Medicaments for the treatment or prevention of cerebral hemorrhage and methods of treating or preventing cerebral hemorrhage using the same

Abstract

Provided is a medicament for treating or preventing cerebral hemorrhage, which contains, as an active ingredient, a compound of the following formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a drug for treating or preventing cerebral hemorrhage and a method of treating or preventing cerebral hemorrhage using the same. BACKGROUND

[0002] Cerebral hemorrhage is a general term for a condition in which bleeding occurs due to rupture of blood vessels in the brain, and can be classified into intracerebral hemorrhage, subarachnoid hemorrhage, etc. according to the site of bleeding. Blood leaked from the blood vessels can form a hematoma, and the hematoma directly damages the brain, or due to the formation of edema, the pressure in the brain can increase, and the brain being compressed causes damage to the brain.

[0003] Until now, there has been no established effective pharmacological treatment method for cerebral hemorrhage, and removal of a hematoma in the brain through surgery, etc. has been used as a treatment method.

[0004] Meanwhile, stachybotrys microspora triprenylphenol (SMTP) compounds are a group of compounds having a triprenylphenol structure produced by filamentous fungi, and are known to have a thrombus dissolution-promoting effect and an angiogenesis-inhibiting effect according to JP 2004-224737 A, JP 2004-224738 A, and WO 2007 / 111203. As for the thrombus dissolution-promoting effect, according to FEBS Letter 1997; 418: 58-62, an action mechanism was proposed in which the SMTP compound induces a conformational change of plasminogen, leading to an increase in the susceptibility of plasminogen to t-PA and an increase in the binding of plasminogen to a thrombus, etc., thereby promoting the dissolution of the thrombus. In addition, according to J Biol Chem 2014; 289: 35826-35838, the SMTP compound was also shown to have an excellent anti-inflammatory effect. SUMMARY

[0005] PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] The present inventors have found that a compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof has an effect of treating or preventing cerebral hemorrhage.

[0007] Surprisingly, although there has been no effective pharmacological treatment method for cerebral hemorrhage so far, the compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof is effective in the treatment or prevention of cerebral hemorrhage.

[0008] JP 2004-224737 A, JP 2004-224738 A and WO 2007 / 111203, FEBS Letter 1997; 418:58-62 and J Biol Chem 2014; 289:35826-35838 do not teach or suggest the effect of the compound of formula (I) on cerebral hemorrhage.

[0009] The problem to be solved by embodiments of the present disclosure is to provide a drug that is excellent in treatment or prevention of cerebral hemorrhage and a new treatment method or prevention method for cerebral hemorrhage.

[0010] Method of solving the problem

[0011] Means for solving the above problem include the following aspects:

[0012] <1> A drug for treating or preventing cerebral hemorrhage, containing, as an active ingredient, a compound of the following formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0013] [Compound 1]

[0014]

[0015] In formula (I), L represents an aliphatic hydrocarbon group having a carbon number of 4 to 10, X represents a hydroxyl group or a carboxyl group, n represents an integer of 0 to 2, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0016] <2> The drug according to <1>, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of the following formula (IA) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0017] [Compound 2]

[0018]

[0019] In formula (IA), X is -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0020] <3> The drug according to <1> or <2>, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of the following formula (II) or formula (III) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0021] [Compound 3]

[0022]

[0023] In formula (II) or formula (III), X 1 , X 2 , and X 3 are each independently -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond, and R 1 represents any one of the following (A) to (D).

[0024] (A) a residue of removing one amino group from an amino compound selected from the group consisting of a natural amino acid, a D-isomer of a natural amino acid, and a compound having at least one carboxyl group replaced with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group among a natural amino acid and a D-isomer of a natural amino acid (however, -(CH)2-OH is excluded),

[0025] (B) an aromatic group having at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a sulfonic acid group, and a secondary amino group as a substituent or a part of a substituent, or an aromatic group containing a secondary amino group and can contain a nitrogen atom,

[0026] (C) an aromatic amino acid residue of the following formula (II-1) (in the formula, R 3 are each independent substituents that can be present or absent, and if present, represent a hydroxyl group, a carboxyl group, or an alkyl group having a carbon number of 1 to 5, n represents an integer of 0 or 1, m represents an integer of 0 to 5, and * represents a binding site),

[0027] [Compound 4]

[0028]

[0029] (D) a substituent represented by -L 1 -L 2 -R 4 (in the formula, L 1 represents a linking group that is an alkylene group having a carbon number of 1 to 4 having a carboxyl group, L 2 represents a linking group represented by -NH-C(=O)- or -NH-C(=S)-NH-, R 4 is a 9-fluorenylalkyloxy group having an alkoxy group having a carbon number of 1 to 3, or a polyheterocyclic group of the following formula (II-2) (in formula (II-2), * represents a binding site).

[0030] [Compound 5]

[0031]

[0032] R 2represents a residue in which two amino groups are removed from an amino compound selected from the group consisting of a natural amino acid having two amino groups, a D-isomer of a natural amino acid having two amino groups, a compound in which at least one carboxyl group of a natural amino acid having two amino groups or a D-isomer of a natural amino acid having two amino groups is replaced with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group, and H2N-CH(COOH)-(CH2) n -NH2(n is an integer of 0 to 9) and H2N-CH(COOH)-(CH2) m -S p -(CH2) q -CH(COOH)-NH2(m, p, and q are each independently an integer of 0 to 9) represents a compound.

[0033] <4> The medicament according to any one of <1> to <3>, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, ester, or solvate thereof, is a compound selected from the group consisting of the following SMTP-0, the following SMTP-1, the following SMTP-4, the following SMTP-5D, the following SMTP-6, the following SMTP-7, the following SMTP-8, the following SMTP-11 to 14, the following SMTP-18 to 29, the following SMTP-36, the following SMTP-37, the following SMTP-42, the following SMTP-43, the following SMTP-43D, the following SMTP-44, the following SMTP-44D, the following SMTP-46, and the following SMTP-47, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0034] [Compound 6]

[0035]

[0036] [Compound 7]

[0037]

[0038] In the formula, * indicates a binding site.

[0039] <5> The medicament according to <4>, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, ester, or solvate thereof, is SMTP-7, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0040] <6> The medicament according to any one of <1> to <5>, wherein the cerebral hemorrhage is intracerebral hemorrhage.

[0041] <7> The medicament according to any one of <1> to <6>, which is administered intracerebrally.

[0042] <8> A method of treating cerebral hemorrhage in a subject, comprising administering to the subject having cerebral hemorrhage an effective amount of a compound of the following formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof for treating cerebral hemorrhage.

[0043] [Compound 8]

[0044]

[0045] In formula (I), L represents an aliphatic hydrocarbon group having a carbon number of 4 to 10, X represents a hydroxyl group or a carboxyl group, n represents an integer of 0 to 2, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0046] <9> A method of preventing cerebral hemorrhage in a subject, comprising administering to the subject at risk of onset of cerebral hemorrhage an effective amount of a compound of the following formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof for preventing cerebral hemorrhage.

[0047] [Compound 9]

[0048]

[0049] In formula (I), L represents an aliphatic hydrocarbon group having a carbon number of 4 to 10, X represents a hydroxyl group or a carboxyl group, n represents an integer of 0 to 2, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0050] <10> The method according to <8> or <9>, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of the following formula (IA) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0051] [Compound 10]

[0052]

[0053] In formula (IA), X is -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0054] <11> The method according to any one of <8> to <10>, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of the following formula (II) or formula (III) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0055] [Compound 11]

[0056]

[0057] In formula (II) or formula (III), X 1 , X 2 , and X 3 are each independently -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond, and R 1 represents any one of the following (A) to (D).

[0058] (A) a residue of removing one amino group from an amino compound selected from the group consisting of a natural amino acid, a D-isomer of a natural amino acid, and a compound having at least one carboxyl group replaced with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group among a natural amino acid and a D-isomer of a natural amino acid (however, -(CH)2-OH is excluded),

[0059] (B) an aromatic group having at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a sulfonic acid group, and a secondary amino group as a substituent or a part of a substituent, or an aromatic group containing a secondary amino group and can contain a nitrogen atom,

[0060] (C) an aromatic amino acid residue of the following formula (II-1) (in the formula, R 3 are each independent substituents that can be present or absent, and if present, represent a hydroxyl group, a carboxyl group, or an alkyl group having a carbon number of 1 to 5, n represents an integer of 0 or 1, m represents an integer of 0 to 5, and * represents a binding site),

[0061] [Compound 12]

[0062]

[0063] (D) a substituent represented by -L 1 -L 2 -R 4 (in the formula, L 1 represents a linking group that is an alkylene group having a carbon number of 1 to 4 having a carboxyl group, L 2 represents a linking group represented by -NH-C(=O)- or -NH-C(=S)-NH-, R 4 is a 9-fluorenylalkyloxy group having an alkoxy group having a carbon number of 1 to 3, or a polyheterocyclic group of the following formula (II-2) (in formula (II-2), * represents a binding site).

