JPH01290630A - Drug preparation for transcutaneous administration - Google Patents

Abstract

PURPOSE:To obtain a drug preparation for transcutaneous administration, exhibiting improved and long-acting transcutaneous adsorption and useful as a preventive and remedy for hypertension by using a specific compound, its salt and ester, a specific aliphatic carboxylic acid, its lower alcohol ester and a specific aliphatic alcohol, etc., as essential components. CONSTITUTION:The objective preparation contains (A) one or more kinds of (R)-3-[(S)-1-lower alkoxycarbonyl-5-(4-piperidyl) pentyl] amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid of formula (R<1> is lower alkyl), its salt and its ester, (B) one or more kinds of 6-20C aliphatic carboxylic acid, its lower alcohol ester and 6-20C aliphatic alcohol and (C) a lower alkylene glycol. The drug preparation is administered at a dose of about 1-200 mg (preferably about 10-30 mg) of the compound of formula once every 1-7 days for the treatment of hypertension of adult.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides (i) (rt)-3 which has angiotensin converting enzyme inhibitory activity and is useful as a preventive and therapeutic agent for hypertension;
-[(S)-1-lower alkoxycarbonyl-5-(4
-piperidyl)pentylcoamino-4-oxo-2,3
,4,5-tetrahydro-1,5-benzothiazepine-
5-acetic acid, i.e., a compound represented by the formula [in the formula, R1 represents a lower alkyl group] [hereinafter abbreviated as compound (I)], a salt of compound (1), and an ester of compound (1), i.e., formula % formula % [In the formula, R1 and R1 each represent a lower alkyl group] One or more compounds [hereinafter abbreviated as compound (II)], (11) aliphatic carbon having 6 to 20 carbon atoms The present invention relates to a transdermal preparation containing an acid, a lower alcohol ester of an aliphatic carboxylic acid having 6 to 20 carbon atoms, 11 or more aliphatic alcohols having 6 to 20 carbon atoms, and (iii) a lower alkylene glycol.

Conventional Technology In recent years, so-called Transdermal Therapeutics have been developed that aim at systemic effects by transdermally absorbing drugs.
icSystem (T'rS), and several formulations have been developed. Examples include TTS such as clonidine, an antihypertensive drug, and nitroglycerin, a drug used to treat angina pectoris. When designing a TTS, it is important to ensure that the amount of drug necessary for treatment is absorbed transdermally and for a sustained period of time. However, since the skin is covered with a stratum corneum to prevent foreign substances from entering the body, it is generally difficult to absorb the drug itself through the skin.

There is a method of using absorption enhancers to promote transdermal absorption of drugs, such as dimethyl sulfoxide (DMSO),
Many transdermal absorption enhancers such as Azone and 2-pyrrolidone have been reported. However, transdermal absorption enhancers do not exhibit their effects in all formulations, but often exhibit their effects in limited formulations, and do not necessarily exhibit their absorption-promoting effects over a long period of time.

Problems to be Solved by the Invention As a result of intensive studies on promoting and sustaining absorption of compounds (1) and (nl), the present inventors found that lower alkylene glycols, aliphatic carboxylic acids, and The present invention was completed based on the discovery that by blending a lower alcohol ester and an aliphatic alcohol, the absorption of these compounds can be promoted and the absorption can be sustained.

Means for Solving the Problems As described above, the present invention comprises (1) compound (I), compound (
1) and one or more types of compound (II) [hereinafter sometimes abbreviated as component (i)], (ii) having 6 to 2 carbon atoms
0 aliphatic carboxylic acids, lower alcohol esters thereof, and aliphatic alcohols having 6 to 20 carbon atoms [hereinafter sometimes abbreviated as component (11)], and (i
ii) Lower alkylene glycol [hereinafter referred to as component (ii)
The purpose of the present invention is to provide a transdermal preparation containing the following (sometimes abbreviated as i).

Examples of the salt of the compound (1) include pharmacologically acceptable salts (metal salts) such as sodium salt, potassium salt, calcium salt, and aluminum salt.

In formulas (1) and (It), the lower alkyl group represented by R1 or R1 is, for example, methyl.

