WO1992013544A1 - Agent for preventing and treating viral myocarditis - Google Patents
Agent for preventing and treating viral myocarditis Download PDFInfo
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- WO1992013544A1 WO1992013544A1 PCT/JP1992/000069 JP9200069W WO9213544A1 WO 1992013544 A1 WO1992013544 A1 WO 1992013544A1 JP 9200069 W JP9200069 W JP 9200069W WO 9213544 A1 WO9213544 A1 WO 9213544A1
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
Definitions
- This invention is based on the formula
- the present invention relates to a prophylactic / therapeutic agent for viral myocarditis comprising as an active ingredient the compound shown in 3 or a pharmaceutically acceptable salt thereof.
- Viral myocarditis is a disease that, when severe, can lead to heart failure and even death.
- various antiviral and immunopotentiating agents have been tried to determine whether they are effective against viral myocarditis, but at present, effective drugs are known. It's a lazy lady.
- the second inventor has been known as a drug for viral infectious disease as a result of an independent study in a situation in which the emergence of an effective drug for viral myocarditis is desired.
- a compound represented by the following formula (I) is expected to be a predictor of viral myocarditis. We have obtained new knowledge that it is effective as a preventive and therapeutic agent, and as a result of further research, we have completed this process.
- the agent for preventing or treating viral myocarditis according to the present invention comprises, as an active ingredient, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
- the agent for preventing and treating viral myocarditis according to the present invention can be used for preventing and treating various types of viral myocarditis in humans and animals.
- Pharmaceutically acceptable salts of compound (I) used as an active ingredient in the present invention include, for example, sodium salt, potassium salt, calcium salt and the like.
- Organic or inorganic salts such as salt, ammonia salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, etc. , Lactate, trifluoroacetate, lactate, maleate, fumarate, tartrate, citrate, methansulfonate, hydrochloride , Sulfate, nitrate, phosphate And acid addition salts with organic acids or inorganic acids.
- Compound (I) contains one or more stereoisomers depending on the asymmetric carbon atom in the molecule, and all of these compounds can be used as the active ingredient of the present invention. Wear .
- the compound (I) used as an active ingredient in the present invention and a pharmaceutically acceptable salt thereof reduce myocardial damage in acute myocarditis and have a remarkable survival rate. Improvement was observed, and viral myocarditis C is a typical virus caused by myocarditis, for example, coxsackie virus, ecovirus, etc. Enterovirus)) as a preventive and therapeutic agent.
- Test Example 1 Anti-encephalomyocarditis virus activity by compound A-administered mouse peritoneal cells and mast cells
- mice BalbZc, male, 5 weeks old, 10 mice per group (30 mice in phosphate-administered saline administration group)
- Compound A administration 1, 0.01 mg / kg, once a day for 3 days intraperitoneally
- Peritoneal cells Collected by centrifugation from the peritoneal lavage fluid of HBSS (3 ml) of the exsanguinated mouse
- Splenocytes The spleen of the exsanguinated mouse was washed with a glass homogenizer, filtered with a metal mesh, lysed with 0.85% NH 4 C1, washed with HBSS, and used for experiments. .
- Experimental system A single eyebrow of BalbZc 3T3 cells (MEM medium containing 10% fetal serum) was infected with encephalomyocarditis (EMC) virus for 1 hour with HOI 1 and then peritoneal cells or Splenocytes were added, and the cells were cultured for 16 hours in a MEM medium containing 0.5% ⁇ fetal serum.
- EMC encephalomyocarditis
- Rhinovirus 5 Virus fi i ⁇ f direct effector-cell EZI ratio (pfxi / ml) Mean ⁇ SD (log)
- EZ I ratio Effector Target cell ratio Mouse peritoneal cavity with PBS-PEC phosphate buffered saline cell
- Test Example 2 Anti-coccalus B3 virus activity by mouse peritoneal cells and splenocytes administered with Compound A
- mice C3HZ He strain, male, 8 weeks old, 10 mice per group (30 mice in phosphate-administered saline administration group)
- Compound A administration 1, 0.01 mg / kg, intraperitoneally once a day for 3 days
- Peritoneal cells Collected by centrifugation from the peritoneal lavage fluid of HBSS (3 ml) of the exsanguinated mouse
- Spleen cells Depleted The spleen of the mouse was crushed with a glass homogenizer, filtered with a metal mesh, lysed with 0.85% NH 4 C1, washed with HBSS, and used for experiments. Using. Experimental system C3HZ He-mass fetal fibroblasts (MEM medium containing 10% fetal serum :) After infecting B3 virus with MOI 1 for 1 hour, peritoneal cells or spleen cells were added, and the cells were cultured for 16 hours in a MEM medium containing 0.5% fetal fetus serum. After freeze-thawing was repeated twice to destroy the cells, the amount of virus in the supernatant was measured by the plaque method using FL cells.
- PE PBS-SC, 0.1 Olmg / kg-SC and 1 mgZ kg-SC have the same meanings as in Test Example 1.
- mice Four week old Balb / c mice were intraperitoneally inoculated with 100 plaquef orming units (pfu;) of encephalomyocarditis C EMC;) virus.
- Compound A was discontinued after daily administration for 4 days.
- the prophylactic and therapeutic agents for viral myocarditis of the present invention are, for example, the active substances of the present invention.
- a solid, semi-solid, or liquid formulation containing the compound in an organic or inorganic carrier or excipient suitable for parenteral or parenteral administration be able to .
- the active ingredient may be, for example, a tablet, pellet, capsule, suppository, suppository, solution, emulsion, suspension, and usually a non-toxic pharmaceutically acceptable carrier. It is used by mixing to form an appropriate dosage form.
- the carriers include water, glucose, lactose, arabia gum, gelatin, mannitol, starch paste, and magnesium paste.
