WO2006051648A1 - トロンビン受容体アンタゴニストを有効成分とするくも膜下出血に伴う血管攣縮の治療剤 - Google Patents
トロンビン受容体アンタゴニストを有効成分とするくも膜下出血に伴う血管攣縮の治療剤 Download PDFInfo
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- WO2006051648A1 WO2006051648A1 PCT/JP2005/016568 JP2005016568W WO2006051648A1 WO 2006051648 A1 WO2006051648 A1 WO 2006051648A1 JP 2005016568 W JP2005016568 W JP 2005016568W WO 2006051648 A1 WO2006051648 A1 WO 2006051648A1
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Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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 or sparfloxacin
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- the present invention relates to a therapeutic agent for subarachnoid hemorrhage.
- SAH Subarachnoid hemorrhage
- Subarachnoid hemorrhage is a disease that bleeds into the cerebrospinal fluid space between the arachnoid and the brain, a thin membrane that wraps around the brain. Because subarachnoid hemorrhage is a bleeding on the surface of the brain rather than in the brain parenchyma, a neurological symptom caused by cerebral vasospasm is rather than a neurological symptom caused by brain compression or necrosis associated with the bleeding. Often it becomes a problem. In other words, cerebral vasospasm that accompanies bleeding is considered to be one of the main factors that determine the prognosis of subarachnoid hemorrhage.
- thrombin is one of blood coagulation factors.
- thrombin has been shown to activate protease-activated receptor (PARI) and to exert a vasoconstriction regulating action.
- the present invention provides a drug effective for cerebral vasospasm associated with subarachnoid hemorrhage.
- the present inventor has clarified that inhibition of PARI can treat subarachnoid hemorrhage without causing new bleeding, and has completed the present invention. That is, the present invention is as follows.
- Prognostic improver for subarachnoid hemorrhage or 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.
- the 2-iminopyrrolidine derivative has the general formula (I)
- a ring is a pyrrolidine ring;
- B ring is a benzene ring or a pyridine ring;
- Rioi, RiQ 2 and RIM are each independently the same or different, a hydrogen atom, a halogen atom, 0 6 alkyl or - alkoxy group;
- R 5 is a hydrogen atom, a Ci ⁇ C 6 alkyl group or Ci ⁇ C 6 alkoxy and 0 6 alkyl group;
- R 6 is a hydrogen atom, - alkyl group or Ci ⁇ C 6
- Y 1 represents a single bond or —CH 2 —;
- Y 2 represents a single bond or one CO—;
- Ari represents a hydrogen atom or formula (II)
- R10, RU, R12, R13 and R14 are each independently, identical or different phase, a hydrogen atom, and 0 6 alkyl group, a hydroxyl group, and 0 6 alkoxy group, a morpholinyl group, a substituted A piperazinyl group which may have a group, a piperidinyl group which may have a substituent or a pyrrolidinyl group which may have a substituent, and further, Rii and Ri 2 , or Ri 2 and R1 3 may be bonded to each other to form a 5- to 8-membered heterocyclic ring.
- a pharmaceutically acceptable salt thereof, or a hydrate thereof 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 containing 2-iminopyrrolidine derivative or an agent for improving prognosis of subarachnoid hemorrhage
- the 2-iminopyrrolidine derivative has the general formula (I I 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;
- XI represents a hydrogen atom or a halogen atom;
- Ar 2 represents a methyl group, A phenyl group which may be 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) Indicate
- W represents one CH— or nitrogen atom
- a 1 represents —CH 2 — or a single bond
- R 3 represents a hydrogen atom or 10 R 5a
- X 2 represents _CH 2 —, an oxygen atom
- Y is a single bond or ( ⁇ to (an alkylene group
- R 4 is a hydrogen atom, 1 OR 6a , a cyano group or —COOR 7
- R 5a , R 6 a and 7 are Each independently, the same or different, each representing a hydrogen atom or a Ci C alkyl group], or a pharmaceutically acceptable salt thereof, or a hydrate thereof, Or an improving agent.
