WO2000055188A1 - Derives de proline substitues et compositions medicinales les contenant - Google Patents

Derives de proline substitues et compositions medicinales les contenant Download PDF

Info

Publication number
WO2000055188A1
WO2000055188A1 PCT/JP2000/001598 JP0001598W WO0055188A1 WO 2000055188 A1 WO2000055188 A1 WO 2000055188A1 JP 0001598 W JP0001598 W JP 0001598W WO 0055188 A1 WO0055188 A1 WO 0055188A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
optionally substituted
stereoisomer
alkyl group
Prior art date
Application number
PCT/JP2000/001598
Other languages
English (en)
Japanese (ja)
Inventor
Takuya Shiraishi
Tsuyoshi Haneishi
Masayuki Haramura
Original Assignee
C & C Research Laboratories
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 C & C Research Laboratories filed Critical C & C Research Laboratories
Priority to AU31925/00A priority Critical patent/AU3192500A/en
Publication of WO2000055188A1 publication Critical patent/WO2000055188A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention has the general formula (1)
  • NH 2 or NH 2 R 5 is a hydrogen atom or a lower alkyl group
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is an optionally substituted lower alkyl group, an optionally substituted aryl group or a substituted CNI optionally substituted lower alkoxy group,
  • R 4 is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, or a lower alkoxycarbonyl group;
  • R. Is a hydrogen atom or a lower alkyl group
  • B is CH 2 or S
  • n shows the integer of 1-3.
  • R 4 is a hydrogen atom, R 3 is not a phenyl group, and b) A is
  • R 3 is not an optionally substituted lower alkyl group or an optionally substituted aryl group,
  • R 3 is not an optionally substituted lower alkyl group or an optionally substituted aryl group;
  • R 3 is not an optionally substituted lower alkyl group or an optionally substituted aryl group.
  • R 3 is not an optionally substituted lower alkyl group or an optionally substituted aryl group.
  • the present invention relates to a body or a pharmaceutically acceptable salt thereof, and more particularly, to a pharmaceutical composition containing a proline derivative having antithrombin inhibitory activity or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a compound represented by the general formula (4) for producing the proline derivative represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted lower alkoxy group,
  • R 4 is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, or a lower alkoxycarbonyl group;
  • R 0 is a hydrogen atom or a lower alkyl group
  • B is CH 2 or S
  • Ra is selected from groups (5) to (10),
  • R 6 represents a lower alkoxycarbonyl group
  • n shows the integer of 1-3. )).
  • Thrombus is composed of aggregated platelets and fibrin, ischemic heart disease such as angina pectoris and myocardial infarction, cerebrovascular disorder such as cerebral infarction, venous thrombosis such as arterial thromboembolism, pulmonary embolism, and generalized blood vessels It is involved in the occurrence and exacerbation of internal blood coagulation syndrome (DIC).
  • thrombosis thromb0sis
  • thromb0sis is a disease in which platelet aggregation and fibrin clots occlude blood vessels.
  • anticoagulants that block fibrin formation can be used to prevent thrombosis.
  • the blood coagulation system involves a number of zymogens (non-activating enzymes) that are activated by multi-step enzymatic reactions.
  • the final stage of the blood coagulation process is the stage in which fibrin clots are formed from fibrinogen by the action of factor Xa by thrombin generated from prothrombin. Therefore, thrombin, a blood clotting enzyme, plays a central role in hemostasis and thrombosis.Thus, substances that can suppress thrombin activity suppress platelet activity and suppress fibrin production and stabilization. Is expected to be used as an effective anticoagulant.
  • the thrombin inhibitor also activates Factor V and Factor VIII by a positive feedback reaction (P0stiTiVefeedbbacckreacntio).
  • Antithrombotic drugs are classified into antiplatelet drugs such as aspirin, dipyridamole, and aprosidil, and anticoagulants such as perfurin, heparin, and argatroban.Of these, most antiplatelet drugs are oral drugs, There are many doubts about the effect. Anticoagulants, on the other hand, have only oral drug, perfurin, which inhibits the production of coagulation factors by antagonizing vitamin K, but has side effects such as skin necrosis and teratogenic effects. Has many effects. Therefore, the emergence of oral anticoagulants having a different mechanism of action from perfurin is desired in clinical settings.
