WO2014046125A1 - Prevention/treatment agent for pulmonary hypertension comprising thrombin receptor antagonist as active component - Google Patents

Prevention/treatment agent for pulmonary hypertension comprising thrombin receptor antagonist as active component Download PDF

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WO2014046125A1
WO2014046125A1 PCT/JP2013/075150 JP2013075150W WO2014046125A1 WO 2014046125 A1 WO2014046125 A1 WO 2014046125A1 JP 2013075150 W JP2013075150 W JP 2013075150W WO 2014046125 A1 WO2014046125 A1 WO 2014046125A1
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pulmonary hypertension
group
therapeutic
par1
prophylactic agent
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PCT/JP2013/075150
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French (fr)
Japanese (ja)
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勝也 平野
弘太郎 阿部
真弓 平野
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エーザイ・アール・アンド・ディー・マネジメント株式会社
国立大学法人九州大学
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Priority to JP2014536875A priority Critical patent/JP6243844B2/en
Publication of WO2014046125A1 publication Critical patent/WO2014046125A1/en

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the present invention relates to a preventive agent and a therapeutic agent for pulmonary hypertension.
  • Pulmonary hypertension is a chronic and progressive intractable disease characterized by progressive pulmonary vascular resistance and increased pulmonary arterial pressure, and conventional treatment is said to have a survival rate of 30% for 5 years. Yes.
  • the three major pathological findings of pulmonary hypertension are (1) vasoconstriction, (2) vascular remodeling, and (3) thrombus formation, which are thought to be involved in the increase in vascular resistance.
  • protease activated receptors form a family of G protein-coupled receptors and mediate various cellular actions by proteases involved in blood coagulation such as thrombin.
  • thrombin induces vascular smooth muscle contraction, migration, and proliferation by activating PAR1 among the four subtypes of PAR.
  • PAR is hardly expressed in smooth muscle, and it is known that the contraction effect by thrombin is hardly observed.
  • the present inventors have revealed that, in the lesioned blood vessel, the expression of PAR is induced in arterial smooth muscle, and the reactivity to thrombin is induced or enhanced (Non-patent Document 2, FIG. 1). .
  • ROCK Rho-associated -kinase
  • ROS reactive oxygen species
  • the present invention has been made in view of such a situation, and an object thereof is to provide a therapeutic or preventive agent for pulmonary hypertension.
  • a therapeutic or preventive agent for pulmonary hypertension comprising a compound having an action of inhibiting the function of protease-activated receptor 1 (PAR1) or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • PAR1 protease-activated receptor 1
  • the therapeutic or prophylactic agent according to the above [1] or [2], wherein the compound having an action of inhibiting the function of the protease activated receptor 1 is a 2-iminopyrrolidine derivative.
  • a therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative has the general formula (I)
  • R 1 and R 2 are each independently the same or different and represent a hydrogen atom, a methoxy group or an ethoxy group
  • X 1 represents a hydrogen atom or a halogen atom
  • Ar 2 represents a methyl group , An ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a phenyl group optionally substituted with one or more substituents selected from the substituents represented by the following formula (II):
  • W represents —CH— or a nitrogen atom
  • a 1 represents —CH 2 — or a single bond
  • R 3 represents a hydrogen atom or —OR 5a
  • X 2 represents —CH 2 —, an oxygen
  • the said therapeutic agent or prophylactic agent which is the compound represented by these, its pharmaceutically acceptable salt, or those hydrates.
  • a therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative The 2-iminopyrrolidine derivative is at least one selected from the group consisting of compounds represented by formulas (III) to (IX), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a therapeutic or prophylactic agent is at least one selected from the group consisting of compounds represented by formulas (III) to (IX), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative The therapeutic or prophylactic agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (III), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a kit for treating or preventing pulmonary hypertension comprising the 2-iminopyrrolidine derivative according to any one of [4] to [7] above.
  • a method for treating or preventing pulmonary hypertension comprising administering to a subject an effective amount of the 2-iminopyrrolidine derivative according to any one of [4] to [7] above.
  • the present invention revealed that thrombin and its receptor play an important role in the onset and pathogenesis of pulmonary hypertension.
  • a compound having an action of inhibiting the function of PAR1 can suppress right ventricular pressure and right ventricular hypertrophy without changing heart rate and systemic systolic blood pressure. Therefore, it can be said that a compound having an action of inhibiting the function of PAR1 is useful as an active ingredient of a therapeutic and prophylactic agent for pulmonary hypertension, which has a low possibility of causing a side effect, and the present invention inhibits the function of PAR1.
  • the present invention provides a therapeutic agent for pulmonary hypertension and a preventive agent for pulmonary hypertension, which comprise a compound having the above-mentioned action as an active ingredient. According to the present invention, a new treatment or prevention method for pulmonary hypertension is provided, and it has become possible to contribute to the treatment or prevention of pulmonary hypertension patients.
  • FIG. 1 It is a figure which shows the effect of Atopaxar (30 mg / kg / day) with respect to monocrotaline induction rat pulmonary hypertension.
  • the left figure shows the effect on systemic systolic blood pressure, and the right figure shows the effect on heart rate.
  • the present invention provides a therapeutic or prophylactic agent for pulmonary hypertension or a therapeutic or prophylactic kit containing a compound having an action of inhibiting the function of PAR1 as an active ingredient.
  • Compound (1) PAR1 that has the function of inhibiting the function of PAR1 PAR1 is one of protease-activated receptors and is a G protein-coupled receptor that is activated when a specific region outside the cell is degraded by proteases.
  • the activation mechanism of PAR1 is shown in FIG. Receptor activation is achieved by binding a specific site on the N-terminal side of the receptor by a serine protease to expose the receptor activation sequence, which becomes a ligand and binds to the ligand binding site of the receptor. Arise.
  • PAR1 agonists As PAR1 agonists, thrombin and trypsin that function as proteases have been found, and synthetic peptides of receptor activation sequences, such as PAR1-AP (PAR1 activating peptide), are also known to function as agonists.
  • PAR1-AP sequence SFLLRN (human, single letter code for amino acid, SEQ ID NO: 1), TFRIFD (frog, single letter code for amino acid, SEQ ID NO: 2) and the like have been identified.
  • Compound having an action of inhibiting the function of PAR1 is the activation of PAR1.
  • the substance is not particularly limited as long as it has a function of suppressing SCH 530348 (N-[(1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9- 9) disclosed in International Publication No. 03/89428.
  • PAR1 antagonists such as [2- [5- (3-Fluorophenyl) pyridin-2-yl] vinyl] -1-methyl-3-oxoperhydronaphtho [2,3-c] furan-6-yl] carbamic acid ester PAR1 desensitization promoter, PAR1 antisense oligonucleotide, PAR1 siRNA, PAR1 neutralizing anti Means the body.
  • Preferred features of the PAR1 inhibitor used in the present invention include a high selectivity for PAR1, an effective action in a therapeutically effective amount, such as an increase in right ventricular pressure and an inhibition of right ventricular hypertrophy In the therapeutically effective amount, serious side effects such as abnormal increase in heart rate and increase in systemic systolic blood pressure, and immediate effect can be mentioned.
  • the PAR1 inhibitor also includes pharmaceutically acceptable salts or hydrates thereof (details will be described later).
  • preferred compounds for use as a therapeutic or preventive agent for pulmonary hypertension include “a compound having an action of inhibiting the function of PAR1”, particularly a PAR1 antagonist or a pharmaceutically acceptable salt thereof. Mention may be made of salts or their hydrates.
  • PAR1 antagonist and “PAR1 antagonist” are antagonists of protease-activated receptor 1, which bind to PAR1 and correspond to a receptor activation sequence present in PAR1.
  • PAR1 desensitization promoting substance means a substance that desensitizes and inactivates protease-activated receptor 1.
  • the PAR1 desensitization promoting substance a substance known in the art can be selected and used. Moreover, it can manufacture using a well-known method in this field
  • PAR1 antisense oligonucleotide is a single-stranded nucleic acid that can bind to mRNA of the protease-activated receptor 1 gene.
  • the length of the antisense oligonucleotide is preferably 10 to 100 bases.
  • Antisense oligonucleotides bind to mRNA to form duplexes and inhibit protein synthesis.
  • PAR1 siRNA is a small double-stranded RNA capable of regulating gene expression by RNA interference in a cell.
  • the length of siRNA is preferably 15 to 30 bases. Since shRNA having a hairpin structure is cleaved intracellularly to generate siRNA, shRNA can also be used as PAR1 siRNA.
  • the PAR1 antisense oligonucleotide or PAR1 siRNA (shRNA) used in the present invention can be designed by a method known in the art and produced using a known chemical synthesis method or biochemical synthesis method.
  • the “PAR1 neutralizing antibody” means an antibody that binds to protease-activated receptor 1 and can inhibit the binding of a ligand to the receptor.
  • PAR1 neutralizing antibodies can be produced using methods known in the art. Further, neutralizing antibodies known in the art may be used.
  • 2-Iminopyrrolidine Derivative As the PAR1 inhibitor or PAR1 antagonist used in the present invention, a 2-iminopyrrolidine derivative can be used.
  • the 2-iminopyrrolidine derivative includes a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • R 1 and R 2 are each independently the same or different and each represents a hydrogen atom, a methoxy group or an ethoxy group;
  • X 1 represents a hydrogen atom or a halogen atom;
  • Ar 2 is substituted with one or more substituents selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (II).
  • W represents —CH— or a nitrogen atom
  • a 1 represents —CH 2 — or a single bond
  • R 3 represents a hydrogen atom or —OR 5a
  • X 2 represents —CH 2 —, an oxygen atom, a single bond or a carbonyl group
  • Y represents a single bond or a C 1 -C 4 alkylene group
  • R 4 represents a hydrogen atom, —OR 6a , a cyano group, or —COOR 7
  • R 5a , R 6a and R 7 are each independently the same or different and each represents a hydrogen atom or a C 1 -C 4 alkyl group.
  • R 1 and R 2 are ethoxy groups, and X 1 is a fluorine atom.
  • halogen atom examples include atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom.
  • C 1 -C 4 alkyl group represents an alkyl group having 1 to 4 carbon atoms
  • suitable groups include, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group
  • suitable groups include linear or branched alkyl groups such as n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, and more preferably methyl group, ethyl group, n-propyl group, iso-propyl group.
  • C 1 -C 4 alkylene group refers to a divalent group derived by further removing one hydrogen atom at an arbitrary position of the C 1 -C 4 alkyl group.
  • methylene group, ethylene group, methylethylene group, propylene group, ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group and the like can be mentioned.
  • n- means normal type or primary substituent
  • sec- means secondary substituent
  • t- (tert-) Means a tertiary substituent
  • i- (iso-) means an isotype substituent
  • the compound that inhibits the function of PAR1 used in the present invention, or a pharmaceutically acceptable salt, or a hydrate thereof can be produced by a person skilled in the art by a known method.
  • the 2-iminopyrrolidine derivative represented by the above general formula (I) can be produced by the method described in WO 02/085855.
