WO2002024654A1 - AMINOHETEROCYCLEN (FAKTOR Xa INHIBITOREN 14) - Google Patents
AMINOHETEROCYCLEN (FAKTOR Xa INHIBITOREN 14) Download PDFInfo
- Publication number
- WO2002024654A1 WO2002024654A1 PCT/EP2001/010786 EP0110786W WO0224654A1 WO 2002024654 A1 WO2002024654 A1 WO 2002024654A1 EP 0110786 W EP0110786 W EP 0110786W WO 0224654 A1 WO0224654 A1 WO 0224654A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- biphenyl
- amino
- isoquinolin
- yloxy
- amide
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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 invention relates to amino heterocycles of the general formula I,
- R 4 , R 5 independently of one another H, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hai, NR 6 COA, NR 6 COAr ' , NR 6 S0 2 A, NR 6 S0 2 Ar', COOR 6 , CON (R 6 ) 2 , CONR 6 Ar ', COR 7 , COAr', S (0) n A
- R b H A, [C (R 7 ) 2 ] n Ar 'or [C (R 7 ) 2 ] n Het R 7 H or AW CONR 6 C (R 6 ) 2 CONR 6 [C (R 6 ) 2 ] ⁇ -, -NR 6 C (R 6 ) 2 CONR 6 [C (R 6 ) 2 ], -, - [C (R 6 ) 2 ] m CONR 6 [C (R 6 ) 2 ] r or - OC (R 6 ) 2 CONR 6 [C (R 6 ) 2 ] r
- Ar unsubstituted or one, two or three times by A, Ar ', Het, OR 6 , N (R 6 ) 2 , N0 2 , CN, Hai, NR 6 COA, NR 6 COAr ' , NR 6 SO 2 A, NR 6 S0 2 Af, COOR 6 , CON (R 6 ) 2 , CONR 6 Ar ', COR 7 , COAr', SO 2 NR 6 S (0) n Ar 'or S (O) n A substituted phenyl or naphthyl
- radicals R 6 given in the above should, if they occur several times in a compound, be independent of one another and each 5 can assume each of the meanings given for R 6 .
- the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcoholates of these compounds. 0
- the human organism has a mechanism by means of which blood clots help to quickly close wounds.
- Blood clots form through a series of zymogen activations.
- the activated form of one factor catalyzes the activation of the next. Since this process is catalytic, even the smallest quantities of the triggering factor are enough to start the cascade.
- the large number of steps results in a large reinforcement, which ensures a quick response to the injury.
- Plasmatic coagulation after a tissue lesion can take place exogenously through the release of tissue thrombokinase.
- the corresponding reaction sequence is referred to as an extravascular system (extrinsic system) and takes place within seconds.
- Coagulation can also be triggered endogenously by platelet breakdown. This sequence of reactions, known as the intravascular system, occurs within minutes. Both systems lead to a final common sequence of steps that lead to the formation of a fibrin island. The intravascular and extravascular systems interact in vivo. Both are necessary for the blood to clot completely.
- Factor X a is a serine protease of the blood coagulation cascade, which is formed by activating factor X. This activation takes place when the intravascular path through the factor IXg, this reaction being stimulated by the antihemophilic factor (VIII a). The factor Xa then converts prothrombin to thrombin.
- the proteolytic enzyme thrombin cleaves fibrinogen into fibrin monomers, which spontaneously assemble into ordered fibrous structures called fibrin. The clot that results from the spontaneous aggregation of fibrin monomers is stabilized by covalent cross-links between the side chains of different molecules in the fibrin fibers.
- factor Xlll a an enzyme that catalyzes factor X.
- factor X is activated by the tissue factor and factor VII.
- factor Xa allows a targeted intervention in the blood coagulation, since no other processes are affected. This is more advantageous than, for example, inhibition of thrombin since thrombin not only catalyzes the conversion of fibrinogen to fibrin, as well as the conversion of factor VIII VIII a, factor V in V a and factor XI XI a, but also for example platelets activated .
- thrombin not only catalyzes the conversion of fibrinogen to fibrin, as well as the conversion of factor VIII VIII a, factor V in V a and factor XI XI a, but also for example platelets activated .
- WO 99/11657 describes 1-amino-7-isoquinoline derivatives which act as inhibitors of serine proteases.
- WO 99/11658 describes m-benzamidine derivatives which act as serine protease inhibitors.
- WO 99/10316 describes 3-amidinoaniline derivatives which act as inhibitors of the activated blood coagulation factor X a .
- the object of the invention is to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
- the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
- they show inhibitory properties for the factors X a and VI l a and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication be used.
- Another preferred group of compounds is formed from the quinoline derivatives of the formula III. Particularly preferred embodiments are summarized in Table 2.
- Another group of preferred isoquinoline derivatives can be represented by the formula IV. Specific compounds that fall into this group are summarized in Table 3.
- the distance between the biphenyl part and the isoquinoline part can be increased by inserting CH 2 groups. Two examples are shown in Tables 6 and 7.