  • Thrombin is the last factor in blood coagulation and acts on fibrinogen to produce fibrin.
  • Thrombin inhibitors include argatroban, tripeptide (a synthetic derivative of D-Phe-Pr0-Arg-H) and hirudin Both are injections, and oral drugs that can be administered for a long period of time are desirable for the treatment and prevention of thrombosis.
  • thrombin receptor expression is more than 10 times higher in vascular smooth muscle several hours after percutaneous coronary angioplasty (PTCA). Drugs may be available. Therefore, the development of thrombin inhibitors that can be taken orally and have few side effects is urgently desired. Disclosure of the invention
  • the present inventors have conducted intensive studies on antithrombin drugs that can be orally administered and have few side effects. As a result, they have found that a specific proline derivative shows an excellent effect, and have reached the present invention.
  • the present invention relates to the general formula (1)
  • X is ⁇ or CH
  • R 5 is a hydrogen atom or a lower alkyl group
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted lower alkoxy group,
  • R 4 is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, or a lower alkoxycarbonyl group;
  • R 0 is a hydrogen atom or a lower alkyl group
  • B is CH 2 or S
  • n shows the integer of 1-3.
  • R 3 is optionally substituted lower alkyl group
  • R 3 is not an optionally substituted lower alkyl group or an optionally substituted aryl group;
  • X is N and Y is When R 3 is an optionally substituted lower alkyl group or a substituted Nor is it a reel group. ) Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. More specifically, a proline derivative having antithrombin inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition containing the salt. Furthermore, the present invention provides a compound represented by the general formula (4) for producing a proline derivative represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted lower alkoxy group,
  • R 4 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group or a lower alkoxycarbonyl group,
  • R. Is a hydrogen atom or a lower alkyl group
  • B is CH 2 or S
  • Ra is selected from groups (5) to (10);
  • R 6 represents a lower alkoxycarbonyl group
  • n shows the integer of 1-3.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, Examples include i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group and the like.
  • the lower alkoxy group means a linear or branched alkyloxy group having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group and the like.
  • An aryl group is a group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, a xylyl group, a biphenyl group, an anthryl group, and a phenanthryl group. Preferable examples include a phenyl group and a naphthyl group.
  • the lower alkylcarbonyl group refers to a group in which a carbonyl group is bonded to a lower alkyl group, and includes a group having 2 to 9, preferably 2 to 7, and more preferably 2 to 5 carbon atoms including the carbon of the carbonyl group.
  • Specific examples include an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, a pivaloyl group and the like, and preferably an acetyl group and a propionyl group.
  • the lower alkylsulfonyl group is a group in which a sulfonyl group is bonded to a lower alkyl group, and has 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example, a methylsulfonyl group, Examples include a tylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i_butylsulfonyl group, an s-butylsulfonyl group, and a t-butylsulfonyl group.
  • a lower alkoxycarbonyl group is a carbonyl group bonded to a lower alkoxy group. And represents a group having 2 to 9, preferably 2 to 7, and more preferably 2 to 5 carbon atoms, including the carbon of the carbonyl group. Specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an ⁇ -propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxy group And a methoxycarbonyl group, preferably an methoxycarbonyl group, and an ethoxycarbonyl group.
  • substituent in the alkoxycarbonyl include an aryl group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxy group, a lower alkoxy group, and a saturated heterocyclic group (where the saturated heterocyclic group is an oxygen atom, a nitrogen atom Or a 3- to 7-membered saturated heterocyclic ring containing one or more hetero atoms selected from the group consisting of sulfur atoms, which may be condensed with another saturated ring.
  • aryloxy groups amino groups which may be protected (where the protecting groups are formyl groups, Tyl, benzoyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, tosyl, fluorenylmethyloxycarbonyl, etc.