[0064] [Compound 13]

[0065]

[0066] R 2represents a residue in which two amino groups are removed from an amino compound selected from the group consisting of a natural amino acid having 2 amino groups, a D-isomer of a natural amino acid having 2 amino groups, a compound in which at least one carboxyl group of a natural amino acid having 2 amino groups or a D-isomer of a natural amino acid having 2 amino groups is replaced with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group, and H2N-CH(COOH)-(CH2) n -NH2(n is an integer of 0 to 9) and H2N-CH(COOH)-(CH2) m -S p -(CH2) q -CH(COOH)-NH2(m, p, and q are each independently an integer of 0 to 9) represents a compound.

[0067] <12> The method according to any one of <8> to <11>, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, ester, or solvate thereof, is a compound selected from the group consisting of the following SMTP-0, the following SMTP-1, the following SMTP-4, the following SMTP-5D, the following SMTP-6, the following SMTP-7, the following SMTP-8, the following SMTP-11 to 14, the following SMTP-18 to 29, the following SMTP-36, the following SMTP-37, the following SMTP-42, the following SMTP-43, the following SMTP-43D, the following SMTP-44, the following SMTP-44D, the following SMTP-46, and the following SMTP-47, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0068] [Compound 14]

[0069]

[0070] [Compound 15]

[0071]

[0072] In the formula, * indicates a binding site.

[0073] <13> The method according to <12>, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, ester, or solvate thereof, is SMTP-7, or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0074] <14> The method according to any one of <8> to <13>, wherein the cerebral hemorrhage is an intracerebral hemorrhage.

[0075] <15> The method according to any one of <8> to <14>, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, ester, or solvate thereof, is administered intracerebrally.

[0076] <16> A compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof for use in the treatment or prevention of cerebral hemorrhage.

[0077] <17> The compound for use according to <16> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of formula (IA) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0078] <18> The compound for use according to <16> or <17> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound of formula (II) or (III) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0079] <19> The compound for use according to any one of <16> to <18> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound selected from the group consisting of SMTP-0, SMTP-1, SMTP-4, SMTP-5D, SMTP-6, SMTP-7, SMTP-8, SMTP-11 to 14, SMTP-18 to 29, SMTP-36, SMTP-37, SMTP-42, SMTP-43, SMTP-43D, SMTP-44, SMTP-44D, SMTP-46 and SMTP-47, or a pharmaceutically acceptable salt, ester or solvate thereof.

[0080] <20> The compound for use according to <19> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is SMTP-7 or a pharmaceutically acceptable salt, ester or solvate thereof.

[0081] <21> The compound for use according to any one of <16> to <20> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the cerebral hemorrhage is intracerebral hemorrhage.

[0082] <22> The compound for use according to any one of <16> to <21> or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is administered intracerebrally.

[0083] <23> Use of a compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof for the manufacture of a medicament for the treatment or prevention of cerebral hemorrhage.

[0084] <24> according to <23> The described use, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvation thereof is a compound of formula (IA) or a pharmaceutically acceptable salt, ester or solvation thereof.

[0085] <25> according to <23> or <24> The intended use, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvation thereof is a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt, ester or solvation thereof.

[0086] <26> according to <23> to <26> For any one of the uses, the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is a compound selected from the group consisting of: SMTP-0, SMTP-1, SMTP-4, SMTP-5D, SMTP-6, SMTP-7, SMTP-8, SMTP-11 to 14, SMTP-18 to 29, SMTP-36, SMTP-37, SMTP-42, SMTP-43, SMTP-43D, SMTP-44, SMTP-44D, SMTP-46 and SMTP-47, or a pharmaceutically acceptable salt, ester or solvate thereof.

[0087] <27> according to <26> The intended use, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvation thereof is SMTP-7 or a pharmaceutically acceptable salt, ester or solvation thereof.

[0088] <28> according to <23> to <27> The use of any one of the above, wherein the cerebral hemorrhage is intracerebral hemorrhage.

[0089] <29> according to <23> to <28> The use of any one of the following, wherein the drug is a drug administered intracerebrally.

[0090] The effects of the invention

[0091] According to embodiments of this disclosure, a drug with excellent therapeutic or preventive effects against cerebral hemorrhage can be provided, as well as a new use of a compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof as a drug. Attached Figure Description

[0092] [ FIG. 1A [Image of brain slices from a study using an animal model of cerebral hemorrhage.]

[0093] [ FIG. 1B [Image of brain slices from a study using an animal model of cerebral hemorrhage.]

[0094] [ FIG. 1C [Image of brain slices from a study using an animal model of cerebral hemorrhage.]

[0095] [ FIG. 2 ] Graph showing the ratio of hematoma volume to whole brain volume in studies using an animal model of intracerebral hemorrhage.

[0096] [ FIG. 3A ] Photographs of Evans blue dye of brain sections in studies using an animal model of intracerebral hemorrhage.

[0097] [ FIG. 3B ] Photographs of Evans blue dye of brain sections in studies using an animal model of intracerebral hemorrhage.

[0098] [ FIG. 3C ] Photographs of Evans blue dye of brain sections in studies using an animal model of intracerebral hemorrhage.

[0099] [ FIG. 3D ] Photographs of Evans blue dye of brain sections in studies using an animal model of intracerebral hemorrhage.

[0100] [ FIG. 4 ] Graph showing the area of regions stained using Evans blue dye in whole brain samples in studies using an animal model of intracerebral hemorrhage.

[0101] [ FIG. 5 ] Graph showing the concentration of Evans blue dye in whole brain samples in studies using an animal model of intracerebral hemorrhage.

[0102] [ FIG. 6 ] Brain MRI images showing hematoma in studies using an animal model of intracerebral hemorrhage.

[0103] [ FIG. 7 ] Graph showing the volume ratio of hematoma in MRI images expressed as a percentage in studies using an animal model of intracerebral hemorrhage.

[0104] [ FIG. 8 ] Graph showing the time course of the volume ratio of hematoma in MRI images (%) in studies using an animal model of intracerebral hemorrhage.

[0105] [ FIG. 9 ] Brain MRI images showing edema in studies using an animal model of intracerebral hemorrhage.

[0106] [ FIG. 10 ] Graph showing the volume ratio of edema in MRI images expressed as a percentage in studies using an animal model of intracerebral hemorrhage.

[0107] [ FIG. 11 ] Graph showing the path of a rat in a Barnes maze test in studies using an animal model of intracerebral hemorrhage.

[0108] [ FIG. 12 ] Graph showing the time taken by rats to reach the escape box in Barnes maze test using a cerebral hemorrhage animal model.

[0109] [ FIG. 13 ] Graph showing the number of holes in which rats made an error stay before reaching the escape box in Barnes maze test using a cerebral hemorrhage animal model.

[0110] [ FIG. 14 ] Graph showing the time change in the time taken by rats to reach the escape box in Barnes maze test using a cerebral hemorrhage animal model.

[0111] [ FIG. 15 ] Graph showing the time change in the number of holes in which rats made an error stay before reaching the escape box in Barnes maze test using a cerebral hemorrhage animal model.

[0112] [ FIG. 16 ] Graph showing the scores of rats in each group in LAN cable walking test using a cerebral hemorrhage animal model.

[0113] [ FIG. 17 ] Hematoxylin and eosin (HE) staining image of brain sections in a study using a cerebral hemorrhage animal model.

[0114] [ FIG. 18 ] Graph showing the hematoma area in the hematoxylin and eosin (HE) staining image of brain sections in a study using a cerebral hemorrhage animal model.

[0115] [ FIG. 19 ] Image of brain sections double-stained with Luxol fast blue and Cresyl violet in a study using a cerebral hemorrhage animal model.

[0116] [ FIG. 20 ] Graph showing the myelin density (average value of the corresponding same side and opposite side of collagenase injection of white matter) in the image of brain sections double-stained with Luxol fast blue and Cresyl violet in a study using a cerebral hemorrhage animal model.

[0117] [ FIG. 21 ] Graph showing the myelin density (value of each sample in the center of white matter) in the image of brain sections double-stained with Luxol fast blue and Cresyl violet in a study using a cerebral hemorrhage animal model.

[0118] [ FIG. 22 ] Antibody staining image of brain sections using an antibody against cleaved caspase-3 in a study using a cerebral hemorrhage animal model.

[0119] [ FIG. 23 ​Antibody staining images of brain sections using an antibody against cleaved caspase-3 in a study using an animal model of cerebral hemorrhage.

[0120] [ FIG. 24 ] Graph showing the number of immunopositive cells per 100 μm 2 of the antibody staining images of brain sections using an antibody against cleaved caspase-3 in a study using an animal model of cerebral hemorrhage.

[0121] [ FIG. 25 ] Antibody staining images of brain sections using an antibody against GFAP in a study using an animal model of cerebral hemorrhage.

[0122] [ FIG. 26 ] Antibody staining images of brain sections using an antibody against GFAP in a study using an animal model of cerebral hemorrhage.