- the preventive or therapeutic agent for myocardial myocarditis may also contain a preservative or a bacteriostat to stably maintain the activity of the impeached component in the desired preparation.
- the amount of the active ingredient contained in the agent for preventing or treating viral myocarditis is an amount sufficient to exert the desired therapeutic effect on the prophylaxis or disease process and condition. .
- this prophylactic / therapeutic agent for viral myocarditis is applied to humans, it is desirable to administer it by a method such as intravenous injection, subcutaneous injection, intramuscular injection or oral administration.
- the dose of the active ingredient, compound (I) or a pharmaceutically acceptable salt of the present invention varies depending on the conditions such as the age of each individual patient to be treated and the degree of illness. However, humans generally receive a daily dose of about 0.01 to 10 mg of active ingredient for prophylactic or therapeutic purposes.
- Example 2 The above is formulated in a conventional manner to give tablets.
- Example 2 The above is formulated in a conventional manner to give tablets.
- the above is formulated in a conventional manner to make a capsule.
- the vial is aseptically dispensed to contain the compound AlOOmg and sealed to remove water and bacterium. Before use, add 2 ml of 0,5% lidocaine injection to make an injection.
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Abstract
An agent for preventing and treating viral myocarditis with excellent efficacity, which contains a compound represented by formula (3) or a pharmaceutically acceptable salt thereof as the active ingredient.
Description
明 細 ¾ 明
発 明 の 名称 Name of the invention
ウ ィ ル ス性心筋炎の予防、 治療剤 Prevention and treatment of viral myocarditis
技術分野 Technical field
こ の発明 は式 This invention is based on the formula
CH。（： CHn ) _ CONHCHCOOH CH. (: CH n ) _ CONHCHCOOH
( C 2 (C 2
COHNCHCOHNCHCOOH COHNCHCOHNCHCOOH
(cv3 ( c v 3
H NCHCOOH CI H NCHCOOH CI
H H
3 で示さ れ る化合物または医薬 と し て許容さ れる そ の塩を有 効成分 と す る ウ ィ ル ス性心筋炎の予防、 治療剤に関す る も の で あ る 。 The present invention relates to a prophylactic / therapeutic agent for viral myocarditis comprising as an active ingredient the compound shown in 3 or a pharmaceutically acceptable salt thereof.
背景技術 Background art
ウ ィ ル ス性心筋炎は重症に な る と 心不全を招来 し 、 死に 至 ら し め る こ と があ る病気であ る 。 従来か ら 、 各種の抗 ゥ ィ ル ス 剤、 免疫亢進剤等が ウ ィ ル ス性心筋 炎 に有効か ど う か試み られて き て い るが、 現在 こ れに有効な薬剤は知 られ て レゝ な レゝ 。 Viral myocarditis is a disease that, when severe, can lead to heart failure and even death. Conventionally, various antiviral and immunopotentiating agents have been tried to determine whether they are effective against viral myocarditis, but at present, effective drugs are known. It's a lazy lady.
二 の発明者は 、 ゥ ィ ル ス性心筋炎 に有効な薬剤の出現が 望 ま れ て い る 状況下 で銳意研究の結果、 ウ ィ ル ス感染症用 薬剤 と し て知 られて い る （ 特開昭 60— 1 04019号公報参照 ） 下記式 （ I 〉 で示さ れ る 化合物が、 ウ ィ ル ス性心筋炎の予
防 、 治療剤と し て有効であ る と い う 新知見を得、 さ ら に研 究 を 進めた結果、 こ の癸明 を完成 し た。 The second inventor has been known as a drug for viral infectious disease as a result of an independent study in a situation in which the emergence of an effective drug for viral myocarditis is desired. (See Japanese Patent Application Laid-Open No. 60-104019) A compound represented by the following formula (I) is expected to be a predictor of viral myocarditis. We have obtained new knowledge that it is effective as a preventive and therapeutic agent, and as a result of further research, we have completed this process.
癸 明 の 開示 Disclosure of Akira Kishi
こ の発 明 の ウ ィ ル ス 性心筋炎の予防、 治療剤は 、 次 式 ( I 〉で示さ れる化合物または医薬 と し て許容さ れる その塩 を有効成分 と する も のであ る 。 The agent for preventing or treating viral myocarditis according to the present invention comprises, as an active ingredient, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
CHQ C CH9 ) _ COHNCHCOOH CH Q C CH 9 ) _ COHNCHCOOH
( CH2 ) 2 CH. (CH 2 ) 2 CH.
COHNCHCOHNCHCOOH 2 COHNCHCOHNCHCOOH 2
H ft NCHCOOH H ft NCHCOOH
2 Two
C O C O
こ の発明の ウ ィ ル ス性心筋炎の予防、 治療剤は、 人およ び動物の各種の ゥ ィ ル ス性心筋炎の予防および治療のため に使用す る こ と がで き る 。 The agent for preventing and treating viral myocarditis according to the present invention can be used for preventing and treating various types of viral myocarditis in humans and animals.
こ の発明で有効成分 と し て使用す る化合物（ I )の医薬 と し て 許容さ れる塩 と して は、 例え ばナ ト リ ウ ム塩、 力 リ ウ ム 塩 、 カ ル シ ウ ム塩、 ア ン モ ニ ゥ ム塩ゝ エ タ ノ ール ァ ミ ン 塩 ， ト リ ェ チ ル ァ ミ ン塩、 ジ シ ク ロ へ キ シ ル ァ ミ ン塩等の 有機 ま た は無機塩、 醉酸塩、 ト リ フ ル ォ ロ 酢酸塩、 乳酸 塩 、 マ レ イ ン酸塩、 フ マ ル酸塩、 酒石酸塩、 く えん酸塩、 メ タ ン ス ル ホ ン酸塩、 塩酸塩、 硫酸塩、 硝酸塩、 り ん酸塩
等 の有機酸ま たは無機酸 と の酸付加塩が挙げ られる 。 Pharmaceutically acceptable salts of compound (I) used as an active ingredient in the present invention include, for example, sodium salt, potassium salt, calcium salt and the like. Organic or inorganic salts such as salt, ammonia salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, etc. , Lactate, trifluoroacetate, lactate, maleate, fumarate, tartrate, citrate, methansulfonate, hydrochloride , Sulfate, nitrate, phosphate And acid addition salts with organic acids or inorganic acids.