  • the proline derivative of the present invention can form a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt examples include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate.
  • Inorganic acid salts such as succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate, etc.
  • Organic acid salts and the like can be mentioned.
  • Compound of the present invention and pharmaceutically acceptable salts thereof can also form hydrates.
  • the compound of the present invention can have various steric structures, all of which are included in the present invention.
  • a compound in which the configuration of the ⁇ -carbon of the ring substituted with R 3 is R a compound in which the configuration of R 3 is R, and a carbon configuration of a cyclic amino acid having R 2
  • Compounds having the S configuration and compounds having the trans configuration at the 1- and 4-positions in the 4-amino-1-aminomethylcyclohexane moiety are preferred.
  • n represents an integer of 1 to 3, among which compounds in which n is 2, that is, compounds in which the ring containing the — (CH 2 ) n — moiety is a 5-membered ring,
  • R 4 is a lower alkyl group which may be substituted
  • Monoaminomethylcyclohexane or a salt thereof constitutes the present invention as a particularly preferred compound.
  • the compound of the present invention can be produced by a combination of reactions suitable for a target compound.
  • a typical reaction scheme is shown below, but is not limited to the following method.
  • P represents an amino protecting group
  • a 1 k represents an optionally substituted lower alkyl group (preferably, a lower alkyl group or a benzyl group)
  • the compound of the formula (1) which can be used as a raw material is obtained by adding an amino protecting group to a substituted proline derivative described in, for example, Journal of Organic Chemistry, 56, 2875-2883 (1991), or Adding an amino-protecting group to the hydroxyproline compound described in tetrahydrone-asymmetry, 5 (1), 119-129 (1994), and tetrahydrone 'Rei-ichi, 39, 5743 (1998); or It can be obtained by carrying out a commonly used hydroxyl group alkylation reaction.
  • Examples of a commonly used alkylation reaction of a hydroxyl group include, for example, a reaction with a halogenated alkyl halide and a reaction with diazomethane.
  • Examples of the base that can be used here include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopyrupyrethylamine, pyridine, 4-dimethylaminopyridine, piperidine and the like. Organic bases and the like are used.
  • the amino protecting group used herein is the same as the above-mentioned amino group which may be protected, and desirably includes a benzyloxycarbonyl group and a t-butoxycarbonyl group.
  • the compound of the formula (3) can be obtained by subjecting the compound of the formula (1) and the compound of the formula (2) to a condensation reaction.
  • the compound of the formula (2) can be generally purchased as a reagent from, for example, Nova Biochem, Bachem AG, Watanabe Chemical Industry Co., Ltd., Kokusan Chemical Co., Ltd., etc., as well as Tetrahydron 'Letter, 38, 6677 (1997 ) Can be obtained by subjecting the protected substituted proline compound described to appropriate amino deprotection. Examples of the amino deprotection reaction used here include a hydrolysis reaction with a strong acid, a hydrogenation reaction, and a reaction with zero-valent palladium.
  • condensation reaction examples include the commonly used active ester method, acid anhydride method, azide method, acid chloride method, various condensing agents, and the like.
  • active ester method acid anhydride method
  • azide method azide method
  • acid chloride method various condensing agents, and the like.
  • Condensing agents include N, N'-dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC I), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), Bop reagent, Pybo p reagent , 2- (1H-benzotriazole-1-yl) 1-1,1,3,3-tetramethylperoniumhexafluorophosphate (HBTU), 2- (1H-benzotriazo-1-yl 1) 1 1, 1, 3, 3—te To tramethylperonium tetrafluoroborate (TBTU), 2- (7-azabenzotriazole_1-yl) — 1,1,3,3-tetramethylperonium Xafluorophosphate (HATU) and the like, for example, commonly used reagents described in Peptide Synthesis Handbook (1998, published by Nova Biochem) and the like can be mentioned.
  • DCC N'-dicyclohexylcar
  • the compound of the formula (2) is used in an amount of 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, relative to the compound of the formula (1).
  • the reaction can usually be carried out at a temperature of -80 to 3O for 0.1 to 72 hours.
