# Patent

## Title
Tricyclic indole compounds having affinity for serotonin receptor

## Abstract

Having an affinity against serotonine receptors, compound (I) shown below is useful as a therapeutic agent against various kinds of diseases of central nervous systems; 




(wherein R1 is hydrogen; R2 is hydrogen or lower alkyl; R3 is hydrogen, —COOR12 and so on; R4 is hydrogen, lower alkyl and so on, or R3 and R4 taken together may form ═O or ═S; R5 is hydrogen, or R3 and R5 taken together may form a bond; R6 is hydrogen, —COOR24 and so on; R7 is hydrogen, halogen, lower alkyl and so on; R8 is hydrogen, lower alkyl, cycloalkyl and so on; R9, R10 and R11 are each independently hydrogen, halogen, lower alkyl and so on).

## Background
This application is a U.S. national stage of International Application No. PCT/JP01/08049 filed Sep. 17, 2001.
1. Techinical Field
The present invention is related to tricyclic indole compounds. Having an affinity against serotonin receptors, the present compounds are useful as medicines, for example, a therapeutic agent for diseases of central nervous system thereof and useful as synthetic intermediates thereof.
2. Background Art
Serotonin (5-hydroxytryptamine) is one of amines, which exists in living body, and has a lot of physiological activities. For example, serotonin is located in granule cell of intestinal basal and promotes the movement of the intestinal tract. And also, on an occasion of bleeding, serotonin is released from platelets into blood and concerned with hemostasis by contracting blood capillary. Apart from this, serotonin works as a neurotransmitter in brain and takes part in modulating mental action, limit of pain, body-temperature and sleep-awakening cycle thereof, through serotonin receptors [Physiol. Rev. 72(1992) 165-229].
It has been reported that serotonin receptors are classified mainly to seven families and by including their subtypes, at least 14 kinds of receptors have been identified until now. Each receptor is reported to be concerned with various kinds of physiological functions and diseases [Pharmacol. Rev. 46(1994) 157-203]. Displaying to have agonistic or antagonistic activities, an agent having a binding affinity against serotonin receptors, is expected to be a therapeutic or prophylactic medicament. [Pharmacol.Rev. 43(1991) 509-525].
Among them, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7 are receptors which have been recently identified and cloned [FEBS Lett. 355(1994) 242-6, FEBS Lett. 333(1993) 25-31, J. Neurochem. 66(1996) 47-56, Neuron, 11(1993) 449-458] and there is few report about the selective agonist and antagonist. Each of these receptors has already been known to be located mainly in central nervous system. For example, it has been reported that 5-HT5A and 5-HT5B receptors are located in hippocampus and cerebral cortex, which are profoundly concerned with learning and memory [FEBS Lett. 355 (1994) 242-6, FEBS Lett. 333 (1993) 25-31], 5-HT6 receptor is located in corpus striatum, which is concerned with motor function [J. Neurochem. 66 (1996) 47-56], and 5-HT7 receptor is located in suprachiasmatic nucleus, which is concerned with mammalian biological clock [Neuron, 11(1993) 449-458]. Therefore, there is a possibility for the selective agonist or antagonist against the receptor to be a therapeutic agent for dementia, Parkinson's disease, psychosis or diseases concerning circannual rhythm thereof. Selective agonists and antagonists against serotonin receptors other than 5-HT5A, 5-HT5B, 5-HT6 and 5-HT7 receptors have already been launched as therapeutic agents for various kinds of diseases.
Furthermore, indole derivatives having an affinity against serotonin receptors have been disclosed; for example, compounds of a 4-membered ring type are disclosed in WO 96/32944, WO 95/28403, EP 0738513 and so on and compounds of a 3-membered ring type are disclosed in GB 2341549, WO 98/00400, JP 99-189585A and so on. However, these indole derivatives do not contain oxygen as an ring element. Moreover, naturally occurring heterocyclyl type of indole derivatives are described in WO 00/59909.
Under the situations mentioned above, development of novel compounds having an affinity against serotonin receptors and medicines containing them have been desired.
DISCLOSURE OF INVENTION
The present inventors have intensively studied to find that tricyclic indole compounds have an affinity against serotonin receptors, and accomplished the present invention shown below.

    (1) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof of the formula: 




wherein
    
        R1 is hydrogen;
        R2 is hydrogen or lower alkyl;
        R3 is hydrogen, —COOR12 (R12 is hydrogen or ester residue) or —CN;
        R4 is hydrogen, lower alkyl, —COOR13 (R13 is hydrogen or ester residue), —CONR14R15 (R14 and R15 are each independently hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R14 and R15 taken together with a neighboring nitrogen atom may form 5- to 7-membered heterocycle), —CN, —NO2, —NR16R17 (R16 and R17 are each independently hydrogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted amino, or R16 and R17 taken together with a neighboring nitrogen atom may form optionally substituted 5- to 7-membered heterocycle), —NR18COR19 (R18 and R19 are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —NR20COOR21 (R20 is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R21 is ester residue), —NR22SO2R23 (R22 is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R23 is lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, or lower alkylamino), —OH, lower alkoxy, —SH, or lower alkylthio, or R3 and R4 taken together may form ═O, ═S, or lower alkylenedioxy;
        R5 is hydrogen, or R3 and R5 taken together may form a bond;
        R6 is hydrogen, —COOR24 (R24 is hydrogen or ester residue), —CN, or —CH2NR25R26 (R25 and R26 are each independently hydrogen, lower alkyl, cycloalkyl, or lower alkenyl);
        R7 is hydrogen, halogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, —COOR34 (R34 is hydrogen or ester residue), —COR35 (R35 is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl) or —CHNOH;
        R8 is hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, —COR27 (R27 is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, —COOR28 (R28 is ester residue), —SO2R29 (R29 is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl) or tri-lower alkylsilyl;
        R9, R10 and R11 are each independently hydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR30 (R30 is hydrogen or lower alkyl), —CONH2, —CHO, —CHNOH, —COOR31 (R31 is hydrogen or ester residue), —NR32R33 (R32 and R33 are each independently hydrogen or lower alkyl), optionally substituted aryl, or optionally substituted heteroaryl.
    
    
    (2) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R2 is hydrogen.
    (3) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R3 is hydrogen.
    (4) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R5 is hydrogen.
    (5) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R3 and R5 taken together may form a bond.
    (6) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R3 and R4 taken together may form ═O, ═S or lower alkylenedioxy.
    (7) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R4 represents —COOR13 (R13 is hydrogen or lower alkyl), —NR16R17 (R16 and R17 are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R16 and R17 taken together may form an optionally substituted 5 to 7 membered heterocyclyl ring with the neighboring nitrogen atom), —NR18COR19 (R18 and R19 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR20COOR21 (R20 is hydrogen, or lower alkyl; R21 is an ester moiety), —NR22SO2R23 (R22 is hydrogen; R23 is lower alkyl or lower alkylamino), —OH, or lower alkoxy.
    (8) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R4 is —COOR13 (R13 is hydrogen or methyl), —NR16R17 (R16 is hydrogen or lower alkyl, R17 is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, optionally substituted amino or R16 and R17 are taken together may form an optionally substituted 5 to 7 membered heterocyclyl ring with the neighboring nitrogen atom), —NR18COR19 (R18 is hydrogen, R19 is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR20COOR21 (R20 is hydrogen or methyl; R21 is methyl), —NR22SO2R23 (R22 is hydrogen; R23 is methyl or methylamino), —OH, or lower alkoxy.
    (9) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R4 is —NH2, —NHCH3 or —N(CH3)2.
    (10) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R6 is hydrogen, COOCH3, COOCH2CH3, CN, or CH2NH2.
    (11) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R6 is hydrogen.
    (12) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R7 is hydrogen, lower alkyl, halogen, phenyl, —COOR34 (R34 is mentioned before), —CHO or —CHNOH.
    (13) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R7 is hydrogen, methyl, ethyl, halogen or phenyl.
    (14) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R8 is hydrogen, optionally substituted lower alkyl, —COR27 (R27 is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR28 (R28 is ester moiety), or —SO2R29 (R29 is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkylsilyl.
    (15) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R8 is hydrogen or —SO2R29 (R20 is mentioned before)
    (16) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein all of R9, R10 and R11 are hydrogen.
    (17) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R2 is hydrogen; R3 and R5 are both hydrogen or taken together may form a bond.
    (18) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 16 and 17, wherein R6 is hydrogen, COOCH3, COOCH2CH3, CN, or CH2NH2; R7 is hydrogen, lower alkyl, halogen or phenyl; R8 is hydrogen, lower alkyl, COPh, or SO2Ph (Ph represents phenyl).
    (19) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R9 is hydrogen or halogen.
    (20) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R9 is hydrogen.
    (21) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R10 is hydrogen.
    (22) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R11 is hydrogen, halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR30 (R30 is hydrogen or lower alkyl), —CONH2, —CHO, —CHNOH, —NR32R33 (R32 and R33 are each independently hydrogen or lower alkyl) or aryl.
    (23) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R11 is hydrogen, halogen, methyl, —CN, or —CONH2.
    (24) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R1, R2, R3, R5, R6, R9, and R10 is hydrogen; R4 is —NH2, —NHCH3, or —N(CH3)2; R7 is hydrogen, halogen, lower alkyl, or phenyl; R8 is hydrogen or —SO2R29 (R29 is mentioned before); R11 is hydrogen, halogen, lower alkyl, —CN, or —CONH2.
    (25) A pharmaceutical composition containing a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.
    (26) A therapeutic or prophylactic medicament against the serotonin receptors mediated diseases, comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.
    (27) A therapeutic or prophylactic medicament according to the above 26, wherein the serotonine receptor is a 5-HT6 receptor.
    (28) A therapeutic or prophylactic medicament according to the above 26, wherein the disease is that of central nervous system.
    (29) A therapeutic or prophylactic medicament according to the above 28, wherein the disease of the central nervous system is schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, pain or migraine.
    (30) A method for treating or preventing the serotonin receptors mediated diseases, which comprises administrating to said mammal an effective amount of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.
    (31) Use of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24, in order to prepare a therapeutic or prophylactic medicament for the serotonin receptors mediated diseases.


BEST MODE FOR CARRYING OUT THE INVENTION
Each group of compound (I) is explained below. Each term used herein is defined to have meanings described below in either case of a single or a joint use with other terms, unless otherwise noted.
“Halogen” refers to F, Cl, Br, I.
“Lower alkyl” includes a straight-chain and branched-chain C1-C6 alkyl group and refers to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl and the like, preferably a C1-C4 alkyl group and more preferably a C1-C3 alkyl group, such as methyl, ethyl, n-propyl, and i-propyl.
“Lower alkenyl” includes a straight-chain and branched-chain C2-C6 alkenyl group and refers to vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 1-pentenyl, prenyl, 2-hexenyl and the like, preferably vinyl, allyl or prenyl and the like.
“Lower alkoxy” includes oxy groups binding to an above mentioned lower alkyl group, and refers to methoxyl, ethoxyl, n-propoxyl, i-propoxyl, tert-butoxy, pentyloxy, hexyloxy and the like, preferably a C1-C4 alkoxyl group and more preferably a C1-C3 alkoxyl group such as methoxyl, ethoxyl, n-propoxyl, and i-propoxyl.
“Cycloalkyl” includes C3-C8 cycloalkyl and refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably a C5-C7 cycloalkyl group such as cyclopentyl, cyclohexyl, and cycloheptyl.
“Cycloalkyl(lower)alkyl” means an above mentioned lower alkyl group bound with an above mentioned cycloalkyl group and refers to cyclopropylmethyl, 2-cyclopropyl ethyl and the like.
“Lower alkylthio” includes a thio group bound with an above mentioned lower alkyl group and refers to methylthio, ethylthio, i-propylthio, tert-butylthio, pentylthio, hexylthio and the like, preferably methylthio.
“Aryl” used herein means a single or fused aromatic hydrocarbon ring system and refers to phenyl, naphthyl (such as α-naphthyl, and β-naphthyl), anthryl, indenyl, phenanthryl and the like, preferably phenyl or naphthyl.
“Lower alkylenedioxy” includes a straight-chain and branched-chain C1-C6 alkylendioxy group, preferably methylenedioxy, ethylenedioxy, or trimethylenedioxy, more preferably ethylenedioxy.
“Aralkyl” used herein means a lower alkyl group bound with an above mentioned aryl group, refers to benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as α-naphthylmethyl), anthrylmethyl such as 9-anthrylmethyl and the like.
“Heteroaryl” used herein means a single or polycyclic aromatic ring system in which the ring contains the same or different heteroatom selected from the group of O, S and N.
The single aromatric ring system includes a 5- to 7-membered ring moiety in which the heterocycle contains 1 to 4 heteroatoms and refers to furyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazinyl, triazinyl and the like, preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.
Polycyclic aromatic ring system includes a di- or tri-heterocyclic moiety in which the heterocycle contains 1 to 5 heteroatoms and refers to benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazoly, benzothiazolyl, benzotriazolyl and the like.
5- to 7-Membered heterocycle formed by “R14 and R15” or “R16 and R17” taken together with the neighboring nitrogen, refers to pyrrolydine, piperidine, azepine, piperazine, morpholine and the like, preferably pyrrolydine, piperazine or morpholine.
Substituents on the aryl, heteroaryl or heterocyclyl ring refer to halogen, hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl, lower alkyl (such as methyl or ethyl), halo-lower alkyl (such as —CCF3), lower alkyl-carbamoyl (such as methylcarbamoyl), lower alkyl-sulfamoyl (such as methylsulfamoyl), lower alkoxy (such as methoxyl), lower alkoxycarbonyl (such as ethoxylcarbonyl), a 5- to 7-membered heterocyclyl group such as isoxazolyl and the like, preferably halogen, methyl, methoxyl, trihalo-methyl such as trifluoromethyl, preferably 1 to 3 of these groups can be substituted.
“Ester” residue refers to lower alkyl, optionally substituted aralkyl and the like, preferably, methyl, ethyl, n-propyl, i-propyl, tert-butyl, benzyl and the like.
“Lower alkyl” or “lower alkenyl” can be optionally substituted, in which a substituent refers to hydroxy, halogen, amino and optionally mono- or di-lower alkyl substituted carbamoyl (such as carbamoyl, and dimethylcarbamoyl), phenyl, phenylamino, cyclohexylamino, lower alkoxy, lower alkoxycarbonyl such as methoxylcarbonyl and the like.
An optional substitutent on amino groups refers to lower alkyl, lower alkoxycarbonyl and the like.
Preferred examples are shown below.

    (1) both of R1 and R5 are hydrogen.
    (2) all of R1, R3, and R5 are hydrogen.
    (3) R1 is hydrogen; R3 and R4 are taken together may form a bond.
    (4) R1 is hydrogen; R3 and R4 are taken together may form ═O or ═S.


Other preferred examples are shown in following tables.












TABLE 1







R2
R3
R4
R6









H
H
H
H



methyl
COOR12
methyl
COOR24



ethyl
CN
ethyl
CN



n-propyl

n-propyl
CH2NR25R26



i-propyl

i-propyl





COOR13





CONR14R15





CN





NO2





NR16R17





NR18COR19





NR20COOR21





NR22SO2R23





OH





methoxyl





ethoxyl





n-propoxyl





i-propoxyl





SH





methyl thio





ethyl thio





n-propylthio





i-propylthio












—O(CH2)2O—




















TABLE 2





R7
R8
R9, R10, R11







H
H
H


F
methyl
F


Cl
ethyl
Cl


Br
n-propyl
Br


I
i-propyl
I


methyl
cyclopropylmethyl
methyl


ethyl
cyclopentyl
ethyl


n-propyl
cyclohexyl
n-propyl


i-propyl
cycloheptyl
i-propyl


cyclopropylmethyl
vinyl
cyclopropylmethyl


cyclopentyl
allyl
cyclopentyl


cyclohexyl
prenyl
cyclohexyl


cycloheptyl
benzyl
cycloheptyl


vinyl
phenethyl
vinyl


allyl
phenyl
allyl


prenyl
2-furyl
prenyl


benzyl
3-furyl
OH


phenethyl
2-pyridinyl
methoxyl


phenyl
3-pyridinyl
ethoxyl


2-furyl
4-pyridinyl
n-propoxyl


3-furyl
2-pyrrolyl
i-propoxyl


2-pyridinyl
3-pyrrolyl
CN


3-pyridinyl
2-thienyl
CHO


4-pridinyl
3-thienyl
SCH3


2-pyrrolyl
COR27
CH═N—OH


3-pyrrolyl
COOR28
CONH2


2-thienyl
SO2R29
phenyl


3-thienyl
Si(iPr)3
CH═CHCO2CH3


CN




















TABLE 3







R12, R13
R14, R16
R15, R17









H
H
H



methyl
methyl
methyl



ethyl
ethyl
ethyl



n-propyl
n-propyl
n-propyl



i-propyl
i-propyl
i-propyl



t-butyl
cyclopropyl methyl
cyclopropylmethyl



benzyl
cyclopentyl
cyclopentyl




cyclohexyl
cyclohexyl




cycloheptyl
cycloheptyl




allyl
allyl




prenyl
prenyl




benzyl
benzyl




phenethyl
phenethyl




phenyl
phenyl




2-furyl
2-furyl




3-furyl
3-furyl




2-pyridinyl
2-pyridinyl




3-pyridinyl
3-pyridinyl




4-pyridinyl
4-pyridinyl




2-pyrrolyl
2-pyrrolyl




3-pyrrolyl
3-pyrrolyl




2-thienyl
2-thienyl




3-thienyl
NHBoc





cyclopropyl





CH2CF3











—CH2CH2CH2CH2—




—CH2CH2CH2CH2CH2—




—CH2CH2CH2CH2CH2CH2—




—CH═CH—CH═CH—




—CH2CH2NHCH2CH2—




—CH2CH2NCH3CH2CH2—




—CH2CH2OCH2CH2—





















TABLE 4







R21
R18, R19, R20, R22
R23









methyl
H
methyl



ethyl
methyl
ethyl



n-propyl
ethyl
n-propyl



i-propyl
n-propyl
i-propyl



t-butyl
i-propyl
cyclopropylmethyl



benzyl
cyclopropylmethyl
cyclopentyl




cyclopentyl
cyclohexyl




cyclohexyl
cycloheptyl




cycloheptyl
vinyl




allyl
allyl




prenyl
prenyl




benzyl
benzyl




phenethyl
phenethyl




phenyl
phenyl




2-furyl
2-furyl




3-furyl
3-furyl




2-pyridinyl
2-pyridinyl




3-pyridinyl
3-pyridinyl




4-pyridinyl
4-pyridinyl




2-pyrrolyl
2-pyrrolyl




3-pyrrolyl
3-pyrrolyl




2-thienyl
2-thienyl




3-thienyl
3-thienyl




CH2N(CH3)2
NHCH3




CF3




CH2NH-cyclohexyl




















TABLE 5







R24
R25, R26









H
H



methyl
methyl



ethyl
ethyl



n-propyl
n-propyl



i-propyl
i-propyl



t-butyl
cyclopropylethyl



benzyl
cyclopentyl




cyclohexyl




cycloheptyl




vinyl




allyl




prenyl





















TABLE 6







R27
R28
R29









H
methyl
methyl



methyl
ethyl
ethyl



ethyl
n-propyl
n-propyl



n-propyl
i-propyl
i-propyl



i-propyl
t-butyl
cyclopropylmethyl



cyclopropylmethyl
benzyl
cyclopentyl



cyclopentyl

cyclohexyl



cyclohexyl

cycloheptyl



cycloheptyl

vinyl



vinyl

allyl



allyl

prenyl



prenyl

benzyl



benzyl

phenethyl



phenethyl

phenyl



phenyl

2-furyl



2-furyl

3-furyl



3-furyl

2-pyridinyl



2-pyridinyl

3-pyridinyl



3-pyridinyl

4-pyridinyl



4-pyridinyl

2-pyrrolyl



2-pyrrolyl

3-pyrrolyl



3-pyrrolyl

2-thienyl



2-thienyl

3-thienyl



3-thienyl

α-naphthyl





mono or diCl-phenyl





CF3-phenyl





Br-phenyl





mono or dimethoxy





phenyl





Br-di F-phenyl





phenyl vinyl





mono or diF-phenyl





Cl-thienyl





isoxyazolylthienyl










The following cases are more preferable.
R2 is more preferably hydrogen or methyl and particularly preferable is hydrogen.
R3 and R5 are more preferably both hydrogen or taken together may form a bond and particularly preferable is hydrogen.
R4 is preferably —COOR13 (R13 is hydrogen or lower alkyl), —NR16R17 (R16 and R17 is each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R16 and R17 taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR18COR19 (R18 and R19 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR20COOR21 (R20 is hydrogen, or lower alkyl; R21 is ester residue), —NR22SO2R23 (R22 is hydrogen; R23 is lower alkyl or lower alkylamino), —OH, lower alkoxy. R4 is preferably —COOR13 (R13 is hydrogen or methyl), —NR16R17 (R16 is hydrogen or lower alkyl, R17 is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R16 and R17 taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR18COR19 (R18 is hydrogen, R19 is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR20COOR21 (R20 is hydrogen or methyl; R21 is methyl), —NR22SO2R23 (R22 is hydrogen; R23 is methyl or methylamino), —OH, lower alkoxy. R4 is preferably —NH2, —NHCH3, or —N(CH3)2.
R6 is more preferably hydrogen, COOMe (Me is methyl), COOEt (Et is ethyl), CN, or CH2NH2, more preferably hydrogen.
R7 is preferably hydrogen, lower alkyl, halogen, phenyl, —COOR34 (R34 is hydrogen or ester residue), —CHO or —CHNOH, more preferably hydrogen, methyl, ethyl, halogen, or phenyl.
R8 is more preferably hydrogen, optionally substituted lower alkyl, —COR27 (R27 is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR28 (R28 is ester residue), or —SO2R29 (R29 is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl, more preferably hydrogen or —SO2R29 (R29 is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl). R29 is more preferably mono- or di-Cl-phenyl, CF3-phenyl, Br-phenyl, mono- or di-methoxyphenyl, phenylvinyl, mono- or di-F-phenyl, Cl-thienyl, naphthyl.
R9 is preferably hydrogen or halogen, more preferably hydrogen.
R10 is preferably hydrogen.
R11 is preferably hydrogen, halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR30 (R30 is hydrogen or lower alkyl), —CONH2, —CHO, —CHNOH, —NR32R33 (R32 and R33 is each independently hydrogen or lower alkyl) or aryl, more preferably hydrogen, halogen, methyl, —CN, or —CONH2.
In a preferred compound among compound (I), R1, R2, R3, R5, R6, R9, and R10 are hydrogen; R4 is —NH2, —NHCH3, or —N(CH3)2; R7 is hydrogen, halogen, lower alkyl or phenyl; R8 is hydrogen or —SO2R29 (R29 is mentioned before); R11 is hydrogen, halogen, lower alkyl, —CN, or —CONH2.
A produg of compound (I) is a derivative of compound (I), which has a chemically or metabolically decomposible group and can get back to a pharmaceutically active present invention compound by the solvolysis or under physiological conditions in vivo. Methods of selection and production of a suitable prodrug derivative has been disclosed, for example in Design of Prodrugs, Elsevier, Amsterdam 1985. Having a carboxylic acid group, the original acidic compound can be exemplified to be reacted with an appropriate alcohol derivative to give the ester derivative or reacted with a suitable amino derivative to give the amide derivative as the prodrug. Having a hydroxyl group, the hydroxyl compound for example can be exemplified to be reacted with appropriate acid halides or acid anhydrides to give the acyloxy derivative as the prodrug. Having an amino group, the amino compound can be exemplified to be reacted with a suitable acid halide or acid anhydride to give the amide compound as the prodrug.
A pharmaceutically acceptable salt of compound (I) or the prodrug refers to those salts, which are obtained by reacting with inorganic acids, inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, ionic halogen and the like, or the internal salt. The inorganic base refers to alkaline metals (Na, K and the like), alkaline-earth metal (Ca, Mg and the like). Organic base refers to trimethylamine, triethylamine, corrine, procaine, ethanolamine and the like. The inorganic acid refers to hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like. The organic acid refers to p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid and the like. Basic amino acid refers to lysine, arginine, ornithine, histidine and the like.
A solvate of compound (I) refers to the hydrate or alcholate and the like. The racemic or the optically active compound (I) and the like are all included in the present invention.
Compound (I) can be prepared from indole derivatives and the like as starting material which are well known or can be obtained easily by the synthesis. General method of preparation is shown below. 




