JP2007084440A - Treating agent of angiospasm accompanying with subarachnoid hemorrhage, containing thrombin receptor antagonist as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a treating agent or prognosis-improving agent of subarachnoid hemorrhage. <P>SOLUTION: This treating agent or prognosis-improving agent of the subarachnoid hemorrhage is provided by containing a compound having a PAR1 inhibitory activity or its pharmaceutically acceptable salt or a hydrate of them. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a therapeutic agent for subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a disease that accounts for 10% of all strokes. Patients who develop subarachnoid hemorrhage often die in severe cases or develop severe disabilities even if saved.
Subarachnoid hemorrhage is a disease that bleeds into the cerebrospinal fluid space between the arachnoid and brain, which is a thin membrane that wraps around the brain. Since subarachnoid hemorrhage is a bleeding on the surface of the brain rather than in the brain parenchyma, rather than neurological symptoms caused by cerebral vasospasm, rather than neurological symptoms caused by brain compression or necrosis associated with the bleeding, There are many cases. In other words, cerebral vasospasm associated with bleeding is considered to be one of the main factors determining the prognosis of subarachnoid hemorrhage.
However, the molecular mechanism that causes cerebral vasospasm has not been clarified so far, and elucidation of the mechanism is also desired for the treatment of subarachnoid hemorrhage.

  By the way, thrombin is one of blood coagulation factors. In addition, it has been clarified that thrombin activates a protease-activated receptor (PAR1) and exhibits a vasoconstriction regulating action.

  So far, the relationship between cerebral vasospasm associated with subarachnoid hemorrhage and thrombin and PAR1 has not been studied in detail, and research on therapeutic agents for subarachnoid hemorrhage through mechanisms related to thrombin and PAR1 has also been conducted. It was not done.

The present invention provides a drug effective for cerebral vasospasm associated with subarachnoid hemorrhage.
So far, it has been reported that administration of antithrombin III, which inhibits thrombin activity, and the synthetic serine protease inhibitor FUT-175, suppresses vasospasm in an animal model of subarachnoid hemorrhage (Tsuratani et.al Stroke, 34: 1497-1500, 2003; Yanamoto et al., Nerosurgery, 30: 358-363, 1992). However, it has been considered difficult to use a thrombin inhibitor as a therapeutic agent for subarachnoid hemorrhage because it may cause new bleeding by inhibiting thrombin activity.

  As a result of intensive studies to solve the above problems, the present inventor has shown that cerebral blood vessels exhibit high contractility via protease activated receptor 1 (PAR1) in an animal model of subarachnoid hemorrhage, and upregulation of PAR1. It has been found that PAR1 desensitization is impaired. Inhibition of PAR1 leads to cerebral vasospasm after subarachnoid hemorrhage, as well as induction of PAR1 itself and impaired desensitization. In addition to relieving vasospasm, it was thought to have the potential to prevent its occurrence.

  Based on the above findings, the present inventor has clarified that inhibition of PAR1 can treat subarachnoid hemorrhage without causing new bleeding, and has completed the present invention. That is, the present invention is as follows.

(1) A therapeutic agent for subarachnoid hemorrhage or a prognostic improvement of subarachnoid hemorrhage containing a compound having an action of inhibiting the function of protease-activated receptor 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof Agent.
(2) The therapeutic agent or ameliorating agent according to (1), wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is an antagonist of protease-activated receptor 1.
(3) The therapeutic or improving agent according to (1) or (2), wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a 2-iminopyrrolidine derivative.

(4) A therapeutic agent for subarachnoid hemorrhage containing 2-iminopyrrolidine derivative or an agent for improving prognosis of subarachnoid hemorrhage,
The 2-iminopyrrolidine derivative has the general formula (I)
[In Formula (I), A ring is a pyrrolidine ring; B ring is a benzene ring or a pyridine ring; R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are each independently the same or different and are each a hydrogen atom, a halogen atom, the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy group; R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; R ⁶ is hydrogen An atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyloxycarbonyl group; Y ¹ is a single bond or —CH ₂ —; Y ² is a single bond or —CO—; Ar ¹ is a hydrogen atom or Formula (II)
(In the formula (II), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, a morpholinyl group, which may have a substituent a piperazinyl group, optionally having an optionally substituted piperidinyl group, or a substituent indicates which may pyrrolidinyl group, further, the R ¹¹ R ¹² or R ¹² and R ¹³ may be bonded to each other to form a 5- to 8-membered heterocyclic ring. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(5) A therapeutic agent for subarachnoid hemorrhage containing 2-iminopyrrolidine derivative or an agent for improving prognosis of subarachnoid hemorrhage,
The 2-iminopyrrolidine derivative has the general formula (III)
[In Formula (III), 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 represents a methyl group A phenyl group optionally substituted with one or more substituents selected from an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (IV): Show
In formula (IV), 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 is a single bond or a _C 1 -C ₄ alkylene group; ^{R 4} is a hydrogen atom, ^{-OR 6a,} a cyano group or a -COOR ^{7; R 5a,} R ^6a and ^{R 7,} respectively independently, the same or different, represent a hydrogen atom or a C ₁ -C ₄ alkyl group. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(6) The therapeutic or improving agent according to (5), wherein R ¹ and R ² are ethoxy groups, and X ¹ is a fluorine atom.

