# Patent

## Title
4-(Substituted aryl)-5-hydroxyisoquinolinone derivative

## Abstract

The invention provides 4-substituted aryl-5-hydroxyisoquinolinone derivatives and their pharmacologically acceptable addition salts with excellent inhibitory effect on poly (ADP-ribose) synthetase.
4-Substituted aryl-5-hydroxyisoquinolinone derivatives, represented by a general formula (1)




and their pharmacologically acceptable addition salts.

## Background
TECHNICAL FIELD
The present invention relates to 4-substituted aryl-5-hydroxyisoquinolinone derivatives, their pharmacologically acceptable addition salts, and an inhibitor of poly (ADP-ribose) polymerase containing these as effective ingredients.
BACKGROUND TECHNOLOGIES
Poly (ADP-ribose) polymerase (hereinafter, abbreviated as “PARP”, another name: poly (ADP-ribose) synthetase) is a protein that regulates the function of nuclear DNA, and an enzyme that is activated by recognizing the damage of DNA to successively transfer poly (ADP-ribose) to acceptor proteins such as DNA-polymerase, utilizing NAD (nicotinamide adenine dinucleotide) being an essential constitutive element in cell as an enzyme substrate. It is considered therefore that the excessive activation of PARP may cause decreased capacity of energy production in cell based on the depletion of NAD essential for the electron transport system and result in cell death (C. Szabo, Free Radic. Biol. Med., 21, 855(1996)). Moreover, PARP has also been attracting attention as an apoptosis-relevant enzyme from the fact that caspase-3, one of the interleukin-1b conversion enzyme-like protease family, cleaves PARP as substrate.
Furthermore, it is reported from an experiment using PARP-knockout mice that the cultured nerve cells obtained from the brain of the knockout mice exhibit resistance to the injury due to nitric oxide and excitatory amino acids such as NMDA (N-methyl-D-aspartate) and that in this knockout mouse, the infarction volume due to cerebral ischemia is reduced by about 80% or more (M. J. L. Eliassonetal., Nature Med., 3, 1089(1997)). From these facts, it is considered that the PARP inhibitor would be effective for cerebral infarction and neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.). Besides, there is a report that describes that it would be effective for diabetes, diseases due to ischemia or ischemia-reperfusion such as cardiac infarction and acute renal failure, circulatory diseases such as septic shock, and inflammatory diseases such as chronic rheumatism and multiple sclerosis (C. Szabo et al., Trend pharmacol. Sci., 19, 287(1998)). It is also reported that the PARP inhibitor would be effective as an antiretrovirus agent including HIV (G. A. Cole et al., Biochem. Biophys. Res. Commun., 180, 504(1991)) and a sensitizer for anticancer therapeutics (C. Arundel-Suto, et al., Radiat. Res., 126, 367 (1991); S. Boulton et al., Br. J. Cancer, 72, 849(1995)).
Based on the facts as above, it is expected that a compound with the PARP inhibitory activity is effective as a preventive and/or therapeutic drug for the diseases originating from excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, cardiac infarction, acute renal failure, etc.), inflammatory diseases (inflammatory enteric disease, multiple cerebrosclerosis, arthritis, chronic rheumatism, etc.), nerve-degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.), diabetes, septic shock, cephalic injury and the like.
There, as compounds with the PARP inhibitory activity known currently, formulae (A) to (P) listed in Table 1










TABLE 1







Relevant Patent




application
Formula









US5756510








(A)



 












(B)



 












(C)



 



WO9704771








(D)



 



WO0121615








(E)



 












(F)



 



WO0029384








(G)



 



WO0185687








(H)



 



WO9959973








(I)



 



WO0042025








(J)



 



JP2001302669








(K)



 



WO0179206








(L)



 



WO0014054








(M)



 



WO0170674








(N)



 












(O)



 












(P)










are known, but all of them are not isoquinolinone derivatives and have different structure from that of the inventive compounds. Moreover, the PARP inhibitory activities disclosed cannot also be said to be sufficient.

Moreover, as compounds having the isoquinolinone structure with the PARP inhibitory activity, in Jpn. Kokai Tokkyo Koho JP 002,124,874, compounds represented by a formula (Q)




(wherein R denotes OR1, lower alkyl group, NR1R2, halogen atom, trifluoromethyl group, COOX2, CN or COX2 (wherein R1 denotes a hydrogen atom, lower alkyl group, benzyl group, lower alkanoyl group or (CH2)n(CHOH)y(CH2)mA (wherein n denotes an integer of 1 to 4, y denotes an integer of 0 or 1, m denotes an integer of 0 to 5, A denotes OR2, N(CH3)2,





R2 denotes a hydrogen atom, lower alkyl group, phenyl group or benzyl group, and X2 denotes a lower alkyl group, aryl group or aralkyl group), X denotes independently OR1, S-alkyl group with C1 ̃4 or NR4R5 (wherein R4 and R5 denote each independently a hydrogen atom, lower alkyl group, benzyl group, lower alkanoyl group or (CH2)n(CHOH)y(CH2)mQ (wherein Q denotes N(CH3)2 or N(CH2CH3)2)), Z denotes —CHR2CHR3—, —CR6═CR3—or —CR3═N— (wherein R3 denotes a hydrogen atom, alkyl group, phenyl group or benzyl group, and R6 denotes a hydrogen atom, lower alkyl group, phenyl group, benzyl group, chlorine atom, bromine atom or NR7R8 (wherein R7 and R8 denote each independently a hydrogen atom or lower alkyl group)), and, when Z is —CR3═N—, N in Z is bound to N on ring), are known, and, in WO9911624, compounds represented by a formula (R)





(wherein X denotes a double bond oxygen atom or hydroxy group, R7 denotes a hydrogen atom or lower alkyl group, Y denotes independently an atom needed for forming monocyclic, bicyclic or tricyclic hydrocarbon ring consisting of 5- to 6-membered ring or condensed ring being a heterocycle, and Z denotes —CHR2CHR3— (wherein R2 and R3 denote each independently a hydrogen atom, alkyl group, aryl group or aralkyl group), —R6C═CR3— (wherein R3 and R6 denote each independently a hydrogen atom, lower alkyl group, aryl group, aralkyl group, halogen atom, —NO2, —COOR7 or —NR7R8 (wherein R8 denotes a hydrogen atom or C1 ̃C9 alkyl group), and R6 and R3 may constitute independently a 5- to 6-membered aromatic ring), —R2C═N—, —CR2 (OH) —NR7 or —C(O)—NR7—), are known. However, in the specifications of these patent applications, isoquinolinones with hydroxy group at 5-position and aryl group at 4-position, which is a feature of the inventive compounds, are not disclosed, and the PARP inhibitory activity of compounds disclosed in these cannot also be said to be sufficient.

Moreover, compounds represented by a formula (S) described in Table 2








TABLE 2








(S)








 








Relevant



patent


application
R1, R2, R3, R4, R5 and R6





US5516941
R1, R2, R3, R4 and R5 denote each a hydrogen atom or



nitroso group, either of R2 and R4 denotes a nitroso



group, and R6 denotes a hydrogen atom.


WO9218123
R1, R2, R3, R4, R5 and R6 denote each independently a



hydrogen atom, hydroxy group, amino group, alkyl group,



alkoxy group, cycloalkyl group, halogen atom, phenyl



group or phenyl group which may be substituted with alkyl



group, alkoxy group, hydroxy group or halogen atom.


WO9426730
R1, R2, R3, R4 and R5 denote each independently a



hydrogen atom, hydroxy group, amino group, nitroso



group, nitro group, halogen atom, (C1–C6)alkyl group,



(C1–C6)alkoxy group, (C3–C7)cycloalkyl group or phenyl



group, and, among R1, R2, R3, R4 and R5, at least two



denote each a hydrogen atom, one denotes a nitro group,



and R6 denotes a hydrogen atom.


WO9622791
R1, R2, R3, R4 and R5 denote each independently a



hydrogen atom, hydroxy group, nitroso group, nitro group,



iodine atom, (C1–C6)alkyl group, (C1–C6)alkoxy group,



(C3–C7)cycloalkyl group or phenyl group, and, among



R1, R2, R3, R4 and R5, at least two denote each a



hydrogen atom, one denotes a nitroso group or nitro group,



and R6 denotes a hydrogen atom.


WO9851307
R1, R2, R3, R4 and R5 denote each independently a



hydrogen atom, hydroxy group, amino group, alkyl group,



alkoxy group, cycloalky group or phenyl group which may



be substituted with alkyl group, alkoxy group, hydroxy



group or halogen atom, and, among R1, R2, R3, R4 and



R5, at least one denotes an amino group, nitroso group or



nitro group.


WO9851308
R1, R2, R3, R4 and R5 denote each independently a



hydrogen atom, hydroxy group, amino group, alkyl group,



alkoxy group, cycloalkyl group or phenyl group which may



be substituted with alkyl group, alkoxy group, hydroxy



group or halogen atom, and, among R1, R2, R3, R4 and



R5, at least one denotes an amino group.









are known, but the isoquinolinone derivatives disclosed in the specifications of these patent applications are only 5-nitrosoisoquinolinones, and there are no descriptions with respect to the isoquinolinone derivatives with hydroxy group at 5-position and aryl group at 4-position, which is a feature of the inventive compounds.

Furthermore, as structure-resemblant compounds with the PARP inhibitory activity, in WO0044726, compounds represented by a formula (T)




[wherein R1 denotes a C1 ̃4 alkyl group substituted with hydroxy group or amino group, or -A1-A2-A3 (wherein A1 denotes —NR3C(O)—, —NR4C(S)—, —NR5SO2— or the like, A2 denotes a C1 ̃8 alkylene group, C2 ̃8 alkenylene group, Cyc1 or the like, and A3 denotes a hydrogen atom, —NR17R18, Cyc2, —OR19 or the like)] (a part was extracted for the explanation of substituents), and, in WO0067734, compounds represented by a formula (U)





[wherein R1 denotes a hydrogen atom, halogen atom, straight chain or branched C1-C6-alkyl group, hydroxy group, nitro group, CF3, CN, NR11R12, NH—CO—R13 or O—C1-C4-alkyl group (wherein R11 and R12 denote each independently a hydrogen atom or C1-C4-alkyl group, and R13 denotes a hydrogen atom, C1-C4-alkyl group, C1-C4-alkyl-phenyl group or phenyl group), A1 denotes a straight chain or branched C0—C6-alkylene group, A2 denotes NR2, NR2-C1-C6-alkyl-, O or the like, and A3 denotes a 5- to 6-membered monocyclic or bicyclic aromatic ring which may have substituents or hetero aromatic ring] (a part was extracted for the explanation of substituents), are known, but all of these are phthalazinone derivatives, hence the structure is different from that of the inventive compounds being isoquinolinone derivatives. In addition, no compounds with hydroxy group at a portion corresponding to 5-position of isoquinolinone, that is, at 5-position of phthalazinone are disclosed.

Moreover, as structure-resemblant compounds of 4-substituted aryl-5-hydroxyisoquinolinone derivatives, in U.S. Pat. No. 4,897,391, as compounds with antiallergy, anti-inflammation and inhibitory effect on abnormal proliferation, compounds represented by a formula (V)




[wherein R1 denotes a hydrogen atom, alkyl group, arylmethyl group or the like, R2 denotes a hydrogen atom, alkyl group, aryl group or the like, R3 denotes a hydrogen atom, alkyl group, arylmethyl group, aryl group or the like, R4 and R6 denote each independently a hydrogen atom, halogen atom, —OR8 (wherein R8 denotes independently a hydrogen atom or alkyl group) or the like, and, between R4 and R6, at least one denotes —SH, —OH, —NHR8 or the like, and R5 and R7 denote each independently a hydrogen atom, halogen atom, —CF3 or the like] (a part was extracted for the explanation of substituents), are known, but all of the compounds described in the specification of this patent application have the same substituents at 5-position and 7-position of isoquinolinone ring, and no compounds with hydroxy group only at 5-position as the inventive compounds do are disclosed. In addition, it is difficult to prepare the compounds with hydroxy group only at 5-position as the inventive compounds through the preparative process disclosed. Further, also with respect to aryl group at 4-position, only phenyl group is disclosed and phenyl group having substituents and hetero aryl group is not disclosed. Also, the PARP inhubitory activity is not described at all.

Moreover, compounds represented by a formula (W) described in Table 3








TABLE 3








(W)








 









Relevant




patent


application
Ring A, ring B and R
Effect





JP05132463
Ring A and ring B are benzene rings
ACAT



which may have substituents, and R
inhibitory



is NHCO—Y—R2.
effect


JP06321906
Ring A and ring B are benzene rings
Antagonism



which may have substituents, and R is
against







tachykinin


 


JP0776573
Ring A and ring B are benzene rings
Inhibition of



which may have substituents, and R is
calcium



(CH2)m—X—CO—Y—(CH2)n—Ar.
release,




protection of




cerebral




ischemic




disorder, anti-




cerebral edema,




protection of




nervous




disorder,




antagonism




against




tachykinin


JP10298164
Ring A and ring B are benzene rings
PDE V



which may have substituents, and R is
inhibitory



—COOR3 or —CON(R4)(R5).
effect


JP200072675
Ring A and ring B are benzene rings
PDE V



which may have substituents, and R is
inhibitory



—COOR3 or —CON(R4)(R5).
effect









are known, but compounds with substituent other than hydrogen atom at 2-position and hydroxy group at 5-position as well are not disclosed in all cases, hence the structure is different from that of the inventive compounds. Alao, the PARP inhibitory activity is not described at all.

The invention is to provide a novel compound with PARP inhibitory activity, the development of which is expected as a preventive and/or therapeutic drug for the diseases originating from excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, cardiac infarction, acute renal failure, etc.), inflammatory diseases (inflammatory enteric disease, multiple cerebrosclerosis, arthritis, chronic rheumatism, etc.), nerve-degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.), diabetes and its complications, cephalic injury and the like.
DISCLOSURE OF THE INVENTION
As a result of diligent studies aiming at the development of a novel compound with PARP inhibitory activity, the inventors have found that 4-substituted aryl-5-hydroxyisoquinolinone derivatives and their pharmacologically acceptable addition salts have excellent PARP inhibitory effect.
Namely, according to the invention, it has been found that 4-substituted aryl-5-hydroxyisoquinolinone derivatives represented by a general formula (1)




[wherein ring Ar denotes a phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring, R1 denotes a hydrogen atom or halogen atom, R2 denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, aralkyloxy group which may have substituents, nitro group, amino group which may have substituents, aralkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, A denotes a C1 ̃C4 alkylene or C2 ̃C4 alkenylene, R3 denotes a hydrogen atom, lower alkyl group which may be substituted with halogen atom, or general formula (2)

-Q1-R5  (2)

(wherein Q1 denotes a C1 ̃C4 alkylene, and R5 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, amino group which may have substituents, lower alkoxycarbonyl group or carboxy group), R4 denotes a lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, general formula (3)

-Q2-R6  (3)

(wherein Q2 denotes a C1 ̃C4 alkylene, and R6 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, lower alkoxycarbonyl group, carboxy group, cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring), or general formula (4)





(wherein R7 and R8 denote identically or differently hydrogen atoms, lower alkyl groups which may be substituted with halogen atom, aralkyl groups which may have substituents, or R7 and R8 are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring), or R3 and R4 are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring], and their pharmacologically acceptable addition salts, and 4-substituted aryl-5-hydroxyisoquinolinone derivatives represented by a general formula (1d)





[wherein R1 denotes a hydrogen atom or halogen atom, R2a denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, nitro group, or amino group which may have substituents, A1 denotes a C1 ̃C4 alkylene, R3a denotes a hydrogen atom or lower alkyl group which may be substituted with halogen atom, R4b denotes a lower alkyl group which may be substituted with halogen atom, or general formula (3a)

-Q2-R6a  (3a)

(wherein Q2 denotes a C1 ̃C4 alkylene, and R6a denotes a cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring), or R3a and R4b are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring], and their pharmacologically acceptable addition salts, have excellent PARP inhibitory effect, leading to the completion of the invention.

In the general formula (1) of the inventive compounds, preferably, compounds, ring Ar being phenyl group, R1 being hydrogen atom, and A being C1 ̃C4 alkylene, are mentioned. As these preferable compounds, for example, compounds listed in following Tables 4 through 12 can be mentioned, but the invention is not confined to these compounds or their pharmacologically acceptable addition salts.







TABLE 4













 











No.
R3
R4







 1
Me
Me



 2
Et
Et



 3
Pr
Pr



 4
Bu
Bu



 5
pentyl
pentyl



 6
Me
Pr



 7
Me
Bu



 8
Me
pentyl



 9
Me
hexyl



10
Me
Ph



11
Me
CH2Ph



12
Me
CH2Ph-4-OMe



13
Me
CH2Ph-3-OMe



14
Me
CH2Ph-4-OH



15
Me
CH2Ph-3-OH



16
Me
CH2Ph-4-NMe2



17
Me
CH2Ph-3-NMe2



18
Me
CH2Ph-4-NH2



19
Me
CH2Ph-3-NH2



20
Me
CH2Ph-4-NO2



21
Me
CH2Ph-3-NO2



22
Me
CH2Ph-4-Cl



23
Me
CH2Ph-3-Cl



24
Me
CH2Ph-4-F



25
Me
CH2Ph-3-F



26
Me
CH2Ph-4-CF3



27
Me
CH2Ph-3-CF3



28
Me
CH2Ph-4-Me



29
Me
CH2Ph-3-Me



30
Me
CH2Ph-4-CO2H



31
Me
CH2Ph-3-CO2H



32
Me
CH2Ph-3,4-(OMe)2



33
Me
CH2Ph-3,5-(OMe)2



34
Me
CH2Ph-3,4,5-(OMe)3



35
Me
CH2Ph-3,4-F2



36
Me
CH2Ph-3,4-Cl2



37
Et
CH2Ph



38
CH2CO2H
CH2Ph



39
CH2CH2NMe2
CH2Ph



40
CH2CH2OH
CH2Ph



41
Me
4-picolyl



42
Me
3-picolyl



43
Me
2-picolyl



44
Me
CH2-1-naphthyl



45
Me
CH2-2-naphthyl



46
CH2CH2OH
CH2CH2OH

















TABLE 5













 











No.
R3
R4







 1
Me
Me



 2
Et
Et



 3
Pr
Pr



 4
Bu
Bu



 5
pentyl
pentyl



 6
Me
Pr



 7
Me
Bu



 8
Me
pentyl



 9
Me
hexyl



10
Me
Ph



11
Me
CH2Ph



12
Me
CH2Ph-4-OMe



13
Me
CH2Ph-3-OMe



14
Me
CH2Ph-4-OH



15
Me
CH2Ph-3-OH



16
Me
CH2Ph-4-NMe2



17
Me
CH2Ph-3-NMe2



18
Me
CH2Ph-4-NH2



19
Me
CH2Ph-3-NH2



20
Me
CH2Ph-4-NO2



21
Me
CH2Ph-3-NO2



22
Me
CH2Ph-4-Cl



23
Me
CH2Ph-3-Cl



24
Me
CH2Ph-4-F



25
Me
CH2Ph-3-F



26
Me
CH2Ph-4-CF3



27
Me
CH2Ph-3-CF3



28
Me
CH2Ph-4-Me



29
Me
CH2Ph-3-Me



30
Me
CH2Ph-4-CO2H



31
Me
CH2Ph-3-CO2H



32
Me
CH2Ph-3,4-(OMe)2



33
Me
CH2Ph-3,5-(OMe)2



34
Me
CH2Ph-3,4,5-(OMe)3



35
Me
CH2Ph-3,4-F2



36
Me
CH2Ph-3,4-Cl2



37
Et
CH2Ph



38
CH2CO2H
CH2Ph



39
CH2CH2NMe2
CH2Ph



40
CH2CH2OH
CH2Ph



41
Me
4-picolyl



42
Me
3-picolyl



43
Me
2-picolyl



44
Me
CH2-1-naphthyl



45
Me
CH2-2-naphthyl



46
CH2CH2OH
CH2CH2OH

















TABLE 6













 












No.
position
Q2
R6







 1
4
CH2
cyclopentyl



 2
4
CH2
cyclohexyl



 3
4
CH2
cyclohexen-1-yl



 4
4
(CH2)2
cyclopentyl



 5
4
(CH2)2
cyclohexyl



 6
4
(CH2)2
cyclohexen-1-yl



 7
4
(CH2)2
Ph



 8
4
(CH2)2
Ph-4-OMe



 9
4
(CH2)2
Ph-4-OH



10
4
(CH2)2
Ph-4-NMe2



11
4
(CH2)2
Ph-4-NH2



12
4
(CH2)2
Ph-4-NO2



13
4
(CH2)2
Ph-4-Cl



14
4
(CH2)2
Ph-4-F



15
4
(CH2)2
Ph-4-CF3



16
4
(CH2)2
Ph-4-Me



17
4
(CH2)2
Ph-4-CO2H



18
4
(CH2)2
4-pyridyl



19
4
(CH2)2
3-pyridyl



20
4
(CH2)2
2-pyridyl



21
4
(CH2)2
1-naphthyl



22
4
(CH2)2
2-naphthyl



23
4
(CH2)3
cyclohexyl



24
4
(CH2)3
Ph



25
4
(CH2)3
Ph-4-OMe



26
4
(CH2)3
Ph-4-OH



27
4
(CH2)3
Ph-4-NMe2



28
4
(CH2)3
Ph-4-NH2



29
4
(CH2)3
Ph-4-NO2



30
4
(CH2)3
Ph-4-Cl



31
4
(CH2)3
Ph-4-CO2H



32
4
(CH2)3
4-pyridyl



33
4
(CH2)3
2-naphthyl



34
4
(CH2)4
cyclohexyl



35
4
(CH2)4
Ph



36
4
(CH2)4
Ph-4-OMe



37
4
(CH2)4
Ph-4-NMe2



38
4
(CH2)4
Ph-4-NH2



39
4
(CH2)4
Ph-4-NO2



40
4
(CH2)4
4-pyridyl



41
4
(CH2)4
2-naphthyl



42
3
CH2
cyclohexyl



43
3
CH2
Ph



44
3
CH2
Ph-4-OMe



45
3
CH2
Ph-4-NMe2



46
3
CH2
Ph-4-NH2



47
3
(CH2)2
cyclohexyl



48
3
(CH2)2
cyclohexen-1-yl



49
3
(CH2)2
Ph



50
3
(CH2)2
Ph-4-OMe



51
3
(CH2)2
Ph-4-NMe2



52
3
(CH2)2
Ph-4-NH2



53
3
(CH2)3
cyclohexyl



54
3
(CH2)3
Ph



55
3
(CH2)3
Ph-4-OMe



56
3
(CH2)3
Ph-4-NMe2



57
3
(CH2)3
Ph-4-NH2



58
3
(CH2)4
cyclohexyl



59
3
(CH2)4
Ph



60
3
(CH2)4
Ph-4-OMe



61
3
(CH2)4
Ph-4-NMe2



62
3
(CH2)4
Ph-4-NH2

















TABLE 7













 








No.
R4





 1
Me


 2
Et


 3
Pr


 4
Bu


 5
pentyl


 6
hexyl


 7
Ph


 8
CH2CO2H


 9
CH2CH2CO2H


10
CH2CH2OH


11
CH2CH2NEt2


12
CH2-cyclohexyl


13
CH2Ph


14
CH2Ph-4-OMe


15
CH2Ph-3-OMe


16
CH2Ph-4-OH


17
CH2Ph-3-OH


18
CH2Ph-4-NMe2


19
CH2Ph-3-NMe2


20
CH2Ph-4-NH2


21
CH2Ph-3-NH2


22
CH2Ph-4-NO2


23
CH2Ph-3-NO2


24
CH2Ph-4-Cl


25
CH2Ph-3-Cl


26
CH2Ph-4-F


27
CH2Ph-3-F


28
CH2Ph-4-CF3


29
CH2Ph-3-CF3


30
CH2Ph-4-Me


31
CH2Ph-3-Me


32
CH2Ph-4-CO2H


33
CH2Ph-3-CO2H


34
CH2Ph-3,4-(OMe)2


35
CH2Ph-3,5-(OMe)2


36
CH2Ph-3,4,5-(OMe)3


37
CH2Ph-3,4-F2


38
CH2Ph-3,4-Cl2


39
4-picolyl


40
3-picolyl


41
2-picolyl


42
CH2-1-naphthyl


43
CH2-2-naphthyl


44
CH2CH2-cyclohexyl


45
CH2CH2-cyclohexen-1-yl


46
CH2CH2Ph


47
CH2CH2Ph-4-OMe


48
CH2CH2Ph-4-OH


49
CH2CH2CH2Ph


50
CH2CH2CH2CH2Ph
















TABLE 8













 