[0123] [ FIG. 27 ] Graph showing the number of immunopositive cells per 100 μm 2 of the antibody staining images of brain sections using an antibody against GFAP in a study using an animal model of cerebral hemorrhage.

[0124] [ FIG. 28 ] Antibody staining images of brain sections using an antibody against Iba-1 in a study using an animal model of cerebral hemorrhage.

[0125] [ FIG. 29 ] Antibody staining images of brain sections using an antibody against Iba-1 in a study using an animal model of cerebral hemorrhage.

[0126] [ FIG. 30 ] Graph showing the number of immunopositive cells per 100 μm 2 of the antibody staining images of brain sections using an antibody against Iba-1 in a study using an animal model of cerebral hemorrhage. DETAILED DESCRIPTION

[0127] The content of the present disclosure will be described in detail below. Although the description required for the configuration described below can be based on representative embodiments of the present disclosure, the present disclosure is not limited to such embodiments.

[0128] In the numerical ranges described in the steps of the present disclosure, the upper limit or lower limit described for one numerical range can be replaced by the upper limit or lower limit of another numerical range described in the steps. Furthermore, in the numerical ranges described in the present disclosure, the upper limit or lower limit of the numerical range can be replaced by the value shown in the embodiments.

[0129] Further, in the present disclosure, unless otherwise specified, the amount of each component in a composition (such as a medicament) refers to the total amount of the applicable plurality of substances present in the composition, when there are a plurality of substances applicable to each component in the composition.

[0130] Further, in the present specification, in the symbols of groups (atomic groups), those not marked as substituted and unsubstituted include those without a substituent as well as those with a substituent.

[0131] Further, the term "process" in the present specification is not only used as the current term of an independent process, but also as the current term of a process that cannot be clearly distinguished from other processes, as long as the desired purpose of the process is achieved.

[0132] Further, in the present disclosure, "mass%" and "weight%" are synonymous, and "mass parts" and "weight parts" are synonymous.

[0133] Further, in the present disclosure, a combination of two or more preferred aspects is a more preferred aspect.

[0134] The present disclosure will be described in detail below.

[0135] (Medicaments)

[0136] A medicament according to the present disclosure is a medicament for treating or preventing cerebral hemorrhage, which contains the above-described compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof as an active ingredient. Here, the pharmaceutically acceptable salt, ester, or solvate of the above-described compound of formula (I) can be obtained from the compound of formula (I) by a conventional method. To this end, in the following description, unless otherwise specified, the description of each case of a salt, ester, or solvate is omitted, and the description of "the compound of formula (I)" should be applied in the same manner as "a pharmaceutically acceptable salt, ester, or solvate of the compound of formula (I)".

[0137] [Compound of formula (I)]

[0138] The medicament of the present disclosure is a compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0139] [Compound 16]

[0140]

[0141] In formula (I), L represents an aliphatic hydrocarbon group having a carbon number of 4 to 10, X represents a hydroxyl group or a carboxyl group, n represents an integer of 0 to 2, and R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0142] The aliphatic hydrocarbon group having 4 to 10 carbon atoms indicated by L can be linear, branched, or cyclic. It can also contain unsaturated bonds. Among them, an aliphatic hydrocarbon group that can contain a linear or branched unsaturated bond is preferred. L is an n+1-valent group.

[0143] In formula (I), the group represented by -L-X n is preferably a group selected from the group consisting of formula (V) and formula (Y1) to (Y4). In formula (V) and formula (Y1) to (Y4), * indicates a binding site to the carbon atom adjacent to the oxygen-containing ring in formula (I) (the carbon atom to which L is bound).

[0144] [Compound 17]

[0145]

[0146] In formula (V), Z 1 and Z 2 are independent hydrogen atoms or hydroxyl groups, or together form a single bond.

[0147] In R of formula (I), as a substituent having a molecular weight of 1,000 or less, a substituent having a molecular weight of 900 or less is preferred from the viewpoint of reducing hematoma and edema described later, a substituent having a molecular weight of 800 or less is more preferred, and a substituent having a molecular weight of 700 or less is further preferred.

[0148] An α-amino acid is one example of R in formula (I) (in this case, the nitrogen atom bound to R is the α-amino group of the α-amino acid). The α-amino acid is not particularly limited, and can be a natural amino acid or an unnatural amino acid. It can also be an amino acid derivative in which a substituent is introduced in a natural amino acid. Furthermore, if the α-amino acid has two or more amino groups, any of the amino groups can be removed. Furthermore, an amino sugar, a heterocyclic group, and the like are examples of R.

[0149] Among them, the α-amino acid is preferably a natural amino acid, a D-isomer of a natural amino acid, or a phenylalanine or a phenylglycine that can have at least one type of substituent selected from the group consisting of a hydroxyl group, a carboxyl group, and an alkyl group having a carbon number of 1 to 5, and more preferably a natural amino acid, a D-isomer of a natural amino acid, or a phenylglycine that can have at least one type of substituent selected from the group consisting of a hydroxyl group, a carboxyl group, and an alkyl group having a carbon number of 1 to 5. Here, the "D-isomer of a natural amino acid" refers to a D-optical isomer (which is substantially L-type) of a natural amino acid.

[0150] The natural amino acid is not particularly limited, as long as it is an amino acid that can naturally exist. Examples include glycine, alanine, threonine, valine, isoleucine, tyrosine, cysteine, cystine, methionine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, hydroxylysine, ornithine, citrulline, homocysteine, 3,4-dihydroxyphenylalanine, homocysteine, diaminopimelic acid, diaminopropionic acid, serine, leucine, phenylalanine, tryptophan, and the like.

[0151] Examples of the substituent in the amino acid derivative in which a substituent is introduced into a natural amino acid include a nitro group, a hydroxyl group, an arylalkyl group having a carbon number of 7 to 16, a urea group, a thiourea group, a carboxyl group, a group formed by removing one hydrogen atom from fluorescamine, and the like. When possible, the substituent in the amino acid derivative can have a further substituent. The substituent of the substituent having a substituent is the same as the substituent in the amino acid derivative.

[0152] The amino sugar in R of Formula (I) is not particularly limited, as long as it is a sugar derivative having at least one amino group. Specific examples can include glucosamine, galactosamine, mannosamine, neuraminic acid, and the like.

[0153] The heterocyclic group in R of Formula (I) is not particularly limited, as long as it is a cyclic group containing a heteroatom, and can be an aliphatic heterocyclic group or an aromatic heterocyclic group. Furthermore, a nitrogen atom, an oxygen atom, a sulfur atom, and the like are examples of the heteroatom.

[0154] Among them, a nitrogen-containing heterocyclic group containing a nitrogen atom as a heteroatom is preferred, a heterocyclic group formed by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, pyridazine, pyrrole, imidazole, pyrazole, and pyrazolone is more preferred, and a heterocyclic group formed by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, and pyrazolone is further preferred. Note that the position of the hydrogen atom removed from the heterocyclic compound is not particularly limited. Among them, removal from a carbon atom on the heterocyclic compound is preferred.

[0155] The heterocyclic group in R can have a substituent. Examples of the substituent in the heterocyclic group include an alkyl group having a carbon number of 1 to 5, an aryl group having a carbon number of 14 or less, a carboxyl group, a carbamoyl group, a sulfonic acid group, and the like. Among them, at least one type selected from the group consisting of a phenyl group and a carbamoyl group is preferred.

[0156] The number of substituents in the heterocyclic group is not particularly limited, but three or less is preferred.

[0157] R in the formula (I) can be an alkyl group. The alkyl group can be a straight chain, a branched chain, or a cyclic group. Among them, a straight chain or a branched chain is preferred, and a straight chain is more preferred. Furthermore, the number of carbons is preferably 2 to 8. Note that the number of carbons of a substituent on the alkyl group is not included in the number of carbons of the alkyl group.

[0158] The alkyl group in R can have a substituent. Examples of the substituent in the alkyl group include an alkyl group having a number of carbons of 1 to 5, an aryl group having a number of carbons of 14 or less, an arylalkyl group having a number of carbons of 16 or less, a hydroxyl group, a carboxyl group, a carbamoyl group, a sulfonic acid group, an amino group, a carbamoyloxy group, a urea group, a thiourea group, an alkyl sulfide group, an alkyl disulfide group, a group formed by removing R from the compound of the formula (I), a group formed by removing one hydrogen atom from fluorescamine, and the like. Among them, at least one type selected from the group consisting of a hydroxyl group, a carboxyl group, an amino group, a carbamoyloxy group, an arylalkyl group having a number of carbons of 7 to 14, a thiourea group, a group formed by removing R from the compound of the formula (I), and a group formed by removing one hydrogen atom from fluorescamine is preferred.

[0159] The number of substituents in the alkyl group is not particularly limited, but three or less is preferred.

[0160] Furthermore, when possible, the substituent in the alkyl group can have a further substituent. The substituent having a substituent is the same as the substituent in the alkyl group.