(The 1st Process)

Compound (III) can be obtained by reacting indole derivative (II) with vinyl compound (IV) (X1 is H) in the presence of a base. This reaction can be accomplished fundamentally according to the Baylis-Hillman vinyl alkylation condition. The reaction temperature can be exemplified to be −20-50° C. and the solvent can be illustrated to be tetrahydrofuran (THF), dioxane, dichloromethane, chloroform and the like. Excess vinyl compound can be used as the solvent, also. As the base, 1,4-diazabicyclo [2,2,2]octane (DABCO), tri-n-butylphosphine and the like can be exemplified. The reaction time is ordinarily several hours to several days.
The preparation of compound (III) is also possible by reacting the acetylene compound R2C≡CR4 (V) with the vinyl compound (III) (X1 is Al(i-Bu)2), obtained from compound R2C≡CR4 (V) and diisopropylaluminumhydride (DIBAL). The reaction to the vinyl aluminum compound can be carried out according to a similar manner of well-known methods (for example: the method is disclosed in J. Org. Chem., 1988, 53, 1037.). The reaction temperature is exemplified to be ordinarily −100 to 50° C. and the solvent is tetrahydrofuran (THF), dioxane, dichloromethane and the like. The reaction temperature is normally several hours to tens of hours.
(The 2nd Process)
Compound (III) is cyclized under a Mitsunobu reaction condition to give compound (I-1) of the present invention. The Mitsunobu reaction can be carried out according to the well-known ordinary method (for example, a method disclosed in Synthesis, 1981,1.). The reaction temperature used are exemplified to be −50-50° C. and the solvent used are exemplified to be tetrahydrofuran (THF), dioxane, benzene, toluene, dichloromethane and the like, respectively. Among reagents, 1,1′-(azodicarbonyl)-diethyl ester, 1,1′-(azodicarbonyl)-diisopropyl ester, 1,1′-(azodicarbonyl)-dipieridine and the like are used in this reaction as diazocarboxylic acid ester derivatives. Further, triphenylphosphine, tri-n-butylphosphine and the like can be exemplified as phosphine derivatives. The reaction time is ordinarily several hours to tens of hours.
Furthermore, compound (I-1) can be obtained by cyclizing compound (III) in the presence of base. Moreover, in order to increase the yield of the reaction, it is preferable that the secondary hydrokyl group is first changed to the appropriate removable group such as acetoxyl group and the like and then the cyclization reaction is carried out in the presence of base. The reaction temperature can be exemplified to be 0-100° C. and the solvents can be exemplified to be tetrahydrofuran (THF), dioxane, toluene, acetone, acetonitrile, and the like, respectively. Potassium carbonate, NaH, pyridine, triethylamine and the like can be exemplified as the base used. The reaction time is ordinarily several hours to tens of hours.
Furthermore, it is possible in the 1st process to convert to compound (I-1) through the only one step by reacting compound (II) with compound (IV) (X1 is H) at relatively high temperature (20-50° C.).
Furthermore, it is possible to convert to compound (I-1) through the only one step by reacting compound (II) and compound (IV) (X1 is —PO(OMe)2) under the presence of base. The reaction temperature is ordinarily −20-50° C. Tetrahydrofuran (THF), dioxane, toluene, dichloromethane and the like can be exemplified as the solvent. Potassium tert-butoxyde and the like can be exemplified as the base. The reaction time is ordinarily several hour to tens of hours.
According to the above reaction, preferably a compound, in which R4 in compound (I-1) is electron-withdrawing group, is obtained. As the electron-withdrawing group, ester group, carboxylic acid group, cyano group, amide group, aldehyde group, nitro group and the like are exemplified.
Compound (I-1) is a compound (I) in the present invention, where R1 and R6 are both hydrogen and R3 and R5 taken together may form a bond. Compound (I-1) can be derived to other compounds of the present invention by chemical modifications. For example, compound (I-1), where R4 is carboxylic acid, can be transferred to the various kinds of ester and amide compounds by converting to the acid chloride with thionyl chloride and the like or to the acid anhydride with ethyl chloroacetate and the like under the existence of base such as triethylamine, followed by reacting with the various kinds of alcohol or amino derivatives. Furthermore, compound (I-1) can also be transferred to the various kinds of ester and amide compounds by using appropriate condensing agents such as dicyclohexylxarbodiimide, carbonyldiimidazole and the like. Further, if the reaction is carried out according to Curtius reaction or Hofmann reaction, compound in which R4 is carbamate can be obtained. Moreover, compound in which R4 is hydroxy (or R3 and R4 taken together may form ═O) can be prepared by the hydrolysis of the compound in which R4 is carbamate. Furthermore, by reduction catalytically or with sodium borotriacetoxyhydride under the presence of appropriate base, compound, in which R3 and R4 taken together may form ═O, can be transferred to compounds in which R4 is various kind of N-alkyl groups.
(The 3rd Process))
Compound (I-2) of the present invention can be obtained by the reduction of compound (I-1). Compound (I-2) is a compound (I) of the present invention, where all of R1, R3, R5 and R6 are hydrogen. The reduction reaction is carried out preferably by a catalytic reduction (Pd/C, H2) thereof. By further chemical modifications of compound (I-2), another compound of the present invention can be obtained. For example, in the case where R4 is primary or secondary amino group, compound (I-2) can be converted to the various kinds of N-sulfonyl or N-acyl compounds by reacting with various kinds of sulfonyl chloride or acyl chloride in the presence of base such as triethylamine and the like. Furthermore, compound (I-2) can be transferred to various kinds of N-alkyl compounds by reacting with various kinds of alkyl halide under the presence of base such as triethylamine and the like or by reduction catalytically or with sodium triacetoxyborohydride in the presence of various kinds of aldehydes or ketones. 




Compound (I-3) of the present invention can be obtained by cyclization of indole derivative (IV) (X2 is a removing group such as lower alkoxy and the like) preferably under the presence of base. Compound (I-3) is a compound in which R3 and R5 taken together may form a bond and R4 is a hydroxy group in compound (I). As the solvent, ether, tetrahydrofuran (THF), dioxane and the like are exemplified. NaH, sodium metal, potassium tert-butoxyde lithium bis(trimethylsilyl)amide and the like are exemplified as the base. The reaction time is ordinarily several hours to tens hours. By this reaction, a preferred compound is obtained, in which R6 is an electron-withdrawing group such as carboxylic acid group, ester group, cyano group.
Moreover, R1 and R2 are preferably hydrogen in the above preparations. Furthermore, if necessary, the group can be protected before the reaction and de-protected after the reaction by the well-known method. For example, R8 in the intermediate is preferably an amino protecting group such as Boc. Compounds obtained by the above method of preparation of the present invention can be transferred to another compound of this invention by further chemical modifications of well-known reaction such as oxidation, reduction, protection, deprotection, rearrangement reaction, halogenation, hydroxylation, alkylation, alkylthiolation, demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation, coupling reaction using transition metals and the like.
Having an affinity against various kinds of serotonin receptors, compound (I) has functions as the agonist or antagonist. Therefore, compound (I) is useful as a therapeutic or prophylactic medicine to various serotonin receptor mediated diseases, such as diseases of central nervous systems such as sleep-awakening lesion, circadian rhythm lesion, anxiously mental disorder, schizophrenia, cerebral stroke, dementia, pain, Alzheimer's disease, Parkinson's disease, depression, anxiety, megrim and the like. A specifically preferable compound (I) described above has an affinity against 5HT1A, 5HT6, 5HT7 among serotonin receptors and more preferably has a high selective affinity against 5HT6. Increase of the selectivity against 5HT6 can be achieved preferably by introducing various kinds of substituents to R7 and R11 and so on. Then, compound (I) is useful to the selectively 5HT6 receptor mediated diseases among the diseases of central nervous system (for example, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, migraine and the like).
Compound (I) can be administrated orally or parenterally to mammals including human. Granule, tabula, capsules, injections, suppositorium and the like can be exemplified as an admirable dosage form. In pharmaceutical manufacturing, if necessary, following various additive agents can be used, for example remedium constituens (lactose, mannitol, crystalline cellulose, starch and the like), disintegrators (carmellose, hydroxypropylmethyl cellulose, polyvinylpolypyrrolidone and the like), binding agent (methylcellose, hydroxypropylcellose, cellose, poloyvinylalcohol and the like), lubricant (Magnesium stearate, talc and the like), stabilizing agent, coloring agent, coating material. Dosage varies depending on the examinee's age, body weight, condition of diseases and dosage forms and so on. Generally, dosage is ca. 0.001 mg to 1 g/day to an adult in oral or parenteral administration. Number of administration time is one to several times/day.
Examples of this invention are described below without limiting the present invention thereto. “Ex” in the Scheme of reaction corresponds to the number of Example, e.g. “Ex 1” means compound (1) obtained by the procedure cited in Example 1.
(Abbreviated Words)


    Me=methyl; Et=ethyl; tBu=t-butyl; nPr=n-propyl; Ph=phenyl; Ts=p-toluene sulfonyl; Bn=benzyl; Ms=methanesulfonyl




EXAMPLE 1 OF REFERENCE





4-Hydroxyindole-3-carbaldehyde (1-1) (R7═R11═H)
Phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature. Water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials. Yield 82%. Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193° C.
1H-NMR(DMSO-d6): 6.54 (1H, dd, J=8.1, 0.9 Hz), 6.95 (1H, dd, J=8.1, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 8.37 (1H, s), 9.64 (1H, s), 10.54 (1H, br s), 12.35 (1H, br s).
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (DMSO-d6)







1-2
Ph
H
239-247
6.57 (1H, dd, J=8.1, 0.9 Hz), 6.95





(dec.)
(1H, dd, J=8.1, 0.9 Hz), 7.17 (1H, t,






J=8.1 Hz), 7.61-7.82 (5H, m), 9.56






(1H, s), 11.05 (1H, s), 12.67 (1H, br s)


1-3
Me
Me
269-272
2.16 (3H, s), 2.66 (3H, s), 6.72 (1H, d,





(dec.)
J=8.1 Hz), 6.93 (1H, d, J=8.1 Hz),






9.64 (1H, br s), 11.05 (1H, s), 12.14






(1H, br s)









EXAMPLE 2 OF REFERENCE





3-Formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester (2-1) (R7═R11═H)
A mixture of the 3-formyl-4-hydroxyindole (1-1) 323 mg, di-tert-butyldicarbonate 458 mg, dimethylaminopyridine 12.5 mg and acetonitrile 25 ml was stirred under cooling in ice for 3 h. The solvent was removed under reduced pressure and the residue obtained was recrystallized from acetone-isopropyl ether to give the titled compound as pale yellow crystals, m.p. 159-161° C.(dec.), 389 mg. Yield 74%.
1H-NMR(CDCl3): 1.71 (9H, s), 6.84 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, t, J=8.1 Hz), 7.61 (1H, dd, J=8.1, 0.9 Hz), 8.25 (1H, s), 9.76 (1H, d, J=0.6 Hz), 10.13 (1H, s).
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (CDCl3)







2-2
Ph
H
154-155
1.26 (9H, s), 6.86 (1H, dd, J=8.4,





(dec.)
0.9 Hz), 7.33 (1H, t, J=8.4 Hz),






7.43-7.53 (5H, m), 7.66 (1H, dd,






J=8.4, 0.9 Hz), 9.36 (1H, s), 10.64






(1H, s)


2-3
Me
Me
177-179
1.71 (9H, s), 2.30 (3H, s), 2.88 (3H, s),





(dec.)
7.09 (1H, d, J=8.4 Hz), 7.39 (1H, d,






J=8.4 Hz), 9.90 (1H, br s), 10.92






(1H, s)









EXAMPLE 3 OF REFERENCE





5-Bromo-3-formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester (2-4)
Compound (2-1) 26.1 g was suspended in dry tetrahydrofuran 260 ml and chloroform 260 ml. Pyridinium bromide perbromide 33.6 g was added to the suspension under cooling in ice and the mixture was stirred at room temperature for 4.5 h. An aqueous sodium hydrogen carbonate 16.77 g solution was added to the reaction mixtures, which were extracted with chloroform. The extracts were washed with water, dried over anhydrous magnesium sulfate, concentrated up to the deposition of crystals and diluted with isopropanol. Appeared crystals were collected by filtration to give the titled compound as yellow crystals. 29.1 g. Yield 86%. m.p. 239-242° C.(dec.)
1H-NMR(CDCl3): 1.71 (9H, s), 7.52 (2H, s), 8.24 (1H, s), 9.75 (1H, s), 10.91 (1H, br s).
Scheme of Reactions, Examples 1-5





Example 1
7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1) (R7═R11═H)
(Method 1)
60% Sodium hydride 23.0 mg was suspended in dry tetrahydrofuran 4 ml. Compound (2-1) 123 mg and trimethyl-2-phosphonoacrylate 116 μl were added with cooling in ice under nitrogen atmosphere and the mixture was stirred for 19 h. Water was added to the mixture with cooling in ice and the mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and chromatographed on silica gel 25 g in ethyl acetate:hexane (1:10) to give the titled compound (3-1) as colorless crystals, 46 mg. Yield 30%.
1H-NMR(CDCl3): 1.69 (9H, s), 3.84 (3H, s), 5.06 (2H, s), 6.85 (1H, dd, J=7.5, 0.6 Hz), 7.24 (1H, t, J=7.5 Hz), 7.74 (1H, s), 7.77 (1H, d, J=7.5 Hz), 8.00 (1H, s).
(Method 2)
Compound (2-1) 140 mg, 1,4-diazabicyclo[2.2.2]octane 70 mg was suspended in methyl acrylate 1.4 ml and the suspension was stirred at room temperature for 4 days. Ethyl acetate was added to the reaction mixtures and the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and chromatographed on silica gel 25 g in ethyl acetate:hexane (1:10) to give titled compound (3-1) as colorless crystals 59 mg. Yield 34%.
(Method 3)
(a) 4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)indole-1-carboxylic acid tert-butyl ester (4-1) (R7═R11═H)
Compound (2-1) 140 mg and 1,4-diazabicyclo[2.2.2]octane 70 mg were suspended in methyl acrylate 1.4 ml with cooling in ice and the suspension was stirred at 4° C. for 24 h. The reaction mixtures was chromatographed on silica gel in ethyl acetate:hexane several times to give the titled compound (4-1) as a colorless oil 178 mg. Yield 96%.
1H-NMR (CDCl3): 1.66 (9H, s), 3.86 (3H, s), 5.05 (1H, br s), 5.63 (1H, s), 5.81 (1H, s), 6.39 (1H, s), 6.78 (1H, dd, J=8.1, 0.9 Hz), 7.24 (1H, t, J=8.1 Hz), 7.31 (1H, s), 7.67 (1H, d, J=8.1 Hz), 9.10 (1H, br s).
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (CDCl3)







4-2
Ph
H
121-122
1.21 (9H, s), 3.82 (3H, s), 5.01 (1H,






br s), 5.51 (2H, s), 6.35 (1H, s), 6.81






(1H, dd, J=7.8, 0.6 Hz), 7.28 (1H, t,






J=8.4 Hz), 7.38-7.40 (5H, m), 7.83






(1H, dd, J=8.4, 0.6 Hz), 9.14 (1H, s)


4-3
Me
Me
155-156.5
1.68 (9H, s), 2.29 (3H, s), 2.48 (3H, s),






3.87 (3H, s), 5.14 (1H, br s), 5.37 (1H,






s), 5.96 (1H, s), 6.30 (1H, s), 7.05 (1H,






d, J=8.4 Hz), 7.56 (1H, d, J=8.4 Hz),






9.27 (1H, s)


4-4
H
Br
Colorless
1.66 (9H, s), 3.85 (3H, s), 5.13 (1H, d,





oil
J=5.4 Hz), 5.62 (1H, s), 5.82 (1H, d,






J=5.4 Hz), 6.39 (1H, s), 7.32 (1H, s),






7.44 (1H, d, J=8.7 Hz), 7.57 (1H, d,






J=8.7 Hz), 9.59 (1H, br s)









(b) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1)
Triethylamine 20.1 mg, 1,1′-(azodicarbonyl)-dipiperidine 42.0 mg and triphenylphosphine 43.9 mg were dissolved in dry tetrahydrofuran 1 ml. Compound (4-1) 37 mg was added to the solution with cooling in ice under nitrogen. The mixture was stirred at room temperature for 17 h. Water was added with cooling in ice and the reaction mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and chromatographed on silica gel 15 g in ethyl acetate:hexane (1:3) to give titled compound (3-1) as colorless crystals, 17. mg. Yield 48%.
(c) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1) (R7═R11═H)
Acetic anhydride 0.38 ml was added to a solution of compound (4-1) 1.32 g in pyridine 13.1 ml with cooling in ice under nitrogen. The mixture was stirred at that temperature for 1 h The solvent was removed by distillation under reduced pressure and the residue obtained was chromatographed on silica gel 60 g in ethyl acetate:hexane (1:3) to give a yellow oil 860 mg. The oily compound 747 mg was dissolved in dioxane 7 ml and potassium carbonate 530.5 mg was added. The mixture was stirred at 80° C. for 6 h, filtered through cerite and chromatographed on silica gel 40 g in ethyl acetate:hexane (1:10) to give the titled compound (3-1) as colorless crystals, 501 mg. Yield 40%, m.p. 124-126° C. (recrystallized from isopropanol)
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (CDCl3)







3-2
Ph
H
151-152
1.26 (9H, s), 3.75 (3H, s), 5.08 (2H, s),






6.87 (1H, dd, J=8.1, 0.9 Hz), 7.27 (1H,






t, J=8.1 Hz), 7.35-7.49 (5H, m), 7.65






(1H, s), 7.87 (1H, dd, J=8.1, 0.9 Hz)


3-3
Me
Me
112-114
1.69 (9H, s), 2.31 (3H, s), 2.70 (3H, s),






3.84 (3H, s), 5.03 (2H, s), 7.04 (1H, d,






J=8.4 Hz), 7.61 (1H, d, J=8.4 Hz),






8.07 (1H, s)


3-4
H
Br
160-161
1.68 (9H, s), 3.84 (3H, s), 5.14 (2H, s),






7.46 (1H, d, J=9.0 Hz), 7.68 (1H, d,






J=9.0 Hz), 7.74 (1H, s), 7.99 (1H, s)









(Method 4)