(7) A therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage, comprising a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative is any one selected from the group consisting of compounds represented by formulas (V) to (XI), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic agent or improving agent.

(8) A therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage, comprising a 2-iminopyrrolidine derivative,
The therapeutic or improving agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (V), a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(9) An antivasospastic agent 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.
(10) The antivasospastic agent according to (9), wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is an antagonist of protease-activated receptor 1.
(11) The antivasospastic agent according to (9) or (10), wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a 2-iminopyrrolidine derivative.

(12) An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative has the general formula (I)
[In Formula (I), A ring is a pyrrolidine ring; B ring is a benzene ring or a pyridine ring; R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are each independently the same or different and are each a hydrogen atom, a halogen atom, the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy group; R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; R ⁶ is hydrogen An atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyloxycarbonyl group; Y ¹ is a single bond or —CH ₂ —; Y ² is a single bond or —CO—; Ar ¹ is a hydrogen atom or Formula (II)
(In the formula (II), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, C ₁ -C _{6 represents an} alkoxy group, a morpholinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group or an optionally substituted pyrrolidinyl group, and R ¹¹ and R ¹² or R ¹² and R ¹³ may be bonded to each other to form a 5- to 8-membered heterocyclic ring. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(13) An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative has the general formula (III)
[In Formula (III), 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 represents a methyl group A phenyl group optionally substituted with one or more substituents selected from an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (IV): Show
In formula (IV), 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 is a single bond or a _C 1 -C ₄ alkylene group; ^{R 4} is a hydrogen atom, ^{-OR 6a,} a cyano group or a -COOR ^{7; R 5a,} R ^6a and ^{R 7,} respectively independently, the same or different, represent a hydrogen atom or a C ₁ -C ₄ alkyl group. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(14) wherein ^{R 1} and ^{R 2} are ethoxy groups, and wherein X ¹ is a fluorine atom (13) antivasospastic agent according.

(15) An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative is any one selected from the group consisting of compounds represented by formulas (V) to (XI), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The antivasospastic agent.

(16) An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The antivasospastic agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (V), a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(17) Subarachnoid hemorrhage characterized by administering an effective amount of a compound having an action of inhibiting the function of protease-activated receptor 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof to a patient Or treatment method for subarachnoid hemorrhage.
(18) A method for treating subarachnoid hemorrhage or a method for improving prognosis of subarachnoid hemorrhage, comprising administering an effective amount of the 2-iminopyrrolidine derivative according to at least one of (4) to (8) to a patient. .

(19) Prevention of vasospasm, comprising administering to a patient an effective amount of a compound having an action of inhibiting the function of protease-activated receptor 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof. Method.
(20) A method for preventing vasospasm, comprising administering an effective amount of the 2-iminopyrrolidine derivative according to at least one of (12) to (16) to a patient.

(21) Use of the 2-iminopyrrolidine derivative according to at least one of (4) to (8) for producing a therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage.
(22) Use of the 2-iminopyrrolidine derivative according to at least one of (12) to (16) for producing an antivasospastic agent.

  The present invention provides a therapeutic agent for subarachnoid hemorrhage, an agent for improving prognosis of subarachnoid hemorrhage, and an anti-vasospasm agent containing a compound having an action of inhibiting the function of PAR1 as an active ingredient. In subarachnoid hemorrhage, PAR1 function is enhanced, which causes high contraction of the basilar artery. In other words, since a compound having an action of inhibiting the function of PAR1 can suppress high contraction of the basilar artery, it is useful as a therapeutic agent for subarachnoid hemorrhage and an active ingredient of an anti-vasospasm agent. is there.

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.

  The present invention was enhanced in patients with subarachnoid hemorrhage based on the new finding that PAR1 is up-regulated and cerebral vasospasm is induced by impaired desensitization of PAR1. A compound having an action of inhibiting the function of PAR1 was found to be effective in the treatment of subarachnoid hemorrhage and was completed. Accordingly, the present invention relates to a compound having an action of inhibiting PAR1 function and suppressing cerebral vasospasm, that is, a therapeutic agent or prognosis improving agent for subarachnoid hemorrhage containing PAR1 inhibitor as an active ingredient, or an anti-vasospasm agent Is to provide. The present invention also provides a method for treating subarachnoid hemorrhage, a method for improving prognosis, or a method for preventing vasospasm, which comprises administering an effective amount of a compound having an action of inhibiting the function of PAR1 to a patient. is there. The blood vessel is preferably a cerebral blood vessel, more preferably a cerebral blood vessel.

