′ is an alkyl group substituted with an optionally esterified carboxyl group.
The squalene synthase inhibitor according to 5. 20. The squalene synthase inhibitor according to claim 15, wherein X ′ is an alkyl group having a hydrogen atom capable of deprotonation and substituted with an optionally substituted heterocyclic residue. 21. A heterocyclic residue is represented by: 21. The squalene synthase inhibitor according to claim 20. 22. The squalene synthase inhibitor according to claim 19, wherein the alkyl group is a linear alkyl group having 1 to 4 carbon atoms. 23. An aromatic heterocycle represented by ring A is: The squalene synthase inhibitor according to claim 15. 24. The squalene synthase inhibitor according to claim 15, wherein the substituent on the ring J ′ is oxo or thioxo. 25. A condensed ring consisting of ring A and ring J ′ is represented by: The squalene synthase inhibitor according to claim 15. 26. The formula: [Wherein R ₁ is hydrogen or an optionally substituted hydrocarbon group, and R ₂ is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic group] A heterocyclic group, 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 group An optionally substituted heterocyclic residue having an optionally substituted amino group or a deprotonable hydrogen atom, ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocycle the, Z ₃ is = N -, - (indicating the R ₇ is hydrogen, an alkyl group or an acyl _{group), - - N (R 7} ) S (O) q - (q is 0, 1
Or 2), —CH ₂ — or —O—, and G is O
Or S is shown. The broken line portion represents a double bond when Z ₃ is = N-, and a single bond when Z ₃ is other than = N-. However, Z ₃ is −
16. The squalene synthase inhibitor according to claim 15, which comprises a compound represented by the formula O, which is O-, and G is S when ring A is an optionally substituted benzene ring. 27. The squalene synthase inhibitor according to claim 26, wherein Z ₃ is S (O) _q (q represents 0, 1 or 2).