化合物（ I )に は そ の分子中の不斉炭素原子に よ る 1 ま た は 2 以上の立体異性体が含まれ、 こ れ ら化合物 も 全て こ の 発 明 の有効成分 と し て使用で き る 。 Compound (I) contains one or more stereoisomers depending on the asymmetric carbon atom in the molecule, and all of these compounds can be used as the active ingredient of the present invention. Wear .
こ の発明で有効成分 と し て使用さ れる化合物（ I )お よ び 医薬 と し て許容さ れ る そ の塩の う ち 、 代表的な化合物を挙 げ る と 次の と お り であ る 。 Among the compound (I) used as an active ingredient in the present invention and its pharmaceutically acceptable salts, typical compounds are as follows. .
化合物 A ： Compound A:
CD) CD)
CH。 CH0 ) _ COHNCHCOOH CH. CH 0 ) _ COHNCHCOOH
COHNCHCOHNCHCOOH CD) (COHNCHCOHNCHCOOH CD)
(CH 2)3 (CH 2) 3
NCHCOOH NCHCOOH
2CD) 2CD)
こ の発明で有効成分 と し て使用さ れ る化合物（ I )お よ び 医薬 と し て許容さ れ る そ の塩は急性期心筋炎 に おけ る 心筋 障害 を 軽減 し 、 生存率の顕著な改善を認め、 ウ ィ ル ス性心 筋 炎 C 代表的 な 心筋 炎起因 ウ ィ ル ス と し て 、 例 え ば コ ク サ ッ キ ー ウ ィ ル ス 、 エ コ ー ウ ィ ル ス等のェ ン テ ロ ウ ィ ル ス が挙 げ られる ） の予防、 治療剤 と し て有用であ る 。 The compound (I) used as an active ingredient in the present invention and a pharmaceutically acceptable salt thereof reduce myocardial damage in acute myocarditis and have a remarkable survival rate. Improvement was observed, and viral myocarditis C is a typical virus caused by myocarditis, for example, coxsackie virus, ecovirus, etc. Enterovirus)) as a preventive and therapeutic agent.
次 に こ の発明の効果を試験例に よ り 説明す る 。
試験例 1 ( 化合物 A投与マ ウ ス腹腔細胞及び胖細胞に よ る 抗脳心筋炎 ウ ィ ル ス活性 ） Next, the effects of the present invention will be described with reference to test examples. Test Example 1 (Anti-encephalomyocarditis virus activity by compound A-administered mouse peritoneal cells and mast cells)
[ 方法 ] [ Method ]
マ ウ ス ： BalbZc系、 雄、 5 週齢、 一群 10匹 （ リ ン酸锾 衝生理食塩水投与群は 30匹 ) Mouse: BalbZc, male, 5 weeks old, 10 mice per group (30 mice in phosphate-administered saline administration group)
化合物 A投与 ： 1 、 0.01mg/kg, 1 日 1 回 3 日 間腹腔内 投与 Compound A administration: 1, 0.01 mg / kg, once a day for 3 days intraperitoneally
腹腔細胞 ： 脱血死マ ウ ス の HBSS ( 3 ml ) に よ る腹腔内洗 液よ り 遠心に よ り 採取 Peritoneal cells: Collected by centrifugation from the peritoneal lavage fluid of HBSS (3 ml) of the exsanguinated mouse
脾細胞 ： 脱血死マ ウ ス の脾臓を ガ ラ ス ホ モ ジナ イ ザーで 泼 し 、 金属 メ ッ シ ュ で濂過後、 0.85% NH4C1で 溶血、 HBSSで洗浄 し 、 実験に用いた。 実験系 ： BalbZc 3T3細胞（10%ゥ シ胎児血清含有 MEM培 地）の単眉 に脳心筋炎（encephalomyocarditis ) ( EMC ) ウ ィ ル ス を HOI 1 で 1 時間感染さ せ た 後、 腹腔細胞又は脾細胞を加え、 0.5%ゥ シ 胎 児血清含有 MEM培地中で 16時間培養 し た。 凍 結 融解を 2 回繰 り 返 し て細胞を破壊後、 上清中の ゥ ィ ル ス量を FL細胞を用いてプ ラ ー ク 法に よ り 測定 し た。
[ 結果 ] ノ ウィルス 5： ウィルス fi i^f直 エフヱクタ-細胞 EZI ratio {pfxi/ ml ) Mean ± SD (log) Splenocytes: The spleen of the exsanguinated mouse was washed with a glass homogenizer, filtered with a metal mesh, lysed with 0.85% NH 4 C1, washed with HBSS, and used for experiments. . Experimental system: A single eyebrow of BalbZc 3T3 cells (MEM medium containing 10% fetal serum) was infected with encephalomyocarditis (EMC) virus for 1 hour with HOI 1 and then peritoneal cells or Splenocytes were added, and the cells were cultured for 16 hours in a MEM medium containing 0.5% 血清 fetal serum. After freezing and thawing were repeated twice to destroy the cells, the amount of virus in the supernatant was measured by the plaque method using FL cells. [Results] Rhinovirus 5: Virus fi i ^ f direct effector-cell EZI ratio (pfxi / ml) Mean ± SD (log)
2.8 10' 2.8 10 '