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 with 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) 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. It is not particularly limited as long as it is a substance having an action of suppressing PAR1 and means PAR1 antagonist, PAR1 desensitization promoting substance, PAR1 antisense oligonucleotide, PAR1 siRNA, PAR1 neutralizing antibody and the like. Preferred features of the PAR1 inhibitor used in the present invention include an action of suppressing cerebral vasospasm, a high selectivity for PAR1, a central action, and a therapeutically effective amount. Severe side effects such as the occurrence of new bleeding and the 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).

  Therefore, in the present invention, preferred compounds for use as a therapeutic agent for subarachnoid hemorrhage, a prognosis improving agent, or an anti-vasospasm agent include “a compound having an action of inhibiting the function of PAR1”, particularly a PAR antagonist. Or a pharmaceutically acceptable salt thereof or a hydrate thereof can be mentioned.

  In the present specification, “PAR1 antagonist” and “PAR1 antagonist” are substances that bind to PAR1 and inhibit the binding of PAR1 to a polypeptide moiety containing a receptor activation sequence (so-called PAR1 antagonist). Means.

(3) 2-Iminopyrrolidine derivative As the PAR1 antagonist used in the present invention, a 2-iminopyrrolidine derivative can be used.

In the present invention, the 2-iminopyrrolidine derivative includes a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
Formula (I)

In general formula (I),
Ring A is a pyrrolidine ring;
Ring B is a benzene ring or a pyridine ring;
R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are each independently the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group;
R ⁵ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group;
R ⁶ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyloxycarbonyl group;
Y ¹ represents a single bond or —CH ₂ —;
Y ² represents a single bond or —CO—;
Ar ¹ represents a hydrogen atom or a group represented by the following formula (II).

Here, in formula (II):
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently the same or different and are each a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a morpholinyl group, A piperazinyl group optionally having a substituent, a piperidinyl group optionally having a substituent, or a pyrrolidinyl group optionally having a substituent;
Further, R ¹¹ and R ¹² or R ¹² and R ¹³ may be bonded to each other to form a 5- to 8-membered heterocyclic ring.

In the present invention, the substituent that the piperazinyl group, piperidinyl group or pyrrolidinyl group may have is not limited, and examples thereof include a hydroxyl group, a cyanomethyl group, a methoxy group, —COCH ₂ OH, and —CH _2. One or more selected from the group consisting of COOCH ₂ CH ₃ can be mentioned.

In the present invention, the 2-iminopyrrolidine derivative includes a compound represented by the following general formula (III), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
Formula (III)

In general formula (III),
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 (IV). An optionally substituted phenyl group,
In formula (IV),
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 is 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.

In formula (III), preferably, ^{R 1} and ^{R 2} is ethoxy group, and, X ¹ is a fluorine atom.

  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.

In the present specification, the “C ₁ -C ₆ alkyl group” means an alkyl group having 1 to 6 carbon atoms, and suitable groups include, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1 -Ethylpropyl group, 2-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1, 2-trimethylpropyl group, 1-propylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-di Examples thereof include straight chain or branched alkyl groups such as methylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, and 3-methylpentyl group, and more preferably methyl group, ethyl group, n-propyl group, and iso-propyl. Group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group and the like.

In the present specification, the “C ₁ -C ₄ alkyl group” means 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, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group and the like.

In the present specification, “C ₁ -C ₆ alkoxy group” means an alkoxy group having 1 to 6 carbon atoms, and suitable groups include, for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec- Propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, n-hexoxy group, 1-ethylpropoxy group, 2-ethylpropoxy group, 1-methylbutoxy group, 2-methylbutoxy group, iso-hexoxy group 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpro Poxy group, 1,1,2-trimethylpropoxy group, 1-propylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy Group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hexyloxy group and the like.

"C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group" as used herein, refers to C ₁ -C ₆ alkyl group substituted by C ₁ -C ₆ alkoxy group.

  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”. .

  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.

  In the (I) and the general formula (III) of the present invention, preferably, the compounds represented by (V) to (XI) or pharmaceutically acceptable salts thereof or hydrates thereof are included, and these compounds One or a plurality of them can be used in appropriate combination.

  The compound that inhibits the function of PAR1 or a pharmaceutically acceptable salt or hydrate thereof used in the present invention can be produced by a person skilled in the art by a known method. And the 2-iminopyrrolidine derivative represented by (III) can be manufactured by the method as described in international publication 02/085855 pamphlet.

In general formula (I) and general formula (III), preferred compounds are compounds represented by formulas (V) to (XI) or pharmaceutically acceptable salts or hydrates thereof, and more preferred. Is a compound represented by the formula (V) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

The compound represented by the formula (V) may be referred to as “E5555” in the present specification.

  The 2-iminopyrrolidine derivatives represented by the formulas (V) to (XI) can be produced by the method described in WO 02/085855.

  In the present invention, the 2-iminopyrrolidine derivative may form a salt with an acid or base. The compound 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 has an action of inhibiting the function of PAR1, and serves as a therapeutic agent for subarachnoid hemorrhage. There is no particular limitation 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.