- R 1 and R 2 are ethoxy groups, and XI is a fluorine atom (5) The therapeutic agent or ameliorating agent described.
- 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 ameliorating agent 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 ameliorating agent 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.
- 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 a compound represented by the formula (V) or a pharmaceutically acceptable salt thereof or a hydrate thereof, or the therapeutic agent or the improvement
- 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 2-iminopyrrolidine derivative has the general formula (I)
- a ring is a pyrrolidine ring;
- B ring is a benzene ring or a pyridine ring;
- RIOI, Rio 2 and R10 3 are each independently the same or different, a hydrogen atom, a halogen atom, ⁇ 6 alkyl group or ⁇ ⁇ 0 6 alkoxy group;
- R 5 is hydrogen atom Child, ⁇ ⁇ 0 6 alkyl or ⁇ - alkoxy ⁇ ⁇ 0 6 alkyl groups;
- R 6 is a hydrogen atom, ⁇ 6 alkyl group or a ⁇ ⁇ 6 Arukiruokishi force Lupo two Le group;
- Y 1 represents a single bond or — CH 2 —;
- Y 2 is a single bond or — C ⁇ ;
- Ari is a hydrogen atom or formula (II)
- Rio, Rn, Ri2, Ri3 and Ri4 are each independently, identical or different phase, a hydrogen atom, and 0 6 alkyl group, a hydroxyl group, Ci ⁇ C 6 alkoxy group, a morpholinyl group, A piperazinyl group which may have a substituent, a piperidinyl group which may have a substituent or a pyrrolidinyl group which may have a substituent; and RU and Ri 2 , or Ri 2 And R1 3 may be bonded to each other to form a 5- to 8-membered heterocyclic ring. ]
- the antivasospastic agent which is a compound represented by: or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- the 2-iminopyrrolidine derivative has the general formula (I I I)
- R 1 and R 2 are each independently the same or different and are each a hydrogen atom, a methoxy group or an ethoxy group;
- Ar 2 represents 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;
- W represents one CH— or nitrogen atom
- a 1 represents one CH 2 — or a single bond
- R 3 represents a hydrogen atom or one OR 5a
- X 2 represents one CH 2 _, an oxygen atom, A single bond or a force group
- Y is a single bond or a Ci C alkylene group
- R 4 is a hydrogen atom, —OR 6 a , a cyano group or one COOR 7
- R 5 a , R 6 a and R 7 Are independently the same or different and each represents a hydrogen atom or a Ci Ca alkyl group.
- the said anti-vasospastic agent which is a compound represented by these, its pharmaceutically acceptable salt, or those hydrates.
- 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 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 antivascular crimp 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 or a prognosis of subarachnoid hemorrhage comprising administering to a patient an effective amount of the 2-iminopyrrolidine derivative according to at least one of (4) to (8) How to improve.
- 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.
- Figure 1 shows the mechanism of PARI activation by thrombin and PARI-activating peptide (PAR1-AP).
- Fig. 2 is a diagram showing the experimental procedure of the Usagi .2 bleeding model.
- FIG. 3 is a diagram showing high potassium depolarization-induced contraction and endothelin-1-induced contraction in the deendothelial basilar artery.
- FIG. 4 is a graph showing the contraction response to thrombin in the rabbit basal artery of the control group and the SAH group.
- FIG. 5 is a graph showing contractile responses to PAR1-AP in the rabbit and basilar arteries 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 GTP r S in toxin-demembraned basilar artery.
- FIG. 8 is a graph showing the contractile response to thrombin and PAR1-AP in the decidualized basilar artery by toxin in the control group and SAH group.
- FIG. 9 is a graph showing changes over time in PARI mRNA up-regulation in the SAH group.
- FIG. 10 shows the effect of 100 M PAR1-AP on the sustained response in the SAH group.
- FIG. 11 is a diagram showing irreversible contraction by thrombin in the SAH group.
- Figure 12 shows the effect of PARI antagonists on the contractile response of thrompine.
- Figure 13 shows the effect of PARI antagonists on the contractile response of thrombin.