4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)-2,5-dimethylindole-1-carboxylic acid tert-butyl ester (4-3) (R7═R11═H)
Diisobutylaluminumhydride (0.9 mol/l hexane solution) 50 ml was added to a mixture of hexamethylphosphorous triamide (8.96) g and dry tetrahydrofuran 80 ml with cooling in ice under a nitrogen atmosphere. The mixture was stirred for 30 min. Methyl propiorate 3.78 g was added and he mixture was stirred for 1 h with cooling in ice. Compound (2-3) 4.36 g was added to the reaction mixture, which was stirred for 10 min and then at room temperature for 2 h. 1N—HCl 50 ml was added with cooling in ice and the mixture was extracted with ethyl acetate. The extracts were washed with 1N—HCl, water, brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 130 g in ethyl acetate:hexane (1:4) to give colorless crystals which were recrystallized from ethyl acetate-hexane to give the titled compound, 4.47 g. Yield 80%, m.p. 155-156.5° C.
Example 2
2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulene-8-carboxylic acid (5-1) (R7═R11═H)
The above obtained compound (3-1) 1.01 g was dissolved in tetrahydrofuran 15 ml and 1 N sodium hydroxide 15 ml was added to the solution. The mixture was stirred for 1 h. Methanol 7.5 ml was added. The mixture was stirred at 50° C. for 3 h, acidified with 2N—HCl 7.5 ml to weakly acidic with cooling in ice and extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid, which was recrystallized from methanol to give the titled compound (5-1), m.p. 230° C.(dec.) as yellow crystals, 450 mg. From the mother liquor, the second crop 134 mg was obtained by crystallization from isopropanol. Yield 88%.
1H-NMR (CD3OD): 4.98 (2H, s), 6.60 (1H, m), 7.02-7.08 (2H, m), 7.55 (1H, s), 8.19 (1H, s).
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (DMSO-d6)







5-2
Ph
H
218-220
4.98 (2H, s), 6.59-6.60 (1H, m),





(dec.)
7.06-7.13 (2H, m), 7.51-7.68 (5H, m),






8.05 (1H, s), 12.27 (1H, br s)


5-3
Me
ME
203-206
2.20 (3H, s), 2.48 (3H, s), 4.87 (2H, s),





(dec.)
6.84-6.89 (2H), 8.03 (1H, s), 11.69






(1H, s), 12.03 (1H, br s)


5-4
H
Br
210-215
4.97 (2H, s), 7.07 (1H, d, J=8.4 Hz),





(dec.)
7.27 (1H, d, J=8.7 Hz), 7.83 (1H, s),






8.09 (1H, s), 12.07 (1H, s)









Example 3
(2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic acid tert-butyl ester (6-1) (R7═H)
Triethylamine 0.38 ml and chloroethyl carbonate 0.26 ml were added to a solution of the compound obtained by Ex. 2 (5-1) 530 mg in dry tetrahydrofuran 5 ml with cooling in ice-methanol bath and the mixture was stirred for 30 min. Then an aqueous solution of sodium azide 320 mg/water 2 ml was added dropwise and the mixture was stirred for 4 h with cooling in ice-methanol bath. Water was added and the reaction mixture was extracted with ethyl acetate. The extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The residue obtained was suspended in toluene 20 ml and heated under reflux at 125° C. for 20 min and concentrated under reduced pressure. The residue obtained was again suspended in t-butanol 20 ml, heated at 100° C. for 2.5 h and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 50 g in ethyl acetate:hexane (1:3) to give brown crystals, which was recrystallized from ether-petrolether to give the titled compound (6-1) m.p. 125-130° C. (dec.) as pale brown crystals, 436 mg. Yield 62%.
1H-NMR (CDCl3): 1.50 (9H, s), 4.76 (2H, s), 6.01 (1H, br s), 6.64 (1H, dd, J=7.2, 1.2 Hz), 6.98-7.12 (3H, m), 8.17 (1H, br s).
Following compounds were obtained, according to the similar treatment.













Compd

m.p.



No
R7
(° C.)
1H-NMR (CDCl3)







6-2
Ph
201-202
1.49 (9H, s), 4.90 (2H, br s), 6.11 (1H, br s),




(dec.)
6.67 (1H, m), 6.88-7.41 (5H, m), 7.49 (1H,





m), 7.59 (1H, d, J=8.4 Hz), 8.24 (1H, br s)









Example 4
(2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic acid tert-butyl ester (7-1) (R7═H)
5% Pd/C 100 mg was added to a solution of the compound obtained in Ex. 3 460 mg in methanol 10 ml. The mixture was stirred in a hydrogen atmosphere for 1.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:3) to give the titled compound (7-1) as a reddish oil, 390 mg. Yield 84%.
1H-NMR (CDCl3): 1.41 (9H, s), 2.98-3.10 (1H, m), 3.26-3.38 (1H, m), 4.23 (1H, d, J=12.0 Hz), 4.27-4.40 (1H, m), 4.48-4.58 (1H, m), 6.67 (1H, dd, J=7.2, 0.9 Hz), 6.98 (1H, br s), 7.02 (1H, dd, J=7.2, 0.9 Hz), 7.09 (1H, t, J=7.2 Hz), 8.13 (1H, br s).
Following compounds were obtained, according to the similar treatment.













Compd

m.p.



No
R7
(° C.)
1H-NMR (CDCl3)







7-2
Ph
188-189
1.38 (9H, s), 3.18 (1H, m), 3.43 (1H, m),





4.29 (1H, d, J=12.0 Hz), 4.39 (1H, m), 4.56





(1H, m), 5.08 (1H, br s), 6.70 (1H, m), 7.04





(1H, m), 7.11 (1H, t, J=7.8 Hz), 7.34-7.55





(5H, m), 8.28 (1H, br s)









Example 5
2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-ylamine (8-1)
The compound obtained in Ex 4 (7-1) 262 mg was dissolved in ethyl acetate 3 ml. A solution of 4 N HCl/ethyl acetate 2 ml was added to the solution with cooling in ice and the mixture was stirred at room temperature for 3 h. Furthermore, 4N-HCl/ethyl acetate 1 ml was added and the mixture was stirred at room temperature for 1 h. After the volatile materials were remove by distillation under reduced pressure up to the half volume, the mixture was diluted with ethyl acetate 10 ml. An aqueous saturated sodium hydrogen solution carbonate was added to alkaline with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a brown oily residue, which was chromatographed on aluminum oxide 40 g in methanol:chloroform (3:97) to give the titled compound (8-1) as brown crystals, 144 mg. Yield 84%.
Further, this oil was recrystallized from isopropanol to give the titled compound (8-1) as gray crystals, 60 mg. m.p. 172-173° C.
1H-NMR (CD3OD): 2.84-2.93 (1H, ddd, J=15.6, 8.7, 1.5 Hz), 3.17-3.25 (1H, m), 3.36-3.43 (1H, m), 4.12-4.25 (2H, m), 6.43-6.50 (1H, m), 6.89-7.00 (3H, m).
Following compounds were obtained, according to the similar treatment.













Compd

m.p.



No
R7
(° C.)
1H-NMR (CDCl3)







8-2
Ph
189-191
3.09 (1H, dd, J=15.6, 8.1 Hz), 3.29 (1H, dd,





J=15.6, 3.6 Hz), 3.59 (1H, m), 4.27-4.36





(2H, m), 6.67 (1H, m), 7.01 (1H, m), 7.10





(1H, t, J=8.1 Hz), 7.34-7.59 (5H, m),





8.25 (1H, br s)









Scheme of Reactions, Examples 6-10 are shown in below





Example 6
8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carbonitrile (10)
Compound (9) 200 mg was dissolved in dry tetrahydrofuran 10 ml. 60% Sodium hydride 72 mg was added to the solution with cooling in ice and the mixture was stirred at room temperature for 2.5 h. After excess sodium hydride was decomposed with ethanol with cooling in ice, 2 N—HCl 1.5 ml was added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 4 g in ether to give an eluent 187 mg which was again chromatographed on silica gel 5 g in ether to give the titled compound (10) as reddish orange crystals, 132 mg. Yield 79.5%.
1H-NMR (CDCl3): 4.80 (2H, s), 6.52 (1H, dd, J=7.5, 0.9 Hz), 6.99 (1H, t, J=7.5 Hz), 7.06 (1H, dd, J=7.5, 0.9 Hz), 7.24 (1H, d, J=2.7 Hz), 11.07 (1H, s), 11.39 (1H, s).
Example 7
(1) 3-Ethoxycarbonylmethyl-1H-indol-4-yloxy)acetic acid ethyl ester (11)
Compound (9) 1.49 g was dissolved in 95% ethanol 45 ml. Concentrated sulfuric acid 4.5 ml was added to the solution. The mixture was heated under reflux for 40 h. After the solvent was removed under reduced pressure, ice-water was added to the mixture, which was extracted with chloroform. The extracts were washed with water dried over anhydrous magnesium sulfate and chromatographed on silica gel 37 g in chloroform. The eluent 1.497 g was recrystallized from acetone-isopropyl ether to give the titled compound (11) as pale gray crystals, 1.304 g, m.p. 90-91.5° C. Yield 70.1%.
1H-NMR (CDCl3): 1.26 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 4.05 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 4.69 (2H, s), 6.36 (1H, dd, J=7.2, 0.9 Hz), 6.97-7.07 (3H, m), 8.07(1H, br s).
(2) 8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acid ethyl-ester (12)
Compound (11) 754 mg was dissolved in dry tetrahydrofuran 20 ml. 60% Sodium hydride 217 mg was added to the solution of with cooling in ice. The mixture was stirred at room temperature for 1 h. To the ice-cold reaction mixture, ethanol 0.5 ml was added and the 2N HCl 3 ml was added to acidify. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 45 g in chloroform. The eluent 198 mg was recrystallized from ether-isopropyl ether to give the titled compound (12) as colorless crystals 195 mg, m.p. 136-137° C. Yield 30.5%.
1H-NMR (CDCl3): 1.44 (3H, t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz), 4.75 (2H, s), 6.56-6.71 (1H, m), 7.02-7.09 (2H, m), 7.50 (1H, d, J=2.7 Hz), 8.20 (1H, br s), 13.02 (1H, s).
Example 8
8-Methoxyl-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acid ethyl ester (13)
A mixture of the compound obtained in Ex. 7 (12) 100 mg, methyl iodide 0.031 ml and potassium carbonate 9 mg in dimethylformamide 3 ml was stirred at room temperature for 15 h. Water was added and the mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 6 g in chloroform. The eluent 102 mg was recrystallized from acetone-ether to give the titled compound (13) as colorless crystals 67 mg, m.p. 183-184° C. Yield 63.8%.
1H-NMR (CDCl3): 1.24-1.29 (3H, m), 1.82 (3H, s), 4.16-4.35 (2H, m), 4.49 (1H, d, J=17.4 Hz), 5.02 (1H, d, J=17.4 Hz), 6.73-6.79 (1H, m), 6.96-6.97(1H, m), 7.02-7.13 (2H, m), 8.35 (1H, br s).
Example 9
(1) 4-Ethoxycarbonylmethoxy-3-ethoxycarbonylmethyl-indole-1-carboxylic acid tert-butyl ester (14)
Compound (11) 1.40 g and di-tert-butyldicarbonate 1.05 g were dissolved in tetrahydrofuran 20 ml and 4-dimethylaminopyridine 28 mg was added. The mixture was allowed to stand at room temperature overnight and concentrated under reduced pressure to remove tetrahydrofurane. The residue obtained was dissolved in toluene and chromatographed on silica gel 10 g in 5% ethyl acetate-toluene to give the titled compound (14) as a colorless oil, 1.789 g. Yield 96.2%.
1H-NMR (CDCl3): 1.26 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz), 1.65 (9H, s), 3.96 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 4.67 (2H, s), 6.52 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.42 (1H, s), 7.80 (1H, d, J=8.1 Hz).
(2) 8-Hydroxy-7H-6-oxa-2-azabenzo[c,d]azulene-2,9-dicarboxlic acid 2-tert-butyl ester 9-ethyl ester (15)
Compound (14) 953 mg was dissolved in dry tetrahydrofuran 15 ml and 1.0 M solution of lithium bistrimethylsilylamide-tetrahydrofuran 3.5 ml was added to the solution with cooling in ice. The mixture was stirred at room temperature for 30 min. A solution of ammonium chloride 375 mg in water 5 ml was added with cooling in ice. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 30 g in chloroform. The eluent 259 mg was recrystallized from ether-isopropyl ether to give the titled compound (15) as colorless crystals, m.p.139.5-140.5° C., 236 mg. Yield 28.0%.
1H-NMR (CDCl3): 1.47 (3H, t, J=7.1 Hz), 1.68 (9H, s), 4.43 (2H, q, J=7.1 Hz), 4.73 (2H, s), 6.80 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.83 (1H, d, J=8.1 Hz), 7.87 (1H, s), 13.27 (1H, s).
Example 10
(1) [3-Ethoxycarbonylmethyl-1-(toluene-4-sulfonyl)-1H-indol-4-yloxy]acetic acid ethyl ester (16)
Compound (11) 305 mg was dissolved in dry tetrahydrofuran 20 ml. 1.0 M Solution of lithium bistrimethylsilylamide-tetrahydrofuran 1.1 ml was added to the solution with cooling in dry ice-acetone bath at −70° C. After the mixture was stirred for 10 min, a solution of p-toluenesulfonyl chloride 229 mg in tetrahydrofuran 3 ml was added at that temperature. The mixture was stirred at room temperature for 2 h. A solution of ammonium chloride 59 mg in water 1 ml was added to the mixture, which was concentrated under reduced pressure to remove tetrahydrofuran. Water was added. The mixture was extracted with chloroform. The extracts were washed with water dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 17 g in chloroform to give the titled compound (16) as a colorless oil 231 mg. Yield 50.2%.
1H-NMR (CDCl3): 1.24 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz), 2.34 (3H, s), 3.94 (2H, s), 4.16 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 4.62 (2H, s), 6.49 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=8.1 Hz), 7.21 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.60 (1H, d, J=8.1 Hz), 7.74 (2H, d, J=8.7 Hz).
(2) 8-Hydroxy-2-(toluene-4-sulfonyl)-2,7-dihydro-6-oxa-2-azabenzo[c,d]-azulene-9-carboxlic acid ethyl ester (17)
Compound (16) 228 mg was dissolved in dry tetrahydrofuran 10 ml and 1.0 M solution of lithium bistrimethylsilylamide tetrahydrofuran 1.05 ml was added to the solution with cooling in ice. The mixture was stirred for 20 min. A solution of ammonium chloride 112 mg in water 1 ml was added to the mixture, which was acidified with dilute hydrochloric acid. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained 279 mg was chromatographed on silica gel 10 g in toluene to give the titled compound (17) as a pale yellow oil 61 mg. Yield 29.8%.
1H-NMR (CDCl3): 1.50 (3H, t, J=7.2 Hz), 2.35 (3H, s), 4.45 (2H, q, J=7.2 Hz), 4.68 (2H, s), 6.78 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t, J=7.8 Hz), 7.23 (2H, d, J=8.1 Hz), 7.67 (1H, dd, J=7.8, 0.9 Hz), 7.77 (2H, d, J=8.7 Hz) 7.80 (1H, s), 13.30 (1H, s).
Scheme of Reactions, Examples 11-16





Example 11
2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (18-1) (R7═R11═H)
Triethylamine 10 ml and ethyl chlorocarbonate 5.6 ml were added to a solution of compound (5-1) 14.85 g in dry tetrahydrofuran 148 ml with cooling in ice-methanol bath. The mixture was stirred at that temperature for 30 min. Then, a solution sodium azide 8.97 g in water 59 ml was added dropwise. The mixture was stirred with cooling in ice for 4 h. To the reaction mixtures water was added. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a yellow solid. The residue obtained was suspended in dioxane 280 ml. After the suspension was heated under reflux for 20 min, 1N HCl 58.3 ml was added with cooling in ice. Again, the mixture was heated under reflux for 20 min and cooled in ice-bath. Water was added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 150 g in ethyl acetate:hexane (1:4) to give brown crystals, which was recrystallized from ether-petroleum ether to give the titled compound 7.94 g, m.p. 128-129° C. Yield 61%.
1H-NMR(CDCl3): 4.11 (2H, d, J=0.6 Hz), 4.69 (2H, s), 6.72-6.79 (1H, m), 6.92-6.95 (1H, m), 7.07-7.14 (2H, m), 8.12 (1H, br s).
Following compounds were obtained, according to the similar treatment.














Compd


m.p.



No
R7
R11
(° C.)
1H-NMR (CDCl3)







18-2
Me
ME
136-139
2.32 (3H, s), 2.33 (3H, s), 3.99 (2H, s),






4.66 (2H, s), 6.89 (1H, d, J=8.4 Hz),






6.92 (1H, d, J=8.4 Hz), 7.77 (1H, br s)


18-3
H
Br
137-138
4.09 (2H, d, J=1.2 Hz), 4.75 (2H, s),






6.95 (1H, m), 7.01 (1H, d, J=8.7 Hz),






7.27 (1H, d, J=8.7 Hz), 8.14 (1H, br s)









Example 12
Dimethyl-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)amine (19-1) (R7═R11═H; R16═R17═Me)
Dimethylamine (2 mol/tetrahydrofuran solution), compound (18-1) 690 mg, sodium triacetoxyborohydride 1.17 g and acetic acid 226 mg were dissolved in tetrahydrofuran 28 ml with cooling in ice. The mixture was stirred at room temperature for 1 h and allowed stand overnight. To the reaction mixture, ice-water and an aqueous sodium hydrogen carbonate solution were added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 30 g in chloroform:methanol (50:1) to give the titled compound as colorless crystals 689 mg. Yield 86%. This was recrystallized from ethyl acetate-hexane to give colorless crystals, m.p. 131-132.5° C.
1H-NMR(CDCl3): 2.42 (6H, s), 2.93-3.24 (3H, m), 4.15 (1H, dd, J=12.3, 6.6 Hz), 4.55 (1H, dd, J=12.3, 1.5 Hz), 6.62 (1H, dd, J=6.6, 0.9 Hz), 6.95-7.09 (3H, m), 8.14 (1H, br s).
Following compounds were obtained, according to the similar treatment.
















Compd








No
R7
R11
R16
R17
m.p. (° C.)
1H-NMR (CDCl3)







19-2
H
H
H
Me
112-116
2.56 (3H, s), 2.99-3.22 (3H, m),







oxalate
4.27-4.38 (2H, m), 6.65 (1H, d, J=








7.5 Hz), 6.96-7.09 (3H, m), 8.24








(1H, br s)


19-3
H
H
H
nPr
137-139
0.93 (3H, t, J=7.5 Hz), 1.54 (2H,








sex, J=7.5 Hz), 2.62-2.80 (2H, m),








2.92-3.02 (1H, m), 3.14-3.25 (2H,








m), 4.19-4.30 (2H, m), 6.44-6.50








(1H, m), 6.90-7.02 (3H, m) CD3OD


19-4
H
H
Et
Et
123-124
1.12 (6H, t, J=7.5 Hz), 2.69 (4H,








q, J=7.5 Hz), 2.90-3.00 (1H, m),








3.20-3.30 (2H, m), 4.08 (1H, dd, J=








11.7, 6.3 Hz), 4.53 (1H, dd, J=








11.7, 2.1 Hz), 6.41-6.48 (1H, m),








6.88-6.95 (2H, m), 7.01-7.03 (1H,








m) CD3OD


19-5
H
H
NPr
nPr
60-61
0.90 (6H, t, J=7.5 Hz), 1.40-1.60








(4H, m), 2.40-2.60 (4H, m), 2.90-








3.01 (1H, m), 3.15-3.35 (2H, m),








4.09 (1H, dd, J=12.3, 6.9 Hz),








4.61 (1H, dd, J=12.3, 1.8 Hz),








6.61 (1H, d, J=7.5 Hz), 6.95-6.98








(2H, m), 7.06 (1H, t, J=7.5 Hz),








8.06 (1H, br s)


19-6
H
H
H
cyclohexyl
141-142
1.00-2.02 (10H, m), 2.64-2.74 (1H,








m), 2.98 (1H, ddd, J=15.3, 8.4,








1.2 Hz), 3.14 (1H, dd, J=15.3, 3.6








Hz), 3.39-3.47 (1H, m), 4.23-4.32








(2H, m), 6.63 (1H, dd, J=7.5, 0.9








Hz), 6.95-6.99 (2H, m), 7.07 (1H, t,








J=7.5 Hz), 8.11 (1H, br s)


19-7
H
H
H
allyl
112-113
3.00-3.18 (2H, m), 3.28-3.49 (1H,








m), 4.27-4.38 (2H, m), 5.08-5.13








(1H, m), 5.18-5.26 (1H, m), 5.86-








5.99 (1H, m), 6.64 (1H, dd, J=








7.8, 1.2 Hz), 6.95-7.00 (2H, m),








7.07 (1H, t, J=7.8 Hz), 8.11 (1H,








br s)


19-8
H
H
H
iPr
133-135
1.10 (3H, d, J=6.0 Hz), 1.11 (3H,








d, J=6.0 Hz), 2.97-3.17 (3H, m),








3.35-3.42 (1H, m), 4.25-4.37 (2H,








m), 6.64 (1H, dd, J=7.5, 0.9








Hz), 6.95-7.00 (2H, m), 7.07 (1H, t,








J=7.5 Hz), 8.10 (1H, br s)


19-9
H
H
H





104-106
2.83 (2H, t, J=7.5 Hz), 2.95-3.17 (4H, m), 3.26-3.33 (1H, m), 4.29 (2H, d, J=3.6 Hz), 6.62 (1H, d, J= 7.5 Hz), 6.93-7.00 (2H, m), 7.07 (1H, t, J=7.8 Hz), 7.18-7.30 (5H, m), 8.08 (1H, br s)