3.7 X 107 7.47 土 0.08 2. 4 X 107 3.7 X 10 7 7.47 Sat 0.08 2.4 X 10 7
4.2 X 10 4.2 X 10
PBS一 PEC 10 4.0 X 106 6.70 土 0.02 * PBS-PEC 10 4.0 X 10 6 6.70 Sat 0.02 *
3.7 X 106
3.7 X 10 6
0. Olmg/ kg— PEC 10 1.7 10 ,6" 6.14 0.17 *,# 0. Olmg / kg—PEC 10 1.7 10, 6 "6.14 0.17 *, #
2.0 X 106 2.0 X 10 6
2.3 X 10' 2.3 X 10 '
ragZ kg一 PEC 10 2.1 X 101 6.36 0.04 *'# ragZ kg per PEC 10 2.1 X 10 1 6.36 0.04 * '#
2.6 X 10 2.6 X 10
5.7 X 10" 5.7 X 10 "
PBS - SC 100 4.2 X 10! 5.65 0.08 PBS-SC 100 4.2 X 10 ! 5.65 0.08
3.8 10' 3.8 10 '
6.0 10' 6.0 10 '
0. Olmg/ kg— SC 100 2.0 X 10' 3.56 0.20 0. Olmg / kg— SC 100 2.0 X 10 '3.56 0.20
4.0 X 10'
4.0 X 10 '
1 mg/ kg一 SC 100 7.0 X 10 ,3" 4.05 0.14 1 mg / kg SC 100 7.0 X 10, 3 "4.05 0.14
1.4 X 104 1.4 X 10 4
EZ I ratio エ フ ェ ク タ ー ： 標的細胞比 PBS一 PEC リ ン酸緩衝生理食塩水投与マ ウ ス腹腔
細胞 EZ I ratio Effector: Target cell ratio Mouse peritoneal cavity with PBS-PEC phosphate buffered saline cell
0. Olmg/ kg- PEC： ィ匕合物 A 0. OlmgZ kg投与マ ウ ス腹腔細 胞 0. Olmg / kg-PEC: I-Drug A 0. OlmgZ kg-administered mouse peritoneal cells
1 mg/ kg- PEC 化合物 A 1 mg/ kg投与マ ウ ス腹腔細跑 PBS一 SC リ ン酸緩衝生理食塩水投与マ ウ ス脾細 胞 1 mg / kg- PEC Compound A Mouse 1 mg / kg administered mouse peritoneal cavity PBS-SC phosphate buffered saline administered mouse spleen cells
0. Olmg/ kg- SC 化合物 A 0. OlmgZkg投与マ ウ ス脾細跑 1 mg/ kg- SC 化合物 A 1 mg/ kg投与マ ウ ス脾細跑 * エ フ ェ ク タ ー細胞無添加と 比べ有意差あ り （ P < 0. 05 ) # 同一 EZ T ratioの PBS - PECあ る いは PBS - SCと 比べ有意 差あ り （ P く 0. 05 ) 0. Olmg / kg-SC compound A 0. OlmgZkg-administered mouse spleen 1 mg / kg-SC compound A 1 mg / kg-administered mouse spleen * Compared with no effector cells Significantly different (P <0.05) # Significantly different from PBS-PEC or PBS-SC with the same EZ T ratio (P <0.05)
試験例 2 ( 化合物 A投与マ ウ ス腹腔細胞及び脾細胞に よ る 抗コ ク サ ツ キ一 B 3 ウ ィ ル ス活性 ；） Test Example 2 (Anti-coccalus B3 virus activity by mouse peritoneal cells and splenocytes administered with Compound A)
[ 方法 ] [ Method ]
マ ウ ス ： C3HZ He系、 雄、 8 週齢、 一群 10匹 （ リ ン酸耰 衝生理食塩水投与群は 30匹 ） Mouse: C3HZ He strain, male, 8 weeks old, 10 mice per group (30 mice in phosphate-administered saline administration group)
化合物 A投与 ： 1 、 0. 01mg/ kg, 1 日 1 回 3 日 間腹腔内 投与 Compound A administration: 1, 0.01 mg / kg, intraperitoneally once a day for 3 days
腹腔細胞 ： 脱血死マ ウ ス の HBSS ( 3 ml ) に よ る腹腔内洗 液よ り 遠心に よ り 採取 Peritoneal cells: Collected by centrifugation from the peritoneal lavage fluid of HBSS (3 ml) of the exsanguinated mouse
脾細胞 脱血死マ ウ ス の脾臓 を ガ ラ ス ホ モ ジ ナ イ ザーで 潰 し 、 金属 メ ッ シ ュ で濂過後、 0. 85% NH4C1で 溶血、 HBSSで洗浄 し 、 実験に用いた。 実験系 C3HZ Heマ ゥ ス胎児由来繊維芽細胞 （ 10% ゥ シ 胎児血清含有 MEM培地 ：） の単層に コ ク サ ツ キ一
B 3 ウ ィ ル ス を MOI 1 で 1 時間慼染さ せた後、 腹腔細胞又は脾細胞 を加え 、 0.5% ゥ シ胎児 血 清含有 MEM培地中で 16時間培養 し た。 凍結融 解 を 2 回繰 り 返 し て細胞を破壊後、 上清中の ウ イ ル ス量を FL細胞を用いてプ ラ ー ク 法に よ り 測定 し た。 Spleen cells Depleted The spleen of the mouse was crushed with a glass homogenizer, filtered with a metal mesh, lysed with 0.85% NH 4 C1, washed with HBSS, and used for experiments. Using. Experimental system C3HZ He-mass fetal fibroblasts (MEM medium containing 10% fetal serum :) After infecting B3 virus with MOI 1 for 1 hour, peritoneal cells or spleen cells were added, and the cells were cultured for 16 hours in a MEM medium containing 0.5% fetal fetus serum. After freeze-thawing was repeated twice to destroy the cells, the amount of virus in the supernatant was measured by the plaque method using FL cells.