No.
R4





 1
Me


 2
Et


 3
Pr


 4
Bu


 5
pentyl


 6
hexyl


 7
Ph


 8
CH2CO2H


 9
CH2CH2CO2H


10
CH2CH2OH


11
CH2CH2NEt2


12
CH2-cyclohexyl


13
CH2Ph


14
CH2Ph-4-OMe


15
CH2Ph-3-OMe


16
CH2Ph-4-OH


17
CH2Ph-3-OH


18
CH2Ph-4-NMe2


19
CH2Ph-3-NMe2


20
CH2Ph-4-NH2


21
CH2Ph-3-NH2


22
CH2Ph-4-NO2


23
CH2Ph-3-NO2


24
CH2Ph-4-Cl


25
CH2Ph-3-Cl


26
CH2Ph-4-F


27
CH2Ph-3-F


28
CH2Ph-4-CF3


29
CH2Ph-3-CF3


30
CH2Ph-4-Me


31
CH2Ph-3-Me


32
CH2Ph-4-CO2H


33
CH2Ph-3-CO2H


34
CH2Ph-3,4-(OMe)2


35
CH2Ph-3,5-(OMe)2


36
CH2Ph-3,4,5-(OMe)3


37
CH2-3,4-F2


38
CH2Ph-3,4-Cl2


39
4-picolyl


40
3-picolyl


41
2-picolyl


42
CH2-1-naphthyl


43
CH2-2-naphthyl


44
CH2CH2-cyclohexyl


45
CH2CH2-cyclohexen-1-yl


46
CH2CH2Ph


47
CH2CH2Ph-4-OMe


48
CH2CH2Ph-4-OH


49
CH2CH2CH2Ph


50
CH2CH2CH2CH2Ph
















TABLE 9













 












No.
position
A
NR3R4







 1
4
(CH2)2
NMe2



 2
4
(CH2)2
NPr2



 3
4
(CH2)2
N(Me)Pr



 4
4
(CH2)2
N(Me)pentyl



 5
4
(CH2)2
N(Me)(CH2)2NMe2



 6
4
(CH2)2
N(Me)CH2-cyclohexyl



 7
4
(CH2)2
N(Me)CH2Ph



 8
4
(CH2)2
N(Me)CH2Ph-4-OMe



 9
4
(CH2)2
N(Me)CH2Ph-3-OMe



10
4
(CH2)2
N(Me)CH2Ph-4-OH



11
4
(CH2)2
N(Me)CH2Ph-3-OH



12
4
(CH2)2
N(Me)CH2Ph-4-NH2



13
4
(CH2)2
N(Me)CH2Ph-4-NMe2



14
4
(CH2)2
N(Me)(CH2)2-cyclohexenyl



15
4
(CH2)2
N(Me)(CH2)2Ph



16
4
(CH2)2
N(Me)(CH2)2Ph-4-OMe



17
4
(CH2)2
N(Me)(CH2)2Ph-4-OH



18
4
(CH2)2
N(Me)(CH2)2Ph-4-NH2



19
4
(CH2)2
N(Me)(CH2)2Ph-4-NMe2



20
4
(CH2)3
NMe2



21
4
(CH2)3
NPr2



22
4
(CH2)3
N(Me)(CH2)2NMe2



23
4
(CH2)3
N(Me)CH2Ph



24
4
(CH2)3
N(Me)CH2Ph-4-OMe



25
4
(CH2)3
N(Me)CH2Ph-4-NMe2



26
4
(CH2)3
N(Me)(CH2)2Ph



27
4
(CH2)3
N(Me)(CH2)2Ph-4-OMe



28
3
(CH2)2
NMe2



29
3
(CH2)2
NPr2



30
3
(CH2)2
N(Me)Pr



31
3
(CH2)2
N(Me)CH2-cyclohexyl



32
3
(CH2)2
N(Me)CH2Ph



33
3
(CH2)2
N(Me)CH2Ph-4-OMe



34
3
(CH2)2
N(Me)(CH2)2-cyclohexenyl



35
3
(CH2)2
N(Me)(CH2)2Ph



36
3
(CH2)3
NMe2



37
3
(CH2)3
N(Me)CH2Ph



38
3
(CH2)3
N(Me)(CH2)2Ph

















TABLE 10













 









No.
A
NR3R4





 1
CH2






 


 2
CH2






 


 3
CH2






 


 4
CH2






 


 5
CH2






 


 6
CH2






 


 7
CH2






 


 8
CH2






 


 9
CH2






 


10
CH2






 


11
CH2






 


12
CH2






 


13
CH2






 


14
CH2






 


15
CH2






 


16
CH2






 


17
(CH2)2






 


18
(CH2)2






 


19
(CH2)2






 


20
(CH2)2






 


21
(CH2)2






 


22
(CH2)3






 


23
(CH2)3






 


24
(CH2)3






 


25
(CH2)3






 


26
(CH2)3




















TABLE 11













 









No.
A
NR3R4





 1
CH2






 


 2
CH2






 


 3
CH2






 


 4
CH2






 


 5
CH2






 


 6
CH2






 


 7
CH2






 


 8
CH2






 


 9
CH2






 


10
CH2






 


11
CH2






 


12
CH2






 


13
CH2






 


14
CH2






 


15
CH2






 


16
CH2






 


17
(CH2)2






 


18
(CH2)2






 


19
(CH2)2






 


20
(CH2)2






 


21
(CH2)2






 


22
(CH2)3






 


23
(CH2)3






 


24
(CH2)3






 


25
(CH2)3






 


26
(CH2)3




















TABLE 12













 









No.
R2
A—NR3R4





 1
4-OMe
3-(CH2NMe2)


 2
4-OMe
3-(CH2NPr2)


 3
4-OMe
3-(CH2N(Me)Pr)


 4
4-OMe
3-(CH2N(Me)CH2-cyclohexyl)


 5
4-OMe
3-(CH2N(Me)CH2Ph)


 6
4-OMe
3-(CH2N(Me)(CH2)2Ph)


 7
4-OH
3-(CH2NMe2)


 8
4-OH
3-(CH2NPr2)


 9
4-OH
3-(CH2N(Me)Pr)


10
4-OH
3-(CH2N(Me)CH2-cyclohexyl)


11
4-OH
3-(CH2N(Me)CH2Ph)


12
4-OH
3-(CH2N(Me)(CH2)2Ph)


13
4-F
3-(CH2NMe2)


14
4-F
3-(CH2NPr2)


15
4-F
3-(CH2N(Me)Pr)


16
4-F
3-(CH2N(Me)CH2-cyclohexyl)


17
4-F
3-(CH2N(Me)CH2Ph)


18
4-F
3-(CH2N(Me)(CH2)2Ph)


19
3-NO2
4-((CH2)2NMe2)


20
3-NO2
4-((CH2)2NPr2)


21
3-NO2
4-((CH2)2N(Me)Pr)


22
3-NO2
4-((CH2)2N(Me)CH2-cyclohexyl)


23
3-NO2
4-((CH2)2N(Me)CH2Ph)


24
3-NO2
4-((CH2)2N(Me)(CH2)2Ph)


25
3-NH2
4-((CH2)2NMe2)


26
3-NH2
4-((CH2)2NPr2)


27
3-NH2
4-((CH2)2N(Me)Pr)


28
3-NH2
4-((CH2)2N(Me)CH2-cyclohexyl)


29
3-NH2
4-((CH2)2N(Me)CH2Ph)


30
3-NH2
4-((CH2)2N(Me)(CH2)2Ph)









In Tables 4 through 12 aforementioned, as more preferable compounds, exemplified nos. 1 to 12, 14, 16, 18, 37 to 39, 42 and 44 described in Table 4, exemplified nos. 1 to 3 described in Table 5, exemplified nos. 2, 6 to 9, and 24 described in Table 6, exemplified nos. 2, 3, 8, 9, 11 to 18, 20, 22, 24, 32, 34, 36, 39, 40 and 48 described in Table 7, exemplified nos. 1 to 17, 20 to 22, 24, 25 and 27 to 29 described in Table 9, exemplified nos. 1 to 4, 6, 7, 9, 10, 14 to 16, 19 to 21 and 24 described in Table 10, exemplified nos. 1 and 2 described in Table 11, and exemplified nos. 2, 8, 19 and 25 described in Table 12 can be mentioned.
In the description of the general formula (1) of the invention, for “halogen atoms” in “lower alkyl group which may be substituted with halogen atom”, “cycloalkyl group which may be substituted with halogen atom” and “lower alkoxy group which may be substituted with halogen atom”, fluorine, chlorine, bromine and iodine are mentioned, for “lower alkyl groups”, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl and iso-propyl are mentioned, for “cycloalkyl groups”, ones with carbon atoms of 3 to 7 such as cyclopropyl, cyclopentyl and cyclohexyl are mentioned, and, for “lower alkoxy groups”, straight chain or branched ones with carbon atoms of 1 to 5 such as methoxy, ethoxy and propoxy are mentioned. Moreover, in the text, for substituents in “cycloalkyl group which may have substituents”, “cycloalkenyl group which may have substituents”, “aralkyl group which may have substituents”, “aralkyloxy group which may have substituents”, “phenyl group which may have substituents”, “naphthyl group which may have substituents”, and “5- or 6-membered heterocycle which may have substituents and its condensed ring”, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, lower alkylthio group, lower alkoxycarbonyl group, nitro group, amino group which may have substituents, cyano group, carboxy group, aldehyde group, lower alkyl group substituted with hydroxy group, lower alkyl group substituted with carboxy group, lower alkyl group substituted with amino group, which may be substituted with lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, lower alkyl group substituted with 5- or 6-membered cycloamino group which may have substituents, lower alkoxy group substituted with hydroxy group, lower alkoxy group substituted with carboxy group, lower alkoxy group substituted with amino group, which may be substituted with lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, lower alkoxy group substituted with 5- or 6-membered cycloamino group which may have substituents, aralkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, 5- or 6-membered heterocycle group which may have substituents, etc. are mentioned, for “lower alkoxycarbonyl groups”, straight chain or branched ones with carbon atoms of 1 to 6 such as methoxycarbonyl and ethoxycarbonyl, for “amino groups which may have substituents”, amino groups, which may be substituted with acyl group, lower alkylsulfonyl group which may be substituted with halogen atom or arylsulfonyl group, for example, with acetyl, methanesulfonyl, phenylsulfonyl or the like, or which may be substituted with lower alkyl group which may be substituted with halogen atom, phenyl group which may have substituents and aralkyl group which may have substituents, are mentioned, for “5- or 6-membered cycloamino groups” in “5- or 6-membered cycloamino group which may have substituents”, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, etc. are mentioned, for “cycloalkenyl groups” in “cycloalkenyl group which may have substituents”, ones with carbon atoms of 5 to 7 such as cyclopentenyl and cyclohexenyl are mentioned, and, for “aralkyl groups” in “aralkyl group which may have substituents” and “aralkyloxy group which may have substituents”, benzyl, diphenylmethyl, phenethyl, phenylpropyl, etc. are mentioned. The substituents referred to so here indicate “substituents” as explained above. Moreover, “heterocycles” in “5- or 6-membered heterocycle and its condensed ring” are saturated or unsaturated monocyclic or polycyclic heterocycle groups which may have substituents and which can contain one or more nitrogen, oxygen or sulfur atoms, and, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, tetrahydropyridyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, etc. are mentioned, and “its condensed ring” indicates benzene-condensed rings of said “heterocycles” (for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc. are mentioned), or condensed rings consisting of two rings selected arbitrarily from said “heterocycles” (for example, imidazopyridine, pyrazolopyridine, imidazopyrimidine, etc. are mentioned).
The compounds represented by the general formula (1) of the invention can be converted to pharmacologically acceptable salts, if need be. For the pharmacologically acceptable salts, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, salts with organic acids such as acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, methanesulfonic acid and tosylic acid, and salts with bases such as sodium salt, potassium salt, calcium salt and ammonium salt are mentioned.
Moreover, the compounds represented by the general formula (1) and their pharmacologically acceptable salts of the invention may be their intramolecular salts, their anhydrides, hydrates or solvates.
The compounds with PARP inhibitory activity of the invention represented by the general formula (1) can be prepared through processes shown below, or in combination of publicly known processes.




In said formulae, ring Ar, A, R1, R2, R3 and R4 denote the same meanings as described above, R9 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, R10 denotes a lower alkyl group which may be substituted with halogen atom, aralkyl group which may have substituents or acyl group, and X denotes a halogen atom.
The conversion from compounds represented by the general formula (5) to compounds represented by the general formula (6) (process I-A) can be performed by using compounds represented by a general formula (8)




(wherein ring Ar, A, R2, R3 and R4 denote the same meanings as described above, R11 and R12 denote identically or differently hydroxy groups, lower alkyl groups or lower alkoxy groups, or R11 and R12 may be bound together to form a 5- or 6-membered cyclic pinacol ester which may be substituted with lower alkyl group), and by reacting for 1 to 48 hours at 20 to 160° C. in a suitable solvent, for example, tetrahydrofuran, N,N-dimethylformamide, benzene, toluene, mixed solvent thereof or the like in the presence of a suitable catalyst, for example, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, (1,1′-bis (diphenylphosphino)ferrocene)palladium(II) chloride or the like, after adding a suitable base, for example, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine or the like.

Compounds, R10 being acyl group, among compounds represented by the general formula (6) can be converted to compounds represented by the general formula (7) (process I-B). Namely, the conversion can be performed by using a suitable base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, ammonia or the like, and by reacting for 0.5 to 24 hours at 0 to 100° C. in a suitable solvent, for example, water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, mixed solvent thereof or the like.
The conversion from compounds represented by the general formula (7) to compounds represented by the general formula (1) (process I-C) can be performed by using a suitable acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or the like, or a suitable dealkylating agent, for example, trimethylsilyl iodide, boron tribromide or the like, and by reacting for 1 to 72 hours at 20 to 120° C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol, dichloromethane, mixed solvent thereof or the like.
Moreover, compounds, R10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (6) can be converted directly to compounds represented by the general formula (1) (process I-D). Namely, the conversion can be performed by using a suitable acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or the like, or a suitable dealkylating agent, for example, trimethylsilyl iodide, boron tribromide or the like, and by reacting for 1 to 72 hours at 20 to 120° C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol, dichloromethane, mixed solvent thereof or the like. Also, it is possible to react these suitable acid and suitable dealkylating agent over twice stepwise.




In said formulae, ring Ar, A, R1, R2, R3, R4, R9, R10 and X denote the same meanings as described above, Aa denotes a single bond, C1 ̃C3 alkylene or C2 ̃C3 alkenylene, and R10a denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents. The conversion from compounds represented by the general formula (5) to compounds represented by the general formula (9) (process II-A) can be performed through the process similar to process I-A, using compounds represented by a general formula (11)




(wherein ring Ar, Aa, R2, R11 and R12 denote the same meanings as described above).

Compounds, R10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (9) can be converted to compounds represented by the general formula (6a) (process II-B). Namely, the conversion can be performed by using compounds represented by a general formula (12)




(wherein R3 and R4 denote the same meanings as described above), and by reacting for 1 to 24 hours at 0 to 60° C. in a suitable solvent, for example, methanol, ethanol, dichloromethane, chloroform, mixed solvent thereof or the like, and, if need be, in the presence of a suitable acid, for example, hydrochloric acid, hydrobromic acid, acetic acid or the like, or a suitable Lewis acid, for example, aluminum chloride, zinc chloride or the like, after adding a suitable reducing agent, for example, lithium borohydride, sodium borohydride, sodium cyanoborohydride or the like.

The conversion from compounds represented by the general formula (6a) to compounds represented by the general formula (1) (process II-C) can be performed through the process similar to process I-D.
Moreover, compounds, R10 being acyl group, among compounds represented by the general formula (9) can be converted to compounds represented by the general formula (10) (process II-D) through the process similar to process I-B.
The conversion from compounds represented by the general formula (10) to compounds represented by the general formula (7) (process II-E) can be performed through the process similar to process II-B, using compounds represented by the general formula (12)




(wherein R3 and R4 denote the same meanings as described above).

The conversion from compounds represented by the general formula (7) to compounds represented by the general formula (1) (process II-F) can be performed through the process similar to process I-C.




In said formulae, ring Ar, A, Aa, R1, R2, R3, R4, R9, R10 and X denote the same meanings as described above.
The conversion from compounds represented by the general formula (5) to compounds represented by the general formula (13) (process III-A) can be performed through the process similar to process I-A, using compounds represented by a general formula (15)




(wherein ring Ar, A, R2, R11 and R12 denote the same meanings as described above).

The conversion from compounds represented by the general formula (13) to compounds represented by the general formula (6) (process III-B) can be performed by using a suitable halogenating agent, for example, thionyl chloride, phosphorus oxychloride, thionyl bromide or the like, and by reacting for 0.5 to 6 hours at −20 to 80° C. without solvent or in a suitable solvent, for example, dichloromethane, chloroform, tetrahydrofuran, mixed solvent thereof or the like, or by using a suitable sulfonylating agent, for example, methanesulfonyl chloride, trifluoromethanesulfonic anhydride or the like, and by reacting for 0.5 to 3 hours at −20 to 60° C. in a suitable solvent, for example, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like, and then by using compounds represented by the general formula (12)




(wherein R3 and R4 denote the same meanings as described above), and by reacting for 1 to 12 hours at 0 to 120° C. in a suitable solvent, for example, methanol, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like, and, if need be, in the presence of a suitable iodide, for example, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like, or a suitable base, for example, triethylamine, pyridine, N,N-diisopropylethylamine or the like.

Compounds, R10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (6) can be converted to compounds represented by the general formula (1) (process III-C) through the process similar to process I-D.
Moreover, compounds, R10 being acyl group, among compounds represented by the general formula (6) can be converted to compounds represented by the general formula (7) (process III-D) through the process similar to process I-B.
Compounds, R10 being acyl group, among compounds represented by the general formula (13) can be converted to compounds represented by the general formula (14) (process III-E) through the process similar to process I-B.
Moreover, compounds represented by the general formula (14) can also be converted from compounds represented by the general formula (10) (process III-F). Namely, the conversion can be performed by using a suitable reducing agent, for example, lithium borohydride, sodium borohydride, sodium cyanoborohydride or the like, and by reacting for 0.5 to 12 hours at 0 to 80° C. in a suitable solvent, for example, methanol, ethanol, isopropanol, tetrahydrofuran, mixed solvent thereof or the like.
The conversion from compounds represented by the general formula (14) to compounds represented by the general formula (7) (process III-G) can be performed by using a suitable halogenating agent, for example, thionyl chloride, phosphorus oxychloride, thionyl bromide or the like, and by reacting for 0.5 to 6 hours at −20 to 80° C. without solvent or in a suitable solvent, for example, dichloromethane, chloroform, tetrahydrofuran, mixed solvent thereof or the like, and then by using compounds represented by the general formula (12)




(wherein R3 and R4 denote the same meanings as described above), and by reacting for 1 to 12 hours at 0 to 120° C. in a suitable solvent, for example, methanol, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like, and, if need be, in the presence of a suitable iodide, for example, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like.

The conversion from compounds represented by the general formula (7) to compounds represented by the general formula (1) (process III-H) can be performed through the process similar to process I-C.
In the Preparative process III aforementioned, compounds represented by the general formula (13a), R10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (13) and compounds represented by the general formula (14) can also be synthesized by a separate synthetic process (Preparative process IV) shown below.




In said formulae, ring Ar, A, Aa, R1, R2, R9, R10, R10a and X denote the same meanings as described above, Ab denotes a single bond or methylene group, and R13 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents.
The conversion from compounds represented by the general formula (5) to compounds represented by the general formula (16) (process IV-A) can be performed through the process similar to process I-A, using compounds represented by a general formula (18)




(wherein ring Ar, Aa, R2, R11, R12 and R13 denote the same meanings as described above).

Moreover, compounds, Aa being C2 ̃C3 alkenylene, among compounds represented by the general formula (16) can also be converted from compounds represented by the general formula (10a) (process IV-B). Namely, the conversion can be performed by using compounds represented by a general formula (19)




(wherein R13 denotes the same meaning as described above, and R14 denotes a lower alkyl group), and by reacting for 1 to 6 hours at −78 to 80° C. in a suitable solvent, for example, methanol, benzene, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like, in the presence of a suitable base, for example, sodium hydride, potassium carbonate, triethylamine, pyridine or the like.

Compounds, A10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (16) can be converted to compounds represented by the general formula (13a) through the process IV-C. Namely, the conversion can be performed by using a suitable reducing agent, for example, lithium borohydride, lithium aluminum hydride or the like, and by reacting for 0.5 to 6 hours at −20 to 60° C. in a suitable solvent, for example, diethyl ether, tetrahydrofuran or the like.
Moreover, compounds, R10 being acyl group, among compounds represented by the general formula (16) can be converted to compounds represented by the general formula (17) through the process IV-D. Namely, the conversion can be performed by using a suitable sodium lower alkoxide, for example, sodium methoxide, sodium ethoxide or the like, and by reacting for 0.5 to 5 hours at −20 to 20° C. in a suitable solvent, for example, methanol, ethanol or the like.
The conversion from compounds represented by the general formula (17) to compounds represented by the general formula (14) (process IV-E) can be performed through the process similar to process IV-C.
Moreover, compounds represented by a general formula (1h) and general formula (1i), A being ethylene or ethenylene and R2 being nitro group which is substituted at ortho position of group -A-NR3R4, among compounds represented by the general formula (1) can also be synthesized, using processes shown below (Preparative process V).




In said formulae, ring Ar, R1, R2, R3, R4, R9, R10, R10a and X denote the same meanings as described above.
The conversion from compounds represented by the general formula (5) to compounds represented by the general formula (20) (process V-A) can be performed through the process similar to process I-A, using compounds represented by a general formula (25)




(wherein ring Ar, R11 and R12 denote the same meanings as described above, and nitro group is substituted at ortho position of methyl group).

Compounds, R10 being lower alkyl group which may be substituted with halogen atom or aralkyl group which may have substituents, among compounds represented by the general formula (20) can be converted to compounds represented by the general formula (21) through process V-B. Namely, the conversion can be performed by using compounds represented by a general formula (26)




(wherein R15 denotes a lower alkyl group), and by reacting for 1 to 24 hours at 100 to 180° C. in a suitable solvent, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone or the like, after adding compounds represented by the general formula (12)





(wherein R3 and R4 denote the same meanings as described above), if need be.

The conversion from compounds represented by the general formula (21) to compounds represented by the general formula (1h) (process V-C) can be performed through the process similar to process I-D.
Compounds, R10 being acyl group, among compounds represented by the general formula (20) can be converted to compounds represented by the general formula (22) through the process similar to process I-B.
The conversion from compounds represented by the general formula (22) to compounds represented by the general formula (23) (process V-E) can be performed through the process similar to process V-B, using N,N-dimethylformamide as a solvent.
Moreover, compounds represented by the general formula (23) can also be converted directly from compounds, R10 being acyl group, among compounds represented by the general formula (20), (process V-F) through the process similar to process V-E.
The conversion from compounds represented by the general formula (23) to compounds represented by the general formula (1h) (process V-G) can be performed through the process similar to process I-D.
Moreover, compounds represented by the general formula (23) can be converted to compounds represented by the general formula (24) through process V-H. Namely, the conversion can be performed by using a suitable reducing agent, for example, sodium borohydride, lithium borohydride or the like, and by reacting for 0.5 to 6 hours at 20 to 80° C. in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran, mixed solvent thereof or the like.
The conversion from compounds represented by the general formula (24) to compounds represented by the general formula (1i) (process V-I) can be performed through the process similar to process I-D.
Moreover, compounds represented by the general formula (1i) can be converted from compounds represented by the general formula (1h) (process V-J) through the process similar to process V-H.
Furthermore, compounds represented by the general formula (1i) can also be converted to compounds, A being ethylene and R2 being amino group which is substituted at ortho position of group -A-NR3R4, among compounds represented by the general formula (1) (process V-K). Namely, the conversion can be performed by using a suitable catalyst, for example, palladium on carbon, platinum on carbon or the like, and by submitting to the hydrogenating reaction for 1 to 12 hours at 20 to 80° C. under ambient pressure or, if need be, under pressure in a suitable solvent, for example, methanol, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like.
In the Preparative processes I through V, compounds represented by the general formula (5), being starting compounds, can be synthesized through processes shown below (Preparative process VI).