Examples include alkyl groups having about 1 to 4 carbon atoms such as ethyl, n-propyl, isopropyl, and lobethyl, and among them, ethyl group is preferred.

Examples of the aliphatic carboxylic acid having 6 to 20 carbon atoms include caproic acid, caprylic acid, and capric acid.

Saturated or unsaturated aliphatic monocarboxylic acids or dicarboxylic acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, tuccinic acid, linoleic acid, oleic acid, linoleic acid, linoleic acid, arachidonic acid, sebasonic acid, etc. Acid can be given.

Examples of lower alcohol esters of aliphatic carboxylic acids having 6 to 20 carbon atoms include lower alcohols (about 1 to 5 carbon atoms) of the aforementioned aliphatic carboxylic acids having 6 to 20 carbon atoms (
Examples, methanol, ethanol.

Examples include propatool, 2-propatool, butanol, pentanol) esters. Lower alcohol esters of aliphatic dicarboxylic acids include mono- and no-esters in which one or both carboxyl groups are esterified. Specific examples of lower alcohol esters of aliphatic carboxylic acids having 6 to 20 carbon atoms include diethyl sebacate and isopropyl myristate.

Examples of the aliphatic alcohol having 6 to 20 Mengki Charcoals include caproyl alcohol and capridal alcohol. Caprylic alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol.

Examples include saturated or unsaturated aliphatic alcohols such as stearyl alcohol, oleyl alcohol, linoleyl alcohol, and lylunyl alcohol.

Examples of the lower alkylene glycol include ethylene glycol (1,2-ethanediol), propylene glycol (1,2-propanediol), and l.

3-propanediol, 1,2-butanediol.

1.3-Butanediol,! , 4-butanediol.

Examples include alkanediols having about 2 to 5 carbon atoms, such as 2,3-butaneol, and 5-bentanediol. Among them, propylene glycol and 1,3-butanediol are preferred.

The amount of component (i) in the transdermal preparation of the present invention is arbitrary, but is preferably about 0.1 to 20% (W/W). Component (11) and component (
Although the amount of iii) is also arbitrary, the amount of component (11) is preferably about 1 to 30% (W/W), more preferably about 2 to 20% (W/W), and The amount of (I) is preferably about 5 to 50% (W/W), more preferably about 10 to 40% (W/W).

The transdermal preparations of the present invention include tape batches, poultices, ointments (including creams), plasters, suppositories, lotions, solutions, suspensions, emulsions, sprays, and the like.

Ointments (including creams), plasters, suppositories, lotions, solutions, suspensions, emulsions, and sprays contain the above component (1).

(ii) and (iii) are added to bases such as solvents, suspending agents, emulsifiers, surfactants, propellants, ointment bases, plaster bases, and suppository bases known in the pharmaceutical field as necessary for preservatives. It is prepared by adding agents (eg, butyl paraoxybenzoate, benzalkonium chloride), transdermal absorption enhancers (eg, eisin, 2-pyrrolidone), anti-inflammatory agents, etc. Tapes, patches, and poultices contain the above components (i) and (ii).
) and (iii) and a base known per se in the pharmaceutical field, and after adding preservatives, transdermal absorption enhancers, anti-inflammatory agents, etc. as necessary, absorb or adhere to a suitable carrier. It can be prepared. Supports include polymer membranes, woven fabrics, and non-woven fabrics.

Examples include paper, and adhesives used in tapes, patches, and poultices include polyalkyl vinyl ether-based, polyalkyl acrylate-based, polyisobutylene-based,
Examples include natural rubber-based 1 synthetic rubber-based adhesives. In addition, animal oil (eg, squalene, squalane), vegetable oil (eg, olive oil, jojoba oil), vaseline, lanolin, etc. may be added to maintain appropriate plasticity and tackiness.

When preparing ointments, adhesives, suppositories, tapes, patches, poultices, etc., ingredients that regulate transdermal absorption, such as phospholipids such as lecithin, sulfacids, solid paraffin, beeswax, carnauba wax, etc. Hydrogenated human oil, lanolin, polyvinyl alcohol, polyethylene glycol, glycerin fatty acid ester (e.g. glycerin monostearate), cholesterol, carbobol, carboxymethyl cellulose, carboquinoethyl cellulose,
Silicone resin, lower (C, , ) alcohol (ethanol, isopropyl alcohol, etc.), etc. can be blended.