- the present invention is based on the new finding that PARI is up-regulated in patients with subarachnoid hemorrhage and that desensitization of PARI is impaired to induce cerebral vasoconstriction. It was found that a compound having an action of inhibiting the function of PARI was effective in treating subarachnoid hemorrhage. Therefore, the present invention provides a treatment for subarachnoid hemorrhage containing a compound having an action of inhibiting PARI function and suppressing cerebral vasospasm, that is, a PARI inhibitor as an active ingredient.
- the present invention provides a therapeutic agent, a prognosis improving agent, or an antivasospastic agent.
- 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 PARI function to a patient.
- the blood vessel is preferably a cerebral blood vessel, more preferably a cerebral blood vessel.
- PARI is one of the protease-activated receptors, and is a G protein-coupled receptor that is activated by degradation of specific areas outside the cell by proteases.
- Figure 1 shows the activation mechanism of PARI. Receptor activation is accomplished by cleaving a specific site on the N-terminal side of the receptor with serine protease, thereby exposing the receptor activation sequence, which becomes a ligand and binds to the ligand binding site of the receptor.
- PARI agonists have been found to be thrombin and trypsin, which function as a protease, and synthetic peptides of receptor activation sequences, such as PARl-AP (PARI activating peptide), are known to function as agonists. It has been.
- SFLLRN human, amino acid one-letter code, SEQ ID NO: 1
- TFRIFD Raster, amino acid one-letter code, SEQ ID NO: 2
- a “compound having an action of inhibiting the function of PAR1” is not particularly limited as long as it has a function of suppressing the activation of PARI.
- PARI antagonists it means PARI desensitization promoters, PARI antisense oligonucleotides, PARI siRNA, PARI neutralizing antibodies, etc.
- Preferred characteristics of the PARI inhibitor used in the present invention include an action to suppress cerebral vasospasm, a high selectivity for PARI, a central action, and a therapeutically effective amount. Can cause serious side effects, such as the absence of new bleeding and immediate action.
- the PARI inhibitor includes pharmaceutically acceptable salts or hydrates thereof (details will be described later). Therefore, in the present invention, preferred compounds for use as therapeutic agents for subarachnoid hemorrhage, prognosis improving agents, or anti-vasospasm agents include “compounds having an action of inhibiting the function of PAR1”, particularly PAR antagonists. Alternatively, pharmaceutically acceptable salts or hydrates thereof can be mentioned.
- PAR1 antagonist and “PAR1 antagonist” are substances that bind to PARI and inhibit the binding of a polypeptide moiety containing a receptor activation sequence and PARI (so-called PARI antagonist). ) Means.
- a 2-iminopyrrolidine derivative can be used as the PARI antagonist 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.
- general formula (I) a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- Ring A is a pyrrolidine ring
- Ring B is a benzene ring or a pyridine ring
- R101, R10 2 and R1 3 are each independently, the same or different, a hydrogen atom, C androgenic atom, ⁇ ⁇ 0 6 alkyl group or Ci ⁇ C 6 alkoxy group;
- R 5 represents a hydrogen atom, an alkyl group, or a Ci to C 6 alkoxy Ci to C 6 alkyl group;
- R 6 represents a hydrogen atom, a C] L to C 6 alkyl group, or an alkyloxy group sulfonyl group; ⁇ represents a single bond or —CH 2 —;
- Y 2 represents a single bond or —CO—
- Ari represents a hydrogen atom or a group represented by the following formula (I I).
- Rio, Ru, R 12 , R 13 and R 14 are each independently the same or different, and include a hydrogen atom, ⁇ ⁇ 6 alkyl group, hydroxyl group, ⁇ ⁇ 6 alkoxy group, morpholinyl group, substituent.
- a piperazinyl group which may have, a piperidinyl group which may have a substituent or a pyrrolidinyl group which may have a substituent,
- Rii and Ri 2 or Ri 2 and R1 3 may be bonded to each other to form a 5- to 8-membered heterocycle.