  • the compound of the formula (3) can be converted to the compound of the formula (4) by performing an appropriate deesterification reaction. Examples of the deesterification reaction used here include alkali hydrolysis, hydrogenation reaction, and reaction with zero-valent palladium.
  • the reaction can be usually performed at a temperature of 180 to 30 ° C. under a pressure of 1 to 10 atm for 0.1 to 72 hours.
  • the compound of the formula (7) By subjecting the compound of the formula (4) to a condensation reaction with the compound of the formula (6), the compound of the formula (7) can be obtained.
  • the compound of the formula (6) is described, for example, in Japanese Patent Application Publication Nos. 8-51 1018, 9-509937, International Patent Publication W ⁇ 96 / 31504, WO 96/03374, It can be synthesized based on the description in WO 96/32110 and the like.
  • the condensation reaction between the compound of the formula (4) and the compound of the formula (6) can be carried out by the same reaction as the condensation reaction in the step of obtaining the compound of the formula (3).
  • the compound of the formula (7) can also be obtained by subjecting a compound of the formula (1) to a condensation reaction with a compound of the formula (5).
  • the compound of the formula (5) can be obtained by a condensation reaction between the compound of the formula (2) and the compound of the formula (6). These condensation reactions can be carried out in the same manner as in the step of obtaining the compound of the formula (3).
  • the compound of the formula (8) can be obtained.
  • the compound of the formula (8) is a compound of the general formula (1) wherein R 4 is a hydrogen atom, and constitutes the present invention per se.
  • This reaction can be performed, for example, by a reaction with a strong acid, a hydrogenation reaction, a reaction with zero-valent palladium, or the like.
  • strong acid that can be used here include trifluoroacetic acid, hydrochloric acid, hydrofluoric acid, methanesulfonic acid, and the like. Desirably, trifluoroacetic acid and hydrochloric acid are used.
  • the catalyst for the hydrogenation reaction that can be used here include palladium carbon, palladium, palladium hydroxide, Raney nickel and the like.
  • the zero-valent palladium include tetrakistriphenylphosphonium palladium.
  • R 4 is an optionally substituted lower alkyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group or a lower alkoxycarbonyl group.
  • Certain compounds can be obtained by subjecting a compound of formula (8) to an alkylation, acylation, or sulfonylation reaction.
  • alkylation reaction include a reaction with an alkyl halide in the presence or absence of a base, reductive alkylation, and the like.
  • Examples of the base that can be used here include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, Examples include organic bases such as piperidine, and desirably include triethylamine and diisopropylethylamine. These reactions can be carried out usually for 0.1 to 72 hours at a temperature of -80 to 200 and a pressure of 1 to 10 atm.
  • the acylation reaction can be carried out in the same manner as the reaction for obtaining the compound of the formula (3).
  • the sulfonylation reaction includes, for example, the reactivity of a sulfonyl halide.
  • the compound of the formula (10) can be obtained by a suitable amino deprotection reaction to obtain a compound of the compound (16). This reaction can be obtained by a method similar to the reaction for obtaining the compound of the formula (8) from the compound of the formula (7).
  • the compound of the formula (17) can be prepared, for example, by adding a compound of the formula (11) to hydrochloric acid, nitric acid, sulfuric acid, or the like in a lower alcohol solvent such as methanol, ethanol, n-propanol or i-propanol, preferably methanol or ethanol. It can be obtained by subjecting it to a strong acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid or the like, preferably hydrochloric acid, and then reacting it with an ammonium salt or ammonia in a suitable solvent.
  • the ammonium salts include hydroxyammonium acetate and the like.
  • the reaction can be usually performed at a temperature of 0 to 200 ° C for 1 to 168 hours.
  • the compound of the formula (18) can be obtained, for example, by a method similar to the reaction for obtaining the compound of the formula (17) from the compound of the formula (11).
  • the compound of the formula (19) can be obtained, for example, by converting the compound of the formula (13) into the compound of the formula (14) in the same reaction as when the compound (8) is obtained, and then reacting with a protected guanidinating reagent.