[ 結果 ] ウィルス: fi ウィルス：！： [Results] Virus: fi Virus :! :
エフヱクタ一 E/T ratio Effector E / T ratio
(pfu/ml) Mean 土 SD ( log) (pfu / ml) Mean Sat SD (log)
1.8 X 10 1.8 X 10
1.7 X 10' 7.26 土 0.03 2.0 X 10' 1.7 X 10 '7.26 Sat 0.03 2.0 X 10'
8. 0 10 8. 0 10
8. 9 X 10 6.91 0, 03 7.4 10 8.9 X 10 6.91 0, 03 7.4 10
PBS一 PEC PBS-PEC
8. 4 10 8. 4 10
10 6.8 X 10 6. 85 ± 0. 05 10 6.8 X 10 6.85 ± 0.05
6.2 X 10 6.2 X 10
5.6 X 10" 5.6 X 10 "
木， # 7.3 X 101 6. 82 0. 05 Thu, # 7.3 X 10 1 6.82 0.05
6 6
6.9 X 10 6.9 X 10
0. Olmg/ kg - PEC 0. Olmg / kg-PEC
1. 5 X 10 1.5 X 10
氺 ， # 氺, #
10 3.2 X 10 6. 45 0. 20 10 3.2 X 10 6.45 0.20
4. 5 X 10
ゥィルス g: ウィルス量平均値 エフ iクタ一 / I ratio 4.5 x 10 Virus g: Average virus load F / I ratio
( f u/ ml ) Mean SD ( log) (fu / ml) Mean SD (log)
6. 6 X 10 6.6 X 10
8.2 X 10' 6. 85 0. 04 8.2 X 10 '6.85 0.04
6. 8 10' 6. 8 10 '
mg/ kg - PEC mg / kg-PEC
3. 1 X 10' 3.1 1 X 10 '
10 4. 0 X 10' 6. 57 0. 06 10 4.0 X 10 '6.57 0.0.06
4. 2 X 10' 4.2 X 10 '
6 6
4. 9 X 10 4. 9 X 10
,6 * , 6 *
50 5. 1 10" 6. 68 0. 03 50 5.1 1 "6.68 0. 03
4. 4 X 106 4.4 x 10 6
PBS一 SC PBS-SC
7. 5 X 10 7.5 x 10
水 water
100 5. 3 X 10 6. 78 0. 07 100 5.3 X 10 6.78 0.07
5. 4 X 10 5.4 x 10
5. 9 X 10° 5. 9 X 10 °
50 3. 9 106 6. 68 士 0. 07 50 3.9 10 6 6.68
4. 8 X 10 4.8 x 10
. Olmg/ kg - SC . Olmg / kg-SC
2. 0 X 10 2.0 X 10
100 2. 9 X 10 6. 40 0.07 100 2.9 X 10 6.40 0.07
2. 8 10 2. 8 10
5. 0 X 10 5.0 X 10
50 4. X 10 6. 65 土 0. 04 * 50 4.X 10 6.65 Sat 0.04 *
4. 3 X 10 4.3 X 10
mg/ kg一 SC mg / kg-SC
1. 9 X 10 1. 9 X 10
100 1. 9 X 10 6. 17 土 0. 16
E/ I ratios PBS- PEC, 0. Olmg/ kg - PEC, 1 mg/ kg- 100 1.9 X 10 6.17 Sat 0.16 E / I ratio s PBS- PEC, 0. Olmg / kg-PEC, 1 mg / kg-
PE PBS - SC、 0. Olmg/ kg - SCお よ び 1 mgZ kg - SCは そ れ ぞれ試験例 1 と 同 じ 意味 PE PBS-SC, 0.1 Olmg / kg-SC and 1 mgZ kg-SC have the same meanings as in Test Example 1.