- the substituent that the piperazinyl group, piperidinyl group or pyrrolidinyl group may have, but is not limited to, for example, a hydroxyl group, a cyanomethyl group, a methoxy group, one COCH 2 OH, and _ Mention may be made of one or more selected from the group consisting of CH 2 COOCH 2 CH3.
- the 2-iminopyrrolidine derivative includes a compound represented by the following general formula (III), 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;
- ⁇ represents a hydrogen atom or a halogen atom
- Ar 2 represents 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):
- W represents —CH— or a nitrogen atom
- a 1 is — CH 2 _ or a single bond
- R 3 is a hydrogen atom or one OR 5 a ;
- X 2 represents one CH 2 —, an oxygen atom, a single bond or a force sulfonyl group
- Y is a single bond or An alkylene group
- R 4 is a hydrogen atom, 10 R 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 Ci C alkyl group.
- R. 1 and R 2 are ethoxy groups, and X 1 is a fluorine atom.
- halogen atom include atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom.
- ⁇ to 0 6 alkyl group means an alkyl group having 1 to 6 carbon atoms
- suitable groups include, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, n —Ptyl 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,
- ⁇ ⁇ Y 4 alkyl group 1 carbon atoms indicates the four alkyl groups, examples of suitable groups such as a methyl group, Echiru group, .eta. propyl, iso one propyl radical, n -Linear or branched alkyl groups such as butyl, iso-butyl, sec butyl, tert butyl, etc., more preferably methyl, ethyl, n-propyl, iso-propyl N-butyl group, iso-butyl group, sec-butyl group, tert-butyl group and the like.
- suitable groups such as a methyl group, Echiru group, .eta. propyl, iso one propyl radical, n -Linear or branched alkyl groups such as butyl, iso-butyl, sec butyl, tert butyl, etc., more preferably methyl, ethyl, n-propyl
- Ci to C 6 alkoxy group means an alkoxy group having 1 to 6 carbon atoms
- 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-dimethylpro Pyroxy 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-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1-propylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 1,3-dimethylbutyloxy group, 2 -Ethylbutoxy group, 1,3-
- Ci ⁇ C 6 alkoxy Ci ⁇ C 6 alkyl group as used herein, means a substituted ⁇ 1-6 alkyl group Ci ⁇ C 6 alkoxy group.
- n— means normal type or primary substituent
- sec— means secondary substituent
- t- (tert-) Means a tertiary substituent
- i— (iso—) means an isotype substituent
- a compound that inhibits the function of PARI 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.
- 2-III minopyrrolidine derivatives represented by (III) can be produced by the method described in WO 02/085855 Pamphlet.
- a preferable compound is a compound represented by formulas (V) to (XI), a pharmaceutically acceptable salt thereof, or a hydrate thereof, more preferably. Is a compound represented by 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.
- the 2-iminopyrrolidine derivative may form a salt with an acid or a base.
- the compound in the present invention includes these pharmaceutically acceptable salts.
- the salt means a “pharmaceutically acceptable salt”, and the pharmaceutically acceptable salt has an action of inhibiting the function of PARI and is a therapeutic agent for subarachnoid hemorrhage. There is no particular limitation 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, perchlorate
- Acid salts for example, phosphates, carbonates, bicarbonates, etc.
- organic carboxylates eg acetates, oxalates, maleates, tartrate, fumarate, kenates, etc.
- organic sulfonates Eg methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, camphor sulfonate, etc.
- amino acid salts eg aspartate, darumarate, etc.
- Quaternary amine salts alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg,
- 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. These optical isomers are also included in the compounds having the action of inhibiting the function of PARI of the present invention.
- optical isomers such as geometric isomers, optical isomers, diastereomers, etc.
- these optical isomers are also included in the compounds having the action of inhibiting the function of PARI of the present invention.
- hydrates of 2-iminopyrrolidine derivatives when hydrates of 2-iminopyrrolidine derivatives exist, these hydrates are also included in the compounds having an action of inhibiting the function of PARI used in the present invention.
