WO1994005290A1 - Inhibiteur d'agregation plaquettaire - Google Patents

Inhibiteur d'agregation plaquettaire Download PDF

Info

Publication number
WO1994005290A1
WO1994005290A1 PCT/JP1993/001209 JP9301209W WO9405290A1 WO 1994005290 A1 WO1994005290 A1 WO 1994005290A1 JP 9301209 W JP9301209 W JP 9301209W WO 9405290 A1 WO9405290 A1 WO 9405290A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
hydrogen atom
ethylene
formula
Prior art date
Application number
PCT/JP1993/001209
Other languages
English (en)
Japanese (ja)
Inventor
Minoru Seto
Tae Sato
Original Assignee
Asahi Kasei Kogyo Kabushiki Kaisha
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Asahi Kasei Kogyo Kabushiki Kaisha filed Critical Asahi Kasei Kogyo Kabushiki Kaisha
Publication of WO1994005290A1 publication Critical patent/WO1994005290A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • the present invention relates to a novel use of an isoquinoline sulfonamide derivative. More specifically, the present invention relates to a platelet aggregation inhibitor containing a specific isoquinoline sulfonamide derivative or an acid addition salt thereof as an active ingredient.
  • the platelet aggregation inhibitor of the present invention provides platelet aggregation induced by changes in basic substances (cells, intima, etc.) that constitute blood vessels (eg, blockage of blood vessels due to atherosclerosis, damage to blood vessels by vascular surgery).
  • the platelet aggregation inhibitor of the present invention can be used for ischemic symptoms such as ulceration of terminal tissues or cold sensation due to chronic arterial occlusion, thrombosis associated with vascular surgery and extracorporeal blood circulation, venous thrombosis, and terminal limbs. It is useful for prevention and treatment of thrombosis and pulmonary thromboembolism.
  • 11 isoquinoline Sulfonyl
  • i- (1-hydroxyl-5-isoquinolinosulfonyl) isoquinoline sulfonamide derivatives such as homopidazine provide vascular smooth muscle relaxing action, blood flow increasing action, and blood pressure lowering action. And it has been reported that it has a cerebral protective action, etc.
  • isoquinoline sulfonamide derivatives such as N— (2-guanidinoethyl) -15-isoquinoline sulfonamide have a vascular smooth muscle relaxing action and a blood flow increasing action.
  • isoquinoline sulfonamide derivatives such as N— (2-guanidinoethyl) -15-isoquinoline sulfonamide have a vascular smooth muscle relaxing action and a blood flow increasing action.
  • the present inventors have surprisingly discovered that a specific isoquinoline sulfone derivative has a platelet aggregation inhibitory activity, Due to its activity, it is caused by chronic arterial occlusion due to changes in basic substances (cells, intima, etc.) that constitute blood vessels (eg, occlusion of blood vessels due to atherosclerosis, or damage to blood vessels due to vascular surgery).
  • a specific isoquinoline sulfone derivative has a platelet aggregation inhibitory activity, Due to its activity, it is caused by chronic arterial occlusion due to changes in basic substances (cells, intima, etc.) that constitute blood vessels (eg, occlusion of blood vessels due to atherosclerosis, or damage to blood vessels due to vascular surgery).
  • the isoquinoline sulfone amide derivative is converted to cerebral heart blood. It is already known that it is effective for the prevention and treatment of vascular thrombosis. This is due to the vasodilator effect of the derivative, and as described above, the isoquinoline sulfone amide derivative is It is surprisingly surprising that it has platelet aggregation inhibitory activity and is effective in preventing and treating various diseases caused by changes in basic substances (cells, intima, etc.) that constitute blood vessels. It is to be done
  • an object of the present invention is to provide a novel platelet aggregation inhibitor which is clinically applicable and highly safe.
  • a platelet aggregation inhibitor comprising an effective amount of an isoquinoline sulfonamide derivative represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof.
  • R 1 represents a hydrogen atom, a chlorine atom or a hydroxyl group
  • R 1 is a hydrogen atom
  • A is an alkyl having 2 to 6 carbon atoms.
  • the alkylene group is unsubstituted or at least one hydrogen bonded to carbon is an alkyl, cinnamyl, phenyl or benzyl group having 1 to 10 carbon atoms.
  • R 2 is a hydrogen atom or a cycloalkyl group having 6 or less carbon atoms
  • R 3 is a hydrogen atom, a straight or branched alkyl group having 1 or 6 carbon atoms; group, cinnamyl group, full Eniru group or downy ⁇ in Njiru group Li
  • R 4 is a hydrogen atom, an alkyl group branches also is properly six linear 1 -C min, phenyl group benzyl group, Benzoiru group, thinner Mi Group, cinnamoyl group, floor group, formula
  • R 5 is a straight-chain or branched alkyl group having 1 to 6 carbon atoms
  • R 6 and R 7 are each independently a hydrogen atom or a methyl group, or R 6 and R 7 are directly bonded to each other to form an alkylene group having 2 or 4 carbon atoms.
  • Amidino group Alternatively, R 2 and R 3 are directly bonded to each other to form an alkylene group having 4 or less carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to carbon atom. It may be substituted with 1 to 10 alkyl groups, phenyl groups or benzoyl groups;
  • R 3 and R 4 are bonded directly or via an oxygen atom to form a 5- to 6-membered heterocyclic ring with an adjacent nitrogen atom;
  • R 1 is a chlorine atom or a hydroxyl group
  • A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to a carbon atom.
  • R 2 and R 3 are each independently a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a carbon atom having 1 to 6 carbon atoms, Represents a cycloalkyl group having a number of 6 or less, or R 2 and R 3 are directly bonded to each other to form an ethylene group or a trimethylene group, and these ethylene groups or In the trimethylene group, at least one hydrogen atom bonded to carbon may be substituted with 1 to 6 carbon atoms;
  • R 4 is a hydrogen atom, 1 to 6 carbon atoms.
  • An alkyl group of the formula (Wherein, R 6 and R 7 each independently represent a hydrogen atom or a methyl group).
  • an effective amount of an isoquinoline sulfone amide derivative represented by the formula (I) or an acid addition salt thereof is administered to a patient suffering from a myocardial disease and / or a myocardial cell disorder or a living body at risk thereof.
  • a method for treating or preventing a myocardial disease and / or a myocardial cell disorder which comprises administering.
  • R 1 is preferably a hydrogen atom or a hydroxyl group.
  • A is an ethylene group or a trimethylene group
  • R 2 and R 3 are directly bonded to each other, and when A is an ethylene group, a trimethylene group, A When is a trimethylene group, it forms an ethylene group, and .R 4 is preferably hydrogen.
  • R 1 is a hydroxyl group
  • A is an ethylene group or a trimethylene group
  • R 2 and R 3 are directly bonded to each other
  • A is an ethylene group
  • the trimethylene group is
  • A is a trimethylene group, it preferably forms an ethylene group
  • R 4 is preferably hydrogen.
  • the isoquinone sulfone amide derivative as an active ingredient of the platelet aggregation inhibitor of the present invention also includes an acid addition salt of the isoquinolin sulfone amide derivative represented by the formula (I).