In said formulae, R1, R9, R10 and X denote the same meanings as described above.
The conversion from compounds represented by the general formula (27) to compounds represented by the general formula (28) (process VI-A) can be performed, using compounds represented by a general formula (32)

R10—X1  (32)

(wherein R10 denotes the same meaning as described above, and X1 denotes a halogen atom), and by reacting for 2 to 48 hours at 0 to 140° C. in a suitable solvent, for example, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like in the presence of a suitable base, for example, sodium hydride, potassium carbonate, triethylamine or the like.

The conversion from compounds represented by the general formula (28) to compounds represented by the general formula (29) (process VI-B) can be performed by using a suitable peroxide, for example, 3-chloroperbenzoic acid, magnesium monoperoxyphthalate or the like, and by reacting for 4 to 72 hours at 0 to 80° C. in a suitable solvent, for example, benzene, dichloromethane, ethyl acetate, methanol or the like.
The conversion from compounds represented by the general formula (29) to compounds represented by the general formula (30) (process VI-C) can be performed by using a suitable acid anhydride, for example, acetic anhydride, trifluoroacetic anhydride or the like, and by reacting for 1 to 24 hours at 40 to 120° C. without solvent or in a suitable solvent, for example, acetic acid, toluene, 1,4-dioxane, mixed solvent thereof or the like, followed by using water and by reacting for 2 to 48 hours at 60 to 120° C. without solvent or in a suitable solvent, for example, acetic acid, methanol, ethanol, acetonitrile, mixed solvent thereof or the like.
The conversion from compounds represented by the general formula (30) to compounds represented by the general formula (31) (process VI-D) can be performed by using compounds represented by a general formula (33)

R9—X2  (33)

(wherein R9 denotes the same meaning as described above, and X2 denotes a halogen atom), and by reacting for 1 to 24 hours at 60 to 110° C. in a suitable solvent, for example, benzene, toluene, ethyl acetate, mixed solvent thereof or the like in the presence of a suitable silver salt, for example, silver oxide, silver trifluoroacetate or the like, or by using a suitable halogenating agent, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride or the like, and by reacting for 0.5 to 12 hours at 0 to 100° C. without solvent or in a suitable solvent, for example, dichloromethane, chloroform, tetrahydrofuran or the like, and then by using compounds represented by a general formula (34)

R9O-M  (34)

(wherein R9 denotes the same meaning as described above, and M denotes sodium or potassium), and by reacting for 0.5 to 12 hours at 0 to 100° C. in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like.

The conversion from compounds represented by the general formula (31) to compounds represented by the general formula (5) (process VI-E) can be performed by using a suitable halogenating agent, for example, bromine, N-bromosuccinimide, N-chlorosuccinimide or the like, and by reacting for 2 to 72 hours at −20 to 120° C. in a suitable solvent, for example, acetic acid, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, mixed solvent thereof or the like.
Moreover, in the Preparative processes I through V, compounds represented by the general formulae (8), (11), (15), (18) and (25) can be synthesized easily through publicly known processes, for example, through the processes described in Tetrahedron Lett., 38, 3447(1997), J. Org. Chem., 60, 7508 (1995), Chem. Rev., 95, 2457 (1995), etc.
In compounds represented by the general formula (1) or compounds represented by the general formula (6) and general formula (7), being synthetic intermediates in the Preparative processes I through III, the conversion of R2 to other substituent in the case of need can also be performed through publicly known processes. For example, compounds, R2 being lower alkoxy group which may be substituted with halogen atom, among compounds represented by the general formula (1) can be converted to compounds, R2 being hydroxy group, among compounds represented by the general formula (1), by using a suitable acid, for example, hydrochloric acid, hydrobromic acid or the like, and by reacting for 1 to 24 hours at 60 to 110° C. without solvent or in a suitable solvent, for example, water, acetic acid, mixed solvent thereof or the like.
Moreover, compounds, R2 being nitro group, among compounds represented by the general formula (1) can be converted to compounds, R2 being amino group, among compounds represented by the general formula (1), by using a suitable catalyst, for example, palladium on carbon, platinum on carbon or the like, and by submitting to the hydrogenating reaction for 1 to 72 hours at 20 to 80° C. under ambient pressure or, if need be, under pressure in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like, and further they can be converted to compounds, R2 being amino group which may have substituents, among compounds represented by the general formula (1), by using a suitable acylating agent, for example, acetic anhydride, acetyl chloride or the like, or a suitable sulfonylating agent, for example, methanesulfonyl chloride, 4-toluenesulfonyl chloride or the like, and by reacting for 1 to 24 hours at 0 to 80° C. in a suitable solvent, for example, chloroform, tetrahydrofuran, N,N-dimethylformamide, mixed solvent thereof or the like without base or in the presence of a suitable base, for example, triethylamine, pyridine or the like.
Similarly, in the case of compounds, R4 being general formula (3) and R6 being phenyl group which may have substituents, naphthyl group which may have substituents or 5- or 6-membered heterocycle which may have substituents and its condensed ring, wherein the substituent is lower alkoxy group which may be substituted with halogen atom or nitro group, among compounds represented by the general formula (1) or compounds represented by the general formula (6) and general formula (7), being synthetic intermediates in the Preparative processes I through III, it is also possible to convert to hydroxy group, amino group and amino group which may have substituents.
Processes for converting R2 in compounds represented by the general formula (1) or compounds represented by the general formula (6) and general formula (7), being synthetic intermediates in the Preparative processes I through III, and the substituent in compounds, R4 being general formula (3) and R6 being phenyl group which may have substituents, naphthyl group which may have substituents or 5- or 6-membered heterocycle which may have substituents and its condensed ring, among compounds represented by the general formula (1) or compounds represented by the general formula (6) and general formula (7), being synthetic intermediates in the Preparative processes I through III, to other substituents, if need be, are not confined to these.
The 4-substituted aryl-5-hydroxyisoquinolinone derivatives represented by the general formula (1) and their addition salts of the invention exhibit excellent PARP inhibitory activity. When using the inventive compounds for therapeutic or preventive agents, they can be used solely or by mixing opportunely with pharmacologically acceptable excipient, diluent or the like, and administered orally in a form of tablet, capsule, granule, powder, syrup or the like, or parenterally in a form of injection, percutaneous absorption, suppository or the like.
Moreover, the inventive compounds can be used in combination with other drugs. In this case, they may be used for combination administrations or formulating agents. As the drugs to be used for combination, fibrinolytic agent, antiplatelet, protector of brain, antiedemic agent, anticoagulant, antipyretic, improver of cerebral circulatory metabolism, antiepileptic, antidepressant, anti-inflammatory drug, ACE inhibitor, antiphlogistic analgesic, blood glucose regulator, etc. are mentioned.
Moreover, the inventive compounds can be used in combination, even in the cases of surgical therapy, hypothermic therapy, hyperbaric oxygen therapy, etc.


BEST MODE FOR CARRYING OUT THE INVENTION
In following, referential examples, examples and test examples will be shown to illustrate the invention in more detail, but the scope of the invention is not confined thereto.
REFERENTIAL EXAMPLE 1
5-Benzoyloxyisoquinoline




To a solution of 5-hydroxyisoquinoline (15.0 g, 103 mmol) in dichloromethane (300 ml) was added triethylamine (10.9 g, 108 mmol), and the mixture was cooled to 0° C. Under stirring, benzoyl chloride (15.2 g, 108 mmol) was added dropwise and the temperature was raised to room temperature. After stirring for 6 hours at room temperature, dichloromethane was added. The solution was washed with saturated aqueous solution of sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and solvent was distilled off, thereby affording 26.6 g of the title compound as a light brown liquid. Yield quantitative. 1H-NMR (DMSO-d6, δ): 7.68(2H, t, J=7.3 Hz), 7.75(1H, d, J=5.9 Hz), 7.79-7.85(3H, m), 8.12-8.16(1H, m), 8.28(2H, d, J=7.3 Hz), 8.55 (1H, d, J=5.9 Hz), 9.45(1H, s).
REFERENTIAL EXAMPLE 2
5-Benzoyloxyisoquinoline N-oxide




To a solution of the compound of Referential example 1 (1.92 g, 7.70 mmol) in dichloromethane (100 ml) was added 3-chloroperbenzoic acid (2.45 g, 9.24 mmol), and the mixture was stirred for 6 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added and the solution was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and solvent was distilled off, thereby affording 2.35 g of the title compound as light brown powder. Yield quantitative. 1H-NMR (DMSO-d6, δ): 7.61(1H, d, J=7.8 Hz), 7.67(2H, t, J=8.3 Hz),7.75 (1H, t, J=7.8 Hz), 7.82(1H, t, J=8.3 Hz), 7.86-7.88(2H, m),8.14(1H, d, J=7.3 Hz), 8.26(2H, d, J=8.3 Hz), 9.07(1H, s).
REFERENTIAL EXAMPLE 3
5-Benzoyloxy-1,2-dihydro-1-oxoisoquinoline




To the compound of Referential example 2 (29.9 g, 123 mmol) was added acetic anhydride (100 mL), and the mixture was refluxed for 4 hours. After the reaction mixture was concentrated under reduced pressure, ethanol (100 ml) and water (50 ml) were added and the mixture was refluxed for 30 minutes. Ethanol was added to the residue obtained by distilling off solvent. The precipitated crystals were collected by filtration, washed with ethanol, and then air-dried, thereby affording 19.0 g of the title compound as brown powder. Yield 64%. 1H-NMR(DMSO-d6, δ): 6.40(1H, d, J=7.3 Hz), 7.21(1H, t, J=6.3 Hz), 7.57 (1H, t, J=7.8 Hz), 7.64-7.72(3H, m), 7.81(1H, t, J=7.3 Hz), 8.16(1H, d, J=7.3 Hz), 8.23(2H, d, J=7.8 Hz), 11.45(1H, brs).
REFERENTIAL EXAMPLE 4
5-Benzoyloxy-1-methoxyisoquinoline




To a solution of the compound of Referential example 3 (22.1 g, 83.3 mmol) in toluene (300 mL) was added silver oxide (I) (57.9 g, 250 mmol) and methyl iodide (30 mL), and the mixture was refluxed for 8 hours. The reaction mixture was filtered using celite and the residue obtained by distilling off solvent was purified by silica gel column chromatography [hexane:ethyl acetate (20:1→10:1)], thereby affording 9.83 g of the title compound as colorless powder. Yield 42%. 1H-NMR(DMSO-d6, δ): 4.10(3H, s), 7.29(1H, d, J=5.8 Hz), 7.66-7.73 (3H, m), 7.77(1H, dd, J=7.8, 1.0 Hz), 7.82(1H, t, J=7.3 Hz),8.05(1H, d, J=5.8 Hz), 8.16(1H, d, J=7.8 Hz), 8.26(2H, d, J=7.3 Hz).
REFERENTIAL EXAMPLE 5
5-Benzoyloxy-4-bromo-1-methoxyisoquinoline




A solution of the compound of Referential example 4 (9.83 g, 35.2 mmol) in N,N-dimethylformamide (200 mL) was cooled to 0° C. and, under stirring, N-bromosuccinimide (6.39 g, 35.9 mmol) was added little by little. After stirring for 30 minutes at 0° C., the temperature was raised to room temperature and the mixture was stirred for 16 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography [hexane:ethyl acetate (20:1→10:1)], thereby affording 11.6 g of the title compound as colorless powder. Yield 92%. 1H-NMR (DMSO-d6, δ): 4.10(3H, s), 7.66(2H, t, J=8.3 Hz), 7.77-7.82 (3H, m), 8.22(2H, d, J=8.3 Hz), 8.26(1H, s), 8.28-8.32(1H, m).
REFERENTIAL EXAMPLE 6
5-Benzoyloxy-4-(4-formylphenyl)-1-methoxyisoquinoline




To a suspension of the compound of Referential example 5 (20.0 g, 55.8 mmol) and 4-formylphenylboric acid (12.6 g, 83.8 mmol) in toluene (50 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane(1:1) complex (1.22 g, 1.67 mmol) and 2 mol/L aqueous solution of sodium carbonate, and the mixture was refluxed for 5 hours. After cooling, the organic layer was separated, dried over anhydrous sodium sulfate, and then solvent was distilled off. A small quantity of ethyl acetate was added to the residue obtained. The crystals were collected by filtration, washed with ethyl acetate, and then air-dried, thereby affording 16.6 g of the title compound as yellow powder. Yield 78%. 1H-NMR (DMSO-d6, δ): 4.15(3H, s), 7.30(2H, t, J=7.8 Hz), 7.42(2H, d, J=7.8 Hz), 7.51-7.55(5H, m), 7.68(1H, d, J=7.3 Hz), 7.78(1H, d, J=7.8 Hz), 7.81(1H, s), 8.32(1H, d, J=8.3 Hz), 9.59(1H, s).
REFERENTIAL EXAMPLE 7
5-Benzoyloxy-4-(3-formylphenyl)-1-methoxyisoquinoline




Using the compound of Referential example 5 (3.58 g, 10.0 mmol) and 3-formylphenylboric acid (2.55 g, 15.0 mmol), through the process similar to Referential example 6, 2.91 g of the title compound were afforded as colorless powder. Yield 76%. 1H-NMR (DMSO-d6, δ): 4.14(3H, s), 7.23-7.33(4H, m), 7.46-7.49(2H, m), 7.53-7.60(2H, m), 7.67(1H, dd, J=7.8, 1.5 Hz), 7.73-7.80(3H, m), 8.32 (1H, dd, J=8.3, 1.5 Hz), 9.77(1H, s).
REFERENTIAL EXAMPLE 8
4-(4-Formylphenyl)-5-hydroxy-1-methoxyisoquinoline




To a suspension of the compound of Referential example 6 (6.65 g, 17.3 mmol) in ethanol-water (2:1, 150 mL) was added 1 mol/L aqueous solution of sodium hydroxide (17.3 mL, 17.3 mmol), and the mixture was refluxed for 1 hour. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane: ethyl acetate=4:1], thereby affording 2.08 g of the title compound as pale yellow powder. Yield 43%. 1H-NMR (DMSO-d6, δ): 4.08(3H, s), 7.05(1H, dd, J=7.8, 1.0 Hz), 7.48 (1H, t, J=7.8 Hz), 7.55(2H, d, J=8.3 Hz), 7.70(1H, s), 7.74(1H, dd, J=8.3, 1.0 Hz), 7.89(2H, d, J=8.3 Hz), 10.04(1H, s), 10.06(1H, s).
REFERENTIAL EXAMPLE 9
4-(3-Formylphenyl)-5-hydroxy-1-methoxyisoquinoline




Using the compound of Referential example 7 (4.46 g, 11.6 mmol), through the process similar to Referential example 8, 2.43 g of the title compound were afforded as a pale yellow amorphous material.
Yield 75%. 1H-NMR (DMSO-d6, δ): 4.07(3H, s), 7.04(1H, dd, J=7.8, 1.0 Hz), 7.47 (1H, t,J=7.8 Hz), 7.58(1H, t, J=7.8 Hz), 7.66-7.70(2H, m), 7.74(1H, dd, J=8.3, 1.0 Hz), 7.85-7.87(2H, m), 10.06(1H, s), 9.80-10.20(1H, br).
REFERENTIAL EXAMPLE 10
5-Benzoyloxy-4-(3-formyl-4-methoxyphenyl)-1-methoxyisoquinoline




Using the compound of Referential example 5 (1.79 g, 5.00 mmol) and 3-formyl-4-methoxyphenylboric acid (1.35 g, 7.50 mmol), through the process similar to Referential example 6, 317 mg of the title compound were afforded as light brown powder. Yield 15%. 1H-NMR (DMSO-d6, δ): 3.55(3H, s), 4.18(3H, s), 6.54(1H, d, J=8.8 Hz),7.29(2H, t, J=7.8 Hz), 7.35-7.40(2H, m), 7.53(1H, t, J=7.8 Hz), 7.60-7.67(3H, m), 7.74-7.76(2H, m), 8.34(1H, dd, J=8.3, 1.0 Hz),10.20 (1H, s).
REFERENTIAL EXAMPLE 11
4-(3-Formyl-4-methoxyphenyl)-5-hydroxy-1-methoxyisoquinoline




Using the compound of Referential example 10 (315 mg, 762 μmol), through the process similar to Referential example 8, 192 mg of the title compound were afforded as pale yellow powder. Yield 81%. 1H-NMR (DMSO-d6, δ): 3.97(3H, s), 4.06(3H, s), 7.03(1H, d, J=7.8 Hz), 7.22(1H, d, J=8.3 Hz), 7.45(1H, t, J=7.8 Hz), 7.60-7.65(3H, m),7.72 (1H, d, J=8.3 Hz), 10.42(1H, s).
REFERENTIAL EXAMPLE 12
5-Benzoyloxy-1-methoxy-4-(4-methyl-3-nitrophenyl)isoquinoline




Using the compound of Referential example 5 (2.51 g, 7.00 mmol) and 4-methyl-3-nitrophenylboric acid (1.90 g, 10.5 mmol), through the process similar to Referential example 6, 2.51 g of the title compound were afforded as colorless powder. Yield 87%. 1H-NMR (DMSO-d6, δ): 2.04(3H, s), 4.14(3H, s), 7.14(1H, d, J=7.8 Hz), 7.38(2H, t, J=7.3 Hz), 7.46(1H, dd, J=7.8, 2.0 Hz), 7.57(2H, dd, J=8.3, 1.0 Hz), 7.62-7.69(2H, m), 7.77-7.81(3H, m), 8.32(1H, dd, J=8.3, 1.0 Hz).
REFERENTIAL EXAMPLE 13
1,5-Dimethoxy-4-[4-(2-dimethylamino)ethyl-3-nitrophenyl]isoquinoline




To a solution of the compound of Referential example 12 (2.07 g, 5.00 mmol) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamidodimethylacetal (3.32 mL, 25.0 mmol), and the mixture was refluxed for 6 hours. After cooling, ethanol (50 mL) and successively sodium borohydride (567 mg, 15.0 mmol) were added to the residue obtained by concentrating the reaction mixture under reduced pressure and the mixture was refluxed for 5 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate (1:1)→ethyl acetate-methanol-triethylamine (10:1:0.1)], thereby affording 498 mg of the title compound as a brown viscous liquid. Yield 26%. 1H-NMR (DMSO-d6, δ): 2.36(6H, s), 2.68(2H, t, J=7.8 Hz), 3.14(2H, brs), 3.56(3H, s), 4.16(3H, s), 7.02(1H, d, J=7.3 Hz), 7.36(1H, d, J=7.8 Hz), 7.48-7.53(2H, m), 7.78(1H, s), 7.88(1H, d, J=2.0 Hz), 7.95(1H, dd, J=8.3, 1.0 Hz).
REFERENTIAL EXAMPLE 14
2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxobororan-2-yl)phenyl]ethanol




To a solution of 2-(4-bromophenyl)ethanol (500 mg, 2.49 mmol) in dimethylsulfoxide (5 mL) were added bis(pinacolato)diboron (632 mg, 2.49 mmol), potassium acetate (733 mg, 7.47 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (1:1) complex (102 mg, 124 μmol), and the mixture was stirred for 5 hours at 120° C. Ice water and toluene were added to the reaction mixture and the insolubles were filtered off. The organic layer was separated, washed with water, then dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane-ethyl acetate=1:1], thereby affording 455 mg of the title compound as a pale yellow oil. Yield 89%. 1H-NMR (CDCl3, δ): 1.34(12H, s), 2.89(2H, t, J=6.3 Hz), 3.87(2H, q, J=6.3 Hz), 7.25(2H, d, J=7.8 Hz), 7.77(2H, d, J=8.3 Hz).
REFERENTIAL EXAMPLE 15
2-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxobororane-2-yl)phenyl]ethanol




Using 2-(3-bromophenyl]ethanol (4.17 g, 20.7 mmol), through the process similar to Referential example 14, 3.98 g of the title compound were afforded as a yellow oil. Yield 77%. 1H-NMR (CDCl3, δ): 1.35(12H, s), 2.88(2H, t, J=6.3 Hz), 3.87(2H, q, J=6.3 Hz), 7.32-7.37(2H, m), 7.67-7.69(2H, m).
REFERENTIAL EXAMPLE 16
3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxobororane-2-yl)phenyl]propanol




Using 3-(4-bromophenyl]propanol (508 mg, 2.36 mmol), through the process similar to Referential example 14, 229 mg of the title compound were afforded as a yellow oil. Yield 37%. 1H-NMR (CDCl3, δ): 1.34(12H, s), 1.86-1.93(2H, m), 2.70-2.75 (2H, m), 3.65-3.69(2H, m), 7.22(2H, d, J=8.3 Hz), 7.74(2H, d, J=7.8 Hz).
REFERENTIAL EXAMPLE 17
5-Benzoyloxy-4-[4-(2-hydroxyethyl)phenyl]-1-methoxyisoquinoline




Using the compound of Referential example 5 (634 mg, 1.77 mmol) and the compound of Referential example 14 (440 mg, 1.77 mmol), through the process similar to Referential example 6, 225 mg of the title compound were afforded as pale yellow powder. Yield 32%. 1H-NMR (CDCl3, δ): 2.45(2H, t, J=6.3 Hz), 3.53(2H, q, J=6.3 Hz), 4.18 (3H, s), 6.89(2H, d, J=7.8 Hz), 7.21(2H, d, J=7.8 Hz), 7.31(2H, t, J=8.3 Hz), 7.38(1H, dd, J=7.8, 1.0 Hz), 7.51-7.55(1H, m), 7.61(1H, t, J=7.8 Hz), 7.68(2H, dd, J=8.3, 1.5 Hz), 7.77(1H, s), 8.34(1H, dd, J=8.3, 1.0 Hz).
REFERENTIAL EXAMPLE 18
5-Benzoyloxy-4-[3-(2-hydroxyethyl)phenyl]-1-methoxyisoquinoline




Using the compound of Referential example 5 (5.07 g, 14.2 mmol) and the compound of Referential example 15 (3.52 g, 14.2 mmol), through the process similar to Referential example 6, 4.05 g of the title compound were afforded as a yellow oil. Yield 71%. 1H-NMR (CDCl3, δ): 2.54-2.64(2H, m), 3.64(2H, q, J=6.3 Hz), 4.18(3H, s), 6.66(1H, d, J=7.3 Hz), 7.02(1H, t, J=7.8 Hz), 7.08(1H, s), 7.17-7.19 (1H, m), 7.28-7.31(2H, m), 7.39(1H, dd, J=7.3, 1.0 Hz), 7.49-7.54(1H, m), 7.59-7.63(3H, m), 7.77(1H, s), 8.34(1H, dd, J=8.3, 1.5 Hz).
REFERENTIAL EXAMPLE 19
5-Benzoyloxy-4-[4-(3-hydroxypropyl)phenyl]-1-methoxyisoquinoline




Using the compound of Referential example 5 (5.12 g, 14.3 mmol) and the compound of Referential example 16 (3.75 g, 14.3 mmol), through the process similar to Referential example 6, 3.03 g of the title compound were afforded as pale yellow powder. Yield 51%. 1H-NMR (CDCl3, δ): 1.52-1.59(2H, m), 2.27(2H, t, J=7.3 Hz), 3.53(2H, q, J=6.3 Hz), 4.18(3H, s), 6.85(2H, d, J=7.8 Hz), 7.18(2H, d, J=7.8 Hz), 7.29(2H, t, J=7.8 Hz), 7.38(1H, dd, J=7.8, 1.0 Hz), 7.50(1H, t, J=7.3 Hz), 7.60(1H, t, J=8.3 Hz), 7.65(2H, dd, J=8.3, 1.0 Hz), 7.78(1H, s),8.33(1H, dd, J=8.3, 1.0 Hz).
REFERENTIAL EXAMPLE 20
5-Benzoyloxy-4-(5-formyl-2-thienyl-1-methoxyisoquinoline




To a solution of the compound of Referential example 5 (1.00 g, 279 mmol) in anhydrous 1,4-dioxane (60 mL) were added 5-formyl-2-thiopheneboric acid (1.31 g, 8.38 mmol), triethylamine (1.17 mL,8.38 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane(1:1) complex (228 mg,280 μmol), and the mixture was refluxed for 9 hours. After cooling, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography [hexane:ethyl acetate (4:3→1:1)], thereby affording 990 mg of the title compound as pale yellow powder.
Yield 91%. 1H-NMR (CDCl3, δ): 4.19(3H, s), 6.92(1H, d, J=3.9 Hz), 7.03(1H, d, J=3.4 Hz), 7.34(2H, t, J=7.8 Hz), 7.47(1H, dd, J=8.3, 1.5 Hz), 7.55(1H, t, J=7.8 Hz), 7.66(1H, t, J=8.3 Hz), 7.82(2H, dd, J=8.3, 1.5 Hz), 7.93(1H, s), 8.35(1H, dd, J=8.3, 1.5 Hz), 9.38(1H, s).
REFERENTIAL EXAMPLE 21
4-(5-Formyl-2-thienyl)-5-hydroxy-1-methoxyisoquinoline