19-10
H
H





137-139
1.80-1.89 (4H, m), 2.70-3.04 (6H, m), 3.37(1H, d, J=14.4 Hz), 4.17 (1H, dd, J=12.3, 6.3 Hz), 4.59 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.10 (1H, br s)


19-11
H
H





115-125 (dec.) oxalate
1.45-1.75 (6H, m), 2.50-2.80 (4H, m), 2.94-3.12 (2H, m), 3.24-3.31 (1H, m), 4.10 (1H, dd, J=12.0, 6.3 Hz), 4.63 (1H, dd, J=12.0, 1.8 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.94-6.98 (2H, m), 7.06 (1H, t, J= 7.8 Hz), 8.10 (1H, br s)


19-12
H
H





183-184 (dec.) oxalate
2.32 (3H, s), 2.40-2.60 (4H, m), 2.62-2.73 (2H, m), 2.80-2.90 (2H, m), 2.95-3.11 (2H, m), 3.22-3.30 (1H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.60 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J= 7.8 Hz), 8.12 (1H, br s)


19-13
H
H





207-208
2.46-2.56 (2H, m), 2.62-2.72 (2H, m), 2.76-2.98 (2H, m), 3.08-3.18 (1H, m), 3.53-3.62 (4H, m), 4.06 (1H, dd, J=12.3, 6.6 Hz), 4.45 (1H, d, J=12.3 Hz), 6.40 (1H, dd, J=6.6, 2.1 Hz), 6.86-6.94 (2H, m), 7.11 (1H, d, J=1.8 Hz), 10.95 (1H, br s) DMSO-d6













19-14
H
H
H
CH2CH2OH
154-157
2.85-3.11 (4H, m), 3.25-3.30 (2H,







(dec.)
m), 3.62 (2H, t, J=5.4 Hz), 4.26-







oxalate
4.42 (2H, m), 6.64 (1H, dd, J=7.5,








0.9 Hz), 6.96-7.10 (3H, m), 8.16








(1H, br s)


19-15
H
Br
H
Me

2.58 (3H, s), 2.91-3.22 (3H, m),








4.34(1H, dd, J=12.6, 6.9 Hz),








4.44(1H, d, J=12.6 Hz), 6.86 (1H,








d, J=8.4 Hz), 6.97 (1H, m), 7.28








(1H, d, J=8.4 Hz), 8.17 (1H, br s)


19-16
H
Br
Me
Me
142-143
2.43 (6H, s), 2.92-3.23 (3H, m),








4.22 (1H, dd, J=12.3, 6.9 Hz),








4.67 (1H, dd, J=12.3, 1.8 Hz),








6.85 (1H, d, J=8.7 Hz), 6.98 (1H,








m), 7.26 (1H, d, J=8.7 Hz), 8.13








(1H, br s)


19-17
Me
Me
Me
Me
144-146
2.28 (3H, s), 2.34 (3H, s), 2.47 (6H,








s), 2.82-3.11 (3H, m), 4.10 (1H,








dd, J=12.0 Hz, 6.6 Hz), 4.58 (1H,








d, J=12.0 Hz), 6.79 (1H, d, J=8.1








Hz), 6.87 (1H, d, J=8.1 Hz), 7.74








(1H, br s)


19-18
Me
Me
H
Me
173-175
2.29 (3H, s), 2.31 (6H, s), 2.57 (3H,







(dec.)
s), 2.80-2.87 (1H, m), 2.97-3.03







oxalate
(1H, m), 3.12-3.20 (1H, m), 4.29-








4.32 (2H, m), 6.79 (1H, d, J=8.1








Hz), 6.87 (1H, d, J=8.1 Hz), 7.79








(1H, br s),


19-19
H
H
H
cyclopropyl
130-131
0.34-0.55 (4H, m), 2.27-2.34 (1H,








m), 3.02-3.18 (2H, m), 3.38-3.44








(1H, m), 4.33-4.44 (2H, m), 6.65








(1H, dd, J=7.5, 0.9 Hz), 6.94-7.07








(3H, m), 8.27 (1H, br s)


19-20
H
H
H
CH2CF3
108-109
3.13 (2H, d, J=5.1 Hz), 3.27-3.44








(3H, m), 4.25 (1H, d, J=12.6 Hz),








4.40 (1H, dd, J=12.6, 6.9 Hz),








6.64 (1H, dd, J=8.1, 0.9 Hz), 6.98








(1H, s), 7.00 (1H, dd, J=8.1, 0.9








Hz), 7.08 (1H, t, J=8.1 Hz), 8.10








(1H, br s)


19-21
H
H
Me
Et
122-124 
1.13 (3H, t, J=7.2 Hz), 2.39 (3H,








s), 2.54-2.79 (2H, m), 2.97-3.27








(3H, m), 4.12 (1H, dd, J=12.3, 6.3








Hz), 4.59 (1H, dd, J=12.3, 1.8








Hz), 6.62 (1H, dd, J=7.5, 0.9 Hz),








6.96-7.09 (3H, m), 8.12 (1H, br s)


19-22
H
H
H
Et
139-141
1.14 (3H, t, J=7.2 Hz), 2.73-2.93








(2H, m), 3.00-3.19 (2H, m), 3.26-








3.33 (1H, m), 4.27-4.37 (1H, m),








6.64 (1H, dd, J=7.5, 0.9 Hz),








6.96-6.99 (2H, m), 7.07 (1H, t, J=








7.5 Hz), 8.15 (1H, br s)









Example 13
(Method 1)
(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)dimethylamine oxalate (20-1) (R7═R11═H)
60% Sodium hydride 17 mg was added to a solution of compound (19-1) 75 mg in dry dimethylformamide 2.5 ml with cooling in ice. The mixture was stirred at 45° C. for 1 h. Benzenesulfonyl chloride 1 ml was added with cooling in ice. The mixture was stirred at room temperature for 21 h. Ice-water and an aqueous sodium hydrogen carbonate solution were added to the mixture, which was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:2) to give the titled compound, 46 mg (yield 37%). This compound was treated with 1 eq. of oxalic acid to give the oxalic acid salt, which was recrystallized from ether-ethanol to give colorless crystals. m.p. 106-109° C.(dec.).
1H-NMR(CDCl3): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz), 7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)
Following compounds were obtained, according to the similar treatment.















Comp







No.
R7
R8
R11
m.p.
1H-NMR (CDCl3)







20-2
H
COPh
H
126-129
2.40 (6H, s), 2.86-3.16 (3H, m), 4.20 (1H,






(dec.)
dd, J=12.3, 6.3 Hz), 4.50 (1H, d, J=






oxalate
12.3 Hz), 6.85 (1H, dd, J=7.2, 0.9 Hz),







7.06 (1H, s), 7.23-7.28 (1H, m), 7.49-7.63







(3H, m), 7.71 (2H, dd, J=8.4, 1.8 Hz),







8.04 (1H, dd, J=8.1, 0.9 Hz)


20-3
H
CH2Ph
H
183-186
2.41 (6H, s), 2.88-3.06 (2H, m), 3.15-3.22






(dec.)
(1H, m), 4.15 (1H, dd, J=12.0, 6.3 Hz),






oxalate
4.54 (1H, dd, J=12.0, 1.8 Hz), 5.23 (2H,







s) 6.61 (1H, dd, J=7.8, 0.6 Hz), 6.85-







6.89 (2H, m), 7.02-7.15 (3H, m), 7.25-







7.33 (3H, m)


20-4
H
CH2CONMe2
H
119-124
2.40 (6H, s), 2.99 (3H, s), 3.04 (3H, s),






(dec.)
2.88-3.22 (2H, m), 3.15-3.22 (1H, m),






oxalate
4.13 (1H, dd, J=12.3, 6.6 Hz), 4.53 (1H,







dd, J=12.3, 1.8 Hz), 4.82 (2H, s), 6.61







(1H, dd, J=8.1, 0.9 Hz), 6.79-7.10 (3H,







m)


20-5
H





H
148-149
2.37 (6H, s), 2.89 (1H, m), 3.06-3.16 (2H, m), 4.15 (1H, dd, J=12.9, 6.9 Hz), 4.43 (1H, d, J=12.9 Hz), 6.71 (1H, dd, J= 7.8, 0.6 Hz), 7.10 (1H, t, J=8.1 Hz), 7.39-7.67 (5H, m), 7.86-8.15 (3H, m), 8.76 (1H, d, J=8.7 Hz)


20-6
H





H
114-118 (dec.) oxalate
2.36 (6H, s), 2.81-3.11 (3H, m), 4.14 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J= 12.6 Hz), 6.76 (1H, dd, J=7.8, 0.9 Hz), 7.18 (1H, t, J=8.4 Hz), 7.23 (1H, t, J= 1.5 Hz), 7.38-7.42 (2H, m), 7.57 (1H, dd, J=8.4, 0.9 Hz), 7.77-7.82 (2H, m)


20-7
H
SO2Et
H
153-155
1.23 (3H, t, J=7.5), 2.41 (6H, s), 2.87-






(dec.)
3.14 (3H, m), 3.28 (3H, q, J=7.5 Hz),






oxalate
4.22 (1H, dd, J=12.3, 6.6 Hz), 4.49 (1H,







d, J=12.3 Hz), 6.82 (1H, d, J=7.8 Hz),







7.19-7.27 (2H, m), 7.50 (1H, J=8.4 Hz)


20-8
H
IPr
H
191-194
1.49 (3H, t, J=6.3 Hz), 1.50 (3H, t, J=






(dec.)
6.3 Hz), 2.42 (6H, s), 2.93-3.24 (3H, m),






oxalate
4.13 (1H, dd, J=12.3, 6.6 Hz), 4.54 (1H,







dd, J=12.3, 1.8 Hz), 4.57-4.66 (1H, m),







6.59 (1H, dd, J=7.8, 1.2 Hz), 6.94 (1H,







d, J=7.5 Hz), 7.01 (1H, s), 7.07 (1H, d, J=







7.8 Hz)


20-9
H





H
142-144 (dec.) oxalate
2.37 (6H, s), 2.81-3.10 (3H, m), 4.16 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, dd, J= 12.3 Hz), 6.78 (1H, d, J=8.4 Hz), 7.00 (1H, dd, J=4.8, 3.9 Hz), 7.21 (1H, t, J= 8.4 Hz), 7.30 (1H, s), 7.53 (1H, dd, J= 5.1, 1.5 Hz), 7.62 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=4.2, 1.5 Hz)


20-10
H





H
119-122 (dec.) oxalate
2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H, m), 4.16 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.78 (1H, dd, J= 8.1, 0.9 Hz), 7.17-7.32 (2H, m), 7.59 (1H, dd, J=8.1, 0.6 Hz), 7.71 (2H, d, J= 8.4 Hz), 8.00 (2H, d, J=8.1 Hz)


20-11
H





H
147-150 (dec.) oxalate
2.37 (6H, s), 2.82-3.12 (3H, m), 4.14 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J= 12.6 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.18 (1H, t, J=8.1 Hz), 7.30 (1H, s), 7.55-7.58 (2H, m), 7.71-7.74 (2H, m)


20-12
H





H
168-171 (dec.) oxalate
2.37 (6H, s), 2.81-3.11 (3H, m), 4.16 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, d, J= 12.3 Hz), 6.77 (1H, dd, J=8.1, 0.3 Hz), 7.20 (1H, t, J=8.1 Hz), 7.30-7.34 (2H, m), 7.57 (1H, d, J=8.1 Hz), 7.64-7.81 (2H, m), 8.01 (1H, t, J=1.8 Hz)


20-13
H





H
173-176 (dec.) oxalate
2.40 (6H, s), 2.86-3.11 (3H, m), 4.21 (1H, dd, J=12.3, 6.6 Hz), 4.60 (1H, d, J= 12.3 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz), 7.09 (1H, t, J=8.1 Hz), 7.23-7.26 (1H, m), 7.36-7.50 (2H, m), 7.55 (1H, s), 7.67 (1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=7.8, 1.5 Hz)


20-14
H





H
140-142 (dec.) oxalate
2.37 (6H, s), 2.81-3.11 (3H, m), 3.80 (3H, s), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, d, J=12.3 Hz), 6.74 (1H, d, J=8.1 Hz), 6.88 (2H, dd, J=6.9, 2.1 Hz), 7.17 (1H, t, J=8.4 Hz), 7.33 (1H, s), 7.58 (1H, d, J=8.1 Hz), 7.82 (1H, dd, J=6.9, 2.1 Hz)


20-15
H





H
123-126 (dec.) oxalate
2.37 (6H, s), 2.82-3.11 (3H, m), 3.85 (3H, s), 3.87 (3H, s), 4.14 (1H, dd, J=12.3, 5.7 Hz), 4.44 (1H, d, J=12.3 Hz), 6.75 (1H, dd, J=7.8, 0.9 Hz), 6.84 (2H, d, J= 8.7 Hz), 7.17 (1H, t, J=8.1 Hz), 7.26- 7.32 (2H, m), 7.51 (1H, dd, J=8.4, 2.1 Hz), 7.61 (1H, dd, J=8.4, 0.6 Hz)


20-16
H





H
169-171 (dec.) oxalate
2.39 (6H, s), 2.85-3.13 (3H, m), 4.19 (1H, dd, J=12.6, 6.3 Hz), 4.46 (1H, d, J= 12.6 Hz), 6.74 (1H, d, J=15.3 Hz), 6.80 (1H, dd, J=8.4, 0.6 Hz), 7.20 (1H, t, J= 8.4 Hz), 7.27-7.45 (6H, m), 7.52 (1H, dd, J=8.1, 0.9 Hz), 7.70 (1H, d, J=15.5 Hz)


20-17
H





H
161-163 (dec.) oxalate
2.39 (6H, s), 2.84-3.09 (3H, m), 4.21 (1H, dd, J=12.3, 5.4 Hz), 4.44 (1H, d, J= 12.3 Hz), 6.77 (1H, dd, J=8.4, 0.9 Hz), 7.13 (1H, t, J=8.4 Hz), 7.25 (1H, dd, J= 8.1, 0.9 Hz), 7.35 (1H, d, J=8.4 Hz), 7.43-7.48 (2H, m), 8.19 (1H, d, J=2.4 Hz)


20-18
H
SO2Ph
Br
89-90
2.39 (6H, s), 2.85-3.10 (3H, m), 4.24 (1H,







dd, J=12.3, 6.3 Hz), 4.54 (1H, d, J=







12.3 Hz), 7.34 (1H, s), 7.39-7.59 (5H, m),







7.84-7.87 (2H, m)


20-19
H





H
143-144 (dec.) oxalate
2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H, m), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.42 (1H, d, J=12.6 Hz), 6.76 (1H, d, J= 7.8 Hz), 7.08-7.21 (3H, m), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, s), 7.56 (1H, d, J=8.4 Hz), 7.87-7.92 (2H, m)


20-20
H





H
128-131 (dec.) oxalate
2.40 (6H, s), 2.85-2.91 (1H, m), 3.07-3.10 (2H, m), 4.21 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.79 (1H, dd, J= 8.1, 0.9 Hz), 7.12 (1H, t, J=8.1 Hz), 7.33-7.42 (3H, m), 7.78 (1H, dd, J=7.2, 6.0 Hz)


20-21
H





H
154-156 (dec.) oxalate
2.38 (6H, s), 2.83-3.13 (3H, m), 4.18 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J= 12.6 Hz), 6.80 (1H, dd, J=8.1, 0.6 Hz), 6.83 (1H, d, J=4.2 Hz), 7.19-7.25 (2H, m), 7.46 (1H, d, J=4.1 Hz), 7.56 (1H, dd, J=8.1, 0.6 Hz)


20-22
H





H
163-164 (dec.) oxalate
2.38 (6H, s), 2.82-3.09 (3H, m), 4.19 (1H, dd, J=12.3, 6.3 Hz), 4.44 (1H, d, J= 12.3 Hz), 6.75-7.03 (3H, m), 7.13 (1H, t, J=8.1 Hz), 7.38-7.41 (2H, m), 8.02-8.11 (1H, m)


20-23
H





H
147-150 (dec.) oxalate
2.39 (6H, s), 2.84-3.10 (3H, m), 3.66 (3H, s), 3.82 (3H, s), 4.18 (1H, dd, J=12.3, 6.6 Hz), 4.44 (1H, d, J=12.3 Hz), 6.72 (1H, dd, J=8.1, 0.9 Hz), 6.81 (1H, d, J= 9.0 Hz), 7.04 (1H, dd, J=9.0, 3.3 Hz), 7.09 (1H, t, J=8.1 Hz), 7.36 (1H, d, J= 8.1 Hz), 7.43 (1H, s), 7.60 (1H, d, J=3.3 Hz)


20-24
H





H
103-104
2.37 (6H, s), 2.82-3.12 (3H, m), 3.79 (3H, s), 3.82 (3H, s), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz), 7.03-7.07 (1H, m), 7.17 (1H, t, J=8.1 Hz), 7.31-7.46 (4H, m), 7.60 (1H, dd, J=8.1, 0.6 Hz)


20-25
H





H
113-115 (dec.) oxalate
2.32 (6H, s), 2.81-3.12 (3H, m), 4.17 (1H, dd, J=12.6, 6.3 Hz), 4.44 (1H, d, J= 12.6 Hz), 6.46 (1H, d, J=1.8 Hz), 6.80 (1H, d, J=7.8 Hz), 7.24 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=3.9 Hz), 7.33 (1H, d, J=3.9 Hz), 7.61 (1H, d, J=7.8 Hz), 7.64 (1H, d, J=3.9 Hz), 8.27 (1H, d, J =1.8 Hz)


20-26(*)
H
SO2Ph
H
98-98
1.09 (3H, t, J=7.2 Hz), 2.34 (3H, s),






(dec.)
2.50-2.74 (2H, m), 2.91-3.16 (3H, m),






oxalate
4.05 (1H, dd, J=12.0, 6.6 Hz), 4.51 (1H,







dd, J=12.0, 0.9 Hz), 6.74 (1H, dd, J=







8.1, 0.6 Hz), 7.17 (1H, t, J=8.1 Hz),







7.34 (1H, s), 7.41-7.61 (5H, m), 7.86-







7.89 (2H, m)


20-27
Me
SO2Ph
Me
155-158
2.24 (3H, s), 2.39 (6H, s), 2.52 (3H, s),






(dec.)
4.05 (1H, dd, J=12.6, 5.7 Hz), 4.46 (1H,






oxalate
d, J=12.6 Hz), 7.01 (1H, d, J=8.7 Hz),







7.38-7.43 (2H, m), 7.49-7.55 (1H, m),







7.71-7.77 (3H, m)





(*)20-26; R4=N(Me)Et 






(Method 2)

(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)dimethylamine (20-1)
n-BuLi (1.56 mol/l hexane solution) 1.39 ml was added to a solution of compound (19-1) 432 mg in dry tetrahydrofuran 10 ml at −70° C. under nitrogen atmosphere. The solution was stirred at that temperature for 1 h and at −30° C. for 1 h. Then, the temperature was again lowered to −70° C. and benezenesulofonyl chloride 396 mg was added dropwise. The reaction temperature was allowed to raise gradually to the room temperature. The mixture was stirred at room temperature, poured to ice and an aqueous ammonium chloride solution and extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide 12 g in chloroform:hexane (8:1) to give the titled compound as crystals. Yield 83%. The product was recrystallized from ethyl acetate isopropyl ether to give colorless crystals. m.p. 114-116° C.
1H-NMR(CDCl3): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz), 7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)
Example 14
(1-Bromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (21), (1,5-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (22) and (1,3-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (23)
N-Bromosuccinimide 214 mg was added to a warm solution of compound (19-1) 216 mg in carbon tetrachloride 33 ml and the mixture was heated under reflux for 2 h. After the reaction ceased, the insoluble materials were removed by filtration and washed with chloroform. The filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in chloroform:methanol (30:1). The eluent was chromatographed on thin silica gel plates in chloroform:methanol (30:1) to give the titled compound (21) 51 mg. Yield 17%. This was recrystallized from ethyl acetate-ether to give crystals, m.p. 170-172° C.
1H-NMR(CDCl3): 2.43 (6H, s), 2.88-3.08 (3H, m), 4.15 (1H, dd, J=12.3, 6.0 Hz), 4.52 (1H, d, J=12.3 Hz), 6.62 (1H, dd, J=7.8, 0.9 Hz), 6.89 (1H, dd, J=8.1, 0.9 Hz), 7.04 (1H, t, J=7.8 Hz), 8.07 (1H, br s)
1,5-Dibromo compound (22) 15 mg was isolated from another fraction. Yield 4% Purifying from ether gave crystals, m.p. 123-126° C.
1H-NMR(CDCl3): 2.44 (6H, s), 2.84-3.08 (3H, m), 4.21 (1H, dd, J=12.0, 6.9 Hz), 4.66 (1H, d, J=12.0 Hz), 6.78 (1H, d, J=8.7 Hz), 7.25 (1H, d, J=8.7 Hz), 8.49 (1H, br s)
The mother liquor of the above mentioned 1,5-dibromo compound (22) was concentrated under reduced pressure and again chromatographed on thin silica gel plates in chloroform:methanol (30:1) to give the 1,3-dibromo compound (23) 8 mg (yield 2%). This was treated with 1 eq. oxalic acid to give the salt, m.p. 147-152° C. (dec.).
1H-NMR(CDCl3): 2.42 (6H, s), 2.90-3.05 (3H, m), 4.09-4.16 (1H, m), 4.50 (1H, d, J=12.0 Hz), 6.53 (1H, d, J=8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 8.22 (1H, br s)
Example 15
2-Chloro-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide (24-1) (R═COCH2Cl)
Compound (8-1) 535 mg was dissolved in dry tetrahydrofuran 15 ml. Triethylamine 345 mg and chloroacetyl chloride 0.25 ml were added to the solution with cooling in ice. The mixture was stirred for 1 h and at room temperature for 30 min. Ice-water was added to the mixture with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 25 g in ethyl acetate:hexane (2:1) to give the titled compound 706 mg (94%) as a colorless oil.
1H-NMR(CDCl3): 3.06-3.14 (1H, m), 3.36-3.43 (1H, m), 3.95-4.06 (2H, m), 4.08-4.16 (1H, m), 4.27 (1H, d, J=11.4 Hz), 4.54-4.64 (2H, m), 6.70 (1H, dd, J=7.5, 1.2 Hz), 6.99 (1H, s), 7.03-7.13 (2H, m), 8.18 (1H, br s)
Following compounds were obtained, according to the similar treatment.