  • These salts are pharmaceutically acceptable non-toxic salts, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid Salts of organic acids such as acid, fumaric acid, maleic acid and methansulphonic acid can be mentioned.
  • the method for producing the isoquinoline sulfonamide derivative represented by the formula (I) is not critical, and it can be produced by various methods.
  • Japanese Unexamined Patent Publication Nos. Sho 61-1526585 and Sho 61-227581 (corresponding US Pat. Nos. 4,678,783) and Sho 5 7 — 1 5 6 4 6 Publication, USP 4, 456, 757, Japanese Patent Application Laid-Open No. 57-200366, USP 4, 560, 755, Japanese Patent Application Japanese Patent Publication No. Sho 58-122 and Japanese Patent Laid-Open Publication No. Sho 58-121, 79, USP 4,525,589, Japanese Patent Publication No. 59-993504 And the methods disclosed in Japanese Patent Application Laid-Open No. 60-81116 (corresponding US Pat. Nos. 4,634,770) can be referred to.
  • 1- (5-isoquinolinylsulfonyl) homopyrazine represented by the formula (IV) can be converted into 5- (isoquinolinesulfonic acid chloride) represented by the formula (V) according to the following reaction formula.
  • the acid addition salt of an isoquinoline sulfonamide derivative can be easily produced by reacting the above-mentioned isoquinoline sulfonamide derivative product with an inorganic acid or an organic acid, and conversely.
  • the produced compound is originally an acid addition salt and the target compound is desired in the form of a free form, it can be easily converted to a free form by treating with an alcohol. You.
  • the isoquinoline sulfonine amide derivative represented by the formula (I) or an acid addition salt thereof, which is an active ingredient of the platelet aggregation inhibitor according to the present invention may be administered alone or may be pharmaceutically acceptable. May be administered as a composition with the carrier, diluent or excipient used.
  • the component ratio in the composition can be appropriately determined depending on the administration route, administration plan and the like.
  • isoquinoline sulfonamide derivative represented by the formula (I) may be used in combination with other drugs depending on the patient's symptoms.
  • the isoquinoline sulfone amide derivative represented by the formula (I) When the isoquinoline sulfone amide derivative represented by the formula (I) is orally administered, tablets, capsules, powders, granules, It can be used in the form of solutions, elixirs and the like, or, for parenteral administration, in the form of injections, suppositories, ointments or nasal drops.
  • Solid carriers used for oral administration include, for example, oligosaccharides such as lactose sucrose and mannitol; starches such as corn and potato crystalline cellulose, calcium phosphate, and synthetic calcium carbonate; Agent: sodium or calcium salt of carboxymethyl cellulose; fatty acid salt such as magnesium stearate; Agar, gum, sodium alginate; polyethylene dalicol.
  • capsules In the case of capsules, tablets, granules, and powders, they are formulated so as to generally contain 1 to 80% by weight, preferably 1 to 60% by weight of an isoquinoline sulfonamide derivative as an active ingredient. .
  • the oral administration is in liquid form, it is preferable to use a solution containing 0.11 to 20% by weight of the active ingredient and a syrup.
  • the carrier is water or ethanol.
  • the isoquinoline sulfonamide derivative represented by the formula (I) as an active ingredient is used to make the solution isotonic.
  • Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection), etc. Is mentioned.
  • these liquid for injection is normally 0.0 1-2 0% by weight, is preferred properly containing from 0.1 to 1 0 weight 0/0 Lee Sokino Li main routine Hon'a Mi de derivative as an active ingredient It is preferable to do so.
  • an isoquinoline sulfonamide derivative When administered as a suppository or ointment (transdermal), it is preferable to prepare a preparation containing 1 to 80% by weight of an isoquinoline sulfonamide derivative as an active ingredient.
  • an isoquinoline sulfonamide derivative examples include animal and plant fats and oils such as serine, paraffin, dense roast, lanolin, and cocoa butter; synthetic fats and oils such as macrogol and witetbuzole; emulsifiers; preservatives; Accelerators and the like can be added.
  • the active ingredient can be formulated with an emulsifier or other enhancer, along with the carriers used in the solutions described above.
  • the dosage of the isoquinoline sulfonamide derivative represented by the formula (I) is determined by the patient's age, health condition, weight, degree of symptoms, type of concurrent treatment, if any, treatment frequency, and desired treatment. Although it varies depending on the nature of the effect, it is generally 0.01 to 40 mg Z kg (body weight) ⁇ day. In particular, in the case of oral administration, a dose of 0.02 to 40 mg / kg (body weight) ⁇ day is preferred, and in the case of parenteral administration, 0.1 mg / kg (body weight) 'day is preferred. I like it. Also, the frequency of administration may be once or several times a day. It is. In the case of intravenous administration, an injection containing the isoquinolinosulfonyl derivative represented by the formula (I) can be administered, for example, for 30 to 60 minutes at a time.
  • the platelet aggregation inhibitor of the present invention can surely inhibit platelet aggregation as shown in the following Examples.
  • Example 1 Example 1
  • test compound was orally administered to 20 ddy mice (male, 5 weeks old) that had been fasted the previous day, and then allowed to stand for 15 minutes, followed by a platelet aggregation inducer, adenosine diphosphate (ADP).
  • ADP adenosine diphosphate
  • the solution (Note 1) was administered via the tail vein to induce acute pulmonary thromboembolism. Then, the number of deaths within 10 minutes after the administration of the ADP solution was observed, and the compound showing 50% suppression of the mortality of the control group (Note 2) was just observed. Concentration IC 5 of things. The value was determined. The results are shown in Table 2 Table 2
  • the concentration of the ADP solution and the dose were set.
  • compound (1) and compound (83) were found to significantly reduce the mortality in a mouse acute pulmonary thromboembolism model. It has been confirmed that the compound represented by the formula (I) is a useful drug for prevention and treatment of various diseases caused by platelet aggregation induced by changes in basic substances constituting blood vessels.
  • the platelet aggregation inhibitor of the present invention containing an effective amount of a specific isoquinoline sulfonamide derivative or an acid-added salt thereof is effective for the change of basic substances (cells, inner membrane, etc.) constituting blood vessels.
  • ischemic symptoms such as ulceration of terminal tissues or cold sensation due to chronic arterial occlusion, thrombosis associated with vascular surgery and extracorporeal blood circulation, venous thrombosis, It is useful for prevention and treatment of terminal limb thrombosis and pulmonary thromboembolism.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