[0161] R in the formula (I) can be an aryl group. The aryl group is preferably an aryl group having a number of carbons of 6 to 14, more preferably an aryl group having a number of carbons of 6 to 10, and further preferably a phenyl group.

[0162] The aryl group in R can have a substituent. Examples of the substituent in the aryl group include an alkyl group having a number of carbons of 1 to 5, an aryl group having a number of carbons of 14 or less, a hydroxyl group, a carboxyl group, a sulfonic acid group, a carbamoyl group, an arylcarbonyl group, and the like. Among them, at least one type selected from the group consisting of a hydroxyl group, a carboxyl group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group is preferred.

[0163] The number of substituents in the aryl group is not particularly limited, but three or less is preferred.

[0164] Furthermore, when possible, the substituent in the aryl group can have a further substituent. The substituent having a substituent is the same as the substituent in the aryl group. Furthermore, when possible, the substituents in the aryl group can be bound together to form a cyclic structure.

[0165] <Method for producing a compound of the formula (I)>

[0166] The compound of formula (I) used in the present disclosure can be obtained by chemical synthesis, or by purification from a culture of a filamentous fungus (e.g., G. microsporum (G. microsporum)). The method of obtaining the compound of formula (I) by purification from a culture of a filamentous fungus includes a method involving purification of the target compound from a culture obtained when a predetermined added organic amino compound is added to a culture medium of G. microsporum. These methods are taught in, for example, JP 2004-224737 A, JP 2004-224738 A, and WO 2007 / 111203.

[0167] The compound of formula (I) used in the present disclosure can be an enantiomer, a diastereomer, or a mixture of enantiomers or diastereomers. The enantiomer, diastereomer, or mixture of enantiomers or diastereomers can be obtained by chemical synthesis, or by purification from a culture of a filamentous fungus. In the case of being obtained by purification from a culture of a filamentous fungus, by culturing the filamentous fungus by adding a D-isomer or L-body of the added organic amino compound, an isomer of the D-isomer or L-body can be obtained.

[0168] <Compound of formula (IA)>

[0169] The compound of formula (I) is preferably a compound of formula (IA) below.

[0170] [Compound 18]

[0171]

[0172] In formula (IA), X is -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond. R represents a hydrogen atom or a substituent having a molecular weight of 1,000 or less.

[0173] R in formula (IA) is the same as R in formula (I), and also the same as the preferred aspect.

[0174] <Compound of formula (II)>

[0175] One specific example of the compound of formula (I) used in the present disclosure is a compound of formula (II) below.

[0176] [Compound 19]

[0177]

[0178] In formula (II), X 1 is -CHY-C(CH3)2Z, Y and Z are each independently -H or -OH, or together form a single bond, and R 1 represents any one of the following (A) to (D).

[0179] (A) a residue of removal of one amino group from an amino compound selected from the group consisting of a natural amino acid, a D-isomer of a natural amino acid, and a compound having at least one carboxyl group substituted with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group in a natural amino acid or a D-isomer of a natural amino acid (however, -(CH)2-OH is excluded),

[0180] (B) an aromatic group having at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a sulfonic acid group, and a secondary amino group as a substituent or a part of a substituent, or an aromatic group containing a secondary amino group and can contain a nitrogen atom,

[0181] (C) an aromatic amino acid residue of the following formula (II-1) (in the formula, R 3 is each independent substituent that can be present or absent, and if present, represents a hydroxyl group, a carboxyl group, or an alkyl group having a carbon number of 1 to 5, n represents an integer of 0 or 1, m represents an integer of 0 to 5, and * represents a binding site with a nitrogen atom in a nitrogen-containing 5-membered ring (a nitrogen atom to which R1 is bound) in formula (II)), and

[0182] [Compound 20]

[0183]

[0184] (D) a substituent represented by -L 1 -L 2 -R 4 (in the formula, L 1 represents a linking group that is an alkylene group having a carbon number of 1 to 4 having a carboxyl group, L 2 represents a linking group represented by -NH-C(=O)- or -NH-C(=S)-NH-, R 4 represents a 9-fluorenylalkoxy group having an alkoxy group having a carbon number of 1 to 3, or a polyheterocyclic group of the following formula (II-2)). In formula (II-2), * represents a binding site with L 2 .

[0185] [Compound 21]

[0186]

[0187] In formula (II), a compound will be described when R 1 is the above (A).

[0188] The above (A) is a residue obtained by removing one amino group from an amino compound selected from the group consisting of a natural amino acid, a D-isomer of a natural amino acid, and a compound in which at least one carboxyl group of a natural amino acid or a D-isomer of a natural amino acid is substituted with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group (however, -(CH)2-OH is excluded).

[0189] The natural amino acid is not particularly limited as long as it is an amino acid that can naturally exist, such as an a-amino acid, a β-amino acid, a γ-amino acid, a δ-amino acid, and the like. Such an amino acid can be obtained from natural products or can be artificially obtained by a method such as organic synthesis.

[0190] The natural amino acid includes, for example, the following. Examples of the a-amino acid include glycine, alanine, threonine, valine, isoleucine, tyrosine, cysteine, cystine, methionine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, hydroxylysine, ornithine, citrulline, homocysteine, 3,4-dihydroxyphenylalanine, homocysteine, diaminopimelic acid, diaminopropionic acid, serine, leucine, phenylalanine, tryptophan, and the like, examples of the β-amino acid include β-alanine and the like, examples of the γ-amino acid include γ-aminobutyric acid, carnitine, and the like, and examples of the δ-amino acid include 5-amino levulinic acid, 5-amino valeric acid, and the like.

[0191] The compound in which at least one carboxyl group of the above natural amino acid or D-isomer of a natural amino acid is substituted with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group includes, for example, amino alcohols and amines. Such an amino alcohol includes, for example, 2-aminoethanol and the like.

[0192] When R 1 is the above (A), specific examples of the compound include the compounds shown in Table 1 below. Note that “added organic amino compound” in the table indicates an added organic amino compound added to a G. candidum medium to obtain the target compound (the same applies hereinafter). In the table, * indicates a binding site to the nitrogen atom in the nitrogen-containing 5-membered ring in the structural formula described at the top of the table (the same applies hereinafter).

[0193] [Table 1]

[0194]

[0195] The compounds shown in Table 1 above can be desirably used as the compound of formula (I) used in the present disclosure.

[0196] In formula (II), compounds when R 1 is the above (B) will be described.

[0197] The above (B) is an aromatic group having at least one selected from the group consisting of a carboxyl group, a hydroxyl group, a sulfonic acid group, and a secondary amino group as a substituent or a part of a substituent, or an aromatic group containing a secondary amino group and can contain a nitrogen atom.

[0198] The aromatic group includes, for example, a group represented by the following structural formula. In each structural formula, * indicates a binding site to the nitrogen atom (R 1 of the nitrogen-containing 5-membered ring in formula (II).

[0199] [Compound 22]

[0200]

[0201] When R 1 is the above (B), specific examples of the compound include the compounds shown in Table 2 below. In the table, * indicates a binding site to the nitrogen atom (R

[0202] [Table 2]

[0203]

[0204] The compounds shown in Table 2 above can be desirably used as the compound of formula (I) used in the present disclosure.

[0205] In formula (II), a compound when R 1 is the above (C) will be described.

[0206] The above (C) is an aromatic amino acid residue of the following formula (II-1) (in the formula, R 3 is a substituent that can be present or absent, and if present, represents at least one substituent selected from the group consisting of a hydroxyl group, a carboxyl group, or an alkyl group having a carbon number of 1 to 5, n represents an integer of 0 or 1, m represents an integer of 0 to 5, and * indicates a binding site. The alkyl group can also have a substituent, and examples of the substituent include a hydroxyl group, an alkenyl group, an amino group, a carboxyl group, a mercaptohydrogen group, and the like).

[0207] [Compound 23]

[0208]

[0209] The aromatic amino acid residue of formula (II-1) includes, for example, a group represented by the following structural formula. * indicates a binding site to the nitrogen atom (R

[0210] [Compound 24]

[0211]

[0212] When R in the above formula (II) 1 When it is (C), specific examples of compounds include those shown in Table 3 below. In the table, * indicates a binding site to the nitrogen atom (the nitrogen atom bound to R) in the nitrogen-containing 5-membered ring of the structural formula described at the top of the table.

[0213] [Table 3]

[0214]

[0215] The compounds shown in Table 3 above can be ideally used as compounds of formula (I) used in this disclosure.

[0216] In equation (II), the following will describe when R 1 It is the compound in (D) above.

[0217] The above (D) is derived from -L 1 -L 2 -R 4 The substituents represented (in the formula, L) 1 L represents a linking group consisting of an alkylene group having 1 to 4 carbon atoms and a carboxyl group. 2 This indicates a linking group represented by -NH-C(=O)- or -NH-C(=S)-NH-, and R 4 The symbol represents a 9-fluorenylalkoxy group having an alkoxy group having 1 to 3 carbon atoms, or a polyhedrally group of formula (II-2). In the formula, * indicates a binding site with a nitrogen atom (the nitrogen atom bound to R1) in the nitrogen-containing 5-membered ring of formula (II).