Compd





No
R
m.p.
1H-NMR (CDCl3)







24-2
COOMe
Colorless
3.02-3.07 (1H, m), 3.33-3.39 (1H,




oil
m), 3.63 (3H, s), 4.23 (1H, d, J=9.3





Hz), 4.34-4.41 (1H, m), 4.53-4.60





(1H, m), 5.25 (1H, br d), 6.67 (1H, d,





J=7.8 Hz), 6.97 (1H, s), 7.00-7.11





(2H, m), 8.14 (1H, br s)


24-3
Ms
Colorless
3.02 (3H, s), 3.07-3.14 (1H, m),




oil
3.35-3.42 (1H, m), 4.19-4.27 (2H,





m), 4.54-4.61 (1H, m), 4.84 (1H, d,





J=8.7 Hz), 6.68 (1H, d, J=7.5 Hz),





7.00-7.12 (3H, m), 8.22 (1H, br s)


24-4
SO2NHMe
Yellow
2.70 (3H, d, J=5.4 Hz), 3.04-3.11




oil
(1H, m), 3.35-3.42 (1H, m), 4.03-





4.28 (3H, m), 4.53-4.60 (1H, m),





4.81 (1H, d, J=8.4 Hz), 6.67 (1H,





dd, J=7.2, 1.2 Hz), 6.98-7.11 (3H,





m), 8.24 (1H, br s)


24-5
COMe
174-176
1.92 (3H, s), 2.99-3.06 (1H, m),





3.35-3.41 (1H, m), 4.21-4.25 (1H,





m), 4.53-4.68 (2H, m), 6.03 (1H, br





s), 6.69 (1H, d, J=7.2 Hz), 6.98 (1H,





s), 7.03-7.13 (2H, m), 8.21 (1H, br s)









Example 16
2-Cyclohexylamino-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide (25-1)
A solution of compound (24-1) 160 mg and cyclohexylamine 360 mg in benzene 4 ml and methanol 4 ml was heated at 60° C. for 21 h and concentrated under reduced pressure. Water was added to the residue obtained. The mixture was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:methanol (30:1) to give the titled compound 161 mg as crystals. Yield 81%. The crude crystalline materials were recrystallized from methanol-ethyl acetate to give colorless crystals, m.p. 184-186° C.
1H-NMR(CDCl3): 0.43-1.04 (4H, m), 1.22-1.57 (6H, m), 1.98-2.07 (1H, m), 3.02-3.46 (4H, m), 4.24-4.29 (1H, m), 4.54-4.59 (2H, m), 6.69 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.11 (3H, m), 7.96 (1H, br s), 8.13 (1H, br s)
Following compounds were obtained, according to the similar treatment.













Compd





No
R
m.p.
1H-NMR (CDCl3)







25-2
NMe2
161-
2.06 (6H, s), 2.84-2.96 (2H, m), 3.06-3.13




162.5
(1H, m), 3.31-3.39 (1H, m), 4.26 (1H, d,





J=11.4 Hz), 4.52-4.62 (2H, m), 6.68 (1H, dd,





J=7.5, 0.9 Hz), 6.97-7.11 (3H, m), 7.53 (1H,





br s), 8.21 (1H, br s)









Scheme of Reactions, Examples 17-25





Example 17
((R)-1-Phenylethyl)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (26)
Sodium triacetoxyborohydride 318 mg and acetic acid 57 μl were added to a solution of compound (18-1) 187.6 mg and (R)-(+)-α-methylbenzylamine 13.7 mg in dry tetrahydrofuran 8 ml at room temperature and the mixture was stirred for 18 h. Water was added. The reaction mixture was made alkaline with an aqueous saturated sodium hydrogencarabonate solution and extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 40 g in ethyl acetate:hexane (1:2) to give the titled compound 250 mg as a colorless oil. Yield 86%. The 1H-NMR shows the titled compound is a mixture of their diastereomers.
1H-NMR(CDCl3): 1.33 (total 6H, d, J=6.6 Hz), 2.98-3.22 (total 6H, m), 4.04-4.41 (total 6H, m), 6.61-6.65 (total 2H, m), 6.91-7.41 (total 16H, m), 8.07 (total 2H, br s).
Example 18
2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide (27) and 2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide (28)
Compound (26) 2.548 g was dissolved in dry tetrahydrofuran 8 ml. A solution of triethylamine 1.34 ml and trifluoroacetic anhydride 2.014 g in dry tetrahydrofuran 1 ml was added to the solution with cooling in ice. The mixture was stirred for 1 h. Furthermore, triethylamine 177 mg, trifluoroacetic anhydride 366 mg were added and the mixture was stirred for 1 h with cooling in ice. The solvents were removed by distillation under reduced pressure. Water was added to the residue. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:5) repeatedly to give the titled compound (27) as a colorless oil, 990 mg (yield 29%) and the titled compound (28) as a colorless oil 1.672 g (yield 49%).
Compound (27)
1H-NMR(CDCl3): 1.82 (3H, d, J=6.9 Hz), 2.07-2.19 (1H, m), 3.54-3.66 (2H, m), 4.43 (1H, dd, J=12.9, 2.4 Hz), 4.81 (1H, dd, J=12.9, 6.0 Hz), 5.40 (1H, q, J=6.9 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.64 (1H, m), 6.94 (1H, dd, J=7.5, 0.9 Hz), 7.04 (1H, t, J=7.5 Hz), 7.27-7.40 (5H, m), 7.96 (1H, br s).
Compound (28)
1H-NMR(CDCl3): 1.72 (3H, d, J=6.9 Hz), 3.00-3.08 (1H, m), 3.55-3.63 (1H, m), 3.85-3.96 (1H, m), 4.10 (1H, dd, J=12.6, 2.4 Hz), 4.63 (1H, dd, J=12.6, 6.3Hz), 5.39 (1H, q, J=6.9 Hz), 6.43 (1H, dd, J=7.5, 1.2 Hz), 6.91-7.01 (3H, m), 7.34-7.44 (5H, m), 8.08 (1H, br s).
Example 19
((R)-1-Phenylethyl)-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (29)
Compound (27) 934 mg was dissolved in ethanol 19 ml and sodium borohydride 364 mg was added to the solution at room temperature. The mixture was stirred for 17 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:1) to give the titled compound (29) 695 mg. Yield 99.9%. Furthermore, the titled compound (29) was treated with a solution of hydrogen chloride in methanol to give the HCl salt, which was recrystallized from methanol-isopropanol to give colorless crystals, m.p. 233-240° C. (dec.). The absolute configuration was determined by an X-ray crystal structure analysis on a single crystal.
1H-NMR(CDCl3): 1.33 (3H, d, J=6.3 Hz), 3.00-3.22 (3H, m), 4.03 (1H, q, J=6.3 Hz), 4.21 (1H, d, J=11.7 Hz), 4.29-4.36 (1H, m), 6.63 (1H, dd, J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 7.20-7.42 (5H, m), 8.07 (1H, br s).
According to the similar manner, ((R)-1-Phenylethyl)-(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (30) was obtained.
1H-NMR(CDCl3): 1.33 (3H, d, J=6.6 Hz), 2.80-3.15 (3H, m), 4.11 (1H, q, J=6.3 Hz), 4.26 (1H, d, J=12.0 Hz), 4.37 (1H, dd, J=12.0, 6.3 Hz), 6.64 (1H, dd, J=7.8, 0.9 Hz), 6.91-6.93 (1H, m), 6.96 (1H, dd, J=7.8, 0.9 Hz), 7.06 (1H, t, J=7.8 Hz), 7.20-7.41 (5H, m), 8.06 (1H, br s).
Example 20
(S)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (31)
Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20% Palladium(II)hydroxide 200 mg was added. A mixture was stirred in a hydrogen atomosphere for 22 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform to give the titled compound (31) as pale brown crystals, 337 mg. Yield 86%. Furthermore, this was recrystallized from methanol-isopropanol to give the titled compound (31) as pale brown crystals, m.p. 202-203° C.
[α]D+38.7±1.6° (C=0.509, methanol, 25° C.)
According to the similar manner, (R)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (32) was obtained.
m.p. 202-203° C. [α]D−38.8±1.6° (C=0.508, methanol, 25° C.)
Example 21
2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethylene ketal (33)
Ethylene glycol 2.56 g and pyridinium p-toluenesulfonate 250 mg were added to a solution of compound (18-1) 1.877 g in benzene 50 ml. The mixture was heated under reflux for 14 h by use of a Dean-Stark apparatus. The reaction mixture separated into two layers. The upper layer was separated by decantation. Water and dioxane were added to the remained black oily part. The insoluble materials were removed by filtration and the filtrate was extracted with toluene. The extracts were washed with brine, treated with char coal, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give brown crystals. The above obtaied upper layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and brine successively, treated with char-coal and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give colorless crystals. The combined crystals were recrystallized from tetrahydrofuran to give the titled compound (33) as colorless crystals, m.p. 200-202° C., 925 mg. Yield 40%.
1H-NMR(DMSO-d6): 3.16 (2H, s), 3.97 (4H, s), 4.13 (2H, s), 6.41 (1H, dd, J=6.6, 1.8 Hz), 6.88-6.96 (2H, m), 7.07 (1H, m), 10.94 (1H, br s).
Example 22
2-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethylene ketal (34)
60% Sodium hydride 33 mg was added to a solution of compound (33) in dry dimethylformamide 2 ml with cooling in ice and the mixture was stirred for 10 min. Then, benzenesulfonyl chloride 152 mg was added. The mixture was heated at 60° C. for 14 h. Ice-water was added to the reaction mixtures, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.
1H-NMR(CDCl3): 3.22 (2H, s), 4.07 (4H, s), 4.16 (2H, s), 6.80 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.33 (1H, m), 7.42-7.58 (3H, m), 7.62 (1H, dd, J=8.4, 0.9 Hz), 7.88-7.92 (2H, m).
Example 23
2-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (35)
Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound (34) 48.4 mg. The mixture was heated at 80° C. for 15 min and concentrated under reduced pressure. Ice-water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:2) to give the titled compound (35) as a colorless oil, 33.2 mg. Yield 78%.
1H-NMR(CDCl3): 4.03 (2H, d, J=1.2 Hz), 4.62 (2H, s), 6.90 (1H, dd, J=7.8, 0.6 Hz), 7.25 (1H, t, J=7.8 Hz), 7.30 (1H, m), 7.44-7.61 (3H, m), 7.73 (1H, dd, J=7.8, 0.6 Hz), 7.88-7.93 (2H, m).
Example 24
2-Benzenesulfonyl-8-pyrrolidin-1-yl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene (36-1) (R4=pyrrolidinyl)
A solution of pyrrolidine 35.4 mg in dry tetrahydrofuran 0.5 ml, sodium triacetoxyborohydride 133.7 mg and acetic acid 26 μl were added to a solution of compound (35) 135.9 mg in dry tetrahydrofuran 3.5 ml at room temperature and the mixture was stirred for 24 h. Water was added to the reaction mixture, which was made alkaline with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 20 g in chloroform to give the titled compound (36-1) as a brown oil, 97.7 mg. Yield 62%. This was treated with 1 eq. oxalic acid to give the salt which was recrystallized from ether-methanol to give colorless crystals, m.p. 170-173° C.(dec.).
1H-NMR(CDCl3): 1.76-1.84 (4H, m), 2.60-3.26 (7H, m), 4.12 (1H, dd, J=12.9, 6.3 Hz), 4.47 (1H, d, J=12.9 Hz), 6.73 (1H, dd, J=8.1, 0.9 Hz), 7.17 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.41-7.61 (4H, m), 7.86-7.90 (2H, m).
Following compounds were obtained, according to the similar treatment.













Compd

m.p.



No
R4
(° C.)
1H-NMR (CDCl3)







36-2
NHMe
208-213
2.52 (3H, s), 2.91-3.15 (3H, m),




(dec.)
4.22-4.27 (2H, m), 6.76 (1H, dd, J=8.1,




oxalate
0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.32-7.34





(1H, m), 7.41-7.58 (3H, m), 7.61 (1H, dd,





J=8.1, 0.9 Hz), 7.86-7.90 (2H, m)


36-3
NEt2
106-108
1.07 (6H, t, J=6.9 Hz), 2.50-3.30 (7H,





m), 3.98-4.05 (1H, m), 4.52 (1H, d,





J=11.7 Hz), 6.74 (1H, dd, J=7.8, 0.9 Hz),





7.17 (1H, t, J=7.8 Hz), 7.33 (1H, s),





7.42-7.62 (4H, m), 7.86-7.90 (2H, m)


36-4
NHBn
208-209
2.94-3.11 (2H, m), 3.20-3.27 (1H, m),




(dec.)
3.86 (1H, d, J=13.2 Hz), 3.95 (1H, d,




oxalate
J=13.2 Hz), 4.27 (2H, d, J=3.9 Hz), 6.77





(1H, d, J=7.8 Hz), 7.15-7.62 (11H, m),





7.86-7.90 (2H, m)









Example 25
2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ol(37)
Compound (18-1) 374.4 mg was suspended in methanol 5 ml and sodium borohydride 75.7 mg was added to the suspension with cooling in ice. The mixture was stirred for 1 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was recrystallized from acetone-isopropanol to give the titled compound (37) as colorless crystals m.p. 169-170° C., 356.5 mg. Yield 94%.
1H-NMR(CD3OD): 2.83-2.93 (1H, m), 3.29-3.38 (1H, m), 4.03-4.17 (2H, m), 4.32 (1H, dd, J=5.4, 2.1 Hz), 6.42-6.48 (1H, m), 6.88-6.95 (1H, m), 6.99 (1H, br s).
Scheme of Reactions, Examples 26-34





Example 26
Dimethyl-(5-phenyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine (38)
Phenylboronic acid 190.1 mg, palladium acetate 13.0 mg, tris(2-methylphenyl)phosphine 30.9 mg and potassium carbonate 691.0 mg were added to a solution of compound (19-16) 296 mg in dry dimethylformamide 6 ml under nitrogen atmosphere. The mixture was heated at 120° C. for 2 h. After cooling, water was added. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:toluene (1:2) to give the titled compound (38) as colorless crystals, 33.0 mg. Yield 11%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 168-170° C.
1H-NMR(CDCl3): 2.42 (6H, s), 2.96-3.28 (3H, m), 4.17 (1H, dd, J=12.3, 6.3 Hz), 4.53 (1H, d, J=12.3 Hz), 7.02 (1H, s), 7.03 (1H, d, J=8.4 Hz), 7.15 (1H, d, J=8.4 Hz), 7.27-7.60 (5H, m).
Example 27
(E)-3-(8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-5-yl)acrylic acid methyl ester (39)
Methyl acrylate 140 μl, triethylamine 217 μl and bis(triphenylphosphine)palladium dichloride 0.2 mg were added to a solution of compound (19-16) 306 mg in dry dimethylformamide 5 ml under nitrogen atmosphere. The mixture was heated at 100° C. for 19 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:1) to give the titled compound as yellow crystals 146.5 mg. Yield 47%. The titled compound was recrystallized from acetone-isopropyl ether to give pale yellow crystals, m.p. 168-170° C.
1H-NMR(CDCl3): 2.43 (6H, s), 2.90-3.22 (3H, m), 3.80 (3H, s), 4.24 (1H, dd, J=12.0, 6.6 Hz), 4.63 (1H, dd, J=12.6, 0.9 Hz), 6.39 (1H, d, J=16.2 Hz), 6.94 (1H, d, J=8.7 Hz), 6.97 (1H, m), 7.34 (1H, d, J=8.7 Hz), 8.22 (1H, br s), 8.25 (1H, d, J=16.2 Hz).
Example 28
Dimethyl-(5-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine (40)
Tri-n-butylvinyltin 952.0 mg, tetrakistriphenylphosphinepalladium 116.1 mg and lithium chloride 254.0 mg were added to a solution of compound (19-16) 592.2 mg in dry dimethylformamide 30 ml under a nitrogen atmosphere. The mixture was heated at 120° C. for 4 h and diluted with ethyl acetate, after cooling. The insoluble materials were removed by filtration through cerite. The filtrate was washed with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:toluene (1:2) to give a colorless oil 602.2 mg. This was chromatographed on silica gel in chloroform:methanol:aq. ammonia (46:10:1) to give a yellow oil 500 mg, which was crystallized from hexane giving the titled compound as colorless crystals, 324 mg. Yield 67%. Furthermore, the titled compound was recrystallized from ether-petroleumether to give colorless crystals, m.p.119-120° C.
1H-NMR(CDCl3): 2.43 (6H, s), 2.93-3.23 (3H, m), 4.12-4.19 (1H, m), 4.61 (1H, dd, J=12.6, 1.5 Hz), 5.13 (1H, dd, J=11.4, 1.5 Hz), 5.62 (1H, dd, J=18.0, 1.5 Hz), 6.91-6.96 (2H, m), 7.22 (1H, dd, J=18.0, 11.4 Hz), 7.34 (1H, d, J=8.4 Hz), 8.08 (1H, br s).
Example 29
(5-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (41)
Compound (40) 242 mg was dissolved in methanol 4 ml and 5% palladium/C 60 mg was added. A mixture was stirred in hydrogen atmosphere at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:2) to give the titled compound as colorless crystals 241.6 mg. Yield 99%. This was recrystallized from acetone-hexane to give the titled compound as colorless crystals, m.p. 91-92° C.
1H-NMR(CDCl3): 1.21 (3H, t, J=7.5 Hz), 2.44 (6H, s), 2.65-2.78 (2H, m), 2.94-3.23 (3H, m), 4.12-4.18 (1H, m), 4.54-4.59 (1H, m), 6.90 (1H, d, J=8.4 Hz), 6.94-6.96 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.96 (1H, br s).
Example 30
(5-Bromo-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (42)
Compound (19-16) 2.00 g was added to a suspension of 60% sodium hydride 300.8 mg in tetrahydrofuran 30 ml with cooling in ice. The mixture was stirred for 1 h. Then, triisopropylsilyl chloride (TIPSCl) 1.6 ml was added with cooling in ice. The mixture was stirred for 4 h with cooling in ice. Water was added to reaction mixture with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give a pale brown oil 2.67 g. This was recrystallized from isopropyl ether to give colorless crystals, m.p. 119-121° C. 1.85 g. Yield 60%.
1H-NMR(CDCl3): 1.13 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.72 (3H, m), 2.45 (6H, s), 3.03-3.26 (3H, m), 4.18-4.24 (1H, m), 4.66 (1H, dd, J=12.3, 1.5 Hz), 6.96 (1H, d, J=8.7 Hz), 7.00 (1H, s), 7.20 (1H, d, J=8.7 Hz).
Example 31
(5-Fluoro-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (43)
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the mixture, which was stirred for 1 h. Then, N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirred for 3.5 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give a yellow oil. This was chromatographed on thin aluminum oxide plates (Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5)) to give the titled compound as a pale yellow oil, 100 mg.
1H-NMR(CDCl3): 1.28 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.70 (3H, m), 2.45 (6H, s), 2.95-3.28 (3H, m), 4.20-4.26 (1H, m), 4.62 (1H, dd, J=11.7, 1.2 Hz), 6.86-6.97 (2H, m), 7.03 (1H, s).
Example 32
Dimethyl-(5-methylsulfanyl-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulen-8-yl)amine (44)
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the solution and the mixture was stirred for 1 h. Then, dimethyldisulfide 185 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give the titled compound as colorless crystals, 289.8 mg. Yield 69%. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 77-79° C.
1H-NMR(CDCl3): 1.13 (18H, d, J=7.5 Hz), 1.58-1.74 (3H, m), 2.45 (total 9H, each s), 2.97-3.30 (3H, m), 4.22 (1H, d, J=12.0, 6.3 Hz), 4.68 (1H, dd, J 12.0, 1.2 Hz), 6.99 (1H, s), 7.04 (1H, d, J=8.4 Hz), 7.10 (1H, d, J=8.7 Hz).
Example 33
8-Dimethylamino-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde (45)
A solution of compound (42) 750 mg in dry tetrahydrofuran 7 ml was cooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml was added dropwise to the solution. The mixture was stirred for 1 h. Dimethylformamide 257 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give the titled compound as yellow oil, 556 mg. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield 59%
1H-NMR(CDCl3): 1.14 (18H, d, J=7.5 Hz), 1.55-1.72 (3H, m), 2.45 (6H, s), 2.97-3.30 (3H, m), 4.29 (1H, dd, J=12.6, 6.3 Hz), 4.65 (1H, d, J=12.6 Hz), 7.04 (1H, s), 7.07 (1H, d, J=9.0 Hz), 7.60 (1H, d, J=8.7 Hz), 10.50 (1H, s).
Example 34
8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde (46-1) (R11═CHO)
Tetra-n-butylammoniumfluoride (1 mol/l tetrahydrofuran solution) 2.2 ml was added to compound (45) 496 mg in tetrahydrofuran 10 ml with cooling in ice. The mixture was stirred for 3 h, diluted with water and ethyl acetate and, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (2:1) to give colorless crystals, 273.2 mg. This was recrystallized from acetone-isopropyl ether to give the titled compound as colorless crystals, m.p.175-176° C., 2654 mg. Yield 88%.
1H-NMR(DMSO-d6): 2.29 (6H, s), 2.78-3.13 (3H, m), 4.31 (1H, dd, J=12.3, 6.6 Hz), 4.58 (1H, d, J=12.3 Hz), 6.99 (1H, dd, J=8.4, 0.9 Hz), 7.23 (1H, s), 7.40 (1H, d, J=8.4 Hz), 10.36 (1H, d, J=0.9 Hz), 11.48 (1H, br s).
Following compounds were obtained, according to the similar treatment.