  • one or a plurality of 2-iminopyrrolidine derivatives represented by the general formula (I) of the present invention, pharmaceutically acceptable salts or hydrates thereof are used in appropriate combination. be able to.
  • preferred compounds are those represented by formulas (III) to (IX) or pharmaceutically acceptable salts or hydrates thereof, more preferably in formula (III) Or a pharmaceutically acceptable salt or hydrate thereof.
  • the compound represented by the formula (III) may be referred to as “E5555” in the present specification.
  • the hydrobromide salt of the compound represented by the formula (III) may be referred to as “Atopaxar”.
  • 2-Iminopyrrolidine derivatives represented by the formulas (III) to (IX) can be produced by the method described in International Publication No. 02/085855 pamphlet.
  • PAR1 inhibitors including 2-iminopyrrolidine derivatives used in the present invention may form salts with acids or bases.
  • the substance in the present invention includes these pharmaceutically acceptable salts.
  • the salt means a “pharmaceutically acceptable salt”, and the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with the compound.
  • hydrohalide for example, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.
  • inorganic acid for example, sulfate, nitrate, perchloric acid
  • phosphate carbonate, bicarbonate, etc.
  • organic carboxylates eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.
  • organic sulfonate For example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.
  • amino acid salts eg aspartate, glutamate, etc.
  • quaternary amines examples thereof include, but are not limited to, salts, alkali metal salts (for example, sodium salts, potassium salts and the like), alkaline earth metal salts (for example
  • the PAR1 inhibitor or 2-iminopyrrolidine derivative used in the present invention has an asymmetric carbon depending on the type of substituent, and there are optical isomers such as geometric isomers, optical isomers, diastereomers, etc. However, these optical isomers are also included in the compound having an action of inhibiting the function of PAR1 of the present invention.
  • the PAR1 inhibitor containing a 2-iminopyrrolidine derivative when a hydrate exists, is also included in the compound having an action of inhibiting the function of PAR1 used in the present invention. It is.
  • the pharmaceutical composition of the present invention comprises a compound having an action of inhibiting the function of PAR1.
  • the compound having an action of inhibiting the function of PAR1 is preferably a PAR1 antagonist, more preferably a 2-iminopyrrolidine derivative represented by the general formula (I), More preferred is at least one compound selected from compounds represented by formulas (III) to (IX), and most preferred is a compound represented by formula (III).
  • the PAR1 inhibitor contained in the therapeutic or preventive agent for pulmonary hypertension of the present invention also includes pharmaceutically acceptable salts or hydrates thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III).
  • a PAR1 inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof suppresses the increase in right ventricular pressure, which is an indicator of pulmonary hypertension, and suppresses right ventricular hypertrophy in pulmonary hypertension model animals. Therefore, the pharmaceutical composition of the present invention containing the substance as an active ingredient is effective in treating or preventing pulmonary hypertension.
  • the pharmaceutical composition of the present invention eliminates symptoms of pulmonary hypertension, reduces symptoms, delays progression, prevents onset of pulmonary hypertension, delays onset, It is useful for reducing the symptoms. That is, the pharmaceutical composition of the present invention can be used as a therapeutic agent for pulmonary hypertension or as a prophylactic agent for pulmonary hypertension.
  • the therapeutic agent or prophylactic agent of the present invention can be administered to a subject in need of treatment or prevention of pulmonary hypertension.
  • the subject is preferably a mammal, such as humans, rats, rabbits, sheep, pigs, cows, cats, dogs and monkeys, with humans being particularly preferred.
  • the therapeutic agent includes a prognosis improving agent and a recurrence preventing agent.
  • the therapeutic agent or prophylactic agent of the present invention may be provided as a kit.
  • the kit of the present invention may contain a container, a label, a package insert, etc. in addition to containing a PAR1 inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a compound having a function of inhibiting the function of PAR1 or a pharmaceutically acceptable salt or hydrate thereof may be used as it is, or a known pharmaceutically acceptable salt.
  • the carrier may be formulated and used as a formulation.
  • pharmaceutically acceptable carriers include excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, A pH adjuster, a preservative, an antioxidant, etc. can be mentioned.
  • the administration form of the therapeutic agent and prophylactic agent of the present invention is not particularly limited, and can be administered orally or parenterally.
  • parenteral administration include intravenous injection, intravenous drip, subcutaneous injection, intradermal injection, intraperitoneal injection, and intramuscular injection.
  • the dosage form used for oral administration include tablets, powders, fine granules, granules, capsules, and syrups.
  • dosage forms used for parenteral administration include suppositories, injections, ointments, and poultices.
  • excipient examples include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, and the like
  • binder examples include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like.
  • magnesium stearate, talc, silica and the like are permitted to be added to pharmaceuticals as a coloring agent, and as a flavoring agent, cocoa powder, mint brain, aromatic acid, etc.
  • Mint oil, Borneolum, cinnamon powder, etc. are used.
  • these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. as required.
  • the injection is a non-aqueous diluent (for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol), suspension agents, solubilizers, and stable agents. It can be prepared by adding an agent, an isotonic agent, a preservative, a pH adjusting agent, a buffering agent and the like. Sterilization of the injection may be performed by filtration sterilization using a filter, blending of a bactericide, and the like. Moreover, an injection can be manufactured as a form of preparation at the time of use.
  • a non-aqueous diluent for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol
  • suspension agents such as olive oil
  • solubilizers such as ethanol
  • stable agents for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol
  • the injection can be an intravenous infusion or a intravenous, subcutaneous or intramuscular injection by a conventional method.
  • suspending agent examples include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
  • solubilizer examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
  • Examples of the stabilizer include sodium sulfite and sodium metasulfite.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
  • the effective dose of the compound having an action of inhibiting the function of PAR1 or its pharmaceutically acceptable salt or hydrate thereof in oral administration is the degree of symptoms, patient age, sex, body weight, sensitivity difference Depending on the administration method, administration timing, administration interval, administration period, properties of the preparation, preparation, type, type of active ingredient, etc., those skilled in the art can appropriately set. For example, 0.1 to 500 mg, preferably 0.5 to 200 mg, more preferably 5 to 200 mg per day can be orally administered to an adult (body weight 60 kg).
  • Effective doses of parenteral administration for example, a compound having an action of inhibiting the function of PAR1 in an injection or a pharmaceutically acceptable salt thereof or a hydrate thereof are determined according to the degree of symptoms, patient age, sex , Body weight, sensitivity difference, administration method, administration timing, administration interval, administration period, formulation properties, preparation, type, type of active ingredient, etc. Or what was melt
  • carriers such as commercially available distilled water for injection, can be suitably administered with respect to the patient who requires treatment.
  • 0.1 to 500 mg, preferably 0.5 to 200 mg, more preferably 5 to 200 mg per day can be administered to an adult (body weight 60 kg).
  • the present invention also provides a treatment for pulmonary hypertension, characterized by administering to a subject an effective amount of a compound or pharmaceutically acceptable salt or hydrate thereof having an action of inhibiting the function of PAR1.
  • the compound having an action of inhibiting the function of PAR1 is preferably a PAR1 antagonist, more preferably a 2-iminopyrrolidine derivative represented by the general formula (I), and more preferably It is at least one compound selected from compounds represented by (III) to (IX), and most preferably a compound represented by formula (III).
  • the PAR1 inhibitor includes a pharmaceutically acceptable salt thereof or a hydrate thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III).
  • the administration route and administration method of the PAR1 inhibitor are not particularly limited, but reference can be made to the description of the pharmaceutical composition of the present invention.
  • the present invention includes a compound having a function of inhibiting the function of PAR1 or a pharmaceutically acceptable salt thereof or a hydrate thereof, preferably pulmonary hypertension, for a therapeutic or preventive agent for pulmonary hypertension.
  • 2-iminopyrrolidine derivatives for the treatment or prevention of diseases.
  • the 2-iminopyrrolidine derivative is preferably a 2-iminopyrrolidine derivative represented by general formula (I), more preferably at least selected from compounds represented by formulas (III) to (IX)
  • One compound most preferably a compound represented by the formula (III).
  • the 2-iminopyrrolidine derivatives include pharmaceutically acceptable salts or hydrates thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III).
  • Monocrotaline-induced rat pulmonary hypertension model was prepared according to the method described in Abe K, Circ Res, 94: 385-393, 2004.
  • Monocrotaline manufactured by Sigma-Aldrich
  • E5555 is a 30 mg / kg dose of 30 mg / kg suspended in 0.5% methylcellulose solution once daily every day from the day of the subcutaneous injection of monocrotaline to the day before the measurement. Used and administered orally.
  • rats were euthanized with a lethal dose of intravenous pentobarbital, the heart was removed, the left ventricle including the right ventricle and the ventricular septum was weighed, and the ratio was used as an index of right ventricular hypertrophy.
  • FIG. 4 shows the effect of Atopaxar (30 mg / kg / day) on monocrotaline-induced rat pulmonary hypertension.
  • the left figure shows the effect on right ventricular pressure, and the right figure shows the effect on right ventricular hypertrophy.
  • FIG. 5 shows the effect of Atopaxar (30 mg / kg / day) on monocrotaline-induced rat pulmonary hypertension.
  • the left figure shows the effect on systemic systolic blood pressure, and the right figure shows the effect on heart rate.
  • the present inventor has revealed that thrombin and its receptor play an important role in the onset and pathogenesis of pulmonary hypertension.
  • a compound having an action of inhibiting the function of PAR1 can suppress right ventricular pressure and right ventricular hypertrophy without changing heart rate and systemic systolic blood pressure. Therefore, it can be said that a compound having an action of inhibiting the function of PAR1 is useful as an active ingredient of a therapeutic and prophylactic agent for pulmonary hypertension, which has a low possibility of causing a side effect, and the present invention inhibits the function of PAR1.
  • the present invention provides a therapeutic agent for pulmonary hypertension and a preventive agent for pulmonary hypertension, which comprise a compound having the above-mentioned action as an active ingredient. According to the present invention, a new treatment or prevention method for pulmonary hypertension is provided, and it has become possible to contribute to the treatment or prevention of pulmonary hypertension patients.

