JPH09315979A - Cholagogic agent - Google Patents
Cholagogic agentInfo
- Publication number
- JPH09315979A JPH09315979A JP13039696A JP13039696A JPH09315979A JP H09315979 A JPH09315979 A JP H09315979A JP 13039696 A JP13039696 A JP 13039696A JP 13039696 A JP13039696 A JP 13039696A JP H09315979 A JPH09315979 A JP H09315979A
- Authority
- JP
- Japan
- Prior art keywords
- nag
- acid
- conjugate
- active ingredient
- acetylglucosamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は次式で表される化合
物又はそれらの生理学的に許容される塩を有効成分とし
て含有する利胆剤に関する。TECHNICAL FIELD The present invention relates to a choleretic agent containing a compound represented by the following formula or a physiologically acceptable salt thereof as an active ingredient.
【０００２】[0002]
【化２】 Embedded image
【０００３】（ＲはＯＨ，ＮＨＣＨ2ＣＨ2ＳＯ3Ｈ又は
ＮＨＣＨ2ＣＯＯＨを表す。）(R represents OH, NHCH 2 CH 2 SO 3 H or NHCH 2 COOH.)
【０００４】[0004]
【発明が解決しようとする課題】近年、ウルソデオキシ
コール酸製剤が、利胆剤として肝内胆汁うっ滞に対し高
い有用性を示すとの報告が、国内外でなされ、その注射
剤の出現が望まれていた。しかしながら、ウルソデオキ
シコール酸の溶解性は非常に低く、又、調製したとして
もその注射剤のpHは高くなり、血管痛を伴うなどの欠点
を有していた。Recently, it has been reported that ursodeoxycholic acid preparations are highly useful as choleretic agents for intrahepatic cholestasis, and the appearance of injections thereof has been reported. Was wanted. However, the solubility of ursodeoxycholic acid was very low, and even if it was prepared, the pH of its injection was high, and it had drawbacks such as vascular pain.
【０００５】最近、タウロウルソデオキシコール酸及び
グリコウルソデオキシコール酸がウルソデオキシコール
酸とほぼ同等の利胆作用を有し、ウルソデオキシコール
酸に比して溶解性が高く、血管への刺激性も弱いことか
ら、注射剤として肝内胆汁うっ滞に有効であると考えら
れてきた。Recently, tauroursodeoxycholic acid and glycoursodeoxycholic acid have almost the same choleretic action as ursodeoxycholic acid, have a higher solubility than ursodeoxycholic acid, and are irritating to blood vessels. Since it is weak, it has been considered to be effective as an injectable drug for intrahepatic cholestasis.
【０００６】Marschallらは健常者の尿中に、代表的ア
ミノ糖であるN-アセチルグルコサミンと抱合した新しい
抱合型胆汁酸が微量存在することを報告した（Journal
of Chromatography.452,459-468(1988))。[0006] Marschall et al. Reported that a small amount of a new conjugated bile acid conjugated with a typical amino sugar, N-acetylglucosamine, was present in the urine of healthy subjects (Journal
of Chromatography. 452, 459-468 (1988)).
【０００７】その後、健常人及び各種慢性肝疾患患者に
ウルソデオキシコール酸製剤を投与した場合、尿中に排
泄されるウルソデオキシコール酸代謝物の約５０％がＮ
−アセチルグルコサミン抱合体であることが明らかにさ
れ、Ｎ-アセチルグルコサミン抱合化はウルソデオキシ
コール酸のような7β位に水酸基を有する胆汁酸に特異
的に起こることが報告されている（Hepatology,20,845-
853(1994) J. LipidRes.,35,1599-1610(1994))。After that, when ursodeoxycholic acid preparations are administered to healthy subjects and patients with various chronic liver diseases, about 50% of ursodeoxycholic acid metabolites excreted in urine are N.
-Acetylglucosamine conjugate, and N-acetylglucosamine conjugation has been reported to occur specifically in bile acids having a hydroxyl group at the 7β position such as ursodeoxycholic acid (Hepatology, 20,845. -
853 (1994) J. Lipid Res., 35, 1599-1610 (1994)).