To a solution of the compound of Referential example 20 (49.3 mg, 127 μmol) in ethanol (3 mL) was added sodium hydrogencarbonate (31.9 mg, 380 μmol), and the mixture was refluxed for 8 hours. After cooling, water was added and the solution was brought to pH 1 using 1 mol/L hydrochloric acid. This was extracted with ethyl acetate, washed with brine, then dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane:ethyl acetate=4:1], thereby affording 30.3 mg of the title compound as pale yellow powder. Yield 84%. 1H-NMR (CDCl3, δ): 4.17(3H, s), 7.14(1H, dd, J=7.8, 1.0 Hz), 7.51(1H, t, J=7.8 Hz), 7.81(1H, d, J=3.4 Hz), 7.92(1H, s), 7.97(1H, dd, J=8.3, 1.0 Hz), 9.96(1H, s).
REFERENTIAL EXAMPLE 22
5-Benzoyloxy-4-(4-formyl-1-naphthyl-1-methoxyisoquinoline




Using the compound of Referential example 5 (1.43 g, 4.00 mmol) and 4-formyl-1-naphthaleneboric acid (1.00 g, 5.00 mmol), through the process similar to Referential example 6, 1.23 g of the title compound were afforded as pale yellow powder. Yield 71%. 1H-NMR (DMSO-d6, δ): 4.19(3H, s), 6.82-6.84(2H, m), 7.09(2H, t, J=7.9 Hz), 7.40-7.52(4H, m), 7.58(1H, dd, J=6.7, 1.2 Hz), 7.65-7.69(1H, m), 7.75-7.82(2H, m), 7.88(1H, s), 8.38(1H, dd, J=7.3, 1.2 Hz), 8.96(1H, d, J=8.6 Hz),9.95(1H, s).
REFERENTIAL EXAMPLE 23
4-(4-Formyl-1-naphthyl)-5-hydroxy-1-methoxyisoquinoline




To a solution of the compound of Referential example 22 (610 mg, 1.41 mmol) in ethanol (15 mL) was added potassium hydroxide (92.0 mg, 1.41 mmol), and the mixture was refluxed for 1 hour. After cooling, the residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography [hexane:ethyl acetate=10:1], then diisopropyl ether was added and the precipitated crystals were collected by filtration, thereby affording 328 mg of the title compound as colorless powder. Yield 71%. 1H-NMR (DMSO-d6, δ): 4.14(3H, s), 6.90(1H, brd, J=6.7 Hz), 7.41-7.50 (3H, m), 7.64-7.70(2H, m), 7.76-7.80(2H, m), 8.22(1H, d, J=6.7 Hz), 9.25 (1H, d, J=9.2 Hz), 9.74(1H, brs), 10.45(1H, s).
REFERENTIAL EXAMPLE 24
5-Benzoyloxy-4-(4-fluoro-3-formylphenyl)-1-methoxyisoquinoline




To a solution of the compound of Referential example 5 (1.79 g, 5.00 mmol) in toluene (50 mL) were added 4-fluoro-3-formylphenylboric acid (1.01 g, 6.00 mmol), 2 mol/L aqueous solution of sodium carbonate (5.00 mL, 10.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane(1:1) complex (204 mg, 250 μmol), and the mixture was refluxed for 5 hours. After cooling, the organic layer was separated, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane:ethyl acetate=4:1], thereby affording 1.58 g of the title compound as colorless powder.
Yield 79%.
1H-NMR (DMSO-d6, δ): 4.14(3H, s), 7.07(1H, dd, J=7.9, 10.4 Hz), 7.40 (2H, t, J=7.9 Hz), 7.54-7.69(6H, m), 7.77-7.80(2H, m), 8.32(1H, d, J=8.6 Hz), 9.92(1H, s).
REFERENTIAL EXAMPLE 25
4-(4-Fluoro-3-formylphenyl)-5-hydroxy-1-methoxyisoquinoline




To a solution of the compound of Referential example 24 (1.58 g, 3.93 mmol) in ethanol (80 mL) was added sodium hydrogen carbonate (991 mg, 11.8 mmol), and the mixture was refluxed for 8 hours. After cooling, brine was added and the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then solvent was distilled off. Dichloromethane was added to the residue obtained, The precipitates were collected by filtration and dried, thereby affording 765 mg of the title compound as pale yellow powder. The filtrate was concentrated and purified by silica gel column chromatography [hexane:ethyl acetate=4:1], thereby affording 155 mg additionally.
Total yield 97%.
1H-NMR (DMSO-d6, δ): 4.07(3H, s), 7.04-7.06(1H, m), 7.39(1H, dd, J=10.4, 7.9 Hz), 7.47(1H, t, J=7.9 Hz), 7.68-7.77(4H, m), 10.05(1H, s), 10.28(1H, s).
REFERENTIAL EXAMPLE 26
Ethyl 4-(5-hydroxy-1-methoxyisoquinoline-4-yl)cinnamate




To a suspension of 60% sodium hydride in oil (301 mg, 7.52 mmol) in tetrahydrofuran (35 mL) was added dropwise ethyl diethylphosphonoacetate (853 μL, 4.30 mmol) under cooling with ice, and the mixture was stirred for 15 minutes. A solution of the compound of Referential example 8 (1.00 g, 3.58 mmol) in tetrahydrofuran (15 mL) was added dropwise thereto, and the mixture was stirred for 4 hours, while gradually returning the temperature to room temperature. The reaction mixture was poured in ice water (100 mL) and stirred for 30 minutes at room temperature. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane:ethyl acetate=4:1], thereby affording 947 mg of the title compound as pale yellow powder. Yield 76%.
1H-NMR (DMSO-d6, δ): 1.26(3H, t, J=7.3 Hz),4.05(3H, s), 4.19(2H, q, J=7.3 Hz), 6.64(1H, d, J=15.9 Hz), 7.01(1H, d, J=7.3 Hz), 7.35(2H, d, J=7.9 Hz), 7.44(1H, t, J=7.9 Hz), 7.65-7.72(5H, m), 9.96(1H, brs).
REFERENTIAL EXAMPLE 27
5-Hydroxy-4-[4-(3-hydroxypropene-1-yl)phenyl]-1-methoxyisoquinoline




To a suspension of lithium aluminum hydride (146 mg, 3.07 mmol) in tetrahydrofuran (10 mL) was added dropwise a solution of the compound of Referential example 26 (537 mg, 1.54 mmol) in tetrahydrofuran (10 mL) under cooling with ice, and the mixture was stirred for 3 hours, while gradually returning the temperature to room temperature. Water (5 mL) and 2 mol/L aqueous solution of sodium hydroxide (1 mL) were added and the mixture was stirred for 30 minutes. This was filtered using celite and the residue was washed with ethyl acetate (20 mL). The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane:ethyl acetate=1:1], thereby affording 173 mg of the title compound as colorless powder. Yield 37%.
1H-NMR(CDCl3, δ): 4.15(3H, s), 4.39(2H, dt, H=5.5, 1.2 Hz), 5.48(1H, s), 6.48(1H, dt, H=15.9, 5.5 Hz), 6.71(1H, d, J=15.9 Hz), 7.10(1H, dd, J=7.3, 1.2 Hz), 7.44-7.50(3H, m), 7.54(2H, d, J=7.9 Hz), 7.73(1H, s),7.93-7.96 (1H, m).
EXAMPLE 1
1,2-Dihydro-4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-oxoisoquinoline




Process 1: To a solution of the compound of Referential example 8 (300 mg, 1.07 mmol) in methanol (15 mL) were added 2 mol/L dimethylamine-methanol solution (3.21 mL, 6.42 mmol) and zinc chloride (73.2 mg, 537 μmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added sodium cyanoborohydride (67.2 mg, 1.07 mmol), and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. A small quantity of dichloromethane was added to the residue obtained. The crystals were collected by filtration, washed with dichloromethane and then air-dried, thereby affording 262 mg of 4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-methoxyisoquinoline as light brown powder. Yield 79%.
1H-NMR (DMSO-d6, δ): 2.19(6H, s), 3.43(2H, s), 4.06(3H, s), 7.01 (1H, d, J=7.8 Hz), 7.25(4H, s), 7.44(1H, t, J=7.8 Hz), 7.64(1H, s), 7.71 (1H, d, J=8.3 Hz), 9.88(1H, s).
Process 2: To a solution of 4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-methoxyisoquinoline (102 mg, 331 μmol) in acetic acid (15 mL) were added 47% hydrobromic acid (1.5 mL) and water (1.5 mL), and the mixture was refluxed for 1 hour. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, which was made basic with saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals were collected by filtration, washed with water, and then air-dried, thereby affording 66.2 mg of the title compound as brown powder. Yield 68%.
1H-NMR (DMSO-d6, δ): 2.17(6H, s), 6.73(1H, d, J=5.4 Hz), 7.00(1H, d, J=6.8 Hz), 7.20(4H, s), 7.31(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.67(1H, bs), 11.27(1H, brs).
HR-MS (m/z): 294.1383 (+1.5 mmu).
EXAMPLES 2 THROUGH 44
Through the processes similar to Example 1, compounds listed in following Table 13 were afforded.







TABLE 13













 











Example
Position
NR3R4







 2
4
NEt2



 3
4
NPr2



 4
4
NBu2



 5
4
N(pentyl)2



 6
4
N(Me)Pr



 7
4
N(Me)Bu



 8
4
N(Me)pentyl



 9
4
N(Me)hexyl



10
4
N(CH2CH2OH)2



11
4
N(Me)Ph



12
4
N(Me)CH2Ph)



