WO1997017972A1

WO1997017972A1 - Cholesterol-lowering composition

Info

Publication number: WO1997017972A1
Application number: PCT/JP1996/003328
Authority: WO
Inventors: Takeshi Sudo; Takashi Mikami; Shinji Suda; Hitoshi Oinuma; Tomohiro Matsushima
Original assignee: Eisai Co., Ltd.
Priority date: 1995-11-13
Filing date: 1996-11-13
Publication date: 1997-05-22
Also published as: JP3662257B2; AU7586796A

Abstract

A new type of cholesterol-lowering composition useful as a drug, which comprises a pharmacologically effective amount of a thiazolo[3,2-a]azepine derivative of general formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier wherein R1 is hydrogen or a a thiol-protecting group; R2 is hydrogen, lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, lower alkoxy or lower alkylthio; R?3 and R4¿ are each independently hydrogen, lower alkyl, lower alkoxy, lower alkylthio, optionally substituted aryl or optionally sustituted heteroaryl, or alternatively R?3 and R4¿ together with the carbon atoms to which they are bonded may form a ring; R?5 and R6¿ are each independently hydrogen or lower alkyl; R7 is hydrogen or a carboxyl-protecting group; and n and m are each independently 0, 1 or 2.

Description

Description Cholesterol-lowering agent composition Background of the invention

Field of the invention

The present invention relates to a new type of cholesterol lowering composition. More specifically, the present invention relates to a cholesterol-lowering agent composition comprising a thiazolo [3,2-a] azepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Description of related technology

With the westernization of dietary habits, it has been a long time since the increase in cardiovascular disease in Japanese people has become a problem. Atherosclerosis and hypertension lead to prolonged treatment, which requires limited and controlled daily life during the treatment. Further progress can lead to serious conditions such as cerebral hemorrhage and rupture of the aneurysm. Therefore, the prevention and treatment of hyperlipidemia, which is a pre-stage of arteriosclerosis and hypertension, is extremely important, and may reduce the incidence of other cardiovascular diseases. Have been.

Therefore, various cholesterol-lowering drugs have been researched and improved to date, but patients who are not sensitive to currently marketed drugs and who have complications have severe restrictions on drug administration. Some patients are being added, and there is still a need for new types of cholesterol-lowering drugs. Disclosure of the Invention Summary of the Invention

An object of the present invention is to provide a novel eve cholesterol-lowering composition comprising a pharmacologically effective amount of a thiazolo [3,2-a] azebine derivative or a pharmacologically acceptable salt thereof and a carrier. Is to provide.

Another object of the present invention is to provide a thiazolo [3,2_a] azepine derivative or a drug thereof. An object of the present invention is to provide a prophylactic or therapeutic method comprising administering a physiologically acceptable salt to a disease for which a cholesterol-lowering effect is effective.

Yet another object of the present invention is to provide a use for lowering cholesterol of a thiazolo [3,2-a] azebine derivative or a pharmacologically acceptable salt thereof.

Still another object of the present invention is to provide a cholesterol-lowering agent containing the thiazolo [3,2-a] azebine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The present inventors have studied the pharmacologic effects of a series of thiazolo [3,2-a] azebine derivatives or pharmacologically acceptable salts thereof in the development of preventive and therapeutic drugs for diseases in which cholesterol-lowering effect is effective. During the process, it was found that the above compound exhibited an excellent cholesterol lowering effect. The present invention has been completed based on this finding.

That is, the first aspect of the present invention relates to a pharmacologically effective amount of a thiazolo [3,2-a] azebine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof. A cholesterol-lowering agent composition comprising an acceptable carrier.

In the formula, R ¹ represents a hydrogen atom or a protecting group for a thiol group. R ² is a hydrogen atom, a lower alkyl group which may have a substituent Ariru group, to which may have a substituent Teroariru group, a lower alkoxy group means a lower alkylthio group _t R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group which may have a substituent, or Or a heteroaryl group which may have a substituent. R ³ and R ⁴ may be combined with the carbon atom to which they are bonded to form a ring.

R ⁵ and R ^s are the same or different from each other, and represent a hydrogen atom or a lower alkyl group.

R ⁷ represents a hydrogen atom or a protecting group for a carbonyl group.

n and m independently represent 0, 1 or 2.

Preferred examples of the cholesterol-lowering agent composition of the first aspect of the present invention are as follows.

1) In a thiazolo [3,2-a] azepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, at least one of R ³ and R ⁴ is not a hydrogen atom, and R ¹ R ² , R ⁵ , R ⁶ , R n and m are as defined above, 2) a thiazolo [3,2-a] azebine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof Wherein neither R ³ nor R ⁴ is a hydrogen atom, and R ¹ R ² , R ′ RR ⁷ , n and m are as defined above,

3) In the thiazolo [3,2_a] azebine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, R ³ is a lower alkyl group, R ⁴ is a hydrogen atom, and I ¹ , R ² , R ′ RR n and m are as defined above,

4) In the thiazolo [3,2-a] azebine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, R ³ is a hydrogen atom, R ⁴ is a lower alkyl group, and II ¹ , R ² , R ⁵ , R ⁶ , R n and m are as defined above,

5) In the thiazolo [3,2-a] azepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, R ³ is a hydrogen atom, R ⁴ is a methyl group, and R \ R ² , R ⁵ , RR ⁷ , n and m are as defined above,

6) In the thiazolo [3,2-a] azebine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, R ² is a branched lower alkyl group, and RRRR ⁵ , R ⁶ , R n and m are as defined above,

7) R ² is the formula ? H ₃

H ₃ C ^ CH

H ₂ , and m = 0, and RR ³ , R \ R ⁵ , R ⁶ , R ⁷ and n are as defined above,

8) Thiazolo [3,2-a] azebin derivative is represented by the formula (Γ),

(1,)

And R ¹ R ² , RR \ R ⁵ , R ^s and R ⁷ are as defined above; 9) a thiazolo [3,2-a] azebine derivative represented by the formula (II) or a pharmacologically active substance thereof; In the acceptable salts, R ³ , R ⁵ , R ⁶ and R ⁷ are hydrogen atoms, R ⁴ is a methyl group, and R ¹ and R ² are as defined above.

The second aspect of the present invention is to administer a thiazolo [3,2-a] azebine derivative represented by the above formula (I: or a pharmacologically acceptable salt thereof to a disease in which a cholesterol-lowering effect is effective. Prevention and treatment methods.

Examples of the disease in which the cholesterol-lowering effect is effective include hyperlipidemia ₍ the third embodiment of the present invention relates to a thiazolo [3,2-a] azepine derivative represented by the above formula (I) or a pharmacology thereof. It relates to the use of reducing the cholesterol of chemically acceptable salts.

A fourth aspect of the present invention is a thiazolo [3,2-a] azepine represented by the above formula (I). The present invention relates to a cholesterol-lowering agent comprising a derivative or a pharmacologically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail.

Detailed description of the invention

In the formula (I), the lower alkyl group in the definitions of R ² , R ³ , R \ R ⁵ and R ⁶ means a linear or branched alkyl group having 1 to 6 carbon atoms. , For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neobentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylbrobi 1- Echiru 1 one Mechiruburobiru means such as one one Echiru one 2-methylpropionitrile building. Of these, preferred are a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and a sec-butyl group.

The lower alkoxy group in the definition of R ² , R ³ and is an alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group and the like.

The lower alkylthio group in the definitions of R ² , R ³ and R ⁴ is an alkylthio group having 1 to 6 carbon atoms, for example, a methylthio group, an ethylthio group, an n-propylthio group, and the like.

In the aryl group which may have a substituent as defined in the definitions of R ² , R ³ and R ⁴ , aryl means phenyl, 1-naphthyl, 2-naphthyl, anthracenyl and the like.

In the optionally substituted heteroaryl group defined in the definition of R ² , R ³ and R ⁴ , the term “heteroaryl” includes 1 to 4 heteroatoms such as a nitrogen atom, a sulfur atom and an oxygen atom. 3-8 membered ring, preferably 5-6 membered ring To taste.

In the “aryl group optionally having substituent (s)” and “heteroaryl group optionally having substituent (s)” in the definition of R ² , R ³ and R ⁴ , “substituent” means methyl Lower alkyl groups such as, ethyl, n-propyl, and t-butyl; halogen atoms such as fluorine, chlorine, bromine and iodine; lower such as methoxy, ethoxy, n-propoxy and t-butoxy. It means an alkoxy group, a nitro group, an amino group which may be mono- or di-substituted, and the like. The aryl group and the heteroaryl group mean those having 1 to 3 of these substituents.