- the group in the biphenyl part can also be varied to vary the activity of the compounds according to the invention. Examples are shown in Table 8. The groups shown there can also be combined with the substitution patterns shown in Tables 1 to 6. Table 8
- substitution pattern in the biphenyl part is not limited to a particular position.
- Another possible structure of the compounds according to the invention is shown in Table 9.
- the compounds of the formulas I to X shown above need not necessarily be in optically pure form. Racemates also have an inhibitory effect. In the optically pure forms, the R- and S- can have different inhibitory effects.
- the compounds of the formula I can be prepared by a process known per se. Some exemplary synthetic routes are presented below.
- connection 4 was established, for example.
- the synthesis starts from 7-HydroxyisochinoIin 201, which under the action of a base, such as Cs 2 C0 3 , in a solvent, such as acetonitrile, with a suitable bromocarboxylic acid ester 202 is converted to isoquinoline derivative 203.
- a base such as Cs 2 C0 3
- a solvent such as acetonitrile
- bromocarboxylic acid ester 202 is converted to isoquinoline derivative 203.
- the carboxylic acid function is released from the ester function of the isoquinoline derivative 203 with the aid of acid.
- the reaction can be carried out, for example, in HCl / dioxane.
- Compound 204 is then obtained as the hydrochloride.
- reaction is then carried out with 2'-methanesulfonyl-biphenyl-4-ylamine 205 (DAPECI, tert-butanol, N-methylmorpholine) to obtain compound 206.
- DAPECI 2'-methanesulfonyl-biphenyl-4-ylamine
- the amino grouping on the isoquinoline ring is introduced by a process which is described in WO 98/57951 is described.
- the nitrogen of the isoquinoline ring is oxidized with m-chloroperbenzoic acid (207) and then the pyridinium salt 208 is prepared by reaction with pyridine and p-toluenesulfonic acid chloride.
- the active ingredient 209 is finally obtained in ethanolamine.
- the compound 204 is reacted with a suitably protected biphenyl derivative 210 to form the compound 211.
- a suitably protected biphenyl derivative 210 to form the compound 211.
- the introduction of the amino group on the isoquinoline skeleton is first the nitrogen oxidizes (212) and then further converted to the pyridinium salt 213. The amino group is then released in ethanolamine (214).
- the tert-butyl protecting group on the sulfamoyl group is cleaved off by the action of acid (trifluoroacetic acid / anisole) to obtain the active ingredient 215.
- the carboxylic acid ester function is introduced by reacting 7-aminoisoquinoline 216 with the ⁇ -diazocarboxylic acid ester 217 with catalysis by rhodium (II) acetate in toluene to give compound 218.
- the synthesis was carried out analogously to BRHenke et al., J.Med.Chem , 1998, 41, 5020-5036. After cleaving the ester 219 with HCl / dioxane, the carboxylic acid 219 is obtained as the hydrochloride.
- the biphenyl part is then introduced into the molecule by reaction with compound 205 (DAPECI / HOBt / NMM) to compound 220.
- the nitrogen adjacent to the isoquinoline part is then selectively protected by reaction with trifluoroacetic anhydride in dichloromethane.
- Compound 221 is obtained.
- the reaction is carried out analogously to M.Pailer and WJ Hübsch, Monthly Magazine for Chemistry, 1966, 97, 1541-1553.
- the amino group on the isoquinoline is then introduced by first oxidizing to compound 222 with MCPBA. Then the amino group is introduced by reaction with p-toluenesulfonyl chloride / pyridine and subsequent release with ethanolamine. Finally, the trifluoroacetyl group is split off with HCl / isopropanol.
- the active ingredient 223 is obtained.
- reaction schemes given above can be varied easily by the person skilled in the art.
- other suitable protective groups can also be used to protect the ester or amine function.
- diastereomers can be formed from them in the usual way by reaction with an optically active release agent, which then usual procedures are separated.
- Chromatographic separation of enantiomers using an optically active separating agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel.
- the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
- the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
- Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
- Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for parenteral use topical application ointments, creams or
- the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
- the specified preparations can be sterilized and / or auxiliaries, such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.
- the compounds of the formula I and their physiologically acceptable salts can be used in combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
- thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
- the substances according to the invention are generally preferably administered in doses between 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
- the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
- the specific dose for each patient depends on various factors, for example on the effectiveness of the particular compound used, on the age, body weight, general state of health, gender, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and Severity of the respective disease to which the therapy applies. Oral application is preferred.