Abstract

　The purpose of the present invention is to provide a treatment agent or a prevention agent for pulmonary hypertension. The present invention relates to a treatment agent or a prevention agent for pulmonary hypertension, the agent comprising a compound having PAR1 antagonism, such as a 2-iminopyrrolidine derivative represented by general formula (1), or a pharmaceutically acceptable salt of the same, or hydrates of the same.

Description

トロンビン受容体アンタゴニストを有効成分とする肺高血圧症の予防治療剤Preventive and therapeutic agent for pulmonary hypertension containing thrombin receptor antagonist as an active ingredient
　本発明は、肺高血圧症の予防剤及び治療剤に関する。 The present invention relates to a preventive agent and a therapeutic agent for pulmonary hypertension.
　肺高血圧症（pulmonary hypertension；ＰＨ）は、進行性の肺血管抵抗および肺動脈圧の上昇を特徴とする慢性かつ進行性の難病であり、従来の治療では５年間の生存率が３０％といわれている。肺高血圧症の3大病理所見は、（１）血管収縮、（２）血管リモデリング、（３）血栓形成であり、これらは血管抵抗性の上昇に関与すると考えられている。血液抗凝固療法が、肺高血圧患者の予後を改善するという報告もあるが（非特許文献１）、肺高血圧症における血栓形成の役割は未だ解明されていない。 Pulmonary hypertension (PH) is a chronic and progressive intractable disease characterized by progressive pulmonary vascular resistance and increased pulmonary arterial pressure, and conventional treatment is said to have a survival rate of 30% for 5 years. Yes. The three major pathological findings of pulmonary hypertension are (1) vasoconstriction, (2) vascular remodeling, and (3) thrombus formation, which are thought to be involved in the increase in vascular resistance. Although there is a report that blood anticoagulation therapy improves the prognosis of patients with pulmonary hypertension (Non-patent Document 1), the role of thrombus formation in pulmonary hypertension has not yet been elucidated.
　肺高血圧を治療するために、過去10余年の間に、プロスタサイクリン製剤、ホスホジエステラーゼ阻害剤、エンドセリン受容体拮抗薬が開発され、予後改善に大きな貢献を果たしてきた。しかしながら、肺高血圧症は未だ予後不良の疾患であり、新たな視点からの病態解明と治療法の開発が急務である。 In the past 10 years, prostacyclin preparations, phosphodiesterase inhibitors, and endothelin receptor antagonists have been developed to treat pulmonary hypertension and have contributed greatly to improving prognosis. However, pulmonary hypertension is still a disease with a poor prognosis, and there is an urgent need to elucidate the pathology from a new viewpoint and develop a treatment method.
　ところで、プロテアーゼ活性化受容体(ＰＡＲ)は、Ｇタンパク質共役受容体の１ファミリーを形成し、トロンビン等の血液凝固に関与するプロテアーゼによる種々の細胞作用を仲介する。トロンビンは、ＰＡＲの４つのサブタイプの中、主にＰＡＲ１を活性化することによって血管平滑筋の収縮、遊走、および増殖を誘導する。体循環系の正常な動脈では、ＰＡＲは平滑筋においてほとんど発現せず、トロンビンによる収縮効果はほぼ観察されないことが知られている。一方、本発明者らは、病変部血管では、動脈平滑筋においてＰＡＲの発現が誘導され、トロンビンに対する反応性が誘導、あるいは、増強されることを明らかにした（非特許文献２、図１）。さらに、本発明者らは、肺動脈平滑筋においてＲＯＣＫ（Rho-associated kinase）の活性上昇とＲＯＳ（reactive oxygen species）の産生が確認されることも見出した（非特許文献３および４、図２）。 By the way, protease activated receptors (PAR) form a family of G protein-coupled receptors and mediate various cellular actions by proteases involved in blood coagulation such as thrombin. Thrombin induces vascular smooth muscle contraction, migration, and proliferation by activating PAR1 among the four subtypes of PAR. In normal arteries of the systemic circulation, PAR is hardly expressed in smooth muscle, and it is known that the contraction effect by thrombin is hardly observed. On the other hand, the present inventors have revealed that, in the lesioned blood vessel, the expression of PAR is induced in arterial smooth muscle, and the reactivity to thrombin is induced or enhanced (Non-patent Document 2, FIG. 1). . Furthermore, the present inventors have also found that increased activity of ROCK (Rho-associated -kinase) and production of ROS (reactive oxygen species) are confirmed in pulmonary artery smooth muscle (Non-Patent Documents 3 and 4, FIG. 2). .
　しかしながら、トロンビンおよびＰＡＲ１と、肺高血圧症の発症、病変形成および病理との関係については未だ解明されておらず、また、トロンビン及びＰＡＲ１に関連するメカニズムを介した肺高血圧症の治療薬の研究も行われていなかった。 However, the relationship between thrombin and PAR1 and the onset, lesion formation and pathology of pulmonary hypertension has not been elucidated, and research on therapeutic agents for pulmonary hypertension through mechanisms related to thrombin and PAR1 has also been conducted. It was not done.
　本発明は、このような状況に鑑みてなされたものであり、肺高血圧症に対する治療剤または予防剤を提供することを目的とする。 The present invention has been made in view of such a situation, and an object thereof is to provide a therapeutic or preventive agent for pulmonary hypertension.
　本発明者は、上記課題を解決するために鋭意研究した結果、ＰＡＲ１が肺高血圧症の新たな治療ターゲットとして有効であること、およびＰＡＲ１を阻害することにより、肺高血圧症を予防または治療することが可能であることを明らかにし、本発明を完成させた。 As a result of intensive studies to solve the above problems, the present inventor has demonstrated that PAR1 is effective as a new therapeutic target for pulmonary hypertension, and prevents or treats pulmonary hypertension by inhibiting PAR1. The present invention has been completed.
　すなわち、本発明は以下に関する。
[１]　プロテアーゼ活性化受容体１（PAR1）の機能を阻害する作用を有する化合物もしくはその薬学的に許容される塩又はそれらの水和物を含有する、肺高血圧症の治療剤又は予防剤。
[２]　プロテアーゼ活性化受容体１の機能を阻害する作用を有する化合物が、PAR1拮抗物質である、上記[１]記載の治療剤又は予防剤。
[３]　プロテアーゼ活性化受容体１の機能を阻害する作用を有する化合物が、２－イミノピロリジン誘導体である、上記[１]又は[２]記載の治療剤又は予防剤。
[４]　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
　前記２－イミノピロリジン誘導体が、一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000005
  
 
[式（Ｉ）中、Ｒ１及びＲ２は、それぞれ独立し、同一又は相異なって、水素原子、メトキシ基又はエトキシ基を；Ｘ1は水素原子又はハロゲン原子を；Ａｒ2は、メチル基、エチル基、メトキシ基、エトキシ基、ｔ－ブチル基、モルホリニル基、又は下記式（ＩＩ）で表される置換基から選ばれる１又は２以上の置換基で置換されていてもよいフェニル基を示し、
Figure JPOXMLDOC01-appb-C000006
  
 
式（ＩＩ）中、Ｗは－ＣＨ－又は窒素原子を；Ａ１は－ＣＨ２－又は単結合を；Ｒ３は水素原子又は－ＯＲ５ａを；Ｘ２は－ＣＨ２－、酸素原子、単結合又はカルボニル基を；Ｙは単結合又はＣ１～Ｃ４アルキレン基を；Ｒ４は水素原子、－ＯＲ６ａ、シアノ基又は－ＣＯＯＲ７を；Ｒ５ａ、Ｒ６ａ及びＲ７は、それぞれ独立し、同一又は相異なって、水素原子又はC１～C４アルキル基を示す。]
で表される化合物、もしくはその薬学的に許容される塩、またはそれらの水和物である、前記治療剤又は予防剤。
[５]　前記Ｒ１及びＲ２がエトキシ基であり、かつ、前記Ｘ1がフッ素原子である、上記[４]記載の治療剤又は予防剤。
[６]　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
　前記２－イミノピロリジン誘導体が、式（ＩＩＩ）～（ＩＸ）で表される化合物からなる群から選ばれる少なくとも１つ、もしくはその薬学的に許容される塩又はそれらの水和物である、前記治療剤又は予防剤。
Figure JPOXMLDOC01-appb-C000007
  
 
[７]　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
　前記２－イミノピロリジン誘導体が、式（ＩＩＩ）で表される化合物もしくはその薬学的に許容される塩又はそれらの水和物である、前記治療剤又は予防剤。
Figure JPOXMLDOC01-appb-C000008
  
 
[８]　上記[４]～[７]のいずれか一項に記載の２－イミノピロリジン誘導体を含む、肺高血圧症の治療用又は予防用キット。
[９]　上記[４]～[７]のいずれか一項に記載の２－イミノピロリジン誘導体の有効量を対象に投与することを含む、肺高血圧症の治療又は予防のための方法。
[１０]　肺高血圧症の治療剤又は予防剤のための、上記[４]～[７]のいずれか一項に記載の２－イミノピロリジン誘導体。 That is, the present invention relates to the following.
[1] A therapeutic or preventive agent for pulmonary hypertension, comprising a compound having an action of inhibiting the function of protease-activated receptor 1 (PAR1) or a pharmaceutically acceptable salt thereof or a hydrate thereof.
[2] The therapeutic or prophylactic agent according to [1] above, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a PAR1 antagonist.
[3] The therapeutic or prophylactic agent according to the above [1] or [2], wherein the compound having an action of inhibiting the function of the protease activated receptor 1 is a 2-iminopyrrolidine derivative.
[4] A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative has the general formula (I)
Figure JPOXMLDOC01-appb-C000005

[In the formula (I), R 1 and R 2 are each independently the same or different and represent a hydrogen atom, a methoxy group or an ethoxy group; X 1 represents a hydrogen atom or a halogen atom; Ar 2 represents a methyl group , An ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a phenyl group optionally substituted with one or more substituents selected from the substituents represented by the following formula (II): Show
Figure JPOXMLDOC01-appb-C000006

In the formula (II), W represents —CH— or a nitrogen atom; A 1 represents —CH 2 — or a single bond; R 3 represents a hydrogen atom or —OR 5a ; X 2 represents —CH 2 —, an oxygen atom, Y represents a single bond or a C 1 -C 4 alkylene group; R 4 represents a hydrogen atom, —OR 6a , a cyano group or —COOR 7 ; R 5a , R 6a and R 7 each represents Independently, the same or different, each represents a hydrogen atom or a C 1 -C 4 alkyl group. ]
The said therapeutic agent or prophylactic agent which is the compound represented by these, its pharmaceutically acceptable salt, or those hydrates.
[5] The therapeutic or prophylactic agent according to the above [4], wherein R 1 and R 2 are ethoxy groups, and X 1 is a fluorine atom.
[6] A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative is at least one selected from the group consisting of compounds represented by formulas (III) to (IX), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. A therapeutic or prophylactic agent.
Figure JPOXMLDOC01-appb-C000007

