WO2004014873A1

WO2004014873A1 - 4-substituted quinazoline-8-carboxyamide derivative and pharmaceutically acceptable addition salt thereof

Info

Publication number: WO2004014873A1
Application number: PCT/JP2003/009789
Authority: WO
Inventors: Futoshi Shiga; Yasuo Takano; Jyunichi Ishiyama
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 2002-08-09
Filing date: 2003-08-01
Publication date: 2004-02-19
Also published as: JPWO2004014873A1; AU2003252314A1

Abstract

A drug exhibiting poly(ADP-ribose) synthetase inhibiting activity, comprising a 4-substituted quinazoline-8-carboxyamide derivative and a pharmaceutically acceptable addition salt thereof as active ingredients. In particular, a 4-substituted quinazoline-8-carboxyamide derivative of the general formula: (1) and a pharmaceutically acceptable addition salt thereof.

Description

Saying Moon Itoda »

4-Substituted quinazoline-8-carboxylic acid amide derivatives and their pharmacologically acceptable addition salts

The present invention provides a 4-substituted quinazolin-8-carboxylic acid amide derivative, a pharmaceutically acceptable addition salt thereof, and a poly (ADP-ribose) synthase inhibitory activity containing these as an active ingredient. About drugs. Background Technology ·

Poly (ADP-ribose) polymerase; abbreviated as “PARP.” Another name: poly (ADP-ribose) synthetase is a protein that regulates nuclear MA function, and It is activated by recognizing the damage of DNA, and uses NAD (nicotinamide adenine dinucleotide), which is an essential component in cells, as an enzyme substrate, and poly (ADP-ribose) as a DNA-polymerase and other proteins. Is an enzyme that is sequentially transferred to Therefore, it is thought that excessive activation of PARP causes a decrease in intracellular energy producing ability due to the depletion of NAD, which is essential for the electron transport system, and leads to cell death (Szabo, Free Radic. Biol. Med., 2Λ, 855 (1996)) _c ) PARP is a substrate of caspase-3, one of the protease-like proteazefamily of leucine-1 / 5 converting enzyme, and is limitedly degraded. Therefore, it is also attracting attention as an apoptosis-related enzyme.

Furthermore, in experiments using PARP-knockout mice, cultured neurons collected from the brains of the knockout mice were damaged by excitatory amino acids such as nitric oxide and NMDA (N-methyl-D-aspartate). Resistant mice, and that the knockout mice were It has been reported that it suppresses occlusion by about 80% or more (MJL Eliasson et al., Nature Med., 3, 1089 (1997)). For these reasons, PARP inhibitors are considered to be effective for cerebral infarction and neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.). Other than this, diabetes, diseases caused by ischemia or ischemia-reperfusion such as myocardial infarction and acute renal failure, cardiovascular diseases such as septic shock, rheumatoid arthritis and multiple sclerosis It has been reported that it is effective for any inflammatory disease (Szabo et al., Trend Pharmacol Sci., 19, 287 (1998)). PARP inhibitors include antiretroviral agents including HIV (GA Cole et al., Biochem. Biophys. Res. Comraun., 180 ^ 504 (1991)) and sensitizers for anticancer therapy (Arundel-Suto, et al., Radiat. Res., 126, 367 (1991); S. Boulton et al., Br. J. Cancer, 72, 849 (19-95)).

Based on the above, compounds having PARP inhibitory activity are useful for diseases caused by excessive PARP activation, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory Diseases (inflammatory bowel disease, multiple sclerosis, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma It is expected to be useful as a prophylactic and / or therapeutic agent for such as.

As a compound having a similar structure to the 4-substituted quinazolin-8-carboxylic acid amide derivative of the present invention, JP-A-62-48669 discloses a compound having the general formula (3)

Wherein the R ² is independently hydrogen atom or a lower alkyl group, halogen, CF _3, CNヽ_{_{_{S0 2 CH 3, N0 2,}}} OHヽ_{^{NH 2, 0R \ NHR 3 (}} R 3 is a hydroxyl group, an amino group, etc. Y represents C (NH) NH ₂ , NHC (NH) NH ₂ or NR ⁴ R ⁵ (R ⁴ and R ⁵ represent a hydrogen atom or a hydroxyl group, an amino group, etc., and n represents 2 to 6 (The description of the substituent is partly excerpted), but JP-A-10-291988 discloses a compound represented by the general formula (4) as a compound useful for treating bone diseases caused by abnormal bone metabolism: ) '

(Wherein, R ¹ represents an optionally substituted heterocyclic group or aryl group, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a halogen atom, etc., and R ⁴ Represents a substituted amino group, a substituted hydrazino group, a substituted or unsubstituted heterocyclic group, etc., R ⁵ , R ⁶ and R ⁷ represent a hydrogen atom, a halogen atom or a lower alkyl group, and A represents (Representing -C0NH-, -NHC0-, etc.) are known. However, all of these compounds have a secondary carboxylic acid amide at the 8-position of the quinoline and a different structure from the compound of the present invention, which is characterized by a primary carboxylic acid amide. There is no description.

W096 / 91474 also discloses a compound having the endoselin converting enzyme inhibitory activity of the general formula (5)

(In the formula, A represents N, CH or S (0) n, n represents 0, 1 or 2, R represents a lower alkyl group, an aryl group, an aryl lower alkyl group, etc., and R ¹ is hydro. R ² represents a hydrogen atom, a lower alkyl group, etc., and R ³ , R ⁴ , R ⁵ , R ⁶ independently represent a hydrogen atom, a halogen atom, a lower alkyl group, CONR ¹ ^ ^12, etc. Wherein R ⁵ and R ⁶ independently represent a hydrogen atom, a lower alkyl group, an aryl group, or the like (substituents are partially excerpted). No. -3144 describes a compound having a strong vasodilator action as a potassium channel opener, which has the general formula (6) '

(Wherein Α and 同一 are the same or different and represent N or CH, and R ¹ and R ² are a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a halogen atom, a cyano group, a nitro group, an acyl group. Represents a hydrogen atom, a lower alkyl group which may have a substituent, or an aryl group which may have a substituent, R ⁴ is a compound represented by a saturated or unsaturated heterocyclic group, an amino group which may have a substituent, or a lower alkoxy group, an aryloxy group, etc. ) However, W096 / 09294 has the general formula (7)

(Where X represents Ν or CH, Υ represents a group W (CH ₂ ), (CH ₂ ) W, W (W represents 0, S (0) ni, and m represents 0 to 2), or NH ^{^a} (H ^a is hydrogen or -C ₈ alkyl group) represent, may be R ^2, R ³ and R ³ 'have identical or different, each § Mi Bruno, hydrogen , halogen, human Dorokishi, 'carboxy, force Rubamoiru, Ulei de, N-~ al kills force Rubamoiru, ^ di- [~ (: ₄ alkyl force Rubamoiru groups represent such, each is hydrogen, Bruno, androgenic, DOO Rifuruoromechiru, (^ - ₍₄ alkyl group, with (represent like ^ - (^ alkoxy group, R ⁵ represents hydrogen, halogen, Application Benefits Furuoromechiru, ~ alkyl group, a ~ alkoxy groups, ^ represents a group ZR ⁷⁾ The compound represented (the description of the substituents is partially excerpted), but W097 / 03069 has the general formula (8)

(Where X represents Ν or CH, Υ represents a group W (CH ₂ ), (CH ₂ ) W or W (W 0 represents S (0) m, m represents 0 to 2), or ^a (R ^a represents hydrogen or represents an ~ alkyl group), mono- or bicyclic ring system U 5-10 membered And, R ³ and 'are the same or different and are respectively amino, hydrogen, halogen, hydroxy, carboxy, carbamoyl, peridode, ^^ ~ ^ alkyl carbamoyl, N, N- Di [~ ^ alkyl] represents a rubamoyl group, etc. is a compound represented by hydrogen, nodogen, trifluoromethyl, ~ ( ₄ alkyl group, (^ ~ represents an alkoxy group) However, these specifications do not disclose a compound having a primary carboxylic acid amide (potassium carbamoyl 'group) at the 8-position of quinazoline, which is a feature of the compound of the present invention. It is not described that it has PARP inhibitory activity.

EP399267 also discloses a compound represented by the general formula (9) as a K + / H + -ATPase and a compound that inhibits gastric acid secretion.

(Wherein, R ¹ represents a hydrogen atom, human Dorokishi group properly represents the (^ - (optionally substituted by _alkoxy group (^ - ₍₄ alkyl group, R ² represents a hydrogen atom or - _(alkyl R ³ represents a group of 1-3 ^-( ₄ alkyl groups and / or a phenyl group optionally substituted by 1-2 halogen atoms, and R ⁴ represents a hydrogen atom or ^ ~ It represents such alkyl Le group, R ⁵ is human Dorokishi group, amino group, (^ - (^ Arukirua amino group, ^ ~ 0 ₆ alkoxycarbonyl group, § amino carbonyl group, such as di (~ alkyl) Aminokaruponiru based Represents a hydrogen atom or a ~ ^ alkyl group, etc. (Substituent theory) Quinolinin, which is a feature of the compound of the present invention, and has a primary carboxylic acid amide (carboxyl group) at the 8-position corresponding to the 8-position of quinazoline. Examples include 2-methyl-4-((3-methyl-2-thenyl) methylamino) quinoline-8-carboxylic acid amide (di (^ 3,

Has only been disclosed, but is not described as having PAHP inhibitory activity.

On the other hand, as compounds having PARP inhibitory activity currently known, first, compounds represented by general formulas (10) to (25) shown in Table 1 (the description of the substituents is omitted) are given. However, these are all compounds having a cyclic amide structure, and have a different structure from the compound of the present invention characterized by a primary carboxylic acid amide. Further, the PARP inhibitory activity of the disclosed compounds is not sufficient.

[table 1 ]

Next, as a compound having a PARP inhibitory activity having a primary carboxylic acid amide, W097 / 4771 includes the general formula (26)

(In the formula, β is a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, a hydroxyxethyl group), an acyl group (for example, an acetyl group or a benzoyl group), or an aryl group which may have a substituent. Represents a group (for example, a phenyl group) or an aralkyl (for example, a benzyl group or a carboxybenzyl group), and R and are a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, a hyboxyloxyshetyl group), and an acyl group ( For example, compounds represented by an acetyl group, a benzoyl group), an aryl group (for example, a phenyl group) or an aralkyl (for example, a benzyl group or a carboxybenzyl group) which may have a substituent are known. However, the structure is different from the compound of the present invention which is characterized by quinazoline-8-carboxylic acid amide. Also, the PARP inhibitory activity of the disclosed compounds is not sufficient.