13
4
N(Me)CH2Ph-4-OMe



14
4
N(Me)CH2Ph-4-NMe2



15
4
N(Me)CH2Ph-4-NH2



16
4
N(Et)CH2Ph



17
4
N(CH2CO2H)CH2Ph



18
4
N(CH2CH2NMe2)CH2Ph



19
4
N(Me)CH2CH2Ph



20
4
N(Me)CH2CH2Ph-4-OMe



21
4
N(Me)CH2CH2CH2Ph



22
4
N(Me)-3-picolyl



23
4
N(Me)CH2-cyclohexyl



24
4
N(Me)CH2CH2-cyclohexenyl



25
4
NHEt



26
4
NHPr



27
4
NHCH2CH2OH



28
4
NHCH2CH2NEt2



29
4
NHCH2CO2H



30
4
NHPh



31
4
NHCH2Ph



32
4
pyrrolidin-1-yl



33
4
piperidin-1-yl



34
4
morpholin-1-yl



35
4
piperazin-1-yl



36
4
1,2,3,4-tetrahydroisoquinolin-1-yl



37
4
4-Ph-piperazin-1-yl



38
4
4-Bn-piperazin-1-yl



39
4
4-piperidinopiperidin-1-yl



40
3
NMe2



41
3
NEt2



42
3
NPr2



43
3
pyrrolidin-1-yl



44
3
piperidin-1-yl










COMPOUND OF EXAMPLE 2
1H-NMR (CDCl3, δ): 1.07(6H, t, J=7.3 Hz), 2.57(4H, q, J=7.3 Hz), 3.64 (2H, s), 6.38(1H, brs), 7.13(1H, dd, J=7.8, 1.5 Hz), 7.40-7.46(3H, m), 7.49(2H, d, J=8.3 Hz), 8.12(1H, dd, J=8.3, 1.5 Hz), 9.38(1H, brs).
Anal. Calcd. for C20H22N2O2.1⁄4H2O: C, 73.48; H, 6.94; N, 8.57(%).
Found: C, 73.40; H, 6.83; N, 8.43(%).
HR-MS (m/z): 322.1681 (+0.0 mmu).
COMPOUND OF EXAMPLE 3
1H-NMR (DMSO-d6, δ): 0.85(6H, t, J=7.3 Hz), 1.43-1.48(4H, m), 2.36 (4H, brs), 3.53(2H, s), 6.73(1H, d, J=5.9 Hz), 7.01(1H, d, J=8.3 Hz), 7.21(4H, s), 7.32(1H, t, J=8.3 Hz), 7.77(1H, d, J=7.8 Hz), 9.61(1H, s), 11.28(1H, brs).
Anal. Calcd. for C22H26N2O2.3⁄4H2O: C, 72.60; H, 7.62; N, 7.70(%).
Found: C, 72.48; H, 7.25; N, 7.67(%).
HR-MS (m/z): 350.1965 (−3.0 mmu).
COMPOUND OF EXAMPLE 4
1H-NMR (DMSO-d6, δ): 0.86(6H, t, J=7.3 Hz), 1.24-1.33(4H, m), 1.39-1.46(4H, m), 2.39(4H, t, J=7.3 Hz), 3.52(2H, s),6.71(1H, d, J=5.9 Hz), 7.01(1H, dd, J=7.8, 1.5 Hz), 7.20(4H, s), 7.31(1H, t, J=7.8 Hz),7.77(1H, dd, J=7.8, 1.0 Hz), 9.58(1H, s),11.24(1H, d, J=5.4 Hz).
Anal. Calcd. for C24H30N2O2.1⁄8H2O: C, 75.71; H, 8.01; N, 7.36(%).
Found: C, 75.65; H, 8.12; N, 7.32(%).
HR-MS (m/z): 378.2275 (−3.2 mmu).
COMPOUND OF EXAMPLE 5
1H-NMR (DMSO-d6, δ): 0.85(6H, t, J=7.3 Hz), 1.23-1.26(6H, m), 1.42-1.45(4H, m), 2.38(4H, t, J=7.3 Hz), 3.52(2H, s), 6.71(1H, s), 7.01 (1H, dd, J=7.8, 1.0 Hz), 7.20(4H, s), 7.32(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.30-9.80(1H, br), 11.10-11.40(1H, br).
Anal. Calcd. for C26H34N2O2.1⁄8H2O: C, 76.39; H, 8.44; N, 6.85(%).
Found: C, 76.36; H, 8.70; N, 6.80(%).
HR-MS (m/z): 406.2613 (−0.7 mmu).
COMPOUND OF EXAMPLE 6
1H-NMR (DMSO-d6, δ): 0.88(3H, t, J=7.3 Hz), 1.45-1.54(2H, m), 2.12 (3H, s), 2.31(2H, t, J=7.3 Hz), 3.45(2H, s), 6.73(1H, d, J=5.9 Hz), 7.00 (1H, d, J=7.8 Hz), 7.20(4H, s), 7.31(1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 9.63(1H, s), 11.26(1H, d, J=4.9 Hz).
Anal. Calcd. for C20H22N2O2. 1/10H2O: C, 74.09; H, 6.90; N, 8.64(%).
Found: C, 74.17; H, 6.97; N, 8.69(%).
HR-FAB+ (m/z): 323.1773 (+1.4 mmu).
COMPOUND OF EXAMPLE 7
1H-NMR (DMSO-d6, δ): 0.88(3H, t, J=7.3 Hz), 1.29-1.34(2H, m), 1.42-1.48(2H, m), 2.12(3H, s), 2.34(2H, t, J=7.3 Hz), 3.45(2H, s), 6.72 (1H, d, J=5.4 Hz), 7.01(1H, d, J=7.8 Hz), 7.20(4H, s), 7.31(1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 9.62(1H, s), 11.26(1H, d, J=4.9 Hz).
Anal. Calcd. for C21H24N2O2. 1/10H2O: C, 74.57; H, 7.21; N, 8.28(%).
Found: C, 74.50; H, 7.25; N, 8.35(%).
HR-MS (m/z): 336.1815 (−2.3 mmu).
COMPOUND OF EXAMPLE 8
1H-NMR (DMSO-d6, δ): 0.87(3H, t, J=6.9 Hz), 1.26-1.30(4H, m), 1.40-1.55(2H, m), 2.11(3H, s), 2.34(2H, t, J=7.3 Hz), 3.45(2H, s), 6.73(1H, d, J=5.9 Hz), 7.00(1H, dd, J=7.8, 1.0 Hz), 7.20(4H, s), 7.32(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.63(1H, s), 11.27(1H, d, J=5.4 Hz).
Anal. Calcd. for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99(%).
Found: C, 75.21; H, 7.51; N, 8.07(%).
HR-FAB+ (m/z): 351.2052 (−2.0 mmu).
COMPOUND OF EXAMPLE 9
1H-NMR (DMSO-d6, δ): 0.86(3H, t, J=6.9 Hz), 1.27-1.31(6H, m), 1.44-1.47(2H, m), 2.11(3H, s), 2.34(2H, t, J=6.9 Hz), 3.45(2H, s), 6.73 (1H, d, J=5.4 Hz), 7.01(1H, d, J=7.8 Hz), 7.20(4H, s), 7.32(1H, t, J=7.8 Hz), 7.70(1H, d, J=7.8 Hz), 9.63(1H, s), 11.27(1H, d, J=4.9 Hz).
Anal. Calcd. for C23H28N2O2. 1/10H2O: C, 75.42; H, 7.76; N, 7.65(%).
Found: C, 75.35; H, 7.74; N, 7.72(%).
HR-MS (m/z): 364.2126 (−2.5 mmu).
COMPOUND OF EXAMPLE 10
1H-NMR (DMSO-d6, δ): 2.57(4H, t, J=6.4 Hz), 3.46-3.51(4H, m), 3.66 (2H, s), 4.39(2H, t, J=5.4 Hz), 6.73(1H, d, J=5.9 Hz), 7.00(1H, d, J=7.8 Hz), 7.19-7.26(4H, m), 7.32(1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz),9.65 (1H, s), 11.27(1H, d, J=5.9 Hz).
Anal. Calcd. for C20H22N2O4. 3/10H2O: C, 66.76; H, 6.33; N, 7.79(%).
Found: C, 66.79; H, 6.34; N, 7.66(%).
HR-FAB+ (m/z): 355.1644 (−1.4 mmu).
COMPOUND OF EXAMPLE 11
1H-NMR (DMSO-d6, δ): 3.03(3H, s), 4.59(2H, s), 6.62(1H, t, J=7.3 Hz), 6.71-6.76(3H, m), 6.99(1H, dd, J=7.8, 1.0 Hz), 7.11-7.22(6H, m), 7.31 (1H, t, J=7.8 Hz), 7.76(1H, dd, J=7.8, 1.0 Hz), 9.65(1H, s), 11.27(1H, d, J=5.9 Hz).
Anal. Calcd. for C23H20N2O2.4⁄5H2O: C, 74.49; H, 5.87; N, 7.55(%).
Found: C, 74.42; H, 5.65; N, 7.42(%).
HR-FAB+ (m/z): 357.1581 (−2.2 mmu).
COMPOUND OF EXAMPLE 12
1H-NMR (DMSO-d6, δ): 2.12(3H, s), 3.51(2H, s), 3.53(2H, s),6.74 (1H, d, J=5.4 Hz), 6.99(1H, dd, J=7.8, 1.0 Hz), 7.22-7.39(10H, m), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.63(1H, s), 11.26(1H, d, J=3.9 Hz).
Anal. Calcd. for C24H22N2O2.1⁄3H2O: C, 76.57; H, 6.02; N, 7.44(%).
Found: C, 76.54; H, 6.01; N, 7.44(%).
HR-MS (m/z): 370.1671 (−1.0 mmu).
COMPOUND OF EXAMPLE 13
1H-NMR (DMSO-d6, δ): 2.09(3H, s), 3.46(2H, s), 3.48(2H, s), 3.74(3H, s), 6.74(1H, d, J=5.4 Hz),6.91(2H, d, J=8.3 Hz),7.00(1H, d, J=7.8 Hz),7.21-7.33(7H, m), 7.75(1H, d, J=7.8 Hz), 9.63(1H, s), 11.27(1H, d, J=5.4 Hz).
Anal. Calcd. for C25H24N2O3. 1/10H2O: C, 74.64; H, 6.06; N, 6.96(%).
Found: C, 74.56; H, 6.17; N, 6.95(%).
HR-FAB+ (m/z): 401.1855 (−1.1 mmu).
COMPOUND OF EXAMPLE 14
1H-NMR(DMSO-d6, δ): 2.08(3H, s), 2.87(6H, s), 3.41(2H, s), 3.46(2H, s), 6.69-6.71(3H, m), 6.95(1H, d, J=7.3 Hz), 7.16(2H, d, J=8.3 Hz), 7.20-7.29(5H, m), 7.72(1H, d, J=7.3 Hz), 11.23(1H, brs).
Anal. Calcd. for C26H27N3O2.1H2O: C, 72.37; H, 6.77; N, 9.74(%).
Found: C, 72.60; H, 6.38; N, 9.73(%).
HR-MS (m/z): 413.2090 (−1.4 mmu).
COMPOUND OF EXAMPLE 15
1H-NMR (DMSO-d6, δ): 2.06(3H, s), 3.44(2H, s), 4.94(2H, s), 6.53 (2H, d, J=7.8 Hz), 6.69(1H, s), 6.92(1H, brs), 7.00(2H, d, J=8.3 Hz), 7.19-7.27(5H, m), 7.69(1H, brs), 11.21(1H, brs).
HR-MS (m/z): 385.1805 (+1.5 mmu).
COMPOUND OF EXAMPLE 16
1H-NMR (DMSO-d6, δ): 1.04(3H, t, J=7.3 Hz), 3.56(2H, s), 3.57 (2H, s),6.73(1H, d, J=5.4 Hz), 6.99(1H, dd, J=7.8, 1.0 Hz), 7.21-7.40(10H, m),7.77(1H, dd, J=7.8, 1.0 Hz), 9.59(1H, s), 11.25 (1H, d, J=4.9 Hz).
Anal. Calcd. for C25H24N2O2: C, 78.10; H, 6.29; N, 7.29(%).
Found: C, 77.88; H, 6.47; N, 7.28(%).
HR-MS (m/z): 384.1802 (−3.5 mmu).
COMPOUND OF EXAMPLE 17
1H-NMR (DMSO-d6, δ): 3.20(2H, s), 3.76(2H, s), 3.79(2H, s),6.74 (1H, d, J=5.4 Hz), 6.99(1H, d, J=7.8 Hz), 7.22-7.40(10H, m),7.77(1H, d, J=7.8 Hz), 9.64(1H, s), 11.28(1H, d, J=5.4 Hz).
Anal. Calcd. for C25H22N2O4. 1/10H2O: C, 72.14; H, 5.37; N, 6.73(%).
Found: C, 72.13; H, 5.49; N, 6.71(%).
HR-FAB+ (m/z): 415.1630 (−2.8 mmu).
COMPOUND OF EXAMPLE 18
1H-NMR (DMSO-d6, δ): 2.10(6H, s), 3.59(2H, s), 3.60(2H, s), 6.72-6.73(1H, m), 7.00(1H, d, J=7.8 Hz), 7.21-7.39(10H, m), 7.77(1H, d, J=8.3 Hz), 9.60(1H, s), 11.27(1H, d, J=5.9 Hz).
Anal. Calcd. for C27H29N3O2.1⁄4H2O: C, 75.06; H, 6.88; N, 9.73(%).
Found: C, 75.04; H, 6.92; N, 9.71(%).
HR-FAB+ (m/z): 428.2350 (+1.2 mmu).
COMPOUND OF EXAMPLE 19
1H-NMR (DMSO-d6, δ): 2.21(3H, s), 2.60-2.64(2H, m), 2.80(2H, t, J=6.8 Hz), 3.54(2H, s), 6.72(1H, s), 7.00(1H, d, J=6.9 Hz), 7.15-7.33 (10H, m), 7.77(1H, d, J=8.3 Hz), 9.65(1H, s), 11.26(1H, s).
Anal. Calcd. for C25H24N2O2.1⁄6H2O: C, 77.49; H, 6.33; N, 7.23(%).
Found: C, 77.49; H, 6.41; N, 7.30(%).
HR-FAB+ (m/z): 385.1923 (+0.7 mmu).
COMPOUND OF EXAMPLE 20
1H-NMR (DMSO-d6, δ): 2.19(3H, s), 2.55-2.59(2H, m), 2.71-2.75(2H, m), 3.53(2H, s), 3.71(3H, s), 6.73(1H, s), 6.84(2H, d, J=8.3 Hz), 6.99-7.01(1H, m), 7.10-7.21(6H, m), 7.31(1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 9.30-9.80(1H, br), 11.10-11.40(1H, br).
HR-FAB+ (m/z): 415.2039 (+1.8 mmu).
COMPOUND OF EXAMPLE 21
1H-NMR (DMSO-d6, δ): 1.76-1.81(2H, m), 2.13(3H, s), 2.38(2H, t, J=7.3 Hz), 2.62(2H, t, J=7.3 Hz), 3.46(2H, s), 6.72-6.74(1H, m), 7.01(1H, d, J=7.8 Hz), 7.15-7.34(10H, m), 7.78(1H, d, J=7.8 Hz), 9.64(1H, s), 11.28 (1H, d, J=5.4 Hz).
Anal. Calcd. for C26H26N2O2. 1/10H2O: C, 78.01; H, 6.60; N, 7.00(%).
Found: C, 78.00; H, 6.58; N, 7.06(%).
HR-FAB+ (m/z): 399.2076 (+0.3 mmu).
COMPOUND OF EXAMPLE 22
1H-NMR (DMSO-d6, δ): 2.12(3H, s), 3.53(2H, s), 3.57(2H, s),6.74 (1H, d, J=5.9 Hz), 7.00(1H, dd, J=7.8, 1.5 Hz), 7.22-7.28(4H, m),7.31 (1H, t, J=7.8 Hz), 7.39(1H, dd, J=7.8,4.9 Hz), 7.76-7.79(2H, m),8.48 (1H, dd, J=4.9,2.0 Hz), 8.55(1H, d, J=2.0 Hz), 9.63(1H, s), 11.28(1H, d, J=5.4 Hz).
Anal. Calcd. for C23H21N3O2.4⁄5H2O: C, 71.60; H, 5.90; N, 10.89(%).
Found: C, 71.52; H, 5.89; N, 10.84(%).
HR-FAB+ (m/z): 409.1943 (+2.7 mmu).
COMPOUND OF EXAMPLE 23
1H-NMR (DMSO-d6, δ): 0.70-0.90(2H, m), 1.10-1.30(3H, m), 1.50-1.70(4H, m), 1.75-1.85(2H, m), 2.10(3H, s), 2.15(2H, d, J=7.3 Hz), 3.43(2H, s), 6.73(1H, d, J=5.4 Hz), 7.01(1H, d, J=7.8 Hz), 7.20(4H, s), 7.32(1H, t, J=7.8 Hz), 7.76-7.78(1H, m), 9.62(1H, s), 11.27(1H, d, J=5.4 Hz).
Anal. Calcd. for C24H28N2O2.1⁄2H2O: C, 74.77; H, 7.58; N, 7.27(%).
Found: C, 74.77; H, 7.37; N, 7.34(%).
HR-FAB+ (m/z): 377.2219 (−1.0 mmu).
COMPOUND OF EXAMPLE 24
1H-NMR (DMSO-d6,δ): 1.48-1.57 (4H, m), 1.90-1.93 (4H, m), 2.10-2.13 (5H, m), 2.42-2.46(2H, m), 3.47(2H, s), 5.40(1H, s), 6.68(1H, s),6.92 (1H, s), 7.19(4H, s), 7.26(1H, t, J=7.8 Hz), 7.69(1H, d, J=7.3 Hz),10.90-11.50(1H, br).
HR-FAB+ (m/z): 415.2039 (+1.8 mmu).
COMPOUND OF EXAMPLE 25
1H-NMR (DMSO-d6, δ): 1.23(3H, t, J=7.3 Hz), 6.73(1H, d, J=5.9 Hz), 7.06 (1H, d, J=7.3 Hz), 7.33-7.42(5H, m), 7.79(1H, d, J=7.8 Hz), 8.71(1H, brs), 9.67(1H, s), 11.36(1H, d, J=5.9 Hz).
HR-MS (m/z): 294.1383 (+1.5 mmu).
COMPOUND OF EXAMPLE 26
1H-NMR (DMSO-d6, δ): 0.88(3H, t, J=7.3 Hz), 1.41-1.50(2H, m), 3.69 (2H, s), 6.71(1H, s), 7.00(1H, d, J=6.8 Hz), 7.19(2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.31(1H, t, J=7.8 Hz), 7.76-7.78(1H, m), 9.20-10.00 (1H, br), 10.90-11.60 (1H, br).
HR-MS (m/z): 308.1547 (+2.2 mmu).
COMPOUND OF EXAMPLE 27
1H-NMR (DMSO-d6, δ): 2.60(2H, t, J=5.9 Hz), 3.49(2H, brs), 3.72(2H, s), 7.00(1H, d, J=7.3 Hz), 7.19-7.25(4H, m), 7.31(1H, t, J=7.8 Hz), 7.77 (1H, d, J=7.8 Hz), 11.28(1H, brs).
HR-MS (m/z): 310.1307 (−1.0 mmu).
COMPOUND OF EXAMPLE 28
1H-NMR (CDCl3, δ): 1.03(6H, t, J=6.8 Hz), 2.58(4H, q, J=6.8 Hz), 2.63-2.76(4H, m), 3.83(2H, s), 6.77(1H, s), 7.12(1H, d, J=7.3 Hz), 7.31-7.42(5H, m), 8.07(1H, d, J=7.3 Hz).
HR-MS (m/z): 365.2134 (+3.1 mmu).
COMPOUND OF EXAMPLE 29
1H-NMR (DMSO-d6, δ): 3.85(2H, s), 4.18(2H, s), 6.74(1H, d, J=5.9 Hz), 7.06(1H, d, J=6.8 Hz), 7.33-7.41(5H, m), 7.79(1H, d, J=7.8 Hz), 9.69 (1H, s), 11.35(1H, d, J=6.3 Hz).
HR-FAB+ (m/z): 325.1163 (−2.5 mmu).
COMPOUND OF EXAMPLE 30
1H-NMR (CDCl3,δ): 4.30(2H, s), 6.57(1H, brs), 6.67(2H, d, J=7.3 Hz), 6.71(1H, d, J=5.9 Hz), 7.00(1H, dd, J=7.8, 1.0 Hz), 7.08(2H, t, J=7.8 Hz), 7.21-7.33(5H, m), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.63(1H, s), 11.28 (1H, d, J=5.9 Hz).
HR-MS (m/z): 342.1353 (−1.6 mmu).
COMPOUND OF EXAMPLE 31
1H-NMR (CDCl3, δ): 3.79(4H, brs), 6.72(1H, d, J=5.9 Hz), 7.01(1H, d, J=8.8 Hz), 7.23-7.41(10H, m), 7.78(1H, d, J=7.8 Hz), 9.63(1H, s), 11.29 (1H, d, J=5.4 Hz).
HR-MS (m/z): 356.1537 (+1.2 mmu).
COMPOUND OF EXAMPLE 32
1H-NMR (DMSO-d6,δ): 1.72(4H, s), 3.62(2H, s), 6.73(1H, d, J=5.9 Hz), 6.99-7.01(1H, m), 7.22(4H, s), 7.32(1H, t, J=7.8 Hz), 7.76-7.78(1H, m), 9.65(1H, s), 11.28(1H, d, J=4.9 Hz).
HR-MS (m/z): 320.1518 (−0.7 mmu).
COMPOUND OF EXAMPLE 33
1H-NMR (DMSO-d6, δ): 1.41(2H, brs), 1.51(4H, brs), 2.35(4H, brs),6.73 (1H, d, J=5.9 Hz), 7.00(1H, d, J=7.8 Hz), 7.20(4H, s), 7.31(1H, t, J=7.8 Hz), 7.77(1H, t, J=7.3 Hz), 9.65(1H, s), 11.27(1H, d, J=5.9 Hz).
HR-MS (m/z): 334.1694 (+1.3 mmu).
COMPOUND OF EXAMPLE 34
1H-NMR (CDCl3, δ): 2.49(4H, brs), 3.58(2H, s), 3.74(4H, t, J=4.9 Hz),6.81(1H, d, J=4.9 Hz), 7.13(1H, dd, J=8.3, 1.5 Hz), 7.42-7.52(5H, m), 8.13(1H, dd, J=8.3, 1.5 Hz), 9.12(1H, brs).
Anal. Calcd. for C20H20N2O3.2⁄3H2O: C, 68.95; H, 6.17; N, 8.04(%).
Found: C, 68.90; H, 6.15; N, 7.99(%).
HR-MS (m/z): 336.1468 (−0.6 mmu).
COMPOUND OF EXAMPLE 35
1H-NMR (DMSO-d6, δ): 2.45(4H, brs), 2.91(4H, t, J=4.8 Hz), 3.50(2H, s), 6.72(1H, s), 7.01(1H, dd, J=7.8, 1.5 Hz), 7.22(4H, s), 7.32(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.5 Hz), 9.64(1H, brs), 11.28(1H, brs).
HR-MS (m/z): 335.1650 (+1.6 mmu).
COMPOUND OF EXAMPLE 36
1H-NMR (DMSO-d6, δ): 2.71(2H, t, J=5.9 Hz), 2.84(2H, t, J=5.9 Hz), 3.58 (2H, s), 3.67(2H, s), 6.75(1H, d, J=4.9 Hz), 7.00-7.02(2H, m), 7.09-7.11(3H, m), 7,23-7.34(5H, m), 7.78(1H, d, J=7.8 Hz), 9.65(1H, s), 11.28(1H, d, J=5.4 Hz).
Anal. Calcd. for C25H22N2O2.1⁄6H2O: C, 77.90; H, 5.84; N, 7.27(%).
Found: C, 77.88; H, 5.93; N, 7.31(%).
HR-MS (m/z): 382.1693 (+1.2 mmu).
COMPOUND OF EXAMPLE 37
1H-NMR (DMSO-d6, δ): 2.55(4H, t, J=4.9 Hz), 3.15(4H, t, J=4.9 Hz),3.55 (2H, s), 6.74-6.79(2H, m), 6.93(2H, d, J=7.8 Hz), 7.01(1H, dd, J=7.8, 1.0 Hz), 7.19-7.24(6H, m), 7,32(1H, d, J=7.8 Hz), 7.78(1H, dd, J=7.8, 1.0 Hz), 9.67(1H, s), 11.27(1H, d, J=5.4 Hz).
Anal. Calcd. for C26H25N3O2.2⁄3H2O: C, 73.74; H, 6.27; N, 9.92(%).
Found: C, 73.65; H, 6.33; N, 9.70(%).
HR-FAB+ (m/z): 412.1999 (−2.6 mmu).
COMPOUND OF EXAMPLE 38
1H-NMR (DMSO-d6, δ): 2.40(8H, brs), 3.46(2H, s), 3.47(2H, s), 6.73 (1H, d, J=5.9 Hz), 6.99(1H, d, J=7.8 Hz), 7.20(1H, s), 7.22-7.34(6H, m), 7.77(1H, d, J=7.8 Hz), 9.64(1H, s), 11.27(1H, d, J=5.4 Hz).
Anal. Calcd. for C27H27N3O2. 1/10H2O: C, 75.89; H, 6.42; N, 9.83(%).
Found: C, 75.84; H, 6.44; N, 9.77(%).
HR-MS (m/z): 425.2122 (+1.9 mmu).
COMPOUND OF EXAMPLE 39
1H-NMR (DMSO-d6, δ): 1.34-1.45(8H, m), 1.65(2H, d, J=11.7 Hz), 1.88 (2H, t, J=11.7 Hz), 2.14(1H, t, J=11.7 Hz), 2.41(4H, brs),2.86(2H, d, J=11.2 Hz), 6.71(1H, s), 6.96(1H, d, J=7.3 Hz), 7.17(4H, s),7,28(1H, t, J=7.8 Hz), 7.72(1H, d, J=7.8 Hz).
HR-FAB+ (m/z): 418.2523 (+2.8 mmu).
COMPOUND OF EXAMPLE 40
1H-NMR (DMSO-d6, δ): 2.15(6H, s), 3.38(2H, s), 6.72(1H, d, J=5.9 Hz), 7.02(1H, d, J=7.8 Hz), 7.14-7.17(3H, m), 7.22-7.26(1H, m),7.32(1H, t, J=7.3 Hz), 7.78(1H, d, J=7.8 Hz), 9.62(1H, s), 11.28 (1H, d, J=4.9 Hz).
Anal. Calcd. for C18H18N2O2.1⁄8H2O: C, 72.89; H, 6.20; N, 9.44(%).
Found: C, 72.86; H, 6.24; N, 9.45(%).
COMPOUND OF EXAMPLE 41
1H-NMR (DMSO-d6, δ): 0.97(6H, t, J=6.8 Hz), 3.52(2H, s), 6.71(1H, brs), 7.01(1H, d, J=7.8 Hz), 7.12(1H, d, J=6.8 Hz), 7.19-7.23(3H, m), 7.32 (1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 11.26(1H, brs).
HR-MS (m/z): 322.1663 (−1.8 mmu).
COMPOUND OF EXAMPLE 42
1H-NMR (DMSO-d6, δ): 0.82(6H, t, J=6.9 Hz), 1.38-1.47(4H, m), 2.35 (4H, t, J=7.3 Hz), 3.52(2H, s), 6.70(1H, d, J=5.4 Hz), 7.01(1H, d, J=6.9 Hz), 7.11(1H, d, J=6.9 Hz), 7.18-7.24(3H, m), 7.32(1H, t, J=7.8 Hz), 7.77 (1H, d, J=7.8 Hz), 9.57(1H, s), 11.24(1H, d, J=4.4 Hz).
Anal. Calcd. for C22H26N2O2.1⁄5H2O: C, 74.63; H, 7.52; N, 7.91(%).
Found: C, 74.55; H, 7.81; N, 8.05(%).
HR-MS (m/z): 350.1974 (−2.0 mmu).
COMPOUND OF EXAMPLE 43
1H-NMR (DMSO-d6, δ): 1.69(4H, s), 2.44(4H, s), 3.57(2H, s), 6.72 (1H, d, J=5.9 Hz), 7.01(1H, dd, J=7.8, 1.0 Hz), 7.13(1H, d, J=7.3 Hz), 7.17-7.25(3H, m), 7.32(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.5 Hz), 9.63(1H, s), 11.28(1H, d, J=5.4 Hz).
Anal. Calcd. for C17H17N3O2. 1/10H2O: C, 74.56; H, 6.32; N, 8.69(%)
Found: C, 74.55; H, 6.49; N, 8.60(%).
COMPOUND OF EXAMPLE 44
1H-NMR (DMSO-d6, δ): 1.37-1.82(6H, m), 2.89(2H, brs), 4.29(2H, brs), 6.83(1H, brs), 7.05(1H, d, J=8.3 Hz), 7.33-7.39(5H, m), 7.80(1H, d, J=8.3 Hz), 9.17(1H, brs), 9.71(1H, s), 11.40(1H, brs).
HR-MS (m/z): 334.1700 (+1.9 mmu).
EXAMPLE 45
1,2-Dihydro-5-hydroxy-4-[4-[(4-nitrobenzyl)aminomethyl]phenyl]-1-oxoisoquinoline




To a solution of the compound of Referential example 8 (200 mg, 716 μmol) in methanol (10 ml) were added zinc chloride (48.8 mg, 358 μmol) and successively 4-nitrobenzylamine (654 mg, 4.30 mmol), and the mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added sodium borohydride (27.1 mg, 716 μmol), and the mixture was stirred for 1 hour at room temperature. Following this, sodium borohydride (27.1 mg, 716 μmol) was added additionally, and the mixture was stirred further for 1 hour. Water was added to the reaction mixture, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. A mixed solution (5 mL) of acetic acid-47% hydrobromic acid-water (8:1:1) was added to the residue, and the mixture was refluxed for 1 hour. After cooling, water was added to the residue obtained by concentrating the reaction mixture under reduced pressure. After the solution was brought to pH 8 with saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate was added and the mixture was stirred for 15 minutes at room temperature. The precipitated crystals were collected by filtration, washed with water and ethyl acetate in order, and then air-dried. These were submitted to silica gel column chromatography [ethyl acetate-methanol-triethylamine=10:1:1] to afford 76.2 mg of the title compound as yellowish brown powder. Yield 26%.
1H-NMR (DMSO-d6, δ): 3.74(2H, s), 3.88(2H, s), 6.72(1H, d, J=5.9 Hz), 7.01-7.03(1H, m), 7.22(2H, d, J=7.8 Hz), 7.28(2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.67(2H, d, J=8.8 Hz), 7.78(1H, dd, J=8.3, 1.5 Hz),8.22(2H, d, J=8.8 Hz), 9.63(1H, s), 11.28(1H, d, J=5.4 Hz).
Anal. Calcd. for C23H19N3O4.4⁄5H2O: C, 66.43; H, 4.99; N, 10.11(%).
Found: C, 66.44; H, 4.75; N, 10.39(%).
HR-FAB+ (m/z): 402.1439 (−1.5 mmu).
EXAMPLES 46 THROUGH 57
Through the process similar to Example 45, compounds listed in following Table 14 were afforded.







TABLE 14













 








Example
R4





46
CH2Ph-4-CO2H


47
CH2Ph-4-Cl


48
CH2Ph-4-NMe2


49
CH2Ph-4-NH2


50
CH2Ph-4-OMe


51
CH2Ph-3-OMe


52
CH2Ph-3,4-(OMe)2


53
CH2Ph-3,4,5-(OMe)3


54
CH2CH2Ph-4-OH


55
4-picolyl


56
3-picolyl


57
CH2-cycloyhexyl









COMPOUND OF EXAMPLE 46
1H-NMR (DMSO-d6, δ): 3.72(2H, s), 3.80(2H, s), 6.72(1H, d, J=4.9 Hz), 7.01(2H, d, J=7.8 Hz), 7.27(2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.49 (2H, d, J=8.3 Hz), 7.77(1H, d, J=8.3 Hz), 7.91(2H, d, J=7.8 Hz), 9.66(1H, s), 11.28(1H, d, J=4.4 Hz).
Anal. Calcd. for C24H20N2O4.2⁄3H2O: C, 69.89; H, 5.18; N, 6.79(%).
Found: C, 69.90; H, 5.02; N, 6.77(%).
HR-FAB+ (m/z): 401.1439 (−1.2 mmu).
COMPOUND OF EXAMPLE 47
1H-NMR (DMSO-d6, δ): 3.68(2H, s), 3.71(2H, s), 7.01(1H, dd, J=7.8, 1.0 Hz), 7.21(2H, d, J=8.3 Hz), 7.26(2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.39-7.42(4H, m), 7.77(1H, dd, J=7.8, 1.5 Hz), 9.40-9.70 (1H, br), 11.10-11.50(1H, br).
HR-FAB+ (m/z): 390.1103 (−3.2 mmu).
COMPOUND OF EXAMPLE 48
1H-NMR (DMSO-d6, δ): 2.86(6H, s), 3.60(2H, s), 3.67(2H, s), 6.68-6.70(2H, m), 7.00(1H, d, J=7.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.20(2H, d, J=7.8 Hz), 7.24(2H, d, J=8.3 Hz), 7.30(1H, t, J=7.8 Hz), 7.74(1H, d, J=7.8 Hz), 9.50-10.20 (1H, br), 11.10-11.50(1H, br).
HR-FAB+ (m/z): 400.1999 (−2.6 mmu).
COMPOUND OF EXAMPLE 49
1H-NMR (DMSO-d6, δ): 3.54(2H, s), 3.67(2H, s), 4.90(2H, s), 6.52(2H, d, J=7.8 Hz), 6.71(1H, s), 6.99-7.01(3H, m), 7.20(2H, d, J=7.8 Hz),7.25 (2H, d, J=7.8 Hz), 7.31(1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 9.60(1H, s), 11.25(1H, s).
Anal. Calcd. for C23H21N3O2.2⁄5H2O: C, 72.96; H, 5.80; N, 11.10(%).
Found: C, 73.03; H, 5.81; N, 10.91(%).
HR-FAB+ (m/z): 372.1711 (−0.1 mmu).
COMPOUND OF EXAMPLE 50
1H-NMR (DMSO-d6, δ): 3.65(2H, s), 3.68(2H, s), 3.74(3H, s), 6.72(1H, s), 6.89(2H, d, J=8.3 Hz), 7.01(1H, d, J=7.8 Hz), 7.19-7.34(7H, m), 7.77 (1H, d, J=7.8 Hz), 9.61(1H, s), 11.26(1H, s).
Anal. Calcd. for C24H22N2O3.1⁄2H2O: C, 72.89; H, 5.86; N, 7.08(%).
Found: C, 72.95; H, 5.73; N, 7.17(%).
HR-MS (m/z): 386.1607 (−2.3 mmu).
COMPOUND OF EXAMPLE 51
1H-NMR (DMSO-d6, δ): 3.69(4H, s), 3.75(3H, s), 6.72(1H, s), 6.80 (1H, dd, J=7.8,2.0 Hz), 6.94(1H, t, J=7.3 Hz), 7.01(1H, d, J=7.8 Hz),7.20-7.27(5H, m), 7.32(1H, t, J=7.8 Hz), 7.77-7.79(1H, m), 9.50-9.70(1H, br), 11.20-11.40(1H, br).
Anal. Calcd. for C24H22N2O3.1⁄6H2O: C, 74.02; H, 5.78; N, 7.19(%).
Found: C, 74.05; H, 5.83; N, 7.18(%).
HR-FAB+ (m/z): 387.1691 (−1.8 mmu).
COMPOUND OF EXAMPLE 52
1H-NMR (DMSO-d6, δ): 3.65(2H, s), 3.68(2H, s), 3.73(3H, s), 3.75(3H, s), 6.84-6.90(2H, m), 6.99-7.02(2H, m), 7.21(2H, d, J=7.8 Hz), 7.26(2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.78(1H, dd, J=7.8, 1.0 Hz), 9.61(1H, s), 11.26(1H, s).
Anal. Calcd. for C25H24N2O4.1⁄5H2O: C, 71.48; H, 5.85; N, 6.67(%).
Found: C, 71.49; H, 5.82; N, 6.63(%).
HR-FAB+ (m/z): 417.1834 (+2.0 mmu).
COMPOUND OF EXAMPLE 53
1H-NMR (DMSO-d6, δ): 3.63(3H, s), 3.66(2H, s), 3.70(2H, s), 3.77(6H, s), 6.69(2H, s), 6.72(1H, s), 7.01(1H, dd, J=7.8, 1.0 Hz), 7.21(2H, d, J=7.8 Hz), 7.27(2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.78(1H, dd, J=7.8, 1.0 Hz), 9.62(1H, s), 11.27(1H, s).
Anal. Calcd. for C26H26N2O5.1⁄5H2O: C, 69.38; H, 5.91; N, 6.22(%).
Found: C, 69.35; H, 5.88; N, 6.25(%).
HR-FAB+ (m/z): 447.1943 (+2.3 mmu).
COMPOUND OF EXAMPLE 54
1H-NMR (DMSO-d6, δ): 2.62-2.72(4H, m), 3.72(2H, s), 6.66(2H, d, J=8.3 Hz), 6.71(1H, s), 6.99-7.01(3H, m), 7.22(2H, d, J=8.3 Hz), 7.31 (1H, t, J=7.8 Hz), 7.76-7.78(1H, m), 9.13(1H, s), 9.60(1H, brs),11.27 (1H, brs).
Anal. Calcd. for C24H22N2O3.1⁄5H2O: C, 73.90; H, 5.79; N, 7.18(%).
Found: C, 73.86; H, 5.95; N, 7.16(%).
HR-FAB+ (m/z): 387.1698 (−1.0 mmu).
COMPOUND OF EXAMPLE 55
1H-NMR (DMSO-d6, δ): 3.70(2H, s), 3.75(2H, s), 6.72(1H, d, J=5.4 Hz),7.01(1H, d, J=7.8 Hz), 7.21(2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 7.32(1H, t, J=7.8 Hz), 7.39(2H, d, J=5.9 Hz), 7.77-7.79 (1H, m), 8.50 (2H, d, J=5.9 Hz), 9.61(1H, s), 11.26(1H, d, J=4.9 Hz).
Anal. Calcd. for C22H19N3O2.1⁄3H2O: C, 72.71; H, 5.45; N, 11.56(%).
Found: C, 72.71; H, 5.49; N, 11.42(%).
HR-MS (m/z): 351.1469 (−0.8 mmu).
COMPOUND OF EXAMPLE 56
1H-NMR (DMSO-d6, δ): 3.80(2H, s), 3.83(2H, s), 6.72(1H, d, J=5.4 Hz), 7.03(1H, d, J=7.8 Hz), 7.24(2H, d, J=8.3 Hz), 7.29-7.34(2H, m),7.39(1H, dd, J=7.8,4.9 Hz), 7.77-7.83(2H, m), 8.49(1H, d, J=4.4 Hz),8.58 (1H, s), 9.63(1H, s), 11.29(1H, d, J=3.9 Hz).
Anal. Calcd. for C22H19N3O2.4⁄5H2O: C, 71.07; H, 5.58; N, 11.30(%).
Found: C, 70.95; H, 5.46; N, 11.24(%).
HR-FAB+ (m/z): 358.1588 (+3.3 mmu).
COMPOUND OF EXAMPLE 57
1H-NMR (DMSO-d6, δ): 0.80-1.00(2H, m), 1,10-1.30(3H, m), 1,40-1.50 (1H, m), 1,60-1.80(5H, m), 2.37(2H, d, J=6.9 Hz), 3.70(2H, s),6.71(1H, s), 7.01(1H, d, J=7.8 Hz), 7.19(2H, d, J=7.8 Hz), 7.24(2H, d, J=7.8 Hz), 7.32(1H, t, J=7.8 Hz), 7.78(1H, d, J=7.8 Hz), 9.40-9.70 (1H, br),11.00-11.50(1H, br).
Anal. Calcd. for C23H26N2O2.1⁄3H2O: C, 74.97; H, 7.29; N, 7.60(%).
Found: C, 74.85; H, 7.30; N, 7.81(%).
HR-MS (m/z): 362.1983 (−1.1 mmu).
EXAMPLE 58
1,2-Dihydro-5-hydroxy-4-[[N-(4-hydroxybenzyl)-N-methyl]aminomethyl]phenyl]-1-oxoisoquinoline