Examples of the thiol protecting group in the definition of R ¹ include lower alkyl groups such as methyl, ethyl, n-propyl, and t-butyl, acetyl, propionyl, butyryl, bivaloyl, palmitoyl, and stearoyl. A group derived from an aliphatic saturated monocarboxylic acid such as a group; a group derived from an aliphatic unsaturated carboxylic acid such as an acryloyl group, a propioyl group, a methacryloyl group, a crotonyl group, an oleoyl group; a benzoyl group; Groups derived from carbocyclic carboxylic acids such as naphthoyl, toluoyl, apotyl, and cinnamoyl; groups derived from heterocyclic carboxylic acids such as furoyl, tenyl, nicotinoyl, and isonicotinoyl A glycoloyl group, a lactoyl group, a glyceroyl group, a maloyl group, Groups derived from hydroxycarponic acid or alkoxycarponic acid such as yl group, benzyloyl group, salicyloyl group, anisyl group, vanilloyl group, and viperiroloyl group.Examples of such groups include acryl group, phenyl, and naphthyl. Examples thereof include heteroaryl groups such as aryl group, furyl, pyridyl, and phenyl, arylalkyl groups such as benzyl group, and heteroarylalkyl groups such as furoylmethyl group, phenylmethyl group, and viridylmethyl group. Of these, an acetyl group is particularly preferred.

Protecting groups for the carbonyl group found in the definition of R ⁷ include lower alkyl groups such as methyl, ethyl, n-butyl, t-butyl, and arylalkyls such as benzyl, 1-naphthylmethyl, and 2-naphthylethyl. Group, a heteroarylalkyl group such as 2-pyridylmethyl, 3-pyridylbuguchi building and 2-chenylethyl. In short, as long as it is displaced in the living body into a lipoxyl group, Anything is acceptable.

In one of R ³ and R ⁴ defined "may form a connexion ring such together with the carbon atom to which they are attached", the ring formed is 5-8 membered saturated or unsaturated ring is preferable.

Pharmaceutically acceptable salts include inorganic salts such as hydrochloride, sulfate and nitrate, and organic salts such as maleate, citrate and acetate, and alkali metals such as sodium and potassium. And salts with amino acids such as aspartate and glutamate.

The present invention also includes hydrates of the above compounds.

The above-mentioned compounds of the present invention can be used as a composition or an agent by a conventional method for the purpose of preventing or treating a disease for which cholesterol lowering effect is effective. For example, when it is prevented or treated by administration, it may be administered orally or parenterally.

The compounds according to the present invention include tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections (including those for infusion), ointments, eye ointments, eye drops , Nasal drops, ear drops, cataplasms, lotions and the like.

The dosage varies significantly depending on the type of disease, degree of symptoms, age of the patient, gender, and susceptibility to the drug, but it is usually about 1 to 1000 mg, preferably 5 to 500 mg per day for an adult. Preferably it is 10 to 200 mg. Usually, one dose is administered in 1 to several divided doses. When the compound of the present invention is administered in the form of an injection, the dose is usually about l-1000 zg / kg-body weight, preferably about 10-300 g / kg-body weight.

In formulating the compounds of the present invention, a common carrier for pharmaceuticals is used, and the formulation can be performed by a conventional method.

That is, when preparing a solid preparation for oral administration, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, an antioxidant, and the like are added to the compound of the present invention as the main drug. The composition is then made into tablets, coated tablets, granules, powders, capsules, etc. in a conventional manner. As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like are used.

Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxybutyryl cellulose, hydroxybutyryl methylcellulose, calcium citrate, dextrin , Pectin and the like, and as the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like are used.

Any coloring agent may be used as long as it is permitted to be added to pharmaceutical products. As a flavoring agent, cocoa powder, heart-shaped brain, aromasan, heart-shaped oil, dragon brain, cinnamon powder and the like are used. Any antioxidant, such as ascorbic acid, or tocopherol, may be used as long as it is permitted to be added to a pharmaceutical. Of course, tablets and granules may be appropriately coated with sugar coating, gelatin coating, or other coatings as necessary.

On the other hand, injections, eye drops, etc. are used in the main drug, pH adjusters, buffering agents,! K It can be produced by adding a turbidity agent, a solubilizing agent, a stabilizing agent, a tonicity agent, an antioxidant, a preservative, and the like, and treating the resulting mixture by an ordinary method. At this time, if necessary, the preparation can be lyophilized. The injection can be administered intravenously, subcutaneously or intramuscularly.

By way of example of the ¾ Nigoka agent, methylcellulose, polysorbate one DOO 8 0, human de Loki Chez chill cellulose, gum arabic, tragacanth powder, also carboxymethyl cellulose sodium, polyoxyethylene sorbitan monolaurate _c, dissolved Examples of adjuvants include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, and polyoxyethylene sorbitan monolaurate.

As a stabilizer, for example, sodium sulfite, sodium metasulfite, or ether is used. As a preservative, for example, methyl paraoxybenzoate, ethyl ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, chlorocreso-chloro Can be mentioned. The pharmaceutical composition of the present invention comprising such a preparation is an effective amount for preventing or treating a disease for which a cholesterol-lowering effect is effective, in an amount effective for the above-mentioned compounds of the present invention or a pharmacologically acceptable thereof. And a salt and at least one of the above-mentioned carriers for pharmaceutical preparations.

Further, the method for preventing or treating a disease in which a cholesterol-lowering effect is effective according to the present invention comprises an effective amount of the compound according to the present invention or a pharmacologically acceptable amount thereof for the prevention or treatment of the disease. Administering the salt to the patient. Examples of the disease for which the cholesterol lowering effect is effective include hyperlipidemia and the like. Here, the “effective amount for preventing or treating the disease” varies depending on the specific type of the disease, the degree of the symptoms, the age of the patient, the sex difference, the sensitivity to the drug, and the like. The pharmaceutical use of the above-mentioned compound group or a pharmacologically acceptable salt thereof according to the present invention is a use for lowering cholesterol.

Further, the cholesterol-lowering agent according to the present invention includes the above-mentioned compound group or a pharmacologically acceptable salt thereof as an active ingredient.

The method for producing a compound group as the active ingredient of the medicament according to the present invention is described in WO94 / 128910 (publication date: December 22, 1994) and WO966 / 02549. (Publication date: February 1, 1996), the main ones are shown below as synthesis examples.

Synthesis example 1

Methyl “3R— (3,6,9?, 9a?) L—6 — {“ (2S, 3S) —1-oxo-1—acetylthio-3-3—methylpentyl 1-amino} —9—methyl 5 —Oxo one-year-old Kutahi-Drothiazolo “3,2-alazepine-1 3 —Carboxylate and

Methyl “3R— (3, 6, 9, 9a?) L— 6— {“ (2S, 3S) —1 oxo-1 2—acetylthio-3-3-methylpentyl 1-amino} —9—methyl 5 —Oxo-octahi-drothiazolo ”3, — 2-a] azebine-1 3 —Carpoxylate

Methyl [3R— (Sc ^ Sa ^ ^ Sa ^)] — 6-amino-19-methyl-1-5-oxooxo-hydrothiazolo [3,2-a] azebine-3-carboxylate and methyl [3R— ( 3-, 6-, 9a, 9a?)] — Synthesis of 6-amino-1-9-methyl-5-oxooxohydrothiazolo [3,2-a] azebine-3-carboxylate

CH ₃ Methyl [3R— (3a, 6a, 9?, 9a?)] — 6-Acetylamino-1-9-methyl-5-oxooxohydrothiazolo [3,2-a] azebine-3-carboxylate and methyl [3R— (3 ，, ひ, ひ, 9a?)] — 6-Acetylamino-19-methyl-5-oxo-one-octahydrothiazolo [3,2-a] azepine-13-carboxylate mixture (2: 1 isomer ratio) ) 2.59 g (8.6 mot) was dissolved in a 10% methanolic hydrochloric acid solution (100 mi) and heated under reflux for 26 hours. After evaporating the solvent under reduced pressure, 2 N hydrochloric acid was added, and the mixture was washed with dichloromethane. Aqueous ammonia was added to the aqueous layer to make it alkaline, extracted with dichloromethane, and the organic layer was dried over anhydrous potassium carbonate. After filtration, the filtrate was concentrated under reduced pressure to give 2.01 g of the title compound mixture (2: 1 isomer ratio) as a colorless oil. The yield was 90%.