Furthermore, W099 / 59973 has the general formula (27)

(Where Y is a fused 5- or 6-membered aromatic or non-aromatic hydrocarbon ring, or a hetero atom containing an oxygen, sulfur, or nitrogen atom Which constitutes a ring), PN is a hydrogen atom, and Y and other hetero atoms are unsubstituted or alkenyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, carboxy, and halogen. X is the 1-position of the ring Y, and C0 ₂ R ⁵ or

_ ° _ H

'--N',

ヽ ΰ selected from R ⁷ , wherein R ⁷ represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, etc., Ιί ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, etc., R ³ , R ⁴ and R ⁵ independently represent an alkyl group, an alkenyl group, a cycloalkyl group, an amino group, a hydroxyl group, etc.), but the quinazoline- It does not include 8-carboxylic acid amide, and differs in structure from the present invention. Also, the disclosed compounds do not have sufficient PARP inhibitory activity.

As similar compounds having a primary carboxylic acid amide and having PARP inhibitory activity, compounds represented by the general formulas (28) to (36) shown in Table 2 (substituents are omitted) Although they are known, they are all different in structure from the compound of the present invention which is characterized by quinazoline-8-carboxylic acid amide. In addition, the disclosed compounds do not have sufficient PARP inhibitory activity.

[2]

The present invention relates to diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple brain sclerosis, arthritis) , Rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc. Another object of the present invention is to provide a novel compound having PARP inhibitory activity, which is expected to be developed as a therapeutic agent. Disclosure of the invention

The present inventors have conducted intensive studies in search of a compound having a novel PARP inhibitory activity, and as a result, have found that the 4-substituted quinazoline-8-carboxylic acid amide derivative of the present invention and its pharmacologically acceptable Excellent PARP inhibitory activity was found for addition salts.

That is, according to the present invention, general formula (1)

[Wherein, R ¹ represents a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally substituted, an aralkyl group optionally substituted, or a general formula (2 )

(In the formula, ring Ar represents a phenyl group, a naphthyl group, a 5- or 6-membered complex ring and a condensed ring thereof,

R ⁶ and R ^ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ^{1 Q} N Lower alkyl group substituted with a group, cyclic alkyl group which may have a substituent, substituted with a halogen atom Which may be a lower alkoxy group, human Dorokishi substituted lower § alkoxy group group, R ⁹ R ^1D N-substituted lower alkoxy group group, a lower alkoxy group substituted by a carboxy group, substituted with a lower alkoxycarbonyl group A lower alkoxy group, an optionally substituted aralkyloxy group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, An optionally substituted naphthyl group, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof)

R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, or a lower alkoxy group optionally substituted with a halogen atom,

X is an oxygen atom or NR ¹¹ (where R ¹¹ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, or a substituent Represents an aralkyl group),

\ R ⁴ are the same or different, a hydrogen atom:., Represents a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkyl group substituted with human Dorokishi group,

R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR ^{1 Q} , C0NR ^{9 10} , A substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5- or 6-membered heterocyclic ring and a fused ring thereof, ^1Q is the same or different and represents a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, or R ⁹ and R ^1Q represent a 5-membered or 6-membered heterocyclic ring which may have a substituent bonded together and a condensed ring thereof, n represents 0 to 3], and a 4-substituted quinazoline-8-carboxylic acid amide derivative and a pharmaceutically acceptable addition salt thereof, represented by the general formula (1-d)

[Wherein, X ^a represents an oxygen atom or NH;

R ³ and R ⁴ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group,

R ⁶ and R ⁷ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, Il ⁹ R ^{1 Q} A lower alkyl group substituted with an N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R ⁹ A lower alkoxy group substituted with an R ^{1 Q} N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group which may have a substituent, and nitro Group, amino group which may have a substituent, phenyl group which may have a substituent, naphthyl group which may have a substituent, 5- or 6-membered heterocyclic group which may have a substituent Rings and Represents a fused ring, R ^9, R ^{1 Q} are the same or different and each represents a hydrogen atom, it may be substituted with a halogen atom a lower alkyl group, an optionally substituted cyclic alkyl group, substituted Represents an optionally substituted aralkyl group, or represents a 5- or 6-membered heterocyclic ring and a condensed ring thereof which may have a substituent by bonding together at R ⁹ and R ^{l fl} ; n represents 0 to 3], a 4-substituted quinazoline-8-carboxylic acid amide derivative, a pharmaceutically acceptable addition salt thereof, and a compound represented by the general formula (1-e):

[Wherein, X ^a represents an oxygen atom or NH;

R ³ and R ⁴ are the same or different and are each substituted with a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, or a hydroxy group;

R ⁶ and R ⁸ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ^{1 Q} N A lower alkyl group substituted with a group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R ⁹ R ^1Q A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5- or 6-membered heterocyclic ring, Contraction Represents a ring, R ^1Q are the same or different, a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom, an optionally substituted cyclic alkyl group, an optionally Ararukiru group which may have a substituent A 5- or 6-membered heterocyclic ring which may be substituted or may have a substituent by bonding together at R ⁹ and R ^{1 Q} And a fused ring thereof,

n represents 0 to 3], and the 4-substituted quinazoline-8-carboxylic acid amide derivative represented by the formula (1) and its pharmacologically acceptable addition salt have excellent PARP inhibitory activity. The invention has been completed.

In the general formula (1) of the compound of the present invention, preferably, a compound in which R ¹ is a general formula (2) is exemplified.

More preferably, there is a compound in which is NR ⁹ R ^1Q , a hydroxyl group, and is a hydrogen atom.

These preferred compounds include, for example, the compounds described in the following Tables 3 to 5, but the present invention is not limited to these compounds or pharmacologically acceptable addition salts thereof.

[Table 3]

6T / lDd

[Table 5]

In Tables 3 to 5, more preferred compounds include, for example, Exemplified No. 11.12, 14, 1517 to 34, 42 to 58, 74 to 93, 113 to 131, 150 to 170 186 to 209. it can.

In the general formula (1) of the present invention, the term "halogen atom" in "lower alkyl ^: alkyl group optionally substituted by halogen atom" and "lower alkoxy group optionally substituted by halogen atom" is used. Includes fluorine, chlorine, bromine, and iodine. The “lower alkyl group” is a straight-chain or branched carbon atom having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, and iso-propyl. Examples of the “lower alkoxy group” include straight-chain or branched ones having 1 to 4 carbon atoms such as methoxy, ethoxy, and propoxy. In the description, “cyclic alkyl group optionally having substituent (s)”, “aralkyl group optionally having substituent (s)”, “phenyl group optionally having substituent (s)”, “substituted In the `` naphthyl group which may be substituted '' and the `` 5- or 6-membered heterocyclic ring which may have a substituent and the condensed ring thereof '' are substituted with a halogen atom, a hydroxyl group or a halogen atom. Lower alkyl groups, lower alkoxy groups optionally substituted with halogen atoms, lower alkylthio groups, lower alkoxycarbonyl groups, nitro groups, optionally substituted amino groups, cyano groups, carboxyl groups , Substituted with an aldehyde group or a hydroxy group A lower alkyl group substituted with a lower alkyl group, a carboxy group, a lower alkyl group optionally substituted with a halogen atom or an amino group optionally substituted with an aralkyl group optionally having a substituent; An alkyl group, a lower alkyl group substituted with a 5- or 6-membered cyclic amino group which may have a substituent, a lower alkoxy group substituted with a hydroxy group, a lower alkoxy group substituted with a carboxy group, A lower alkyl group optionally substituted with a halogen atom or an optionally substituted aralkyl group, a lower alkoxy group substituted with an amino group optionally substituted with a substituent, a 5-membered optionally substituted substituent As an example, a lower alkoxy group substituted with a 6-membered cyclic amino group and the like can be mentioned. The term "lower alkoxycarbonyl group" means methoxycarbonyl or ethoxycarbonyl. Straight-chain or branched ones having 1 to 6 carbon atoms, such as bonyl; and the "amino group optionally having a substituent" is a lower alkylsulfonyl optionally substituted with an acyl group or a halogen atom. Group, arylsulfonyl group, for example, acetyl, methanesulfonyl, .phenylsulfonyl, etc., or a lower alkyl group optionally substituted with a halogen atom, or a substituent. A phenyl group or a phenylamino group which may have a substituent or may be substituted by a aralkyl group, and may be a `` 5- or 6-membered cyclic amino group which may have a substituent ''; The term “5- or 6-membered cyclic amino group” in [1] includes pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl and the like. The substituent here refers to the “substituent” described above.

The “cyclic alkyl group” includes those having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, and cyclohexyl, and is referred to as “heterocycle” in “5- or 6-membered heterocycle and fused ring thereof”. ] Is a saturated or unsaturated monocyclic or polycyclic, which may have one or more substituents. Heterocyclic group which can contain one or more nitrogen, oxygen and sulfur atoms, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, chenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyriyl Examples thereof include jyl, pyrimidyl, pyridazyl, and pyracyl. “The condensed ring” is a benzene condensed ring of the above “heterocycle” (for example, indolyl, tetrahydroquinolyl, benzoxaxazolidinyl, benzoyl) Thiazolidinyl, benzofurel, benzothenyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc.) or a condensed ring composed of two rings arbitrarily selected from the above “heterocycle” Ring (eg, imidazopyridine, pyrazo Mouth pyridine, imidazopyrimidine and the like). ·

The compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable salt, if necessary. Pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acid salts such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid and tosylic acid. And base salts such as sodium salts, calcium salts, calcium salts, and ammonium salts.

Further, the compound represented by the general formula (1) and a pharmacologically acceptable salt thereof of the present invention may be an inner salt thereof, an anhydride thereof, a hydrate or a solvate thereof.

The compound represented by the general formula (1) having the PARP inhibitory activity of the present invention can be synthesized from a known compound by a combination of known methods. For example, among the compounds represented by the general formula (1), the compound represented by the general formula (1-h) in which X is an oxygen atom can be easily synthesized by the following method (Production method I). Can be. <Production method I>

I-H

In the above ^{formula,, \ R \ R 4,} R 5, R 9, R 1G, n represents the agreed definitions as those described above.

The conversion of the compound represented by the general formula (37) to the compound represented by the general formula (38) (Step IA) can be carried out without solvent or in a suitable solvent such as water, acetic acid, hydrochloric acid, sulfuric acid, or the like. In a solvent, use a suitable oxidizing agent such as selenium dioxide. 9789

The reaction can be carried out at 20 to 250 ° C for 0.1 to 10 hours using chromium oxide, chromium oxide, potassium permanganate, or the like.

The conversion of the compound represented by the general formula (38) to the compound represented by the general formula (39) (Step IB) can be carried out without a solvent or with a suitable solvent such as benzene, chloroform, In a solvent such as 2-dichloroethane, use a suitable halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc., and react for 60 to 60 hours at L30 ° C for 0.5 to 6 hours. The reaction can be carried out by reacting at 0.1 to 3 hours at 0 to 60 ° C. with ammonia in a suitable solvent such as water, methanol, tetrahydrofuran, etc. .