Examples of the solvent include water, ethanol, and glycerin. Suspending agents and emulsifying agents include gum arabic, carboxymethylcellulose, methylcellulose, sodium alginate, and carrageenan. As a surfactant, Tween 80 (polysorbate 80
), 5pan 60 (sorbitan monostearate), etc. Nonflammable liquefied gas (
For example, freon). Examples of ointment bases include petrolatum, paraffin, vegetable oil, animal oil, lanolin, waxes, and macrogol. Examples of plaster bases include beeswax, paraffin, carbowax, and glycerin fatty acid esters. Suppository bases include cocoa butter, lanolin fat, macrogol, witepsol, grizzero gelatin, and the like.

The application of the transdermal preparation of the present invention to the skin of the body varies depending on the symptoms of the subject, but when administered for the purpose of treating hypertension in adults, as component (1)! Same amount 1-20
About 0mg (preferably about 10-30mg) from 1 to 7
Once daily (preferably once a day) administration (applying, spraying,
It is performed by rectal insertion and application).

The transdermal preparation of the present invention can be prepared by methods known per se, such as those described in the Japanese Pharmacopoeia.

The compound of component (i) can be synthesized, for example, by the method described below.

(II[) (V) [In the formula, R' and R'' have the same meanings as above. -butoxycarbonyl), W is a halogen or R35ot o
(In the formula, R3 represents a lower (C, -,) alkyl group, trifluoromethyl group, phenyl group or p-tolyl group)
The reaction of compound (1) with compound (IV) is usually carried out using water or other organic solvents (e.g., acetonitrile, dimethylformamide, dimethylsulfoquine, tetrahydrofuran, benzene, toluene) alone or in combination. In the presence or absence, -20° to +15
Performed at 0°C. At this time, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethylamine, etc. may be present in the reaction system for the purpose of accelerating the reaction rate.

The reaction for removing the protecting group Z is carried out in water or an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof.
Normal acids (e.g. hydrogen chloride, hydrogen bromide,
Hydrogen fluoride, hydrogen iodide.

Sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid.

trifluoroacetic acid).

The hydrolysis reaction of compound (n) is carried out at -20°C to +150°C in water or an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof. Usually bases (e.g., sodium hydroxide, potassium hydroxide).

potassium carbonate, sodium bicarbonate, sodium carbonate,
sodium acetate).

The elimination reaction of compound (n) is carried out under the same conditions as the above-mentioned removal reaction of protecting group Z.

In formula (1), a compound in which R2 is a lower alkyl group other than a tert- group in formula (III) and a compound in which R1 is a tert-butyl group in formula (IV) is an rj'/+' tert-butyl group. A reaction is carried out using a compound having a butyl group as a raw material, and a compound of the resulting formula (I [) in which R'h<tert-butyl group and R1 is a lower alkyl group other than a tert-butyl group is subjected to a hydrolysis reaction. Obtained by subjecting to. In addition, in formula (1), the compound in which R1 is a lower alkyl group other than a tert-butyl group, the compound in which R' is a tert-butyl group in formula (Iff), and the compound in which R1 is a tert-butyl group in formula (Iff)
In V), a compound in which R1 is a lower alkyl group other than a tert-butyl group is used as a raw material to react, and the resulting formula (
n), R1 is a lower alkyl group other than a tert-butyl group, and R2 is a tert-butyl group, which can be obtained by subjecting a compound to an elimination reaction.

In formula (V), a compound in which R1 is a lower alkyl group other than a tert-butyl group, R'' is a tert-butyl group, and Z is a benzyloxycarbonyl group is subjected to a reaction for removing the protecting group Z. Compound (1) can also be obtained by a Yolly process.