  In the present invention, the 2-iminopyrrolidine derivative has an asymmetric carbon depending on the type of substituent, and optical isomers such as geometric isomers, optical isomers, diastereomers, etc. may exist. Isomers are also included in the compounds having an action of inhibiting the function of PAR1 of the present invention.

  In the present invention, when hydrates of 2-iminopyrrolidine derivatives exist, these hydrates are also included in the compound having an action of inhibiting the function of PAR1 used in the present invention.

2. Therapeutic agent and prognostic agent for anti-arachnoid hemorrhage and anti-vasospasm agent The pharmaceutical composition of the present invention, ie, the therapeutic agent and prognostic agent for anti-arachnoid hemorrhage and the anti-vasospasm agent of the present invention inhibit PAR1 function. It includes a compound having an action. In the therapeutic agent, ameliorating agent and antivasospastic agent of the present invention, the compound having an action of inhibiting PAR1 function is preferably a PAR1 antagonist, more preferably represented by the general formula (I) or (III) It is a 2-iminopyrrolidine derivative, more preferably at least one compound selected from compounds represented by formulas (V) to (XI), and most preferably a compound represented by formula (V). The PAR1 inhibitor contained in the therapeutic agent and prognosis improving agent for subarachnoid hemorrhage and the antivasospastic agent of the present invention also includes pharmaceutically acceptable salts thereof or hydrates thereof.

  The PAR1 inhibitor contained in the pharmaceutical composition of the present invention has an action of inhibiting the function of PAR1 that is up-regulated or PAR1 in which the desensitization mechanism is impaired. That is, the pharmaceutical composition of the present invention is effective in improving cerebral vasospasm due to subarachnoid hemorrhage. Since cerebral vasospasm is one of the factors that determine the prognosis of subarachnoid hemorrhage, the pharmaceutical composition of the present invention containing a PAR1 inhibitor is used as a therapeutic agent and a prognosis improving agent for subarachnoid hemorrhage. It can be used as an anti-vasospastic agent.

  Since the PAR1 inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof has an action of inhibiting the function of PAR1, the therapeutic agent or prognosis improving agent or anti-vasospasm of the subarachnoid hemorrhage according to the present invention is provided. It is useful as an active ingredient of the agent.

  As used herein, the term “antivasospasm” means a pharmaceutical composition that prevents, suppresses and / or stops vasospasm associated with subarachnoid hemorrhage.

  As the therapeutic agent and prognostic agent and antivasospastic agent of the present invention, it is also known that the compound having a function of inhibiting the function of PAR1 or a pharmaceutically acceptable salt or a hydrate thereof is used as it is. It is also possible to formulate by blending a pharmaceutically acceptable carrier. 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.

  Moreover, the administration form of the therapeutic agent, prognosis improving agent and anti-vasospasm agent of the present invention is not particularly limited, and can be administered orally or parenterally based on the above dosage form. Examples of parenteral administration include intravenous injection, intravenous drip, subcutaneous injection, intradermal injection, intrathecal injection, and intraperitoneal injection. The dosage forms for formulation include tablets, powders, fine granules, granules, capsules, syrups, etc. used for oral dosage forms, and suppositories, injections, ointments used for parenteral dosage forms. Agents, bapping agents and the like.

When preparing an oral preparation for use in an oral dosage form, excipients, and further binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. were added to the active ingredients as necessary. Thereafter, tablets, coated tablets, granules, fine granules, powders, capsules and the like can be obtained by conventional methods.
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.

  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.

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.
Examples of the solubilizer 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, and 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 1 to 100 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 | 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 1 to 100 mg per day can be administered to an adult (body weight 60 kg).

  The present invention also provides a treatment for subarachnoid hemorrhage, characterized by administering an effective amount of a compound or a pharmaceutically acceptable salt or hydrate thereof having an action of inhibiting the function of PAR1 to a patient. Methods and methods for improving prognosis and methods for inhibiting vasospasm 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) or (III), More preferred is at least one compound selected from compounds represented by formulas (V) to (XI), and most preferred is a compound represented by formula (V). In the method of the present invention, the PAR1 inhibitor includes a pharmaceutically acceptable salt thereof or a hydrate thereof. 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.

  Furthermore, the present invention includes the use of a 2-iminopyrrolidine derivative for the manufacture of a therapeutic or prognostic agent for subarachnoid hemorrhage or an antivasospastic agent. In the use of the present invention, the 2-iminopyrrolidine derivative is preferably a 2-iminopyrrolidine derivative represented by the general formula (I) or (III), more preferably represented by the formulas (V) to (XI). And at least one compound selected from the compounds represented by formula (V). The 2-iminopyrrolidine derivatives include pharmaceutically acceptable salts or hydrates thereof.

EXAMPLES Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to the examples.