The conversion of the compound represented by the general formula (39) to the compound represented by the general formula (40) (step Ί-C) is carried out by using a suitable solvent, for example, solvent, ethanol, In tetrahydrofuran, Ν, Ν-dimethylformamide, or a mixture thereof, use an appropriate catalyst, for example, palladium-carbon, platinum-carbon, etc. at normal pressure or under pressure if necessary. The reaction can be carried out by subjecting to a hydrogenation reaction at 80 ° C. for 1 to 72 hours.

'' The conversion of the compound represented by the general formula (40) to the compound represented by the general formula (41) (Step ID) is carried out by using a suitable solvent such as tetrahydrofuran, 1,4-dioxane, In a solvent such as Ν, Ν-dimethylformamide or a mixture thereof, in the presence of a suitable base, for example, triethylamine, pyridine, 4-dimethylaminopyridine, and the like, a compound represented by the general formula (42)

(Wherein, R ¹ has the same meaning as described above, and R ¹² represents a halogen atom.) After reacting at 50 to 100 ° C. for 1 to 10 hours, A suitable solvent such as water, tetrahydrofuran, 1,4-dioxa 9789

The reaction is carried out at 50 to 100 ° C for 1 to 10 hours using a suitable base such as sodium hydroxide or potassium hydroxide in a solvent such as methane or a mixture thereof. Can be performed.

The conversion of the compound represented by the general formula (41) into the compound represented by the general formula (1-h) (step I-E) is carried out by using a suitable solvent such as Ν, Ν-dimethylformamide, Ν In a solvent such as, Ν-dimethylacetamide or tetrahydrofuran, in the presence of a suitable base, for example, sodium carbonate, potassium carbonate, triethylamine, pyridine, etc., the general formula (43)

R ³ R ⁴

To the sea (CH ₂ ) _n — R ⁰ (43)

(Wherein R ³ , H ⁴ , R ⁵ , and n have the same meanings as described above, and Y represents a lower alkylsulfonyloxy group optionally substituted with a halogen atom or a halogen atom). The reaction can be carried out using a compound at 20 to 80 ° C for 1 to 24 hours.

In the compound represented by the general formula (1-h), is a halogen atom. In the compound IF, the compound represented by the general formula (1-h) is It can be converted to a compound represented by the general formula (1-i), which is NR ⁹ R ^1Q . That is, in a suitable solvent such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, tetrahydrofuran or the like (an appropriate iodide salt such as sodium iodide, if necessary) , And an iodide-powered room may be added), and the general formula (44)

R ⁹

Η-Ν

R ¹⁰ (44)

(Wherein, R ⁹ and R ^1D have the same meanings as described above) The reaction can be carried out at 60 to 180 ° C for 1 to 24 hours.

Among the compounds represented by the general formula (1-h), the compound in which R ⁵ is a lower alkoxycarbonyl group is obtained by the process IG, wherein R ⁵ is selected from the compounds represented by the general formula (1-h) It can be converted to a compound represented by the general formula (l_j) which is a carboxy group. That is, in a suitable solvent, for example, a solvent such as water, methanol, ethanol, or the like, an appropriate alcohol, for example, 20 to 100% by using a hydroxide, sodium hydroxide, carbonate, or the like. The reaction can be carried out at 0.5 ° C. for 0.5 to 10 hours.

Among the compounds represented by the general formula (1-h), the compound represented by the general formula (1-k) wherein R ⁵ is C0NR ⁹ R ^1G is a compound represented by the general formula (1-j) From the process IH. That is, in a solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, tetrahydrofuran and the like, a suitable condensing agent, for example, 1- [3- (dimethyl. Lamino) p.mouth pill] -3-ethylcarbodiimide, dicyclohexylcarbodiimide, etc. (if necessary, by adding an appropriate base such as triethylamine, pyridine, 4-dimethylaminopyridine, etc.) General formula (44) θ

R

/

Η-Ν

\ Ten

R (44)

(Wherein R ⁹ and R ^1Q have the same meanings as described above), and the reaction is carried out at 0 to 80 ° C. for 1 to 36 hours.

Also have PARP inhibitory activity of the present invention, among the compounds represented by the general formula (1), compound X is represented by the general formula is NR ¹¹ (Bok 1), for example Can be easily synthesized by the following method (Production method II)

In the above formula, R ² , R ³ , R ⁴ヽ R ⁵ヽ R ^u and n have the same meanings as described above, and Z represents a halogen atom.

The conversion of the compound represented by the general formula (41) to the compound represented by the general formula (45) (Step II-A) is carried out without a solvent or an appropriate solvent such as water, acetic acid, or a mixture thereof. The reaction can be carried out by using a suitable acid such as hydrochloric acid or hydrobromic acid in the above solvent at 60 to 130 ° C. for 3 to 48 hours.

The conversion of the compound represented by the general formula (45) to the compound represented by the general formula (46) (Step Π-B) may be carried out without solvent or in an appropriate solvent such as benzene, chloroform, In a solvent such as 2-dichloroethane, use a suitable halogenating agent, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc., and react at 60 to 130 ° C for 0.5 to 10 hours to obtain an acid. After converting the lipohydrate into an appropriate solvent, for example, in an appropriate solvent such as water, methanol, tetrahydrofuran or the like with ammonia at 0 to 60 ° C for 0.1 to 3 hours The reaction can be performed during the reaction.

Conversion of the compound represented by the general formula (46) to the compound represented by the general formula U-1) wherein X is ¹¹ among the compounds represented by the general formula (1) (Step II-C) Is dissolved in a suitable solvent such as Ν, Ν-dimethylformamide, Ν-, Ν-dimethylacetamide, Ν-methylpyrrolidone, 1,3-dimethylimidazolone (if necessary, Natural iodide, for example, sodium iodide or iodinated power may be added), a general formula (47)

(Wherein, R ⁴ , R ⁵ , ¹ , '!! have the same meanings as described above), and 60 to 150. The reaction can be performed by reacting at C for 1 to 24 hours. .

The compound represented by the general formula (45) can also be synthesized using the following method (Production method II).

(51) (45)

In the above formula, and β ² have the same meanings as described above. Conversion of the compound represented by the general formula (48) to the compound represented by the general formula (49) (Step III-A), the conversion of the compound represented by the general formula (49) into the compound represented by the general formula (50) (Step III-B), the conversion of the compound represented by the general formula (50) to the compound represented by the general formula (51) (Step III-C) and the conversion of the compound represented by the general formula (51) The conversion of the compound represented by the general formula (45) into the compound represented by the general formula (45) (Steps III-D) can be carried out in the steps IB, Step IC, Step ID and _{C The} compound represented by the general formula (1) which can be carried out according to the process IA, or the general formula (41), (45), (46) which is a synthetic intermediate in the production methods I, II and III and among the compounds you express by (51), the compound wherein R ¹ in formula (2), a known method may be converted if necessary the R ^6, R ⁷ and R ⁸ in the other substituents By line I can. For example, among the compounds represented by the general formula (1), R ¹ is the general formula (2), and at least one of R ⁶ , R ^{7 and} β ⁸ may be substituted with a halogen atom. Compounds that are alkoxy groups can be obtained in the absence of a solvent or in a suitable solvent such as water, acetic acid, or a mixture of these using a suitable acid such as hydrochloric acid, hydrobromic acid, etc. After reacting for 1 to 24 hours, use a suitable chlorinating agent, for example, thionyl chloride, oxychlorine, etc. in a solvent without solvent or in a suitable solvent, for example, dichloromethane, chloroform, tetrahydrofuran, etc. At 20 to 130 ° C for 1 to 10 hours, and then 0 to 60 ° C in an appropriate solvent such as water, methanol, tetrahydrofuran or a mixture thereof at 0 to 60 ° C. .;! After reacting for 3 hours, among the compounds represented by the general formula (1), R ¹ is the general formula (2), and at least one of R ⁶ and is a hydroxyl group It can be converted to a compound, and in a suitable solvent, for example, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, etc., and a suitable alkylating agent, for example, rhodoethane, ethyl bromoacetate, etc. Using a suitable base, such as carbonic acid 0-80 ° C in the presence of calcium, triethylamine, pyridine, etc. (if necessary, an appropriate iodide such as sodium iodide or potassium iodide may be added) By reacting at for 1 to 24 hours, the compound represented by the general formula (1) is represented by the general formula (2), and any one of R ⁶ ′, R ⁷ or The above can be converted to a compound which is a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group substituted by a lower alkoxycarbonyl group.

Further, among the compounds represented by the general formula (1), a compound in which R ¹ is the general formula (2) and at least one of β ^{7 and} R ⁸ is a nitrogen atom is an appropriate compound. In a solvent such as methanol, ethanol, tetrahydrofuran, Ν, Ν-dimethylformamide or a mixture thereof, a suitable catalyst, such as palladium-carbon, '.platinum-carbon, etc. or ^need: pressure in response to, by subjecting the 1-72 hour hydrogenation reaction at 20 to 80 ° C, the compounds represented by the general formula (1), R ¹ is the general formula (2) Yes, it can be converted to a compound in which one or more of V or R ⁸ is an amino group, and furthermore, a suitable solvent, for example, chloroform, tetrahydrofuran, N, N-dimethyl A suitable acylating agent such as acetic anhydride in formamide or a mixture thereof By reacting at 0 to 80 ° C for 1 to 24 hours using acetyl chloride or the like in the presence of no base or a suitable base, for example, triethylamine, pyridine, etc., the compound represented by the general formula (1) is obtained. Of the compounds represented by the formula (1), R ¹ is a compound of the general formula (2), and at least one of R ⁶ or R is an amino group which may have a substituent. .

Of a compound represented by the general formula (1) or a compound represented by the general formula (41), (45), (46) or (51) which is a synthetic intermediate in the production methods I, II and III Among them, in the compound in which R ¹ is the general formula (2), the method of converting β ⁷ and R ⁸ to other substituents as necessary is not limited thereto. Not something.

The 4-substituted quinazoline-8-carboxylic acid amide derivative represented by the general formula (1) of the present invention and the addition salt thereof show excellent PARP inhibitory activity. When the compound of the present invention is used as a therapeutic or prophylactic agent, it may be used alone or mixed with a pharmacologically acceptable excipient, diluent, or the like at appropriate times, to give tablets, capsules, granules, and powders. It can be administered orally with a syrup or the like, or parenterally with an injection or transdermal absorber, suppository or the like.