【０００８】しかしながら、代謝物である７−Ｎ−アセ
チルグルコサミン抱合体が、胆汁分泌促進作用を有する
ことは知られていない。However, it is not known that the metabolite, 7-N-acetylglucosamine conjugate, has a bile secretion promoting action.
【０００９】[0009]
【課題を解決するための手段】本発明者はウルソデオキ
シコール酸の代謝物の薬効薬理試験を検討する過程でウ
ルソデオキシコール酸、タウロウルソデオキシコール酸
及びグリコウルソデオキシコール酸の各７−Ｎ−アセチ
ルグルコサミン抱合体に胆汁分泌促進作用を見出し、本
発明を完成させた。Means for Solving the Problems In the course of studying the pharmacological efficacy test of ursodeoxycholic acid metabolites, the present inventor used 7-N each of ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid. The acetylglucosamine conjugate was found to have a bile secretagogue action, and the present invention was completed.
【００１０】本発明によれば、ウルソデオキシコール
酸、タウロウルソデオキシコール酸及びグリコウルソデ
オキシコール酸の各７−Ｎ−アセチルグルコサミン抱合
体（以下各々、「ＵＤＣ−ＮＡＧ」、「ＴＵＤＣ−ＮＡ
Ｇ」、「ＧＵＤＣ−ＮＡＧ」と表す。）を有効成分とす
る利胆剤が提供される。 本発明に使用するＵＤＣ−Ｎ
ＡＧ、ＴＵＤＣ−ＮＡＧ、ＧＵＤＣ−ＮＡＧは、生理学
的に許容される塩であっても良く、生理学的に許容され
る塩としては、ナトリウム塩やカリウム塩が挙げられ
る。According to the present invention, 7-N-acetylglucosamine conjugates of ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid (hereinafter referred to as "UDC-NAG" and "TUDC-NA", respectively).
G ”and“ GUDC-NAG ”. ) Is provided as an active ingredient. UDC-N used in the present invention
AG, TUDC-NAG, and GUDC-NAG may be physiologically acceptable salts, and examples of the physiologically acceptable salts include sodium salt and potassium salt.
【００１１】ＵＤＣ−ＮＡＧはウルソデオキシコール酸
のカルボキシル基と３位水酸基を保護した後、７位にＮ
−アセチルグルコサミンを結合することにより得ること
ができる。 また、ＴＵＤＣ−ＮＡＧ及びＧＵＤＣ−Ｎ
ＡＧは、ＵＤＣ−ＮＡＧから合成することができる。UDC-NAG protects the carboxyl group and the hydroxyl group at the 3-position of ursodeoxycholic acid and then N at the 7-position.
-It can be obtained by coupling acetylglucosamine. In addition, TUDC-NAG and GUDC-N
AG can be synthesized from UDC-NAG.
【００１２】[0012]
（利胆作用）Wistar系雄性ラットに麻酔下外胆汁ろうを
増設し、３０分間胆汁を採取した後、ＵＤＣ−ＮＡＧ、
ＴＵＤＣ−ＮＡＧ及びＧＵＤＣ−ＮＡＧの0.3及び0.6μ
mol/min/100gを大腿静脈より２時間持続投与し、経時的
に胆汁流量を測定した。(Celebratory effect) An external bile fistula was added under anesthesia to Wistar male rats, and after collecting bile for 30 minutes, UDC-NAG,
0.3 and 0.6μ of TUDC-NAG and GUDC-NAG
Mol / min / 100g was continuously administered through the femoral vein for 2 hours, and the bile flow was measured over time.
【００１３】その結果、ＵＤＣ−ＮＡＧ、ＴＵＤＣ−Ｎ
ＡＧ及びＧＵＤＣ−ＮＡＧは低用量でウルソデオキシコ
ール酸、タウロウルソデオキシコール酸及びグリコウル
ソデオキシコール酸よりも強い利胆作用を示すことが示
唆された。As a result, UDC-NAG, TUDC-N
It was suggested that AG and GUDC-NAG have stronger choleretic effects than ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid at low doses.