[7] A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
The therapeutic or prophylactic agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (III), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
Figure JPOXMLDOC01-appb-C000008

[8] A kit for treating or preventing pulmonary hypertension, comprising the 2-iminopyrrolidine derivative according to any one of [4] to [7] above.
[9] A method for treating or preventing pulmonary hypertension, comprising administering to a subject an effective amount of the 2-iminopyrrolidine derivative according to any one of [4] to [7] above.
[10] The 2-iminopyrrolidine derivative according to any one of [4] to [7] above, for a therapeutic or preventive agent for pulmonary hypertension.
　本発明により、トロンビンとその受容体が肺高血圧の発症と病態形成に重要な役割を果たすことが明らかになった。ＰＡＲ１の機能を阻害する作用を有する化合物は、心拍および全身収縮期血圧を変化させることなく、右心室圧および右心室肥大を抑制することが可能である。したがって、ＰＡＲ１の機能を阻害する作用を有する化合物は、副作用を引き起こす可能性の低い、肺高血圧症の治療剤および予防剤の有効成分として有用であるといえ、本発明により、ＰＡＲ１の機能を阻害する作用を有する化合物を有効成分として含む肺高血圧症の治療剤および肺高血圧症の予防剤が提供される。本発明により、肺高血圧症の新たな治療法または予防法が提供され、肺高血圧症患者の治療または予防に貢献することが可能となった。 The present invention revealed that thrombin and its receptor play an important role in the onset and pathogenesis of pulmonary hypertension. A compound having an action of inhibiting the function of PAR1 can suppress right ventricular pressure and right ventricular hypertrophy without changing heart rate and systemic systolic blood pressure. Therefore, it can be said that a compound having an action of inhibiting the function of PAR1 is useful as an active ingredient of a therapeutic and prophylactic agent for pulmonary hypertension, which has a low possibility of causing a side effect, and the present invention inhibits the function of PAR1. The present invention provides a therapeutic agent for pulmonary hypertension and a preventive agent for pulmonary hypertension, which comprise a compound having the above-mentioned action as an active ingredient. According to the present invention, a new treatment or prevention method for pulmonary hypertension is provided, and it has become possible to contribute to the treatment or prevention of pulmonary hypertension patients.
肺動脈平滑筋のトロンビンに対する反応性を示す模式図である。It is a schematic diagram which shows the reactivity with respect to thrombin of pulmonary artery smooth muscle. 肺動脈平滑筋のトロンビンに対する反応性を示す模式図である。It is a schematic diagram which shows the reactivity with respect to thrombin of pulmonary artery smooth muscle. トロンビン及びPAR1-活性化ペプチド（PAR1-AP）によるPAR1の活性化機構を示す図である。It is a figure which shows the activation mechanism of PAR1 by thrombin and PAR1-activating peptide (PAR1-AP). モノクロタリン誘発ラット肺高血圧症に対するAtopaxar（30 mg/kg/day）の効果を示す図である。左図は右心室圧における効果を示し、右図は右心室肥大における効果を示す。It is a figure which shows the effect of Atopaxar (30 mg / kg / day) with respect to monocrotaline induction rat pulmonary hypertension. The left figure shows the effect on right ventricular pressure, and the right figure shows the effect on right ventricular hypertrophy. モノクロタリン誘発ラット肺高血圧症に対するAtopaxar（30 mg/kg/day）の効果を示す図である。左図は全身収縮期血圧における効果を示し、右図は心拍における効果を示す。It is a figure which shows the effect of Atopaxar (30 mg / kg / day) with respect to monocrotaline induction rat pulmonary hypertension. The left figure shows the effect on systemic systolic blood pressure, and the right figure shows the effect on heart rate.
　以下、本発明を詳細に説明する。以下の実施の形態は、本発明を説明するための例示であり、本発明をこの実施の形態にのみ限定する趣旨ではない。本発明は、その要旨を逸脱しない限り、さまざまな形態で実施をすることができる。また、本明細書において引用した刊行物は、全体を通して本明細書に組み込むものとする。 Hereinafter, the present invention will be described in detail. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof. In addition, publications cited in this specification are incorporated herein in their entirety.
　本発明は、PAR1の機能を阻害する作用を有する化合物を有効成分として含有する、肺高血圧症の治療剤もしくは予防剤または治療用もしくは予防用キットを提供するものである。 The present invention provides a therapeutic or prophylactic agent for pulmonary hypertension or a therapeutic or prophylactic kit containing a compound having an action of inhibiting the function of PAR1 as an active ingredient.
１．PAR1の機能を阻害する作用を有する化合物
（１）PAR1
　PAR1は、プロテアーゼ活性化受容体（protease-activated receptor）の一つであり、その細胞外の特定の領域がプロテアーゼによって分解を受けることにより活性化されるGタンパク質共役型受容体である。PAR1の活性化機構を図３に示す。受容体の活性化は、受容体のN末端側の特定部位がセリンプロテアーゼによって切断されることにより受容体活性化配列が露出し、これがリガンドとなって受容体のリガンド結合部位に結合することにより生ずる。PAR1のアゴニストは、プロテアーゼとして機能するトロンビン、トリプシンが見出されているほか、受容体活性化配列の合成ペプチド、例えばPAR1-AP（PAR1 activating peptide）もアゴニストとして機能することが知られている。このPAR1-APの配列には、SFLLRN（ヒト、アミノ酸一文字表記、配列番号１）、TFRIFD（カエル、アミノ酸一文字表記、配列番号２）などが同定されている。 1. Compound (1) PAR1 that has the function of inhibiting the function of PAR1
PAR1 is one of protease-activated receptors and is a G protein-coupled receptor that is activated when a specific region outside the cell is degraded by proteases. The activation mechanism of PAR1 is shown in FIG. Receptor activation is achieved by binding a specific site on the N-terminal side of the receptor by a serine protease to expose the receptor activation sequence, which becomes a ligand and binds to the ligand binding site of the receptor. Arise. As PAR1 agonists, thrombin and trypsin that function as proteases have been found, and synthetic peptides of receptor activation sequences, such as PAR1-AP (PAR1 activating peptide), are also known to function as agonists. In this PAR1-AP sequence, SFLLRN (human, single letter code for amino acid, SEQ ID NO: 1), TFRIFD (frog, single letter code for amino acid, SEQ ID NO: 2) and the like have been identified.
（２）PAR1の機能を阻害する作用を有する化合物
　本明細書において、「PAR1の機能を阻害する作用を有する化合物」（本明細書において、「PAR1阻害物質」ともいう）は、PAR1の活性化を抑制する作用を有する物質であれば特に限定されず、国際公開０３／８９４２８号パンフレットに開示されているＳＣＨ５３０３４８（Ｎ－［（１Ｒ，３ａＲ，４ａＲ，６Ｒ，８ａＲ，９Ｓ，９ａＳ）－９－［２－［５－（３－Ｆｌｕｏｒｏｐｈｅｎｙｌ）ｐｙｒｉｄｉｎ－２－ｙｌ］ｖｉｎｙｌ］－１－ｍｅｔｈｙｌ－３－ｏｘｏｐｅｒｈｙｄｒｏｎａｐｈｔｈｏ［２，３－ｃ］ｆｕｒａｎ－６－ｙｌ］ｃａｒｂａｍｉｃ　ａｃｉｄ　ｅｔｈｙｌ　ｅｓｔｅｒ）等のPAR1拮抗物質の他、PAR1脱感作促進物質、PAR1アンチセンスオリゴヌクレオチド、PAR1 siRNA、PAR1中和抗体などを意味する。本発明に使用するPAR1阻害物質の好ましい特徴としては、PAR1に対して高い選択性を有していること、治療有効量において有効な作用、例えば右心室圧の上昇や右心室の肥大に対する阻害作用を示すこと、治療有効量において重篤な副作用、例えば心拍の異常亢進や全身収縮期血圧の上昇を生じないこと、及び即効性があることなどを挙げることができる。また、本発明においてPAR1阻害物質は、その薬学的に許容される塩またはそれらの水和物（詳細は後述する）も含まれる。 (2) Compound having an action of inhibiting the function of PAR1 In the present specification, “compound having an action of inhibiting the function of PAR1” (also referred to as “PAR1 inhibitor” in the present specification) is the activation of PAR1. The substance is not particularly limited as long as it has a function of suppressing SCH 530348 (N-[(1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9- 9) disclosed in International Publication No. 03/89428. PAR1 antagonists such as [2- [5- (3-Fluorophenyl) pyridin-2-yl] vinyl] -1-methyl-3-oxoperhydronaphtho [2,3-c] furan-6-yl] carbamic acid ester PAR1 desensitization promoter, PAR1 antisense oligonucleotide, PAR1 siRNA, PAR1 neutralizing anti Means the body. Preferred features of the PAR1 inhibitor used in the present invention include a high selectivity for PAR1, an effective action in a therapeutically effective amount, such as an increase in right ventricular pressure and an inhibition of right ventricular hypertrophy In the therapeutically effective amount, serious side effects such as abnormal increase in heart rate and increase in systemic systolic blood pressure, and immediate effect can be mentioned. In the present invention, the PAR1 inhibitor also includes pharmaceutically acceptable salts or hydrates thereof (details will be described later).
　したがって、本発明において、肺高血圧症の治療剤又は予防剤として使用するための好ましい化合物には、「PAR1の機能を阻害する作用を有する化合物」、特にPAR1拮抗物質もしくはその薬学的に許容される塩又はそれらの水和物を挙げることができる。 Therefore, in the present invention, preferred compounds for use as a therapeutic or preventive agent for pulmonary hypertension include “a compound having an action of inhibiting the function of PAR1”, particularly a PAR1 antagonist or a pharmaceutically acceptable salt thereof. Mention may be made of salts or their hydrates.
　本明細書において、「PAR1拮抗物質」、「PAR1の拮抗物質」とは、プロテアーゼ活性化受容体１の拮抗物質であり、PAR1に結合し、PAR1に存在する受容体活性化配列に相当する配列を含むポリペプチド部分とPAR1との結合を阻害する物質（いわゆる、PAR1アンタゴニスト）を意味する。
　また、本明細書において、「PAR1脱感作促進物質」とは、プロテアーゼ活性化受容体１を脱感作し、不活性化させる物質を意味する。PAR1脱感作促進物質は、当分野で公知の物質を選択し、使用することができる。また、当分野で公知の方法を用いて製造することができる。
　また、本明細書において、「PAR1アンチセンスオリゴヌクレオチド」とは、プロテアーゼ活性化受容体１遺伝子のｍＲＮＡに結合し得る一本鎖核酸である。アンチセンスオリゴヌクレオチドの長さは、好ましくは１０～１００塩基である。アンチセンスオリゴヌクレオチドは、ｍＲＮＡに結合して二重鎖を形成し、タンパク質の合成を抑制する。また、本明細書において、「PAR1 siRNA」とは、細胞においてＲＮＡ干渉により遺伝子発現を調節し得る低分子二本鎖ＲＮＡである。siRNAの長さは、好ましくは１５～３０塩基である。ヘアピン構造を有するshRNAは、細胞内で切断されsiRNAを生じるため、PAR1 siRNAとしてshRNAを用いることもできる。本発明で用いられるPAR1アンチセンスオリゴヌクレオチドまたはPAR1 siRNA（shRNA）は、当分野で公知の方法で設計し、公知の化学合成法又は生化学的合成法を用いて製造することができる。
　また、本明細書において、「PAR1中和抗体」とは、プロテアーゼ活性化受容体１に結合し、受容体へのリガンドの結合を阻害し得る抗体を意味する。PAR1中和抗体は、当分野で公知の方法を用いて製造することができる。また、当分野で公知の中和抗体を使用してもよい。 In the present specification, “PAR1 antagonist” and “PAR1 antagonist” are antagonists of protease-activated receptor 1, which bind to PAR1 and correspond to a receptor activation sequence present in PAR1. Means a substance (so-called PAR1 antagonist) that inhibits the binding of PAR1 to a polypeptide moiety containing
In the present specification, “PAR1 desensitization promoting substance” means a substance that desensitizes and inactivates protease-activated receptor 1. As the PAR1 desensitization promoting substance, a substance known in the art can be selected and used. Moreover, it can manufacture using a well-known method in this field | area.
In the present specification, “PAR1 antisense oligonucleotide” is a single-stranded nucleic acid that can bind to mRNA of the protease-activated receptor 1 gene. The length of the antisense oligonucleotide is preferably 10 to 100 bases. Antisense oligonucleotides bind to mRNA to form duplexes and inhibit protein synthesis. In the present specification, “PAR1 siRNA” is a small double-stranded RNA capable of regulating gene expression by RNA interference in a cell. The length of siRNA is preferably 15 to 30 bases. Since shRNA having a hairpin structure is cleaved intracellularly to generate siRNA, shRNA can also be used as PAR1 siRNA. The PAR1 antisense oligonucleotide or PAR1 siRNA (shRNA) used in the present invention can be designed by a method known in the art and produced using a known chemical synthesis method or biochemical synthesis method.
In the present specification, the “PAR1 neutralizing antibody” means an antibody that binds to protease-activated receptor 1 and can inhibit the binding of a ligand to the receptor. PAR1 neutralizing antibodies can be produced using methods known in the art. Further, neutralizing antibodies known in the art may be used.
（３）２－イミノピロリジン誘導体
　本発明に使用するPAR1阻害物質またはPAR1の拮抗物質として、２－イミノピロリジン誘導体を用いることができる。 (3) 2-Iminopyrrolidine Derivative As the PAR1 inhibitor or PAR1 antagonist used in the present invention, a 2-iminopyrrolidine derivative can be used.
　本発明において、２－イミノピロリジン誘導体には、以下の一般式（Ｉ）で表される化合物もしくはその薬学的に許容される塩又はそれらの水和物が含まれる。 In the present invention, the 2-iminopyrrolidine derivative includes a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof.
　一般式（Ｉ）
Figure JPOXMLDOC01-appb-C000009
  