To a solution of the compound of Example 13 (168 mg, 420 μmol) in acetic acid (4 ml) was added 47% hydrobromic acid (2 ml), and the mixture was refluxed for 6 hours. After cooling, water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the solution was brought to pH 8 with saturated aqueous solution of sodium hydrogencarbonate. This was extracted with ethyl acetate-methanol mixed solution (10:1), dried over anhydrous sodium sulfate, and then solvent was distilled off. A small quantity of ethyl acetate was added to the residue obtained. The crystals were collected by filtration, washed with ethyl acetate, and then air-dried, thereby affording 130 mg of the title compound as colorless powder. Yield 79%.
1H-NMR (DMSO-d6, δ): 2.08(3H, s), 3.40(2H, s), 3.47(2H, s), 6.71-6.74(3H, m), 6.99(1H, dd, J=7.8, 1.0 Hz), 7.14(2H, d, J=8.3 Hz), 7.21(2H, d, J=8.3 Hz), 7.25(2H, d, J=8.3 Hz), 7.31(1H, t, J=7.8 Hz), 7.77(1H, dd, J=7.8, 1.0 Hz), 9.27(1H, s), 9.63(1H, s), 11.27(1H, d, J=5.9 Hz).
Anal. Calcd. for C24H22N2O3.1⁄5H2O: C, 73.90; H, 5.79; N, 7.18(%).
Found: C, 73.93; H, 5.75; N, 7.13(%).
HR-FAB+ (m/z): 387.1704 (−0.4 mmu).
EXAMPLE 59
1,2-Dihydro-5-hydroxy-4-[4-[(3-hydroxybenzyl)aminomethyl]phenyl]-1-oxoisoquinoline




Using the compound of Example 51 (100 mg, 259 μmol), through the process similar to Example 58, 76.7 mg of the title compound were afforded as light brown powder. Yield 79%.
1H-NMR (DMSO-d6, δ): 3.63(2H, s), 3.68(2H, s), 6.72-6.80(3H, m), 7.00(1H, d, J=7.3 Hz), 7.08-7.11(1H, m), 7.21(2H, d, J=6.9 Hz), 7.26 (2H, d, J=6.9 Hz), 7.32(1H, t, J=7.8 Hz), 7.77 (1H, d, J=7.3 Hz), 9.26 (1H, s), 9.62(1H, s), 11.27(1H, s).
Anal. Calcd. for C23H20N2O3.1⁄6H2O: C, 73.58; H, 5.46; N, 7.46(%).
Found: C, 73.56; H, 5.47; N, 7.41(%).
HR-FAB+ (m/z): 373.1533 (−1.9 mmu).
EXAMPLE 60
1,2-Dihydro-5-hydroxy-4-[4-[(4-hydroxybenzyl)aminomethyl]phenyl]-1-oxoisoquinoline hydrobromide




To a solution of the compound of Example 50 (195 mg, 505 μmol) in acetic acid (4 mL) was added 47% hydrobromic acid (2 mL), and the mixture was refluxed for 8 hours. After cooling, water was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The precipitated crystals were collected by filtration, washed with water, and then air-dried, thereby affording 208 mg of the title compound as colorless powder. Yield 91%.
1H-NMR (DMSO-d6, δ): 3.98(2H, s), 4.06(2H, s), 6.73(1H, d, J=5.4 Hz), 6.80(2H, d, J=8.3 Hz), 7.06(1H, dd, J=7.8, 1.0 Hz), 7.27-7.39 (7H, m), 7.79(1H, dd, J=7.8, 1.0 Hz), 9.61(1H, s), 9.64(1H, s), 11.33(1H, d, J=5.4 Hz).
HR-FAB+ (m/z): 373.1568 (+1.6 mmu).
EXAMPLE 61
1,2-Dihydro-5-hydroxy-1-oxo-4-[4-[(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)methyl]phenyl]isoquinoline




Using the compound of Referential example 8 (200 mg, 716 μmol) and 4-hydroxy-4-phenylpiperidine (762 mg, 4.30 mmol), through the process similar to Example 1, 126 mg of the title compound were afforded as colorless powder. Yield 42%.
1H-NMR (DMSO-d6, δ): 2.69(2H,s), 3.10(2H,d,J=2.9 Hz), 3.61(2H,s), 6.17(1H,s), 6.75(1H,d,J=3.3 Hz), 7.01(1H,d,J=7.8 Hz), 7.18-7.35(8H, m), 7.43-7.45(2H,m), 7.76-7.78(1H,m), 9.68(1H,s), 11.27(1H,s).
Anal. Calcd. for C27H24N2O2.3⁄5H2O: C, 77.34; H, 6.06; N, 6.68;(%).
Found: C, 77.31; H, 5.91; N, 6.69;(%).
HR-MS (m/z): 408.1829 (−0.9 mmu).
EXAMPLE 62
4-[4-[(4-Benzyl-1,2,3,6-tetrahydropyridine-1-yl)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline and 4-[4-[(4-benzyl-4-hydroxypiperidino)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 8 (200 mg, 716 μmol) and 4-benzyl-4-hydroxypiperidine (822 mg, 4.30 mmol), through the process similar to Example 1, 51.9 mg (yield 17%) of 4-[4-[(4-benzyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline and 164 mg (yield 52%) of 4-[4-[(4-benzyl-4-hydroxypiperidino)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline were afforded as colorless powder.
4-[4-[(4-Benzyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline
1H-NMR (DMSO-d6, δ): 1.95(2H,s), 2.89(2H,s), 3.26(2H,s), 3.52(2H,s), 5.40(1H,s), 6.72(1H,d,J=5.9 Hz), 6.98-7.00(1H,m), 7.16-7.23(7H,m), 7.27-7.33(3H,m), 7.77(1H,dd,J=7.8,1.0 Hz), 9.63(1H,s), 11.27 (1H, d,J=5.4).
Anal. Calcd. for C28H26N2O2.1⁄2H2O: C, 77.93; H, 6.31; N, 6.49;(%).
Found: C, 78.07; H, 6.32; N, 6.44;(%).
HR-FAB+ (m/z): 423.2076 (+0.4 mmu).
4-[4-[(4-Benzyl-4-hydroxypiperidino)methyl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline
1H-NMR(DMSO-d6, δ): 1.35-1.38(2H,m), 1.47-1.54(2H,m),2.27-2.32 (2H,m), 2.67(2H,s), 3.43(2H,s), 4.14 (1H,s),6.72(1H,d,J=5.9 Hz), 6.99-7.00(1H,m), 7.16-7.27(9H,m), 7.31 (1H,t,J=7.8 Hz),7.77(1H, dd,J=7.8,1.0 Hz), 9.62(1H,s), 11.26 (1H,d,J=5.4).
Anal. Calcd. for C28H28N2O3.1⁄5H2O: C, 75.72; H, 6.45; N, 6.31;(%).
Found: C, 75.71; H, 6.52; N, 6.31;(%).
HR-MS (m/z): 441.2159 (−1.9 mmu).
EXAMPLE 63
1,2-Dihydro-4-[3-(dipropylamino)methyl-4-methoxyphenyl]-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 11 (190 mg, 614 μmol) and dipropylamine (506 μL, 3.69 mmol), through the process similar to Example 1, 148 mg of the title compound were afforded as colorless powder. Yield 62%.
1H-NMR (DMSO-d6, δ): 0.80(6H,t,J=7.3 Hz), 1.36-1.43(4H,m), 2.35 (4H,t,J=7.3 Hz), 3.51(2H,s), 3.78(2H,s), 6.67(1H,d,J=5.9 Hz),6.87 (1H,d,J=8.3 Hz), 7.01(1H,dd,J=7.8,1.0 Hz), 7.08(1H,dd, J=8.3,2.4 Hz), 7.25(1H,d,J=2.4 Hz), 7.31(1H,t,J=7.8 Hz), 7.75-7.77 (1H,m),9.49(1H, s), 11.20(1H,d,J=5.4 Hz).
Anal. Calcd. for C23H28N2O3.1⁄5H2O: C, 71.92; H, 7.45; N, 7.29;(%).
Found: C, 71.86; H, 7.46; N, 7.14;(%).
HR-MS (m/z): 380.2090 (−1.0 mmu).
EXAMPLE 64
1,2-Dihydro-4-[3-(dipropylamino)methyl-4-hydroxyphenyl]-5-hydroxy-1-oxoisoquinoline




To a solution of the compound of Example 63 (84.6 mg, 222 μmol) in dichloromethane (5 mL) was added 1 mol/L boron tribromide-dichloromethane solution (1.11 mL, 1.11 mmol), and the mixture was refluxed for 24 hours. After cooling, the reaction mixture was poured in ice water and the solution was brought to pH 8 with sodium carbonate. This was extracted using dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by Chromatolex NH column chromatography [ethyl acetate-methanol=20:1], thereby affording 69.8 mg of the title compound as colorless powder. Yield 86%.
1H-NMR (DMSO-d6, δ): 0.85(6H,t,J=7.3 Hz), 1.47-1.53(4H,m), 2.42-2.46(4H,m), 3.70(2H,s), 6.62(1H,d,J=7.8 Hz), 6.67(1H,d,J=5.9 Hz), 6.95-7.01(3H,m), 7.30(1H,t,J=7.8 Hz), 7.76(1H,d,J=8.3 Hz), 9.20-9.80(1H,br), 11.19(1H,d,J=4.9 Hz).
HR-MS (m/z): 366.1954 (−1.0 mmu).
EXAMPLE 65
1,2-Dihydro-4-[4-(2-dimethylamino)ethyl-3-nitrophenyl]-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 13 (574 mg, 1.50 mmol), through the process similar to Example 64, 61.5 mg of the title compound were afforded as yellow powder. Yield 11%.
1H-NMR (DMSO-d6, δ): 2.20(6H,s), 2.98(2H,t,J=7.8 Hz), 6.89(1H,d, J=5.4 Hz), 7.04(1H,d,J=7.8 Hz), 7.35(1H,t,J=7.8 Hz), 7.45(1H,d, J=8.3 Hz), 7.55(1H,dd,J=7.8,1.5 Hz), 7.77-7.79(2H,m), 9.90(1H,s), 11.42 (1H,d,J=5.4 Hz).
Anal. Calcd. for C19H19N3O4.1⁄3H2O: C, 63.50; H, 5.52; N, 11.69;(%).
Found: C, 63.51; H, 5.64; N, 11.53;(%).
HR-MS (m/z): 353.1413 (−1.0 mmu).
EXAMPLE 66
4-[3-Amino-4-(2-dimethylamino)ethylphenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




To a solution of the compound of Example 65 (46.0 mg, 130 μmol) in methanol-N,N-dimethylformamide (3:1, 4 mL) was added 10% palladium on carbon (moisture 51.1%, 5.00 mg), and the mixture was stirred for 2 hours at room temperature under hydrogen current (ambient pressure). Catalyst was filtered off using celite and solvent was distilled off. Acetone was added to the residue obtained. The crystals were collected by filtration, washed using acetone, and then air-dried, thereby affording 35.4 mg of the title compound as light brown powder.
Yield 84%.
1H-NMR (DMSO-d6, δ): 2.21(6H,s), 2.42(2H,t,J=7.8 Hz), 2.57(2H,t, J=7.8 Hz), 4.77(2H,s), 6.42(1H,dd,J=7.8,1.5 Hz), 6.54(1H,d,J=2.0 Hz), 6.65(1H,s), 6.84(1H,d,J=7.8 Hz), 6.95(1H,d,J=7.3 Hz), 7.28(1H,t,J=7.8 Hz), 7.71(1H,d,J=7.3 Hz), 9.10-10.10(1H,br),10.80-11.30(1H,br).
HR-MS (m/z): 323.1647 (+1.4 mmu).
EXAMPLE 67
1,2-Dihydro-4-[[4-(2-dimethylamino)ethyl]phenyl]-5-hydroxy-1-oxoisoquinoline




Process 1: To a solution of the compound of Referential example 17 (200 mg, 501 μmol) in tetrahydrofuran (5 mL) were added triethylamine (100 μL, 720 μmol) and methanesulfonyl chloride (60.0 μL, 780 μmol) under cooling with ice, and the mixture was stirred for 30 minutes at room temperature. Ice water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was dissolved in N,N-dimethylformamide (10 mL) and, after 2 mol/L dimethylamine-tetrahydrofuran solution (5.00 mL, 10.0 mmol) and potassium iodide (83.2 mg, 501 μmol) were added, the mixture was stirred for 7 hours at 100° C. in a sealed tube. After cooling, water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the solution was brought to pH 9 using sodium carbonate. This was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was dissolved in ethanol (20 mL) and, after 1 mol/L aqueous solution of potassium hydroxide (5.00 mL, 5.00 mmol) was added, the mixture was refluxed for 1 hour. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then solvent was distilled off. The residue obtained was purified by silica gel column chromatography [ethyl acetate-methanol=1:1], thereby affording 98.7 mg of 4-[4-[2-(dimethylamino)ethyl]phenyl]-5-hydroxy-1-methoxyisoquinoline as pale yellow powder. Yield 61%.
1H-NMR (CDCl3,δ): 2.34(6H,s), 2.59-2.63(2H,m), 2.83-2.88 (2H,m), 4.15(3H,s), 7.07(1H,dd,J=7.8,1.0 Hz), 7.36(2H,d,J=8.3 Hz), 7.41(2H, d,J=8.3 Hz), 7.47(1H,t,J=7.8 Hz), 7.72(1H,s), 7.93(1H,dd, J=8.3,1.0 Hz).
Process 2: To a solution of 4-[4-[2-(dimethylamino)ethyl]phenyl]-5-hydroxy-1-methoxyisoquinoline (91.3 mg, 283 μmol) in acetic acid (5 mL) were added 47% hydrobromic acid (0.5 mL) and water (0.5 mL), and the mixture was stirred for 1 hour at 100° C. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The solution was brought to pH 8 with saturated aqueous solution of sodium hydrogencarbonate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography [ethyl acetate-methanol=1:1], washed with ethyl acetate and water in order, and then air-dried, thereby affording 37.2 mg of the title compound as pale yellow powder. Yield 43%.
1H-NMR (DMSO-d6, δ): 2.20(6H,s), 2.72(2H,t,J=7.3 Hz), 6.71(1H,d, J=5.9 Hz), 6.99(1H,d,J=7.8 Hz), 7.13(2H,d,J=7.8 Hz), 7.17(2H,d, J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.76-7.78(1H,m), 9.64(1H,s), 11.26 (1H,d,J=4.9 Hz).
Anal. Calcd. for C19H20N2O2.1⁄4H2O: C, 72.94; H, 6.60; N, 8.95;(%).
Found: C, 72.87; H, 6.49; N, 8.92;(%).
HR-FAB+ (m/z): 309.1579 (−2.4 mmu).
EXAMPLES 68 THROUGH 92
Through the process similar to Example 67, compounds listed in following Table 15 were afforded.







TABLE 15













 