Compd

m.p.



No
R11
(° C.)
1H-NMR (CDCl3)







46-2
F
148-150
2.44 (6H, s), 2.93-3.25 (3H, m), 4.24 (1H,





dd, J=12.3, 6.6 Hz), 4.63 (1H, dd, J=12.3,





1.2 Hz), 6.83 (1H, dd, J=8.7, 3.6 Hz), 6.97





(1H, dd, J=11.4, 8.7 Hz), 7.01 (1H, m), 8.04





(1H, br s)


46-3
SMe
112-113
2.44 (3H, s), 2.44 (6H, s), 2.97-3.24 (3H,





m), 4.24 (1H, dd, J=12.3, 6.3 Hz), 4.69 (1H,





dd, J=12.3, 2.1 Hz), 6.94 (1H, d, J=8.4 Hz),





6.97-6.99 (1H, m), 7.19 (1H, d, J=8.7 Hz),





8.09 (1H, br s)









Scheme of Reactions, Examples 35-37





Example 35
8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde Oxime (47)
Hydroxylamine hydrogenchloride 83.4 mg and sodium acetate 98.4 mg were added to a suspension of compound (46-1) 244 mg in 95% ethanol 10 ml. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. Water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogencarbonate solution. Colorless precipitates appeared and were collected by filtration, washed with methanol-ethyl acetate to give the titled compound as colorless crystals, m.p. 230-235° C.(dec.), 228 mg. Yield 88%.
1H-NMR(DMSO-d6): 2.28 (6H, s), 2.73-3.12 (3H, m), 4.15 (1H, dd, J=12.0, 6.6 Hz), 4.49 (1H, d, J=12.3 Hz), 6.93 (1H, d, J=7.8 Hz), 7.13 (1H, br d, J=2.7 Hz), 7.38 (1H, d, J=8.7 Hz), 8.39 (1H, s), 10.66 (1H, s), 11.12 (1H, br s).
Example 36
8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbonitrile (48)
Triethylamine 33 μl and trichloroacetyl chloride 13 μl were added to a solution of compound (47) 28.9 mg in dichloromethane 2 ml with cooling ice and the mixture was stirred with cooling in ice and at room temperature for 18 h. A saturated sodium hydrogencarbonate solution was added thereto for alkalinization. The mixture was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound 26.3 mg as colorless crystals. Yield 98%. Furthermore, the titled compound was recrystallized from methanol-isopropyl ether to give colorless crystals, m.p. 205-207° C.
1H-NMR(CD3OD): 2.41 (6H, s), 2.89-3.23 (3H, m), 4.39 (1H, dd, J=12.6, 6.9 Hz), 4.64 (1H, d, J=12.6 Hz), 7.03 (1H, d, J=8.7 Hz), 7.17 (1H, d, J=8.7 Hz), 7.18 (1H, m).
Example 37
8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo [cd]azulene-5-carboxylic acid amide (49)
Polyphophoric acid 420 mg was added to compound (48) 31.6 mg under an argon atmosphere and the mixture was heated at 90° C. for 6 h. Ice-water was added to the reaction mixture, which was made alkaline with an aqueous 5 N-sodium hydroxide solution and extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound as colorless crystals, 20.9 mg. Yield 62%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.
1H-NMR(DMSO-d6): 2.29 (6H, s), 2.76-3.13 (3H, m), 4.24 (1H, dd, J=12.0, 6.0 Hz), 4.64 (1H, d, J=12.3 Hz), 6.97 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=2.1 Hz), 7.22 (1H, br s), 7.66 (1H, d, J=8.7 Hz), 7.68(1H, br s), 11.20 (1H, br s)
Scheme of Reactions, Examples 38-40





Example 38
N-Cyclopropyl-2,2,2-trifluoromethyl-N-(2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)acetamide (50)
Compound (19-19) 355 mg was dissolved in dry tetrahydrofuran 11 ml. A solution of triethylamine 178 mg and trifluoroacetic anhydride 344 mg in dry tetrahydrofuran 0.5 ml was added to the solution with cooling in ice. The mixture was stirred with cooling in ice for 2 h. Triethylamine 78 mg and trifluoroacetic anhydride 156 mg in dry tetrahydrofuran 0.2 ml were again added. The mixture was stirred with cooling in ice for 2 h and concentrated under reduced pressure. Water was added to the residue, which was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 15 g in chloroform:hexane (4:1) to give the titled compound as pale yellow crystals, 415 mg (yield 82%), m.p. 49-53° C.
1H-NMR(CDCl3): 0.94-1.06 (4H, m), 3.04-3.14 (2H, m), 3.64-3.74 (1H, m), 4.10-4.15 (1H, m), 4.46 (1H, dd, J=12.6, 1.8 Hz), 4.70 (1H, dd, J=12.6, 6.6 Hz), 6.64 (1H, dd, J=7.5, 1.2 Hz), 6.97 (1H, s), 7.00 (1H, dd, J=8.1, 1.2 Hz), 7.08 (1H, d, J=8.1 Hz), 8.17 (1H, br s)
Example 39
N-(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)-N-cyclopropyl-2,2,2,-trifluoroacetamide (51)
60% Sodium hydride 56 mg was added to a solution of compound (50) 324 mg in dimethylformamide 12 ml with cooling in ice and the mixture was stirred at room for 1 h. Benzenesulfonyl chloride 238 mg was added dropwise with cooling in ice and then, the mixture was stirred at 40° C. for 21 h. Ice-water and then an aqueous sodium hydrogencarbonate solution were added to the reaction mixture, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:2) to give the titled compound as a colorless oil, 130 mg (yield 28%).
1H-NMR(CDCl3): 0.88-1.05 (4H, m), 3.03-3.09 (2H, m), 3.58-3.68 (1H, m), 3.99-4.06 (1H, m), 4.40 (1H, dd, J=12.9, 1.5 Hz), 4.59 (1H, dd, J=12.9, 6.3 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.20 (1H, t, J=8.1 Hz), 7.34 (1H, s), 7.44-7.66 (4H, m), 7.86-7.90 (2H, m)
Example 40
(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)cyclopropylamine (52)
Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodium hydrogenborohydride 42 mg was added to the solution at room temperature and the mixture was stirred for 23 h. Water was added with cooling in ice to the reaction mixture, which was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil, 98 mg. Yield 96%. The titled compound was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from isopropanol-ether to give colorless crystals, m.p. 119-122° C. (dec.).
1H-NMR(CDCl3): 0.30-0.49 (4H, m), 2.21-2.27 (1H, m), 2.94-3.12 (2H, m), 3.31-3.37 (1H, m), 4.29-4.31 (2H, m), 6.77 (1H, d, J=7.8 Hz), 7.19 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.42-7.63 (4H, m), 7.86-7.90 (2H, m)
Scheme of Reactions, Examples 41-44





Example 41
(2-Benzenesulfonyl-1-iodo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (53)
LDA was prepared by addition of n-BuLi (1.56 mol/l hexane solution) 1.08 ml to a solution of diisopropylamine 255 μl in dry tetrahydrofuran 3 ml at −70° C. Then, a solution of compound (20-1) 500 mg in dry tetrahydrofuran 2 ml was added at that temperature to the mixture, which was stirred for 2 h. Then, a solution of iodine 426 mg in dry tetrahydrofuran 2 ml was added and the mixture was stirred for 2 h. Ice was added to the reaction mixtures, which was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give the titled compound as colorless crystals 514 mg. Yield 76%. This was recrystallized from from acetone-isopropyl ether to give colorless crystals, m.p. 136-137° C.
1H-NMR(CDCl3): 2.36 (6H, s), 2.87-2.97 (3H, m), 4.08-4.14 (1H, m), 4.41 (1H, d, J=12.6 Hz), 6.75 (1H, d, J=7.5 Hz), 7.40-7.45 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (2H, m), 7.96 (1H, d, J=7.8 Hz).
Example 42
(2-Benzenesulfonyl-1-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (54)
Tri-n-butyl(vinyl)tin 484.4 mg, tetrakis(triphenylphosphine)palladium 690 mg and lithium chloride 127.7 mg were added to a solution of compound (53) 491 mg in dry dimethylformamide 10 ml under nitrogen atmosphere. The mixture was heated at 100° C. for 3 h, diluted with ethyl acetate after cooling and filtered through cerite to remove the insoluble materials. The filtrate was washed with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was pulverized in hexane, collected by filtration and chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as colorless crystals 602.2 mg. Yield 79%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 133-134° C.
1H-NMR(CDCl3): 2.53 (6H, s), 2.78-3.10 (3H, m), 4.11 (1H, dd, J=12.6, 6.6 Hz), 4.41 (1H, d, J=12.6 Hz), 5.36 (1H, dd, J=17.7, 1.5 Hz), 5.69 (1H, dd, J=11.4, 1.5 Hz), 6.77 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H, dd, J=18.0, 11.4 Hz), 7.19 (1H, t, J=8.1 Hz), 7.34-7.53 (3H, m), 7.73-7.76 (2H, m), 7.87 (1H, dd, J=8.4, 0.9 Hz).
Example 43
(2-Benzenesulfonyl-1-ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (55)
Compound (54) 200.1 mg was dissolved in a mixture of methanol 8 ml and tetrahydrofuran 4 ml. 10% Pd/C 49.8 mg was added. The mixture was stirred under hydrogen atmosphere for 18 h at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil 198 mg. Yield 98%. This was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 193-194° C.(dec.).
1H-NMR(CDCl3): 1.28 (3H, t, J=7.5 Hz), 2.41 (6H, s), 2.89-3.07 (5H, m), 4.07-4.13 (1H, m), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd, J=7.8, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 7.37-7.43 (2H, m), 7.49-7.54 (1H, m), 7.71-7.75 (2H, m), 7.83 (1H, dd, J=8.1, 0.9 Hz).
Example 44
(1-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (56-1)
Magnesium (turning) 246 mg was added to compound (55) in methanol 9 ml and the mixture was stirred at room temperature for 3 h. Ice was added to the reaction mixture which was diluted with chloroform. The insoluble materials were filtered off through cerite and the filtrate was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (2:1) to give the titled compound as a pale yellow oil 97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 236-237° C. (dec.).
1H-NMR(CDCl3): 1.29 (3H, t, J=7.5 Hz), 2.45 (6H, s), 2.75 (2H, q, J=7.5 Hz), 2.86-3.13 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.54 (1H, d, J=12.3 Hz), 6.59 (1H, dd, J=7.5, 0.9 Hz), 6.91 (1H, dd, J=8.1, 0.9 Hz), 6.99 (1H, t, J=7.8 Hz), 7.90 (1H, br s).
Following compounds were obtained, according to the similar treatment.













Compd





No
R7
m.p.
1H-NMR (CDCl3)







56-2
vinyl
195-198
2.43 (6H, s), 2.64-3.25 (3H, m), 4.12




(dec.)
(1H, dd, J=12.0, 6.3 Hz), 4.54 (1H,




oxalate
dd, J=12.0, 2.1 Hz), 5.27 (1H, d,





J=11.4 Hz), 5.43 (1H, d, J=11.4 Hz),





6.58 (1H, dd, J=7.8, 0.9 Hz), 6.79





(1H, dd, J=17.7, 11.4 Hz), 6.91 (1H,





dd, J=8.1, 0.9 Hz), 7.06 (1H, t,





J=8.1 Hz), 8.11 (1H, br s),









Example 45





N-(2,7,8,9-Tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)hydrazinecarboxylic acid tert-butyl ester (57)
t-Butylbuthoxycarbonyl hydrazide 139 mg was added to a solution of compound (18-1) 170 mg in dry tetrahydrofuran 6 ml. The mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. Trifluoroacetic acid 0.7 ml and triethylsilane 212 mg were added to the residue. The mixture was stirred for 80 min. 1N-HCl and then potassium hydroxide pellets were added to the reaction mixture with cooling in ice to alkaline. The mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (4:1) to give the titled compound as crystals, 158 mg (yield 58%). The crude crystalline materials were recrystallized from hexane-ethyl acetate to give pale yellow crystals, m.p. 171-173° C.(dec.).
1H-NMR(CDCl3): 1.46 (9H, s), 2.84-2.93 (1H, m), 3.17-3.24 (2H, m), 3.59-3.66 (1H, m), 4.23 (1H, dd, J=12.3, 7.2 Hz), 4.37 (1H, d, J=12.3 Hz), 6.21 (1H, br s), 6.61 (1H, d, J=7.5 Hz), 6.96-7.08 (3H, m), 8.11 (1H, br s)
Example A
As examples of a compound (I), compounds (I-a) and compounds (I-b) shown in Table 7-28 and Table 29-42, respectively.








TABLE 7








(I-a)

