 
　一般式（Ｉ）中、
　Ｒ１及びＲ２は、それぞれ独立し、同一又は相異なって、水素原子、メトキシ基又はエトキシ基を；
　Ｘ1は水素原子又はハロゲン原子を；
　Ａｒ2は、メチル基、エチル基、メトキシ基、エトキシ基、ｔ－ブチル基、モルホリニル基、又は下記の式（ＩＩ）で表される置換基から選ばれる１又は２以上の置換基で置換されていてもよいフェニル基を示し、
Figure JPOXMLDOC01-appb-C000010
  
 
式（ＩＩ）中、
　Ｗは－ＣＨ－又は窒素原子を；
　Ａ１は－ＣＨ２－又は単結合を；
　Ｒ３は水素原子又は－ＯＲ５ａを；
　Ｘ2は－ＣＨ２－、酸素原子、単結合又はカルボニル基を；
　Ｙは単結合又はＣ１～Ｃ４アルキレン基を；
　Ｒ４は水素原子、－ＯＲ６ａ、シアノ基又は－ＣＯＯＲ７を；
　Ｒ５ａ、Ｒ６ａ及びＲ７は、それぞれ独立し、同一又は相異なって、水素原子又はC１～C４アルキル基を示す。 Formula (I)
Figure JPOXMLDOC01-appb-C000009

In general formula (I),
R 1 and R 2 are each independently the same or different and each represents a hydrogen atom, a methoxy group or an ethoxy group;
X 1 represents a hydrogen atom or a halogen atom;
Ar 2 is substituted with one or more substituents selected from a methyl group, an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (II). An optionally substituted phenyl group,
Figure JPOXMLDOC01-appb-C000010

In formula (II),
W represents —CH— or a nitrogen atom;
A 1 represents —CH 2 — or a single bond;
R 3 represents a hydrogen atom or —OR 5a ;
X 2 represents —CH 2 —, an oxygen atom, a single bond or a carbonyl group;
Y represents a single bond or a C 1 -C 4 alkylene group;
R 4 represents a hydrogen atom, —OR 6a , a cyano group, or —COOR 7 ;
R 5a , R 6a and R 7 are each independently the same or different and each represents a hydrogen atom or a C 1 -C 4 alkyl group.
　一般式（Ｉ）において、好ましくは、Ｒ１及びＲ２がエトキシ基であり、かつ、Ｘ1がフッ素原子である。 In the general formula (I), preferably, R 1 and R 2 are ethoxy groups, and X 1 is a fluorine atom.
　本明細書において「ハロゲン原子」は、例えばフッ素原子、塩素原子、臭素原子、ヨウ素原子などの原子が挙げられ、好ましくはフッ素原子、塩素原子、臭素原子である。 In the present specification, examples of the “halogen atom” include atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably a fluorine atom, a chlorine atom and a bromine atom.
　本明細書において「C1～C4アルキル基」は、炭素数が１から４個のアルキル基を示し、好適な基としては例えばメチル基、エチル基、ｎ－プロピル基、ｉｓｏ－プロピル基、ｎ－ブチル基、ｉｓｏ－ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基等の直鎖又は分枝状アルキル基があげられ、より好ましくはメチル基、エチル基、ｎ－プロピル基、ｉｓｏ－プロピル基、ｎ－ブチル基、ｉｓｏ－ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基等である。 In the present specification, the “C 1 -C 4 alkyl group” represents an alkyl group having 1 to 4 carbon atoms, and suitable groups include, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, Examples thereof include linear or branched alkyl groups such as n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, and more preferably methyl group, ethyl group, n-propyl group, iso-propyl group. Group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group and the like.
　本明細書において「C１～C４アルキレン基」は、C１～C４アルキル基の任意の位置の水素原子をさらに１個除いて誘導される二価の基を示し、好適な基としては例えば、メチレン基、エチレン基、メチルエチレン基、プロピレン基、エチルエチレン基、1,1－ジメチルエチレン基、1,2－ジメチルエチレン基等が挙げられる。 In the present specification, the “C 1 -C 4 alkylene group” refers to a divalent group derived by further removing one hydrogen atom at an arbitrary position of the C 1 -C 4 alkyl group. For example, methylene group, ethylene group, methylethylene group, propylene group, ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group and the like can be mentioned.
　また、本明細書において「置換基を有していてもよい」とは、「置換可能な部位に、任意に組み合わせて１又は複数個の置換基を有してもよい」と同意義である。 Further, in the present specification, “may have a substituent” has the same meaning as “may have one or a plurality of substituents in any combination at a substitutable site”. .
　本明細書において「ｎ－」とはノルマルタイプ又は１級置換基であることを意味し、「ｓｅｃ－」とは２級置換基であることを意味し、「ｔ－（ｔｅｒｔ－）」とは３級置換基であることを意味し、「ｉ－（ｉｓｏ－）」とはイソタイプの置換基であることを意味する。 In the present specification, “n-” means normal type or primary substituent, “sec-” means secondary substituent, and “t- (tert-)” Means a tertiary substituent, and “i- (iso-)” means an isotype substituent.
　本発明において使用する前記PAR1の機能を阻害する化合物もしくは薬学的に許容される塩またはそれらの水和物は、当業者であれば公知の方法で製造することができる。例えば、前記の一般式（Ｉ）で表される２－イミノピロリジン誘導体は、国際公開02/085855号パンフレットに記載の方法で製造することができる。 The compound that inhibits the function of PAR1 used in the present invention, or a pharmaceutically acceptable salt, or a hydrate thereof can be produced by a person skilled in the art by a known method. For example, the 2-iminopyrrolidine derivative represented by the above general formula (I) can be produced by the method described in WO 02/085855.
　本発明において、本発明の一般式（Ｉ）で表される２－イミノピロリジン誘導体もしくはその薬学的に許容される塩又はそれらの水和物の中から１個又は複数個を適宜組み合わせて使用することができる。 In the present invention, one or a plurality of 2-iminopyrrolidine derivatives represented by the general formula (I) of the present invention, pharmaceutically acceptable salts or hydrates thereof are used in appropriate combination. be able to.
　一般式（Ｉ）において、好ましい化合物は、式（ＩＩＩ）～（ＩＸ）で表される化合物もしくはその薬学的に許容される塩又はそれらの水和物であり、より好ましくは式（ＩＩＩ）で表される化合物もしくはその薬学的に許容される塩又はそれらの水和物である。
Figure JPOXMLDOC01-appb-C000011
  
  In general formula (I), preferred compounds are those represented by formulas (III) to (IX) or pharmaceutically acceptable salts or hydrates thereof, more preferably in formula (III) Or a pharmaceutically acceptable salt or hydrate thereof.
Figure JPOXMLDOC01-appb-C000011
　式（ＩＩＩ）で表される化合物は、本明細書において「E5555」と称する場合もある。また、式（ＩＩＩ）で表される化合物の臭化水素酸塩は、「Atopaxar」と称する場合もある。
Figure JPOXMLDOC01-appb-C000012
  