[0218] [Compound 25]

[0219]

[0220] When R in the above formula (II) 1 When it is (D), specific examples of compounds include those shown in Table 4 below. In the table, * indicates a binding site to the nitrogen atom (the nitrogen atom bound to R) in the nitrogen-containing 5-membered ring of the structural formula described at the top of the table.

[0221] [Table 4]

[0222]

[0223] The compounds shown in Table 4 above can be ideally used as compounds of formula (I) used in this disclosure.

[0224] <Compound of Formula (III)>

[0225] One specific example of the compound of formula (I) used in the present disclosure is the following compound of formula (III).

[0226] [Compound 26]

[0227]

[0228] In formula (III), X 2 and X 3 are independently -CHY-C(CH3)2Z, and Y and Z are each independently -H or -OH, or together form a single bond. R 2 represents a residue from an amino compound selected from the group consisting of a natural amino acid having 2 amino groups, a D-isomer of a natural amino acid having 2 amino groups, a compound having at least one carboxyl group substituted with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group in a natural amino acid having 2 amino groups or a D-isomer of a natural amino acid having 2 amino groups, and H2N-CH(COOH)-(CH2) n -NH2(n is an integer of 0 to 9) and H2N-CH(COOH)-(CH2) m -S p -(CH2) q -CH(COOH)-NH2(m, p, and q are each independently an integer of 0 to 9) indicates a compound.

[0229] n represents an integer of 0 to 9, preferably 0 to 6, more preferably 1 to 5, and further preferably 1 to 4.

[0230] m represents an integer of 0 to 9, preferably 0 to 4, more preferably 1 to 3, and further preferably 1 or 2.

[0231] p represents an integer of 0 to 9, preferably 0 to 4, more preferably 1 to 3, and further preferably 1 or 2.

[0232] q represents an integer of 0 to 9, preferably 0 to 4, more preferably 1 to 3, and further preferably 1 or 2.

[0233] When p is 0, m+q is preferably an integer of 0 to 9, more preferably 0 to 6, further preferably 1 to 5, and particularly preferably 1 to 4.

[0234] Natural amino acids having two amino groups include, for example, hydroxylysine, citrulline, cystine, homocystine, diaminopimelic acid, diaminopropionic acid, lysine, and ornithine as a- amino acids.

[0235] Compounds in which at least one of the carboxyl groups of the naturally occurring amino acids having two amino groups and the D-isomer of the naturally occurring amino acids having two amino groups is substituted with a hydrogen atom, a hydroxyl group, or a hydroxymethyl group include H2N-(CH2) k -NH2(k is an integer of 1 to 10, preferably 1 to 6, and more preferably 1 to 4).

[0236] Specific examples of the compound of formula (III) include the compounds shown in Table 5 below. In the table, * indicates the binding site to the nitrogen atom in the nitrogen-containing 5-membered ring in the structural formula described at the top of the table (the nitrogen atom to which R is bound)

[0237] [Table 5]

[0238]

[0239] The compounds shown in Table 5 above can be desirably used as the compound of formula (I) used in the present disclosure.

[0240] Specific examples of the compound of formula (I) other than the compound of formula (II) or (III) include the compounds shown in Tables 6 to 8 below. In Table 7, * indicates the binding site to the nitrogen atom in the nitrogen-containing 5-membered ring in the structural formula described at the top of the table ((Ib) or (Ic)). In Table 8, * indicates the binding site to the nitrogen atom in the nitrogen-containing 5-membered ring in the structural formula described at the top of the table ((Id) or (Ie)).

[0241] [Table 6]

[0242]

[0243] [Table 7]

[0244]

[0245] [Table 8]

[0246]

[0247] The compounds shown in Tables 6 to 8 above can be desirably used as the compound of formula (I) included in a medicament.

[0248] Among the above compounds, SMTP-0, SMTP-1, SMTP-4, SMTP-5D, SMTP-6, SMTP 7, SMTP-8, SMTP-11 to 14, SMTP-18 to 29, SMTP-36, SMTP-37, SMTP-42, SMTP-43, SMTP-43D, SMTP-44, SMTP-44D, SMTP-46, and SMTP-47 are preferred as the compound of formula (I), SMTP-7, SMTP-19, SMTP-22, SMTP-43, and SMTP-44D are more preferred, and SMTP-7 is further preferred. One of these compounds can be used alone or two or more can be used in any combination.

[0249] The compound of formula (I) used in the present disclosure can be any one of a free form, a pharmaceutically acceptable salt, or an ester form, or a solvate form. Inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or citric acid, formic acid, fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid are ideal forms of the pharmaceutically acceptable salts of the compound of formula (I) used in the present disclosure. In addition, compounds containing alkali metals or alkaline earth metals such as sodium, potassium, calcium, magnesium, etc., basic amines, or basic amino acids are also ideal forms of the pharmaceutically acceptable salts of the compound of formula (I) used in the present disclosure. Furthermore, alcohols, carboxylic acids, etc. having a carbon number of 1 to 10, preferably methanol, ethanol, acetic acid, or propionic acid, etc. are ideal forms of the pharmaceutically acceptable esters of the compound of formula (I) used in the present disclosure. In addition, water, etc. are ideal forms of the pharmaceutically acceptable solvates of the compound of formula (I) used in the present disclosure.

[0250] The above description of specific examples of the compound of formula (I) such as SMTP-7 also includes salts, esters, solvates, and other forms thereof.

[0251] (Use of the compound of formula (I))

[0252] The use of the compound of formula (I) includes use for treating or preventing cerebral hemorrhage. In other words, according to the present disclosure, there is also provided a compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof for use in treating or preventing cerebral hemorrhage. The details of the use method, etc. in this case are the same as those in the following method of treating or preventing cerebral hemorrhage, and the preferred aspects are also the same. The compound of formula (I) is useful, for example, in the following method of treating or preventing cerebral hemorrhage. The compound of formula (I) is effective not only in reducing or eliminating hematoma caused by cerebral hemorrhage, but also in reducing or eliminating edema. Since hematoma and edema are different phenomena, it is surprising that the compound of formula (I) has an effect on both hematoma and edema.

[0253] According to the present disclosure, there is also provided use of a compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof in the manufacture of a medicament for treating or preventing cerebral hemorrhage.

[0254] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof is administered to a subject for treating or preventing cerebral hemorrhage that is not associated with cerebral infarction (in other words, is not associated with cerebral infarction).

[0255] (Method for treating or preventing cerebral hemorrhage)

[0256] The method for treating or preventing cerebral hemorrhage of the present disclosure is a method for treating or preventing cerebral hemorrhage in a subject, which comprises administering to a subject having cerebral hemorrhage or at risk of onset of cerebral hemorrhage an effective amount for treating or preventing cerebral hemorrhage of a compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

[0257] By using the method for treating or preventing cerebral hemorrhage of the present disclosure, it is possible to obtain effects such as inhibiting exacerbation of cerebral hemorrhage, reducing or alleviating symptoms of cerebral hemorrhage, or inhibiting onset of cerebral hemorrhage, reducing the risk of onset of cerebral hemorrhage, or delaying onset of cerebral hemorrhage, and the like. More specifically, in the brain, effects such as reducing or eliminating a hematoma that has occurred, reducing or eliminating edema that has occurred, and restoring brain function. Note that, here, a "subject having cerebral hemorrhage" includes not only a subject in which cerebral hemorrhage is occurring, but also a subject in which cerebral hemorrhage has stopped but has some damage caused by cerebral hemorrhage (e.g., a hematoma is present, edema is present, brain function is impaired, and the like).

[0258] In the present disclosure, "treatment" is a term that includes control of exacerbation and alleviation or relief of symptoms, as long as the symptoms are improved or inhibited.

[0259] In the present disclosure, "prevention" means inhibition of onset, reduction of the risk of onset, delay of onset, and the like.

[0260] The compound of formula (I) (including a pharmaceutically acceptable salt, ester or solvate thereof; the same applies hereinafter) can be used for treating a subject who has found symptoms of cerebral hemorrhage (including a subject who has damage due to cerebral hemorrhage, although the hemorrhage itself has stopped, as described above), and for preventing cerebral hemorrhage in a subject who has not actually experienced cerebral hemorrhage but is at risk of onset of cerebral hemorrhage (particularly a subject in which onset of cerebral hemorrhage is predicted).

[0261] The compound of formula (I) can be used to eliminate symptoms caused by cerebral hemorrhage, inhibit development of the above-described symptoms, or alleviate the above-described symptoms. However, these effects should not be interpreted as limiting, as it can be compounded depending on the time of use or symptoms at the time of use.