【００１４】（急性毒性）５週令のＩＣＲ系雄性マウス
を用い、各７−Ｎ−アセチルグルコサミン抱合体及びタ
ウロウルソデオキシコール酸の単回静脈内投与での急性
毒性（LD50）を測定した。毒性はタウロウルソデオキシ
コール酸が最も強くＬＤ50: 600〜800mg/kg)、ＵＤＣ−
ＮＡＧ、ＴＵＤＣ−ＮＡＧ、ＧＵＤＣ−ＮＡＧのＬＤ50
値は、順に1200〜1600mg/kg, 2000mg/kg以上, 2000mg/k
g以上であった。(Acute toxicity) Using 5-week-old male ICR mice, the acute toxicity (LD 50 ) after single intravenous administration of each 7-N-acetylglucosamine conjugate and tauroursodeoxycholic acid was measured. . Toxicity tauroursodeoxycholic acid strongest LD 50: 600~800mg / kg), UDC-
LD 50 of NAG, TUDC-NAG, GUDC-NAG
The values are 1200 to 1600mg / kg, 2000mg / kg or more, 2000mg / k
g or more.
【００１５】本発明のＵＤＣ−ＮＡＧ、ＴＵＤＣ−ＮＡ
Ｇ及びＧＵＤＣ−ＮＡＧは、水溶性が高いので、精製水
や生理食塩水で水性製剤とすることができる。その際に
は、各７−Ｎ−アセチルグルコサミン抱合体は１−１４
％（Ｗ／Ｖ）の濃度で含有されていることが好ましい。UDC-NAG, TUDC-NA of the present invention
Since G and GUDC-NAG have high water solubility, they can be made into an aqueous preparation with purified water or physiological saline. In that case, each 7-N-acetylglucosamine conjugate was 1-14.
% (W / V) is preferable.
【００１６】各７−Ｎ−アセチルグルコサミン抱合体の
患者への投与量は、年齢、症状等により異なるが、成人
に対し１日あたり、静注でＵＤＣ−ＮＡＧでは40-1400m
g、ＧＵＤＣ−ＮＡＧでは40-1500mg、ＴＵＤＣ−ＮＡＧ
では50-1600mg、好ましくは各々120-700mg,130-700mg,1
40-800mgを用いる。The dose of each 7-N-acetylglucosamine conjugate to a patient varies depending on age, symptoms, etc., but it is 40-1400 m / day for UDC-NAG by intravenous injection to an adult.
g, 40-1500 mg for GUDC-NAG, TUDC-NAG
50-1600 mg, preferably 120-700 mg, 130-700 mg, 1
Use 40-800 mg.
【００１７】以下に製剤例をもって具体的に説明する
が、本発明はこれに限定されるものではない。The formulation examples will be specifically described below, but the present invention is not limited thereto.
【００１８】[0018]
［実施例１］ＵＤＣ−ＮＡＧ５０ｇを生理食塩水１００
０ｍｌに溶解し、０．２μｍメンブランフィルターで濾
過し、５ｍｌをアンプルに充填・熔閉した後、３０分間
煮沸滅菌して、５％（Ｗ／Ｖ）含有注射剤を製造した。[Example 1] UDC-NAG 50 g was added to physiological saline 100.
It was dissolved in 0 ml, filtered through a 0.2 μm membrane filter, filled with 5 ml in an ampoule, sealed by boiling, and sterilized by boiling for 30 minutes to prepare a 5% (W / V) -containing injection.
【００１９】［実施例２］ＧＵＤＣ−ＮＡＧ３０ｇ、Ｄ
−マンニトール４２ｇを精製水で全量１０００ｍｌに調
製した溶液を用いて、実施例１におけると同様に処理し
て、ＧＵＤＣ−ＮＡＧを３％含有する注射剤を製造し
た。[Example 2] GUDC-NAG 30g, D
-Mannitol 42g was prepared in a total volume of 1000 ml with purified water and treated in the same manner as in Example 1 to prepare an injection containing 3% GUDC-NAG.