  • the compound of formula (15) can be obtained by deprotection or by reacting the compound of formula (14) with a guanidinating reagent.
  • Examples of the guanidinating reagent used herein include thiourea and 1H-pyrazolyl 1-carboxamidine.
  • Examples of the protected guanidinating reagent include N, N′-di-tert-butyloxycarbo. Nilthiourea, ⁇ , ⁇ '-di-t-butyroxycarbone 1H-pyrazole-1-carboxamidine, N, ⁇ ' —Dibenzyloxycarbonylthiourea, N, N ′ dibenzyloxycarbonyl 1 H-pyrazole-11-carboxamidine and the like.
  • the reaction of the protected guanidinating reagent or the guanidinating reagent is usually carried out in the presence or absence of a base in a temperature range of 80 to 30 ° C for 0.1 to 72 hours. It can.
  • a base examples include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.
  • Organic base such as S, and desirably triethylamine.
  • the deprotection reaction of the compound of the formula (15) can be carried out in the same manner as in obtaining the compound of the formula (8).
  • the compound of the general formula (1) thus obtained can be isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization and various types of chromatography.
  • the compound of the present invention can be formulated together with suitable excipients, diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc.
  • suitable excipients granules, fine granules, powders, tablets, capsules, syrups, solutions, suspensions, emulsions, freeze-dried agents, etc., used as oral or intravenous, intramuscular or subcutaneous injections can do.
  • It can also be formulated into cataplasms, ointments, etc. and used as a transdermal absorbent. It can also be used as a suppository.
  • liquid preparations for oral administration ie emulsions, syrups, suspensions, solutions and the like
  • inert diluents such as water or vegetable oils
  • they may be contained in capsules of an absorbable substance such as gelatin.
  • preparations for parenteral administration that is, solvents or suspensions used in the production of injections, suppositories, etc.
  • the compound of the present invention is usually in the range of 0.1 to 180 mg / day, preferably 1 to 600 mg / day, or once a day or at appropriate intervals. May be administered in two or three divided doses, or may be administered intermittently.
  • reaction solution is concentrated under reduced pressure, and the residue is subjected to column chromatography (Fuji Siricia DM1020: mobile phase ethyl acetate) to give trans-4-tert-butyloxycarbonylamino-[(S) -N- [ 620 mg (1.01 mmol: 45% yield) of (2R, 3S) - ⁇ '-(3'-carboethoxypropyl) phenylprolyl] prolyl] -aminomethylcyclohexane are obtained.
  • reaction solution is washed with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered off magnesium sulfate, and concentrated under reduced pressure.
  • the residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate) to give trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N, -methyl
  • yield 61 sulfurylphenylphenylprolyl] prolyl] -aminomethylcyclohexane.
  • the substituted proline derivative of the present invention has excellent antithrombin activity, is orally administrable, has few side effects, and is useful as a drug such as an antithrombotic therapeutic. is there.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de proline représentés par la formule générale (1), leurs stéréoisomères, ou leurs sels acceptables au plan pharmaceutique, ces composés se caractérisant par le fait qu'ils possèdent une excellente activité antithrombotique, ce qui les rend utiles comme médicaments antithrombotiques, et peuvent être administrés par voie orale tout en présentant peu d'effets secondaires. Dans la formule (1) selon l'invention, R1 représente (2), etc. (A représentant (a), (b) ou (c); R2 représente un hydrogène ou un alkyle inférieur; R3 représente un alkyle inférieur éventuellement substitué, un aryle éventuellement substitué ou un alcoxy inférieur éventuellement substitué; R4 représente un hydrogène, un alkyle inférieur éventuellement substitué, un alkylcarbonyle inférieur éventuellement substitué, un alkylsufonyle inférieur éventuellement substitué ou un alcoxycarbonyle inférieur éventuellement substitué; R0 représente un hydrogène ou un alkyle inférieur; B représente CH2 ou S, et n désigne un entier de 1 à 3.
PCT/JP2000/001598 1999-03-16 2000-03-16 Derives de proline substitues et compositions medicinales les contenant WO2000055188A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31925/00A AU3192500A (en) 1999-03-16 2000-03-16 Substituted proline derivatives and medicinal compositions containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/70634 1999-03-16
JP7063499 1999-03-16