* エ フ ；! ク タ一細胞無添加 と 比べ有意差あ り （ P < 0. 05 ) # 同一 EZ T ratioの PBS— PECあ る い は PBS— SCと 比べ有 意 差あ り （ P く 0. 05 ) 試験例 3 ( コ ク サ ツ キ一 B 3 ウ ィ ル ス に よ る マ ウ ス心筋炎 に対す る化合物 A の治療効果 ） * F;! Significantly different from that without the addition of single cells (P <0.05) # Significantly different from PBS-PEC or PBS-SC with the same EZ T ratio (P 0.05) Test Example 3 (Therapeutic effect of compound A on mouse myocarditis caused by coxsackie B3 virus)
C 3 H系 3 週齢雄性マ ウ ス に 3 X 1 05 p f uの コ ク サ ツ キ一 B 3 ウ ィ ル ス （CB3)を腹腔内接種 し た。 1 又は g/ kg/ dayの化合物 A の腹腔内投与を感染 日 よ り 開始 し た。 CB3の ウ ィ ル ス量定量は感染 3 日 後に行 っ た。 生存数及び心筋の 病理学的検討は感染 20日 後に行 っ た。 病理学的変化は 0 か ら 4 + に ス コ ア一化 し た。 化合物 例 生存数 ―心筋病理変化 む臓内 ウ ィ ル ス量 A ( g 数 （20日 後） 壊死 浸潤 （ 3 日 後， log1 Q 3 X 1 0 5 pfu co click service tools keys B 3 U I ls e a (CB3) were inoculated intraperitoneally with C 3 H system 3 Shuyowaiyuseima c scan. Intraperitoneal administration of compound A at 1 or g / kg / day was started on the day of infection. Quantitative virus determination of CB3 was performed 3 days after infection. Survival numbers and myocardial pathological examination were performed 20 days after infection. Pathological changes scored from 0 to 4+. Compound Example survival - myocardial pathological changes continuously populations in their gut U I ls e amount A (g number (20 days later) after necrosis infiltration (3 days, log 1 Q
/ kg ) pf u/mg ) 〉 / kg) pf u / mg)〉
1 20 6 3. 0土 0. 9 2. 7土 0. 8 3. 6土 0. 4 ( 9)1 20 63.0 Sat 0.9.2.7 Sat 0.8.3.6 Sat 0.4 (9)
10 20 12* 1. 4士 0. 9* 1. 3士 0. 7* 3. 2土 0. 4* ( 10) 対照 20 6 3. 0土 0. 6 2. 5土 0. 5 3. 7土 0. 4 ( 10) 10 20 12 * 1. 4 people 0.9 * 1. 3 people 0.7 * 3. 2 Sat 0.4 * (10) Control 20 6 3.0 Sat 0.6 2.5 Sat 0.5 3. 7 Sat 0.4 (10)
* p < 0. 05 * p <0.05
10 U g/ kgの化合物 A は 、 マ ウ ス CB3心筋炎モ デル に おい て 感染 と 同時に投与を 開始す る と 、 心筋内の ウ ィ ル ス増殖 の抑制、 炎症反応及び心筋障害の減少及び生存率の増加を も た ら し た 。
試験例 4 When 10 U g / kg of Compound A is administered simultaneously with infection in a mouse CB3 myocarditis model, it inhibits viral growth in the myocardium, reduces inflammatory response and myocardial damage, There was an increase in survival. Test example 4
( 1 ) 方法 (1) Method
4 週齢の Balb/cマゥ ス に脳心筋炎 (encephalomyocarditis) C EMC；) ウ ィ ル ス 100 plaquef orming units ( pf u；) を腹腔 内 に接種 した。 実験 1 と して、 化合物 A を 0.01mg/kg ( グ ル ー プ 1, η = 10 ) , 1 mg/ lsg ( グル ー プ 2, ιι-10 ) ウ イ ル ス接種前日 よ り 腹腔内投与 し 、 グル ー プ 3 ( 1 mg/ kg, n= 10 ) で は ウ ィ ル ス接種当 日 よ り 投与 し た。 対照群 （ n = 9 ) は燐酸緩衝液を投与 した。 化合物 Aは 4 日 間連日投与後中 止 し 、 その 4 B後 （ ウ ィ ル ス接種 8 日後 ：） 屠殺 して心筋内 ウ ィ ル ス量測定、 病理組蛾学的検索を行った。 また、 実験 2 と し て生存率比較の為、 化合物 Aを 0. Olmg/ kg グルー ブ 5，η = 10 ) , 1 mgZlsg ( グループ 6 , n=l 0 ) で ウ ィ ル ス接 種前日 よ り 、 l mgZkg ( グループ 7， n-10 ) で ウ ィ ル ス 接 種当 日 よ り 14日 間連日投与 し 、 接種 14日後の生存率を対照 群グループ 8 C n=10 ) と 比較 した。 Four week old Balb / c mice were intraperitoneally inoculated with 100 plaquef orming units (pfu;) of encephalomyocarditis C EMC;) virus. In Experiment 1, Compound A was administered intraperitoneally 0.01 mg / kg (group 1, η = 10), 1 mg / lsg (group 2, ιι-10) from the day before virus inoculation Group 3 (1 mg / kg, n = 10) was administered on the day of virus inoculation. The control group (n = 9) received phosphate buffer. Compound A was discontinued after daily administration for 4 days. After 4B (8 days after virus inoculation), the animals were sacrificed, and the amount of virus in the myocardium was measured, and a histopathological search was performed. In order to compare the survival rates in Experiment 2, Compound A was treated with 0.1 Olmg / kg group 5, η = 10) and 1 mg Zlsg (group 6, n = l 0) on the day before virus inoculation. In addition, lmgZkg (group 7, n-10) was administered daily for 14 days from the day of virus inoculation, and the survival rate 14 days after inoculation was compared with that in the control group (8C n = 10).
C 2 ) 結果 C 2) Result
1)実験 1 ： ウ ィ ル ス接種 8 日 後の心筋内 ウ ィ ル ス 量 1) Experiment 1: Myocardial viral load 8 days after virus inoculation
log10pf uZ mg ) log 10 pf uZ mg)
グ レーブ mg Grave mg
1 2.68 0.35 1 2.68 0.35
2 2.77 0.17 2 2.77 0.17
3 2.46 0.35 3 2.46 0.35
対照 3.33 0.26 Control 3.33 0.26
いずれも対照に比 し有意に （ P く 0.025 ) 減少 し た
組幟学的検索で は グ ループ 2 に お い て 細胞浸潤 （ P < 0 . 05 ) 、 心筋細胞壊死 （ P < 0 . 0 25 ) が対照に 比 し 有意 に 軽減 し た。 All were significantly (P <0.025) decreased compared to the control In a group-based search, cell infiltration (P <0.05) and cardiomyocyte necrosis (P <0.025) were significantly reduced in Group 2 compared to controls.