Compd





No
R4
R7
R8













1
COOH
H
H


2
COOMe
H
H


3
COOEt
H
H


4
COO-tBu
H
H


5
CONH2
H
H


6
CONHMe
H
H


7
CONHEt
H
H


8
CONH-nPr
H
H


9
CONMe2
H
H


10
CONEt2
H
H


11
CON(nPr)2
H
H


12
CONHPh
H
H


13





H
H


14





H
H


15





H
H


16
NH2
H
H


17
NHMe
H
H


18
NHEt
H
H


19
NH-nPr
H
H


20
NMe2
H
H


21
NEt2
H
H


22
N(nPr)2
H
H


23





H
H


24





H
H


25





H
H


26
NHCOMe
H
H


27
NHCOEt
H
H



















TABLE 8





Compd





No
R4
R7
R8


















1
NHCO-nPr
H
H


2
NHCOPh
H
H


3
NMeCOMe
H
H


4
N(nPr)COMe
H
H


5
NMeCOPh
H
H


6
N(nPr)COPh
H
H


7
NHCOOMe
H
H


8
NHCOOEt
H
H


9
NHCOO-tBu
H
H


10
NHCOOCH2Ph
H
H


11
NMeCOOMe
H
H


12
N(nPr)COOMe
H
H


13
NMeCOOOH2Ph
H
H


14
N(nPr)COOCH2Ph
H
H


15
NHSO2Me
H
H


16
NHSO2Et
H
H


17
NHSO2Ph
H
H


18
NHTs
H
H


19
NMeSO2Me
H
H


20
N(nPr)SO2Me
H
H


21
NMeSO2Ph
H
H


22
N(nPr)SO2Ph
H
H


23
COOH
Me
H


24
COOMe
Me
H


25
COOEt
Et
H


26
COO-tBu
nPr
H


27
CONH2
Me
H


28
CONHMe
Me
H


29
CONHEt
Et
H


30
CONH-nPr
nPr
H


31
CONMe2
Me
H


32
CONEt2
Et
H


33
CON(nPr)2
nPr
H


34
CONHPh
Me
H


35





Me
H


36





Et
H


37





nPr
H


38
NH2
Me
H


39
NHMe
Me
H


40
NHEt
Et
H



















TABLE 9





Compd





No
R4
R7
R8


















1
NH-nPr
nPr
H


2
NMe2
Me
H


3
NEt2
Et
H


4
N(nPr)2
nPr
H


5





Me
H


6





Et
H


7





nPr
H


8
NHCOMe
Me
H


9
NHCOEt
Et
H


10
NHCO-nPr
nPr
H


11
NHCOPh
Me
H


12
NMeCOMe
Me
H


13
N(nPr)COMe
Et
H


14
NMeCOPh
nPr
H


15
N(nPr)COPh
Me
H


16
NHCOOMe
Me
H


17
NHCOOEt
Et
H


18
NHCOO-tBu
nPr
H


19
NHCOOCH2Ph
Me
H


20
NMeCOOMe
nPr
H


21
N(nPr)COOMe
nPr
H


22
NMeCOOCH2Ph
Me
H


23
N(nPr)COOCH2Ph
nPr
H


24
NHSO2Me
Me
H


25
NHSO2Et
Et
H


26
NHSO2Ph
nPr
H


27
NHTs
Et
H


28
NMeSO2Me
Me
H


29
N(nPr)SO2Me
nPr
H


30
NMeSO2Ph
Me
H


31
N(nPr)SO2Ph
Me
H


32
COOH
Br
H


33
COOMe
Br
H


34
COOEt
CN
H


35
COO-tBu
Br
H


36
CONH2
Br
H


37
CONHMe
Br
H


38
CONHEt
CN
H


39
CONHn-Pr
Br
H


40
CONMe2
Br
H


41
CONEt2
CN
H


42
CON(nPr)2
Br
H



















TABLE 10





Compd





No
R4
R7
R8


















1
CONHPh
CN
H


2





Br
H


3





Br
H


4





CN
H


5
NH2
Br
H


6
NHMe
Br
H


7
NHEt
CN
H


8
NH-nPr
Br
H


9
NMe2
Br
H


10
NEt2
CN
H


11
N(nPr)2
Br
H


12





Br
H


13





CN
H


14





Br
H


15
NHCOMe
Br
H


16
NHCOEt
Br
H


17
NHCO-nPr
CN
H


18
NHCOPh
Br
H


19
NMeCOMe
Br
H


20
N(nPr)COMe
Br
H


21
NMeCOPh
CN
H


22
N(nPr)COPh
Br
H


23
NHCOOMe
Br
H


24
NHCOOEt
CN
H


25
NHCOO-tBu
Br
H


26
NHCOOCH2Ph
Br
H


27
NMeCOOMe
CN
H


28
N(nPr)COOMe
Br
H


29
NMeCOOCH2Ph
Br
H


30
N(nPr)COOCH2Ph
CN
H


31
NHSO2Me
Br
H


32
NHSO2Et
Br
H


33
NHSO2Ph
Br
H


34
NHTs
CN
H


35
NMeSO2Me
Br
H


36
N(nPr)SO2Me
Br
H


37
NMeSO2Ph
Br
H


38
N(nPr)SO2Ph
CN
H


39
COOH
Ph
H



















TABLE 11





Compd





No
R4
R7
R8


















1
COOMe
Ph
H


2
COOEt
Ph
H


3
COO-tBu
Ph
H


4
CONH2
Ph
H


5
CONHMe
Ph
H


6
CONHEt
Ph
H


7
CONH-nPr
Ph
H


8
CONMe2
Ph
H


9
CONEt2
Ph
H


10
CON(nPr)2
Ph
H


11
CONHPh
Ph
H


12





Ph
H


13





Ph
H


14





Ph
H


15
NH2
Ph
H


16
NHMe
Ph
H


17
NHEt
Ph
H


18
NH-nPr
Ph
H


19
NMe2
Ph
H


20
NEt2
Ph
H


21
N(nPr)2
Ph
H


22





Ph
H


23





Ph
H


24





Ph
H


25
NHCOMe
Ph
H


26
NHCOEt
Ph
H


27
NHCO-nPr
Ph
H


28
NHCOPh
Ph
H


29
NMeCOMe
Ph
H


30
N(nPr)COMe
Ph
H


31
NMeCOPh
Ph
H


32
N(nPr)COPh
Ph
H


33
NHCOOMe
Ph
H


34
NHCOOEt
Ph
H


35
NHCOO-tBu
Ph
H


36
NHCOOCH2Ph
Ph
H


37
NMeCOOMe
Ph
H


38
N(nPr)COOMe
Ph
H



















TABLE 12





Compd





No
R4
R7
R8


















1
NMeCOOCH2Ph
Ph
H


2
N(nPr)COOCH2Ph
Ph
H


3
NHSO2Me
Ph
H


4
NHSO2Et
Ph
H


5
NHSO2Ph
Ph
H


6
NHTs
Ph
H


7
NMeSO2Me
Ph
H


8
N(nPr)SO2Me
Ph
H


9
NMeSO2Ph
Ph
H


10
N(nPr)SO2Ph
Ph
H


11
COOH
H
Me


12
COOMe
H
Me


13
COOEt
H
Me


14
COO-tBu
H
Me


15
CONH2
H
Me


16
CONHMe
H
Me


17
CONHEt
H
Me


18
CONHn-Pr
H
Me


19
CONMe2
H
Me


20
CONEt2
H
Me


21
CON(nPr)2
H
Me


22
CONHPh
H
Me


23





H
Me


24





H
Me


25





H
Me


26
NH2
H
Me


27
NHMe
H
Me


28
NHEt
H
Me


29
NH-nPr
H
Me


30
NMe2
H
Me


31
NEt2
H
Me


32
N(nPr)2
H
Me


33





H
Me


34





H
Me


35





H
Me


36
NHCOMe
H
Me


37
NHCOEt
H
Me



















TABLE 13





Compd





No
R4
R7
R8


















1
NHCO-nPr
H
Me


2
NHCOPh
H
Me


3
NMeCOMe
H
Me


4
N(nPr)COMe
H
Me


5
NMeCOPh
H
Me


6
N(nPr)COPh
H
Me


7
NHCOOMe
H
Me


8
NHCOOEt
H
Me


9
NHCOO-tBu
H
Me


10
NHCOOCH2Ph
H
Me


11
NMeCOOMe
H
Me


12
N(nPr)COOMe
H
Me


13
NMeCOOCH2Ph
H
Me


14
N(nPr)COOCH2Ph
H
Me


15
NHSO2Me
H
Me


16
NHSO2Et
H
Me


17
NHSO2Ph
H
Me


18
NHTs
H
Me


19
NMeSO2Me
H
Me


20
N(nPr)SO2Me
H
Me


21
NMeSO2Ph
H
Me


22
N(nPr)SO2Ph
H
Me


23
COOH
Me
Me


24
COOMe
Me
Me


25
COOEt
Et
Me


26
COO-tBu
Me
Me


27
CONH2
nPr
Me


28
CONHMe
Me
Me


29
CONHEt
Et
Me


30
CONH-nPr
nPr
Me


31
CONMe2
Me
Me


32
CONEt2
Et
Me


33
CON(nPr)2
nPr
Me


34
CONHPh
Me
Me


35





Me
Me


36





Et
Me


37





nPr
Me



















TABLE 14





Compd





No
R4
R7
R8


















1
NH2
Me
Me


2
NHMe
Me
Me


3
NHEt
Me
Me


4
NH-nPr
Et
Me


5
NMe2
Me
Me


6
NEt2
nPr
Me


7
N(nPr)2
nPr
Me


8





Me
Me


9





Et
Me


10





Me
Me


11
NHCOMe
nPr
Me


12
NHCOEt
Me
Me


13
NHCO-nPr
Et
Me


14
NHCOPh
Me
Me


15
NMeCOMe
nPr
Me


16
N(nPr)COMe
Me
Me


17
NMeCOPh
Et
Me


18
N(nPr)COPh
Me
Me


19
NHCOOMe
nPr
Me


20
NHCOOEt
Me
Me


21
NHCOO-tBu
Et
Me


22
NHCOOCH2Ph
Me
Me


23
NMeCOOMe
nPr
Me


24
N(nPr)COOMe
Me
Me


25
NMeCOOCH2Ph
nPr
Me


26
N(nPr)COOCH2Ph
Me
Me


27
NHSO2Me
Et
Me


28
NHSO2Et
nPr
Me


29
NHSO2Ph
Me
Me


30
NHTs
nPr
Me


31
NMeSO2Me
Me
Me


32
N(nPr)SO2Me
Et
Me


33
NMeSO2Ph
Me
Me


34
N(nPr)SO2Ph
Et
Me


35
COOH
Br
Me


36
COOMe
Br
Me


37
COOEt
CN
Me


38
COO-tBu
CN
Me





















TABLE 15







Compd






No
R4
R7
R8





















1
CONH2
Br
Me



2
CONHMe
Br
Me



3
CONHEt
CN
Me



4
CONH-nPr
Br
Me



5
CONMe2
Br
Me



6
CONEt2
CN
Me



7
CON(nPr)2
Br
Me



8
CONHPh
CN
Me



9





Br
Me



10





CN
Me



11





Br
Me



12
NH2
Br
Me



13
NHMe
CN
Me



14
NHEt
CN
Me



15
NH-nPr
Br
Me



16
NMe2
Br
Me



17
NEt2
CN
Me



18
N(nPr)2
Br
Me



19





Br
Me



20





CN
Me



21





Br
Me



22
NHCOMe
Br
Me



23
NHCOEt
Br
Me



24
NHCO-nPr
CN
Me



25
NHCOPh
Br
Me



26
NMeCOMe
Br
Me



27
N(nPr)COMe
CN
Me



28
NMeCOPh
Br
Me



29
N(nPr)COPh
Br
Me



30
NHCOOMe
CN
Me



31
NHCOOEt
Br
Me



32
NHCOO-tBu
Br
Me



33
NHCOOCH2Ph
Br
Me



34
NMeCOOMe
CN
Me



35
N(nPr)COOMe
Br
Me






















TABLE 16







Compd






No
R4
R7
R8





















1
NMeCOOCH2Ph
Br
Me



2
N(nPr)COOCH2Ph
CN
Me



3
NHSO2Me
Br
Me



4
NHSO2Et
Br
Me



5
NHSO2Ph
CN
Me



6
NHTs
Br
Me



7
NMeSO2Me
Br
Me



8
N(nPr)SO2Me
CN
Me



9
NMeSO2Ph
Br
Me



10
N(nPr)SO2Ph
Br
Me



11
COOH
Ph
Me



12
COOMe
Ph
Me



13
COOEt
Ph
Me



14
COO-tBu
Ph
Me



15
CONH2
Ph
Me



16
CONHMe
Ph
Me



17
CONHEt
Ph
Me



18
CONH-nPr
Ph
Me



19
CONMe2
Ph
Me



20
CONEt2
Ph
Me



21
CON(nPr)2
Ph
Me



22
CONHPh
Ph
Me



23





Ph
Me



24





Ph
Me



25





Ph
Me



26
NH2
Ph
Me



27
NHMe
Ph
Me



28
NHEt
Ph
Me



29
NH-nPr
Ph
Me



30
NMe2
Ph
Me



31
NEt2
Ph
Me



32
N(nPr)2
Ph
Me



33





Ph
Me



34





Ph
Me



35





Ph
Me






















TABLE 17







Compd






No
R4
R7
R8





















1
NHCOMe
Ph
Me



2
NHCOEt
Ph
Me



3
NHCO-nPr
Ph
Me



4
NHCOPh
Ph
Me



5
NMeCOMe
Ph
Me



6
N(nPr)COMe
Ph
Me



7
NMeCOPh
Ph
Me



8
N(nPr)COPh
Ph
Me



9
NHCOOMe
Ph
Me



10
NHCOOEt
Ph
Me



11
NHCOO-tBu
Ph
Me



12
NHCOOCH2Ph
Ph
Me



13
NMeCOOMe
Ph
Me



14
N(nPr)COOMe
Ph
Me



15
NMeCOOCH2Ph
Ph
Me



16
N(nPr)COOCH2Ph
Ph
Me



17
NHSO2Me
Ph
Me



18
NHSO2Et
Ph
Me



19
NHSO2Ph
Ph
Me



20
NHTs
Ph
Me



21
NMeSO2Me
Ph
Me



22
N(nPr)SO2Me
Ph
Me



23
NMeSO2Ph
Ph
Me



24
N(nPr)SO2Ph
Ph
Me



25
COOH
H
COPh



26
COOMe
H
COPh



27
COOEt
H
COPh



28
COO-tBu
H
COPh



29
CONH2
H
COPh



30
CONHMe
H
COPh



31
CONHEt
H
COPh



32
CONH-nPr
H
COPh



33
CONMe2
H
COPh



34
CONEt2
H
COPh



35
CON(nPr)2
H
COPh



36
CONHPh
H
COPh



37





H
COPh



38





H
COPh



39





H
COPh






















TABLE 18







Compd






No
R4
R7
R8





















1
NH2
H
COPh



2
NHMe
H
COPh



3
NHEt
H
COPh



4
NH-nPr
H
COPh



5
NMe2
H
COPh



6
NEt2
H
COPh



7
N(nPr)2
H
COPh



8





H
COPh



9





H
COPh



10





H
COPh



11
NHCOMe
H
COPh



12
NHCOEt
H
COPh



13
NHCO-nPr
H
COPh



14
NHCOPh
H
COPh



15
NMeCOMe
H
COPh



16
N(nPr)COMe
H
COPh



17
NMeCOPh
H
COPh



18
N(nPr)COPh
H
COPh



19
NHCOOMe
H
COPh



20
NHCOOEt
H
COPh



21
NHCOO-tBu
H
COPh



22
NHCOOCH2Ph
H
COPh



23
NMeCOOMe
H
COPh



24
N(nPr)COOMe
H
COPh



25
NMeCOOCH2Ph
H
COPh



26
N(nPr)COOCH2Ph
H
COPh



27
NHSO2Me
H
COPh



28
NHSO2Et
H
COPh



29
NHSO2Ph
H
COPh



30
NHTs
H
COPh



31
NMeSO2Me
H
COPh



32
N(nPr)SO2Me
H
COPh



33
NMeSO2Ph
H
COPh



34
N(nPr)SO2Ph
H
COPh



35
COOH
Me
COPh



36
COOMe
Me
COPh



37
COOEt
Et
COPh



38
COO-tBu
nPr
COPh



39
CONH2
Me
COPh






















TABLE 19







Compd






No
R4
R7
R8





















1
CONHMe
Et
COPh



2
CONHEt
nPr
COPh



3
CONH-nPr
Me
COPh



4
CONMe2
Et
COPh



5
CONEt2
nPr
COPh



6
CON(nPr)2
nPr
COPh



7
CONHPh
Me
COPh



8





nPr
COPh



9





Et
COPh



10





Me
COPh



11
NH2
Et
COPh



12
NHMe
Me
COPh



13
NHEt
Et
COPh



14
NH-nPr
nPr
COPh



15
NMe2
Me
COPh



16
NEt2
Et
COPh



17
N(nPr)2
nPr
COPh



18





Me
COPh



19





Me
COPh



20





Me
COPh



21
NHCOMe
Et
COPh



22
NHCOEt
Et
COPh



23
NHCO-nPr
Et
COPh



24
NHCOPh
nPr
COPh



25
NMeCOMe
nPr
COPh



26
N(nPr)COMe
nPr
COPh



27
NMeCOPh
Et
COPh



28
N(nPr)COPh
Et
COPh



29
NHCOOMe
Et
COPh



30
NHCOOEt
Me
COPh



31
NHCOO-tBu
Me
COPh



32
NHCOOCH2Ph
Me
COPh



33
NMeCOOMe
Et
COPh



34
N(nPr)COOMe
nPr
COPh



35
NMeCOOCH2Ph
nPr
COPh



36
N(nPr)COOCH2Ph
nPr
COPh



37
NHSO2Me
Me
COPh



38
NHSO2Et
Et
COPh






















TABLE 20







Compd






No
R4
R7
R8





















1
NHSO2Ph
nPr
COPh



2
NHTs
Me
COPh



3
NMeSO2Me
Et
COPh



4
N(nPr)SO2Me
nPr
COPh



5
NMeSO2Ph
Me
COPh



6
N(nPr)SO2Ph
Me
COPh



7
COOH
Br
COPh



8
COOMe
Br
COPh



9
COOEt
CN
COPh



10
COO-tBu
Br
COPh



11
CONH2
CN
COPh



12
CONHMe
Br
COPh



13
CONHEt
CN
COPh



14
CONH-nPr
Br
COPh



15
CONMe2
Br
COPh



16
CONEt2
CN
COPh



17
CON(nPr)2
Br
COPh



18
CONHPh
Br
COPh



19





CN
COPh



20





Br
COPh



21





Br
COPh



22
NH2
CN
COPh



23
NHMe
Br
COPh



24
NHEt
CN
COPh



25
NH-nPr
Br
COPh



26
NMe2
Br
COPh



27
NEt2
Br
COPh



28
N(nPr)2
CN
COPh



29





Br
COPh



30





Br
COPh



31





CN
COPh



32
NHCOMe
Br
COPh



33
NHCOEt
CN
COPh



34
NHCO-nPr
Br
COPh



35
NHCOPh
CN
COPh



36
NMeCOMe
Br
COPh



37
N(nPr)COMe
CN
COPh






















TABLE 21







Compd






No
R4
R7
R8





















1
NMeCOPh
CN
COPh



2
N(nPr)COPh
Br
COPh



3
NHCOOMe
Br
COPh



4
NHCOOEt
CN
COPh



5
NHCOO-tBu
Br
COPh



6
NHCOOCH2Ph
Br
COPh



7
NMeCOOMe
CN
COPh



8
N(nPr)COOMe
Br
COPh



9
NMeCOOCH2Ph
Br
COPh



10
N(nPr)COOCH2Ph
CN
COPh



11
NHSO2Me
Br
COPh



12
NHSO2Et
Br
COPh



13
NHSO2Ph
CN
COPh



14
NHTs
Br
COPh



15
NMeSO2Me
Br
COPh



16
N(nPr)SO2Me
CN
COPh



17
NMeSO2Ph
CN
COPh



18
N(nPr)SO2Ph
CN
COPh



19
COOH
Ph
COPh



20
COOMe
Ph
COPh



21
COOEt
Ph
COPh



22
COO-tBu
Ph
COPh



23
CONH2
Ph
COPh



24
CONHMe
Ph
COPh



25
CONHEt
Ph
COPh



26
CONH-nPr
Ph
COPh



27
CONMe2
Ph
COPh



28
CONEt2
Ph
COPh



29
CON(nPr)2
Ph
COPh



30
CONHPh
Ph
COPh



31





Ph
COPh



32





Ph
COPh



33





Ph
COPh



34
NH2
Ph
COPh



35
NHMe
Ph
COPh



36
NHEt
Ph
COPh






















TABLE 22







Compd






No
R4
R7
R8





















1
NH-nPr
Ph
COPh



2
NMe2
Ph
COPh



3
NEt2
Ph
COPh



4
N(nPr)2
Ph
COPh



5





Ph
COPh



6





Ph
COPh



7





Ph
COPh



8
NHCOMe
Ph
COPh



9
NHCOEt
Ph
COPh



10
NHCO-nPr
Ph
COPh



11
NHCOPh
Ph
COPh



12
NMeCOMe
Ph
COPh



13
N(nPr)COMe
Ph
COPh



14
NMeCOPh
Ph
COPh



15
N(nPr)COPh
Ph
COPh



16
NHCOOMe
Ph
COPh



17
NHCOOEt
Ph
COPh



18
NHCOO-tBu
Ph
COPh



19
NHCOOCH2Ph
Ph
COPh



20
NMeCOOMe
Ph
COPh



21
N(nPr)COOMe
Ph
COPh



22
NMeCOOCH2Ph
Ph
COPh



23
N(nPr)COOCH2Ph
Ph
COPh



24
NHSO2Me
Ph
COPh



25
NHSO2Et
Ph
COPh



26
NHSO2Ph
Ph
COPh



27
NHTs
Ph
COPh



28
NMeSO2Me
Ph
COPh



29
N(nPr)SO2Me
Ph
COPh



30
NMeSO2Ph
Ph
COPh



31
N(nPr)SO2Ph
Ph
COPh



32
COOH
H
SO2Ph



33
COOMe
H
SO2Ph



34
COOEt
H
SO2Ph



35
COO-tBu
H
SO2Ph



36
CONH2
H
SO2Ph



37
CONHMe
H
SO2Ph






















TABLE 23







Compd






No
R4
R7
R8





















1
CONHEt
H
SO2Ph



2
CONH-nPr
H
SO2Ph



3
CONMe2
H
SO2Ph



4
CONEt2
H
SO2Ph



5
CON(nPr)2
H
SO2Ph



6
CONHPh
H
SO2Ph



7





H
SO2Ph



8





H
SO2Ph



9





H
SO2Ph



10
NH2
H
SO2Ph



11
NHMe
H
SO2Ph



12
NHEt
H
SO2Ph



13
NH-nPr
H
SO2Ph



14
NMe2
H
SO2Ph



15
NEt2
H
SO2Ph



16
N(nPr)2
H
SO2Ph



17





H
SO2Ph



18





H
SO2Ph



19





H
SO2Ph



20
NHCOMe
H
SO2Ph



21
NHCOEt
H
SO2Ph



22
NHCO-nPr
H
SO2Ph



23
NHCOPh
H
SO2Ph



24
NMeCOMe
H
SO2Ph



25
N(nPr)COMe
H
SO2Ph



26
NMeCOPh
H
SO2Ph



27
N(nPr)COPh
H
SO2Ph



28
NHCOOMe
H
SO2Ph



29
NHCOOEt
H
SO2Ph



30
NHCOO-tBu
H
SO2Ph



31
NHCOOCH2Ph
H
SO2Ph



32
NMeCOOMe
H
SO2Ph



33
N(nPr)COOMe
H
SO2Ph



34
NMeCOOCH2Ph
H
SO2Ph



35
N(nPr)COOCH2Ph
H
SO2Ph



36
NHSO2Me
H
SO2Ph



37
NHSO2Et
H
SO2Ph






















TABLE 24







Compd






No
R4
R7
R8





















1
NHSO2Ph
H
SO2Ph



2
NHTs
H
SO2Ph



3
NMeSO2Me
H
SO2Ph



4
N(nPr)SO2Me
H
SO2Ph



5
NMeSO2Ph
H
SO2Ph



6
N(nPr)SO2Ph
H
SO2Ph



7
COOH
Me
SO2Ph



8
COOMe
Me
SO2Ph



9
COOEt
Et
SO2Ph



10
COO-tBu
nPr
SO2Ph



11
CONH2
Me
SO2Ph



12
CONHMe
Me
SO2Ph



13
CONHEt
Et
SO2Ph



14
CONH-nPr
nPr
SO2Ph



15
CONMe2
Me
SO2Ph



16
CONEt2
Me
SO2Ph



17
CON(nPr)2
Me
SO2Ph



18
CONHPh
Et
SO2Ph



19





Et
SO2Ph



20





Et
SO2Ph



21





nPr
SO2Ph



22
NH2
nPr
SO2Ph



23
NHMe
nPr
SO2Ph



24
NHEt
Et
SO2Ph



25
NH-nPr
Me
SO2Ph



26
NMe2
nPr
SO2Ph



27
NEt2
Et
SO2Ph



28
N(nPr)2
Et
SO2Ph



29





Me
SO2Ph



30





Me
SO2Ph



31





Me
SO2Ph



32
NHCOMe
Et
SO2Ph



33
NHCOEt
Et
SO2Ph



34
NHCO-nPr
Et
SO2Ph



35
NHCOPh
Me
SO2Ph



36
NMeCOMe
Me
SO2Ph






















TABLE 25







Compd






No
R4
R7
R8





















1
N(nPr)COMe
Me
SO2Ph



2
NMeCOPh
nPr
SO2Ph



3
N(nPr)COPh
nPr
SO2Ph



4
NHCOOMe
nPr
SO2Ph



5
NHCOOEt
Me
SO2Ph



6
NHCOO-tBu
Et
SO2Ph



7
NHCOOCH2Ph
nPr
SO2Ph



8
NMeCOOMe
Me
SO2Ph



9
N(nPr)COOMe
Et
SO2Ph



10
NMeCOOCH2Ph
nPr
SO2Ph



11
N(nPr)COOCH2Ph
Me
SO2Ph



12
NHSO2Me
Et
SO2Ph



13
NHSO2Et
nPr
SO2Ph



14
NHSO2Ph
Me
SO2Ph



15
NHTs
Me
SO2Ph



16
NMeSO2Me
Me
SO2Ph



17
N(nPr)SO2Me
nPr
SO2Ph



18
NMeSO2Ph
nPr
SO2Ph



19
N(nPr)SO2Ph
nPr
SO2Ph



20
COOH
Br
SO2Ph



21
COOMe
CN
SO2Ph



22
COOEt
Br
SO2Ph



23
COO-tBu
CN
SO2Ph



24
CONH2
Br
SO2Ph



25
CONHMe
Br
SO2Ph



26
CONHEt
Br
SO2Ph



27
CONH-nPr
Br
SO2Ph



28
CONMe2
CN
SO2Ph



29
CONEt2
CN
SO2Ph



30
CON(nPr)2
CN
SO2Ph



31
CONHPh
Br
SO2Ph



32





Br
SO2Ph



33





Br
SO2Ph



34





CN
SO2Ph



35
NH2
Br
SO2Ph



36
NHMe
CN
SO2Ph






















TABLE 26







Compd






No
R4
R7
R8





















1
NHEt
Br
SO2Ph



2
NH-nPr
CN
SO2Ph



3
NMe2
Br
SO2Ph



4
NEt2
Br
SO2Ph



5
N(nPr)2
CN
SO2Ph



6





Br
SO2Ph



7





Br
SO2Ph



8





Br
SO2Ph



9
NHCOMe
CN
SO2Ph



10
NHCOEt
Br
SO2Ph



11
NHCO-nPr
CN
SO2Ph



12
NHCOPh
Br
SO2Ph



13
NMeCOMe
Br
SO2Ph



14
N(nPr)COMe
CN
SO2Ph



15
NMeCOPh
Br
SO2Ph



16
N(nPr)COPh
Br
SO2Ph



17
NHCOOMe
CN
SO2Ph



18
NHCOOEt
Br
SO2Ph



19
NHCOO-tBu
Br
SO2Ph



20
NHCOOCH2Ph
Br
SO2Ph



21
NMeCOOMe
CN
SO2Ph



22
N(nPr)COOMe
Br
SO2Ph



23
NMeCOOCH2Ph
Br
SO2Ph



24
N(nPr)COOCH2Ph
Br
SO2Ph



25
NHSO2Me
CN
SO2Ph



26
NHSO2Et
Br
SO2Ph



27
NHSO2Ph
Br
SO2Ph



28
NHTs
CN
SO2Ph



29
NMeSO2Me
Br
SO2Ph



30
N(nPr)SO2Me
Br
SO2Ph



31
NMeSO2Ph
CN
SO2Ph



32
N(nPr)SO2Ph
Br
SO2Ph



33
COOH
Ph
SO2Ph



34
COOMe
Ph
SO2Ph



35
COOEt
Ph
SO2Ph



36
COO-tBu
Ph
SO2Ph



37
CONH2
Ph
SO2Ph






















TABLE 27







Compd






No
R4
R7
R8





















1
CONHMe
Ph
SO2Ph



2
CONHEt
Ph
SO2Ph



3
CONH-nPr
Ph
SO2Ph



4
CONMe2
Ph
SO2Ph



5
CONEt2
Ph
SO2Ph



6
CON(nPr)2
Ph
SO2Ph



7
CONHPh
Ph
SO2Ph



8





Ph
SO2Ph



9





Ph
SO2Ph



10





Ph
SO2Ph



11
NH2
Ph
SO2Ph



12
NHMe
Ph
SO2Ph



13
NHEt
Ph
SO2Ph



14
NH-nPr
Ph
SO2Ph



15
NMe2
Ph
SO2Ph



16
NEt2
Ph
SO2Ph



17
N(nPr)2
Ph
SO2Ph



18





Ph
SO2Ph



19





Ph
SO2Ph



20





Ph
SO2Ph



21
NHCOMe
Ph
SO2Ph



22
NHCOEt
Ph
SO2Ph



23
NHCO-nPr
Ph
SO2Ph



24
NHCOPh
Ph
SO2Ph



25
NMeCOMe
Ph
SO2Ph



26
N(nPr)COMe
Ph
SO2Ph



27
NMeCOPh
Ph
SO2Ph



28
N(nPr)COPh
Ph
SO2Ph



29
NHCOOMe
Ph
SO2Ph



30
NHCOOEt
Ph
SO2Ph



31
NHCOO-tBu
Ph
SO2Ph



32
NHCOOCH2Ph
Ph
SO2Ph



33
NMeCOOMe
Ph
SO2Ph



34
N(nPr)COOMe
Ph
SO2Ph



35
NMeCOOCH2Ph
Ph
SO2Ph



36
N(nPr)COOCH2Ph
Ph
SO2Ph




















TABLE 28





Compd





No
R4
R7
R8







1
NHSO2Me
Ph
SO2Ph


2
NHSO2Et
Ph
SO2Ph


3
NHSO2Ph
Ph
SO2Ph


4
NHTs
Ph
SO2Ph


5
NMeSO2Me
Ph
SO2Ph


6
N(nPr)SO2Me
Ph
SO2Ph


7
NMeSO2Ph
Ph
SO2Ph


8
N(nPr)SO2Ph
Ph
SO2Ph

















TABLE 29








(I-b)


