Compound (If) can also be synthesized by condensing a compound represented by the formula (1) in which R1 is hydrogen or a lower alkyl group with a compound represented by the formula [wherein R'' has the same meaning as above]. The condensation reaction conditions include, for example, reaction conditions using condensation reagents (e.g., dicyclohexylcarbodiimide, carbodiimidazole, noethyl cyanophosphate, diphenylphosphate azide), acid catalysts (e.g., hydrogen chloride, Examples include reaction conditions using hydrogen hydride, p-+-luenesulfonic acid), etc. The reaction is carried out in the presence or absence of an appropriate solvent at temperatures ranging from -20° to +!
Performed at 50°C.

Compounds (1) and (Il) can be isolated from the reaction mixture using conventional separation and purification means such as extraction, concentration, neutralization, filtration, column chromatography, and thin layer chromatography.

The salt of the compound (1) described above may be obtained by the reaction itself for producing the compound (1), but if necessary, the salt of the compound (1) can also be obtained by adding an alkali or base.

As compounds (D and (Il)), pharmacologically acceptable salts thereof such as acid addition salts (e.g., hydrochloride, hydrobromide, acetate) may be used. Salts may be obtained by the reaction itself to produce compounds (r) and ([1), but if necessary, salts of compounds (1) and ([[) can also be obtained by adding an acid.

Although typical manufacturing methods for compounds (1) and (II) and their salts have been described above, the manufacturing methods should not be limited to the above-mentioned typical manufacturing methods.

In addition, compounds (II[) and (IV) are disclosed in JP-A-60-
It can be synthesized according to the method described in Japanese Patent No. 231668.

Actions and Effects The transdermal preparation of the present invention provides compounds (+) and (II
) is absorbed transdermally in sufficient quantity and the absorption is sustained. Therefore, the transdermal preparation of the present invention can be applied to the skin of the body of a mammal (eg, human, monkey, dog, cat, rat) as a preventive treatment for hypertension.

In addition, after being absorbed, compounds (1) and (II) are enzymatically hydrolyzed in vivo to form the active form, (R)-
Converted to 3-[(S)-1-carboxy-5-(4-piperidyl)pentylcoamino-4-oxo-2,3゜4.5-tetrahydro-1,5-benzothiazepine-5-acetic acid. Ru. In order to achieve the purpose of the present invention, that is, to improve the absorption rate, to prolong the absorption, and to prolong the inhibition of angiotensin converting enzyme, a novel compound (R)-3-[(S)
-Ethoxycarbonyl-5-(4-piperidyl)pentylcoamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester and its acid addition salts preferable.

EXAMPLES The present invention will be explained in more detail by showing Examples, Comparative Examples, and Production Examples below, but the present invention should not be limited to these.

Example 1 [Preparation of transdermal preparation] 2 g of compound (1) [R'-ethyl] and 5 g of oleic acid.

Mix 20 g of propylene glycol and 5 g of polyethylene glycol 400. This is mixed with 68 g of an aqueous solution containing 5 g of Hibiswako-104 prepared separately, and then sodium hydroxide (1.7 g) is added to gel it to obtain a transdermal preparation.

[Transdermal absorption experiment]

Depilated abdominal skin of 9-week-old male SD rats (2 x 3
A transdermal preparation was applied (or patched) to the area (cm) and sealed with Saran wrap. Percutaneous absorption was evaluated by determining the inhibition rate (%) of angiotensin converting enzyme (ACE) over time. In addition, angiotensin I is 300 n
g/kg (rat) was administered intravenously.

Moreover, the sustainability of absorption was determined by the number of hours for which the inhibition rate (%) of angiotensin converting enzyme remained at 70% or more.

[Results] ACE was inhibited 100% for 24 hours and 70% or more for 72 hours, and compound (r) was absorbed sufficiently and for a long time.

Example 2 [Preparation of transdermal preparation] Compound (1) [r('-ethyl]l Og, 10 g of oleic acid, and 40 g of propylene glycol are mixed.

40 g of a silicone resin adhesive dissolved in 200 g of ethyl acetate is added and mixed, spread uniformly on a polyethylene sheet, and after distilling off the solvent, a tape is prepared.

[Transdermal absorption experiment] The same procedure as in Example 1 was carried out.

[Result] ACE! 00% for 48 hours and more than 70% for 120 hours, compound (1) was absorbed well and for a long time.