2 )実験 2 ： 接種 1 4日 後の生存率 2) Experiment 2: Survival rate 14 days after inoculation
グループ 生存率 （ ％ ) Group survival rate (%)
5 80 5 80
6 70 6 70
7 60 7 60
対照 20 Control 20
い ずれも対照に比 し 有意に高値であ っ た （ P < 0. 01 ) こ の発 明 の ウ ィ ル ス 性心筋炎の予防、 治療剤は 、 例 え ば 、 こ の発明の有効物質 を経 口 または非経 口投与に適 し た 有機 も し く は無機担体も し く は賦形剤 と 混合 し て含有す る 固体状、 半固体状または液体状の製剤の形で使用す る こ と がで き る 。 有効成分は 、 例え ば、 錠剤、 ペ レ ツ ト 、 カ ブセ ル 、 坐剤、 溶液、 ェマ ル ジ ヨ ン 、 懸濁液お よ び通常無毒で 医薬 と し て許容さ れ る担体 と 混合 し て適当な剤形に し て使 用さ れ る 。 こ こ で担体 と し て は 水、 ぶ ど う 糖、 乳糖、 ァ ラ ビ ァ ゴ ム 、 ゼ ラ チ ン 、 マ ン ニ ト ー ル 、 で ん粉ペー ス ト 、 マ グ ネ シ ゥ ム ト リ シ リ ケー ト 、 タ ル ク 、 メ チ ル セ ル ロ ー ス 、 ポ リ エ チ レ ン グ リ コ ー ル 、 と う も ろ こ し で ん粉、 ケ ラ チ ン 、 ロ イ ド シ リ カ 、 馬銓塞でん粉、 尿素お よ び固体状、 半固体状、 ま たは液体状の製剤を製造す る際使用に適 し た 他の担体であ り 、 さ ら に また補助剤、 安定化剤、 濃稠化剤 お よ び着色剤な らびに香料を使用 し て も よ い。 こ の ウ ィ ル
ス 性心筋炎の予防、 治療剤は また、 所望の製剤中の有劾成 分の活性を安定に維持するために保存剤または静菌剤を含 ませ る こ と もでき る。 こ のウ ィ ル ス性心筋炎の予防、 治療 剤中 に含有さ れる有効成分の量は、 予防または疾患の過程 と 状態に対 し て所望の治療効果を発揮するのに充分な量で あ る 。 Both were significantly higher than the control (P <0.01). The prophylactic and therapeutic agents for viral myocarditis of the present invention are, for example, the active substances of the present invention. In a solid, semi-solid, or liquid formulation containing the compound in an organic or inorganic carrier or excipient suitable for parenteral or parenteral administration be able to . The active ingredient may be, for example, a tablet, pellet, capsule, suppository, suppository, solution, emulsion, suspension, and usually a non-toxic pharmaceutically acceptable carrier. It is used by mixing to form an appropriate dosage form. Here, the carriers include water, glucose, lactose, arabia gum, gelatin, mannitol, starch paste, and magnesium paste. Resilicate, talc, methylcellulose, polyethylene glycol, corn starch, keratin, roydoshi Rica, Magnus starch, urea and other carriers suitable for the preparation of solid, semi-solid or liquid preparations, as well as auxiliary substances, Stabilizers, thickeners, coloring agents and fragrances may be used. This Will The preventive or therapeutic agent for myocardial myocarditis may also contain a preservative or a bacteriostat to stably maintain the activity of the impeached component in the desired preparation. The amount of the active ingredient contained in the agent for preventing or treating viral myocarditis is an amount sufficient to exert the desired therapeutic effect on the prophylaxis or disease process and condition. .
こ の ウ ィ ル ス性心筋炎の予防、 治療剤を人に適用する場 合、 静脈内注射、 皮下注射、 筋肉内注射または経口投与等 の ¾法で投与する こ と が望ま し い。 こ の発明の有効成分、 化合物（ I )または医薬と し て許容される塩の投与量は、 処 置すベ き 個 々 の患者それぞれの年齢および疾病の程度等の 条件に よ って変化するが、 人に対 して一般的には有効成分 1 日投与量約 0. 01〜 l OmgZ l gが予防または治療のために投 与さ れ る。 When this prophylactic / therapeutic agent for viral myocarditis is applied to humans, it is desirable to administer it by a method such as intravenous injection, subcutaneous injection, intramuscular injection or oral administration. The dose of the active ingredient, compound (I) or a pharmaceutically acceptable salt of the present invention varies depending on the conditions such as the age of each individual patient to be treated and the degree of illness. However, humans generally receive a daily dose of about 0.01 to 10 mg of active ingredient for prophylactic or therapeutic purposes.
次に こ の発明の実施例を示す。 Next, examples of the present invention will be described.
実施例 1 Example 1
( 錠剤 ） (Tablets)
化合物 A 200mg Compound A 200mg
マ ン ニ ト ー ル 400mg Mannitol 400mg
ス ア リ ン酸マ グ ネ シ ウ ム 1 Omg Sulfonic acid magnesium 1 Omg
で ん粉 5 Omg Starch 5 Omg
上記を常法に よ り 製剤 し 、 錠剤と す る。
実施例 2 The above is formulated in a conventional manner to give tablets. Example 2
cカ ブセ ル剤 ） c Case)
化合物 A 300mg Compound A 300mg
ス テ ア リ ン酸 マ グ ネ シ ウ ム 15mg Magnesium stearate 15mg
上記 を常法に よ り 製剤 し カ プ セ ル剤 と す る 。 The above is formulated in a conventional manner to make a capsule.
実施例 3 ( 注射剤 ） Example 3 (injection)
化合物 A lOOmgを含有す る よ う に バ イ ア ル に無菌的 に 分 配 し 、 密封 し て水分及びバ ク テ リ ア を除去す る 。 使用前に リ ド カ イ ン 0, 5%注射液 2 mlを添加 し て注射剤 と す る 。
The vial is aseptically dispensed to contain the compound AlOOmg and sealed to remove water and bacterium. Before use, add 2 ml of 0,5% lidocaine injection to make an injection.