Further, the compound of the present invention can be used in combination with other drugs. In this case, it may be administered in combination or as a combination drug. Drugs used in combination include thrombolytics, antiplatelet drugs, cerebral protective drugs, anti-edema drugs, anticoagulants, antipyretics, cerebral circulation metabolism improvers, antiepileptic drugs, antidepressants, Examples include anti-inflammatory drugs, ACE inhibitors, anti-inflammatory analgesics, and glycemic control drugs. ·

Further, the compound of the present invention can be used in combination for surgical therapy, hypothermia therapy, hyperbaric oxygen therapy and the like. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the scope of the present invention is not limited thereto. Reference Example 1> 2-Ditoly sophthalic acid

To a suspension of 2-nitro-2-xylene (15.1 g, 100 mmol) in water (300 mL) was added potassium permanganate (79.0 g, 500ππηο1) little by little at 80 ° C while heating. • The mixture was stirred at 100 ° C for 3 hours. After cooling, insolubles were filtered off using celite. The filtrate was washed with ethyl acetate and adjusted to pH 1 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 14.9 g of the title compound as a colorless powder. yield %.

丄1 -丽_{R (DMS0- d 6, δ)} :!. 7.82 (1Η, t, J = 7.8Hz), 8.19 (2H} d, J = 7.8Hz), 13.00- 15.00 (2H, br) ° Reference Example 2> 2-2 Troisflic acid amide

To a solution of the compound of Reference Example 1 (1.27 g, 6.02 mmol) in 1,2-dichloroethane (12 mL) was added Ν, Ν-dimethylformamide (46.6 〃L, 602 〃mol) and then thionyl chloride (963 L, 13.2 mmol) and heated under reflux for 2.5 hours. After cooling, the residue obtained by concentration under reduced pressure was dissolved in a small amount of tetrahydrofuran, and added dropwise to concentrated aqueous ammonia (15 mL) under ice-cooling. After stirring at the same temperature for 30 minutes. The precipitated crystals are collected by filtration, washed with water, and air-dried to give a colorless powder. 637 mg of the compound was obtained. Yield 51%.

_{- NM (DMS0-d 6,} δ):. 7.67- 7.74 (3H 5 m), 7.77 (2H, s), 8.27 (2Η; s) ° Reference Example 3> 2-Aminoi soft Yuru acid § Mi de

To a suspension of the compound of Reference Example 2 (635 mg, 3.04 nmol) in methanolic root tetrahydrofuran (4: 1, 25 mL) was added 10% palladium-carbon (ice 51.Γ, 63.5 mg), and the mixture was stirred at room temperature. 'The mixture was stirred for 4 hours under a hydrogen stream (normal pressure). Ν, Ν-Dimethylformamide was added to dissolve the precipitated crystals, and the catalyst was removed by filtration using Celite 10, and the solvent was distilled off. Diisopropyl ether was added to the obtained residue, and the crystals were collected by filtration, washed with diisopropyl ether, and air-dried to obtain 540 mg of the title compound as a yellow powder. Yield 99%, -丽_{R (DMS0- d 6, ό "} ): 6.49 (1H, t, J = 7.8Hz), 7.22 (2H, s), 7.66 (2H, d, J = 7.8Hz), 7.84 (2H, s), 7.97 (2H, s). Reference Example 4> 3,4-Dihydro-2--4-oxo-2-phenylquinazoline-8-force rubonic acid amide

To a suspension of the compound of Reference Example 3 (400 mg, 2.23 mmol) in tetrahydrofuran (20 mL) was added pyridine (361 L, 4.46 mmol), 4-dimethylaminopyridinine (13.7 mg, 112 mol) and benzoyl chloride ( 311 L, 2.68 mmol) were added in that order, and the mixture was heated under reflux for 4 hours. A 20% aqueous sodium hydroxide solution (20 mL) was added to the reaction solution, and the mixture was further heated under reflux for 4 hours. After cooling, the mixture was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. This was washed successively with water and Ν, Ν-dimethylformamide and then air-dried to obtain 321 mg of the title compound as a colorless powder. Yield 54%. ·: - ^ - NMR (MS0 -d 6, d): 7.59 - 7.66 (4H, m), 7.93 (1H, s), 8.08- 8 · 10 (2Η, m), 8.34 (1H 5 dd, J = 7.8, 1.5Hz), 8.53 (1H, dd, J = 7.3, 1.5Hz), 9.68 (1H, s), 12.92 (1H, s).

<Reference Examples 5 to 8> In the same manner as in Reference Example 4, the compounds shown in Table 6 below were obtained.

6]

《Compound of Reference Example 5》-

-丽 R (MS0-d ₆ , δ): 3.87 (3H, s), 7.15 (2H, d, J = 8.8 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.93 (1H ₅ d, J = 2.9Hz), 8.09 (2H, d, J 8.8Hz), 8.32 (1H, dd, J = 7.8, 2.0Hz), 8.51 (1H ₃ dd, J = 7.8, 2.0Hz), 9.75 (1H, d , J = 3.4Hz), 12.78 (1H, s).

<< Compound of Reference Example 6 >>

-丽 R (DMS0- d ₆ , δ): 3.88 (3H, s), 7.21 (1H, dd, J = 8.3, 2.4Hz), 7.52 (1H, t, J = 7.8Hz), 7.60-7.96 (3H , m), 7.93 (1H, s), 8.34 (1H, dd, J-7.8, 1.5Hz), 8.52 (1H, dd, J = 7.8, 1.5Hz), 9.69 (1H, d, J = 3.4Hz) , 12.9K1H, s).

<< Compound of Reference Example 7 >>

_{NMR (DMS0- d 6, δ)} : 7.61 - 7.75 (2H, m), 7.89 (1H, s), 7.97- 8.00 (1H, m), 8.15-8.19 (1H, m), 8.33 (1H, dd, J2 7.8, 1.5Hz) ₃ 8.47 (1H, dd, J = 7.8, 1.5Hz), 9.30 (1H ₃ s), 12.95 (1H, s). << Compound of Reference Example 8 >>

丽_{R (DMS0- d 6, ό "} ): 3.85 (6H, s), 6.77 (1H, t, J = 2.0Hz), 7.29 (2H, d, J = 1.5Hz), 7.62 (1H, t, J 7.8Hz), 7.98 (1H, d, J 2.9Hz), 8.33 (1H, dd, J = 7.8, 1.5Hz), 8.52 (1H, dd, J = 7.8, 1.5Hz), 969 (1Η , D, J = 2.9 Hz), 12.88 (1H, s). Reference Example 9> 3,4-dihydro-4-oxo-2-phenylquinazoline-8-force rubonic acid

To a solution of the compound of Reference Example 4 (160 mg, 603 mol) in acetic acid (4 mL) was added: hydrobromic acid (2 mL), and the mixture was heated under reflux for 16 hours. After cooling, water was added, and the precipitated crystals were collected by filtration, washed with water, and air-dried to give 156 mg of the title compound as a colorless powder. 97% yield.

^{1 H-NMR (DMS0-d} 65 δ): 7.63 - 7.73 (4H, m), 8.07- 8.09 (2H, m), 8.4K1H, dd, J two 7.8, '1.5Hz), 8.49 ( 1H, dd, J 7.8, 1.5 Hz), 13.20 (1H, s), 15.55 (1H, s). Reference Examples 10 to 13> By the same method as in Reference Example 9, the compounds shown in Table 7 below were obtained. [Table 7]

<< Compound of Reference Example 10 >>

! H-NMRCDMSO-de, δ): 698 (2Η, d, J 8.8 Hz), 7.63 (1Η, t, J = 7.8 Hz), 7.97 (2Η, d, J = 8.8 Hz), 8.36 ( 1Η ₃ dd, J = 7.8, 1.5Hz), 8.47 (1Η, dd, J = 7.8, 1.5Hz), 10.52 (1H, s), 12.70-13.30 (1H, br), 15.60-16.20 (1H, br) .

<< Compound of Reference Example 11 >>

-Marauder R (DMS0- d ₆ , δ): 7.06-7.09 (1Η ₅ m), 7.41-7.45 (2Η _} m), 7.50 (1Η, d, J = 7.8 Hz), 7.68 (1H, t, J = 7.8Hz), 8.39 (1H, d, J 8.3Hz), 8.48 (1H, d, J = 7.8Hz), 10.04 (1H _S s), 13.11 (1H, s), 15.65 (1H, s).

<< Compound of Reference Example 12 >>

^ - NMR (DMS0-, δ) : 7.67- 7.79 (2H 3 m), 7.97- 8.00 (1H,), 8.15 - 8.20 (1Η, HI), 8.38- 8.43 (2Η, m), 13.19 (1Η, t , J two 1.5Hz), 14.88 (1H, d, J = 2.0Hz). << Compound of Reference Example 13 >>

^ -NMRCDMSO-de, δ): 6.53 (1H, d, J = 2.0 Hz), 6.91 (2H, d, J: 2.0 Hz), 7.68 (1H, t, J = 7.8 Hz), 8.39 (1H, d , J = 7.8 Hz), 8.50 (1H ₃ d, J 2 7.8 Hz), 9 · 84 (2Η, s), 13.01 (1H, s), 15.75 (1H, s). 2-Nito-benzoic acid amide

Thionyl chloride (10 mL) was added to 3-methyl-2-nitrobenzoic acid (5.00 g, 27.6 mmol), and the mixture was heated under reflux for 2 hours. After cooling, the residue obtained by concentration under reduced pressure was added with tetrahydrofuran (10 mL), further concentrated aqueous ammonia (40 mL) was added, and the mixture was stirred for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was washed with water and air-dried to obtain 4.62 g of the title compound as a colorless powder. Yield 93%.

-丽 R (body SO- d ₆ , δ): 2.79 (3H ₃ s), 7.55-7.58 (3H, m) ₃ 7.68 (1H, brs), 8.19 (1H, brs). Amino-3-methylbenzoic acid amide

Using the compound of Reference Example 14 (3.00 g, 16.7 mmol), By the method, 2.77 g of the title compound was obtained as a colorless powder. Yield quantitative.丽_{R (MS0- d 6, δ)} : 2.07 (3H, s), 6.40 (2H, s), 6.44 (1H, t, J = 7.3Hz), 7.06 (1H 5 d, J = 7.3Hz), 7.07 (1H, brs), 7.42 (1H, d, J2 7.3Hz), 7.73 (1H, brs). Reference Example 16> 3,4-Dihydro-2- (4-methoxyphenyl) -8 Methyl-4-oxoquinazoline

Using the compound of Reference Example 15 (1.00 g, 6.66 mmol) and the same method as in Reference Example 4, 2.29 g of the title compound was obtained as a colorless powder. Yield quantitative. ':-Marauder R (DMS0- d ₆ , δ): 2.6Κ3Η, s), 3.85 (3H, s), 7.10 (2H, t, J = 8.8 Hz), 7.36 (1H, t, J = 7.3 Hz) , 7.68 (1H, d, J = 7.3Hz), 7.97 (1H, d, J = 7.3Hz) ₃ 8.24 (2H, d, J2 8.8Hz), 12.41 (1H, brs). , 4-Dihydro-2--2- (4-methoxyphenyl) -4_oxoquinazolin-8-carboxylic acid

To a suspension of the compound of Reference Example 16 (1.54 g, 5.78 maraudal 01) in water (301 ^) was added a permanganate-potassium rim (4.57 g, 28.9 nimol) over 2 hours at 80 ° C while heating. Attachment After stirring at the same temperature for 5 hours, the mixture was further stirred at 100 ° C for 3 hours. After cooling, insolubles were filtered off using celite. The filtrate was washed with ethyl acetate and adjusted to pH 1 with concentrated hydrochloric acid. This was extracted with dichloromethan, dried over anhydrous sodium sulfate, and the solvent was distilled off. Diisopropyl ether was added to the obtained residue, and the crystals were collected by filtration and air-dried to obtain 39.6 mg of the title compound as a pale yellow powder. Yield 3%.