Example 3 [Preparation of transdermal preparation] Compound (II) [R'=rt'=ethyl] 5 g and propylene glycol 20 g, l,3-butylene glycol 1
0 g and 10 g of lauric acid are mixed and dissolved. this,
1 of separately prepared polyvinyl alcohol.

After mixing with 55 g of an aqueous solution containing g, the mixture is gelled at a low temperature to form a sheet-shaped transdermal preparation.

[Transdermal absorption experiment] The same procedure as in Example 1 was carried out.

[Results] ACE was inhibited 100% for 24 hours and 70% or more for 72 hours, and compound (n) was absorbed sufficiently and for a long time.

Example 4 [Preparation of transdermal preparation] 10 g of compound (1) [R' = ethyl], 30 g of propylene glycol, 20 g of lauryl alcohol, and 40 g of an acrylic resin adhesive dissolved in ethyl acetate (200 g) were mixed and spread on a polyethylene sheet. After uniformly spreading and removing the solvent, it is used as a tape.

[Transdermal absorption experiment] The same procedure as in Example 1 was carried out.

[Results] Compound (1) inhibited ACE by 100% for 48 hours and 70% or more for 96 hours, and was sufficiently absorbed for a long time.

Reference Example 1 [Preparation of transdermal absorption preparation] Compound ([)[R'=ethyl] 10g, oleic acid 0.
5 g of polyethylene glycol, 4.5 g of propylene glycol, 1.5 g of polyethylene glycol 400, and 70 g of silicone resin dissolved in 200 g of ethyl acetate were added and mixed, spread uniformly on a polyethylene sheet, and after distilling off the solvent, a tape preparation was prepared.

[Transdermal absorption experiment] The same procedure as in Example 1 was carried out.

[Results] ACE was only inhibited by 30% for 5 hours, and sufficient absorption was not observed, indicating that it was ineffective.

Production example 1 3(R)-benzyloxycarbonylamino-2゜3-
Dihydro-1,5(5H)-benzothiazepin-4-one (Joel 5lade et al., J, Org, Ch
ew,.

28, p. 1517, 1985) in 50 d of N,N-dimethylformamide, add 4.5 g of ethyl chloroacetate, 5.1 g of potassium carbonate, and 0.5 g of potassium iodide, and stir at room temperature for 10 hours. . Add 200ml of water to the reaction solution and extract with 200ml of ethyl acetate. The extract was reduced to 0. After washing with 10 ml of IN hydrochloric acid and 100 ml of water, drying over anhydrous magnesium sulfate, and evaporating under reduced pressure.

The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate = 2:I) to obtain 3(
R)-benzyloxycarbonylamino-4-oxo-
12.2 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester are obtained as an oil.

IRv"""cm-'+1750.1725.16
70(C=O)ax [α]D-183° (cm0.86. in methanol) Production Example 2 3(R)-benzyloxycarbonylamino-4-year-old xo2.3,4.5-tetrahydro-1 , 12 g of 5-benzothiazepine-5-acetic acid ethyl ester to 10 g of acetic acid
d, add 40M1 of 30% hydrogen bromide-acetic acid solution, and leave at room temperature for 1.5 hours. Add a mixture of ether and Ishiura ether (l: 1.400 d) to the reaction solution and mix. After decanting and removing the supernatant, 300% ethyl acetate and 200% water were added, and the mixture was neutralized with baking soda. The ethyl acetate layer was washed with 100% of water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 3(R)-amino-4-oxo 2,3
, 4,5-tetrahydro-1,5-benzothiazepine-
5.5 g of 5-acetic acid ethyl ester precipitates as crystals. Melting point 111-1138C Elemental analysis value C,,H,.

Calculated value as N, O, S: C55,70,1+5
．． 75. N 9.99 Actual value: C55,69,H
5,75,N 9.86[α]D-259°(cm0.
86. in methanol) Production Example 3 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 2.3g and ethyl (R)-6 =(1-benzyloxycarbonyl-4-piperidyl)-2-mesyloxyhexanoate ([αcoD+I5°, c=0.5
2. (in methanol) and stirred at 90° C. for 32 hours. The resulting oil was dissolved in 200 d of ethyl acetate, washed with 100 d of a 5% aqueous phosphoric acid solution and 1 oad of water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 3:2), and from the first fraction,
3 (R)-[5-(1-benzyloxycarbonyl-
0.36 g of 4-piperidyl)-1(R)-ethoxycarbonylpentylcoamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester is a colorless oil. obtained as.