- the pharmaceutical composition of the present invention that is, the therapeutic agent for subarachnoid hemorrhage, the prognosis improving agent and the antivasospastic agent of the present invention contain a compound having an action of inhibiting PARI function.
- the compound having an action of inhibiting PARI function is preferably a PARI antagonist, more preferably represented by the general formula (I) or (III) 2-iminopyrrolidine derivatives, more preferably at least one compound selected from compounds represented by formulas (V) to (XI), most preferably a compound represented by formula (V) .
- the PARI inhibitor contained in the therapeutic agent and prognosis improving agent for subarachnoid hemorrhage and the antivascular crimping agent of the present invention also includes pharmaceutically acceptable salts or hydrates thereof.
- the PARI inhibitor contained in the pharmaceutical composition of the present invention has an action of inhibiting the function of PARI that has been upregulated, or PARI with impaired desensitization mechanism. That is, the pharmaceutical composition of the present invention is effective in improving cerebral vasospasm due to subarachnoid hemorrhage.
- the pharmaceutical composition of the present invention containing a PARI inhibitor is used as a therapeutic agent and prognosis improving agent for subarachnoid hemorrhage. It can also be used as an antivasospastic agent.
- the PARI inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof has an action of inhibiting the function of PARI, the therapeutic agent or prognosis improving agent or anti-vasospasm of the subarachnoid hemorrhage of the present invention. It is useful as an active ingredient of the agent.
- antivasospasm means a pharmaceutical composition that prevents, inhibits, or stops vasospasm associated with subarachnoid hemorrhage.
- a compound having a function of inhibiting the function of PARI or a pharmaceutically acceptable salt or a hydrate thereof is used as it is.
- pharmaceutically acceptable carrier examples include excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, and surfactants. , PH adjusting agents, preservatives, antioxidants and the like.
- the administration form of the therapeutic agent, prognosis improving agent and anti-vasospastic agent of the present invention is not particularly limited, and can be administered orally or parenterally based on the above-mentioned dosage form.
- parenteral administration include intravenous injection, intravenous infusion, 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 used for parenteral dosage forms, Examples include ointments and poultices.
- 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.
- excipients include lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, and silicon dioxide.
- binders include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxy Propylmethylcellulose, etc., lubricants such as magnesium stearate, talc, silica, etc. are permitted to be added to pharmaceuticals as colorants, while flavoring agents include cocoa powder, hearth Powered brain, aromatic acid, heart power oil, Borneolum, cinnamon powder, etc. are used.
- these tablets and condyles may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
- an 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, etc.), suspending agents, dissolving, etc. It can be prepared by adding adjuvants, stabilizers, tonicity agents, preservatives, pH adjusters, buffers, etc.
- the Sterilization of injections may be performed by filter sterilization using a filter, blending of bactericides, and the like. Injectables can also be manufactured in the form of preparation at the time of use.
- injections can be infused intravenously, intravenously, subcutaneously, or intramuscularly by conventional methods.
- 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 sorbate monolaurate, macaque gall, and castor oil fatty acid ethyl ester.
- stabilizers include sodium sulfite and sodium metasulfite
- preservatives include methyl parabenzoate, ethyl parabenzoate, sorbic acid, phenol, cresol, and chlorocresol. wear.
- the effective dose of a compound having the action of inhibiting the function of PARI or its pharmaceutically acceptable salt or hydrate thereof when administered orally is the degree of symptoms, the age of the patient, sex, body weight, although it varies depending on sensitivity difference, administration method, administration timing, administration interval, administration period, nature of the preparation, preparation, type, type of active ingredient, etc., those skilled in the art can appropriately set it.
- an adult body weight 60 kg
- Parenteral administration for example, the effective dose of a compound having an action of inhibiting the function of PARI in an injection or a pharmaceutically acceptable salt thereof or a hydrate thereof is determined by the degree of symptom, patient age, sex , Body weight, sensitivity difference, administration method, administration timing, between administrations It varies depending on the interval, administration period, nature of the formulation, formulation, type, type of active ingredient, etc., but can be set as appropriate by those skilled in the art, and is pharmaceutically acceptable such as physiological saline or commercially available distilled water for injection. What is dissolved or suspended in a suitable carrier to an appropriate concentration can be appropriately administered to a patient in need of treatment.