- reaction mixture is poured into water and the precipitate is filtered off: 2- (isoquinolin-7-yloxy) pentanoic acid- (2'-methanesulfonyl-biphenyl-4-yl) -amide as a colorless solid; ESI-MS 475.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01985251A EP1322618A1 (de) | 2000-09-19 | 2001-09-18 | AMINOHETEROCYCLEN (FAKTOR X a? INHIBITOREN 14) |
JP2002529067A JP2004513888A (ja) | 2000-09-19 | 2001-09-18 | アミノ複素環式化合物(第Xa因子阻害剤14) |
CA002422067A CA2422067A1 (en) | 2000-09-19 | 2001-09-18 | Aminoheterocycles (factor xa inhibitors 14) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10046272A DE10046272A1 (de) | 2000-09-19 | 2000-09-19 | Aminoheterocyclen (Faktor Xa Inhibitoren 14) |
DE10046272.3 | 2000-09-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002024654A1 true WO2002024654A1 (de) | 2002-03-28 |
Family
ID=7656743
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2001/010786 WO2002024654A1 (de) | 2000-09-19 | 2001-09-18 | AMINOHETEROCYCLEN (FAKTOR Xa INHIBITOREN 14) |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1322618A1 (de) |
JP (1) | JP2004513888A (de) |
CA (1) | CA2422067A1 (de) |
DE (1) | DE10046272A1 (de) |
WO (1) | WO2002024654A1 (de) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6642252B2 (en) | 2000-11-07 | 2003-11-04 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors |
US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
EP1594845A2 (de) * | 2003-02-11 | 2005-11-16 | Bristol-Myers Squibb Company | Als serinproteaseinhibitoren geeignete benzolacetamidverbindungen |
US7030141B2 (en) | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
WO2010117084A1 (en) * | 2009-04-10 | 2010-10-14 | Banyu Pharmaceutical Co.,Ltd. | Novel isoquinoline derivatives |
US9241942B2 (en) | 2007-06-08 | 2016-01-26 | Mannkind Corporation | IRE-1α inhibitors |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011657A1 (en) * | 1997-08-29 | 1999-03-11 | Proteus Molecular Design Ltd. | 1-amino-7-isoquinoline derivatives as serine protease inhibitors |
WO2000024718A1 (en) * | 1998-10-23 | 2000-05-04 | Akzo Nobel N.V. | Serine protease inhibitor |
WO2000071507A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2000071512A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2000071510A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2001055146A1 (en) * | 2000-01-29 | 2001-08-02 | Lg Chem Investment Ltd. | FACTOR Xa INHIBITORS WITH ARYL-AMIDINES AND DERIVATIVES, AND PRODRUGS THEREOF |
-
2000
- 2000-09-19 DE DE10046272A patent/DE10046272A1/de not_active Withdrawn
-
2001
- 2001-09-18 JP JP2002529067A patent/JP2004513888A/ja active Pending
- 2001-09-18 CA CA002422067A patent/CA2422067A1/en not_active Abandoned
- 2001-09-18 WO PCT/EP2001/010786 patent/WO2002024654A1/de not_active Application Discontinuation
- 2001-09-18 EP EP01985251A patent/EP1322618A1/de not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999011657A1 (en) * | 1997-08-29 | 1999-03-11 | Proteus Molecular Design Ltd. | 1-amino-7-isoquinoline derivatives as serine protease inhibitors |
WO2000024718A1 (en) * | 1998-10-23 | 2000-05-04 | Akzo Nobel N.V. | Serine protease inhibitor |
WO2000071507A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2000071512A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2000071510A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
WO2001055146A1 (en) * | 2000-01-29 | 2001-08-02 | Lg Chem Investment Ltd. | FACTOR Xa INHIBITORS WITH ARYL-AMIDINES AND DERIVATIVES, AND PRODRUGS THEREOF |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6642252B2 (en) | 2000-11-07 | 2003-11-04 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors |
US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
US7030141B2 (en) | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
US7407974B2 (en) | 2001-11-29 | 2008-08-05 | Pfizer Inc. | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
US7407972B2 (en) | 2001-11-29 | 2008-08-05 | Pfizer Inc. | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
EP1594845A2 (de) * | 2003-02-11 | 2005-11-16 | Bristol-Myers Squibb Company | Als serinproteaseinhibitoren geeignete benzolacetamidverbindungen |
JP2006517589A (ja) * | 2003-02-11 | 2006-07-27 | ブリストル−マイヤーズ スクイブ カンパニー | セリンプロテアーゼ・インヒビターとして有用なベンゼンアセトアミド化合物 |
EP1594845A4 (de) * | 2003-02-11 | 2008-05-21 | Bristol Myers Squibb Co | Als serinproteaseinhibitoren geeignete benzolacetamidverbindungen |
US9241942B2 (en) | 2007-06-08 | 2016-01-26 | Mannkind Corporation | IRE-1α inhibitors |
US9546149B2 (en) | 2007-06-08 | 2017-01-17 | Mannkind Corporation | IRE-1α inhibitors |
US9981901B2 (en) | 2007-06-08 | 2018-05-29 | Fosun Orinove Pharmatech, Inc. | IRE-1α inhibitors |
WO2010117084A1 (en) * | 2009-04-10 | 2010-10-14 | Banyu Pharmaceutical Co.,Ltd. | Novel isoquinoline derivatives |
Also Published As
Publication number | Publication date |
---|---|
EP1322618A1 (de) | 2003-07-02 |
DE10046272A1 (de) | 2002-03-28 |
JP2004513888A (ja) | 2004-05-13 |
CA2422067A1 (en) | 2003-03-12 |
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