  The compound represented by the formula (III) may be referred to as “E5555” in the present specification. In addition, the hydrobromide salt of the compound represented by the formula (III) may be referred to as “Atopaxar”.
Figure JPOXMLDOC01-appb-C000012
　式（ＩＩＩ）～（ＩＸ）で表される２－イミノピロリジン誘導体は、国際公開02/085855号パンフレットに記載の方法で製造することができる。 2-Iminopyrrolidine derivatives represented by the formulas (III) to (IX) can be produced by the method described in International Publication No. 02/085855 pamphlet.
　本発明において使用する２－イミノピロリジン誘導体を含むPAR1阻害物質は、酸又は塩基と塩を形成する場合もある。本発明における当該物質は、これらの薬学的に許容される塩をも包含する。本明細書において、塩は「薬学的に許容される塩」を意味し、薬学的に許容される塩は当該化合物と薬学的に許容される塩を形成するものであれば特に限定されない。具体的には、例えば、ハロゲン化水素酸塩（例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等）、無機酸塩（例えば硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩等）、有機カルボン酸塩（例えば酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩等）、有機スルホン酸塩（例えばメタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩等）、アミノ酸塩（例えばアスパラギン酸塩、グルタミン酸塩等）、四級アミン塩、アルカリ金属塩（例えばナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例えばマグネシウム塩、カルシウム塩等）等が挙げられるが、これに限定されない。 PAR1 inhibitors including 2-iminopyrrolidine derivatives used in the present invention may form salts with acids or bases. The substance in the present invention includes these pharmaceutically acceptable salts. In the present specification, the salt means a “pharmaceutically acceptable salt”, and the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with the compound. Specifically, for example, hydrohalide (for example, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid (for example, sulfate, nitrate, perchloric acid) Salt, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonate ( For example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary amines Examples thereof include, but are not limited to, salts, alkali metal salts (for example, sodium salts, potassium salts and the like), alkaline earth metal salts (for example, magnesium salts and calcium salts), and the like.
　また、本発明において使用されるPAR1阻害物質または２－イミノピロリジン誘導体は、置換基の種類によっては不斉炭素を有し、幾何異性体、光学異性体、ジアステレオマーなどの光学異性体が存在しうるが、これら光学異性体も本発明のPAR1の機能を阻害する作用を有する化合物に含まれる。 In addition, the PAR1 inhibitor or 2-iminopyrrolidine derivative used in the present invention has an asymmetric carbon depending on the type of substituent, and there are optical isomers such as geometric isomers, optical isomers, diastereomers, etc. However, these optical isomers are also included in the compound having an action of inhibiting the function of PAR1 of the present invention.
　また、本発明において、２－イミノピロリジン誘導体を含むPAR1阻害物質は、水和物が存在する場合には、これら水和物も本発明に使用するPAR1の機能を阻害する作用を有する化合物に含まれる。 In the present invention, the PAR1 inhibitor containing a 2-iminopyrrolidine derivative, when a hydrate exists, is also included in the compound having an action of inhibiting the function of PAR1 used in the present invention. It is.
２．肺高血圧症の治療剤及び予防剤
　本発明の医薬組成物、すなわち、本発明の肺高血圧症の治療剤及び予防剤は、PAR1の機能を阻害する作用を有する化合物を含むものである。本発明の治療剤および予防剤において、PAR1の機能を阻害する作用を有する化合物は、好ましくはPAR1拮抗物質であり、より好ましくは一般式（Ｉ）で表される２－イミノピロリジン誘導体であり、さらに好ましくは式（ＩＩＩ）～（ＩＸ）で表される化合物から選択される少なくとも１つの化合物であり、最も好ましくは式（ＩＩＩ）で表される化合物である。本発明の肺高血圧症の治療剤又は予防剤に含まれるPAR1阻害物質には、その薬学的に許容される塩またはそれらの水和物も含まれる。好ましくは、式（ＩＩＩ）で表される化合物の臭化水素酸塩である。 2. Therapeutic agent and preventive agent for pulmonary hypertension The pharmaceutical composition of the present invention, that is, the therapeutic agent and preventive agent for pulmonary hypertension of the present invention comprises a compound having an action of inhibiting the function of PAR1. In the therapeutic agent and prophylactic agent of the present invention, the compound having an action of inhibiting the function of PAR1 is preferably a PAR1 antagonist, more preferably a 2-iminopyrrolidine derivative represented by the general formula (I), More preferred is at least one compound selected from compounds represented by formulas (III) to (IX), and most preferred is a compound represented by formula (III). The PAR1 inhibitor contained in the therapeutic or preventive agent for pulmonary hypertension of the present invention also includes pharmaceutically acceptable salts or hydrates thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III).
　PAR1阻害物質もしくはその薬学的に許容される塩またはそれらの水和物は、肺高血圧症モデル動物において肺高血圧症の指標となる右心室圧の上昇を抑制する作用、右心室肥大を抑制する作用、および肺高血圧症の発症を予防する作用を有するため、当該物質を有効成分として含む本発明の医薬組成物は、肺高血圧の治療または予防に有効である。特に、本発明の医薬組成物は、肺高血圧症の症状を消失させること、症状を軽減すること、進行を遅延させること、肺高血圧症の発症を防止すること、発症を遅延させること、発症時の症状を軽減することなどに有用である。すなわち、本発明の医薬組成物は、肺高血圧の治療剤として、または肺高血圧の予防剤として用いることができる。 A PAR1 inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof suppresses the increase in right ventricular pressure, which is an indicator of pulmonary hypertension, and suppresses right ventricular hypertrophy in pulmonary hypertension model animals. Therefore, the pharmaceutical composition of the present invention containing the substance as an active ingredient is effective in treating or preventing pulmonary hypertension. In particular, the pharmaceutical composition of the present invention eliminates symptoms of pulmonary hypertension, reduces symptoms, delays progression, prevents onset of pulmonary hypertension, delays onset, It is useful for reducing the symptoms. That is, the pharmaceutical composition of the present invention can be used as a therapeutic agent for pulmonary hypertension or as a prophylactic agent for pulmonary hypertension.
　本発明の治療剤または予防剤は、肺高血圧症の治療または予防の必要のある対象に投与することができる。対象は、哺乳動物が好ましく、例えばヒト、ラット、ウサギ、ヒツジ、ブタ、ウシ、ネコ、イヌ、サルであり、中でもヒトが好ましい。 The therapeutic agent or prophylactic agent of the present invention can be administered to a subject in need of treatment or prevention of pulmonary hypertension. The subject is preferably a mammal, such as humans, rats, rabbits, sheep, pigs, cows, cats, dogs and monkeys, with humans being particularly preferred.
　本発明において、治療剤には予後改善剤および再発予防剤なども含まれる。 In the present invention, the therapeutic agent includes a prognosis improving agent and a recurrence preventing agent.
　また、本発明の治療剤または予防剤は、キットとして提供されてもよい。本発明のキットは、PAR1阻害物質もしくはその薬学的に許容される塩またはそれらの水和物を含む他、容器、ラベル、添付文書等を含めることができる。 Moreover, the therapeutic agent or prophylactic agent of the present invention may be provided as a kit. The kit of the present invention may contain a container, a label, a package insert, etc. in addition to containing a PAR1 inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof.
　本発明の治療剤及び予防剤には、前記PAR1の機能を阻害する作用を有する化合物もしくは薬学的に許容される塩又はそれらの水和物をそのまま用いてもよいし、公知の薬学的に許容される担体などを配合して製剤化して用いてもよい。このような薬学的に許容される担体としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、安定化剤、乳化剤、吸収促進剤、界面活性剤、ｐＨ調整剤、防腐剤、抗酸化剤などを挙げることができる。 In the therapeutic agent and prophylactic agent of the present invention, a compound having a function of inhibiting the function of PAR1 or a pharmaceutically acceptable salt or hydrate thereof may be used as it is, or a known pharmaceutically acceptable salt. The carrier may be formulated and used as a formulation. Examples of such pharmaceutically acceptable carriers include excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, A pH adjuster, a preservative, an antioxidant, etc. can be mentioned.
　また、本発明の治療剤及び予防剤の投与形態は特に限定されず、経口又は非経口的に投与することができる。非経口投与の形態として、例えば静脈内注射、点滴静注、皮下注射、皮内注射、腹腔内注射、又は筋肉内注射などが挙げられる。経口投与に用いられる剤形としては、錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤などが挙げられる。非経口投与に用いられる剤形としては、坐剤、注射剤、軟膏剤、バップ剤などが挙げられる。 The administration form of the therapeutic agent and prophylactic agent of the present invention is not particularly limited, and can be administered orally or parenterally. Examples of parenteral administration include intravenous injection, intravenous drip, subcutaneous injection, intradermal injection, intraperitoneal injection, and intramuscular injection. Examples of the dosage form used for oral administration include tablets, powders, fine granules, granules, capsules, and syrups. Examples of dosage forms used for parenteral administration include suppositories, injections, ointments, and poultices.
　経口投与に用いられる経口用製剤を調製する場合には、有効成分に賦形剤、さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤などを加えた後、常法により錠剤、被覆錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤等とすることができる。 When preparing an oral preparation to be used for oral administration, it is usually necessary to add an excipient to the active ingredient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like. According to the method, tablets, coated tablets, powders, fine granules, granules, capsules, syrups and the like can be obtained.
　賦形剤としては、例えば、乳糖、コーンスターチ、白糖、ぶどう糖、ソルビット、結晶セルロース、二酸化ケイ素などが、結合剤としては、例えばポリビニルアルコール、エチルセルロース、メチルセルロース、アラビアゴム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等が、滑沢剤としては、例えばステアリン酸マグネシウム、タルク、シリカ等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、ココア末、ハッカ脳、芳香酸、ハッカ油、龍脳、桂皮末等が用いられる。これらの錠剤、顆粒剤には糖衣、ゼラチン衣、その他必要により適宜コーティングすることは勿論差し支えない。 Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, and the like, and examples of the binder include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like. However, as a lubricant, for example, magnesium stearate, talc, silica and the like are permitted to be added to pharmaceuticals as a coloring agent, and as a flavoring agent, cocoa powder, mint brain, aromatic acid, etc. Mint oil, Borneolum, cinnamon powder, etc. are used. Of course, these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. as required.
　本発明において、注射剤は、必要により主薬に非水性の希釈剤（例えばプロピレングリコール、ポリエチレングリコールなどのグリコール、オリーブ油などの植物油、エタノールなどのアルコール類など）、懸濁剤、溶解補助剤、安定化剤、等張化剤、保存剤、pH調整剤、緩衝剤などを添加して調製することが可能である。注射剤の無菌化は、フィルターによる濾過滅菌、殺菌剤の配合などにより行えばよい。また、注射剤は、用時調製の形態として製造することができる。すなわち、凍結乾燥法などによって無菌の固体組成物とし、使用前に無菌の注射用蒸留水又は他の溶媒に溶解して使用することができる。貼布剤として経皮吸収により投与する場合には、塩を形成しない、いわゆるフリー体を選択することが好ましい。注射剤は、常法により点滴静注剤、あるいは静脈、皮下、筋肉内注射剤とすることができる。 In the present invention, if necessary, the injection is a non-aqueous diluent (for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol), suspension agents, solubilizers, and stable agents. It can be prepared by adding an agent, an isotonic agent, a preservative, a pH adjusting agent, a buffering agent and the like. Sterilization of the injection may be performed by filtration sterilization using a filter, blending of a bactericide, and the like. Moreover, an injection can be manufactured as a form of preparation at the time of use. That is, it can be used as a sterile solid composition by lyophilization, etc., and dissolved in sterile water for injection or other solvent before use. When administering by transdermal absorption as a patch, it is preferable to select a so-called free body that does not form a salt. The injection can be an intravenous infusion or a intravenous, subcutaneous or intramuscular injection by a conventional method.