[0262] Examples of when symptoms of cerebral hemorrhage are observed, or when symptoms of cerebral hemorrhage are predicted to occur, include during or after treatment for intracerebral hemorrhage, subarachnoid hemorrhage, etc. Alternatives include administration of thrombolytic agents (such as alteplase and urokinase) for a period of time after their administration, when cerebral hemorrhage is predicted due to their use; these drugs often have hemorrhage-related side effects. Prophylactic use is also possible during these periods. The risk of cerebral hemorrhage can also be determined by brain imaging, blood tests, and other physiological marker tests. For subjects identified as having this risk, compound (I) can even be administered prophylactically before the actual manifestation of cerebral hemorrhage.

[0263] Cerebral hemorrhage refers to a condition where a blood vessel in the brain ruptures, causing bleeding. The blood leaking from the vessel forms a hematoma, along with edema in the surrounding area. The hematoma and edema compress normal brain tissue and impair brain function. Compound (I) is effective not only in reducing or eliminating hematomas but also in reducing or eliminating edema. Since hematomas and edema are distinct phenomena, it is surprising that compound (I) has an effect on both.

[0264] Based on the location of the hemorrhage, cerebral hemorrhage can be broadly classified into intracerebral hemorrhage and subarachnoid hemorrhage. Subarachnoid hemorrhage is mainly caused by the rupture of cerebral aneurysms. Intracerebral hemorrhage refers to bleeding in various regions of the brain, including, for example, hemorrhage in the putamen, thalamus, subcortical, cerebellum, and pons. Compound (I) is effective against both intracerebral hemorrhage and subarachnoid hemorrhage.

[0265] Traditionally, surgical procedures such as neck clamps and endovascular surgery have been used for subarachnoid hemorrhage, and surgical procedures such as hematoma evacuation have been used for intracerebral hemorrhage. Surprisingly, the compound of formula (I) is able to treat or prevent intracerebral hemorrhage through pharmacological intervention.

[0266] Intracerebral hemorrhage is a condition fundamentally different from cerebral infarction. In one embodiment, the compound of formula (I) is administered to a subject for the treatment or prevention of intracerebral hemorrhage without cerebral infarction (in other words, unrelated to cerebral infarction). The treatment or prevention methods disclosed herein are applicable to intracerebral hemorrhage and subarachnoid hemorrhage.

[0267] Although this depends on the type of coexisting compound, the severity of cerebral hemorrhage, etc., a single effective dose of the compound of formula (I) (total amount of the compound of formula (I)) for an adult is preferably administered at 0.001 mg / kg to 100 mg / kg, and more preferably at 0.01 mg / kg to 30 mg / kg. The number of times of administration of the compound of formula (I) is not particularly limited, and can be used once, repeatedly, or continuously. The interval of administration and the cycle of administration can be selected by a person skilled in the art depending on clinical findings, imaging findings, blood findings, comorbidities, medical history, etc.

[0268] When the compound of formula (I) is used for repeated administration, an aspect of continuous administration for 1 hour to 24 hours per day from the viewpoint of contacting a continuously affected area with the compound of formula (I) is also preferable.

[0269] The method of administration is not particularly limited, and various administration routes can be selected, such as intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, oral administration, and intracerebral administration.

[0270] Intracerebral administration can be performed by, for example, using a microsyringe equipped with a microneedle, inserting the microneedle into a guide cannula implanted in the brain, and injecting a drug solution to a predetermined brain site. From the viewpoint of dose reduction, intracerebral administration is preferable.

[0271] The drug of the present disclosure can be used for humans without limitation. The drug can also be used for other applicable targets, including non-human animals, such as livestock, such as cows, horses, sheep, and pets, such as dogs, cats, and monkeys.

[0272] <Use with other drugs>

[0273] The compound of formula (I) can be used alone or together with at least one or more other drugs (for example, an antihypertensive drug).

[0274] <Pharmaceutical composition>

[0275] The compound of formula (I) can be used in a pharmaceutical composition. That is, a pharmaceutical composition containing the compound of formula (I) and at least one of a pharmaceutically acceptable carrier and a formulation additive is provided. The use, dose, method of administration, etc. of the pharmaceutical composition are the same as those of the drug of the present disclosure, and can be used, for example, in the therapeutic or prophylactic method of cerebral hemorrhage of the present disclosure.

[0276] That is, a pharmaceutical composition containing the compound of formula (I) and at least one of a pharmaceutically acceptable carrier and a formulation additive is provided.

[0277] A method of treating cerebral hemorrhage in a subject, comprising administering to a subject having cerebral hemorrhage a therapeutically effective amount of a pharmaceutical composition of the present disclosure for cerebral hemorrhage; and

[0278] A method of preventing cerebral hemorrhage in a subject, comprising administering to a subject at risk of onset of cerebral hemorrhage a prophylactically effective amount of a pharmaceutical composition of the present disclosure against cerebral hemorrhage.

[0279] The type of carrier and formulation additives optionally contained in the pharmaceutical composition is not particularly limited. The pharmaceutical composition of the present disclosure can be formulated using the compound of formula (I) of the present disclosure and a pharmaceutically acceptable solid carrier (e.g., gelatin or lactose) or a liquid carrier (e.g., water, physiological saline, or an aqueous glucose solution).

[0280] Examples

[0281] Several embodiments of the present disclosure are described below, but the embodiments of the present disclosure are not limited thereto. Note that, unless otherwise specified, "%" is based on mass.

[0282] <Preparation of SMTP-7>

[0283] SMTP-7 was purified from a culture obtained when L-ornithine was added as an added organic amino compound to the medium of the G. fimbriatum IFO 30018 strain using the method taught in JP 2004-224738 A. A 50 mg / mL solution was prepared by adding a 0.3 N (0.3 mol / L) NaOH solution and physiological saline (0.9% NaCl) to the dried solid of SMTP-7 obtained by purification. Then, the concentration of SMTP-7 was adjusted to a concentration of 10 mg / mL and a slightly alkaline pH using a 0.3 N (0.3 mol / L) HC1 solution and physiological saline, and the solution was filter-sterilized, subdivided, and stored frozen at -30°C. SMTP-7 was diluted as needed using physiological saline.

[0284] SMTP-7 was used as a test solution in the following experiments, in which the above-mentioned frozen-stored solution was dissolved to 2 mg / mL in a physiological saline solution immediately before testing.

[0285] Each drug in the experiments was diluted as needed using physiological saline.

[0286] <Example 1>

[0287] Preparation of rats

[0288] Male SD rats (8 to 10 weeks old, body weight 250-300 g) were placed under a 12-hour light / dark cycle and a temperature of 22°C ± 1°C. The rats were housed in plastic cages and allowed free access to water and food. The number of rats used in each experiment was n = 4, unless otherwise specified. In addition, components other than those listed in the injection solutions were physiological saline.

[0289] Rats were anesthetized with isoflurane (1.5% isoflurane + 66% NO + 33% O2) and then a syringe was used to inject collagenase from Clostridium histolyticum (type IV, manufactured by Sigma-Aldrich) at a concentration of 0.25 U / μL at a rate of 0.2 μL / min for 5 minutes at a transverse position 3 mm from the center of the brain, at the level of the bregma in the anterior-posterior direction, and 5 mm behind the vascular stripe, and then the syringe needle was left in place for 10 minutes and then slowly withdrawn (0.5 mm per minute) over another 10 minutes. Care was taken to prevent backflow during the injection. In the following description, the day of the collagenase injection is referred to as day 0. This collagenase injection caused intracerebral hemorrhage and hematoma formation.

[0290] Twenty-four hours after the collagenase injection (i.e., day 1 after the collagenase injection), a test solution (saline, a 2 mg / mL solution of SMTP-7) was injected at a rate of 0.2 μL / min for 10 minutes through the same injection route as the collagenase injection. A test group that did not receive the test solution was also included. Care was taken to prevent backflow during the injection. As during the collagenase injection, the syringe needle was left in place for 10 minutes after the injection and then slowly withdrawn (0.5 mm per minute) over another 10 minutes.