On décrit un inhibiteur d'agrégation plaquettaire, ou un de ses sels, qui contient un dérivé d'isoquinolinesulfonamide représenté par la formule générale (I) où R1 représente H, Cl ou OH; A, R?2, R3 et R4¿ représentent chacun un substituant sélectionné en fonction de R1, A représentant C¿1?-C6 alkylène éventuellement remplacé par alkyle, cinnamyle, phényle ou benzyle, R?2 et R3¿ représentant chacun indépendamment H, C¿1?-C6 alkyle, C6 cycloalkyle ou cycloalkyle inférieur cynnamyle, phényle ou benzyle, ou bien R?2 et R3¿ pouvant se combiner pour représenter alkylène, et R4 représentant H, C¿1?-C6 alkyle, phényle, benzyle, benzoyle, cinnamyle, cinnamoyle, furoyle, (a) ou (b) ou bien R?4¿ pouvant se combiner avec R3 pour représenter une chaîne carbone où peut s'interposer un atome d'oxygène; R5 représente C¿1?-C6 alkyle; et R?6 et R7¿ sont choisis chacun en fonction de R1 pour représenter H ou CH¿3?, ou bien R?6 et R7¿ peuvent se combiner pour représenter C¿2?-C4 alkylène.
PCT/JP1993/001209 1992-09-03 1993-08-27 Inhibiteur d'agregation plaquettaire WO1994005290A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4235841A JPH0680569A (ja) 1992-09-03 1992-09-03 血小板凝集阻害剤
JP4/235841 1992-09-03