Preparation of Rabbit Double-hemorrhage Model A rabbit double-hemorrhage model was prepared as a model animal for subarachnoid hemorrhage. Using the obtained rabbit double bleeding model, the role of PAR1 in regulating vascular tension in subarachnoid hemorrhage (SAH) was clarified.
First, autologous arterial blood was administered 2.5 ml each in the cisterna mellitus twice on day 0 and day 2. Hereinafter, this group is also referred to as “SAH group” in the present invention. A control group was a model in which the same amount of physiological saline was administered instead of autologous arterial blood. On day 7, the rabbits of each group were euthanized, the endothelium was removed from the excised basilar artery, and a ring-shaped specimen (500 μm in width) was prepared (FIG. 2). Using the endothelium-removed basilar artery ring specimen prepared in this example, experiments on the contraction reaction in the following examples were performed.

Depolarization by high potassium and contraction in endothelium-removed basilar artery induced by endothelin-1
Depolarization stimulation by 118 mM K + and contraction in the deendothelial basilar artery induced by 100 nM endothelin-1 (ET-1) were measured. Endothelin-1 is a substance that acts on vascular smooth muscle to contract blood vessels.
The results are shown in FIG. The vertical axis shows the magnitude of the contractile force of the ring specimen, the left graph shows the magnitude of the contractile force when stimulated with 118 mM K +, and the right graph shows the magnitude of the contractile force when stimulated with 100 nM endothelin-1. This is expressed in% when the magnitude of contractile force upon stimulation with mM K + is taken as 100%. As a result, the contraction response to depolarization by 118 mM K + and the contraction response to endothelin-1 in the SAH group were the same as those in the control group, and there was no difference.

Contractile response to thrombin in rabbit basilar artery The contractile response to thrombin in the rabbit basilar artery of the control and SAH groups was measured. After a contractile response by depolarization stimulation with 118 mM K +, the basilar artery ring specimen was stimulated with thrombin. Thrombin is an endogenous ligand for PAR1.

  The results are shown in FIG. The upper left and lower left panels show changes in contractile force with time when the magnitude of contractile force upon depolarization stimulation with 118 mM K + is taken as 100%. The right graph shows the magnitude of the contractile force with respect to the thrombin concentration. In the control group, thrombin (1 unit / ml) did not induce contraction, and thrombin (10 units / ml) showed only mild transient contraction (21.3 of 118 mM K + -induced contraction). ± 1.2%) (Figure 4). On the other hand, in the SAH group, thrombin induced a remarkable sustained contraction from 0.3 units / ml, and the contractile force at 1 unit / ml was 73.1 ± 2.8% (FIG. 4).

Contractile response to PAR1-AP in rabbit basilar artery An experiment similar to Example 3 was performed using PAR1-AP (PAR1-activating peptide) instead of thrombin.
The results are shown in FIG. PAR1-AP (10 μM) induced contraction only in the SAH group (52.6 ± 6.1%) (FIG. 5). 100 μM PAR1-AP induced transient contraction in the control group, but increased and sustained contraction in the SAH group.

Inhibitory effect by heparinized autologous blood on increase of contractile response in SAH group As shown in Example 3 and Example 4, in SAH group, an increase in contractile response by thrombin and PAR1-AP was observed. In order to clarify the influence of heparin on the increase in the contractile response, an experiment was conducted using a model in which autologous blood heparinized according to the method of Example 1 was injected twice. Heparin is an anticoagulant that forms a complex with antithrombin III to inactivate blood clotting factors.

  The results are shown in FIG. In the model injected with heparinized autologous blood, the increase in contractile response to thrombin was significantly reduced (41.6 ± 3.0% at 1 unit / ml) (FIG. 6, upper “SAH + heparin”). In addition, the increase in contractile response to PAR1-AP was also significantly reduced (FIG. 6, lower row “SAH + heparin”). Therefore, it was shown that it is a blood coagulation factor in autologous blood that is inactivated by heparin that induces high contractility by thrombin and PAR1-AP.

α-Toxin Demembranous Contraction Response in Basilar Artery (1) Increased Ca2 + Concentration and Contraction Response Induced by GTPγS α-toxin is a substance that permeates cell membranes. GTPγS, which activates G protein and contraction reaction with increasing calcium ion concentration in rabbit basilar artery treated with α-toxin to make it permeable (hereinafter also referred to as “α-toxin demembrane basilar artery”) The contraction response due to was measured.
The results are shown in FIG. The left panel of FIG. 7 shows the magnitude of the contractile force with respect to the logarithm of the calcium ion concentration (M), and the right panel shows the magnitude of the contractile force when stimulated with 10 μM GTPγS (the magnitude of the contractile force when 10 μM calcium ion concentration is applied) %). As a result, in the SAH group α-toxin demembranulated basilar artery, the contraction reaction with increasing calcium concentration and the contraction reaction with GTPγS addition were the same as those in the control group α-toxin demembranulated basilar artery There was no significant difference.