-Marauder R (DMS0- d ₆ , δ): 3.89 (3H, s), 7.20 (2H, d, J = 9.3Hz), 7 ・ 66 (1Η, t, J = 7.8Hz), 8.08 (2H, d , J = 9.3Hz), 8.39 (1H, dd, J = 7.8, 1.5Hz), 8.48 (1H, d, J = 7.8, 1.5Hz), 13.07 (1H, s), 15.8K1H, s) Example 18> 4-Kuguchi-2- (4-Methoxyphenyl) quinazoline-8-Rubonic acid amide

Thionyl chloride (2 mL) was added to the compound of Reference Example 17 (38.0 mg, 128 mol), and the mixture was heated under reflux for 2 hours. After cooling, the residue obtained by concentration under reduced pressure was dissolved in a small amount of tetrahydrofuran, added dropwise to concentrated aqueous ammonia (2 mL) at room temperature, and stirred at the same temperature for 1 hour. The reaction solution was diluted with water, and the precipitated crystals were collected by filtration and air-dried to obtain 34.3 mg of the title compound as a colorless powder. Yield 85%.

δ): 3 · 89 (3Η, s), 7 · 18 (2Η, d, J 2 8.8 Hz), 7.88 (1H, t, J = 7.3 Hz), 8.13 (1H, s), 8.36 (2H, d , J = 8.8Hz) _} 8.45 (1H ₃ dd, J = 8.3, 1.5Hz), 8.67 (1H, dd, J 7.3, 1.5Hz), 9.4K1H, s).

<Reference Examples 19 to 23> The compounds shown in Table 8 below were obtained in the same manner as in Reference Example 18. 8]

23 OH H OH

<< Compound of Reference Example 19 >>

! H-NMRiDMSO-de, ό "): 7.64-7.66 (3 Η, m), 7.94 (1 Η, t, J = 7.3 Hz) _: 8.13 (1H, s), 8.41-8.44 (2H, m), 8.49 ( 1H _} dd, J = 8.3, 1.5Hz) 8.69 (1H, dd, J = 7.3, 1.5Hz), 9.34 (1H, s).

<< Compound of Reference Example 20 >>

iH-NMR (丽_{SO- d 6, δ): 6} · 98 (2Η, d, J = 8.8Hz), 7.85 (1H 3 t, J: 7.8Hz), 8.09 (1H, s), 8.26 (2H, d, J = 8.8Hz), 8.43 (1H, dd, J: 8.3, 1.5Hz), 8.67 (1H, dd, J = 7.3, 1.5Hz), 9.49 (1H, s), 10.32 (1H _: s). << Compound of Reference Example 21 >>

iH-丽_{R (DMS0-d 6, δ} ): 7.01 - .04 (1H, m), 7.43 (1H, t, J two 7.8Hz), 7.85- 7.86 (2H, m), 7.93 (1H, t, J = 7.8Hz) ₃ 8.16 (1H, s), 8.48 (1H, dd, J 8.3, 1.5Hz), 8.70 (1H, dd, J 7.3, 1.5Hz), 9.39 (1H, s), 9.88 ( 1H ₃ s).

<< Compound of Reference Example 22 >>

丽 R (DMS0- d ₆ ,): 7.68-7.75 (1Η, m), 7.95 (1H, t, J = 7.3 Hz), 8.09 (1H, d, J = 1.0 Hz), 8.27-8.34 (2H, m ), 8.48 (1H, d, J = 7.8 Hz), 8.62 (1H, d, J two 7.3 Hz), 8.96 (1H, s).

<< Compound of Reference Example 23 >>

-丽_{R (DMS0- d 6,: 6.46} (1H, d, J = 2.4Hz), 7.32 (2H, d, J = 2.4Hz), 7.92 (1H, t, J two 7 · 3Ηζ), 8.17 (1H , d, J = 10 Hz), 8.47 (1Η, .dd, J = 8.3, 1.5 Hz), 8.71 (1H, dd, J2 7.3 ₃ 1.5 Hz), 9.81 (1H, s), 9.68 (2H, s ).

<Reference Example 24> 3,4-Dihydroxy mouth-4-oxo-2- (2-Chenyl) quinazoline-8-carboxylic acid amide

Using the compound of Reference Example 3 (500 mg, 2.79 mmol) and 2-thenoyl chloride (356 L, 3.35 mmol), 552 mg of the title compound as a colorless powder was obtained in the same manner as in Reference Example 4. 73% yield.

6.7Hz) ₎ 7.98 (1H, d, J = 5.5Hz), 8.05 (lH, d, J = 2.4Hz), 8.29-8.32 (2H, m), 8.53 (1H, d, J2 6.7Hz), 9.57 (lH, d, J2 3.1 Hz), 13.04 (lH, brs). Reference Example 25> 3,4-dihydro-4-oxo-2- (2-phenyl) quinazoline-

8-carboxylic acid

Using the compound of Reference Example 24 (552 mg, 2.03 mmol), 507 mg of the title compound as a pale yellow powder was obtained in the same manner as in Reference Example 9. Yield 92%.

O-NMR iDMSO-de, δ): 7.34 (lH, t, J = 4.3 Hz), 7.64 (lH, t, J = 7.6 Hz), 8.05 (1H, d, J = 4.9 Hz), 8.34-8.38 (2H , m), 8.45 (lH, dd, J = 7.6, 1.2Hz), 13.27 (1H, brs), 15.06 (lH, brs).,

<Reference Example 26> 3,4-dihydro-2- (2_naphthyl) -4-oxoquinazoline 8-carboxylic acid

Using the compound of Reference Example 3 (500 mg, 2.79 mmol) and 2-naphthoyl chloride (639 mg, 3.35 mmol), 610 mg of a colorless powder was obtained in the same manner as in Reference Example 4.

The obtained colorless powder (301 mg) was used in the same manner as in Reference Example 9. 274 mg of the title compound was obtained as a pale yellow powder.

7.9Hz), 8.10 (2H, d, J = 7.9Hz), 8.18 (1H, d, J-2 8.6Hz), 8.43 (1H, d, J = 7.9Hz), 8.50 (1H, d, J-2 7 3Ηζ), 877 (1Η, s), 13.32 (lH, brs), 15.56 (1H, brs).

<Reference Example 27> 4-chloro-2- (2-Chenyl) quinazoline-8-carboxylic acid K

Using the compound of Reference Example 25 (375 mg, 1.38 mmol), in the same manner as in Reference Example 18, the title compound was obtained as pale yellow powder by the following method: 385 mg. 96% yield. ¹ H-NMR (DMSO-d ₆ , δ): 7.32 (1H, t, J = 4.3 Hz), 7 · 89 (1Η, t, J = 7.9 Hz), 7.96 (1H, d, J = 4.3 Hz) , 8.09 (1H, d, J = 2.4Hz), 8.18 (1H, brs), 8.46 (1H, d, J = 8.6Hz), 8.73 (1H, d, J = 7.3Hz), 9.38 (1H, brs) Reference Example 28> 4-Chloro-2- (2-naphthyl) quinazoline-8-carboxylic acid amide F

Same as Reference Example 18 using the compound of Reference Example 26 (375 mg, 1.38 mmol) 9789

By the method described in 49, 292 mg of the title compound was obtained as a pale yellow powder. Yield quantitative ₍ ¹ H-NMR (DMSO-d ₆ , δ): 7.63-7.70 (2H, m), 7.93-7.97 (lH, m), 8.04 (1H, d, J = 7.3 Hz), 8.15- 8.22 (3H _; m), 8.47 (lH, dd, J = 8.9, 1.8Hz), 8.51 (1H, dd, J2 8.3, 1.8Hz), 8.69 (lH, dd, J = 7.3, 1.8Hz), 9.06 (1H, s), 9.35 (1H _; brs). Example 1> 2- (4-Methoxyphenyl) -4- [2- (pyrrolidine-tolyl) ethyl] aminoquinazolin-8-carvone Acid amide

1- (2-Aminoethyl) pyrrolidine (66.5 L, 525 imol) was added to a solution of the compound of Reference Example 18 (33. Omg, 105 mol) in Ν, Ν-dimethylaminoformamide (1 mL), and The mixture was stirred at 150 ° C for 5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography [ethyl acetate-methanol-2-100: 1] to give 26.2 mg of the title compound as a colorless powder. Yield 64%.

-丽 R (DMS0-d ₆ ,): 1.70 (4H, t, J = 3.4 Hz), 2.56 (4H, s), 2.78 (2H, t, J = 6.8 Hz), 3.81 (2H, t, J 6.4Hz), 3.85 (3H, s), 7.12 (2H, d, J = 9.3Hz), 7.56 (1H, t, J = 7.8Hz), 7.93 (1H, d, J = 4.4Hz), 8.3K2H, d, J 2 8.8Hz), 8.42 (1H, dd, J: 8.3, 1.0Hz), 8.55 (1H, dd, J = 7.3, 1.0Hz), 8.62 (1H, t, J = 5.4Hz), 10.65 ( 1H, d, J = 4.9Hz).

HR-FAB + (m / z): 392.2071 (-1.6 jobs u). <Examples 2 to 11> In the same manner as in Example 1, the compounds shown in Table 9 below were obtained.