- the present invention is also characterized in that an effective amount of a compound or a pharmaceutically acceptable salt or an hydrate thereof having an action of inhibiting the function of the PARI is administered to a patient. It also provides methods of treatment, prognosis improvement, and vasospasm inhibition.
- the compound having an action of inhibiting the function of PARI is preferably a PARI antagonist, more preferably a 2-iminopyrrolidine derivative represented by the general formula (I) or (III).
- the PARI inhibitor includes a pharmaceutically acceptable salt thereof or a hydrate thereof.
- the administration route and administration method of the PARI inhibitor are not particularly limited, but the description of the pharmaceutical composition of the present invention can be referred to.
- the present invention also includes the use of a 2_iminopyrrolidine derivative for the manufacture of a therapeutic agent or prognosis improving agent for subarachnoid hemorrhage or an antivasospastic agent.
- the 2-iminopyrrolidine derivative is preferably a 2-iminopyrrolidine derivative represented by the general formula (I) or (I I I), more preferably
- Example 1 Preparation of a two-tailed rabbit bleeding model
- a rabbit double-hemorrhage model was created.
- SAH subarachnoid hemorrhage
- the control group was a model in which the same amount of physiological saline was administered instead of autologous arterial blood.
- Example 2 High potassium depolarization and endothelin-1 induced contraction in the deendothelial basilar artery
- Endothelin-1 is a substance that acts on vascular smooth muscle and has the effect of contracting blood vessels.
- the contractile response to thrombin was measured in the rabbit and basilar artery of the control and SAH groups. 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 PARI. The results are shown in Fig. 4. The upper left and lower left panels show the changes in contractile force over time when the magnitude of contractile force upon depolarization stimulation with 118 mM K + is taken as 100%. The graph on the right shows the magnitude of the contractile force with respect to ⁇ longbin concentration.
- Example 3 As shown in Example 3 and Example 4, an increase in contractile response by thrompine and PAR1-AP was observed in the SAH group.
- 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.
- Toxins are substances that provide permeability to cell membranes.
- ⁇ toxin-demembraned basilar artery treated with ⁇ -toxin to make it transparent, the contractile reaction associated with the increase in calcium ion concentration and G protein are activated. The contractile response due to GTP r S was measured.
- FIG. 7 shows the magnitude of contractile force against the logarithm of calcium ion concentration '(M), and the right panel shows the magnitude of contractile force during 10 i M GTP r S stimulation (10 M calcium ion concentration). %) With respect to the strength of the contraction force at the time.
- the detoxified basilar artery of the toxin group contracted with increasing calcium concentration and contracted with the addition of GTP r S, and contracted in the alpha group of toxin-detoxified basilar artery in the control group. There was no significant difference.
- Thrombin and PAR1-AP did not affect the contraction response by calcium ions in the control group splenic permeabilized basilar artery, whereas thrombin and PAR1-AP did not affect thrombin and detoxified basilar artery in SAH group. Both PARI- ⁇ s significantly increased the response.
- PARI in the basilar artery on days 3, 5, 7, and 15 after the first autologous blood injection The amount of mRNA was examined by in situ hybridization.
- the hybridization probe for PARI mRNA was prepared from human PARI cDNA using in vitro transcription and labeled with digoxigenin. The specimen was treated with this probe for 1 mm. After washing the unbound probe, an anti-digoxigenin antibody to which alkaline phosphatase was bound was allowed to act. Next, a color reaction is performed using diaminobenzidine,
- FIG. 9 The results are shown in FIG.
- the lower right graph in FIG. 9 is a plot of the amount of mRNA on each of the above days after in situ hybridization. In situ hybridization revealed that PARI mRNA in the SAH basilar artery was up-regulated.