¹ H-NMR (400MHz, CDCi ₃ ) (5; 5.35 (2 / 3H, dd, J = 3.2,6.8Hz), 4.99 (l / 3H, t, J-6.8Hz),

4.76 (2 / 3H, d, J = 10.0Hz), 4.78-4.70 (l / 3H, m), 3.78 (3x2 / 3H, s),

3.76 (3xl / 3H, s), 3.55 (2 / 3H, dd, J = 2.2,10.6Hz), 3.49 (l / 3H, dd, J = 2.0,1 0.8Hz),

3.30 (l / 3H, dd ₎ J = 6.0,11.6Hz), 3.21 (2 / 3H, dd, J = 3.2,12.0Hz) _>

3.11 (l / 3H ₎ dd, J = 7.2,11.6Hz) _J 3.09 (2 / 3H, dd, J = 6.4,12.0Hz),

2.12-1.50 (7H, m), l.12 (3xl / 3H, d, J = 6.8Hz), l.00 (3 x2 / 3H, d, J = 6.8Hz Methyl [3R- (3,6,9?, 9a?)] — 6-Amino-9-methyl-15-oxo-octahydrothiazolo [3,2-a] azebine-13-Carboxylate and methyl [3R— ( 3-, 6-, 9-, 9a?)] — 6-amino-1 9-methyl-5-oxo hydrothiazolo [3,2-a] azebin-13-carboxylate mixture (2 isomer ratio) 1) To 2.01 g (7.8 mmo ^) of a solution of (2S, 3S) -2-acetylthio-1-methylpentanoic acid 1.78 g (9.3 orchids) of tetrahydrofuran (100 πι ^) was added under ice cooling. 1.79 g (9.3 mmo ^) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (DEC'HCl), 1.03 (9.3 moe) of N-methylmorpholine, 1-hydroxy-1Η-benzotriazole Monohydrate (HOBT) 1.26g (9.3mmo ^) After a nitrogen atmosphere, water was added to the stirred. The reaction solution at room temperature for 18 hours, followed by extraction with acetic acid Echiru, organic The layer was washed with IN hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 3: 1). As a first eluate, methyl [3R- (3,6,9?, 9a ^)] — 6 — {[(2S, 3S) —1—oxo-1—2—acetylthio—3—methylbentyl] amino} —9—methyl—5—oxo 837 mg of hydrothiazolo [3,2-a] azebine-3-potassium lipoxylate were obtained. Yield was 42%. The absolute configuration of the compound was determined by a NOE experiment.

'Η-thigh (400MHz, CDCf ₃ ) d; 7.37 (lH, d, J = 6.0Hz), 5.36 (lH, dd, J = 3.0,7.0Hz),

4.80 (lH, d, J = 9.5Hz), 4.53 (lH, m), 3.97 (lH, d, J = 7.0Hz), 3.79 (3H ₎ s),

3.22 (lH, dd, J = 3.0,11.5Hz), 3.10 (lH, dd, J = 7.0,11.5Hz), 2.38 (3H, s),

2.14-1.90 (3H, m) ₅ 1.78-1.62 (3H, m), 1.57 (lH, m), 1.16 (lH, m),

1.00 (3H, d, J = 6.5Hz), 0.99 (3H, d, J = 7.0Hz), 0.88 (3H, t, J = 7.5Hz)

NOE (5; 1.00 (9-Me) → 4.80 (H9a)

3.10 (H2H U → 4.80 (H9a), 5.36 (H3)

3.22 (H2?) ^ → 1.95 (H9), 3.79 (3-C00Me)

4.53 (H6) i → 4.80 (H9a)

As a second eluate, colorless oily methyl [3R— (3, 6, 9, 9a?)] — 6-{[(2S, 3S) -1 1-oxo-1 2-acetylacetyl-3-methyl [Pentyl] amino} 1-Methyl-5-oxo-one-year-old hydrothiazolo [3,2-a] azebin-13-force Rupoxylate 532 mg was obtained. Yield was 16%. The absolute configuration of the compound was determined by a N〇E experiment.

-Spirit (400MHz, CdC £ ζ) δ; 7.32 (1H, brd, J = 6.1Hz), 5.20 (1H, s),

5.00 (lH, dd, J = 6.0,6.4Hz), 4.48 (lH, m), 3.96 (lH, d, J = 6.6Hz), 3.78 (3H, s),

3.32 (lH, dd, J = 6.0) 11.7Hz), 3.13 (lH, dd, J = 6.4,11.7Hz), 2.37 (3H 5 s),

2.20-1.50 (7H, m) _J 1.15 (lH ₎ m), 1.10 (3H, d, J = 7.4Hz), 0.98 (3H, d, J = 6.8Hz) ₎

0.87 (3H, t, J = 7.2Hz)

NOE δ; 1.10 (9-Me → 3.32 (H2), 3.78 (3-COOMe) 3.13 (Η2α) j → 5.20 (H9a), 5.00 (H3)

4.48 (Η6) 5.20 (H9a)

Synthesis example 2

r3R- (3a, 6,9?, 9a 3) 1-6-1-{"(2S, 3S) —1-oxo-1-2-thio-3-3-methylpentyl 1-amino} —9-methyl-5-oxo Hydrothiazolo 3,2-alazepine-3-carboxylic acid

Methyl obtained in Synthesis Example 1 [3R— (3α, 6,9?, 9a?)] — 6-{{(2S, 3S) -1oxo-l2- acetylacetylthio-3-methylpentyl] amino} Dissolve 167 mg (0.39 mmo ^) of 1-9-methyl-5-oxobenzoic acid hydrothiazolo [3,2-a] azebine-13-carboxylate in 5 m of degassed ethanol and oxidize with 1 N aqueous solution under ice-cooling 2.0 m (2.0 t of) of lithium aqueous solution was added, and the mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction solution was acidified by adding 2N hydrochloric acid 7.5 under ice cooling, diluted with water, and extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained amorphous was recrystallized (dichloromethane / hexane) and dried in warm air at 50 ° C for 12 hours to obtain 118 mg of the title compound as white crystals. . The yield was 81%.

^{1 H-NMR (400MHz, CDC} 3) d; 7.66 (^, (1, J = 6.5Hz), 5.39 (lH, dd, J = 3.0,7.0Hz), 4.86 (lH, d, J = 9.5Hz) _{, 4.60 (lH l m),} 3.29 (lH, dd, J = 3.0,12.0Hz))

3.22 (lH, dd, J = 7.0,9.0Hz), 3.13 (lH, dd, J = 7.0,12.0Hz), 2.10-1.90 (4H, m), 1.87 (lH ₎ d _} J = 9.0Hz), 1.81 -1.64 (2H ₎ m) ₎ 1.61 (lH, m), 1.21 (lH, m),

1.03 (3H, d, J = 7.0Hz), 1.00 (3H, d, J = 7.0Hz), 0.90 (3H, t, J-7.0Hz) Synthesis example 3

Methyl (3R, 6S, 7aR, llaR, llbR)-6-U (2S, 3S) -1 1-oxo-2- 2-acetyl-thio 3-methyl-pentyl 1-amino} -5-oxo-1 2,3,5,6 , 7,7a, lla, llb-octahydrocyclohexyl [cl thiazolo "3,2-alazepine-13-carboxylate"

Methyl (3R, 6S, 7aR, llaR, llbR) -6-Amino-5-oxo-1,2,3,5,6,7,7a, 11a, lib—Oxyhydrocyclohexyl [c] thiazolo [3, Synthesis of 2-a] azebine-3—force lipoxylate

CH3 methyl (3R, 6S, 7aR, llaR, llbR) -6-acetylamino-5-oxo-1,2,3,5,6,7,7a, lla, llb, llb-octyhydrocyclohexyl [c] thiazolo [3, In the same manner as in Synthesis Example 1 except for using 2-a] azepine-3-carboxylate, 0.23 g of the title compound was obtained. The yield was 57%.

'H-NMR (400MHz, CDC 3) 5 5.08 (lH, s), 4.94 (lH, t, J = 6.8Hz), 3.78 (3H, s)) 3.54- 3.52 (lH, m), 3.27 (lH, dd, J = 6.8,11.6Hz), 3.11 (lH, dd, J = 6.8,11.6Hz), 2.23-1.18 (14H, m)

Using the compound obtained above, 0.32 g of the title compound was obtained in the same manner as in Synthesis Example 1. The yield was 88%.

¹ H-NMR (00MHz, CDC £ ₃ ) (5; 7.33 (1H, brd, J = 6. OHz), 5.14 (1H, s),

4,96 (lH, t, J = 6.6Hz) ₎ 4.57-4.52 (lH _J m), 3.97 (lH, d, J = 6.8Hz), 3.79 (3H, s), 3,30 (iH, dd, J = 6,6,11.6Hz), 3.14 (lH, dd, J = 6,6, ll, 6Hz), 2.38 (3H, s), 2.40-0.85 (15H, m), 0.99 (3H ₎ d, J = 6.8Hz), 0.89 (3H, t, J = 7.4Hz)

Synthesis example 4

(3R, 6S, 7aR, llaR, llbR) -61-U (2S, 3S)-1-oxo-1 2-thio-1 3-methylpentyl 1-amino} -1-5-oxo-1,2,3,5,6,7 , 7a, na, llb—Octahydrocyclohexyl c] _thiazolo “2-alazepine-1-3-propyl

Using the compound obtained in Synthesis Example 3, in the same manner as in Synthesis Example 2, 0.18 g of the title compound as white crystals was obtained. The yield was 63%.