(2) Contractile response to thrombin and PAR1-AP Next, the contractile response of α-toxin defilmed basilar artery to thrombin and PAR1-AP was measured.
The results are shown in FIG. Thrombin and PAR1-AP had no effect on calcium ion contraction response in the alpha toxin-permeable basilar artery of the control group, whereas thrombin and PAR1 Both -AP significantly increased the response.
In the SAH group, it was shown that the sensitivity to thrombin and PAR1-AP was increased, while the sensitivity to calcium ions causing muscle contraction and GTPγS that activates G protein was not changed.

Time-dependent change in PAR1 mRNA up-regulation in SAH group After the first autologous blood injection, the amount of PAR1 mRNA in the basilar artery on days 3, 5, 7 and 15 was examined by in situ hybridization.
The basilar artery was removed and a frozen specimen was prepared. Hybridization probes for PAR1 mRNA were prepared from human PAR1 cDNA using in vitro transcription and labeled with digoxigenin. Samples were treated with this probe overnight. After washing the unbound probe, an anti-digoxigenin antibody to which alkaline phosphatase was bound was allowed to act. Subsequently, a color reaction was carried out using diaminobenzidine to detect PAR1 mRNA. The developed image was observed with a microscope, and the obtained image was analyzed with an analysis program to quantify the expression level.

  The results are shown in FIG. The graph on the lower right of FIG. 9 is a plot of the amount of mRNA on each of the above days on which in situ hybridization was performed. In situ hybridization revealed that PAR1 mRNA in SAH basilar artery was up-regulated.

Changes in SAH group of magnitude and duration of contractile response to 100μM PAR1-AP
The magnitude and duration of the contractile response induced by 100 μM PAR1-AP were examined.
The results are shown in FIG. The SAH group contraction induced by 100 μM PAR1-AP increased at 5 days after autologous blood injection in the magnitude of peak contractile force and persistence of contractile force compared to the control group, 7 days Further increased by eye.
Therefore, it was shown that the desensitization mechanism of PAR1 was inhibited in the SAH group.

Irreversible contraction by thrombin
On day 7 of SAH, the contractile response induced by 100 μM PAR1-AP was terminated by washing away and removing 100 μM PAR1-AP (FIG. 11 left panel). On the other hand, the contraction response induced by 1 unit / ml thrombin was not changed by washing and showed irreversible contraction (right panel of FIG. 11).
Therefore, it was shown that the contraction reaction by PAR1-AP is reversible, whereas the contraction reaction by thrombin is irreversible.

Effect of PAR1 antagonist on contractile response in rabbit basilar artery by thrombin-1
The contractile response of the rabbit basilar artery to thrombin in the control group (sham operation group), the SAH group, and the group in which the PAR1 antagonist was coexisted with the SAH group was measured. Stimulation was performed by the same method as in Example 3.
In this example, “sham surgery group (sham)” (control rabbit) is a rabbit brain tank in which 3 ml of physiological saline was injected twice on days 0 and 2, and “SAH group” ( In the subarachnoid hemorrhage model), 3 ml of autologous blood was injected twice into the rabbit cerebral tank on the 0th and 2nd days, and the “SAH + E5555 group” (E5555-administered subarachnoid hemorrhage model) Shows the injection of 3 ml of autologous blood mixed with 600 μg E5555 twice on the 0th and 2nd days.
The PAR1 antagonist used in this example is E5555 represented by the formula (V) (International Publication No. 02/085855 pamphlet).
On day 7, the basilar artery was removed and the contractile response to 118 mM K + and 1 unit / ml thrombin was evaluated.

The results are shown in FIG. FIG. 12 shows a typical actual record of the contractile response.
FIG. 12A shows the contractile response to thrombin of the basilar artery in the sham operation, the SAH group, and the SAH + E5555 group from the top. In the sham-operated group, 1 unit / ml thrombin slightly contracted the isolated basilar artery. In SAH, a large contractile response was observed by stimulation with 1 unit / ml thrombin. In the subarachnoid hemorrhage model (SAH + E5555) coadministered with E5555, contraction due to 1 unit / ml thrombin was slight.
FIG. 12B shows dose response curves of the contractile response caused by thrombin in the SAH group and the sham operation group. As a result, the contractile response caused by thrombin was enhanced in the basilar artery of the subarachnoid hemorrhage model.
FIG. 12C shows the preventive action of E5555 against thrombin hyperconstriction caused by subarachnoid hemorrhage. The contractile response to 1 unit / ml thrombin in the sham-operated group, SAH group, and SAH + E5555 group was compared. The results are shown as mean ± standard error (number of experiments = 3). As a result, the co-administration of E5555 with autologous blood significantly suppressed the increased reactivity to thrombin caused by subarachnoid hemorrhage.

  This result indicates that PAR1 is also involved in the impaired hypersensitivity induction and desensitization by autologous blood, and that this hypercontraction induction and desensitization impairment is suppressed by PAR1 antagonists. . PAR1 was found to be involved in both the induction of high contractility after bleeding and vasospasm. In other words, it was shown that PAR1 inhibitors not only relieve cerebral vasospasm after subarachnoid hemorrhage but also prevent the occurrence, and can be a therapeutic agent for subarachnoid hemorrhage with a new mechanism of action .