Publications (1)

Publication Number Publication Date
WO1994005290A1 true WO1994005290A1 (fr) 1994-03-17

Family

ID=16992065

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001209 WO1994005290A1 (fr) 1992-09-03 1993-08-27 Inhibiteur d'agregation plaquettaire

Country Status (2)

Country Link
JP (1) JPH0680569A (fr)
WO (1) WO1994005290A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089426A1 (fr) * 2002-04-19 2003-10-30 Asahi Kasei Pharma Corporation Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee
US7109208B2 (en) 2001-04-11 2006-09-19 Senju Pharmaceutical Co., Ltd. Visual function disorder improving agents
CN103864760A (zh) * 2014-03-10 2014-06-18 洪军 一种盐酸法舒地尔化合物
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2142065T3 (es) * 1995-07-03 2000-04-01 Asahi Chemical Ind Clorhidratos de 1-(5-isoquinoleinsulfonil)homopiperazina hidratado.
US5733904A (en) * 1996-04-10 1998-03-31 Asahi Kasei Kogyo Kabushiki Kaisha Method for prevention and treatment of viral infectious diseases for viral suppression
SI0956865T2 (sl) * 1996-08-12 2011-04-29 Mitsubishi Pharma Corp Zdravila, ki obsegajo inhibitor Rho-kinaze
EP1065200A4 (fr) * 1998-03-19 2003-01-02 Ajinomoto Kk Derives d'aminoisoquinoleine
AU4144400A (en) 1999-04-27 2000-11-10 Mitsubishi Pharma Corporation Preventives/remedies for liver diseases