-NMR OOMHz'CDC) 6; 7.33 (lH, brd, J = 6.0Hz), 5.14 (lH, s),

4.96 (lH, t, J = 6.6Hz), 4.57-4.52 (lH, m), 3.97 (lH, d, J = 6.8Hz), 3.79 (3H ₎ s) ₎ 3.30 (lH, dd, J = 6.6, 11.6Hz), 3.14 (lH, dd, J = 6.6,11.6Hz), 2.38 (3H, s), 2.40-0.85 (15H, m), 0.99 (3H, d, J = 6.8Hz), 0.89 (3H, (t, J = 7.4Hz)

Synthesis example 5

Thiothio-3-methylpentyl 1amino} -1-methyl-5-oxo Drothiazolo "3,2-alazebine-3-carboxylate and

Methyl “3R— (3,6a, 8a, 9a i—61-U (2S, 3S) —1-oxo-1—2-acetylthio—3-methylpentyl 1-amino} —8-methyl-5—oxo-octahydro thithiazolo 3,2-a] azebine 3-caprolepoxylate

Methyl [3R— (3α, 6α, 8h, 9a?)] — 6-amino-8-methyl-5-oxo-octathiodrothiazolo [3,2-a] azepine-13-carpoxylate and methyl [3R— (3h , 6,8?, 9a?)] — Synthesis of a mixture of 6-amino-18-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-13-carboxylate

Methyl [3R— (3α, 6h, 8h, 9a?)] — 6-acetylamine 8-methyl-5-oxo hydrothiazolo [3,2-a] azebine 3-pothopoxylate and methyl [3R -(3a, 6 », 8?, 9a?)] — 6-Acetylamino-18-methyl-5-oxo-oxohydrothiazolo [3,2-a] azepine-13-A mixture of about 1: 1 of 3-carboxylate 940 mg (3.12 Was dissolved in 10% methanolic hydrochloric acid solution 24 and refluxed under heating for 24 hours After distilling off the solvent under reduced pressure, water was added and the mixture was washed with dichloromethane, and a saturated aqueous sodium hydrogen carbonate solution was added to the obtained aqueous layer to form an aqueous solution. The extract was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (form: methanol: aqueous ammonia = 98: 2: 0.2). And two titles 220 mg of an approximately 1.4: 1 mixture of compounds was obtained, with a yield of 27%.

¹ H-NMR (400 MHz, CDC ₃ ) 6; 5.29 (lHx 1.4 / 2.4, dd, J22.46.4Ηζ),

5.00 (lHxl.4 / 2.4, d, J = 10.4Hz), 3.78 (3Hxl.4 / 2.4, s),

3.54 (lHxl.4 / 2.4, dd, J = 1.2,10.8Hz), 3.26 (lHxl.4 / 2.4, dd, J = 2.4,11.6Hz),

3.17 (lHxl.4 / 2.4, dd, J = 6.4,11.6Hz), 1.43-2.05 (7Hxl.4 / 2.4, m), 1.00 (3H l.4 / 2.4, d, J = 6.8Hz)

and

'Η-NMR (400MHz, CD (^ ₃ ) 5; 5.21 (lHxl.0 / 2.4, dd, J = 3.2,6.4Hz),

5.15 (lHxl.O / 2.4, dd, J = 2.2,10.2Hz), 3.78 (3Hxl.0 / 2.4, s), 3.71 (lHxl.0 / 2.4, dd, J = 3.2,10.8Hz) ₎ 3.27 (lHxl.0 / 2.4, dd ₎ J = 3.2,12.0Hz),

3.18 (lHxl.O / 2.4, dd, J = 6.4,12.0Hz) ₎ 1.60-2.33 (7Hxl.0 / 2.4, m), 1.16 (3Hxl.0 / 2.4, d, J = 7.2Hz)

Methyl [3R— (3,6,8?, 9a?)] — 6-amino-8-methyl-1-5-oxo-octahydrothiazolo [3,2-a] azebine-1 3 —Carboxylate and methyl [3R— (3,6,8,9a?)] — 6-Amino-8-methyl-1-5-oxooxotahydrothia V mouth [3,2-a] azebine Mixture of one 3-carboxylate

(Isomer ratio 1: 1.4) A solution of 214 mg (1.12 mmo ^) of (2S, 3S) -2-acetylthio-3-methylpentanoic acid in 215 mg (0.83 mmo ^) of tetrahydrofuran (17 m) was cooled on ice. added. To this solution was added 207 mg (1.08 mmof) of 1-ethyl-3- (3-dimethylaminobutyral) carbodiimide hydrochloride (DE C · HC f), 0.12 of N-methylmorpholine (1.08), After 166 mg (1.08 nuno ^) of 1 H-benzotriazole monohydrate (HOB T) was sequentially added, the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluted with hexane: ethyl acetate 3: 1) to give a mixture of the title compounds (isomer ratio 1: 1.3). 4 mg were obtained. Further, this mixture is applied to a preparative column YMC-Pack SIL (SH-043-5).

(Eluted with hexane: ethyl acetate = 4: 1) Separated and purified, and from the first eluate, methyl [3R— (3,6,8 ^, 9ay5)] — 6-{[( 2S.3S) -l-oxo-l-acetylthio-l-methylpentyl] amino}-8-methyl-l-oxolose Hydrothiazolo [3,2-a] azebine-l-carboxylate (97 mg) was obtained. The yield was 27%. The absolute configuration of the compound was determined by a NOE experiment.

1H-NMR (400MHz, CDC ^ ₃ ) 5; 7.26 (lH, brd, J = 6.1Hz), 5.21 (lH, dd, J = 2.9,6.6 Hz),

5.20 (lH, dd ₎ J = 1.5,10.6Hz), 4.75 (lH, ddd, J = 5.0,6.1 ₎ 9.0Hz),

3.95 (lH, d, J = 7.1Hz), 3.79 (3H, s), 3.28 (lH, dd, J = 2.9,12.0Hz), 3,20 (lH, dd, J = 6.6,12.0Hz), 2.37 (3H, s), 2.30-1.10 (8H, m),

1.26 (3H, d, J = 7.1Hz), 0.99 (3H, d, J = 6.6Hz), 0.88 (3H, t, J = 7.4Hz)

NOE d; 1.26 (8-Me) φ → 4.75 (H6 a), 5.20 (H9aa), 1.68 (H9o:)

5.20 (H9a) 1,68 (H9), 4.75 (H6)

2.28 (Η8?) 1.68 (H9)

Colorless crystalline methyl from the second eluate [3R— (3,6,8,9a / 5)] — 6-{[(2S, 3S) —1-oxo-1-2-acetylthio-3-methyl [Pentyl] amino} —8-methyl-1-5-oxo-one-butahydrothiazolo [3,2-a] azepine-13-carboxylate was obtained in an amount of 136 mg. The yield was 38%. The absolute configuration of the compound was determined by a NOE experiment.

^{1 H-NMR (400MHz, CDC} ^ 3); 7.38 (lH, brd, J = 6.0Hz), 5.27 (lH, dd, J = 2.4,6.4 Hz),

5.03 (lH, d, J = 10.4Hz), 4.55 (lH, dd, J = 6.4,10.0Hz), 3.97 (lH, d, J = 6.8Hz), 3.79 (3H, s), 3.27 (lH, dd , J = 2.4 _> 11.8Hz), 3.19 (lH, dd, J = 6.4,11.8Hz), 2.38 (3H, s), 2.15-l.ll (8H, m) ₎ 0.99 (6H, d, J = 6.8 Hz) ₎ 0.89 (3H, t, J = V.4Hz) NOE δ; 2.09 (H8) ^ → 1.88 (H9a), 1.92 (H7 «), 4.55 (H6), 5.03 (H9a)

5.03 (H9a) 1.88 (H9h), 4.55 (H6)

4.55 (H6) l → 1.92 (H7a)

Synthesis Example 6

“3R— (3,6,8,9a?) L— 6 — {“ (2S, 3S) -1-oxo-1 2-thio-1 3-methylpentyl 1-amino} -1-8-methylocta Hydro-5-oxothiazolo “3,2-alazebine-3-carboxylate

Methyl [3R— (3,6,8,9a?)] —— 6-[[(2S.3S) -1 oxo-1-2-acetylthio-13-methylpentyl] amino obtained in Synthesis Example 5 }-8-Methyl-1-octahydro-1-5-oxothiazolo [3,2-a] azepine-13-carboxylate 13 Omg (0.30 mmol was dissolved in degassed EtOH4.3 ^. Then, 1 N under ice cooling Aqueous lithium hydroxide solution 2.1 was added, and the mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere, and acidified by adding 1.5 mi of 2N hydrochloric acid under ice-cooling, water was added, extracted with dichloromethane, and washed with saturated saline. The obtained amorphous was recrystallized (ethyl acetate-hexane) and dried in warm air at 50 ° C. for 24 hours to obtain 90 mg of the title compound. there were.