[0291] On day 7 after the collagenase injection, the rats were sacrificed and 3 mm thick brain sections were prepared. During section preparation, 0.1 M PBS (pH 7.4) containing 4% paraformaldehyde solution was used for fixation. Microphotographs of these sections are shown in FIGS. 1A-1C FIGS. 1A-1C In

[0292] In addition, the ratio of hematoma volume to whole brain volume was also measured using ImageJ. The results are shown in FIG. 2 Note that in the figures of the present disclosure, the vertical axis is the ratio of hematoma volume to whole brain sample volume, expressed in percent, ** indicates a p-value of a t-test for a significant difference of less than 0.01, and *** indicates a p-value of a t-test for a significant difference of less than 0.001 (the meaning of ** and *** is the same). In addition, the bars in the figures represent standard deviation. As shown in FIGS. 1A-1C and FIG. 2 As shown in

[0293] <Example 2> ​

[0294] The same experiment as in Example 1 was performed again. However, in Example 2, one hour before sacrifice (day 7), physiological saline containing 2% Evans blue was injected into the tail vein at a volume of 4 mL per kg of body weight. Evans blue has the property of binding to albumin in the blood, and as a result of the collagenase injection, the hematoma was stained due to the rupture of the blood-brain barrier. Micrographs of the whole brain and 3 mm thick sections were shown. FIGS. 3A-3D In the middle, and using ImageJ to determine the total area (mm²) of the Evans blue stained region from the slice. 2 ) and staining density are shown FIG. 4 and FIG. 5 middle. FIG. 3D The appearance of Evans blue staining on blood clots is also shown. FIG. 4 In the middle, the vertical axis represents the area (mm) of the Evans blue stained region in the whole brain sample. 2 Furthermore, * indicates a p-value less than 0.05 in a t-test indicating a significant difference, and ** indicates a p-value less than 0.01 in a t-test indicating a significant difference (the * and ** have the same meaning below). FIG. 5 In the diagram, the vertical axis represents the concentration of Evans blue, expressed as absorbance at a wavelength of 620 nm. For example... FIGS. 3A-3D , FIG. 4 and FIG. 5 As shown, individuals injected with a test solution containing SMTP-7 exhibited a significant reduction in hematoma.

[0295] <Example 3>

[0296] Collagenase and test solution injections were performed as described in Example 1, and rat brains were measured by small animal MRI on days 1 and 7 following collagenase injection (PharmaScan manufactured by Bruker BioSpin). Measurements were performed using a magnetic field of 7T, echo time (TE) = 4 ms, repetition time (TR) = 800 ms, 256 × 256 matrix, slice thickness of 0.8 mm, and an average scan time of approximately 5 minutes and 7 seconds to obtain T2-weighted images. For MRI measurements, rats were anesthetized with 2.5% to 3% isoflurane + NO + O2, and measurements were performed while the rats were still alive. Results are as follows... FIG. 6 As shown. In FIG. 6 In the diagram, "ICH baseline 24 hours" represents rat brain images on day 1 after collagenase injection, "TTT 1 week" represents rat brain images on day 7 after injection of the test solution containing SMTP-7, "No TTT 1 week" represents rat brain images on day 7 without injection of the test solution, and "Mediator 1 week" represents rat brain images on day 7 after injection of saline instead of the test solution. FIG. 6"TTT 1 week" shows four samples, and "No TTT 1 week" and "Vehicle 1 week" each show three samples. The volume of the hematoma was measured based on these MRI measurements using ImageJ. The hematoma volume at day 7 after collagenase injection is shown in FIG. 7 The change in hematoma volume at day 1 after collagenase injection is shown in FIG. 8 In FIG. 7 , the vertical axis shows the volume ratio of the hematoma in the T2-weighted MRI images in percent. Furthermore, "ICH baseline" indicates the rat at day 1 after collagenase injection, "ICH" indicates the rat at day 7 after collagenase injection without injection of the test solution, "Vehicle" indicates the rat at day 7 after injection of physiological saline instead of the test solution, and "Treatment" indicates the rat at day 7 after injection of the test solution containing SMTP-7. In FIG. 8 , the horizontal axis indicates the number of days after collagenase injection, and the vertical axis indicates the ratio of the hematoma volume in percent of the brain volume at each time point. Furthermore, the perihematoma edema and the resulting mass effect were observed. The results are shown in FIG. 9 In FIG. 9 , "ICH baseline 24h" indicates the rat brain image at day 1 after collagenase injection, "TTT 1 week" indicates the rat brain image at day 7 after injection of the test solution containing SMTP-7, "No TTT 1 week" indicates the rat brain image at day 7 without injection of the test solution, and "Vehicle 1 week" indicates the rat brain image at day 7 after injection of physiological saline instead of the test solution. As shown in FIG. 9 "TTT 1 week" shows four samples, and "No TTT 1 week" and "Vehicle 1 week" each show three samples. Furthermore, the volume of the brain edema was determined based on these observations using ImageJ. The brain edema volume at day 7 after collagenase injection is shown in FIG. 10 In FIG. 10 , the vertical axis shows the ratio of the brain edema volume in percent of the brain volume, "ICH baseline" indicates the rat at day 1 after collagenase injection, "ICH" indicates the rat at day 7 after collagenase injection without injection of the test solution, "Vehicle" indicates the rat at day 7 after injection of physiological saline instead of the test solution, and "Treatment" indicates the rat at day 7 after injection of the test solution containing SMTP-7. As shown in FIGS. 6-10 , the individual injected with the test solution containing SMTP-7 shows a significant reduction of the hematoma and the edema in the brain.

[0297] <Example 4>

[0298] Collagenase injection and test solution injection were performed as in Example 1, and Barnes maze test (Barnes maze test) was performed on day 7 after collagenase injection. This test allows evaluation of spatial learning and memory. The test was performed using a gray acrylic platform with a diameter of 122 cm, and 18 holes were arranged on the periphery of the acrylic platform. The behavior of the rats was observed by placing a camera on the head of the rat. Evaluation was made according to the time required to find the escape chamber. Training was performed by performing the test twice a day, and the test was performed until day 10 after collagenase injection. In each test, the rat started from the start box provided at the center of the maze, stayed in the start box for 30 seconds, and was then allowed to freely explore the maze. Once the rat reached the escape chamber, the rat was allowed to stay in the escape chamber for 30 seconds before being returned to the home cage. If the rat did not reach the escape chamber within the maximum test time of 300 seconds, the rat was picked up and stayed in the escape chamber for 30 seconds before being returned to the home cage. The time required to reach the escape chamber and the number of holes in which the mouse made a mistake were evaluated. Note that in Example 4, rats that did not receive any treatment were also tested as controls. The paths of the rats on day 7 (training day 1 in the figure) and day 10 (training day 4 in the figure) after collagenase injection are shown in FIG. 11 FIG. 11 In this, FIG. 12 and FIG. 13 show the time required to reach the escape chamber and the number of holes in which a mistake was made on day 10 after collagenase injection. In this, FIGS. 12-15 FIG. 14 and FIG. 15 show the time change in the time required and the number of error holes per day from day 7 to day 10 after collagenase injection, i.e., the degree of learning. FIG. 14 FIG. 15 Day 1 in FIGS. 11-15 indicates day 7 after collagenase injection. As shown in , individuals injected with a test solution containing SMTP-7 showed a significant improvement in learning ability.

[0299] <Example 5>

[0300] ​​Collagenase injection and test solution injection were performed as in Example 1, and the motor function of the rats was evaluated by making the rats walk on a local area network (LAN) cable. The rats were placed on the LAN cable, 60 cm above the ground along the length of the LAN cable, and observed for 60 seconds for hemiplegia, posture on the cable, activity, and recovery force. The following criteria were used to assign a score for each item, and a total score (0 to 10) was obtained.

[0301] [right side paralysis]

[0302] [front legs]

[0303] 0 points if right side paralysis is present

[0304] 1 point if right side paralysis is not present

[0305] [rear legs]

[0306] 0 points if right side paralysis is present

[0307] 1 point if right side paralysis is not present

[0308] [posture on the cable]

[0309] 0 points if unable to hold for 10 seconds

[0310] 1 point if able to hang for 10 seconds or more, but unable to maintain a posture across the LAN cable for 30 seconds

[0311] 2 points if able to maintain a posture across the LAN cable for 30 seconds or more, but unable to maintain a posture along the LAN cable for 30 seconds

[0312] 3 points if able to maintain a posture along the LAN cable for 30 seconds or more

[0313] [activity]

[0314] [continuity of activity]

[0315] 0 points if unable to maintain activity for 10 seconds

[0316] 1 point if able to maintain activity for 10 seconds or more

[0317] [posture recovery]

[0318] 0 points if unable to recover posture when losing balance

[0319] 1 point if able to recover posture when losing balance

[0320] [travel distance]

[0321] 0 points if unable to move 10 cm

[0322] 1 point if able to move 10 cm or more

[0323] <Resilience>

[0324] It fell from the LAN cable, 0 points.

[0325] Not dropped from the LAN cable, 2 points

[0326] The results are as follows FIG. 16 As shown. FIG. 16 The vertical axis in the figure shows the total scores mentioned above. Note that in Example 5, rats that did not receive any treatment were also tested as a control. FIG. 16 In the diagram, "ICH" indicates rats that received collagenase injection but not the test solution, "mediator" indicates rats that received saline instead of the test solution, "treatment" indicates rats that received the test solution containing SMTP-7, and "control" indicates healthy rats that did not receive collagenase injection. FIG. 16 As shown, individuals injected with a test solution containing SMTP-7 exhibited significant improvements in motor performance.

[0327] <Example 6>

[0328] Collagenase injection and test solution injection were performed as in Example 1, and brain tissue samples were obtained on day 7 post-injection. Specifically, rats were deeply anesthetized with isoflurane, perfused with physiological saline, and further perfused with 0.1M phosphate-buffered saline (PBS; pH 7.4) containing 4% formaldehyde. The brains were removed and post-fixed overnight at 4°C using the aforementioned PBS solution containing 4% formaldehyde as a fixative, and stored in PBS containing 10%, 20%, and 30% sucrose until tissue sedimentation. Sections were cut coronally using a brain slicer (manufactured by Harvard Apparatus), embedded in the optimal cutting temperature (OCT) compound, frozen with liquid nitrogen, and cut into sections of approximately 2 mm thickness (10 μm to 12 μm) using a cryotome. Sections corresponding to the midline at the level of the anterior fontanelle were stained with hematoxylin-eosin (HE). This micrograph is shown below. FIG. 17 As shown. The display scale is 100 μm (the same in subsequent photomicrographs). In FIG. 17 In the diagram, "ICH" indicates rats that were injected with collagenase but not with the test solution, "mediator" indicates rats that were injected with saline instead of the test solution, and "SMTP-7" indicates rats that were injected with a test solution containing SMTP-7. Hematoma area (mm²) on these sections was measured using ImageJ. 2 )like FIG. 18 As shown. FIG. 18 The vertical axis in the figure represents the area (mm²) of the hematoma region identified by HE staining. 2). In addition, "ICH" indicates rats that were injected with collagenase but not the test solution, "Vehicle" indicates rats that were injected with saline instead of the test solution, and "Treatment" indicates rats that were injected with the test solution containing SMTP-7. As shown in FIG. 17 and FIG. 18 individuals injected with the test solution containing SMTP-7 showed a significant reduction in the size of the hematoma.

[0329] <Example 7>

[0330] Ten-micron thick sections prepared as in Example 6 were double-stained with Luxol Fast Blue and cresyl violet to visualize white matter lesions (demyelination) within the corpus callosum. This micrograph is shown in FIG. 19 In FIG. 19 , "ICH" indicates rats that were injected with collagenase but not the test solution, "Vehicle" indicates rats that were injected with saline instead of the test solution, and "SMTP-7" indicates rats that were injected with the test solution containing SMTP-7. In addition, myelin density in the white matter was also measured at the ipsilateral site to the collagenase injection site, the contralateral site to the collagenase injection site, and the central site. The results are shown in FIG. 20 and FIG. 21 In FIG. 20 , the vertical axis shows the myelin density (average value) in the white matter. In FIG. 20 , "ipsilateral" means ipsilateral to the collagenase injection, and "contralateral" means contralateral to the collagenase injection (and similarly below). In FIG. 21 , the vertical axis shows the myelin density (value per solid) in the central white matter. In FIG. 20 and FIG. 21 , "ICH" indicates rats that were injected with collagenase but not the test solution, "Vehicle" indicates rats that were injected with saline instead of the test solution, and "Treatment" indicates rats that were injected with the test solution containing SMTP-7. As shown in FIGS. 19-21 , individuals injected with the test solution containing SMTP-7 showed a significant inhibition of the lesion in the hematoma.

[0331] <Example 8>

[0332] Ten-micron to 12 μm thick sections (midline - 3 mm, under the level of the lambdoidal fontanel) prepared as in Example 6 were treated with a 10% bovine serum albumin (BSA) solution at room temperature for 2 hours to block non-specific binding sites, and the blocked sections were incubated with an antibody against cleaved caspase-3 (Asp 175) (9661, Cell Signaling Technology). In addition, the sections were exposed to a biotinylated secondary antibody (1:200; Vector Laboratory) and visualized using 50 mmol / L Tris-HCl (pH = 7.6) containing 0.01% diaminobenzidine tetrahydrochloride and 0.005% hydrogen peroxide. Photomicrographs are shown in FIG. 22 and FIG. 23 In FIG. 22 and FIG. 23 , "ICH" indicates rats that were injected with collagenase but not with the test solution, "Vehicle" indicates rats that were injected with saline instead of the test solution, and "Treatment" indicates rats that were injected with the test solution containing SMTP-7.

[0333] In addition, two 100 μm 2 regions of interest (ROI) were randomly selected in the cerebral cortex, and the number of immunopositive cells in each ROI was counted and averaged. In FIG. 24 , the vertical axis represents the number of immunopositive cells per 100 μm 2 ROI, "ICH" indicates rats that were injected with collagenase but not with the test solution, "Vehicle" indicates rats that were injected with saline instead of the test solution, and "Treatment" indicates rats that were injected with the test solution containing SMTP-7. Results are shown in FIG. 24 As shown in FIGS. 22-24 , the number of cells expressing the apoptosis marker caspase-3 was significantly reduced in individuals injected with the test solution containing SMTP-7, both ipsilaterally (ipsilateral / Ipsilateral) and contralaterally (contralateral / Contralateral).

[0334] <Example 9>

[0335] The antibody staining test was performed as in Example 8, except that an anti-GFAP antibody (astrocytes; mouse mAb 3670; Cell Signaling Technology) was used instead of an antibody against cleaved caspase-3 (Asp 175). Photomicrographs are shown in FIG. 25 and FIG. 26 , and the number of immunopositive cells is shown in FIG. 27 As shown in FIGS. 25-27As shown in FIG. 10, the results of immunostaining using an antibody against GFAP (an astrocyte marker) showed that neuronal damage was significantly inhibited in the individual injected with the test solution containing SMTP-7.

[0336] <Example 10>

[0337] The antibody staining test was performed as in Example 8, except that an anti-Iba-1 antibody (019-19741; Wako; Cell Signaling Technology) was used instead of an antibody against cleaved caspase-3 (Asp175). Micrographs are shown in FIG. 11, and the number of immunopositive cells is shown in FIG. 12. FIG. 28 and FIG. 29 As shown in FIG. 11, the results of immunostaining using an antibody against Iba-1 (a macrophage / microglia-specific marker) showed that inflammation was also significantly inhibited in the individual injected with the test solution containing SMTP-7. FIG. 30 As shown in FIG. 12, the number of immunopositive cells was significantly reduced in the individual injected with the test solution containing SMTP-7. FIGS. 28-30 As shown in FIG. 11, the results of immunostaining using an antibody against Iba-1 (a macrophage / microglia-specific marker) showed that inflammation was also significantly inhibited in the individual injected with the test solution containing SMTP-7.

[0338] The above results show that the compound of formula (I) has excellent therapeutic and prophylactic effects on cerebral hemorrhage.

[0339] All documents, patent applications, and technical standards described in this specification are herein incorporated by reference to the same extent as if each individual document, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. Use of a compound in the preparation of a medicament for the treatment or prevention of hematoma or edema, wherein the compound is SMTP-7 or a pharmaceutically acceptable salt thereof, and wherein the medicament is formulated for administration to a subject suffering from cerebral hemorrhage of SMTP-7 or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the subject suffering from cerebral hemorrhage is a subject whose cerebral hemorrhage has stopped but who has injury caused by the cerebral hemorrhage.

3. The use according to claim 1, wherein the cerebral hemorrhage is intracerebral hemorrhage.

4. The use according to claim 1, wherein the drug is formulated for intracerebral administration.

5. The use according to claim 1, wherein the drug is administered intravenously.

6. The use according to claim 1, wherein the drug is used to prevent cerebral hemorrhage.

7. The use according to claim 1, wherein the drug is also used to reduce apoptosis.

8. The use according to claim 7, wherein the apoptosis is contralateral.

9. The use according to claim 7, wherein the apoptosis is ipsilateral.

10. The use according to claim 1, wherein the drug is further used to inhibit neuronal damage.

11. The use according to claim 1, wherein the drug is also used to suppress inflammation.

12. The use according to claim 1, wherein the drug improves learning ability.

13. The use according to claim 1, wherein the drug improves motor function.

14. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of cerebral hemorrhage, wherein said compound is SMTP-7.

15. Use of the compound in the preparation of a medicament for the treatment or prevention of cerebral hemorrhage, wherein said compound is SMTP-7.

16. The use according to claim 14 or 15, wherein the cerebral hemorrhage is intracerebral hemorrhage.

17. The use according to claim 14 or 15, wherein the drug is formulated for intracerebral administration.

18. The use according to claim 14 or 15, wherein the compound reduces or eliminates hematoma.

19. The use according to claim 14 or 15, wherein the compound reduces or eliminates edema.

20. The use according to claim 14 or 15, wherein the compound reduces or eliminates hematoma and edema.

21. The use according to claim 14 or 15, wherein the drug is used to prevent cerebral hemorrhage.

22. The use according to claim 14 or 15, wherein the drug is further used to reduce apoptosis.

23. The use according to claim 22, wherein the apoptosis is contralateral.

24. The use according to claim 22, wherein the apoptosis is ipsilateral.

25. The use according to claim 14 or 15, wherein the drug is further used to inhibit neuronal damage.

26. The use according to claim 14 or 15, wherein the drug is further used to suppress inflammation.

27. The use according to claim 14 or 15, wherein the drug improves learning ability.

28. The use according to claim 14 or 15, wherein the drug improves motor function.

29. The use according to claim 14 or 15, wherein the drug is administered intravenously.

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