【００２０】［実施例３］ＴＵＤＣ−ＮＡＧ１００ｇ、
Ｄ−マンニトール３４ｇを用いて、実施例２におけると
同様に処理して、ＧＵＤＣ−ＮＡＧを１０％含有する注
射剤を製造した。[Example 3] TUDC-NAG 100g,
The same procedure as in Example 2 was carried out using 34 g of D-mannitol to produce an injection containing 10% GUDC-NAG.
【００２１】[0021]
【発明の効果】本発明の、ウルソデオキシコール酸、タ
ウロウルソデオキシコール酸及びグリコウルソデオキシ
コール酸の各７−Ｎ−アセチルグルコサミン抱合体は水
溶性に優れ、胆汁分泌促進作用を有することから、利胆
剤として有用である。The 7-N-acetylglucosamine conjugates of ursodeoxycholic acid, tauroursodeoxycholic acid and glycoursodeoxycholic acid of the present invention are excellent in water solubility and have a bile secretion promoting action, It is useful as a choleretic agent.
【図１】各種胆汁酸及びそれらの7−Ｎ−アセチルグル
コサミン抱合体の正常ラットの胆汁流量に及ぼす影響を
示す図である。FIG. 1 shows the effect of various bile acids and their 7-N-acetylglucosamine conjugates on the bile flow in normal rats.
Claims (2)
ＯＨを表す。）で表される化合物又はそれらの生理学的
に許容される塩を有効成分とする利胆剤。(1) Formula 1 (R is OH, NHCH 2 CH 2 SO 3 H or NHCH 2 CO
Represents OH. B) a choleretic agent containing a compound represented by the formula (4) or a physiologically acceptable salt thereof as an active ingredient
剤。2. The choleretic agent according to claim 1, wherein the dosage form is an injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13039696A JPH09315979A (en) | 1996-05-24 | 1996-05-24 | Cholagogic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13039696A JPH09315979A (en) | 1996-05-24 | 1996-05-24 | Cholagogic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09315979A true JPH09315979A (en) | 1997-12-09 |
Family
ID=15033310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13039696A Pending JPH09315979A (en) | 1996-05-24 | 1996-05-24 | Cholagogic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH09315979A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001021642A1 (en) * | 1999-09-22 | 2001-03-29 | Aventis Pharma Deutschland Gmbh | 4-benzylaminoquinoline conjugates with bile acid and their heteroanalogues, methods for producing the same, medicaments containing these compounds and their use |
| JP2003508513A (en) * | 1999-09-02 | 2003-03-04 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Bile acid-substituted phenylalkenoylguanidines, methods for their preparation, their use as medicaments or diagnostics, and medicaments containing them |
-
1996
- 1996-05-24 JP JP13039696A patent/JPH09315979A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003508513A (en) * | 1999-09-02 | 2003-03-04 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Bile acid-substituted phenylalkenoylguanidines, methods for their preparation, their use as medicaments or diagnostics, and medicaments containing them |
| JP4768941B2 (en) * | 1999-09-02 | 2011-09-07 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Bile acid-substituted phenylalkenoylguanidines, processes for their preparation, their use as medicaments or diagnostics, and medicaments containing them |
| WO2001021642A1 (en) * | 1999-09-22 | 2001-03-29 | Aventis Pharma Deutschland Gmbh | 4-benzylaminoquinoline conjugates with bile acid and their heteroanalogues, methods for producing the same, medicaments containing these compounds and their use |
| JP2003510255A (en) * | 1999-09-22 | 2003-03-18 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 4-Benzylaminoquinoline conjugates with bile acids and their hetero-analogs, their preparation, medicaments containing these compounds and their use |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Effective date: 20060608 Free format text: JAPANESE INTERMEDIATE CODE: A131 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20061102 |