lH-NMR (400 MHz, CDC ₃ ) (5; 7.61 (lH, brd, J = 6.4 Hz), 5,29 (lH, dd, J = 2.4, 6.4

Hz),

5.07 (lH, d, J = 10.4Hz), 4.62 (lH, dd, J = 6.8,11.2Hz), 3.37 (lH, dd, J = 2.4,12.0Hz),

3.22 (lH, dd, J = 6.4,8.8Hz), 3.21 (lH, dd, J = 6.4,12.0Hz) ₎ 2.19-1.18 (8H, m) ₎ 1.87 (lH, d, J = 8.8Hz), 1.01 (3H, d, J = 6.4Hz), 1.00 (3H, d, J = 6.8Hz),

0.91 (3H, t, J = 7.4Hz)

Synthesis Example 7

"3R— (3,6,8,9a?) L—6-{[(2S.3S) -1-oxo-1-2-thio-3-3-methylpentyl 1-amino} -1-methyl-1-octahydro-1 5-oxothiazolo "3,2-alazepine-3-carboxylic acid

Methyl obtained in Synthesis Example 5 [3R— (3h, 6h, 8 ?, 9a?)] — 6-{[(2S.3S) -1 oxo-l-acetylthio-l-methylpentyl] amino}ー 8—Methyl mono 93 mg (0.216 bandages) of kutahydro-5-oxothiazolo [3,2-a] azebine-13-carboxylate were dissolved in degassed ethanol 3.1. Next, 1.5N aqueous 1N lithium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After 2N hydrochloric acid (1.1) was added to the mixture under ice-cooling to make it acidic, water was added and the mixture was extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained amorphous was recrystallized (dichloromethane / hexane) and dried with warm air at 50 ° C for 24 hours to obtain 66 mg of the title compound. The yield was 82%.

1 H-thigh (400 MHz, CDC ₃ ) d; 7.49 (lH, brd, J = 6.0 Hz), 5.27-5.21 (2H, m), 4.84-4.77 (lH, m), 3.37 (lH, dd, J = 2.4,12.0Hz), 3.22 (lH, dd , J = 7.0,12.0Hz), 3.19 (lH) dd, J = 7.2 J 8.8Hz), 1.88 (lH, d, J = 8.8Hz), 2.33-1.58 ( 7H, m), 1.28 (3H, d, J = 7.2Hz), 1.30-1.18 (lH, m), 1.00 (3H, d, J = 6.8Hz),

0.90 (3H, t, J = 7.2Hz)

Synthesis Example 8

R— (3,6,9,9a ^), 1-6 — {"(2S, 3S) -1-oxo-1 2-thio-1 3-methylpentyl 1amino} -1-methyl-5-oxo-1-octahydrothia V mouth "3,2-alazebin-3-3-Rubonic acid

Methyl obtained in Synthesis Example 1 [3R— (3, 6, 9, 9 &?)] — 6 — {[(2S, 3S) -1-oxo-1 2-acetylthio-13-methylpentyl] amino } —9-Methyl-5-oxo-octahydrothiazolo [3,2-a] azepine-13-capillolate 1.43 g (3.33 Dissolve the thighs in 30 W of degassed ethanol and add N-aqueous lithium hydroxide aqueous solution 20 (20 mo was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction solution was acidified by adding 2 N hydrochloric acid 50 under ice cooling, and diluted with water. Then, it was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained amorphous recrystallized (dichloromethane / hexane) was dried with warm air at 50 ° C for 12 hours to obtain 1.10 g of the title compound as white crystals. The yield was 89%.

^ -NMRi ^ OMHz.CDCi ₃ ) 6; 7.57 (lH, brd, J = 6.4Hz), 5.25 (lH, s),

5.08 (lH, dd, J = 3.2,6.8Hz), 4.60 (lH, m), 3.48 (iH, dd, J = 3.2, il.6Hz), 3.25 (lH, dd ₎ J = 6.4,8.4Hz), 3.13 (lH ₎ dd, J = 6.8,11.6Hz), 2.16-1.54 (7H, m) ₅ 1.85 (lH, d, J = 8.4Hz), 1.24 (lH, m), 1.03 (3H, d, J = 6.4Hz), 1.01 (3H, d, J = 6.4Hz),

0.91 (3H, t, J = 7.2Hz)

Synthesis Example 9

r3R- (3,6a, 9?, 9a?) 1-6-{[(2S.3S) -1 1-oxo-2- 2-acetylthio-3-methylpentyl] amino} -1-methyl-5-oxo-octahydrothia mouth ^ 2- al7 zebin 1—force Ron 歷

[3R— (3,6,9?, 9a?)]] — 6 — {[(2S, 3S) —1-oxo-1-2-thio-3-methylpentyl] obtained in Synthesis Example 2 Dissolve 522 mg (1.39 mmo ^) of amino-9-methyl-5-oxomonohydrothiazolo [3,2-a] azepine-13-carbonic acid in acetonitrile (15 mf) -tetrahydrofuran (15 mf) and add nitrogen Under an atmosphere, at room temperature, 54 mg (0.42 nuno ^) of anhydrous copartic chloride and 170 (1.81 mmo ^) of acetic anhydride were added, and the mixture was stirred for 5 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the obtained amorphous is recrystallized (to ethyl acetate). Xane) and 50. Drying with warm air at C for 18 hours gave 439 mg of the title compound as white crystals. The yield was 76%.

^{1 H-NMR (400MHz, CDC} ^ 3) d; 7.38 (lH, brd, J = 6.0Hz), 5 · 39 (1H, dd, J = 2.8, 6.4

Hz),

4.83 (lH, d, J = 9.6Hz), 4.56 (lH, m), 3.96 (lH, d, J = 6.8Hz) ₎

3.29 (lH, dd, J = 2.8,11.6Hz), 3,12 (lH, dd, J = 6.4,11.6Hz),

2.38 (3H ₎ s), 2.14-1.88 (4H _J m), 1.77-1.64 (2H _} ), 1.58 (lH, Di) _J 1.16 (lH, iD), 1.01 (3H, d, J = 7.2Hz), 1.00 (3H ₎ d, J = 6.8Hz), 0.88 (3H, t, J = 7.2Hz)

Synthesis example 10

[3R— (3,6,9?, 9a?) L— 6- {f (2S, 3S) —1-oxo-1 2-propionylthio 3-methylpentyl 1-amino} —9-methyl-1 5— Oxosokyu hydrothiazolo, 2-alazebine-l3-potassium

[3R— (3,6,9 ^, 9a / 3)] -6-{[(2S, 3S) -1 2-thio-3-methylpentyl] amino} 19-methyl-1-5-oxo-octahydrothiazolo [3,2-a] azebine-3-carbonic acid 60 mg (0.16 thigh), brovionyl chloride 17 ( 0.19 M) and 6 mg (0.05 mmoe) of anhydrous cobalt chloride to give 30 mg of the title compound as white crystals. The yield was 44%.

'H-NMRC ^ OMHz.CDC ^ ₃ ) (5; 7.40 (lH _> brd, J = 6.4Hz) ₎ 5.39 (lH, dd, J = 2.4,6.8 Hz),

4.83 (lH, d, J = 9.6Hz), 4.56 (lH, m), 3.98 (lH, d, J = 6.8Hz),

3.29 (lH ₎ dd, J = 2.8,11.6Hz), 3.11 (lH, dd, J = 6.8 ₎ 11.6Hz), 2.63 (2H, q, J = 7.6 Hz),

2.16- 1.88 (4H, m), 1.76- 1.64 (2H, in), 1.57 (lH, m), 1.19 (3H, t, J = 7.6Hz),

1.17 (lH, m), 1.01 (3H, d, J = 6.8Hz), 1.00 (3H, d ₎ J = 6.8Hz) ₎ 0.88 (3H, t, J = 7.2Hz)

Synthesis example 1 1

i3R— (3,6,9?, 9a 5) l— 6-{[(2S, 3S) -1 1-oxo-1 2-benzoylthio-3-methylpentyl 1-amino} -9-methyl-5-oxo-1 Octahydrothiazolo Γ3,2-alazebine-3-carboxylate

H In the same manner as in Synthesis Example 9, [3R— (3,6,9?, 9a?)]-6-{[(2S.3S) -1 2-thio-3-methylpentyl] amino} 1-9-methyl-5-oxo-butahydrothiazolo [3,2-a] azebine-13-caprolonic acid 434 mg (1.16 mmo ^), benzoic anhydride 300 mg ( 1.33 liters) and 45 mg (0.35 mof) of anhydrous cobalt chloride gave 490 mg of the title compound as white crystals. The yield was 88%.