Effect of PAR1 antagonist on contractile response in rabbit basilar artery by thrombin-2
As in Example 10, the contractile response of the rabbit basilar artery to thrombin in the control group (sham surgery group), the SAH group, and the group in which the PAR1 antagonist was coexisted with the SAH group was measured.
In this example, 3 ml of autologous blood mixed with 60 ng, 600 ng, 6 μg, and 60 μg of E5555 were injected twice into the rabbit brain cistern on the 0th and 2nd days, respectively.

A typical actual record of the contractile response is shown in FIG.
FIG. 13A shows the contractile response to thrombin of the basilar artery in the SAH group and SAH + E5555 (6 μg) group from the top. In the subarachnoid hemorrhage model (SAH + E5555) in which E5555 was coadministered with autologous blood, the contraction by 1 unit / ml thrombin was slight compared with the SAH group.
FIG. 13B shows the dose-dependent preventive effect of E5555 against the thrombin hyperconstriction response caused by subarachnoid hemorrhage. The contractile response to 1 unit / ml thrombin in the sham-operated group (control) and SAH + E5555 group was compared. The results are shown as mean ± standard error. As a result, co-administration of autologous blood and E5555 suppressed the hyperresponsiveness to thrombin caused by subarachnoid hemorrhage from 60 ng E5555 in a dose-dependent manner. In particular, in the SAH + E5050 (6 μg) group and the SAH + E5050 (60 μg) group, the contractile reaction was significantly suppressed compared to the SAH group.

  Example 11 shows that E5555 has a preventive action at a lower dose than the dose shown in Example 10 against the thrombin hyperconstriction response caused by subarachnoid hemorrhage.

Thus, thrombin induces a highly contractile response in the rabbit double hemorrhage model, and this high contractile response is thought to be due to impaired PAR1 up-regulation and receptor desensitization. In SAH, activation of thrombin, an endogenous agonist of PAR1, is thought to show a key role in the development of vasospasm after bleeding.
Since the high contractility of the basilar artery due to the enhanced PAR1 was suppressed by the PAR1 inhibitor, the PAR1 inhibitor is useful as a therapeutic agent for subarachnoid hemorrhage, a prognosis improving agent, and an antivasospastic agent. I can say that.

  The present invention provides a therapeutic agent for subarachnoid hemorrhage, an agent for improving prognosis of subarachnoid hemorrhage, and an anti-vasospasm agent containing a compound having an action of inhibiting the function of PAR1 as an active ingredient. In subarachnoid hemorrhage, PAR1 function is enhanced, which causes high contraction of the basilar artery. In other words, since a compound having an action of inhibiting the function of PAR1 can suppress high contraction of the basilar artery, it is useful as a therapeutic agent for subarachnoid hemorrhage and an active ingredient of an anti-vasospasm agent. is there.

FIG. 1 is a diagram showing the activation mechanism of PAR1 by thrombin and PAR1-activating peptide (PAR1-AP). FIG. 2 is a diagram showing an experimental procedure of a rabbit double bleeding model. FIG. 3 is a diagram showing high potassium depolarization-induced contraction and endothelin-1-induced contraction in the endothelium-removed basilar artery. FIG. 4 is a diagram showing contractile responses to thrombin in the rabbit basilar artery of the control group and the SAH group. FIG. 5 is a diagram showing the contractile response to PAR1-AP in the rabbit basilar artery of the control group and the SAH group. FIG. 6 is a diagram showing the inhibitory action of heparinized autologous blood on the enhanced contractile action in the SAH group. FIG. 7 is a graph showing an increase in calcium ion (Ca ²⁺ ) concentration and contraction response induced by GTPγS in α-toxin-demembraned basilar artery. FIG. 8 is a diagram showing the contractile response to thrombin and PAR1-AP in the demembranated basilar artery by α-toxin in the control group and the SAH group. FIG. 9 is a diagram showing changes over time in the up-regulation of PAR1 mRNA in the SAH group. FIG. 10 is a diagram showing the effect of 100 μM PAR1-AP on the persistent response in the SAH group. FIG. 11 is a diagram showing irreversible contraction by thrombin in the SAH group. FIG. 12 shows the effect of a PAR1 antagonist on the contractile response by thrombin. FIG. 13 shows the effect of a PAR1 antagonist on the contractile response by thrombin.