Claims
(1) 式 (1 set
CH C CH ) _ CONHCHCOOH CH C CH) _ CONHCHCOOH
(C 2 ?H3 (C 2 ? H 3
COHNCHCOHNCHCOOH COHNCHCOHNCHCOOH
青 Blue
CH2^3 C H 2 ^ 3
H.NCHCOOH H.NCHCOOH
2 の で示さ れる化合物または医薬 と し て許容される その塩を有 囲 The compound represented by 2 or a pharmaceutically acceptable salt thereof is enclosed.
効成分 と する ウ イ ル ス性心筋炎の予防、 治療剤。 Prevention and treatment of viral myocarditis as an active ingredient.
(2) 式 Equation (2)
CH。（ CHn ) _ CONHCHCOOH CH. (CH n) _ CONHCHCOOH
a 5 a 5
(C 2 (C 2
COHNCHCOHNCHCOOH COHNCHCOHNCHCOOH
(CH 2 ( CH 2
Hr CHCOOH H r CHCOOH
で示さ れる化合物または医薬 と し て許容さ れる その塩を ゥ ィ ル ス 性心筋炎患者に投与す る こ と を特徴 と す る ゥ ィ ル ス 性心筋 炎の治療法。
A method for treating dilated myocarditis, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof to a patient with dilated myocarditis.
3) ウ ィ ル ス性心筋炎の予防、 治療剤を製造す る ための式 3) Formula for manufacturing a prophylactic and / or therapeutic agent for viral myocarditis
CH。（ CHfl ) _ CONHCHCOOH CH. (CH fl ) _ CONHCHCOOH
(CV2 CH, (C V 2 CH,
COHNCHCOHNCHCOOH 2)3 COHNCHCOHNCHCOOH 2) 3
H2NCHCOOH H 2 NCHCOOH
で示さ れ る化合物ま たは医薬 と し て許容さ れ る そ の塩の用 途。 The use of the compound or a pharmaceutically acceptable salt thereof represented by.
(4) 化合物が式 (4) the compound has the formula
CH CH
CD) CD)
(CIV3 ( CI V 3
NCHCOOH NCHCOOH
2CD) 2CD)
で示 さ れ る化合物であ る請求の範囲第 1 項記載の予防、 治 療剤。
( 5》 化合物が式 The preventive or therapeutic agent according to claim 1, which is a compound represented by the formula: (5) The compound has the formula
CD) CD)
CH ( CH ) COHNCHCOOH CH (CH) COHNCHCOOH
I CD) I CD)
Hゥ NCHCOOH H ゥ NCHCOOH
"CD) "CD)
で示さ れる化合物であ る請求の範囲第 2 項記載の治療法 (6) 化合物が式 4. The method of claim 2, wherein the compound is a compound represented by the formula:
CD) CD)
CHff CHn)_ COHN H
CH ff CH n ) _ COHN H
COHNCHCOHNCHCOOH I CD) (COHNCHCOHNCHCOOH I CD)
(CH2)3 (CH 2 ) 3
H NCHCOOH H NCHCOOH
2CD) 2CD)
示さ れる化合物であ る請求の範囲第 3 項記載の用途
The use according to claim 3 which is the indicated compound
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9834691 | 1991-01-30 | ||
| JP3/98346 | 1991-01-30 | ||
| JP25408991 | 1991-06-27 | ||
| JP3/254089 | 1991-06-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992013544A1 true WO1992013544A1 (en) | 1992-08-20 |
Family
ID=26439535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1992/000069 WO1992013544A1 (en) | 1991-01-30 | 1992-01-28 | Agent for preventing and treating viral myocarditis |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1992013544A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0488041A2 (en) * | 1990-11-26 | 1992-06-03 | Fujisawa Pharmaceutical Co., Ltd. | A pharmaceutical composition for cytomegalovirus infection |
| CN104258297A (en) * | 2014-10-15 | 2015-01-07 | 鲁翠花 | Traditional Chinese medicine for treating qi stagnation and blood stasis type viral myocarditis and preparation method of traditional Chinese medicine |
| CN111514237A (en) * | 2020-05-29 | 2020-08-11 | 中国人民解放军陆军第八十二集团军医院 | Traditional Chinese medicine composition for treating viral myocarditis and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60104019A (en) * | 1983-11-10 | 1985-06-08 | Fujisawa Pharmaceut Co Ltd | Drug for viral disease |
| JPH02288894A (en) * | 1979-10-11 | 1990-11-28 | Fujisawa Pharmaceut Co Ltd | New peptide, salt of same peptide allowable as drug and production thereof |
-
1992
- 1992-01-28 WO PCT/JP1992/000069 patent/WO1992013544A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02288894A (en) * | 1979-10-11 | 1990-11-28 | Fujisawa Pharmaceut Co Ltd | New peptide, salt of same peptide allowable as drug and production thereof |
| JPS60104019A (en) * | 1983-11-10 | 1985-06-08 | Fujisawa Pharmaceut Co Ltd | Drug for viral disease |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0488041A2 (en) * | 1990-11-26 | 1992-06-03 | Fujisawa Pharmaceutical Co., Ltd. | A pharmaceutical composition for cytomegalovirus infection |
| EP0488041A3 (en) * | 1990-11-26 | 1993-04-14 | Fujisawa Pharmaceutical Co., Ltd. | A pharmaceutical composition for cytomegalovirus infection |
| CN104258297A (en) * | 2014-10-15 | 2015-01-07 | 鲁翠花 | Traditional Chinese medicine for treating qi stagnation and blood stasis type viral myocarditis and preparation method of traditional Chinese medicine |
| CN111514237A (en) * | 2020-05-29 | 2020-08-11 | 中国人民解放军陆军第八十二集团军医院 | Traditional Chinese medicine composition for treating viral myocarditis and preparation method thereof |
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