'H-MRC ^ OMHz.CDC ^ ₃ ) 5; 8.00-7.96 (2H, m), 7.62-7.42 (4H, ni),

5.38 (lH, dd, J = 2.4,6.4Hz), 4.84 (lH, d, J = 9.6Hz), 4.59 (lH, m),

4.20 (lH, d ₎ J = 7.2Hz) ₎ 3.27 (lH ₎ dd, J = 2.4 ₎ 11.6Hz) ₎ 3.10 (lH, dd, J = 6.4,11.6Hz),

2.22- 1.60 (7H, ni), 1.25 (lH, ni), 1.06 (3H, d, J = 6.8Hz), 1.00 (3H, d, J = 6.8Hz), 0.92 (3H, t, J = 7.2Hz) )

Synthesis example 1 2

"3R— (3,6,9 ^, 9a 3) l—6-1 (" (2S, 3S) —1-oxo-2— (1,1,1-dimension Tylpropionyl) thio 3-methylpentyl 1-amino} —9-methyl-5-oxo-octahydrothiazo “3,2-alazepine-13-carbonic acid

[3R— (3,6,9?, 9a5)] — 6-{[(2S, 3S) -1 oxo 1 2 obtained in Synthesis Example 2 in the same manner as in Synthesis Example 9. —Thio-3-methylpentyl] amino} 1-9-methyl-5-oxobenzoylhydrothiazolo [3,2-a] azebine-13-Carbonic acid 54 mg (0.14 thigh, Vivaloyl chloride 27 (0.22 banned W), anhydrous cobalt chloride 6 mg (from 0.05 thigh, 58 mg of the title compound was obtained as white crystals. The yield was 88%.

NMR (400 MHz, CDC) <5; 7.41 (lH, brd, J = 6.0 Hz), 5.39 (lH, dd, J = 2.4, 6.4 Hz),

4.83 (lH, d, J = 9.6Hz), 4.56 (lH, m), 3.92 (lH, d, J = 6.8Hz),

3.29 (lH, dd ₎ J = 2.4 ₎ 11.6Hz) ₎ 3.10 (lH, dd, J = 6.4 ₎ 11.6Hz), 2.18-1.52 (7H, m) ₎ 1.25 (9H, s), 1.20 (lH, Bi) , 1.01 (3H, d, J = 6.8Hz), 1.00 (3H, d, J = 6.8Hz), 0.87 (3H, t, J = 7.2Hz)

Synthesis Example 1 3

f3R— (3,6,9?, 9a?) l—6 — {“(2S, 3S) -1-oxo-2- (4-morpholinyl) acetylthio-3-methylbenzyl 1amino} — 9-Methyl-5-oxo-octahydrothiazolo H ^ -alazebine

Under a nitrogen atmosphere, 44 mg (0.24 mmol) of 4-morpholinylacetic acid hydrochloride was dissolved in deaerated water-free N, N-dimethylformamide (1.2 mf), and then N, N, 1-carbodiimidazole under ice-cooling. 27.3 mg (1.68 mmo ^) was added, and the mixture was stirred at room temperature for 1 hour. [3R— (3,6a, 95,9a 3)] — 6 — {[(2S, 3S) -1-oxo-1 2-thio-1 3-methylpentyl] amino} 1 obtained in Synthesis Example 2 9 Add a solution of 60 mg (0.16 tW) of demethylated anhydrous tetrahydrofuran (1.6 £) of monomethyl-5-oxohydrotathiazolo [3,2-a] azebine-3-butyric acid under ice cooling, and add room temperature. The mixture was further stirred for 2 days. After concentrating the reaction solution, ethyl acetate and saturated saline were added to carry out liquid separation, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained amorphous was recrystallized (ethyl acetate-ether-hexane) and dried at 50 ° C with warm air to obtain 68 mg of the title compound as white crystals. . The yield was 85%.

^{1 H-NMR (400MHz, CDCi} 3) <5; 7.40 (lH, brd, J = 6.0Hz), 5.35 (lH, dd, J = 2.4,6.8 Hz),

4.82 (lH ₎ d, J = 9.2Hz), 4.55 (lH, i), 3.92 (lH, d, J = 6.8Hz), 3.77 (4H, t, J = 4.4Hz),

3.31 (2H, s), 3.28 (lH, dd, J = 2.4,11.6Hz), 3.12 (lH, dd, J = 6.8,11.6Hz), 2.62 (4H, m), 2.14-1.52 (7H, m) , 1.17 (lH, m), 1.01 (3H, d, J = 6.4Hz),

1.00 (3H, d, J = 6.8Hz), 0.87 (3H, t ₅ J = 7.6Hz)

Synthesis Example 14

f3R— (3,6,9?, 9a?) l— 6— {i (2S, 3S) —1oxo-1 2 -— (4-thiomorpholinyl) acetylthio-3-3-methylpentyl 1-amino} -9— Methyl-5 Kiritoctahydrothiazolo-3,2-alazebine-3-3-Luroponic acid

[3R— (3h, 6h, 9 ?, 9a ^)] — 6-{[(2S.3S) -1 monooxo obtained in Synthesis Example 2 in the same manner as in Synthesis Example 13 1- 2-thio-3-methylpentyl] amino} — 9-methyl-5-oxobenzoic-hydrothiazolo [3,2-a] azebine-3-force rubonic acid 70 mg (0.19, ο, 4-thiomorpholinylacetic acid hydrochloride 55 mg (0.28 From the dragon of) and 33 mg (0.21 mol) of Ν, Ν'-carposimidazole, 81 mg of the title compound was obtained as white crystals, and the yield was 84%.

'Η-thigh (400MHz, CDC ₃ ) 5; 7.40 (lH, brd, J = 6.4Hz), 5.33 (lH, m),

4.83 (lH, d, J = 9.6Hz), 4.56 (lH, m), 3.89 (lH, d, J = 7.2Hz), 3.32-3.26 (lH, ni), 3.30 (2H, s), 3.12 (lH , Dd, J = 6.4, 11.2Hz), 2.88-2.82 (2H, m), 2.76-2.70 (2H, m),

2.14-1.90 (4H ₎ m) ₎ 1.78-1.54 (3H ₎ m), 1.18 (lH, m), 1.01 (3H ₎ d, J = 6.8Hz) ₎ 1.00 (3H, d, J = 6.4Hz), 0.90 (3H, t, J = 7.6Hz)

Synthesis Example 1 5

R— (3,6,9?, 9a?) 1—6 — {“(2S, 3S) —1-oxo-1—2- (4-dioxothiomorpholinyl) acetylthio-3-amino-1-methyl} 1—1 Methyl-5-oxo-hydrothiazolo “3,2-alazepine-13-carboxylic acid

[3R— (3, 6, 9/3, 9 a ^)] — 6-{[(2S, 3S) -1-1 obtained in Synthesis Example 2 in the same manner as in Synthesis Example 13 Oxo-2-3-thio-3-methylpentyl] amino} -1-methyl-5-oxo-octahydrothiazolo [3,2-a] azepine-13-force rubonic acid 70 nig (0.19 w & oe), 4-di 73 mg (0.21 nuno ^) of oxothiomorpholinylacetic acid 54 mg (0.28 maraud of) and N, N, -carbodiimidazole gave 73 mg of the title compound as white crystals. The yield was 71%.

'H-NMR (400MHz, CDC ^ ₃ ) (5; 7.50 (lH, brd, J = 6.4Hz), 5.27 (lH, dd, J = 3.2,6.8 Hz),

4.81 (lH ₎ d, J = 9.6Hz) ₎ 4.55 (lH, m), 3.96 (lH ₎ d, J = 6.4Hz), 3.46 (2H, s), 3.27 (lH, dd, J = 3.2,12.0Hz ), 3.24-3.10 (5H, ni), 2.18-1.92 (4H ₎ ni),

1.76-1.63 (2H ₎ m) ₎ 1.55 (lH, m), 1.17 (lH, m) ₎ 1.01 (3H, d ₎ J = 6.8Hz),

1.00 (3H, d, J = 6.8Hz), 0.90 (3H, t, J = 7.6Hz)

Synthesis Example 1 6

[3R— (3α, 6h, 9?, 9a?)] — 6-1 (“(2S, 3S) —1-oxo-1—2-nicotinyl-thio-3—methylpentyl 1-amino} —9-methyl-1-5- Oxo-octahydrothia V

CH ₃₀

COOH [3R— (3,6,9 / 5,9a?)]-6-{[(2S, 3S) -1-oxo-one obtained in Synthesis Example 2 in the same manner as in Synthesis Example 9. 2-thio-3-methylpentyl] amino} —9-methyl-5-oxo-octahydrothiazolo [3,2-a] azebine-3-butyric acid 50 ig (0.13 mo (), nicotinic acid 18 mg (0.15 mmo ^) and 23 mg (0.14 wsioi) of N, N, one-carpoimidazole afforded 28 mg of the title compound as white crystals, yield 44%.