Claims (22)

  A therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage, 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.   The therapeutic agent or ameliorating agent according to claim 1, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is an antagonist of protease-activated receptor 1.   The therapeutic or improving 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. A therapeutic agent for subarachnoid hemorrhage containing 2-iminopyrrolidine derivative or an agent for improving prognosis of subarachnoid hemorrhage,
The 2-iminopyrrolidine derivative has the general formula (I)
[In Formula (I), A ring is a pyrrolidine ring; B ring is a benzene ring or a pyridine ring; R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are each independently the same or different and are each a hydrogen atom, a halogen atom, the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy group; R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; R ⁶ is hydrogen An atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyloxycarbonyl group; Y ¹ is a single bond or —CH ₂ —; Y ² is a single bond or —CO—; Ar ¹ is a hydrogen atom or Formula (II)
(In the formula (II), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, C ₁ -C _{6 represents an} alkoxy group, a morpholinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group or an optionally substituted pyrrolidinyl group, and R ¹¹ and R ¹² or R ¹² and R ¹³ may be bonded to each other to form a 5- to 8-membered heterocyclic ring. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. A therapeutic agent for subarachnoid hemorrhage containing 2-iminopyrrolidine derivative or an agent for improving prognosis of subarachnoid hemorrhage,
The 2-iminopyrrolidine derivative has the general formula (III)
[In Formula (III), 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 represents a methyl group A phenyl group optionally substituted with one or more substituents selected from an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (IV): Show
In formula (IV), 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 is a single bond or a _C 1 -C ₄ alkylene group; ^{R 4} is a hydrogen atom, ^{-OR 6a,} a cyano group or a -COOR ^{7; R 5a,} R ^6a and ^{R 7,} respectively independently, the same or different, represent a hydrogen atom or a C ₁ -C ₄ alkyl group. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic or improving agent according to claim 5, wherein R ¹ and R ² are ethoxy groups, and X ¹ is a fluorine atom. A therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage, comprising a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative is any one selected from the group consisting of compounds represented by formulas (V) to (XI), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The therapeutic agent or improving agent.
A therapeutic agent for subarachnoid hemorrhage or an agent for improving prognosis of subarachnoid hemorrhage, comprising a 2-iminopyrrolidine derivative,
The therapeutic or improving agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (V), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  An antivasospastic agent 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.   The antivasospastic agent according to claim 9, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is an antagonist of protease-activated receptor 1.   The antivasospastic agent according to claim 9 or 10, wherein the compound having an action of inhibiting the function of protease-activated receptor 1 is a 2-iminopyrrolidine derivative. An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative has the general formula (I)
[In Formula (I), A ring is a pyrrolidine ring; B ring is a benzene ring or a pyridine ring; R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are each independently the same or different and are each a hydrogen atom, a halogen atom, the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy group; R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group; R ⁶ is hydrogen An atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyloxycarbonyl group; Y ¹ is a single bond or —CH ₂ —; Y ² is a single bond or —CO—; Ar ¹ is a hydrogen atom or Formula (II)
(In the formula (II), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently the same or different and represent a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, C ₁ -C _{6 represents an} alkoxy group, a morpholinyl group, an optionally substituted piperazinyl group, an optionally substituted piperidinyl group or an optionally substituted pyrrolidinyl group, and R ¹¹ and R ¹² or R ¹² and R ¹³ may be bonded to each other to form a 5- to 8-membered heterocyclic ring. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative has the general formula (III)
[In Formula (III), 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 represents a methyl group A phenyl group optionally substituted with one or more substituents selected from an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (IV): Show
In formula (IV), 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 is a single bond or a _C 1 -C ₄ alkylene group; ^{R 4} is a hydrogen atom, ^{-OR 6a,} a cyano group or a -COOR ^{7; R 5a,} R ^6a and ^{R 7,} respectively independently, the same or different, represent a hydrogen atom or a C ₁ -C ₄ alkyl group. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The antivasospastic agent according to claim 13, wherein R ¹ and R ² are ethoxy groups, and X ¹ is a fluorine atom. An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The 2-iminopyrrolidine derivative is any one selected from the group consisting of compounds represented by formulas (V) to (XI), or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The antivasospastic agent.
An antivasospastic agent containing a 2-iminopyrrolidine derivative,
The antivasospastic agent, wherein the 2-iminopyrrolidine derivative is a compound represented by the formula (V), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  A method for treating subarachnoid hemorrhage, comprising administering to a patient an effective amount of a compound having an action of inhibiting the function of protease-activated receptor 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof. Or a method for improving the prognosis of subarachnoid hemorrhage.   A method for treating subarachnoid hemorrhage or a method for improving prognosis of subarachnoid hemorrhage, comprising administering an effective amount of the 2-iminopyrrolidine derivative according to at least one of claims 4 to 8 to a patient.   A method for preventing vasospasm, comprising administering to a patient an effective amount of a compound having an action of inhibiting the function of protease-activated receptor 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof.   A method for preventing vasospasm, comprising administering an effective amount of the 2-iminopyrrolidine derivative according to at least one of claims 12 to 16 to a patient.   Use of the 2-iminopyrrolidine derivative according to at least one of claims 4 to 8 for producing a therapeutic agent for subarachnoid hemorrhage or a prognosis improving agent for subarachnoid hemorrhage.   Use of the 2-iminopyrrolidine derivative according to at least one of claims 12 to 16 for the manufacture of an antivasospastic agent.