[Table 9]

^R l ^R4 Example R ^a R ^b R ^c C (R ³ ) (R ⁴ )-(CH ₂ ) _n -R ⁵

To HN (CH ₂ ) _n --R ⁵ 2 HHH (CH ₂ ) ₂ -pyrrolidin-l-yl

Υ: Ϊ 3 H OH H (CH ₂ ) 2 ~ pyrrolidin-l-yl

, 4 OH HH (CH ₂ ) ₂ -pyrrolidin-l-yl

CONH ₂ 5 FFH (CH ₂ ) ₂ -pyrrolidin-l-yl

6 OH H OH (CH ₂ ) ₂ -pyrrolidin- 1 -yl

7 H OH H CH (CH ₂ OH) ₂

8 OH HH CH (CH ₂ OH) ₂

9 OH H OH CH (CH ₂ OH) ₂

10 H OH HC (CH ₂ OH) ₃

11 OH H OH C (CH ₂ OH) ₃

<< Compound of Example 2 >>

^ -Title R (DMS0-, δ): 1.69 (4Η, s), 2.56 (4Η, s), 2.79 (2Η, t, J = 6.9Hz) _} 3.81-3.86 (2H, m), 7.56-7.62 ( 4H, m), 7.94 (1H, d, J = 3.4Hz), 8.35-8.37 (3H, ni), 8.45 (1H, d, J = 7.8Hz), 8.57 (1H, d, J = 7.3Hz), 8.68 (1H, d, J = 4.9Hz), 10.60 (1H 5 d, J = 4.4Hz) Anal Calcd for C 21 H 23 N 5 0 · 1 / 10H 2 0:.. C, 69.44; H, 6.44; N, 19.28 (50.

Found: C, 69.46; H, 6.54; N, 19.02 (%).

HR-FAB + (m / z): 362.1991 (+ 1.0mmu). << Compound of Example 3 >>

- negation _{R (DMS0- d 6, δ)} : 1.69- 1.71 (4Η, m), 2.53- 2.55 (4H, m) 3 2.73 - 2.79 (2H, m), 3.79- 3.83 (2H, m), 6.91 ( 2H, d, J = 8.8Hz), 7.53 (1H, t, J 7.8Hz), 7.88 (1H, d, J = 4.4Hz), 8.21 (2H, d, J 8.8Hz), 8.4K1H, dd , J = 7.8, 1.5Hz), 8.53 - 8.58 (2H, m), 10.72 (1H 3 d, J = 4.4Hz).

Anal. Calcd for C ₂₁ H ₂₃ N ₅ 0 ₂ · 1 / 4H ₂₀ : C, 66.04 H, 6.20; N, 18.34 (¾).

Found: C, 65.95; H, 6.32; N, 18.35 (%).

HR-FAB + (m / z): 378.1929 (-O.lmmu).

<< Compound of Example 4 >>

! H-NMRCDMSO-de, δ): 1.70 (4H ₅ s), 2.56 (4H ₃ s), 2.78 (2H, t, J = 6.9 Hz), 3.83 (2H, q, J 6.4 Hz), 6.93- 6.95 (1H, m), 7.34 (1H, t, J = 7.3Hz), 7.59 (1H, t, J = 7.3Hz), 7.77- 7.79 (2H 3 m), 7.96 (1H, d, J two 4.4Hz ), 8.45 (1H, d, J = 7.8Hz), 8.57 (1H, d, J = 7.3Hz), 8.64 (1H, t, J = 5.4Hz), 9.70 (1H, s), 10.62 (1H, d , J = 4.4Hz). H -FAB + (m / z): 378.1939 (+ 0.9mmu).

<< Compound of Example 5 >>

-丽_{R (DMS0- d 6, δ)} : 1.70 (4Η, t, J = 3.4Hz), 2 · 56 (4Η, s), 2.77 (2H 3 t, J two 6.8Hz), 3.79- 3.84 (2H , m), 7.60-7.68 (2H ₃ m), 7.93 (1H, s), 8.19-8.28 (2H, m), 8.45 (1H, d, J = 8.3 Hz), 8.54 (1H, dd, J = 7.3 , 1.5Hz), 8.75 (1H, d, J = 4.9Hz), 10.18 (1H, d, J2 3.9Hz).

_{_{. Anal Calcd for C 21 H 21}} F 2 N 5 0 - 1 / 10H 2 0: C, 63.18; H, 5.35; N, 17.54 (50. JP2003 / 009789

52

Found: C, 63.14; H, 5.19; N, 17.48 (%).

HR-FAB + (m / z): 398.1800 (+0.8 leakage u).

<< Compound of Example 6 >>

iH- NMR (thigh _{SO- d 6, δ): 1} · 87 (2Η, brs), 2.02 (2Η 3 brs), 3.11 (2Η, brs), 3.54 (2Η, brs), 3.69 (2Η, brs), 4.03 (2Η, brd), 6.42 (1Η, s),

7.26 (2Η, s), 7.63 (1Η, t, J = 7.8Hz), 7.99 (1H, d ₃ J = 3.9Hz),

8.5K1H, d, J = 7.8Hz), 8.61 (1H, d, J = 7.3Hz), 8.92 (1H, s),

9.52 (2H, s), 10.13 (1H, s), 10.55 (1H 3 d, J two 4.4 Hz).

_{_{. Anal Calcd for C 21 H 23}} N 5 0 3 · HC1 · H 2 0: C, '56.31; H, 5.85; N,

15.64 (50.

Found: C, 56.34; H, 5.70; N, 15.6G (%).

HR-FAB + (m / z): 394.1869 (-l.Ommu).

<< Compound of Example 7 >> '

-Band H (DMS0-d _fi , δ): 3.7Κ4Η, t, J = 5.4Hz), 4.59- 4.64 (1H, m), 4.79 (2H, t, J = 5.4Hz), 6.92 (2H, d, J = 8.8Hz), 7.53 (1H, t, J = 7.8Hz), 7.88 (1H, d, J = 3.9Hz), 8.03 (1H, d, J = 7.8Hz), 8.21 (2H, d, J = 8.8Ηζ), 8.53—8.56 (2H, m), 10.75 (1H, d, J two 4.4Hz). HR-FAB + (m / z): 355.1394 (-1.3mmu).

<< Compound of Example 8 >>

iH- 丽 R (DMS0-d ₆ , δ): 3.67-3.77 (4H, m), 4.62-4.66 (1H ₃ m), 4.79 (2H, t, J = 5.9 Hz), 6.93-6.95 (1H, m ), 7.34 (1H, t, J = 7.8Hz), 7.59 (1H, t, J = 7.8Hz), 7.77-7.79 (2H, m), 7.96 (1H, d, J2 4.4Hz), 8.11 (1H ₅ d, J two 7.8Hz), 8.57- 8.59 (2H, m), 9.70 (1H, d, J = 7.3Hz), 10.64 (1H, d, J = 4.4Hz). _{_{. Anal Calcd for C 18 H 18}} N 4 0 4 - 1 / 10H 2 0: C, 60.70; H, 5.15; N,

Found: C, 60.64; H, 5.28; N, 15.54 (¾).

HR-FAB + (m / z): 355.1384 (-2.3 bandits u).

<< Compound of Example 9 >>

-丽 R (DMS0-d ₆ , δ): 3.66-3.77 (4H, m), 4.60-4.65 (1H, ra), 4.78 (2H, t, J = 5.4Hz), 6.39 (1H, t, J = 2.0Hz), 7.22 (2H, d, J = 2.4Hz), 7.58 (1H ₃ t, J = 7.3Hz), 7.98 (1H, d, J = 4.4Hz), 8.06 (1H, d, J = 7.3Hz) ), 8.56- 8.59 (2H ₅ m), 9.48 (2H, s), 10.64 (1H, d, J = 4.9 Hz).

_{_{. Aaal Calcd for C 18 H 18}} N 4 0 5 · 2 / 5H 2 0:. C, 57.26; H, 5.02;, 14.84 (¾).

Found: C, 57.25; H, 5.04; N, 14.70 (¾).

HR-FAB + (m / z): 371.1366 (+ l.lmmu).

<< Compound of Example 10 >>

- negation _{R (DMS0 - d 6, δ} ): 3.98 (6H, d, J = 5.9Hz), 4.78 (3H, t, J. = 5.9Hz), 6.93 (2H, d, J = 8.8Hz), 6.96 (1H, s), 7.54 (1H, t, J 2 7.8Hz), 7.86 (1H, d, J = 2.9Hz), 8.12 (2H, d, J = 8.8Hz), 8.43 — 8.45 (1H, ra) , 8.54— 8.56 (1H, m) ₃ 10.02 (1H, s), 10.67 (1H, d, J-4.4Hz).

_{_{Anal. Calcd for C 19 H 2}} . _{_{N 4 0 5 · 1 / 2H}} 2 0: C, 58.01; H, 5.38; N, 14.24 (¾).

Found: C, 58.12; H, 5.24; N, 13.99 (¾).

HR-FAB + (m / z): 385.1517 (+0.5 t). << Compound of Example 11 >>

^ -丽_{R (MS0- d 6, δ)} : 3.97 (6H, d, J two _{5.9Hz), 4.74 (3H 5 t} , J = 5.9Hz), 6.41 (1H 5 t, J two 2.0 Hz), 6.98 (1H, s), 7.13 (2H, d, J two 2.0 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.94 (1H, d, J two 3.9 Hz), 8.48 (iH, d ₃ J = _{8.3Hz), 8.57- 8.59 (lH 3} m), 9.52 (2H, s), 10.59 (1H, d, J two 4.9 Hz).

HR-FAB + (in / z): 401.1479 (+1.7 strokes).

Example 12 4- [3- (dimethylamino) propyl] amino-2-phenylquinazolin-8-carboxylic acid amide

Using the compound of Reference Example 19 (100 mg, 352 mol) and Ν, Ν-dimethyl_1,3-propanediamine (221 L, 1.76 mmol), the title compound was obtained as a pale yellow powder in the same manner as in Example 1. 97.4 mg was obtained. 79% yield.

δ): 1.85-1.92 (2H, m), 2.18 (6H, s), 2,38 (2H, t, J = 6.7 Hz), 3.74 (2H, q, J = 6.7 Hz), 7.56-7.62 (4H , m), 7.94 (1H, d, J = 3.6 Hz), 8.36-8.38 (2H, m) ₅ 8.43 (lH, d, J = 7.9 Hz), 8.58 (1H, d, J = 7.9 Hz), 8.77 (1H, t, J = 5.5Hz), 10.62 (1H, d, J2 4.3Hz). HR-FAB + (m / z): 350.1982 (+ 0.1mmu).

Example 13 4- [2- (ethoxycarbonyl) ethyl] amino-2-phenylquinazoline-8-carboxylic acid amide

Using the compound of Reference Example 19 (100 mg, 352 mol) and /?-Alaninetyl ester hydrochloride (270 mg, 1.76 mmol), 26.Omg of the title compound as a colorless powder was obtained in the same manner as in Example 1. . Yield 20%.