¹ H-NMR (400 MHz, CDC ₃ ) (5; 9.17 (lH, br), 8.80 (lH, br), 8.22 (lH ₎ brd ₎ J = 8.4

Hz),

7.58 (lH, br), 7.43 (lH ₎ m), 5.27 (lH, br), 4.82 (lH, br) ₎ 4.60 (lH ₎ br),

4.23 (lH, brd ₎ J = 7.2Hz), 3.34 (lH ₎ br) _} 3.12 (lH, br), 2.24-1.92 (4H ₎ m), 1.80-1.58 (3H, m), 1.24 (lH, m) , l.06 (3H, d, J = 6.8Hz), 1.00-0.84 (6H, m) Synthesis example 1 7

“3R— (3,6,9,9a?) L—6 — {“ (2S, 3S) —1-oxo-1 2-acetylthio-3-methylpentyl 1-amino} —9-methyl-5-oxo-1 Octahydrothiazo 2-〖-al_zebi ^ "3-Rubonic acid

In the same manner as in Synthesis Example 9, [3R— (3, 6, 9, 9a ^)]-1 6 — {[(2S, 3S) —1oxo1 2 obtained in Synthesis Example 8 —Thio-3- 3-methylpentyl] amino} -1 9 —methyl-5-oxobenzoylhydrothiazolo [3,2-a] azepine-13-carboxylic acid 212 mg (0.57 nuno £), acetic anhydride 64 (0.68 mmo ^) ), 22 mg of anhydrous chloride (0.17 mmo) to give 163 mg of the title compound as white crystals.

The yield was 69%.

^! H-thigh (400Hz, CDC) 5; 7.30-7.20 (lH, m), 5.28 (lH, s), 5.08 (lH, dd, J = 2.4,6.4Hz) ₎ 4.59 (lH, m), 3.95 (lH, d, J = 7.2Hz),

3.48 (lH, dd, J = 2.4,11.6Hz) ₎ 3.12 (lH, dd, J = 6.4,11.6Hz) ₎ 2.40 (3H, s), 2.16-1.52 (7H, m), 1.18 (lH, m) , 1.01 (3H, d, J = 6.4Hz), 1.00 (3H, d, J = 7.2Hz) ₎ 0.91 (3H, t, J = 7.2Hz)

Synthetic 1 8

f3R— (3,6,9,9a?) l— 6— {“(2S, 3S) -1-oxo-1 2-benzoylthio-3-methylpentyl] amino} —9-methyl-5-oxo 1-year-old Kutahydrothiazolo f3,2-a ~ lazebine-1-3-carboxylate

[3R— (3,6,9,9a?)]-6 — {[(2S, 3S) -1-oxo-1 2 obtained in Synthesis Example 8 in the same manner as in Synthesis Example 9. —Thio-3-methylpentyl] amino} -19—Methyl-5-oxo-octahydrothiazolo [3,2-a] azebine-3-carboxylate 265 mg (0.71 W), benzoic anhydride 176 mg ( From 0.78 mmo ^) and 28 mg (0.21 mmo ^) of anhydrous chlorinated chloride, 163 mg of the title compound was obtained as white crystals. The yield was 48%.

'H-NMR (400 MHz, CDC ₃ ) d; 7.99 (2H ₎ in), 7.60-7.40 (4H, m), 5.22 (lH, s) ₎ 5.03 (lH, br), 4.60 (lH, m), 4.08 (lH, br), 3.42 (lH, br), 3.03 (lH, br),

2.20- 1.60 (7H, m), l.24 (lH, m), 1.10-0.90 (9H, m)

Synthesis Example 1 9

Methyl f3R— (3α, 6hi, 9; g, 9ag) l— 6-{[(2S, 3S) -1-oxo-1 2-acetylthio-3-methylpentyl] amino} -1-9-ethyl-5-oxo 1-day evening thiothiazolo ^ 2-a] _azebin-1-3-hydroxyloxylate

Methyl [3R— (3a, 6a, 9/5, 9a?)] — Synthesis of 6-amino-9-ethyl-5-oxooxohydrothiazolo [3,2-a] azebine-13-caprolepoxylate

Methyl [3R— (3h, 6h, 9 ?, 9a 5)] — 6-acetylamino-1 9-ethyl-5-oxooctahydrothiazolo [3,2-a] azebine-3-carboxylate 1.3 g (4.13 mmoi) was dissolved in a 10% methanolic hydrochloric acid solution (50 mi) and heated under reflux for 2 days. After evaporating the solvent under reduced pressure, water was added, and the mixture was washed with dichloromethane.c To the obtained aqueous layer, a saturated aqueous sodium hydrogen carbonate solution was added to make the mixture viscous, extracted with dichloromethane, and dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure to give 0.83 g of the title compound as a colorless oil. The yield was 74%.

'H-NMR (400 MHz, CDCi ₃ ) d; 5.32 (lH, dd, J = 3.5, 6.8 Hz), 4.89 (lH, d, J = 9.2 Hz) ₎ 3.78 (3H, s), 3.55 (lH, dd) , J = 2.0, 10.5Hz), 3.21 (lH, dd, J = 3.5,11.6Hz),

3.09 (lH, dd, J = 6.8,11.6Hz), 2.20-1.40 (9H, m), 0.92 (3H, t, J = 7.6Hz)

Methyl [3R— (3,6,9?, 9a?)] — 6—amino-1-9—ethyl-5-oxo-octahydrothiazolo [3,2-a] azevin obtained above 0.83 g (3.05 moi) of 3-hydroxypropyloxylate was added to (2S, 3S) -2-acetylthio-13-methylpentane. 0.70 g (3.66 thighs of tetrahydrofuran (50 m)) solution was added under ice-cooling, and 1-ethyl-3- (3-dimethylaminobutyryl) carbodiimide hydrochloride (DEC'HC1) was added to the solution. 0.70 g (3.66 nuno ^), N-methylmorpholine 0.4 W (3.66 thigh W), 1-hydroxy-1H-benzotriazole monohydrate (HOBT) 0.50 g (9.3 鼸 W) are added sequentially, and then under a nitrogen atmosphere. After stirring at room temperature for 18 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 3: 1) to obtain 476 mg of the title compound as a colorless oil. Was 35%.

1 H-MR (400MHz, CDC ^ ₃ ) 6; 7.36 (lH ₎ d, J = 6.0Hz), 5.34 (lH, dd, J = 3.2,6.4Hz), 4.86 (lH _J d, J = 9.6Hz) ₎ 4.54 (lH, m) ₎ 3.97 (lH, d, J = 6.8Hz) ₎ 3.78 (3H _> s) _> 3.21 (lH, dd, J = 3.2,12.0Hz), 3.11 (lH, dd, J = 6.4 , 12.0Hz), 2.38 (3H, s), 2.16-2.04 (2H, m), 1.82-1.52 (6H, m), 1.31 (lH, m), 1.16 (lH, m),

0.99 (3H, d, J = 6.4Hz) ₎ 0.91 (3H, t, J = 7.2Hz), 0.88 (3H, t, J = 7.2Hz)

Synthesis Example 20

[3R- (3a, 6a, 9?, 9a 3) l-6— {[(2S, 3S) -1-oxo-1 2-thio-3-methylpentyl 1amino} -1-ethyl-1 5-oxooxota Hydrothiazolo "3,2-alazebin-3-3-Rubonic acid

Methyl [3R— (3a, 6a, 9 ?, 9a?)] — 6-{[(2S.3S) 1-oxo-1-2-acetylthio-1-3-methylpentyl] amino} obtained in Synthesis Example 19 9-Ethyl • 5-Oxo-octahydrothiazolo [3,2-a] azebine 1-3-hydroxyloxyl 476 mg (1.07 mmo ^) was dissolved in 10.7 degassed ethanol, and 5.36 m of a 1N lithium hydroxide aqueous solution degassed under ice-cooling was added, followed by stirring at room temperature under a nitrogen atmosphere for 1 hour. The reaction solution was acidified by adding 2 N hydrochloric acid under ice-cooling, diluted with water, and extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting amorphous was triturated with hexane and collected by filtration. This was dried in warm air at 50 ° C for 12 hours to obtain 300 mg of the title compound. The yield was 72%.