Example
position
n
NR3R4





68
4
2
NPr2


69
4
2
N(Me)Pr


70
4
2
N(Me)pentyl


71
4
2
N(Me)(CH2)2NMe2


72
4
2
N(Me)CH2-cyclohexyl


73
4
2
N(Me)CH2Ph


74
4
2
N(Me)CH2Ph-4-OMe


75
4
2
N(Me)CH2Ph-3-OMe


76
4
2
N(Me)CH2Ph-4-NH2


77
4
2
N(Me)CH2Ph-4-NMe2


78
4
2
N(Me)(CH2)2-cyclohexenyl


79
4
2
N(Me)(CH2)2Ph


80
4
2
N(Me)(CH2)2Ph-4-OMe


81
4
2
1,2,3,4-tetrahydroisoquinolin-2-yl


82
4
2
4-Ph-1,2,3,6-tetrahydropyridin-1-yl


83
4
2
4-Bn-piperazin-1-yl


84
3
2
NMe2


85
3
2
NPr2


86
4
3
NMe2


87
4
3
NPr2


88
4
3
N(Me)(CH2)2NMe2


89
4
3
N(Me)CH2Ph-4-OMe


90
4
3
N(Me)CH2Ph-4-NMe2


91
4
3
N(Me)(CH2)2Ph-4-OMe


92
4
3
4-Bn-piperazin-1-yl









COMPOUND OF EXAMPLE 68
1H-NMR (DMSO-d6, δ): 0.92(6H,brs), 1.30-1.90(4H,br), 2.80-3.30 (4H,br), 6.70(1H,d,J=5.9 Hz), 7.03(1H,d,J=7.8 Hz), 7.22(4H,brs), 7.33(1H,t,J=7.8 Hz), 7.78(1H,d,J=7.8 Hz), 9.61(1H,s), 11.29(1H,d,J=5.9 Hz).
HR-FAB+ (m/z): 365.2246 (+1.7 mmu).
COMPOUND OF EXAMPLE 69
1H-NMR (DMSO-d6, δ): 0.85(3H,t,J=7.3 Hz), 1.39-1.48(2H,m), 2.22 (3H,s), 2.32(2H,t,J=7.3 Hz), 2.52-2.56(2H,m), 2.69-2.73(2H,m), 6.71(1H,d,J=5.4 Hz), 6.99(1H,dd,J=7.8,1.5 Hz), 7.13(2H,d,J=8.3 Hz), 7.17(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8,1.0 Hz), 9.62(1H,brs), 11.26(1H,d,J=5.9 Hz).
Anal. Calcd. for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33;(%).
Found: C, 74.86; H, 7.24; N, 8.39;(%).
HR-FAB+ (m/z): 337.1938 (+2.2 mmu).
COMPOUND OF EXAMPLE 70
1H-NMR (DMSO-d6, δ): 0.87(3H,t,J=7.3 Hz), 1.23-1.32(4H,m), 1.39-1.46(2H,m), 2.23(3H,s), 2.36(2H,brs), 2.56(2H,brs), 2.72(2H,t,J=7.8 Hz), 6.71(1H,d,J=5.9 Hz), 6.99(1H,d,J=7.8 Hz), 7.13(2H,d, J=8.3 Hz), 7.17(2H,d,J=7.8 Hz), 7.31(1H,t,J=7.8 Hz), 7.76-7.78(1H,m), 9.62 (1H,brs), 11.26(1H,d,J=5.4 Hz).
Anal. Calcd. for C23H28N2O2.1⁄5H2O: C, 75.05; H, 7.78; N, 7.61;(%)
Found: C, 75.00; H, 7.84; N, 7.77;(%).
HR-FAB+ (m/z): 365.2197 (−3.2 mmu).
COMPOUND OF EXAMPLE 71
1H-NMR (DMSO-d6, δ): 2.14(6H,s), 2.24(3H,s), 2.30-2.34(2H,m), 2.45-2.48(2H,m), 2.56-2.60(2H,m), 2.70-2.73(2H,m), 6.71(1H,d, J=5.4 Hz), 6.99(1H,dd,J=7.8,1.0 Hz), 7.13(2H,d,J=8.3 Hz), 7.17 (2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8,1.0 Hz), 9.50-9.80(1H,br), 11.25(1H,d,J=4.9 Hz).
Anal. Calcd. for C22H27N3O2.1⁄5H2O: C, 71.59; H, 7.48; N, 11.39;(%).
Found: C, 71.57; H, 7.50; N, 11.29;(%).
HR-MS (m/z): 365.2078 (−2.6 mmu).
COMPOUND OF EXAMPLE 72
1H-NMR (DMSO-d6, δ): 0.70-1.00(2H,br), 1.10-1.30(4H,m), 1.50-1.80(6H,m), 2.00-2.40(4H,br), 2.60-2.90(2H,br), 6.70(1H,d, J=6.1 Hz), 7.00(1H,d,J=6.7 Hz), 7.10-7.25(4H,m), 7.32(1H,t,J=7.9 Hz), 7.77 (1H,d,J=7.9 Hz), 9.61(1H,s), 11.20-11.30(1H,m).
HR-FAB+ (m/z): 391.2389 (+0.3 mmu).
COMPOUND OF EXAMPLE 73
1H-NMR (DMSO-d6, δ): 2.20(3H,s), 2.59(2H,t,J=7.8 Hz), 2.79(2H,t, J=7.8 Hz), 3.55(2H,s), 6.71(1H,d,J=5.9 Hz), 6.98-7.00(1H,m), 7.11 (2H,d,J=8.3 Hz), 7.16(2H,d,J=8.3 Hz), 7.22-7.33(6H,m), 7.77 (1H,dd, J=7.8,1.0 Hz), 9.61(1H,s), 11.26(1H,d,J=5.4 Hz).
Anal. Calcd. for C25H24N2O2.2⁄5H2O: C, 76.66; H, 6.38; N, 7.15;(%).
Found: C, 76.73; H, 6.28; N, 7.10;(%).
HR-MS (m/z): 384.1803 (−3.5 mmu).
COMPOUND OF EXAMPLE 74
1H-NMR (DMSO-d6, δ): 2.20(3H,brs), 2.54-2.58(2H,m), 2.70-2.85 (2H,m), 3.48(2H,brs), 3.73(3H,s), 6.71(1H,d,J=5.5 Hz), 6.87(2H, d,J=7.3 Hz), 6.99(1H,d,J=7.9 Hz), 7.11(2H,d,J=7.9 Hz), 7.16(2H,d, J=7.9 Hz), 7.20(2H,d,J=6.7 Hz), 7.31(1H,t,J=7.9 Hz), 7.77(1H,d,J=7.3 Hz), 9.61(1H,s), 11.26(1H,d,J=6.1 Hz).
Anal. Calcd. for C26H26N2O3.1⁄2H2O: C, 73.74; H, 6.43; N, 6.61;(%).
Found: C, 73.52; H, 6.28; N, 6.50;(%).
HR-MS (m/z): 414.1957 (+1.4 mmu).
COMPOUND OF EXAMPLE 75
1H-NMR DMSO-d6, δ): 2.22(3H,s), 2.57-2.61(2H,m), 2.77-2.81(2H,m), 3.52(2H,s), 3.72(3H,s), 6.72(1H,d,J=5.9 Hz), 6.79-6.81(1H,m), 6.85-6.87(2H,m), 6.99(1H,dd,J=7.8,1.5 Hz), 7.11(2H,d,J=8.3 Hz), 7.16(2H, d,J=8.3 Hz), 7.22(1H,t,J=7.8 Hz), 7.31(1H,t,J=7.8 Hz), 7.76-7.78 (1H,m), 9.61(1H,s), 11.26(1H,d,J=5.4 Hz).
Anal. Calcd. for C26H26N2O3.1⁄6H2O: C, 74.80; H, 6.36; N, 6.71;(%).
Found: C, 74.81; H, 6.35; N, 6.75;(%).
HR-MS (m/z): 414.1977 (+3.3 mmu).
COMPOUND OF EXAMPLE 76
1H-NMR (DMSO-d6, δ): 2.19(3H,brs), 2.76(2H,brs), 4.93(2H,brs), 6.50(2H,d,J=8.3 Hz), 6.71(1H,d,J=5.9 Hz), 6.93(2H,d,J=8.3 Hz), 6.98 (1H,d,J=7.8 Hz), 7.09(2H,d,J=8.3 Hz), 7.16(2H,d,J=8.3 Hz), 7.31(1H,t, J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.61(1H,s), 11.25(1H, d,J=6.3 Hz).
Anal. Calcd. for C25H25N3O2.1⁄5H2O: C, 74.49; H, 6.35; N, 10.42;(%).
Found: C, 74.47; H, 6.37; N, 10.32;(%).
HR-FAB+ (m/z): 400.2002 (−2.3 mmu).
COMPOUND OF EXAMPLE 77
1H-NMR (DMSO-d6, δ): 2.20(3H,brs), 2.78(2H,brs), 2.87(6H,s), 3.45 (2H,s), 6.67(2H,d,J=8.8 Hz), 6.71(1H,d,J=5.9 Hz), 6.99(1H,d,J=7.8 Hz), 7.10(4H,d,J=8.8 Hz), 7.16(2H,d,J=8.3 Hz), 7.31(1H,t, J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.62(1H,s), 11.26(1H,d,J=5.9 Hz).
HR-MS (m/z): 427.2286 (+2.7 mmu).
COMPOUND OF EXAMPLE 78
1H-NMR (DMSO-d6, δ): 1.47-1.57(4H,m), 1.90-2.00(4H,m), 2.06 (2H,t, J=7.3 Hz), 2.24(3H,s), 2.45(2H,t,J=7.3 Hz), 2.57(2H,t,J=7.8 Hz), 2.72(2H,t,J=7.8 Hz), 5.40(1H,s), 6.70(1H,d,J=5.9 Hz), 7.00 (1H,d,J=7.8 Hz), 7.13(2H,d,J=8.3 Hz), 7.17(2H,d,J=7.8 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.62(1H,s), 11.26(1H,d,J=5.9 Hz).
HR-FAB+ (m/z): 403.2401 (+1.6 mmu).
COMPOUND OF EXAMPLE 79
1H-NMR (DMSO-d6, δ): 2.32(3H,s), 2.63-2.73(8H,m), 6.71(1H,d, J=5.4 Hz), 7.00(1H,d,J=7.8 Hz), 7.12-7.33(10H,m), 7.77(1H,d, J=7.8 Hz), 9.62(1H,s), 11.26(1H,d,J=5.4 Hz).
Anal. Calcd. for C26H26N2O2.1⁄5H2O: C, 77.66; H, 6.62; N, 6.97;(%).
Found: C, 77.57; H, 6.65; N, 6.94;(%).
HR-FAB+ (m/z): 399.2053 (−2.0 mmu).
COMPOUND OF EXAMPLE 80
1H-NMR (DMSO-d6, δ): 2.74(8H,brs), 3.72(3H,s), 6.71(1H,d,J=5.9 Hz), 6.87(2H,d,J=8.3 Hz), 7.01(1H,d,J=7.8 Hz), 7.17-7.19(6H,m), 7.32 (1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8,1.5 Hz), 9.63(1H,s), 11.28(1H,d, J=5.4 Hz).
HR-FAB+ (m/z): 429.2146 (−3.2 mmu).
COMPOUND OF EXAMPLE 81
1H-NMR (DMSO-d6, δ): 2.70-2.77(4H,m), 2.82-2.88(4H,m), 3.66(2H,s), 6.72(1H,d,J=5.9 Hz), 6.99(1H,d,J=6.8 Hz), 7.07-7.13(4H,m), 7.18(4H, s), 7.31(1H,t,J=7.8 Hz), 7.77(1H,t,J=6.8 Hz), 9.63(1H,s), 11.26(1H, d,J=5.4 Hz).
Anal. Calcd. for C26H24N2O2.1⁄5H2O: C, 78.05; H, 6.15; N, 7.00;(%).
Found: C, 78.03; H, 6.16; N, 6.86;(%).
HR-MS (m/z): 396.1801 (−3.7 mmu).
COMPOUND OF EXAMPLE 82
1H-NMR (DMSO-d6, δ): 2.65-2.69(2H,m), 2.74-2.77(2H,m), 2.80-2.84 (2H,m), 3.19(2H,d,J=2.4 Hz), 6.19(1H,s), 6.72(1H,d,J=5.9 Hz), 6.99 (1H,d,J=7.8 Hz), 7.18(4H,s), 7.24(1H,t,J=7.8 Hz), 7.29-7.36(3H,m), 7.44(2H,d,J=7.3 Hz), 7.77(1H,d,J=7.8 Hz), 9.63(1H,s), 11.26(1H,d, J=5.9 Hz).
Anal. Calcd. for C28H26N2O2.2⁄3H2O: C, 77.40; H, 6.34; N, 6.45;(%).
Found: C, 77.42; H, 6.23; N, 6.54;(%).
HR-MS (m/z): 422.1951 (−4.3 mmu).
COMPOUND OF EXAMPLE 83
1H-NMR (DMSO-d6, δ): 2.20-2.50(8H,m), 2.73(2H,t,J=7.8 Hz), 3.46 (2H,s), 6.71(1H,d,J=5.9 Hz), 6.99(1H,dd,J=7.8,1.0 Hz), 7.13(2H,d, J=7.8 Hz), 7.17(2H,d,J=7.8 Hz), 7.22-7.34(6H,m), 7.77(1H,dd, J=7.8, 1.0 Hz), 9.61(1H,s), 11.25(1H,d,J=5.4 Hz).
Anal. Calcd. for C28H29N3O2.1⁄4H2O: C, 75.73; H, 6.70; N, 9.46;(%).
Found: C, 75.70; H, 6.74; N, 9.32;(%).
HR-MS (m/z): 439.2274 (+1.5 mmu).
COMPOUND OF EXAMPLE 84
1H-NMR (DMSO-d6, δ): 2.18(6H,s), 2.46(2H,t,J=7.3 Hz), 2.70(2H,t, J=7.3 Hz), 6.72(1H,d,J=5.4 Hz), 7.01(1H,dd,J=7.8,1.0 Hz), 7.07-7.11 (3H,m), 7.19(1H,t,J=7.8 Hz), 7.32(1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8, 1.0 Hz), 9.64(1H,brs), 11.26(1H,d,J=4.9 Hz).
Anal. Calcd. for C19H20N2O2.1⁄3H2O: C, 72.59; H, 6.63; N, 8.91;(%).
Found: C, 72.70; H, 6.63; N, 8.83;(%).
HR-MS (m/z): 308.1517 (−0.7 mmu).
COMPOUND OF EXAMPLE 85
1H-NMR (DMSO-d6, δ): 0.85(6H,t,J=7.3 Hz), 1.46(4H,brs), 2.67(8H, brs), 6.72(1H,d,J=5.9 Hz), 7.02(1H,d,J=7.8 Hz), 7.11-7.21(4H,m), 7.32(1H,t,J=7.8 Hz), 7.78(1H,d,J=7.8 Hz), 9.60(1H,brs), 11.29(1H, brs).
HR-MS (m/z): 364.2132 (−1.9 mmu).
COMPOUND OF EXAMPLE 86
1H-NMR (DMSO-d6, δ): 1.67-1.75(2H,m), 2.14(6H,s), 2.24(2H,t,J=7.3 Hz), 2.59(2H,t,J=7.8 Hz), 6.71(1H,d,J=5.9 Hz), 6.99(1H,dd,J=7.8,1.0 Hz), 7.11(2H,d,J=8.3 Hz), 7.17(2H,d,J=7.8 Hz), 7.31(1H,t, J=7.8 Hz), 7.77(1H,dd,J=8.3,1.0 Hz), 9.62(1H,s), 11.25(1H,d, J=4.9 Hz).
Anal. Calcd. for C20H22N2O2.1⁄8H2O: C, 73.99; H, 6.91; N, 8.63;(%).
Found: C, 73.94; H, 6.99; N, 8.59;(%).
HR-MS (m/z): 322.1707 (+2.6 mmu).
COMPOUND OF EXAMPLE 87
1H-NMR (DMSO-d6, δ): 0.86(6H,t,J=7.3 Hz), 1.34-1.43(4H,m), 1.65-1.73(2H,m), 2.33(4H,t,J=7.3 Hz), 2.41(2H,t,J=6.8 Hz), 2.59(2H,t,J=7.3 Hz), 6.71(1H,d,J=5.9 Hz), 7.00(1H,d,J=7.8 Hz), 7.11(2H,d,J=7.8 Hz), 7.17(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.76-7.78(1H,m),9.61 (1H,s), 11.25(1H,d,J=5.4 Hz).
Anal. Calcd. for C24H30N2O2.4⁄5H2O: C, 73.36; H, 8.11; N, 7.13;(%).
Found: C, 73.10; H, 8.06; N, 7.00;(%).
HR-MS (m/z): 378.2341 (+3.3 mmu).
COMPOUND OF EXAMPLE 88
1H-NMR (DMSO-d6, δ): 1.67-1.75(2H,m), 2.13(6H,s), 2.16(3H,s), 2.29-2.40(6H,m), 2.59(2H,t,J=7.3 Hz), 6.71(1H,d,J=5.4 Hz), 6.99(1H, d,J=7.8 Hz), 7.11(2H,d,J=7.8 Hz), 7.17(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.63(1H,brs), 11.25(1H,d,J=5.4 Hz).
Anal. Calcd. for C23H29N3O2.1⁄4H2O: C, 71.94; H, 7.74; N, 10.94;(%).
Found: C, 71.98; H, 7.81; N, 10.95;(%).
HR-MS (m/z): 379.2263 (+0.3 mmu).
COMPOUND OF EXAMPLE 89
1H-NMR (DMSO-d6, δ): 1.78(2H,brs), 2.13(3H,brs), 2.38(2H,brs), 2.60(2H,t,J=7.8 Hz), 3.73(3H,s), 6.71(1H,d,J=5.9 Hz),6.89(2H,d,J=8.8 Hz), 7.00(1H,d,J=7.8 Hz), 7.10(2H,d,J=8.3 Hz), 7.16(2H,d, J=7.8 Hz), 7.22(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d, J=7.8 Hz), 9.62(1H,s), 11.26(1H,d,J=5.9 Hz).
Anal. Calcd. for C27H28N2O3. 11/10H2O: C, 72.33; H, 6.79; N, 6.25;(%).
Found: C, 72.29; H, 6.57; N, 6.33;(%).
HR-MS (m/z): 428.2100 (+0.0 mmu).
COMPOUND OF EXAMPLE 90
1H-NMR (DMSO-d6, δ): 1.74-1.78(2H,m), 2.09(3H,s), 2.34(2H,t,J=7.3 Hz), 2.59(2H,t,J=7.3 Hz), 2.86(6H,s), 6.68(2H,d,J=8.8 Hz), 6.71(1H,d, J=4.4 Hz), 7.00(1H,d,J=7.8 Hz), 7.08-7.11(4H,m), 7.15(2H,d,J=7.8 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d,J=8.3 Hz), 9.61 (1H,brs),11.26(1H, brs).
Anal. Calcd. for C28H31N3O2.H2O: C, 73.18; H, 7.24; N, 9.14;(%).
Found: C, 73.35; H, 7.11; N, 8.88;(%).
HR-MS (m/z): 441.2381 (−3.6 mmu).
COMPOUND OF EXAMPLE 91
1H-NMR (DMSO-d6, δ): 1.75(2H,brs), 2.33(3H,brs), 2.55-2.68(8H, m), 3.71(3H,s), 6.71(1H,d,J=5.4 Hz), 6.85(2H,d,J=8.8 Hz), 7.00(1H,d,J=7.8 Hz), 7.10(2H,d,J=8.8 Hz), 7.14-7.18(4H,m), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.60(1H,s), 11.26(1H,d,J=5.4 Hz).
HR-MS (m/z): 442.2234 (−2.3 mmu).
COMPOUND OF EXAMPLE 92
1H-NMR (DMSO-d6, δ): 1.69-1.76(2H,m), 2.30(2H,t,J=7.8 Hz), 2.38 (8H,brs), 2.59(2H,t,J=7.8 Hz), 3.45(2H,s), 6.71(1H,s),6.99(1H,d,J=7.8 Hz), 7.10(2H,d,J=7.8 Hz), 7.16(2H,d,J=7.8 Hz), 7.22-7.33(6H,m), 7.77(1H,dd,J=7.8,1.0 Hz), 9.59 (1H,brs), 11.24(1H,brs).
Anal. Calcd. for C29H31N3O2.1⁄3H2O: C, 75.79; H, 6.95; N, 9.14;(%).
Found: C, 75.75; H, 7.03; N, 9.09;(%).
HR-MS (m/z): 453.2405 (−1.1 mmu).
EXAMPLE 93
1,2-Dihydro-5-hydroxy-4-[4-[2-[N-(4-hydroxybenzyl)-N-methyl]aminoethyl]phenyl]-1-oxoisoquinoline




Using the compound of Example 74 (94.6 mg, 228 μmol), through the process similar to Example 58, 61.5 mg of the title compound were afforded as light brown powder. Yield 67%.
1H-NMR(DMSO-d6, δ): 2.94(4H,brs), 6.71(1H,d,J=5.9 Hz), 6.81(2H,brs), 7.01(1H,d,J=6.8 Hz), 7.16-7.21(6H,m),7.32(1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8,1.0 Hz), 9.62(1H,s), 11.29(1H,d,J=5.9 Hz).
HR-FAB+ (m/z): 401.1826 (−3.9 mmu).
EXAMPLE 94
1,2-Dihydro-5-hydroxy-4-[4-[2-[N-[2-(4-hydroxyphenyl)ethyl]-N-methyl]aminoethyl]phenyl]-1-oxoisoquinoline




Using the compound of Example 80 (129 mg, 301 μmol), through the process similar to Example 58, 106 mg of the title compound were afforded as light brown powder. Yield 83%.
1H-NMR (DMSO-d6, δ): 2.31(3H,brs), 2.60-2.73(8H,m), 6.66(2H,d, J=8.3 Hz), 6.71(1H,d,J=5.4 Hz), 6.99-7.02(3H,m), 7.13(2H,d,J=8.3 Hz), 7.17(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.14 (1H,s), 9.64(1H,brs), 11.26(1H,d,J=5.4 Hz).
Anal. Calcd. for C26H26N2O3.1⁄2H2O: C, 73.74; H, 6.44; N, 6.61;(%).
Found: C, 73.55; H, 6.27; N, 6.62;(%).
HR-FAB+ (m/z): 415.2044 (+2.3 mmu).
EXAMPLE 95
1,2-Dihydro-5-hydroxy-4-[4-[3-[N-(4-hydroxybenzyl)-N-methyl]aminopropyl]phenyl]-1-oxoisoquinoline




Using the compound of Example 89 (231 mg, 539 μmol), through the process similar to Example 58, 175 mg of the title compound were afforded as colorless powder. Yield 78%.
1H-NMR (DMSO-d6, δ): 1.81(2H,brs), 2.13(3H,brs), 2.60(2H,t,J=7.8 Hz), 6.70-6.74(3H,m), 7.00(1H,d,J=7.3 Hz), 7.11-7.18(6H,m),7.31 (1H,t,J=7.8 Hz), 7.77(1H,d,J=7.8 Hz), 9.29(1H,brs), 9.60(1H,brs), 11.26(1H,d,J=5.9 Hz).
HR-MS (m/z): 414.1945 (+0.1 mmu).
EXAMPLE 96
1,2-Dihydro-5-hydroxy-4-[4-[3-[N-[2-(4-hydroxyphenyl)ethyl]-N-methyl]aminopropyl]phenyl]-1-oxoisoquinoline




Using the compound of Example 91 (361 mg, 816 μmol), through the process similar to Example 58, 312 mg of the title compound were afforded as pale yellow powder. Yield 89%.
1H-NMR (DMSO-d6, δ): 1.65-1.80(2H,m), 2.24(3H,brs), 2.33(2H,brs), 2.54-2.60(6H,m), 6.66(2H,d,J=8.3 Hz), 6.71(1H,d,J=5.9 Hz),6.99(1H,d, J=7.8 Hz), 7.00(2H,d,J=8.3 Hz), 7.09(2H,d,J=7.8 Hz), 7.16(2H,d,J=8.3 Hz), 7.31(1H,t,J=7.8 Hz), 7.77(1H,dd,J=7.8,1.0 Hz),9.12 (1H,brs), 9.66(1H,brs), 11.25(1H,d,J=5.4 Hz).
HR-FAB+ (m/z): 428.2122 (+2.3 mmu).
EXAMPLES 97 THROUGH 103
Using the compound of Referential example 8 or the compound of Referential example 9, through the process similar to Example 45, compounds listed in following Table 16 were afforded.







TABLE 16













 











Example
Position
NR3R4







 97
4
4-(pyrrolidin-1-yl)piperidin-1-yl



 98
4
NH(CH2)3OH



 99
3
N(Me)CH2Ph



100
3
N(Me)(CH2)2Ph



101
3
N(Me)(CH2)3Ph



102
3
N(Me)Pr



103
3
N(Me)CH2Ph-4-OMe










COMPOUND OF EXAMPLE 97
1H-NMR (DMSO-d6, δ): 1.35-1.43(2H,m), 1.65(4H,brs), 1.80(2H,d,J=11.0 Hz), 1.93-1.99(2H,m), 2.46(4H,brs), 2.80(2H,d,J=11.0 Hz),3.44 (2H,s), 6.73(1H,d,J=4.9 Hz), 7.01(1H,d,J=6.7 Hz), 7.20(4H,s),7.31 (1H,t,J=7.9 Hz), 7.77(1H,d,J=7.3 Hz), 9.75(1H,brs),11.27(1H,d,J=5.5 Hz).
HR-MS (m/z): 403.2234 (−2.6 mmu).
COMPOUND OF EXAMPLE 98
1H-NMR (DMSO-d6, δ): 1.57-1.63(2H,m), 2.58(2H,t,J=6.7 Hz), 3.48(2H, t,J=6.1 Hz), 3.68(2H,s), 6.71(1H,s), 7.00(1H,d,J=7.9 Hz), 7.18-7.24 (4H,m), 7.31(1H,t,J=7.9 Hz), 7.77(1H,d,J=7.9 Hz), 11.25(1H,brs).
HR-MS (m/z): 324.1457 (−1.7 mmu).
COMPOUND OF EXAMPLE 99
1H-NMR (DMSO-d6, δ): 2.11(3H,s), 3.50(2H,s), 3.51(2H,s), 6.73(1H,d, J=5.5 Hz), 7.01(1H,d,J=7.9 Hz), 7.14-7.33(10H,m), 7.78(1H,d,J=7.9 Hz), 9.61(1H,s), 11.27(1H,brd,J=5.5 Hz).
Anal. Calcd. for C24H22N2O2. 1/10H2O: C, 77.44; H, 6.01; N, 7.53;(%).
Found: C, 77.20; H, 6.13; N, 7.31;(%).
HR-MS (m/z): 370.1674 (−0.7 mmu).
COMPOUND OF EXAMPLE 100
1H-NMR (DMSO-d6, δ): 2.20(3H,s), 2.59(2H,t,J=6.7 Hz), 2.77(2H,t, J=7.3 Hz), 3.53(2H,s), 6.70(1H,d,J=5.5 Hz), 7.02(1H,dd,J=7.9,1.2 Hz), 7.10-7.23(9H,m), 7.32(1H,t,J=7.9 Hz), 7.78(1H,dd,J=7.9,1.2 Hz),9.60 (1H,brs), 11.28(1H,brd,J=5.5 Hz).
Anal. Calcd. for C25H24N2O2. 1/10H2O: C, 77.73; H, 6.31; N, 7.25;(%).
Found: C, 77.64; H, 6.51; N, 7.04;(%).
HR-MS (m/z): 384.1867 (+3.0 mmu).
COMPOUND OF EXAMPLE 101
1H-NMR (DMSO-d6, δ): 1.75(2H,quin,J=7.3 Hz), 2.12(3H,s),2.36(2H,t, J=7.3 Hz), 2.58(2H,t,J=7.3 Hz), 3.45(2H,s),6.71(1H,d,J=5.5 Hz),7.01 (1H,d,J=7.3 Hz), 7.12-7.19(6H,m), 7.22-7.26(3H,m),7.32(1H,t,J=7.9 Hz),7.77(1H,dd,J=7.9,1.2 Hz), 9.62(1H,brs), 11.27(1H,brd,J=5.5 Hz).
Anal. Calcd. for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03;(%).
Found: C, 78.19; H, 6.75; N, 6.96;(%).
HR-MS (m/z): 398.2013 (+1.9 mmu).
COMPOUND OF EXAMPLE 102
1H-NMR (DMSO-d6, δ): 0.85(3H,t,J=7.3 Hz),1.47(2H,quin,J=7.3 Hz), 2.12(3H,s), 2.31(2H,br), 3.45(2H,brs), 6.72(1H,d,J=5.5 Hz), 7.01(1H, dd,J=6.7,1.2 Hz), 7.13-7.26(4H,m), 7.32(1H,t,J=7.9 Hz),7.77(1H,dd, J=6.7,1.2 Hz), 9.61(1H,brs), 11.26(1H,brd,J=5.5 Hz).
Anal. Calcd. for C20H22N2O2. 3/10H2O: C, 73.28; H, 6.95; N, 8.55;(%).
Found: C, 73.05; H, 6.97; N, 8.30;(%).
HR-FAB+ (m/z): 323.1731 (−2.8 mmu).
COMPOUND OF EXAMPLE 103
1H-NMR (DMSO-d6, δ): 2.09(3H,s), 3.44(2H,s), 3.47(2H,s), 3.73(3H,s), 6.73(1H,d,J=5.5 Hz), 6.88(2H,d,J=8.6 Hz), 7.01(1H,dd,J=6.7, 1.2 Hz), 7.14-7.16(1H,m), 7.21-7.28(5H,m), 7.32(1H,t,J=7.9 Hz), 7.78(1H,dd, J=6.7,1.2 Hz), 9.61(1H,s), 11.27(1H,brd,J=5.5 Hz).
HR-FAB+ (m/z): 401.1833 (−3.2 mmu).
EXAMPLE 104
1,2-Dihydro-5-hydroxy-1-oxo-4-[3-[(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)methyl]phenyl]isoquinoline




Using the compound of Referential example 9 (200 mg, 716 μmol) and 4-hydroxy-4-phenylpiperidine (762 mg, 4.30 mmol), through the process similar to Example 45, 208 mg of the title compound were afforded as brown powder. Yield 71%.
1H-NMR (DMSO-d6, δ): 2.46(2H,brs), 2.66(2H,t,J=5.5 Hz), 3.08(2H, d,J=2.4 Hz), 3.58(2H,s), 6.13(1H,s), 6.73(1H,s), 7.01(1H,dd,J=6.7, 1.2 Hz), 7.15-7.17(1H,m), 7.21-7.33(8H,m), 7.39-7.41(2H,m),9.64 (1H,brs), 11.26(1H,br).
HR-FAB+ (m/z): 409.1915 (−0.1 mmu).
EXAMPLES 105 THROUGH 108
Using the compound of Referential example 21, through the process similar to Example 45, compounds listed in following Table 17 were afforded.