1H-NMR (DMSO-d ₆ , δ): 1.13 (3H, t, J two 6.7 Hz), 2.82 (2H, t, J two 6.7 Hz), 3.95 (2H ₅ q, J = 6.7 Hz), 4.05 ( 2H, q, J = 6.7Hz), 7.56-7.58 (3H, m), 7.6l (lH, t, J = 7.9Hz), 7.95 (lH, d, J = 4.3Hz), 8.35-8.38 (2H, m), 8.44 (lH, dd, J = 7.9, 1.2Hz), 8.58 (1H, dd, J2 7.9, 1.2Hz), 8.78 (1H, t, J = 5.5Ηζ), 10.56 (1H, d, J = 4.3Hz).

HR-FAB + (m / z): 365.1607 (-0.7mmu).

Example 14 4- (l, 3-dihydroxypropane-2-yl) amino-2- (2-thenyl) quinazoline-8-carboxylic acid amide

Using the compound of Reference Example 27 (100 mg, 345 mol) and serinol (158 mg, 1.73 mmol), 88.7 mg of the title compound as a colorless powder was obtained in the same manner as in Example 1. Yield 75%.

4.9Hz), 4.51- 4.55 (lH, m), 4.79 (2H, brs), 7.23-7.27 (lH, m), 7.55 (lH, t, J = 7.3Hz), 7.78 (lH, d, J = 4.9Hz), 7: 90-7.99 (2H, m) , 8.16 (1H, d _; J = 7.3Hz), 8.55- 8.57 (2H, m), 10.41 (1H, d, J = 3.1Hz).

HR-FAB + (m / z): 345.1033 (+1.2 mmu). Example 15> 4- [tris (hydroxymethyl) methyl] amino-2- (2-Chenyl) quinazoline-8-carboxylic acid Amid

Using the compound of Reference Example 27 (100 mg, 345 zmol) and tris (hydroxymethyl) aminoaminomethane (210 mg, 1.73 mmol), 48.9 mg of the title compound as a colorless powder was obtained in the same manner as in Example 1. Yield 40% _c ! H-NMR iDMSO-de, δ): 3.96 (6H, s), 4.77 (3H, brs), 7.04 (lH, s), 7.25 (1H, t, J = 3.7 Hz), 7.55 ( lH, t, J = 7.9Hz), 7.78 (1H, d, J = 5.5Hz), 7.86 (1H, d, J = 3.7Hz), 7.92 (lH, d, J = 4.3Hz), 8.47 (lH _; d, J-7.9 Hz), 8.55 (1H, d, J = 7.3 Hz), 10.39 (1H, d, J-4.3 Hz).

HR-FAB + (m / z): 375.1122 (-0.5 mmu). Example 16> 4- [2- (Pyridin-1-yl) ethyl] amino-2- (2-phenyl) quinazoli -8-carboxylic acid amide

Using the compound of Reference Example 27 (100 mg, 345 zmol) and 1 · (2-aminoethyl) pyrrolidine (217 zL, 1.73 mmol), a pale yellow powder was obtained in the same manner as in Example 1. 55, 4 mg of the title compound were obtained. Yield 44%.

δ): 1.70 (4H, s), 2.60 (4H, brs), 2.79 (2H, brs), 3.77-3.81 (2H, m), 7.24 (lH, t, J = 4.9Hz), 7.56 (lH, t , J = 7.9Hz), 7.78 (1H, d, J: 4.9Hz), 7.92-7.94 (2H, m), 8.40 (lH, d, J2 7.9Hz), 8.56 (1H, d, J = 7.3Hz) ), 8.70 (lH, t, J = 4.9 Hz), 10.39 (lH, d, J = ■ 3.7 Hz).

HR-FAB + (m / z): 368.1549 (+ 0.4mmu).

Example 17 4- (l, 3-Dihydroxypropane-2-yl) amino-2- (2-naphthyl) quinazoline-8-carboxylic acid amide

Using the compound of Reference Example 28 (100 mg, 300 mol) and serinol (137 mg, 1.50 mmol), 97.3 mg of the title compound as a colorless powder was obtained in the same manner as in Example 1. Yield 84%.

δ): 3.76 (4H _; s), 4.72-4.77 (lH, m), 4.84 (2H, s) brs), 7.60-764 (3Η, m), 7.96-8.03 (2H, m), 8.08-8.10 (2H, m): 8.18 (1H, d, J = 7.3Hz), 8.44 (lH, d, J = 8.6Hz), 8.60 (2H, t, J 8.6Hz), 8.94 (1H, s), 10.67 (lH, d, J = 3.7Hz).

HR-FAB + (m / z): 389.1627 (+ 1.3mmu).

<Example 18> 4- [Tris (hydroxymethyl) methyl] amino-2_ (2-naphthyl) quinazoline-8-carboxylic acid amide

Using the compound of Reference Example 28 (92.3 mg, 277 mol) and tris (hydroxymethyl) aminoaminomethane (168 mg, 1.39 mmol), 44.3 mg of the title compound as a colorless powder was obtained in the same manner as in Example 1. Obtained. Yield 38% ₍ iH-NMi DMSO-de, δ): 4.04 (6H, s), 4.85 (3H, brs), 7.08 (1H, s), 7.60-7.64 (3H, m), 7.95 (1H, d , J = 3.1Hz), 8.00- 8.01 (1H, m), 8.07-8.1l (2H, m), 8.34 (lH, d, J = 8.6Hz), 8.52 (1H, d, J = 8.6Hz), 8.58 (1H, d, J 2 7.3Hz), 8.81 (1H, s), 10,62 (1H, d, J = 3.1Hz).

HR-FAB + (m / z): 419.1734 (+ 1.5mmu).

<Example 19> 4- [2- (pyrrolidine-1-yl) ethyl] amino-2- (2_naphthyl) quinazoline-8-carboxylic acid amide

Using the compound of Reference Example 28 (100 mg, 300 mol) and 1_ (2-aminoethyl) pyrrolidine (188 / L, 1.50 mmol), the title compound as a pale yellow powder was obtained in the same manner as in Example 1. 70.3 mg was obtained. Yield 57%.

δ): 1.72 (4H, s), 2.61 (4Η, brs), 2.83 (2Η, t, J 二 6.7 ·), 3.88-3.93 (2Η, m), 7.60-7.64 (3Η, m), 7.96 (1Η, d, J2 3.1 Hz), 8.00-8.05 (2H, m), 8.09 (1H, d, J = 8.6 Hz), 8.43 (lH, dd, J2 8.6, 1.8 Hz), 8.47 (1H , d, J = 7.9 Hz), 8.58 (1H, d _; J = 7.3 Hz), 8.71 -8.74 (1H, m), 8.96 (lH, s), 10.64 (lH _; d, J = 3.1 Hz).

HR-FAB + (m / z): 412.2158 (+ 2.0mmu).

<Example 20> 4- (2-chloroethoxy) -2-phenylquinazoline-8-carbonic acid amide

To a suspension of the compound of Reference Example 4 (100 mg, 352 / mol) in Ν, Ν-dimethylformamide (5 mL) was added 1-bromo-2-cyclohexane (157 L, 1.89 mmol). And potassium carbonate (104 mg, 754 mol) were added, and the mixture was stirred at 80 ° C for 3 hours. The residue obtained by concentrating the reaction solution is subjected to chromatographic NH column chromatography [ethyl hexane monoacetate = 1: 1]. By purifying with, 42.2 mg of the title compound was obtained as a colorless powder. Yield 34%.

! H-NMRCDMSO-dg, δ): 4.18-4.20 (2H, m), 5.03-5.05 (2H, m), 7.61-7.64 (3H, m), 7.80 (1H, t, J-7.3Hz), 8 09 (1Η, m), 8.39 (lH, dd, J2 8.1, 1.5 Hz), 8.42-8.45 (2H, m), 8.69 (1H, dd, J2 7, 6, 1.5 Hz), 9.93-9.96 (lH, m).

HR-MS (m / z): 327.0769 (-0.5mmu). Test example> Inhibition experiment on PARP activity

PARP (Trevigen 4667-050-01) was diluted 35 times with a buffer consisting of 50 ol / L Tris-HCl (pH 7.8), lOOmmol / L KC1 and lmmol / L dithiothreitol for use in experiments. Was. '

117.6mmol / L DOO squirrel - HC1 (pH8.0), 11.8mmol / L MgCl 2, 5.9mmol / L di Chiosurei torr and 0.4 mmol / L NAD consisting buffer 76.5〃L,

[ ¹⁴ C] NAD (NEN Life Science Products, Inc. NEC743, 370 kBq / mL) 2.5 zL, activated DNA (Trevigen 4667-50-06) 1 06L, test compound or test compound solvent 10 L and 35-fold dilution The PARP solution lO ^ L was placed in a plastic test tube, mixed well, and heated to 25 ° C in a water bath. Ten minutes later, the reaction was stopped by the addition of 1 mL of ice-cold 20% trichloroacetic acid, and the test tube was left on ice overnight. The precipitate was collected on a glass fiber filter by suction filtration and washed five times with 5% trichloroacetic acid. The radioactivity on the filter was measured with a liquid scintillation counter. The enzyme activity in the absence of the test compound was defined as 100 ° /, and the concentration ( _IC5Q value) of the test compound that reduced this to 50% was calculated. [Table 10]

Table 10 shows the test results. From these results, it was confirmed that the novel 4-substituted quinazoline-8-carboxylic acid amide derivative and the salt thereof of the present invention have excellent PARP 'inhibitory activity. . Industrial applicability

As described above, the compound of the present invention is a novel 4-substituted quinazoline-8-potassium sulfonic acid amide derivative and a salt thereof, and has excellent PARP inhibitory activity. .

Compounds having PARP inhibitory activity include diseases caused by excessive PARP activation, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple occurrences) Prevention and / or treatment of cerebral sclerosis, arthritis, rheumatoid arthritis, etc., neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc. Useful as

Claims

General formula (1)

[Wherein, R ¹ is a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally substituted, an aralkyl group optionally substituted, or a general formula (2)

R ⁶ and R \ R ⁸ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ^1Q A lower alkyl group substituted with an N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R ⁹ R ^1Q Lower alkoxy group substituted with N group, lower alkoxy group substituted with carboxy group, lower alkoxy group substituted with lower alkoxyl group, aralkyloxy group optionally having substituent (s), nitro Group, amino group which may have a substituent, A phenyl group, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof)

ΕΛ R ⁴ is the same or different and represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by a halogen atom, or a lower alkyl group substituted by a hydroxy group;

^ Is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted 'cyclic alkyl group, an optionally substituted lower alkoxy group, a carboxy. Group, a lower alkoxycarbonyl group, NR ⁹ R ^1Q , C0NR ⁹ R ¹⁰ , a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof,

R ^1Q is the same or different and represents a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, Or a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof which may have a substituent bonded together at R ⁹ and R ¹⁰ ,

n represents 0 to 3], and a 4_-substituted quinazolin-8-carboxylic acid amide derivative and a pharmacologically acceptable addition salt thereof.