　懸濁剤としては、例えば、メチルセルロース、ポリソルベート80、ヒドロキシエチルセルロース、アラビアゴム、トラガント末、カルボキシメチルセルロースナトリウム、ポリオキシエチレンソルビタンモノラウレートなどを挙げることができる。 Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
　溶解補助剤としては、例えばポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、ヒマシ油脂肪酸エチルエステルなどを挙げることができる。 Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
　また、安定化剤としては、例えば亜硫酸ナトリウム、メタ亜硫酸ナトリウム等を、保存剤としては、例えばパラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸、フェノール、クレゾール、クロロクレゾールなどを挙げることができる。 Examples of the stabilizer include sodium sulfite and sodium metasulfite. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
　経口投与における前記PAR1の機能を阻害する作用を有する化合物もしくはその薬学的に許容される塩又はそれらの水和物の有効な投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、投与間隔、投与期間、製剤の性質、調剤、種類、有効成分の種類等によって異なるが、当業者であれば適宜設定することができる。例えば、成人（体重６０Ｋｇ）に１日あたり０．１～５００ｍｇ、好ましくは０．５～２００ｍｇ、より好ましくは５～２００ｍｇを経口投与することができる。 The effective dose of the compound having an action of inhibiting the function of PAR1 or its pharmaceutically acceptable salt or hydrate thereof in oral administration is the degree of symptoms, patient age, sex, body weight, sensitivity difference Depending on the administration method, administration timing, administration interval, administration period, properties of the preparation, preparation, type, type of active ingredient, etc., those skilled in the art can appropriately set. For example, 0.1 to 500 mg, preferably 0.5 to 200 mg, more preferably 5 to 200 mg per day can be orally administered to an adult (body weight 60 kg).
　非経口投与、例えば注射剤における前記PAR1の機能を阻害する作用を有する化合物もしくはその薬学的に許容される塩又はそれらの水和物の有効な投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、投与間隔、投与期間、製剤の性質、調剤、種類、有効成分の種類等によって異なるが、当業者であれば適宜設定することができ、生理食塩水又は市販の注射用蒸留水などの薬学的に許容される担体中に、適当な濃度になるように溶解又は懸濁したものを、処置を必要とする患者に対し、適宜投与することができる。例えば、注射剤の場合、成人（体重６０Ｋｇ）に１日あたり０．１～５００ｍｇ、好ましくは０．５～２００ｍｇ、より好ましくは５～２００ｍｇを投与することができる。 Effective doses of parenteral administration, for example, a compound having an action of inhibiting the function of PAR1 in an injection or a pharmaceutically acceptable salt thereof or a hydrate thereof are determined according to the degree of symptoms, patient age, sex , Body weight, sensitivity difference, administration method, administration timing, administration interval, administration period, formulation properties, preparation, type, type of active ingredient, etc. Or what was melt | dissolved or suspended so that it might become a suitable density | concentration in pharmacologically acceptable support | carriers, such as commercially available distilled water for injection, can be suitably administered with respect to the patient who requires treatment. For example, in the case of an injection, 0.1 to 500 mg, preferably 0.5 to 200 mg, more preferably 5 to 200 mg per day can be administered to an adult (body weight 60 kg).
　本発明は、また、前記PAR1の機能を阻害する作用を有する化合物もしくは薬学的に許容される塩又はそれらの水和物の有効量を対象に投与することを特徴とする、肺高血圧症の治療方法及び予防方法をも提供する。本発明の方法において、PAR1の機能を阻害する作用を有する化合物は、好ましくはPAR1拮抗物質であり、より好ましくは一般式（Ｉ）で表される２－イミノピロリジン誘導体であり、さらに好ましくは式（ＩＩＩ）～（ＩＸ）で表される化合物から選択される少なくとも１つの化合物であり、最も好ましくは式（ＩＩＩ）で表される化合物である。本発明の方法において、PAR1阻害物質には、その薬学的に許容される塩、またはそれらの水和物も包含される。好ましくは、式（ＩＩＩ）で表される化合物の臭化水素酸塩である。本発明の方法において、PAR1阻害物質の投与径路および投与方法は特に限定されないが、上記本発明の医薬組成物の記載を参照することができる。 The present invention also provides a treatment for pulmonary hypertension, characterized by administering to a subject an effective amount of a compound or pharmaceutically acceptable salt or hydrate thereof having an action of inhibiting the function of PAR1. Methods and prevention methods are also provided. In the method of the present invention, the compound having an action of inhibiting the function of PAR1 is preferably a PAR1 antagonist, more preferably a 2-iminopyrrolidine derivative represented by the general formula (I), and more preferably It is at least one compound selected from compounds represented by (III) to (IX), and most preferably a compound represented by formula (III). In the method of the present invention, the PAR1 inhibitor includes a pharmaceutically acceptable salt thereof or a hydrate thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III). In the method of the present invention, the administration route and administration method of the PAR1 inhibitor are not particularly limited, but reference can be made to the description of the pharmaceutical composition of the present invention.
　さらに、本発明には、肺高血圧症の治療剤又は予防剤のための、前記PAR1の機能を阻害する作用を有する化合物もしくは薬学的に許容される塩又はそれらの水和物、好ましくは肺高血圧症の治療剤又は予防剤のための、２－イミノピロリジン誘導体も含まれる。ここで、２－イミノピロリジン誘導体は、好ましくは一般式（Ｉ）で表される２－イミノピロリジン誘導体であり、より好ましくは式(ＩＩＩ）～（ＩＸ）で表される化合物から選択される少なくとも１つの化合物であり、最も好ましくは式(ＩＩＩ）で表される化合物である。上記の２－イミノピロリジン誘導体には、その薬学的に許容される塩またはそれらの水和物も包含される。好ましくは、式（ＩＩＩ）で表される化合物の臭化水素酸塩である。 Furthermore, the present invention includes a compound having a function of inhibiting the function of PAR1 or a pharmaceutically acceptable salt thereof or a hydrate thereof, preferably pulmonary hypertension, for a therapeutic or preventive agent for pulmonary hypertension. Also included are 2-iminopyrrolidine derivatives for the treatment or prevention of diseases. Here, the 2-iminopyrrolidine derivative is preferably a 2-iminopyrrolidine derivative represented by general formula (I), more preferably at least selected from compounds represented by formulas (III) to (IX) One compound, most preferably a compound represented by the formula (III). The 2-iminopyrrolidine derivatives include pharmaceutically acceptable salts or hydrates thereof. Preferably, it is a hydrobromide of the compound represented by the formula (III).
　以下、実施例により本発明を具体的に説明するが、本実施例により本発明は限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the examples.
　Abe K, Circ Res, 94: 385-393, 2004に記載の方法に従い、モノクロタリン誘発ラット肺高血圧モデルを作製した。5ないし6週齢（体重250-300 g）の雄性Sprague Dawleyラット（ＳＤラット）に、モノクロタリン（シグマアルドリッチ社製）を60 mg/kgの用量で１回皮下に注入した。E5555（Atopaxar）は、モノクロタリンを皮下注した当日から測定の前日まで毎日１回、0.5％メチルセルロース液に6 mg/mlの濃度に懸濁させたものを30 mg/kgの用量で、ゾンデを用いて、経口投与した。E5555非治療の肺高血圧モデルには、0.5％メチルセルロース液を同量、同期間投与した（図４および５における「ＭＣＴ」）。モノクロタリンおよびE5555を投与しない正常対象群には同週齢を用いた（図４および５における「Ｎｏｒｍａｌ」）。
　モノクロタリン注入3週間後に、右室収縮期圧、体動脈圧、心拍数、右室左室重量比（右室肥大）を測定した。ペントバルビタール（30 mg/kg）静脈麻酔下に、右心カテーテル法により右室収縮期圧を測定した。コンダクタンスカテーテルを用いて、頸動脈より体動脈圧、心拍数を測定した。測定後、ラットを致死量のペントバルビタール静注にて安楽死させ、心臓を摘出し、右室および心室中隔を含む左室の重量を測定し、その比を右室肥大の指標とした。 Monocrotaline-induced rat pulmonary hypertension model was prepared according to the method described in Abe K, Circ Res, 94: 385-393, 2004. Monocrotaline (manufactured by Sigma-Aldrich) was injected subcutaneously once at a dose of 60 mg / kg into male Sprague Dawley rats (SD rats) 5 to 6 weeks old (body weight 250-300 g). E5555 (Atopaxar) is a 30 mg / kg dose of 30 mg / kg suspended in 0.5% methylcellulose solution once daily every day from the day of the subcutaneous injection of monocrotaline to the day before the measurement. Used and administered orally. In the pulmonary hypertension model not treated with E5555, the same amount of 0.5% methylcellulose solution was administered during the same period (“MCT” in FIGS. 4 and 5). The same age group was used for a normal subject group to which monocrotaline and E5555 were not administered (“Normal” in FIGS. 4 and 5).
Three weeks after the injection of monocrotaline, the right ventricular systolic pressure, body arterial pressure, heart rate, and right ventricular left ventricular weight ratio (right ventricular hypertrophy) were measured. Right ventricular systolic pressure was measured by right heart catheterization under intravenous anesthesia with pentobarbital (30 mg / kg). Using a conductance catheter, body artery pressure and heart rate were measured from the carotid artery. After the measurement, rats were euthanized with a lethal dose of intravenous pentobarbital, the heart was removed, the left ventricle including the right ventricle and the ventricular septum was weighed, and the ratio was used as an index of right ventricular hypertrophy.
　図４は、モノクロタリン誘発ラット肺高血圧症に対するAtopaxar（30 mg/kg/day）の効果を示す。左図は右心室圧における効果を示し、右図は右心室肥大における効果を示す。
　図５は、モノクロタリン誘発ラット肺高血圧症に対するAtopaxar（30 mg/kg/day）の効果を示す。左図は全身収縮期血圧における効果を示し、右図は心拍における効果を示す。
　これらの結果より、ＰＡＲ１の機能を阻害する作用を有する化合物は、心拍および全身収縮期血圧を変化させることなく、非治療のモノクロタリン誘発肺高血圧症群と比較して右心室圧および右心室肥大を有意に抑制することが明らかとなった（p＜０．０１）。したがって、ＰＡＲ１の機能を阻害する作用を有する化合物は、肺高血圧症の治療および予防に有用であることが示された。 FIG. 4 shows the effect of Atopaxar (30 mg / kg / day) on monocrotaline-induced rat pulmonary hypertension. The left figure shows the effect on right ventricular pressure, and the right figure shows the effect on right ventricular hypertrophy.
FIG. 5 shows the effect of Atopaxar (30 mg / kg / day) on monocrotaline-induced rat pulmonary hypertension. The left figure shows the effect on systemic systolic blood pressure, and the right figure shows the effect on heart rate.
From these results, the compound having the action of inhibiting the function of PAR1 did not change the heart rate and the systemic systolic blood pressure, and compared with the untreated monocrotaline-induced pulmonary hypertension group, the right ventricular pressure and the right ventricular hypertrophy Was found to be significantly suppressed (p <0.01). Therefore, it has been shown that compounds having an action of inhibiting the function of PAR1 are useful for the treatment and prevention of pulmonary hypertension.
　本発明者により、トロンビンとその受容体が肺高血圧の発症と病態形成に重要な役割を果たすことが明らかになった。ＰＡＲ１の機能を阻害する作用を有する化合物は、心拍および全身収縮期血圧を変化させることなく、右心室圧および右心室肥大を抑制することが可能である。したがって、ＰＡＲ１の機能を阻害する作用を有する化合物は、副作用を引き起こす可能性の低い、肺高血圧症の治療剤および予防剤の有効成分として有用であるといえ、本発明により、ＰＡＲ１の機能を阻害する作用を有する化合物を有効成分として含む肺高血圧症の治療剤および肺高血圧症の予防剤が提供される。本発明により、肺高血圧症の新たな治療法または予防法が提供され、肺高血圧患者の治療または予防に貢献することが可能となった。 The present inventor has revealed that thrombin and its receptor play an important role in the onset and pathogenesis of pulmonary hypertension. A compound having an action of inhibiting the function of PAR1 can suppress right ventricular pressure and right ventricular hypertrophy without changing heart rate and systemic systolic blood pressure. Therefore, it can be said that a compound having an action of inhibiting the function of PAR1 is useful as an active ingredient of a therapeutic and prophylactic agent for pulmonary hypertension, which has a low possibility of causing a side effect, and the present invention inhibits the function of PAR1. The present invention provides a therapeutic agent for pulmonary hypertension and a preventive agent for pulmonary hypertension, which comprise a compound having the above-mentioned action as an active ingredient. According to the present invention, a new treatment or prevention method for pulmonary hypertension is provided, and it has become possible to contribute to the treatment or prevention of pulmonary hypertension patients.