Publications (1)

Publication Number Publication Date
WO2000055188A1 true WO2000055188A1 (fr) 2000-09-21

Family

ID=13437281

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/001598 WO2000055188A1 (fr) 1999-03-16 2000-03-16 Derives de proline substitues et compositions medicinales les contenant

Country Status (3)

Country Link
KR (1) KR20020004971A (fr)
AU (1) AU3192500A (fr)
WO (1) WO2000055188A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002100830A1 (fr) * 2001-06-08 2002-12-19 Glaxo Group Limited Derives de pyrrolidine servant d'inhibiteurs du facteur xa
US7084139B2 (en) 2001-06-08 2006-08-01 Smithkline Beecham Corporation Pyrrolidin-2-one derivatives as inhibitors of factor Xa
CN110498808A (zh) * 2019-09-16 2019-11-26 浙江晖石药业有限公司 一种合成（2s,3r）-3-取代苯基吡咯烷-2-羧酸的中间体及其制备方法和应用
CN112867706A (zh) * 2018-05-29 2021-05-28 奥默罗斯公司 Masp-2抑制剂和使用方法
US11584714B2 (en) 2018-05-29 2023-02-21 Omeros Corporation MASP-2 inhibitors and methods of use
US11661418B2 (en) 2019-12-04 2023-05-30 Omeros Corporation MASP-2 inhibitors and methods of use
US11807641B2 (en) 2019-12-04 2023-11-07 Omeros Corporation MASP-2 inhibitors and methods of use
US12030853B2 (en) 2020-12-04 2024-07-09 Omeros Corporation MASP-2 inhibitors and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185390A2 (fr) * 1984-12-21 1986-06-25 Richter Gedeon Vegyeszeti Gyar R.T. Tripeptidyl-argininaldéhyde, son procédé de préparation et les médicaments le contenant, de même que les N-(monoalkyl) et N,N-di-(alkyl)-Xxx-L-proline-dipeptide
WO1992007869A1 (fr) * 1990-11-06 1992-05-14 Thrombosis Research Institute Inhibiteurs et substrats de thrombine
WO1996040741A1 (fr) * 1995-06-07 1996-12-19 Ortho Pharmaceutical Corporation Heterocycles peptidyliques utiles dans le traitement de pathologies associees a la thrombine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185390A2 (fr) * 1984-12-21 1986-06-25 Richter Gedeon Vegyeszeti Gyar R.T. Tripeptidyl-argininaldéhyde, son procédé de préparation et les médicaments le contenant, de même que les N-(monoalkyl) et N,N-di-(alkyl)-Xxx-L-proline-dipeptide
WO1992007869A1 (fr) * 1990-11-06 1992-05-14 Thrombosis Research Institute Inhibiteurs et substrats de thrombine
WO1996040741A1 (fr) * 1995-06-07 1996-12-19 Ortho Pharmaceutical Corporation Heterocycles peptidyliques utiles dans le traitement de pathologies associees a la thrombine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517879B2 (en) 2001-06-08 2009-04-14 Glaxo Group Limited Pyrrolidine derivatives as factor Xa inhibitors
US7084139B2 (en) 2001-06-08 2006-08-01 Smithkline Beecham Corporation Pyrrolidin-2-one derivatives as inhibitors of factor Xa
WO2002100830A1 (fr) * 2001-06-08 2002-12-19 Glaxo Group Limited Derives de pyrrolidine servant d'inhibiteurs du facteur xa
US7186717B2 (en) 2001-06-08 2007-03-06 Smithkline Beecham Corporation Pyrrolidine derivatives as Factor Xa inhibitors
US7226929B2 (en) 2001-06-08 2007-06-05 Smithkline Beecham Corporation Pyrrolidin-2-one derivatives as inhibitors of factor xa
US7282497B2 (en) 2001-06-08 2007-10-16 Glaxo Group Limited Pyrrolidin-2-one derivatives as inhibitors of factor xa
US7326785B2 (en) 2001-06-08 2008-02-05 Glaxo Group Limited Pyrrolidine derivatives as factor XA inhibitors
US7429587B2 (en) 2001-06-08 2008-09-30 Glaxo Group Limited Pyrrolidine derivatives as factor Xa inhibitors
AU2002311451B2 (en) * 2001-06-08 2006-03-02 Glaxo Group Limited Pyrrolidine derivatives as factor Xa inhibitors
CN112867706A (zh) * 2018-05-29 2021-05-28 奥默罗斯公司 Masp-2抑制剂和使用方法
EP3802489A4 (fr) * 2018-05-29 2022-04-13 Omeros Corporation Inhibiteurs de masp -2 et procédés d'utilisation
US11584714B2 (en) 2018-05-29 2023-02-21 Omeros Corporation MASP-2 inhibitors and methods of use
AU2019277150B2 (en) * 2018-05-29 2023-08-24 Omeros Corporation MASP-2 inhibitors and methods of use
IL278989B1 (en) * 2018-05-29 2024-06-01 Omeros Corp MASP-2 suppressors and methods of using them
CN110498808A (zh) * 2019-09-16 2019-11-26 浙江晖石药业有限公司 一种合成（2s,3r）-3-取代苯基吡咯烷-2-羧酸的中间体及其制备方法和应用
US11661418B2 (en) 2019-12-04 2023-05-30 Omeros Corporation MASP-2 inhibitors and methods of use
US11807641B2 (en) 2019-12-04 2023-11-07 Omeros Corporation MASP-2 inhibitors and methods of use
US12030853B2 (en) 2020-12-04 2024-07-09 Omeros Corporation MASP-2 inhibitors and methods of use