TABLE 17













 








Example
NR3R4





105
NMe2


106
N(Me)Bu


107
pyrrolidin-1-yl


108
N(Me)CH2Ph









COMPOUND OF EXAMPLE 105
1H-NMR (DMSO-d6, δ): 2.19(6H,s), 3.56(2H,s), 6.73(1H,d,J=3.7 Hz), 6.77(1H,d,J=3.7 Hz), 6.89(1H,s), 7.00(1H,d,J=7.3 Hz), 7.30(1H,t, J=7.3 Hz), 7.71(1H,d,J=7.3 Hz).
HR-MS (m/z): 300.0923 (−0.9 mmu).
COMPOUND OF EXAMPLE 106
1H-NMR (DMSO-d6, δ): 0.87(3H,t,J=7.3 Hz), 1.23-1.34(2H,m), 1.40-1.47(2H,m), 2.17(3H,s), 2.36(2H,t,J=7.3 Hz), 3.63(2H,s), 6.73(1H,d, J=3.7 Hz), 6.77(1H,d,J=3.1 Hz), 6.90(1H,s), 7.03(1H,d, J=7.3 Hz), 7.32(1H,t,J=7.9 Hz), 7.75(1H,d,J=7.9 Hz), 9.74(1H,s), 11.34 (1H,s).
HR-MS (m/z): 342.1385 (−1.7 mmu).
COMPOUND OF EXAMPLE 107
1H-NMR (DMSO-d6, δ): 1.71(4H,s), 3.74(2H,s),6.72(1H,d,J=3.1 Hz), 6.78(1H,d,J=3.1 Hz), 6.91(1H,s), 7.03(1H,d,J=7.9 Hz),7.32(1H,t, J=7.9 Hz), 7.74(1H,d,J=7.9 Hz), 9.75(1H,s), 11.34(1H,s).
HR-MS (m/z): 326.1107 (+1.8 mmu).
COMPOUND OF EXAMPLE 108
1H-NMR (DMSO-d6, δ): 2.17(3H,s), 3.55(2H,s), 3.70(2H,s),6.75(1H,d, J=3.0 Hz), 6.82(1H,d,J=3.0 Hz), 6.92(1H,s), 7.03(1H,d,J=7.9 Hz), 7.25-7.35(7H,m), 7.75(1H,d,J=7.9 Hz), 9.75(1H,brs), 11.35(1H,brs).
HR-MS (m/z): 376.1257 (+1.1 mmu).
EXAMPLE 109
1,2-Dihydro-5-hydroxy-4-[4-[(N-methyl-N-propyl)aminomethyl]-1-naphthyl]-1-oxoisoquinoline




Using the compound of Referential example 23 (100 mg, 304 μmol) and N-methylpropylamine (187 μL, 1.82 mmol), through the process similar to Example 45, 25.5 mg of the title compound were afforded as grayish white powder. Yield 26%.
1H-NMR (DMSO-d6, δ): 0.88(3H,t,J=7.3 Hz), 1.55(2H,quin,J=7.3 Hz), 2.15(3H,s), 2.43(2H,t,J=7.3 Hz), 3.86(2H,s), 6.81-6.84(2H,m),7.27-7.35(3H,m), 7.38-7.50(3H,m), 7.81(1H,dd,J=6.7,1.2 Hz), 8.29(1H,d, J=7.9 Hz), 9.31(1H,s), 11.34(1H,brd,J=5.5 Hz).
HR-FAB+ (m/z): 373.1930 (+1.4 mmu).
EXAMPLE 110
4-[4-[(N-Benzyl-N-methyl)aminomethyl]-1-naphthyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 23 (100 mg, 304 μmol) and N-methylbenzylamine (235 μL, 1.82 mmol), through the process similar to Example 45, 44.4 mg of the title compound were afforded as colorless powder. Yield 35%.
1H-NMR (DMSO-d6, δ): 2.12(3H,s), 3.63(2H,s), 3.91-3.99(2H,m), 6.81-6.83(2H,m), 7.21-7.36(8H,m), 7.44-7.53(3H,m), 7.80(1H,d, J=7.9 Hz), 8.27(1H,d,J=8.6 Hz), 9.28(1H,s), 11.34(1H,brd,J=5.5 Hz).
HR-MS (m/z): 421.1895 (−2.1 mmu).
EXAMPLE 111
1,2-Dihydro-5-hydroxy-1-oxo-4-[4-[(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)methyl]-1-naphthyl]isoquinoline




Using the compound of Referential example 23 (100 mg, 304 μmol) and 4-hydroxy-4-phenylpiperidine (323 mg, 1.82 mmol), through the process similar to Example 45, 76.4 mg of the title compound were afforded as colorless powder. Yield 55%.
1H-NMR (DMSO-d6, δ): 2.74-2.84(3H,m), 3.19(3H,br), 4.03(2H,s), 6.18(1H,brs), 6.83-6.84(2H,m), 7.22-7.52(11H,m), 7.15-7.17(1H,m), 7.81(1H,d,J=7.9 Hz), 8.31(1H,d,J=8.6 Hz), 9.34(1H,s), 11.35(1H,brd, J=4.9 Hz).
HR-FAB+ (m/z): 459.2072 (−0.1 mmu).
EXAMPLES 112 THROUGH 116
Using the compound of Referential example 25, through the process similar to Example 45, compounds listed in following Table 18 were afforded.







TABLE 18













 








Example
NR3R4





112
NMe2


113
N(Me)pentyl


114
N(Me)CH2Ph


115
pyrrolidin-1-yl


116
NH(CH2)3OMe









COMPOUND OF 112
1H-NMR (DMSO-d6, δ): 2.32(6H,s), 3.63-3.65(2H,m), 6.76(1H,d,J=6.1 Hz), 7.03-7.05(1H,m), 7.11(1H,t,J=8.6 Hz), 7.23-7.26(1H,m),7.29-7.34(2H,m), 7.78(1H,dd,J=7.9,1.2 Hz), 9.70(1H,s),11.32(1H,d,J=4.9 Hz).
Anal. Calcd. for C18H17FN2O2.3⁄4H2O: C, 66.35; H, 5.72; N, 8.60;(%).
Found: C, 66.34; H, 5.54; N, 8.43;(%).
HR-MS (m/z): 312.1261 (−1.3 mmu).
COMPOUND OF EXAMPLE 113
1H-NMR (DMSO-d6, δ): 0.81(3H,t,J=6.7 Hz), 1.21-1.25(4H,m), 1.42-1.45(2H,m), 2.13(3H,s), 2.33(2H,t,J=7.3 Hz), 3.49(2H,s), 6.72(1H,d, J=5.5 Hz), 7.00-7.08(2H,m), 7.15-7.19(1H,m), 7.24(1H,dd,J=7.3,2.4 Hz), 7.32(1H,t,J=7.9 Hz), 7.77(1H,d,J=7.9 Hz), 9.64(1H,s),11.28(1H, d,J=5.5 Hz).
HR-MS (m/z): 368.1884 (−1.6 mmu).
COMPOUND OF EXAMPLE 114
1H-NMR (DMSO-d6, δ): 2.11(3H,s), 3.54(2H,s), 3.56(2H,s), 6.75 (1H,d,J=5.5 Hz), 7.02(1H,d,J=7.3 Hz), 7.08(1H,dd,J=9.8,8.6 Hz), 7.17-7.25(2H,m), 7.28-7.34(6H,m), 7.78(1H,dd,J=7.9,1.2 Hz), 9.66 (1H,s), 11.29(1H,d,J=5.5 Hz).
Anal. Calcd. for C24H21FN2O2: C, 74.21; H, 5.45; N, 7.21;(%).
Found: C, 74.09; H, 5.46; N, 7.23;(%).
HR-MS (m/z): 388.1583 (−0.4 mmu).
COMPOUND OF EXAMPLE 115
1H-NMR (DMSO-d6, δ): 1.68(4H,brs), 3.63(2H,brs), 6.74(1H,d,J=5.5 Hz), 7.01-7.08(2H,m), 7.16-7.19(1H,m), 7.26(1H,d,J=7.3 Hz), 7.32(1H,t,J=7.9 Hz), 7.77(1H,dd,J=7.9,1.2 Hz), 9.67(1H,s), 11.28 (1H,dd,J=4.3,1.2 Hz).
Anal. Calcd. for C20H19FN2O2.1⁄5H2O: C, 70.24; H, 5.72; N, 8.19;(%).
Found: C, 70.21; H, 5.54; N, 8.18;(%).
HR-MS (m/z): 338.1429 (−0.1 mmu).
COMPOUND OF EXAMPLE 116
1H-NMR (DMSO-d6, δ): 1.63(2H,t,J=6.7 Hz), 2.55(2H,t,J=6.7 Hz),3.16 (3H,s), 3.71(2H,s), 6.74(1H,s), 7.00-7.06(2H,m), 7.12-7.16 (1H,m), 7.30-7.34(2H,m), 7.77(1H,d,J=7.9 Hz), 9.50-9.90 (1H,br),11.29(1H, d,J=1.8 Hz).
HR-MS (m/z): 356.1568 (+3.2 mmu).
EXAMPLE 117
4-[4-(3-Dimethylaminopropene-1-yl)phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Process 1: To a solution of the compound of Referential example 27 (26.1 mg, 84.9 μmol) in dichloromethane (3 mL) was added thionyl chloride (7.44 μL, 102 μmol), and the mixture was stirred for 1 hour, while gradually returning the temperature to room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with brine, then dried over anhydrous sodium sulfate, and solvent was distilled off. After this was dissolved in tetrahydrofuran (3 mL), 2 mol/L dimethylamine-tetrahydrofuran solution (255 μL, 510 μmol) was added, and the mixture was stirred for 6 hours at 100° C. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure and purified by chromatolex NH column chromatography [ethyl acetate-methanol=10:1], thereby affording 17.1 mg of 4-[4-(3-dimethylaminopropene-1-yl)phenyl]-5-hydroxy-1-methoxyisoquinoline as colorless powder. Yield 60%.
1H-NMR (CDCl3, δ): 2.31(6H,s), 3.13(2H,d,J=6.7 Hz), 4.15(3H,s), 6.35(1H,dt,J=15.9,6.7 Hz), 6.59(1H,d,J=16.5 Hz), 7.08(1H,dd,J=7.3, 1.2 Hz), 7.43-7.53(5H,m), 7.72(1H,s), 7.93(1H,dd,J=7.9, 1.2 Hz).
Process 2: Using 4-[4-(3-dimethylaminopropene-1-yl)phenyl]-5-hydroxy-1-methoxyisoquinoline (15.0 mg, 44.9 μmol), through the process similar to Process 2 in Example 1, 12.7 mg of the title compound were afforded as light brown powder. Yield 88%.
1H-NMR (DMSO-d6, δ): 2.18(6H,s), 3.03(2H,d,J=6.7 Hz), 6.27(1H,dt, J=16.5,6.7 Hz), 6.54(1H,d,J=15.9 Hz), 6.74(1H,d,J=6.1 Hz), 7.02(1H,d, J=7.3 Hz), 7.21(2H,J=8.6 Hz), 7.30-7.36(3H,m), 7.77(1H,d, J=7.3 Hz), 9.67(1H,s), 11.29(1H,d,J=5.5 Hz).
HR-MS (m/z): 320.1501 (−2.4 mmu).
EXAMPLE 118
4-[4-[3-(Pyrrolidine-1-yl)propene-1-yl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 27 (50.0 mg, 163 μmol) and pyrrolidine (81.6 μL, 978 μmol), through the process similar to Example 117, 17.1 mg of the title compound were afforded as colorless powder. Yield 30%.
1H-NMR (DMSO-d6, δ): 1.70(4H,brs), 2.47(4H,brs), 3.20(2H,d,J=6.7 Hz), 6.32(1H,dt,J=15.9,6.7 Hz), 6.55(1H,d,J=15.9 Hz), 6.74(1H,s),7.02(1H,d,J=7.3 Hz), 7.21(2H,J=7.9 Hz), 7.30-7.36(3H,m), 7.77(1H,d,J=7.9 Hz), 9.64(1H,brs), 11.29(1H,brs).
HR-MS (m/z): 346.1670 (−1.1 mmu).
EXAMPLE 119
4-[4-[3-[(N-Benzyl-N-methyl)amino]propene-1-yl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 27 (50.0 mg, 163 μmol) and N-methylbenzylamine (126 μL, 978 μmol), through the process similar to Example 117, 3.1 mg of the title compound were afforded as colorless powder. Yield 5%.
1H-NMR (DMSO-d6, δ): 2.15(3H,s), 3.17(2H,d,J=6.7 Hz), 3.53(2H,s), 6.34(1H,dt,J=15.9,6.7 Hz), 6.55-6.60(1H,m), 6.74(1H,s), 7.01(1H,d, J=7.9 Hz), 7.21(2H,d,J=7.9 Hz), 7.24-7.34(6H,m), 7.37(2H,d,J=7.9 Hz), 7.77(1H,d,J=7.9 Hz), 9.68(1H,s), 11.29(1H,s).
HR-MS (m/z): 396.1853 (+1.5 mmu).
EXAMPLE 120
4-[4-[3-(4-Phenyl-1,2,3,6-tetrahydropyridine-1-yl)propene-1-yl]phenyl]-1,2-dihydro-5-hydroxy-1-oxoisoquinoline




Using the compound of Referential example 27 (50.0 mg, 163 μmol) and 4-hydroxy-4-phenylpiperidine (173 mg, 978 μmol), through the process similar to Example 117, 28.5 mg of the title compound were afforded as colorless powder. Yield 40%.
1H-NMR (DMSO-d6, δ): 2.68-2.71(2H,m), 3.14(2H,s), 3.24(2H,d,J=6.1 Hz), 6.18(1H,s), 6.35(1H,dt,J=15.9,6.7 Hz), 6.51(1H,d,J=15.9 Hz), 6.75(1H,d,J=4.3 Hz), 7.02(1H,d,J=7.9 Hz), 7.21-7.35 (3H,m),7.38(2H, d,J=7.9 Hz), 7.44(2H,d,J=7.9 Hz), 7.78(1H,d,J=7.9 Hz), 9.68(1H,s), 11.30(1H,d,J=4.9 Hz).
HR-MS (m/z): 434.1966 (−2.8 mmu).
EXAMPLE 121
1,2-Dihydro-4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-oxoisoquinoline methanesulfonate




To a suspension of the compound of Example 1 (414 mg, 1.41 mmol) in methanol (15 mL) was added methanesulfonic acid (101 μL, 1.55 mmol), and the mixture was stirred for 30 minutes at room temperature. Acetone was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The precipitated crystals were collected by filtration, washed with acetone, and then dried, thereby affording 492 mg of the title compound as light brown powder. Yield 88%.
1H-NMR (DMSO-d6, δ): 2.32(3H,s), 2.77(6H,d,J=4.9 Hz), 4.32(2H,d, J=4.9 Hz), 6.77(1H,d,J=6.1 Hz), 7.05(1H,dd,J=7.9,1.2 Hz), 7.32-7.43 (5H,m), 7.79(1H,dd,J=7.9,1.2 Hz), 9.58(1H,brs),9.70(1H,s),11.36 (1H,d,J=6.1 Hz).
Anal. Calcd. for C18H18N2O2.CH4O3S.1⁄3H2O: C, 57.56; H, 5.76; N,7.07;(%).
Found: C, 57.49; H, 5.56; N, 6.85;(%).
EXAMPLE 122
1,2-Dihydro-4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-oxoisoquinoline hydrochloride




To a suspension of the compound of Example 1 (200 mg, 679 μmol) in methanol (10 mL) was used 1 mol/L hydrochloric acid (679 μL,679 μmol), and, through the process similar to Example 121, 237 mg of the title compound were afforded as light brown powder. Yield quantitative.
1H-NMR (DMSO-d6, δ): 2.71(6H,d,J=4.9 Hz), 4.29(2H,d,J=5.5 Hz),6.77 (1H,d,J=5.5 Hz), 7.08(1H,dd,J=7.9,1.2 Hz), 7.34(1H,t,J=7.9 Hz),7.36 (2H,d,J=7.9 Hz), 7.48(2H,d,J=7.9 Hz), 7.78(1H,dd,J=7.9,1.2 Hz),9.79 (1H,s), 10.63(1H,brs), 11.37(1H,d,J=5.5 Hz).
Anal. Calcd. for C18H18N2O2.HCl.H2O: C, 61.98; H, 6.07; N, 8.03;(%).
Found: C, 61.94; H, 5.75; N, 7.77;(%).
EXAMPLE 123
1,2-Dihydro-4-[4-(dimethylaminomethyl)phenyl]-5-hydroxy-1-oxoisoquinoline hydrobromide




To a suspension of the compound of Example 1 (200 mg, 679 μmol) in methanol (10 mL) was used 1 mol/L hydrobromic acid (679 μL, 679 μmol), and, through the process similar to Example 121, 250 mg of the title compound were afforded as light brown powder. Yield 97%.
1H-NMR (DMSO-d6, δ): 2.69(6H,s), 4.21(2H,s), 6.77(1H,d,J=5.5 Hz), 7.04-7.06(1H,m), 7.32-7.41(5H,m), 7.79(1H,d,J=6.7 Hz),9.69(1H, s), 9.40-10.00(1H,br), 11.35(1H,d,J=5.5 Hz).
Anal. Calcd. for C18H18N2O2.HBr.1⁄5H2O: C, 57.07; H, 5.16; N, 7.39;(%).
Found: C, 57.07; H, 5.32; N, 7.05;(%).
TEST EXAMPLE
Inhibitory Experiment Against PARP Activity
PARP (Trevigen 4667-050-01) was diluted 35 times with a buffer consisting of 50 mmol/L Tris-HCl (pH 7.8), 100 mmol/L KCl and 1 mmol/L dithiothreitol to use for the experiment. In a plastic test tube were placed 76.5 μL of buffer consisting of 117.6 mmol/L Tris-HCl (pH 8.0), 11.8 mmol/L MgCl2, 5.9 mM dithiothreitol and 0.4 mmol/L NAD, 2.5 μL of [14C]NAD (NEN Life Science Products, Inc. NEC743, 370 kBq/mL), 1 μL of activated DNA (Trevigen 4667-50-06), testing compound or 10 μL of solvent for testing compound and 10 μL of the 35 times diluted PARP solution. After mixing well, the contents were warmed to 25° C. in a water bath. After 10 minutes, the reaction was stopped by adding 1 mL of ice-cold 20% trichloroacetic acid and the test tube was left on ice. The precipitates were collected on a glass fiber filter by suction filtration and washed 5 times with 5% trichloroacetic acid. The radioactivity on the filter was measured with liquid scintillation counter. The enzyme activity in the absence of testing compound was made to be 100%, and the concentration to decrease this to 50% (IC50 value) was calculated.







TABLE 19













 











IC50


Example
NR3R4
(nmol/L)





 1
NMe2
30


12
N(Me)CH2Ph
54


19
N(Me)(CH2)2Ph
41


21
N(Me)(CH2)3Ph
47


23
N(Me)CH2-cyclohexyl
126 


32
pyrrolidin-1-yl
33


61
4-Ph-1,2,3,6-tetrahydropyridin-1-yl
20









Results of this test are shown in Table 19. From these results, it was confirmed that the novel 4-substituted aryl-5-hydroxyisoquinolinone derivatives and their salts of the invention have excellent PARP inhibitory activity.
INDUSTRIAL APPLICABILITY
Based on the fact as above, the inventive compounds are novel 4-substituted aryl-5-hydroxyisoquinolinone derivatives and their salts, which have excellent PARP inhibitory activity. The inventive compounds with PARP inhibitory activity are useful as a preventive and/or therapeutic drugs for the diseases originating from excessive activation of PARP, for example, various ischemic diseases (cerebral infarction, cardiac infarction, acute renal failure, etc.), inflammatory diseases (inflammatory enteric disease, multiple cerebrosclerosis, arthritis, chronic rheumatism, etc.), nerve-degenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson disease, etc.), diabetes, septic shock, cephalic injury and the like.

## Claims

1. A 4-substituted aryl-5-hydroxyisoquinolinone compound represented by a formula (1)



wherein ring Ar denotes a phenyl group, naphthyl group, 5- or 6-membered aromatic heterocycle or its condensed ring, R1 denotes a hydrogen atom or halogen atom, R2 denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, aralkyloxy group which may have substituents, nitro group, amino group which may have substituents, aralkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5-or 6-membered heterocycle which may have substituents and its condensed ring, A denotes a C1 ̃C4 alkylene or C2 ̃C4 alkenylene, R3 denotes a hydrogen atom, lower alkyl group which may be substituted with halogen atom, or formula (2)


-Q1-R5  (2)


wherein Q1 denotes a C1 ̃C4 alkylene, and R5 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, amino group which may have substituents, lower alkoxycarbonyl group or carboxy group, R4 denotes a lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, formula (3)


-Q2R6  (3)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, lower alkoxycarbonyl group, carboxy group, cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or formula (4)




wherein R7 and R8 denote identically or differently hydrogen atoms, lower alkyl groups which may be substituted with halogenatom, aralkyl groups which may have substituents, or R7 and R8 are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or R3 with R4 are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

2. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1a)



wherein ring Ar denotes a phenyl group, naphthyl group, 5- or 6-membered aromatic heterocycle or its condensed ring, R1 denotes a hydrogen atom or halogen atom, R2a denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, nitro group, or amino group which may have substituents, A denotes a C1 ̃C4 alkylene or C2 ̃C4 alkenylene, R3 denotes a hydrogen atom, lower alkyl group which may be substituted with halogen atom, or formula (2)


-Q1-R5  (2)


wherein Q1 denotes a C1 ̃4 alkylene, and R5 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, amino group which may have substituents, lower alkoxycarbonyl group or carboxy group, R4 denotes a lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, formula (3)


-Q2-R6  (3)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, lower alkoxycarbonyl group, carboxy group, cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or formula (4)




wherein R7 and R8 denote identically or differently hydrogen atoms, lower alkyl groups which may be substituted with halogenatom, aralkyl groups which may have substituents, or R7 and R8 are bound together to form a 5- or 6- membered heterocycle which may have substituents and its condensed ring, or R3 and R4 are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

3. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1b)



wherein ring Ar denotes a phenyl group, naphthyl group, 5- or 6-membered aromatic heterocycle or its condensed ring, R1 denotes a hydrogen atom or halogen atom, R2a denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, nitro group, or amino group which may have substituents, A1 denotes a C1 ̃C4 alkylene, R3a denotes a hydrogen atom or lower alkyl group which may be substituted with halogen atom, R4a denotes a lower alkyl group which may be substituted with halogen atom, cycloalkyl group which may have substituents, formula (3)


-Q2R6  (3)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6 denotes a hydroxy group, lower alkoxy group which may be substituted with halogen atom, lower alkoxycarbonyl group, carboxy group, cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or formula (4)




wherein R7 and R8 denote identically or differently hydrogen atoms, lower alkyl groups which may be substituted with halogenatom, aralkyl groups which may have substituents, or R7 and R8 are bound together to form a 5- or 6- membered heterocycle which may have substituents and its condensed ring, or R3a and R4a are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

4. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1c)



wherein ring Ar denotes a phenyl group, naphthyl group, 5- or 6-membered aromatic heterocycle or its condensed ring, R1 denotes a hydrogen atom or halogen atom, R2a denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, nitro group, or amino group which may have substituents, A1 denotes a C1 ̃C4 alkylene, R3a denotes a hydrogen atom or lower alkyl group which may be substituted with halogen atom, R4b denotes a lower alkyl group which may be substituted with halogen atom, or formula (3a)


-Q2R6a  (3a)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6a denotes a cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or R3a and R4b are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

5. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1d)



wherein R1 denotes a hydrogen atom or halogen atom, R2a denotes a hydrogen atom, halogen atom, hydroxy group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group which may be substituted with halogen atom, nitro group, or amino group which may have substituents, A1 denotes a C1 ̃C4 alkylene, R3a denotes a hydrogen atom or lower alkyl group which may be substituted with halogen atom, R4b denotes a lower alkyl group which may be substituted with halogen atom, or formula (3a)


-Q2R6a  (3a)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6a denotes a cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or R3a and R4b are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

6. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1e)



wherein R1a denotes a hydrogen atom, R2b denotes a hydrogen atom, A1 denotes a C1 ̃-C4 alkylene, and R3b and R4c are bound together to form a 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

7. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1f)



wherein R1a denotes a hydrogen atom, R2b denotes a hydrogen atom, A1 denotes a C1 ̃4 alkylene, R3c denotes a lower alkyl group which may be substituted with halogen atom, and R4d denotes a lower alkyl group which may be substituted with halogen atom, or a pharmacologically acceptable addition salt thereof.

8. The 4-substituted aryl-5-hydroxyisoquinolinone compound of claim 1, represented by a formula (1g)



wherein R1a denotes a hydrogen atom, R2b denotes a hydrogen atom, A1 denotes a C1 ̃C4 alkylene, R3d denotes a hydrogen atom or lower alkyl group which may be substituted with halogen atom, R4e denotes formula (3a)


-Q2-R6a  (3a)


wherein Q2 denotes a C1 ̃C4 alkylene, and R6a denotes a cycloalkyl group which may have substituents, cycloalkenyl group which may have substituents, phenyl group which may have substituents, naphthyl group which may have substituents, or 5- or 6-membered heterocycle which may have substituents and its condensed ring, or a pharmacologically acceptable addition salt thereof.

9. The compound of claim 1, wherein the compound represented by said formula (1) is selected from the group consisting of 1,2-dihydiro-4-[4-(dimethylaminomethyl) phenyl]-5-hydroxy-1-oxoisoquiinoline, 1,2-dihydro-5-hydroxy-4-[4-[(N-methylbenzylamino)methyl]phenyl]-1-oxoisoquinoline, 1,2-dihydro-5-hydroxy-4-[4-[(N-methyl-2-phenylethylamino)methyl]phenyl]-1-oxoisoquinoline, 1,2- dihydro-5-hydroxy-4-[4-[(N-methyl-3-phenylpropylamino)methyl]phenyl]-1- oxoisoquinoline, 1,2-dihydro-5-hydroxy-4-[4-[(N-methylcyclohexylmethylamino) methyl]phenyl]-1-oxoisoquinoline, 1,2-dihydro-5-hydroxy-1-oxo-4-[4-[(pyrrolidin-1-yl)methyl]phenyl]isoquinoline and 1,2-dihydro-5-hydroxy-1-oxo-4-[4-[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]phenyl]isoquinoline.

10. An inhibitor of poly (ADP-ribose)synthetase comprising at least one compound according to claim 1.

11. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1 and at least one of a pharmacologically acceptable excipient or diluent.

12. A method for inhibiting poly (ADP-ribose) synthetase, comprising administering a therapeutically effective amount of the compound of claim 1 to a human being or an animal.