Claims (10)

  1. 　プロテアーゼ活性化受容体１の機能を阻害する作用を有する化合物もしくはその薬学的に許容される塩又はそれらの水和物を含有する、肺高血圧症の治療剤又は予防剤。 A therapeutic or prophylactic agent for pulmonary hypertension, comprising a compound having an action of inhibiting the function of protease-activated receptor 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  2. 　プロテアーゼ活性化受容体１の機能を阻害する作用を有する化合物が、PAR1拮抗物質である、請求項１記載の治療剤又は予防剤。 The therapeutic or prophylactic agent according to claim 1, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a PAR1 antagonist.
  3. 　プロテアーゼ活性化受容体１の機能を阻害する作用を有する化合物が、２－イミノピロリジン誘導体である、請求項１又は２記載の治療剤又は予防剤。 The therapeutic or prophylactic agent according to claim 1 or 2, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a 2-iminopyrrolidine derivative.
  4. 　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
    　前記２－イミノピロリジン誘導体が、一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
      
     
    [式（Ｉ）中、Ｒ１及びＲ２は、それぞれ独立し、同一又は相異なって、水素原子、メトキシ基又はエトキシ基を；Ｘ1は水素原子又はハロゲン原子を；Ａｒ2は、メチル基、エチル基、メトキシ基、エトキシ基、ｔ－ブチル基、モルホリニル基、又は下記式（ＩＩ）で表される置換基から選ばれる１又は２以上の置換基で置換されていてもよいフェニル基を示し、
    Figure JPOXMLDOC01-appb-C000002
      
     
    式（ＩＩ）中、Ｗは－ＣＨ－又は窒素原子を；Ａ１は－ＣＨ２－又は単結合を；Ｒ３は水素原子又は－ＯＲ５ａを；Ｘ２は－ＣＨ２－、酸素原子、単結合又はカルボニル基を；Ｙは単結合又はＣ１～Ｃ４アルキレン基を；Ｒ４は水素原子、－ＯＲ６ａ、シアノ基又は－ＣＯＯＲ７を；Ｒ５ａ、Ｒ６ａ及びＲ７は、それぞれ独立し、同一又は相異なって、水素原子又はC１～C４アルキル基を示す。]
    で表される化合物、もしくはその薬学的に許容される塩、またはそれらの水和物である、前記治療剤又は予防剤。     A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
    The 2-iminopyrrolidine derivative has the general formula (I)
    Figure JPOXMLDOC01-appb-C000001

    [In the formula (I), R 1 and R 2 are each independently the same or different and represent a hydrogen atom, a methoxy group or an ethoxy group; X 1 represents a hydrogen atom or a halogen atom; Ar 2 represents a methyl group , An ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a phenyl group optionally substituted with one or more substituents selected from the substituents represented by the following formula (II): Show
    Figure JPOXMLDOC01-appb-C000002

    In the formula (II), W represents —CH— or a nitrogen atom; A 1 represents —CH 2 — or a single bond; R 3 represents a hydrogen atom or —OR 5a ; X 2 represents —CH 2 —, an oxygen atom, Y represents a single bond or a C 1 -C 4 alkylene group; R 4 represents a hydrogen atom, —OR 6a , a cyano group or —COOR 7 ; R 5a , R 6a and R 7 each represents Independently, the same or different, each represents a hydrogen atom or a C 1 -C 4 alkyl group. ]
    The said therapeutic agent or prophylactic agent which is the compound represented by these, its pharmaceutically acceptable salt, or those hydrates.
  5. 　前記Ｒ１及びＲ２がエトキシ基であり、かつ、前記Ｘ1がフッ素原子である、請求項４記載の治療剤又は予防剤。 The therapeutic or prophylactic agent according to claim 4, wherein R 1 and R 2 are ethoxy groups, and X 1 is a fluorine atom.
  6. 　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
    　前記２－イミノピロリジン誘導体が、式（ＩＩＩ）～（ＩＸ）で表される化合物からなる群から選ばれる少なくとも１つ、もしくはその薬学的に許容される塩又はそれらの水和物である、前記治療剤又は予防剤。
    Figure JPOXMLDOC01-appb-C000003
      
          A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
    The 2-iminopyrrolidine derivative is at least one selected from the group consisting of compounds represented by formulas (III) to (IX), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. A therapeutic or prophylactic agent.
    Figure JPOXMLDOC01-appb-C000003
  7. 　２－イミノピロリジン誘導体を含有する肺高血圧症の治療剤又は予防剤であって、
    　前記２－イミノピロリジン誘導体が、式（ＩＩＩ）で表される化合物もしくはその薬学的に許容される塩又はそれらの水和物である、前記治療剤又は予防剤。
    Figure JPOXMLDOC01-appb-C000004
      
          A therapeutic or prophylactic agent for pulmonary hypertension containing a 2-iminopyrrolidine derivative,
    The therapeutic or prophylactic agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (III), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
    Figure JPOXMLDOC01-appb-C000004
  8. 　請求項４～７のいずれか一項に記載の２－イミノピロリジン誘導体を含む、肺高血圧症の治療用又は予防用キット。 A kit for treating or preventing pulmonary hypertension, comprising the 2-iminopyrrolidine derivative according to any one of claims 4 to 7.
  9. 　請求項４～７のいずれか一項に記載の２－イミノピロリジン誘導体の有効量を対象に投与することを含む、肺高血圧症の治療又は予防のための方法。 A method for treating or preventing pulmonary hypertension, comprising administering an effective amount of the 2-iminopyrrolidine derivative according to any one of claims 4 to 7 to a subject.
  10. 　肺高血圧症の治療剤又は予防剤のための、請求項４～７のいずれか一項に記載の２－イミノピロリジン誘導体。 The 2-iminopyrrolidine derivative according to any one of claims 4 to 7, which is used as a therapeutic or preventive agent for pulmonary hypertension.
PCT/JP2013/075150 2012-09-20 2013-09-18 Prevention/treatment agent for pulmonary hypertension comprising thrombin receptor antagonist as active component WO2014046125A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1391451A1 (en) * 2001-04-19 2004-02-25 Eisai Co., Ltd. 2-iminopyrrolidine derivates
WO2011015381A1 (en) * 2009-08-05 2011-02-10 Celltrend Gmbh Method for prognosis of pulmonary arterial hypertension by detecting anti-par1-antibodies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1391451A1 (en) * 2001-04-19 2004-02-25 Eisai Co., Ltd. 2-iminopyrrolidine derivates
WO2011015381A1 (en) * 2009-08-05 2011-02-10 Celltrend Gmbh Method for prognosis of pulmonary arterial hypertension by detecting anti-par1-antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAKI, J. ET AL.: "Thrombin activation of proteinase-activated receptor 1 potentiates the myofilament Ca2+ sensitivity and induces vasoconstriction in porcine", BRITISH JOURNAL OF PHARMACOLOGY, vol. 159, no. 4, 2010, pages 919 - 927 *

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