2. —General formula (1 -a)

[In the formula, ring Ar represents a phenyl group, a naphthyl group, a 5- or 6-membered complex ring and a condensed ring thereof,

R ⁸ is the same or different and is substituted by a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted by a halogen atom, a lower alkyl group substituted by a hydroxy group, or an R ¹ QN group A lower alkyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may be substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, an R ⁹ R ^{1 Q} N group A lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an optionally substituted aralkyloxy group, a nitro group, a substituent group An amino group which may have a substituent, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5- or 6-membered heterocyclic ring which may have a substituent, and Its fused ring Represents, represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted by a halogen atom, a Makoto換 which may be lower § alkoxy group Ha port Gen atoms,

X is an oxygen atom or NR ^{1 1} (wherein, R ¹¹ is a hydrogen atom, may be substituted with a halogen atom a lower alkyl group, an optionally substituted cyclic aralkyl kill group, which may have a substituent Represents a good aralkyl group)

R ⁴ is the same or different and is a hydrogen atom, a halogen atom, a halogen Represents a lower alkyl group optionally substituted with an atom, a lower alkyl group substituted with a hydroxy group,

Is a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR ⁹ R ^{1 Q} , C0NR ⁹ R ^10. may have a substituent I Fuweniru group, an optionally substituted naphthyl group, a heterocyclic ring and a condensed ring thereof 5- may have a substituent or 6-membered, R ⁹ And R ^1Q are the same or different and represent a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, or an aralkyl group optionally having a substituent. Or a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof, which may be substituted by R ⁹ and R ^{1 G} together, and ■ -n represents 0 to 3] A 4-substituted quinazolin-8-carboxylic acid amide derivative according to claim 1 represented by Pharmacologically acceptable addition salts.

3 · General formula (1-b)

R \ R ⁸ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, and a R ⁹ R ^1Q N group Substituted with lower alkyl group, optionally substituted cyclic alkyl group, substituted with halogen atom A lower alkoxy group substituted with a hydroxy group, a lower alkoxy group substituted with a R ⁹ R ^{1 Q} N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group. A lower alkoxy group substituted with an alkyl group, an optionally substituted aralkyloxy group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, Represents a naphthyl group which may have a substituent, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, and H ² is substituted with a hydrogen atom, a halogen atom, a hydroxyl group, or a halogen atom. Represents a lower alkyl group which may be substituted, a lower alkoxy group which may be substituted with a halogen atom,

X is an oxygen atom or NR ¹¹ (where R ¹¹ is a hydrogen atom or a halogen atom. An optionally substituted lower alkyl group, an optionally substituted cyclic alkyl group, or an optionally substituted Represents an aralkyl group),

Represents the same or different and represents a hydrogen atom, a parogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkyl group substituted by a hydroxy group,

R ^{1 Q} is the same or different and represents a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, Or a 5-membered or 6-membered heterocyclic ring which may be substituted with R ⁹ and R ^{1 G} together and a condensed ring thereof,

n represents 0 to 3], and the 4-substituted quinazoline-8-carboxylic acid amide derivative and a pharmaceutically acceptable addition salt thereof according to claim 1.

4. General formula (1-c:

R ⁶ and R \ R ⁸ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ^{1 Q} lower alkyl group substituted with N group, cyclic alkyl group optionally having substituent (s), lower alkoxy group optionally substituted with halogen atom, lower alkoxy group substituted with hydroxy group, R ⁹ A lower alkoxy group substituted with a R ^{1 G} N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, and an optionally substituted aralkyloxy group; A nitro group, an amino group optionally having a substituent, a phenyl group optionally having a substituent, a naphthyl group optionally having a substituent, a 5-membered group optionally having a substituent or 6-membered heterocycle and its Represents a fused ring, R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, may be substituted with a halogen atom a lower alkyl group, a lower § alkoxy group may be substituted with a C port Gen atoms,

X is an oxygen atom or NR ¹¹ (where R ¹¹ is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, or a substituent R ³ and R ⁴ are the same or different and are each substituted with a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, or a hydroxy group. Represents a lower alkyl group,

RR ^{1 Q} are the same or different and represent a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, or an aralkyl group optionally having a substituent. Or a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof which may have a substituent bonded together at R ⁹ and R ^{1 Q} ,

n represents 0 to 3], and the 4-substituted quinazoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof.

5. — General formula (l_ d)

[Wherein X ^A represents an oxygen atom or NH,

R ⁴ is the same or different and represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group,

R ⁶ and R ⁸ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ¹ DN A lower alkyl group substituted with a group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, E ⁹ R ^{1 ()} A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, or a lower alkoxycarbonyl group; Substituted lower alkoxy group, optionally substituted aralkyloxy group, nitro group, optionally substituted amino group, optionally substituted phenyl group, substituted group A substituted or unsubstituted 5- or 6-membered heterocyclic ring and a condensed ring thereof, wherein R ⁹ and R ^{1 Q} are the same or different and are substituted with a hydrogen atom or a halogen atom. Represents a lower alkyl group, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or has a substituent by bonding together at R ⁹ and R ^{1 Q.} Represents a 5- or 6-membered heterocyclic ring and a fused ring thereof,

n represents 0 to 3], and the 4-substituted quinazolin-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof.

6 General formula (1-e)

[Wherein, X ^a represents an oxygen atom or NH;

Represents the same or different and represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group,

R ⁶ , R ⁷ , and R ⁸ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R ⁹ R ^{l fl} Lower alkyl group substituted with N group, cyclic alkyl group which may have a substituent, substitution with halogen atom A lower alkoxy group substituted with a hydroxy group, a lower alkoxy group substituted with an R ⁹ R ^{1 Q} N group, a lower alkoxy group substituted with a carboxy group, or a lower alkoxycarbonyl group which may be substituted with a hydroxy group. A substituted lower alkoxy group, an optionally substituted aralkyl group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, Represents a naphthyl group which may be substituted, a 5- or 6-membered heterocyclic ring which may be substituted and a condensed ring thereof, wherein R ⁹ R ^1Q are the same or different and are substituted by a hydrogen atom or a halogen atom. A lower alkyl group, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or R ⁹ and R ^{1 Q} are bonded together to have a substituent. 5 or 6 members And a fused ring thereof,

n represents 0 to 3], and the 4-substituted quinazolin-8-carboxylic acid amide derivative and a pharmaceutically acceptable addition salt thereof according to claim 1.

7 · General formula (1-f)

[Wherein, X ^a represents an oxygen atom or NH;

RR \ R ⁸ are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, a R ⁹ R ^{1 Q} N group Substituted with a lower alkyl group, an optionally substituted cyclic alkyl group, substituted with a halogen atom A lower alkoxy group substituted with a hydroxy group, a lower alkoxy group substituted with a β1 ⁽⁾ group, a lower alkoxy group substituted with a carboxy group, or a lower alkoxycarbonyl group substituted with a hydroxy group Lower alkoxy group, aralkyl group which may have a substituent, nitro group, amino group which may have a substituent, phenyl group which may have a substituent, substituent Represents a naphthyl group which may have a substituent, a 5- or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof, wherein R ⁹ and R ^1G are the same or different and are substituted with a hydrogen atom or a halogen atom A lower alkyl group which may be substituted, a cyclic alkyl group which may have a substituent or an aralkyl group which may have a substituent, or a substituent formed by bonding together at R ⁹ and R ^1Q May have 5 members or 6 A 4-membered heterocyclic ring and a condensed ring thereof.] And a pharmaceutically acceptable addition salt thereof.

8. General formula (1-g)

[Wherein, X ^a represents an oxygen atom or NH;

R ³ \ R ^4a are the same or different and represent a hydrogen atom or a hydroxymethyl group,

R ⁶ is the same or different and is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, or a hydroxy group A lower alkyl group substituted with a group, a lower alkyl group substituted with a ^ R ¹ QN group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, hydroxy. A lower alkoxy group substituted with an R ⁹ R ¹ QN group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxy carbonyl group, or a substituent. An aralkyloxy group, a nitro group, an amino group which may have a substituent, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, Represents a 5- or 6-membered heterocyclic ring and a condensed ring thereof, wherein R ⁹ and R ^{1 Q} are the same or different and each represents a lower alkyl group or a substituent which may be substituted with a hydrogen atom or a halogen atom. Rings that may be present Alkyl group, or represents an optionally Ararukiru group which may have a substituent, or beta ⁹ and heterocycle and its condensed ring together bonded to 5-membered and may have a substituent or 6-membered between R ^{1 Q} The 4-substituted quinazoline-8-carboxylic acid amide derivative according to claim 1, which is represented by the following formula: and a pharmacologically acceptable addition salt thereof.

9. The compound represented by the general formula (1) is 2- (4-hydroxyphenyl) -4- [2- (pyridin-1-yl) ethyl] aminoquinazolin-8- Oleic acid amide, 2- (3-hydroxyphenyl) -4- [2- (piperidine-:!-Yl) ethyl] aminoquinazoline-8-carboxylic acid amide, 4- ( 1,3-dihydroxypropane-2-yl) amino-2- (4-hydroxyphenyl) quinazoline-8-aminocarboxylic acid amide, 4- (1,3-dihydroxypropane-2-y) 2. The compound according to claim 1, wherein the compound is l) amino-2- (3-hydroxyphenyl) quinazoline-8-carboxylic acid amide.

10. One or more of the 4-substituted quinazoline-8-carboxylic acid amide derivatives according to any one of claims 1 to 9 and pharmacologically acceptable addition salts thereof. A poly (ADP-ribose) synthase inhibitor comprising the above as an active ingredient.

11. The active ingredient comprises one or more of the 4-substituted quinazoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. A medicament characterized in that:

12. The active ingredient comprises one or more of the 4-substituted quinazolin-8-potassium amide derivatives and the pharmaceutically acceptable addition salts thereof according to any one of claims 1 to 9. A prophylactic and / or therapeutic agent for ischemic disease (cerebral infarction, myocardial infarction, acute renal failure, etc.).

13. The active ingredient contains at least one of the 4_-substituted quinazolin-8-potassium amide derivatives and the pharmaceutically acceptable addition salts thereof according to any one of claims 1 to 9. A prophylactic and / or therapeutic agent for inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis, rheumatoid arthritis, etc.).

14. The active ingredient comprises one or more of the 4-substituted quinazoline-8-potassium amide derivatives according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. A prophylactic and / or therapeutic agent for neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.).

15. The active ingredient comprises one or more of the 4-substituted quinazolin-8-potassium amide derivatives according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. Diabetes and its Prevention and / or treatment of complications.

16. The 4-substituted quinazoline according to any one of claims 1 to 9

-A therapeutic agent for head trauma, which comprises an 8-carboxylic acid amide derivative and one or more pharmacologically acceptable addition salts thereof as an active ingredient.