- Example 8 Changes in contractile response to 100 M PAR1-AP and duration in SAH group
- the contraction response of the rabbit basal artery to thrombin was measured in the control group (sham surgery group), the SAH group, and the group in which the PARI antagonist was present in the SAH group. Stimulation was performed by the same method as in Example 3.
- “sham surgery group (sham)” (control rabbit) is the one in which 3 ml of physiological saline was injected into the rabbit cistern twice on days 0 and 2, and “SAH group” ( (Subarachnoid hemorrhage model) shows that 3 ml of autologous blood was injected twice into the rabbit cistern on day 0 and day 2.
- SAH + E5555 group (E5555 administration subarachnoid hemorrhage model) The figure shows a case where 3 ml of autologous blood mixed with 600 / ig E5555 was injected into the cerebral cistern twice on the 0th and 2nd days.
- the PARI antagonist used in this example is E5555 represented by the formula (V) (International Publication No. 02/085855 pamphlet).
- Figure 12 shows a typical record of the contractile response.
- FIG. 12 shows the contractile response to thrombin of the basilar artery in the sham surgery, SAH group, and SAH + E5555 group from the top.
- 1 unit / ml thrombin slightly contracted the isolated basilar artery.
- SAH a large contraction reaction was observed with 1 unit / ml thrombin stimulation.
- SAH + E5555 subarachnoid hemorrhage model
- Figure 12 B shows the dose response curves for the thrombin-induced contraction response in the SAH and sham groups.
- the contractile response caused by thrombin was enhanced in the basilar artery of the subarachnoid hemorrhage model.
- C in Figure 12 shows the protective effect of E5555 on the thrombin hyperconstriction caused by subarachnoid hemorrhage.
- the co-administration of E5555 with autologous blood significantly suppressed the increased reactivity to sputum thrombin, which caused subarachnoid hemorrhage.
- PARI is also involved in the induction of high contractility and desensitization by autologous blood, and that this high contractility induction and desensitization is inhibited by PARI antagonists.
- PARI was found to be involved in both induction of high contractility after bleeding and vasospasm.
- PARI inhibitors not only ameliorate cerebral vasospasm after subarachnoid hemorrhage, but may prevent the occurrence, and are shown to be a therapeutic agent for subarachnoid hemorrhage with a new mechanism of action. It was.
- Example 1 1 Effect of PARI antagonist on thrombin-induced contraction in rabbit basilar artery 1
- FIG. 13 shows the contractile response to thrombin of the basilar artery in the SAH group and SAH + E5555 (6 / ig) group from the top.
- SAH + E5555 subarachnoid hemorrhage model
- Figure 13 B shows the dose-dependent preventive effect of E5555 against the thrombin hyperconstriction 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 result is expressed as the average soil standard error.
- co-administration of autologous blood and E5555 caused subarachnoid hemorrhage.
- Increased reactivity to thrombin was suppressed in a dose-dependent manner from 60 ng of E5555.
- the SAH + E5050 (6 / ig) group and the SAH + 5050 (60 g) group significantly suppressed the contractile response 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 reaction caused by subarachnoid hemorrhage.
- thrombin induces a highly contractile response in the double-rabbit hemorrhage model, which may be due to impaired PARI upregulation and receptor desensitization.
- SAH activation of thrombin, the endogenous PARI agonist, is thought to play a key role in the development of vasospasm after bleeding.
- the PARI inhibitor was a therapeutic agent for subarachnoid hemorrhage, a prognosis improving agent, and an antivasospastic agent. It can be said that it is useful.
- a therapeutic agent for subarachnoid hemorrhage an agent for improving prognosis of subarachnoid hemorrhage and an anti-vasospasm agent comprising a compound having an action of inhibiting the function of PARI as an active ingredient.
- the function of PARI is enhanced, which causes high contraction of the basilar artery.
- PARI function-inhibiting compounds can suppress high contraction of the basilar artery, and as an active ingredient in the treatment of subarachnoid hemorrhage, prognosis improving agent and anti-vasospasm agent Useful.