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57156463A (en) * 1981-03-20 1982-09-27 Asahi Chem Ind Co Ltd Isoquinoline derivative
JPS61227581A (ja) * 1985-04-02 1986-10-09 Asahi Chem Ind Co Ltd 血管拡張剤
JPH0215067A (ja) * 1988-07-04 1990-01-18 Hokuriku Seiyaku Co Ltd イソキノリンスルホンアミド誘導体
JPH02256617A (ja) * 1989-03-30 1990-10-17 Asahi Chem Ind Co Ltd 脳細胞機能障害改善剤
JPH02273610A (ja) * 1989-04-17 1990-11-08 Chugai Pharmaceut Co Ltd 発毛促進剤
EP0457295A2 (fr) * 1990-05-16 1991-11-21 The Rockefeller University Utilisation d'un modulateur de la phosphorylation des protéines comme médicament dans le traitement de l'amyloidose associé à la maladie d'Alzheimer
JPH04264030A (ja) * 1991-02-19 1992-09-18 Asahi Chem Ind Co Ltd 抗喘息剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57156463A (en) * 1981-03-20 1982-09-27 Asahi Chem Ind Co Ltd Isoquinoline derivative
JPS61227581A (ja) * 1985-04-02 1986-10-09 Asahi Chem Ind Co Ltd 血管拡張剤
JPH0215067A (ja) * 1988-07-04 1990-01-18 Hokuriku Seiyaku Co Ltd イソキノリンスルホンアミド誘導体
JPH02256617A (ja) * 1989-03-30 1990-10-17 Asahi Chem Ind Co Ltd 脳細胞機能障害改善剤
JPH02273610A (ja) * 1989-04-17 1990-11-08 Chugai Pharmaceut Co Ltd 発毛促進剤
EP0457295A2 (fr) * 1990-05-16 1991-11-21 The Rockefeller University Utilisation d'un modulateur de la phosphorylation des protéines comme médicament dans le traitement de l'amyloidose associé à la maladie d'Alzheimer
JPH04264030A (ja) * 1991-02-19 1992-09-18 Asahi Chem Ind Co Ltd 抗喘息剤

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7109208B2 (en) 2001-04-11 2006-09-19 Senju Pharmaceutical Co., Ltd. Visual function disorder improving agents
US7696194B2 (en) 2001-04-11 2010-04-13 Senju Pharmaceutical Co., Ltd. Visual function disorder improving agents
WO2003089426A1 (fr) * 2002-04-19 2003-10-30 Asahi Kasei Pharma Corporation Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee
CN103864760A (zh) * 2014-03-10 2014-06-18 洪军 一种盐酸法舒地尔化合物
CN103864760B (zh) * 2014-03-10 2016-08-17 洪军 一种盐酸法舒地尔化合物
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10961200B2 (en) 2014-12-29 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US11247971B2 (en) 2014-12-29 2022-02-15 The Trustees Of The University Of Pennsylvania Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Also Published As

Publication number Publication date
JPH0680569A (ja) 1994-03-22

Similar Documents

Publication Publication Date Title
US4256751A (en) Tetrahydroisoquinoline derivatives
US4200640A (en) Nitric ester of N-(2-hydroxyethyl)nicotinamide and pharmaceutical use
JP2002537258A5 (fr)
US5747507A (en) Cardio-protective agent
US4416893A (en) Substituted 1,2,5-oxadiazole-2-oxides in human cardiovascular system disease
UA63032C2 (en) Drug for treating hypertension
JPH0469377A (ja) ジフェニルメチルピペラジン誘導体
WO1994005290A1 (fr) Inhibiteur d'agregation plaquettaire
JP3408546B2 (ja) 抗喘息剤
US4711893A (en) Use of hydroxyindole derivatives in lowering blood pressure
WO2000024397A1 (fr) Composition de medicament immunomodulateur
CA1088944A (fr) Procede d'obtention d'ester nitrique de n-(2- hydroxyethyl) nicotinamide
JPH07277979A (ja) 過粘性症候群治療または予防剤
JPH0812581A (ja) 虚血性心疾患治療剤
EP0342577B1 (fr) Utilisation des dérivés de dihydropyridine pour la prévention ou le traitement des maladies de la circulation cérébrale
US5747495A (en) Method for treating hypertension using pyrazolopyrimidine derivatives
JP4426654B2 (ja) 免疫調節用医薬組成物
JPH02129183A (ja) １−アニリノ−４−（１ｈ−イミダゾール−１−イル）フタラジン誘導体及びそれを有効成分とする血小板凝集抑制剤
JP2532918B2 (ja) グアニジノ安息香酸誘導体を有効成分として含有する抗動脈硬化剤
JP3247763B2 (ja) キサンチン誘導体からなる血液循環の中断による神経損傷の治療用医薬
JPH0138089B2 (fr)
JPH0647540B2 (ja) 虚血性心疾患・不整脈治療・予防剤
WO1996025932A1 (fr) Medicament preventif et curatif, pour la pneumonie interstitielle, les maladies inflammatoires intestinales ou l'epaississement des vaisseaux, contenant des composes de quinolizinone, des sels de ces composes ou des hydrates
US3721738A (en) Treatment and prophylaxis of thrombovascular diseases with 2-imidazolone derivatives
JP2955768B2 (ja) 新規なジアゾシン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA FI KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA