WO2001079184A1

WO2001079184A1 - Substituted piperazine compounds

Info

Publication number: WO2001079184A1
Application number: PCT/JP2001/003107
Authority: WO
Inventors: Toru Kodo; Yukihiro Ohno; Ken-Ichi Ohtani; Hiroshi Aino
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 2000-04-18
Filing date: 2001-04-10
Publication date: 2001-10-25
Also published as: JPWO2001079184A1; AU2001248748A1

Abstract

Compounds of the general formula (1), prodrugs thereof, or pharmaceutically acceptable salts of both exhibit poly(ADP-ribose) polymerase (PARP) inhibiting activity and are useful as remedies for diseases due to enhanced PARP activity, e.g., ischemic brain diseases: wherein X1-X2- is C(=O)-N(R7)- or C(R8)=N- (wherein R7 is hydrogen, optionally substituted alkyl, or the like and R8 is optionally substituted alkyl or the like); R?1, R2, R3 and R4¿ are each independently hydrogen, optionally substituted alkyl, or the like; R5 is either nil or one or more substituents on piperazine ring which may be the same or different from each other and are each optionally substituted alkyl or the like; and R6 is hydrogen, optionally substituted alkyl, or the like.

Description

Description Substituted pyrazines Technical field

The present invention relates to a compound having an inhibitory action on poly (ADP-ribose) polymerase (PARP, also known as poly (ADP-ribose) synthetase). Compounds having a PARP inhibitory activity include diseases caused by enhanced PARP activity, such as cerebral ischemic injury (eg, stroke, sequelae after stroke (disorders associated with stroke and sequelae after stroke (eg, exercise)). Disorders), cerebral edema, etc.), neurodegenerative diseases (eg, Parkinson's disease, Alzheimer's disease, Huntington's chorea, etc.), brain contusion, head trauma, spinal injury, diabetes, ischemic heart disease ( For example, myocardial infarction, angina pectoris, arrhythmia, etc., organ damage due to ischemia or reperfusion of ischemia (eg, myocardial ischemia-reperfusion injury, acute renal failure, renal ischemia, organ transplantation, percutaneous Disorders caused by surgical procedures such as coronary angioplasty, etc., inflammation (eg, arthritis, rheumatoid arthritis, sepsis), inflammatory enteritis (eg, colitis, Crohn's disease) Etc.), cancer, cachexia (force hex), renal disorder, osteoporosis, acute and chronic pain (eg, neurogenic pain), sepsis (eg, endotoxin shock), skeletal muscle degeneration, muscular dystrophy It is useful as a therapeutic agent for skin aging, immune system aging, AIDS, and changes in gene expression in senescent cells.

In particular, cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, cerebral contusion, head trauma, spinal injury, dysuria, ischemic heart disease It is useful as a remedy for myocardial infarction, myocardial ischemia reperfusion, angina, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, skin aging, etc. Background art

Examples of compounds having a poly (ADP-ribose) polymerase inhibitory activity include dihydroisoquinolinone derivatives and isoquinolinone derivatives (for example, described in Anti-cancer Drug Design (1991), 7, 107-117), Nsamide derivatives (for example, international public Open (WO) No. 99/47494), tetracyclic compounds (for example, described in International Publication (WO) No. 99/11645) and the like. (AD P-ribose) Polymerase inhibitory activity has been reported (for example,

J. Biol. Chem. (1992), 267 (3), 1569-1575 and International Publication (WO) No. 99/11624). Disclosure of the invention

In recent years, there has been a demand for inventions and development of compounds having stronger PARP inhibitory activity and less side effects than those in which various PARP inhibitors having various structures have been found as described above.

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that the compound represented by the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention as necessary) (Sometimes abbreviated as abbreviated) Power S Excellent poly (AD P-ribose) polymerase inhibitory activity. The compound of the present invention is particularly superior in action as compared with the compound specifically described in the above-mentioned International Publication (W 0) No. 9981624. The present invention relates to the following.

[1] General formula (1)

[Wherein, one X ¹ — X ² — represents a group represented by the formula: one C (= 0) -N (R ⁷ ) — or _C (R ⁸ ) = N—, R ⁷ is a hydrogen atom, Substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted A substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group, and R ⁸ is a substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkyl alkyl group, a substituted or unsubstituted arylalkyl group, Substituted or Mu置conversion aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted Ashiru group, a halogen atom or wherein: A OR ^8a, one NH _2, one NHR ^8a, - NR ^8a ^{^{_{R 8b, _SR 8a, _S0 2}}} NH 2, one S0 ₂ represents a NHR ^Sa or single S0 ₂ NR ^8a R ^8b groups represented by (R ^8a and R ^8b are each independently a substituted or unsubstituted alkyl Represents a group).

R \ RR ³ and R ⁴ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl Group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted aromatic group, substituted or unsubstituted saturated heterocyclic group, substituted or unsubstituted acyl Represents a group, a nitrogen atom, a nitro group, or a group represented by the formula: one OR ^la , one NR ^la R ^lb, or one SR ^la (R ^la and R ^lb are each independently a hydrogen atom or substituted Or an unsubstituted alkyl group).

R ⁵ is a substituent on the piperazine ring, which may be absent or one or more, the same or different, and may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, substituted or unsubstituted Represents a saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom, a nitro group, or a group represented by the formula: one OR ^5a , one NR ^5a R ^5b or one SR ^5a (R ^5a and R ^5a ^5b each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group.

R ⁶ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycle alkyl group, a substituted or unsubstituted cycle group Represents an alkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acryl group.

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising a poly (ADP-ribose) polymerase inhibitor.

(2) Cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, cerebral bruise, head injury, spinal injury, glucoseuria, ischemic heart The polysaccharide according to (1), which is a therapeutic agent for diseases, myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging. (ADP-ribose) Polymerase inhibitor.

[3] Use of the compound of the general formula (1) according to [1] or a prodrug thereof or a pharmaceutically acceptable salt thereof in the production of a poly (ADP-ribose) polymerase inhibitor.

[4] [1] The compound of the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof according to [1], wherein ischemic injury, stroke, sequela after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, brain contusion, head trauma, spinal cord injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia reperfusion injury, angina, arrhythmia, arthritis, rheumatoid arthritis, Inflammatory bowel disease, sepsis, cancer, or skin aging Use in the manufacture of therapeutic agents.

[5] administering to the patient in need of treatment a compound of the general formula (1) according to [1] or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the poly (ADP-ribose) in the patient is obtained. ) A method for inhibiting polymerase.

(6) administering to a patient in need of treatment a compound of the general formula (1) according to (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof, cerebral ischemic injury, stroke, Sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alcheimer's disease, Huntington's chorea, cerebral contusion, head trauma, spinal injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia reperfusion injury How to treat angina, arrhythmia, arthritis, rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging.

[7] General formula (1)

[Wherein, — X ¹ — X ² — represents a group represented by the formula: 1 C (= 0) 1 N (R ⁷ ) —, and R ⁷ is a hydrogen atom, a substituted or unsubstituted alkyl group, Or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted Or an unsubstituted cycloalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group R ⁸ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, Or an unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom, or a formula: _OR ^8a , one NH _2, one NHR ^8a, one NR ^8a R ^8b, one SR ^8a, one _{_{_{SO 2 NH 2, _80 2]}}} ^ 111 8 £ 1 or _30 _2] ^ 1 1 ⁸¹ ^ represents a group represented by (R ^8a And R ^8b each independently represent a substituted or unsubstituted alkyl group).

R \ R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted Cycloalkyl group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted aromatic group, substituted or unsubstituted saturated heterocyclic group, substituted or unsubstituted acyl group Represents a group, a nitrogen atom, a nitro group, or a group represented by the formula: _OR ^la , one NR ^la R ^lb or one SR ^la (R ^la and R ^lb are each independently a hydrogen atom or Or an unsubstituted alkyl group).

R ⁵ is a substituent on the piperazine ring, which may be absent or one or more, the same or different, and may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted Represents a saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom, a nitro group, or a group represented by the formula: —OR ^5a , one NR ^5a R ^5b or one SR ^5a (R ^5a and R ^5b Each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group. R ⁶ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkyl Represents an alkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group.

] Or a prodrug thereof or a pharmaceutically acceptable compound thereof.

[8] The compound of [7], wherein R ⁶ is a hydrogen atom, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[9] The compound according to [7] or [8], wherein the substituent on the piperazine ring represented by R ⁵ is absent, a prodrug thereof, or a pharmaceutically acceptable salt thereof. [10] The compound of [7], [8] or [9], wherein R ⁷ is a hydrogen atom, or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[11] The compound according to [7], [8], [9] or [10], wherein R ¹ R ² , R ³ and R ⁴ are hydrogen atoms, or a prodrug thereof or a pharmaceutically acceptable salt thereof. Salt.

[12] A drug containing the compound according to any one of [7] to [11], or a prodrug thereof, or a pharmaceutically acceptable salt thereof. [13] the medical device of [12], which is a poly (ADP-ribose) polymerase inhibitor; [14] Cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, cerebral bruise, head injury, spinal injury, diabetes, ischemic heart disease The pharmaceutical according to [13], which is a therapeutic agent for myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, arthritis, rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging.

[15] a poly (ADP-ribose) polymerase inhibitor of the compound according to any one of [7] to [11] or a prodrug thereof or a pharmaceutically acceptable salt thereof; Use in manufacturing.

[16] The compound according to any one of [7] to [11] or a prodrug thereof or a pharmaceutically acceptable salt thereof, for cerebral ischemic injury, stroke, sequela after stroke, and cerebral edema , Neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, brain contusion, head trauma, spinal cord injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, Use in the manufacture of a remedy for arthritis, rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging.

[17] a patient comprising administering a compound according to any one of [7] to [11] or a prodrug thereof or a pharmaceutically acceptable salt thereof to a patient in need of treatment; For inhibiting poly (AD P-ribose) polymerase in Escherichia coli.

[18] A brain disease comprising administering to a patient in need of treatment a compound according to any one of [7] to [11] or a prodrug thereof or a pharmaceutically acceptable salt thereof. Blood disorder, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, cerebral contusion, head injury, spinal injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia Recurrence disorder, angina; arrhythmia, arthritis, rheumatoid arthritis, inflammation 'I live enteritis, sepsis, cancer, or skin aging. In the present specification, a compound represented by the general formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof is abbreviated as a compound of the present invention as necessary. Various groups in the present invention will be described below. Unless otherwise specified, the following description also applies to the case where each of the fundamentals is a part of the basics. Examples of the alkyl group include straight-chain or branched groups such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, and octyl. Alkyl groups with 8 or less carbon atoms are mentioned.

Examples of the alkenyl group include alkenyl groups having 6 or less carbon atoms such as vinyl, aryl, propenyl, 2-propenyl, butenyl, pentenyl and hexenyl. Examples of the alkynyl group include alkynyl groups having 6 or less carbon atoms such as ethynyl, propargyl, butynyl and pentynyl.

Examples of the cycloalkyl group include 3- to 8-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Examples of the cycloalkenyl group include a 3- to 8-membered double ring such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, and 3-cyclohexenyl. Examples thereof include a cycloalkenyl group having one bond.

Examples of the cycloalkylalkyl group include a group in which the above-mentioned alkyl group is substituted by the above-mentioned cycloalkyl group.

The aromatic group includes an aryl group and a heteroaryl group.

Examples of the aryl group include aryl groups having 10 or less carbon atoms, such as a phenyl group and a naphthyl group. Examples of the heteroaryl group include a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms, and a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom. A group of the formula, a 5-membered monocyclic group containing one oxygen atom or one sulfur atom, a bicyclic group containing 1 to 4 nitrogen atoms and fused with a 6-membered ring and a 5- or 6-membered ring Specific examples thereof include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chenyl, 3-cheninole, 3-oxaziazolinolene, 2- ^ midazolyl, 2 —Thiazolinole, 3-^^ sothiazolinole, 2-oxazorifre, 3-isoxazolyl, 2-furyl, 3-furyl, 3-pyrrolyl, 2-quinolinole, 8-quinolinyl, 2-quinazolinyl, 8-purinyl, 1-phthalazinyl, etc. Can be

Examples of the halogen atom include iodine, fluorine, chlorine and bromine atoms. Examples of the arylalkyl group include an alkyl group substituted by the aryl group.

Examples of the saturated heterocyclic group include a 5- to 8-membered ring group having one nitrogen atom such as 1-piperidinyl and 1-pyrrolidinyl, and a 6- to 8-membered group having two nitrogen atoms such as 1-piperazinyl. And a 6- to 8-membered ring group having one nitrogen atom and one oxygen atom such as morpholino.

Examples of the substituent for the saturated heterocyclic group and the saturated heterocyclic carbonyl group include a substituent on a carbon atom such as a hydroxyl group, a carboxyl group, a halogen atom, an alkoxycarbonyl group, and the like; an alkyl group as a substituent on a nitrogen atom; Alkoxycarbonyl group and the like can be mentioned.

Examples of the acryl group include a formyl group, for example, an alkanoyl group having 2 to 6 carbon atoms such as acetyl and propanol, and a carbon atom having 4 to 7 carbon atoms such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl. A cycloalkenecarbonyl group having 4 to 7 carbon atoms such as cyclopentenecarbonyl and cyclohexenecarbonyl; for example, an arylo group having 7 to 11 carbon atoms such as benzoyl, toluoyl and naphthoyl, for example Nitrogen atom, oxygen atom, sulfur source such as 2-piperidinecarbonyl and 3-morpholinecarbonyl And a saturated heterocyclic carbonyl group having a 5- or 6-membered saturated hetero ring containing 1 or 2 heteroatoms selected from the group consisting of 2-furoyl, 3-furoyl, 2-tenoyl, 3-tenoyl, and nicotinol And a heteroaromatic acyl group having a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, such as isonicotinoyl.

Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkanoyl, cycloalkanecarbonyl, cycloalkenecarbonyl, and arylalkyl groups may have one or the same substituent (s). The substituent may be, for example, a nitrogen atom, a cyano group, a phenoxy group, a benzyloxy group, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, Amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, lower alkoxycarbonylamino group, carboxyl group, lower alkoxycarbonyl group, lower Archi Examples include a ruthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkanoylamino group, a lower alkylsulfonamide group, a tri-lower alkylsilyl group, a phthalimide group, a heteroaryl group, and a saturated heterocyclic group. .

The substituents on the aryl group of the aromatic group, arylo group and heteroaromatic acyl group, and the aryl portion of the arylalkyl group may be one or the same or different, and may be, for example, a nitrogen atom, a cyano atom. Group, trifluoromethyl group, nitro group, hydroxyl group, methylenedioxy group, lower alkyl group, lower alkoxy group, benzyloxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, and carbamoyl Group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, or lower alkylsulfone Amid group And the like.

Lower means that the alkyl moiety of the substituent is a lower alkyl group. Examples of such a lower alkyl group include groups having 4 or less carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Among the compounds represented by the general formula (1), a compound in which one X ¹ —X ² — is a group represented by the formula: _C (R ⁸ ) = N— is a known compound or a known compound Can be synthesized by a known method. For example, it can be obtained by a method described in Japanese Patent Application Laid-Open Publication No. Hei 7572/1998. Further, among the compounds represented by the general formula (1), a compound represented by —X ¹ —X ² —Formula: 1 C (= 0) —N (R ⁷ ) is a known compound. Can be synthesized by combining known methods. For example, it can be synthesized by the following method.

(A)

[Wherein, RR ² , R ³ , R ⁴ and R ⁵ represent the same meaning as described above. R ^6a represents a group other than a hydrogen atom in the definition of R ⁶ above]

The compound represented by the general formula (2) is a known compound, or can be synthesized from a known compound by combining known methods. For example, it can be obtained by the method described in Cem. Pharm. Bull. (1972), 20 (7), 1513-1521 and the like. Step (a) is a reaction in which a compound represented by the formula (2) is reacted with an N_-substituted piperazine represented by the formula (3) to give a compound represented by the formula (4). It can be carried out by heating at 80 ° C to 220 ° C, preferably 100 ° C to 200 ° C, usually in a solvent such as ethylene dalicol or dioxane or in the absence of a solvent (for example, Acta Chim. Acad. Sci. Hung. (1980), 105 (3), 175-188). Step (b) is a reaction in which a compound represented by the formula (2) is reacted with a piperazine represented by the formula (5) to give a compound represented by the formula (6). This can be done in the same way as a). At this time, the piperazine represented by the formula (5) has two secondary amide moieties, and thus is preferably used in an excess amount. Step (c) is a reaction in which a group represented by the formula: _R ^6a is introduced into the compound represented by the formula (6) to give a compound represented by the formula (4). Various derivatives can be produced using a general method commonly used in the production of such derivatives.

For example, when an alkyl group is introduced, for example, an alkyl group or a halogenated alkyl group (chlorine, bromine or iodine is used as a halogen atom) in the presence of a base such as potassium carbonate, for example, acetonitrile or dimethylformamide It can be produced in a solvent, for example, at 0 ° C. at the boiling point of the solvent.Alternatively, a ketone or an aldehyde can be used to prepare a reducing agent such as sodium cyanoborohydride in a solvent such as methanol. For example, there is a method in which the compound is produced in the presence of hydrogen chloride, acetic acid, or the like, for example, at 0 ° C. and at the boiling point of the solvent. In addition, when an acyl group is introduced, it can be produced, for example, using an acid halide in the presence of a base such as triethylamine in a solvent such as methylene chloride or tetrahydrofuran, for example, at 0 ° C at the boiling point of the solvent. Alternatively, a carboxylic acid may be used, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodi Imido (WSC), benzotriazolyl-1-yl lute tris (dimethinoleamino) phosphonium.hexafluorophosphoride salt (BOP), diphenylphosphonyl azide (DPPA), N, N-carbonyldiimidazole (Angew. Chem. Int. In the presence of a condensing agent such as Ed. Engl., Vol. 1, 351 (1962)), for example, N-hydroxysuccinimide (HONS u), 1-hydroxybenzotriazole (HOB t: ), 3-hydroxy_4-monooxo_3,4-dihydro-1,2,3-benzotriazine (HOOb t) and other aromatic hydrocarbon solvents such as benzene, toluene and xylene. , Tetrahydrofuran, 1,4-dioxane and other ether solvents, dichloromethane, chloroform, halogenated hydrocarbon solvents such as 1,2-dichloroethane, dimethyl Formamide, amide Solvent such as dimethyl § Seto amides can be prepared in a basic solvent or a mixed solvent thereof, such as pyridine. By converting the hydrogen of the 2-position mono-NH— group of the compound represented by the formula (4) to a group other than a hydrogen atom in R ⁷ , the compound represented by the general formula (1): — X ^A compound in which ¹ — X ² — is a group represented by the formula: C (式 O) —N (R ⁷ ) — can be synthesized. The reaction may be carried out in a conventional manner, for example, by reacting a compound represented by the formula: R ⁷ X ³ (X ³ represents a halogen atom such as bromine) in the presence of a base such as potassium carbonate in the presence of DMF or the like. Reaction in a solvent at room temperature to 100 ° C., preferably at about 70 ° C. (Chem. Pharm. Bull., 42 (8), 1601-1604), or a compound represented by the formula: R ⁷ OH A reaction method in the presence of enylphosphine and getyl azodicarboxylate, in an acetonitrile-based solvent such as THF, usually at a temperature of 10 ° C to 100 ° C, preferably -5 ° C to 25 ° C. (Chem.

Pharm. Bull., 42 (8), 1601-1604). In each of the above production steps, when the starting compound for each reaction has a group active in the reaction, such as a hydroxyl group, an amino group or a carboxylic acid group, these groups may be added to an appropriate protecting group if necessary. The target compound can be obtained by removing the protecting group after performing each reaction or after performing several reactions. As a protecting group for protecting a hydroxyl group, an amino group, a carboxyl group, or the like, an ordinary protecting group used in the field of synthetic organic chemistry may be used, and such a protecting group may be introduced and removed according to a usual method. (Eg, the method described in Protective Groups in Organic Synthesis, JOHN WILLEY & SONS, 1991).

For example, a protecting group for a hydroxyl group includes a methoxymethyl group and a tetrahydroviranyl group, and a protecting group for an amino group includes a tert-butyloxycarbonyl group. Such a hydroxyl-protecting group can be removed, for example, by reacting in a solvent such as aqueous methanol, aqueous ethanol, or aqueous tetrahydrofuran in the presence of an acid such as a base, sulfuric acid, or acetic acid. The protecting group can be removed, for example, by reacting in a solvent such as hydrated tetrahydrofuran, methylene chloride, chloroform, or hydrated methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid. When the carboxyl group is protected, the form of protection includes, for example, tert-butyl ester, orthoester, acid amide and the like. In the case of tert-butyl ester, such a protective group is removed, for example, by reacting in the presence of hydrochloric acid in a solvent containing water, and in the case of the ortho ester, for example, aqueous methanol, water-containing tetrahydrofuran, The treatment is carried out by treating with an acid in a solvent such as water-containing 1,2-dimethoxyethane, followed by treatment with an alkali such as sodium hydroxide. In the case of an acid amide, for example, the presence of an acid such as hydrochloric acid or sulfuric acid The reaction can be performed in a solvent such as water, hydrated methanol, or hydrated tetrahydrofuran. The compounds represented by the formula (1) include those having an optically asymmetric center, and therefore, they may be in a racemic form or in an optically active form when an optically active starting material is used. Obtainable. If necessary, the obtained racemate can be physically or optically resolved into its optical antipodes by known methods. Preferably, a diastereomer is formed from a racemate by a reaction using an optically active resolving agent. Different diastereomers can be separated by known methods such as fractional crystallization. “Prodrugs” include those that are readily hydrolyzed in vivo and reproduce the compound of the formula (1). For example, in the case of a compound having a carboxyl group, the carboxyl group becomes an alkoxycarbonyl group. Or an alkylthiocarbonyl group, or a compound that has become an alkylaminocarbonyl group. For example, in the case of a compound having an amino group, a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group and becomes an alkoxycarbonylamino group, and acyloxymethyl A compound that has become an amino group or a compound that has become hydroxylamine. Further, for example, in the case of a compound having a hydroxyl group, a compound in which the hydroxyl group is substituted with the above-mentioned acyl group to form an acyloxy group, a compound which becomes a phosphoric ester, or a compound which becomes an acyloxymethyloxy group is used. No. Examples of the alkyl moiety of the group used in these prodrugs include the above-mentioned alkyl groups, and the alkyl group may be substituted (for example, by an alkoxy group having 1 to 6 carbon atoms). Preferable examples include, for example, a compound in which a carboxyl group is an alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbinole, and other lower (for example, having 1 to 6 carbon atoms) alkoxyl carbonyl, methoxymethoxycarbonyl, and ethoxycarbonyl. Lower (for example, having 1 to 6 carbon atoms) alkoxycarbonyl substituted by an alkoxy group such as methoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, and pivaloyloxymethoxycarbonyl. The compound represented by the formula (1) or a prodrug thereof can be converted into a pharmaceutically acceptable salt, if necessary. Examples of such salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, and aspartic acid. Salts with organic carboxylic acids such as glutamic acid and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid and dihydroxybenzenesulfonic acid Salt; and

For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, dicyclohexylamine salt, N, N and salts with dibenzylethylenediamine. Further, the compound represented by the formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof may be an anhydride, hydrate or solvate thereof. The compounds of the present invention can be administered orally or parenterally when using them as medicaments. That is, it can be orally administered in a commonly used dosage form, for example, a powder, granule, tablet, capsule, syrup, suspension or the like, or, for example, a solution, emulsion, or suspension thereof. Can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. The above-mentioned suitable dosage form can be produced, for example, by mixing the compound of the present invention with an acceptable usual carrier, excipient, binder, stabilizer, or diluent. When used in the form of an injection, an acceptable buffer, solubilizing agent and isotonic agent can be added in parallel. The dosage and number of administrations vary depending on, for example, the target disease, symptoms, age, body weight, and dosage form, but are usually 0.1 to 2000 _mg, preferably 1 to 200 _mg once a day for an adult. It can be administered in several divided doses (eg, 2-4 times). Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. The compound names shown in the following Examples and Test Examples do not always follow the IUPAC nomenclature. Example 1 Production of 4- (1-piperazinyl) -1- (2H) -phthalazinone hydrochloride

(1) 4- (1-Piperazinyl) _ 1 (2H) —phthalazinone

(4) A mixture of 4.12 g (22.8 mmol) of monochloro-1 (2H) -phthalazinone, 1.90 g (138 mmol) of piperazine and 40 mL of ethylene glycol at 190-200 ° C for 6.5 hours Stirred. The reaction mixture was cooled to room temperature, 5% aqueous potassium carbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution, dried over anhydrous potassium carbonate, filtered, and concentrated. The resulting Zan查silica gel column chromatography (S i 0 _2, black hole Holm: methanol: triethylamine down = 20: 2: 1) to give 4_ (1-piperazinyl) Single 1 (2H) - Futaraji Non 4.18 g (80%) was obtained.

^{_{1 HNMR (DMSO- d 6) 8}} ; 12.09 (s, 1H), 8.21 (d, 1H, J = 7.5Hz), 7.92- 7.79 (m, 3H), 2.98-2.96 (m, 4H), 2.91-2.89 (m, 4H).

(2) 4- (1-piperazinyl) 1 1 (2H) -phthalazinone hydrochloride

4_ (1-Piperazinyl) 1 1 (2H)-Dissolve 4.13 g (17.9 mmol) of phthalazinone in 16 OmL of isopropyl alcohol at about 70 ° C, cool the solution to about 40 ° C, To this, 5.38 mL (21.5 mmol) of 4N monodioxane hydrochloride was added dropwise. The mixture was heated to about 7 (TC, stirred at about 70 ° C for 1 hour, cooled to room temperature with stirring, further cooled with ice, and the solid was filtered.The solid was washed with cold isopropyl alcohol. 4.33 g of the obtained 4.58 g solid was recrystallized and recrystallized (water / acetonitrile) to give 4- (1-piperazinyl) -1-1 (2H) -phthalazinone hydrochloride 3.49 g I got

^ NMR (DMSO-d ₆ ) 8; 12.23 (s, 1H), 9.35 (brs, 2H), 8.25-8.22 (m, 1H), 7.99 (d, 1H, J = 7.7 Hz), 7.94-7.82 (m , 2H), 3.29 (s, 8H).

Melting point: 300 ° C or higher Test example

[Reagents and equipment] -DNA (sonicated) (Nacalai Tesque)

-Nicotinamide adenine dinucleotide (NAD: Nacalai Tesque)

'[ ³ H] NAD ([adenine-2, 8-]-thigh) (NEN® Life Science Products, Inc. (USA), specific activity 1402 GBq / mmol)

PARP (Human PARP recombinant, 660 units / mg) (Trevigen, Inc. (USA))

• Benzamide (Wako Pure Chemical Industries, Ltd.)

• 96 ゥ L plate (Round bottom perfect plate, made of polypropylene) (CORNING Costar (USA))

-Glass fiber filter for 96mm plate: Printed filter matt B (double thickness, 90X 120 thighs) (PerkinElmer, In (USA))

■ Solid scintillator sheet: MeltiLex (TM) A (73X 109 mm, ~ 4 g count) (PerkinElmer, Inc. (USA))

• Sample bag for inclusion of filter + scintillator (PerkinElmer, In (USA)) [Test method]

A buffer (50% Tris-HCl (pH 8.0) / 25 mM MgCl ₂ aqueous solution) was used for the preparation of each solution. Test compound solution 201 / well, 1 M [ ³ H] NAD containing 10 g / ml DNA (specific activity 7 kBq / ml) 30 wells, unit / ml (6 g / ml) PP solution (50 1 / well) was added sequentially, and the reaction was allowed to proceed at room temperature for 1.5 hours (final concentrations of each reagent in the reaction solution were: DNA: 3 g / ml, [¾] NAD: 0.3 MZ Specific activity 2.1 kBq / ml, PP: 2 units / ml (3 μg / ml)). The reaction was stopped by the addition of 2 βM of benzamide at 9 β1 / Pell (2 after addition), and the 液 in the reaction mixture was reduced with a cell harvester (HARVESTER 96 (registered trademark), T0MTEC Inc. (USA) ) Collected on glass fiber filter for plate and filter. The glass fiber filter was passed through 80% ethanol immediately before recovery of PAP. After PARP recovery, each well of the plate was washed four times with 80% ethanol, and the washing solution was also passed through the glass fiber filter. Heat the glass fiber filter in a microwave oven for 3 to 4 minutes to dry, place two solid scintillator sheets on top of each other and place in a sample bag. And sealed. This was placed on a heater at about 50 ° C to heat-melt the scintillator and permeate the filter. After returning to room temperature, the plate counter (1450 MicroBeta (registered trademark) TriLux, PerkinElmer, Inc.) (US)), the force (cpm) of [¾] in poly (ADP-ribose) added to PMP was measured (10 min / plate). The inhibition rate for PARP activity was calculated using the following equation. Inhibition rate (%) = [1— (Compound added count (cpi) —

(cpm)) I (Count of the reagent without added compound (cpm)-

(Backdaland count = Compound · No PARP added ゥ L count (cpm))

For each test compound, the inhibition rate was measured at n = 2, and the IC ₅ was determined. Values were calculated.

〔Test results〕

1- [4- (2-furoyl) 1-2-piperazinyl] -4-phenylphthalazine hydrochloride

IC ₅₀ = 0.36,

1-Black mouth 4- (1-Piperazinyl) phthalazine hydrochloride:

I C 50 = 0.28 A M,

4- (1-Piperazinyl) _1 (2H) -phthalazinone hydrochloride (compound of Example 1):

I C g o = 0.034 Industrial potential

The compound of the present invention has a PARP inhibitory action, and thus, for example, a disease caused by enhanced PARP activity, for example, cerebral ischemic injury, neurodegenerative disease, cerebral contusion, head injury, spinal injury, diabetes, ischemic heart Disease, organ damage due to ischemia or ischemia reperfusion, inflammation, inflammatory bowel disease, cancer, cachexia, renal disorder, osteoporosis, acute and chronic pain, sepsis, skeletal muscle degeneration, muscular dystrophy, skin aging, immunity It can be used as a therapeutic agent for system aging, AIDS, changes in gene expression of senescent cells, etc.

Claims

The scope of the claims

1. General formula (1)

[Wherein, one Xi—X ² — represents a group represented by the formula: one C (-0) -N (R ⁷ ) — or _C (R ⁸ ) = N—, wherein R ⁷ is a hydrogen atom, Or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted R ⁸ is a substituted or unsubstituted aromatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group; Unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkyl alkyl group, substituted or unsubstituted arylalkyl group, Or Mu置conversion aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted Ashiru group, a halogen atom or a group represented by ^{_{formula,: - OR 8a, _NH 2}} , one NHR ^{^8a,} - NR ^8a R ^8b , — SR ^8a , — S0 ₂ NH ₂ , — S0 ₂ NHR ^8a or a group represented by S0 ₂ NR ^8a R ^8b (R ^8a and R ^8b are each independently a substituted or unsubstituted alkyl Represents a group). RR ² , R ³ and R ⁴ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycle Alkyl group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted aromatic group, substituted or unsubstituted saturated heterocyclic group, substituted or unsubstituted Represents an acyl group, a halogen atom, a nitro group, or a group represented by the formula: —OR ^la , —NR ^la R ^lb or one SR ^la (R ^la and R ^lb are each independently a hydrogen atom, Or a substituted or unsubstituted alkyl group).

R ⁵ is a substituent on the piperazine ring, which may be absent or one or more, the same or different, and may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted Ashiru group, a halogen atom, a nitro group, or the formula: a oR ^5a, one NR ^5a R ^5b or - represents a group represented by SR ^5a (R ^5a and R ^5b Each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group. '

2. Cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, brain contusion, head injury, spinal injury, diabetes Disease, ischemic heart disease, myocardial infarction, myocardial ischemia reperfusion injury, angina pectoris, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging. 2. The poly (ADP-ribose) polymerase inhibitor according to 1.

3. Use of the compound of the general formula (1) according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt thereof in the production of a poly (ADP-ribose) polymerase inhibitor.

4. Cerebral ischemic injury, stroke, sequela after stroke, cerebral edema, neurodegenerative disease, Parkinson's, of the compound of general formula (1) according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt thereof. Disease, Alzheimer's disease, Huntington's chorea, brain contusion, head trauma, spinal cord injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia-regurgitation, angina, arrhythmia, arthritis, rheumatoid arthritis, inflammation Use in the manufacture of a medicament for the treatment of enteritis, sepsis, cancer, or skin aging.

5. A poly (ADP-ribose in a patient, comprising administering to the patient in need of treatment a compound of general formula (1) according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt thereof. ) A method for inhibiting polymerase.

6. A cerebral ischemic injury, a stroke, a stroke comprising administering to a patient in need of treatment a compound of the general formula (1) according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt thereof. Sequelae after, brain edema, neurodegenerative disease, Parkinson's disease, Alheimer's disease, Huntington's disease, brain contusion, head trauma, spinal injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia-reperfusion injury, stenosis How to treat heart disease, arrhythmias, arthritis, rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging.

7. General formula (1)

[Wherein, one Xi—X ² — represents a group represented by the formula: _C (= O) —N (R ⁷ ) —, and R ⁷ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted Substituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkylalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted R ⁸ is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted substituted or unsubstituted alkenyl group, An alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted Aromatic group, substituted or unsubstituted saturated heterocyclic group, substituted or unsubstituted acyl group, halogen atom, or formula: _OR ^8a , —NH ₂ , 1 NHR ^8a , — NR ^8a R ^8b , — SR ^8a , one S0 ₂ NH ₂ , -S0 ₂ NHR ^8a or _S0 ₂ NR ^8a represents a group represented by R ^8b (R ^8a and R ^8b each independently represent a substituted or unsubstituted alkyl group ).

R \ R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted Cycloalkyl group, substituted or unsubstituted cycloalkylalkyl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted aromatic group An aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom, a nitro group, or a formula represented by one OR ^la , one NR ^la R ^lb, or —SR ^la (R ^la and R ^lb each independently represent a hydrogen atom or a substituted or unsubstituted alkyl group).

R ⁵ is a substituent on the piperazine ring, which may be absent or one or more, the same or different, and may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted Or an unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, substituted or unsubstituted Represents a saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom, a nitro group, or a group represented by the formula: one OR ^5a , one NR ^5a R ^5b or —SR ^5a (R ^5a and R ^5a ^5b each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group.

R ⁶ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl Represents a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group.

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein R ⁶ is a hydrogen atom, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

9. there is no substituent on the piperidines Rajin ring represented by R ^5, acceptable salts according to claim 7 or 8 compound or a prodrug thereof, or their pharmaceutically described.

10. The compound according to claim 7, 8 or 9, wherein R ⁷ is a hydrogen atom, a free drug or a pharmaceutically acceptable salt thereof.

1 1. The compound according to claim 7, 8, 9 or 10, wherein R \ R ² , R ³ and R ⁴ are hydrogen atoms, a prodrug thereof or a pharmaceutically acceptable salt thereof.

12. A medicament comprising the compound according to any one of claims 7 to 11 or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

13. The medical device according to claim 12, which is a poly (ADP-ribose) polymerase inhibitor.

14. Cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, cerebral contusion, head trauma, spinal injury, glucoseuria, ischemic heart disease 14. The medicament according to claim 13, which is a therapeutic agent for myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory enteritis, sepsis, cancer, or skin aging.

15. Use of a compound according to any one of claims 7 to 11 or a prodrug thereof or a pharmaceutically acceptable salt thereof in the manufacture of a poly (ADP-ribose) polymerase inhibitor. .

16. The compound according to any one of claims 7 to 11 or a prodrug thereof or a pharmaceutically acceptable salt thereof, for cerebral ischemic injury, stroke, sequela after stroke, cerebral edema, and nerve. Degenerative diseases, Parkinson's disease, Alzheimer's disease, Huntington's chorea, brain contusion, head trauma, spinal cord injury, diabetes, ischemic heart disease, myocardial infarction, myocardial ischemia reemergence, angina, arrhythmia, arthritis, Rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or Use in the manufacture of a remedy for skin aging.

17. A method comprising administering to a patient in need of treatment a compound according to any one of claims 7 to 11 or a prodrug thereof or a pharmaceutically acceptable salt thereof. Poly (ADP-ribose) A method of inhibiting polymerase.

18. A cerebral brain comprising administering to a patient in need of treatment a compound according to any one of claims 7 to 11 or a prodrug thereof or a pharmaceutically acceptable salt thereof. Blood disorder, S¾ 'stroke, sequelae after stroke, brain edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, brain contusion, head injury, spinal injury, diabetes, ischemic heart disease, myocardial infarction A method for treating myocardial ischemia-reperfusion injury, angina, arrhythmias, arthritis, rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, or skin aging.