-Awake (400MHz, CDC 3) 6; 7.66 (lH, d, J = 6.4Hz), 5.36 (lH, dd, J = 3.2,6.4Hz)

4.91 (lH, d, J = 9.2Hz), 4.61 (lH, m), 3.28 (lH, dd, J = 3.2,12.0Hz),

3.22 (lH ₎ dd, J = 6.8,8.8Hz), 3.13 (lH, dd, J = 6.4,12.0Hz), 2.16-2.08 (2H, m), 1.98 (lH, m), 1.87 (lH, d, J = 8.8Hz), 1.84-1.56 (5H, m), 1.38-1.18 (2H, m), 0.99 (3H, d, J = 6.4Hz), 0.93 (3H, t, J = 7.2Hz), 0.90 ( (3H, t, J = 7.6Hz)

Synthesis Example 2 1

Methyl {3R- “3,6a, 9an} -6— {2S, 3S) —1-oxo-1 2-acetylthio-3-methylpentyl 1-amino} octahydro-1 5-oxothiazolo [3,2-azepine-1 3 —Carboxylate

Methyl {3R— [3,6,9a?]} — 6-Amino-hydroxy-5-oxothiazo-mouth [3,2-a] azebine-3-carboxylate 225 mg (0.92 mmo ^) of methylene chloride solution (17 m) was cooled at 0 ° C under ice cooling. Next, 193 mg (1.01 mmo ^) of (2S, 3S) -2-acetylthio-3-methylpentanoic acid in methylene chloride (6 ΰί £) and 296 mg (1.20 mmo ^) of EEDQ were successively added to this solution. added. Subsequently, the ice bath was removed, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere, and then concentrated to an evaporator. This residue is then dissolved in ethyl acetate, 1 N hydrochloric acid, saturated N After washing with an aHCO ₃ aqueous solution and a saturated saline solution, each was dried over magnesium sulfate. This was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain 206 mg of the title compound as amorphous. The yield was 54%.

¹ H-Awake (400MHz, CDC ₃ ) 5; 0.88 (3H, t, J = 7.6Hz), 0.99 (3H, d, J = 6.8Hz), 1.10-1.22 (lH, m), 1.51-1.70 (2H , m), 1.82-2.14 (6H, m), 2.38 (3H, s),

3.20 (lH, dd ₎ J = 6.4 _> 11.8Hz), 3.28 (lH, dd, J = 2.4,11.8Hz) ₎ 3.79 (3H, s) ₎ 3.98 (lH, d, J = 6.8Hz), 4.54 (lH , dd, J = 6.4 _J 10.4Hz) ₎ 5.02 (lH, d, m, J = 8.8Hz) _J 5.23 (lH, dd, J = 2.4 _J 6.4Hz), 7.41 (lH ₎ d, J = 6.0Hz)

Synthesis Example 22

{3R-i3a, 6a, 9a? U-6-{[(2S, 3S) -1 1-oxo-1 2-thio-3-methylpentyl 1-amino] octahydro-5-oxothiazolo "3,2-alazebin-13-carpon" Interception

Methyl {3R— [3,6,9a?]} — 6 — {[(2S, 3S) -1 oxo-1 2-acetylthio-13-methylpentyl] amino} obtained in Synthesis Example 21 200 mg (0.48 mmo i) of quinohydro-5-oxothiazolo [3,2-a] azebine-13-carboxylate was placed in a flask, and degassed ethanol 8 was added thereto, followed by cooling to 0 ° C under a nitrogen atmosphere. To this was added 3.8 g of a degassed 1N aqueous lithium hydroxide solution, and the mixture was stirred at room temperature for 50 minutes. 2N Hydrochloric acid 2.9 was added at 0 ° C to make it acidic, and extracted with methylene chloride. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue solid was recrystallized from hexane-methylene monochloride to obtain 150 mg of the title compound as white crystals. The yield was 87%.

¹ H-wake (shelf MHz, CDC ^ ₃ ) (5; 0.90 (3H, t, J = 7Hz), 1.00 (3Η, d, J = 7Hz),

1.24 (1Η, πι), 1.55-1.74 (2H, m), 1.87 (lH, d, J = 8Hz), l.90-2.10 (6H, m), 3.20 (lH, dd, J = 6,12Hz) ₎ 3.24 (lH, d, J = 7Hz), 3.36 (lH, dd, J = 2,12Hz), 4.62 (lH, dd ₎ J = 6, 10Hz), 5.07 (lH ₎ tl ike, J = 6Hz>, 5.29 (lH, dd, J = 2, 6Hz), 7.69 (lH.d, J = 6Hz)

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the plasma total cholesterol level of beagle dogs (male) before and after drug administration-Figure 2 shows the plasma total cholesterol level of beagle dogs (female) before and after drug administration c Figure 3 shows the drug administration 2 shows the values of plasma phospholipids in the beagle dog (male) before and after.

FIG. 4 shows plasma phospholipid values of beagle dogs (females) before and after drug administration.

FIG. 5 shows the change rate of plasma total cholesterol in beagle dogs (males) before and after drug administration (when the value before the start of administration was 100%).

FIG. 6 shows the change rate of plasma total cholesterol in beagle dogs (females) before and after drug administration (when the value before administration was set to 100%).

FIG. 7 shows the change rate of plasma phospholipids in beagle dogs (male) before and after drug administration (when the value before administration was set to 100%).

FIG. 8 shows the change rate of plasma phospholipids in beagle dogs (females) before and after drug administration (when the value before administration was set to 100%).

Example

Next, pharmacological experimental examples will be given in order to detail the usefulness of the medicament according to the present invention. Example of pharmacological experiment

Measurement of plasma total cholesterol and phospholipids using beagle dogs

1) Experimental method

10-month-old beagle dogs were orally administered 10 and 30 mg / kg of Compounds A and B in gelatin capsules once a day for Ί days. Blood was collected from the cephalic vein 6 days before the first day of administration and the day after the first administration and the last administration, and total cholesterol and phospholipids in plasma were measured. The following kits and equipment were used for the measurement.

Total cholesterol: AU500 / 550 reagent "Katayama" T-CHO test

(Made by Katayama Chemical Co., Ltd.)

Phospholipid: Phospholipid OA Test Co. (Wako Pure Chemical Industries, Ltd.) <Measuring equipment>

Olympus Automatic Analyzer AU550 (Olympus Co., Ltd.)

Compound A: [3R— (3, 6, 9, 9a?)] — 6-{[(2S, 3S) -1-oxo-

2-Acetylthio-3-3-methylpentyl] amino} —9-methyl 5-5-oxo-octahydrothiazolo [3,2-a] azebine-1-3-Rubonic acid

Compound B: [3-(3a, 6,9j36-{[(2S, 3S) -1-oxo-

2-Acetylthio-1-3-methylpentyl] amino} -91-methyl 5-hydroquinazolo [3,2-a] azebine

3—Rupulonic acid

2) Experimental results

The results obtained by the above method are shown in FIGS. 1 to 8 (the start date of administration is shown as day 0).

Administration of 10 and 30 mg / kg of Compounds A and B to beagle dogs clearly reduced plasma total cholesterol and phospholipids.

Claims

The scope of the claims

1. Contains a pharmacologically effective amount of a thiazolo [3,2-a] azepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. Cholesterol lowering agent composition.

In the formula, R ¹ represents a hydrogen atom or a protecting group for a thiol group. R ² represents a hydrogen atom, a lower alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, a lower alkoxy group, or a lower alkylthio group ₍ R ³ and R ⁴ is the same or different and represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. R ³ and R ⁴ may be combined with the carbon atom to which they are bonded to form a ring.

R ⁵ and R ⁶ are the same or different from each other, and represent a hydrogen atom or a lower alkyl group. R ⁷ represents a hydrogen atom or a protecting group for a carbonyl group.

n and m independently represent 0, 1 or 2.

2. At least one of R ³ and R ⁴ is not a hydrogen atom, A composition according to claim 1.

3. The composition according to claim 1, wherein neither R ³ nor R ⁴ is a hydrogen atom.

4. The composition according to claim 1, wherein R ³ is a lower alkyl group and R ⁴ is a hydrogen atom.

5. The composition according to claim 1, wherein R ³ is a hydrogen atom and R ⁴ is a lower alkyl group.

6. The composition according to claim 1, wherein R ³ is a hydrogen atom and R ⁴ is a methyl group.

7. The composition of placing serial to any one of claims 1 to 6 R ² is a lower alkyl group branched.

8. R ² is the formula

CH ₃

H ₃ C, CH

Represented by H _2, the composition according to any one of claims 1 to 6, which is m = 0.

9. The composition according to any one of claims 1 to 6, wherein the thiazolo [3,2-a] azevin derivative is represented by the formula (（).

Wherein I ¹ , R ³ , RR ⁵ , R ⁶ and R ⁷ have the same meaning as described above.

10. RRR ⁶ and R ⁷ are hydrogen atoms and R ⁴ is a methyl group. 10. The composition according to 9.

11. A method for preventing or treating a disease for which cholesterol-lowering action is effective, comprising administering the thiazolo [3,2-a] azepine derivative or a pharmacologically acceptable salt thereof according to claim 1. .

12. The method for preventing or treating according to claim 11, wherein the disease is hyperlipidemia.

13. Use of the thiazolo [3,2-a] azepine derivative according to claim 1 or a pharmacologically acceptable salt thereof for lowering cholesterol.

14. A cholesterol-lowering agent comprising the thiazolo [3,2-a] azepine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.