IRvneaLcm-': 3330(N)1), 173
5,1690.1680 a 1(S)-ethoxycarbonylpentylcoamino-4-oxo-2,3,4
,5-tetrahydro-1,5-benzothiazepine-5-
0.73 g of acetic acid ethyl ester is obtained as a colorless oil.

IRv""'cm-': 3320 (NH), 173
5,1690.1680ax (C=O) Iff]D-113° (cm0.37. in methanol)
Production Example 4 3(R1-[5-(1-benzyloxycarbonyl-4
-Piperidyl-1(S)-ethquinecarbonylpentylcoamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 0.4 g of ethyl ester was added to 2 hours of acetic acid. Dissolve, add 30% hydrogen bromide-acetic acid solution, and leave at room temperature for 2 hours. ether to
The supernatant liquid was decanted, the supernatant liquid was removed by decanting, saturated sodium bicarbonate solution (10 mm) was added to the residue, and the mixture was extracted with 50 tablespoons of ethyl acetate. After washing the extract with water, drying with anhydrous magnesium sulfate,
Distill under reduced pressure. Dissolve the residual oil in 50 g of ether,
Add 0.5 N of hydrogen chloride-ethyl acetate solution and collect the precipitated powder by filtration to obtain 3(R)-[+(S)-ethoxycarbonyl-5-(4-piperidyl)pentylcoamino-4-oxo -2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetic acid ethyl ester dihydrochloride 0.22 g is obtained.

[α, -108° (cm0.61. in methanol) S
IMS spectrum (m/e): 506 (MH”) Elemental analysis value Ct s H3s N 30 s S・2
Calculated value as HCI・5/2H,O: C50,12,H7,44,N 6.75
Actual value: C50.02; I+ 7.54. N
6.63 Production Example 5 3(R)-(S)-carboxy-5-(4-piperidyl)pentylcoamino-4-oxo-2,3,4°5-
Tetrahydro-1,5-benzothiazepine-5-acetic acid [
JP-A-60-231668] 2.0g was dissolved in 8N hydrogen chloride-ethanol solution and left at room temperature for 2 days. After distilling off under reduced pressure, 50 g of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate and 30 g of dichloromethane. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 3(R),-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentylcoamino-4-oxo- 2,3,4,5-tetrahydro-1゜5
-Benzothiazepine-5-acetic acid ethyl ester 2.1
g is obtained as a colorless oil.

I Rv ""tcm-': 1740.1660 (C=
O) IIlaX [αColo-154° (c=0.46. in methanol) Production Example 6 3(R)-[5-(1-benzyloxycarbonyl-4
-piperidyl)-1(S)-ethoxycarbonylpentylcoamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-
Dissolve 0.9 g of butyl ester in 3 d of acetic acid, add 4 ml of 30% hydrogen bromide-acetic acid solution, and let stand at room temperature for 1.5 hours. Add 100% ether, shake, remove the supernatant liquid by decanting, and neutralize the residue by adding aqueous sodium bicarbonate. The mixture is made weakly acidic by adding acetic acid and purified by MCI gel column chromatography (water:methanol=1+2). After concentrating the effluent under reduced pressure and lyophilizing it, 3 (R)-[1(
S)-Ethoxycarbonyl-5-(4-piperidyl)pentylcoamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 0.59
g is obtained as a colorless powder.

Claims (2)

[Claims] (1)(i)(R)-3-[(S)-1-lower alkoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,
5-benzothiazepine-5-acetic acid, one or more of its salts and its esters, (ii) aliphatic carboxylic acids having 6 to 20 carbon atoms, lower alcohol esters thereof, and 6 carbon atoms
one or more of ~20 aliphatic alcohols, and (iii
) A transdermal preparation containing lower alkylene glycol. (2) (R)-3-[(S)-ethoxycarbonyl-5
-(4-piperidyl)pentyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester or a salt thereof.