Also Published As

Publication number Publication date
KR20020004971A (ko) 2002-01-16
AU3192500A (en) 2000-10-04

Similar Documents

Publication Publication Date Title
US6420438B1 (en) 1-amino-7-isoquinoline derivatives as serine protease inhibitors
US7001907B2 (en) Peptide-containing α-ketoamide cysteine and serine protease inhibitors
US6020334A (en) Piperazinones, their production and use
JPH11508242A (ja) アリールスルホニルアミノベンゼン誘導体およびＸａ因子阻害物質としてのその使用
JP2004514669A (ja) セリンプロテアーゼ阻害剤として有用な酸誘導体
AU2001295507B2 (en) Novel compounds inhibiting factor Xa activity
US7220781B2 (en) Meta-benzamidine derivatives as serine protease inhibitors
JP2004517060A (ja) セリンプロテアーゼ抑制剤として有用な酸誘導体
RU2253651C2 (ru) N-гуанидиноалкиламиды, их получение, их применение и содержащие их фармацевтические препараты
EP0841918B1 (fr) Inhibiteurs de thrombine
WO2000055188A1 (fr) Derives de proline substitues et compositions medicinales les contenant
WO2005030706A1 (fr) Derive carboxamide du type amide
EP1236712B1 (fr) Derive de l'acide amidinophenylpyruvique
US5559150A (en) N,N-disulfonylated aminobenzene carboxlic acids and the use thereof as thrombin inhibitors
KR100584032B1 (ko) 항혈전제로서의 비스피페리딘
JPH06172288A (ja) 新規なフェニルアラニン誘導体またはその塩
US20060058389A1 (en) Novel compounds that inhibit factor xa activity
KR100377557B1 (ko) 아실 구아니딘 작용기를 갖는 선택적 트롬빈 억제제
JP2000001480A (ja) ２―ピペラジノン―１―酢酸誘導体、その製造法および用途
CZ2003452A3 (en) Data processing system, with an Internet connection facility has a structured program loaded in memory for use in assigning predetermined data from a multiplicity of data to hierarchical memory addresses
MXPA00003419A (en) PEPTIDE-CONTAINING&agr;-KETOAMIDE CYSTEINE AND SERINE PROTEASE INHIBITORS

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 605615

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1020017011826

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1020017011826

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
WWW Wipo information: withdrawn in national office

Ref document number: 1020017011826

Country of ref document: KR