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Abstract
Description
Claims
Priority Applications (3)
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US11/667,420 US20080194559A1 (en) | 2004-11-09 | 2005-09-02 | Remedy for Angiospasm Accompanying Subarachnoid Hemorrhage Containing Thrombin Receptor Antagonist as the Active Ingredient |
EP05782159A EP1813282A4 (en) | 2004-11-09 | 2005-09-02 | MEANS FOR THE TREATMENT OF ANGIOSPASM IN SUBARACHO-OAL BLOODING WITH THROMBIN RECEPTOR ANTAGONIST AS AN ACTIVE AGENT |
US12/456,548 US20100063048A1 (en) | 2004-11-09 | 2009-06-17 | Remedy for angiospasm accompanying subarachnoid hemorrhage containing thrombin receptor antagonist as the active ingredient |
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US62641204P | 2004-11-09 | 2004-11-09 | |
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PCT/JP2005/005068 WO2006051623A1 (ja) | 2004-11-09 | 2005-03-15 | トロンビン受容体アンタゴニストを有効成分とするくも膜下出血に伴う血管攣縮の治療剤 |
JPPCT/JP2005/005068 | 2005-03-15 |
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JP5571389B2 (ja) | 2008-01-11 | 2014-08-13 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 医薬組成物、医薬組成物製造のための2−イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット |
EP2240179B1 (de) * | 2008-02-05 | 2016-08-17 | Sanofi | Imidazopyridazine als par1-inhibitoren, ihre herstellung und verwendung als arzneimittel |
RU2499797C2 (ru) | 2008-02-05 | 2013-11-27 | Санофи-Авентис | Триазолопиридазины в качестве ингибиторов par1, их получение и применение в качестве лекарственных средств |
MX2010007893A (es) | 2008-02-05 | 2010-08-09 | Sanofi Aventis | Sales de triazolio como inhibidores del par1, produccion de las mismas, y uso como medicamentos. |
DE102014108210A1 (de) | 2014-06-11 | 2015-12-17 | Dietrich Gulba | Rodentizid |
EP4070658A1 (de) | 2021-04-06 | 2022-10-12 | BIORoxx GmbH | Verwendung von blutgerinnungshemmenden verbindungen als rodentizide |
Citations (2)
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WO2002071847A1 (en) * | 2001-03-08 | 2002-09-19 | Emory University | Treatment of neurodegenerative diseases and conditions using pari antagonists |
WO2002085855A1 (fr) * | 2001-04-19 | 2002-10-31 | Eisai Co., Ltd. | Derives de 2-iminopyrrolidine |
Family Cites Families (1)
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US5502187A (en) * | 1992-04-03 | 1996-03-26 | The Upjohn Company | Pharmaceutically active bicyclic-heterocyclic amines |
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2005
- 2005-09-02 WO PCT/JP2005/016568 patent/WO2006051648A1/ja not_active Application Discontinuation
- 2005-09-02 EP EP05782159A patent/EP1813282A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002071847A1 (en) * | 2001-03-08 | 2002-09-19 | Emory University | Treatment of neurodegenerative diseases and conditions using pari antagonists |
WO2002085855A1 (fr) * | 2001-04-19 | 2002-10-31 | Eisai Co., Ltd. | Derives de 2-iminopyrrolidine |
Non-Patent Citations (3)
Title |
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See also references of EP1813282A4 * |
WANG HS ET AL: "Endothelial Cells Exhibit Differential Chemokinetic and Mitogenic Responsiveness to Alpha-Thrombin.", JOURNAL OF SURGICAL RESEARCH., vol. 68, no. 2, 1997, pages 139 - 144, XP002990141 * |
WHITE RP ET AL: "Comparison of Responses Elicited by Alpha-Thrombin in Isolated Canine Basilar, Coronary, Mesenteric, and Renal Arteries.", BLOOD VESSELS., vol. 21, no. 1, 1984, pages 12 - 22, XP002990140 * |
Also Published As
Publication number | Publication date |
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EP1813282A4 (en) | 2011-03-02 |
EP1813282A1 (en) | 2007-08-01 |
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