Compd






No
R4
R6
R7
R8














1
COOH
H
H
H


2
COOMe
H
H
H


3
COOEt
H
H
H


4
COO-tBu
H
H
H


5
CONH2
H
H
H


6
CONHMe
H
H
H


7
CONHEt
H
H
H


8
CONH-nPr
H
H
H


9
CONMe2
H
H
H


10
CONEt2
H
H
H


11
CON(nPr)2
H
H
H


12
CONHPh
H
H
H


13





H
H
H


14





H
H
H


15





H
H
H


16
NHCOOMe
H
H
H


17
NHCOOEt
H
H
H


18
NHCOO-tBu
H
H
H


19
NHCOOCH2Ph
H
H
H


20
NMeCOOMe
H
H
H


21
N(nPr)COOMe
H
H
H


22
NMeCOOCH2Ph
H
H
H


23
N(nPr)COOCH2Ph
H
H
H


24
COOH
H
Me
H


25
COOMe
H
Me
H


26
COOEt
H
Et
H




















TABLE 30





Compd






No
R4
R6
R7
R8



















1
COO-tBu
H
nPr
H


2
CONH2
H
Me
H


3
CONHMe
H
Me
H


4
CONHEt
H
Et
H


5
CONH-nPr
H
nPr
H


6
CONMe2
H
Me
H


7
CONEt2
H
Me
H


8
CON(nPr)2
H
Me
H


9
CONHPh
H
Et
H


10





H
Et
H


11





H
Et
H


12





H
Et
H


13
NHCOOMe
H
nPr
H


14
NHCOOEt
H
nPr
H


15
NHCOO-tBu
H
nPr
H


16
NHCOOCH2Ph
H
Me
H


17
NMeCOOMe
H
Et
H


18
N(nPr)COOMe
H
nPr
H


19
NMeCOOCH2Ph
H
Me
H


20
N(nPr)COOCH2Ph
H
nPr
H


21
COOH
H
Br
H


22
COOMe
H
Br
H


23
COOEt
H
CN
H


24
COO-tBu
H
Br
H


25
CONH2
H
Br
H


26
CONHMe
H
CN
H


27
CONHEt
H
Br
H


28
CONH-nPr
H
CN
H


29
CONMe2
H
Br
H


30
CONEt2
H
Br
H


31
CON(nPr)2
H
CN
H


32
CONHPh
H
Br
H


33





H
Br
H


34





H
CN
H


35





H
Br
H




















TABLE 31





Compd






No.
R4
R6
R7
R8



















1
NHCOOMe
H
Br
H


2
NHCOOEt
H
CN
H


3
NHCOO-tBu
H
Br
H


4
NHCOOCH2Ph
H
CN
H


5
NMeCOOMe
H
Br
H


6
N(nPr)COOMe
H
CN
H


7
NMeCOOCH2Ph
H
Br
H


8
N(nPr)COOCH2Ph
H
CN
H


9
COOH
H
Ph
H


10
COOMe
H
Ph
H


11
COOEt
H
Ph
H


12
COO-tBu
H
Ph
H


13
CONH2
H
Ph
H


14
CONHMe
H
Ph
H


15
CONHEt
H
Ph
H


16
CONH-nPr
H
Ph
H


17
CONMe2
H
Ph
H


18
CONEt2
H
Ph
H


19
CON(nPr)2
H
Ph
H


20
CONHPh
H
Ph
H


21





H
Ph
H


22





H
Ph
H


23





H
Ph
H


24
NHCOOMe
H
Ph
H


25
NHCOOEt
H
Ph
H


26
NHCOO-tBu
H
Ph
H


27
NHCOOCH2Ph
H
Ph
H


28
NMeCOOMe
H
Ph
H


29
N(nPr)COOMe
H
Ph
H


30
NMeCOOCH2Ph
H
Ph
H


31
N(nPr)COOCH2Ph
H
Ph
H


32
COOH
H
H
Me


33
COOMe
H
H
Me


34
COOEt
H
H
Me


35
COO-tBu
H
H
Me


36
CONH2
H
H
Me


37
CONHMe
H
H
Me




















TABLE 32





Compd






No
R4
R6
R7
R8



















1
CONHEt
H
H
Me


2
CONH-nPr
H
H
Me


3
CONMe2
H
H
Me


4
CONEt2
H
H
Me


5
CON(nPr)2
H
H
Me


6
CONHPh
H
H
Me


7





H
H
Me


8





H
H
Me


9





H
H
Me


10
NHCOOMe
H
H
Me


11
NHCOOEt
H
H
Me


12
NHCOO-tBu
H
H
Me


13
NHCOOCH2Ph
H
H
Me


14
NMeCOOMe
H
H
Me


15
N(nPr)COOMe
H
H
Me


16
NMeCOOCH2Ph
H
H
Me


17
N(nPr)COOCH2Ph
H
H
Me


18
COOH
H
Me
Me


19
COOMe
H
Me
Me


20
COOEt
H
Et
Me


21
COO-tBu
H
nPr
Me


22
CONH2
H
Me
Me


23
CONHMe
H
Me
Me


24
CONHEt
H
Me
Me


25
CONH-nPr
H
Et
Me


26
CONMe2
H
Et
Me


27
CONEt2
H
Et
Me


28
CON(nPr)2
H
nPr
Me


29
CONHPh
H
nPr
Me


30





H
nPr
Me


31





H
Me
Me


32





H
Et
Me


33
NHCOOMe
H
nPr
Me


34
NHCOOEt
H
Me
Me




















TABLE 33





Compd






No
R4
R6
R7
R8



















1
NHCOO-tBu
H
Et
Me


2
NHCOOCH2Ph
H
nPr
Me


3
NMeCOOMe
H
Me
Me


4
N(nPr)COOMe
H
Me
Me


5
NMeCOOCH2Ph
H
Et
Me


6
N(nPr)COOCH2Ph
H
nPr
Me


7
COOH
H
Br
Me


8
COOMe
H
CN
Me


9
COOEt
H
Br
Me


10
COO-tBu
H
CN
Me


11
CONH2
H
Br
Me


12
CONHMe
H
CN
Me


13
CONHEt
H
Br
Me


14
CONH-nPr
H
CN
Me


15
CONMe2
H
Br
Me


16
CONEt2
H
CN
Me


17
CON(nPr)2
H
Br
Me


18
CONHPh
H
CN
Me


19





H
Br
Me


20





H
Br
Me


21





H
CN
Me


22
NHCOOMe
H
CN
Me


23
NHCOOEt
H
Br
Me


24
NHCOO-tBu
H
CN
Me


25
NHCOOCH2Ph
H
Br
Me


26
NMeCOOMe
H
Br
Me


27
N(nPr)COOMe
H
CN
Me


28
NMeCOOCH2Ph
H
Br
Me


29
N(nPr)COOCH2Ph
H
Br
Me


30
COOH
H
Ph
Me


31
COOMe
H
Ph
Me


32
COOEt
H
Ph
Me


33
COO-tBu
H
Ph
Me


34
CONH2
H
Ph
Me


35
CONHMe
H
Ph
Me


36
CONHEt
H
Ph
Me


37
CONH-nPr
H
Ph
Me




















TABLE 34





Compd






No
R4
R6
R7
R8



















1
CONMe2
H
Ph
Me


2
CONEt2
H
Ph
Me


3
CON(nPr)2
H
Ph
Me


4
CONHPh
H
Ph
Me


5





H
Ph
Me


6





H
Ph
Me


7





H
Ph
Me


8
NHCOOMe
H
Ph
Me


9
NHCOOEt
H
Ph
Me


10
NHCOO-tBu
H
Ph
Me


11
NHCOOCH2Ph
H
Ph
Me


12
NMeCOOMe
H
Ph
Me


13
N(nPr)COOMe
H
Ph
Me


14
NMeCOOCH2Ph
H
Ph
Me


15
N(nPr)COOCH2Ph
H
Ph
Me


16
COOH
H
H
COPh


17
COOMe
H
H
COPh


18
COOEt
H
H
COPh


19
COO-tBu
H
H
COPh


20
CONH2
H
H
COPh


21
CONHMe
H
H
COPh


22
CONHEt
H
H
COPh


23
CONH-nPr
H
H
COPh


24
CONMe2
H
H
COPh


25
CONEt2
H
H
COPh


26
CON(nPr)2
H
H
COPh


27
CONHPh
H
H
COPh


28





H
H
COPh


29





H
H
COPh


30





H
H
COPh


31
NHCOOMe
H
H
COPh


32
NHCOOEt
H
H
COPh


33
NHCOO-tBu
H
H
COPh


34
NHCOOCH2Ph
H
H
COPh




















TABLE 35





Compd






No
R4
R6
R7
R8



















1
NMeCOOMe
H
H
COPh


2
N(nPr)COOMe
H
H
COPh


3
NMeCOOCH2Ph
H
H
COPh


4
N(nPr)COOCH2Ph
H
H
COPh


5
COOH
H
Me
COPh


6
COOMe
H
nPr
COPh


7
COOEt
H
Et
COPh


8
COO-tBu
H
Et
COPh


9
CONH2
H
Et
COPh


10
CONHMe
H
Me
COPh


11
CONHEt
H
Me
COPh


12
CONH-nPr
H
Me
COPh


13
CONMe2
H
nPr
COPh


14
CONEt2
H
nPr
COPh


15
CON(nPr)2
H
nPr
COPh


16
CONHPh
H
Me
COPh


17





H
Et
COPh


18





H
nPr
COPh


19





H
Me
COPh


20
NHCOOMe
H
Me
COPh


21
NHCOOEt
H
Me
COPh


22
NHCOO-tBu
H
Et
COPh


23
NHCOOCH2Ph
H
nPr
COPh


24
NMeCOOMe
H
Et
COPh


25
N(nPr)COOMe
H
nPr
COPh


26
NMeCOOCH2Ph
H
Me
COPh


27
N(nPr)COOCH2Ph
H
Me
COPh


28
COOH
H
Br
COPh


29
COOMe
H
CN
COPh


30
COOEt
H
Br
COPh


31
COO-tBu
H
CN
COPh


32
CONH2
H
Br
COPh


33
CONHMe
H
Br
COPh


34
CONHEt
H
CN
COPh


35
CONH-nPr
H
CN
COPh


36
CONMe2
H
Br
COPh




















TABLE 36





Compd






No
R4
R6
R7
R8







 1
CONEt2
H
Br
COPh


 2
CON(nPr)2
H
Br
COPh


 3
CONHPh
H
Br
COPh


 4





H
CN
COPh


 5





H
CN
COPh


 6





H
Br
COPh


 7
NHCOOMe
H
CN
COPh


 8
NHCOOEt
H
Br
COPh


 9
NHCOO-tBu
H
CN
COPh


10
NHCOOCH2Ph
H
Br
COPh


11
NMeCOOMe
H
CN
COPh


12
N(nPr)COOMe
H
Br
COPh


13
NMeCOOCH2Ph
H
Br
COPh


14
N(nPr)COOCH2Ph
H
Br
COPh


15
COOH
H
Ph
COPh


16
COOMe
H
Ph
COPh


17
COOEt
H
Ph
COPh


18
COO-tBu
H
Ph
COPh


19
CONH2
H
Ph
COPh


20
CONHMe
H
Ph
COPh


21
CONHEt
H
Ph
COPh


22
CONH-nPr
H
Ph
COPh


23
CONMe2
H
Ph
COPh


24
CONEt2
H
Ph
COPh


25
CON(nPr)2
H
Ph
COPh


26
CONHPh
H
Ph
COPh


27





H
Ph
COPh


28





H
Ph
COPh


29





H
Ph
COPh


30
NHCOOMe
H
Ph
COPh


31
NHCOOEt
H
Ph
COPh


32
NHCOO-tBu
H
Ph
COPh




















TABLE 37





Compd






No
R4
R6
R7
R8







 1
NHCOOCH2Ph
H
Ph
COPh


 2
NMeCOOMe
H
Ph
COPh


 3
N(nPr)COOMe
H
Ph
COPh


 4
NMeCOOCH2Ph
H
Ph
COPh


 5
N(nPr)COOCH2Ph
H
Ph
COPh


 6
COOH
H
H
SO2Ph


 7
COOMe
H
H
SO2Ph


 8
COOEt
H
H
SO2Ph


 9
COO-tBu
H
H
SO2Ph


10
CONH2
H
H
SO2Ph


11
CONHMe
H
H
SO2Ph


12
CONHEt
H
H
SO2Ph


13
CONHn-Pr
H
H
SO2Ph


14
CONMe2
H
H
SO2Ph


15
CONEt2
H
H
SO2Ph


16
CON(nPr)2
H
H
SO2Ph


17
CONHPh
H
H
SO2Ph


18





H
H
SO2Ph


19





H
H
SO2Ph


20





H
H
SO2Ph


21
NHCOOMe
H
H
SO2Ph


22
NHCOOEt
H
H
SO2Ph


23
NHCOO-tBu
H
H
SO2Ph


24
NHCOOCH2Ph
H
H
SO2Ph


25
NMeCOOMe
H
H
SO2Ph


26
N(nPr)COOMe
H
H
SO2Ph


27
NMeCOOCH2Ph
H
H
SO2Ph


28
N(nPr)COOCH2Ph
H
H
SO2Ph


29
COOH
H
Me
SO2Ph


30
COOMe
H
Et
SO2Ph


31
COOEt
H
nPr
SO2Ph


32
COO-tBu
H
Et
SO2Ph


33
CONH2
H
nPr
SO2Ph


34
CONHMe
H
Me
SO2Ph


35
CONHEt
H
Me
SO2Ph


36
CONH-nPr
H
nPr
SO2Ph




















TABLE 38





Compd






No
R4
R6
R7
R8







 1
CONMe2
H
nPr
SO2Ph


 2
CONEt2
H
Et
SO2PII


 3
CON(nPr)2
H
Et
SO2Ph


 4
CONHPh
H
nPr
SO2Ph


 5





H
nPr
SO2Ph


 6





H
nPr
SO2Ph


 7





H
Me
SO2Ph


 8
NHCOOMe
H
Me
SO2Ph


 9
NHCOOEt
H
Me
SO2Ph


10
NHCOO-tBu
H
Et
SO2Ph


11
NHCOOCH2Ph
H
Et
SO2Ph


12
NMeCOOMe
H
Et
SO2Ph


13
N(nPr)COOMe
H
Me
SO2Ph


14
NMeCOOCH2Ph
H
Me
SO2Ph


15
N(nPr)COOCH2Ph
H
Me
SO2PIi


16
COOH
H
Br
SO2Ph


17
COOMe
H
Br
SO2Ph


18
COOEt
H
Br
SO2Ph


19
COO-tBu
H
CN
SO2Ph


20
CONH2
H
Br
SO2Ph


21
CONHMe
H
Br
SO2PIi


22
CONHEt
H
Br
SO2Ph


23
CONH-nPr
H
CN
SO2Ph


24
CONMe2
H
Br
SO2Ph


25
CONEt2
H
Br
SO2Ph


26
CON(nPr)2
H
Br
SO2Ph


27
CONHPh
H
CN
SO2Ph


28





H
Br
SO2Ph


29





H
Br
SO2Ph


30





H
Br
SO2Ph


31
NHCOOMe
H
Br
SO2Ph


32
NHCOOEt
H
CN
SO2Ph


33
NHCOO-tBu
H
Br
SO2Ph




















TABLE 39





Compd






No
R4
R6
R7
R8







 1
NHCOOCH2Ph
H
Br
SO2Ph


 2
NMeCOOMe
H
Br
SO2Ph


 3
N(nPr)COOMe
H
CN
SO2Ph


 4
NMeCOOCH2Ph
H
Br
SO2Ph


 5
N(nPr)COOCH2Ph
H
Br
SO2Ph


 6
COOH
H
Ph
SO2Ph


 7
COOMe
H
Ph
SO2Ph


 8
COOEt
H
Ph
SO2Ph


 9
COO-tBu
H
Ph
SO2Ph


10
CONH2
H
Ph
SO2Ph


11
CONHMe
H
Ph
SO2Ph


12
CONHEt
H
Ph
SO2Ph


13
CONH-nPr
H
Ph
SO2Ph


14
CONMe2
H
Ph
SO2Ph


15
CONEt2
H
Ph
SO2Ph


16
CON(nPr)2
H
Ph
SO2Ph


17
CONHPh
H
Ph
SO2Ph


18





H
Ph
SO2Ph


19





H
Ph
SO2Ph


20





H
Ph
SO2Ph


21
NHCOOMe
H
Ph
SO2Ph


22
NHCOOEt
H
Ph
SO2Ph


23
NHCOO-tBu
H
Ph
SO2Ph


24
NHCOOCH2Ph
H
Ph
SO2Ph


25
NMeCOOMe
H
Ph
SO2Ph


26
N(nPr)COOMe
H
Ph
SO2Ph


27
NMeCOOCH2Ph
H
Ph
SO2Ph


28
N(nPr)COOCH2Ph
H
Ph
SO2Ph


29
OH
COOMe
H
H


30
OMe
COOMe
H
H


31
OH
COOMe
Me
H


32
OMe
COOMe
Me
H


33
OH
COOMe
Br
H


34
OMe
COOMe
Br
H


35
OH
COOMe
Ph
H


36
OMe
COOMe
Ph
H


37
OH
COOMe
H
Me


38
OMe
COOMe
H
Me




















TABLE 40





Comp






No
R4
R6
R7
R8



















1
OH
COOMe
Me
Me


2
OMe
COOMe
Et
Me


3
OH
COOMe
Br
Me


4
OMe
COOMe
Br
Me


5
OH
COOMe
Ph
Me


6
OMe
COOMe
Ph
Me


7
OH
COOMe
H
COPh


8
OMe
COOMe
H
COPh


9
OH
COOMe
Me
COPh


10
OMe
COOMe
nPr
COPh


11
OH
COOMe
Br
COPh


12
OMe
COOMe
CN
COPh


13
OH
COOMe
CN
COPh


14
OMe
COOMe
Ph
COPh


15
OH
COOMe
H
SO2Ph


16
OMe
COOMe
CN
SO2Ph


17
OH
COOMe
Et
SO2Ph


18
OMe
COOMe
Me
SO2Ph


19
OH
COOMe
CN
SO2Ph


20
OMe
COOMe
Br
SO2Ph


21
OH
COOMe
Ph
SO2Ph


22
OMe
COOMe
CN
SO2Ph


23
OH
COOEt
H
H


24
OMe
COOEt
H
H


25
OH
COOEt
nPr
H


26
OMe
COOEt
Et
H


27
OH
COOEt
Br
H


28
OMe
COOEt
CN
H


29
OH
COOEt
Ph
H


30
OMe
COOEt
CN
H


31
OH
COOEt
H
Me


32
OMe
COOEt
H
Me


33
OH
COOEt
nPr
Me


34
OMe
COOEt
CN
Me


35
OH
COOEt
Br
Me


36
OMe
COOEt
CN
Me


37
OH
COOEt
Ph
Me


38
OMe
COOEt
Ph
Me


39
OH
COOEt
H
COPh


40
OMe
COOEt
CN
COPh


41
OH
COOEt
Me
COPh




















TABLE 41





Comp






No
R4
R6
R7
R8



















1
OMe
COOEt
Et
COPh


2
OH
COOEt
Br
COPh


3
OMe
COOEt
CN
COPh


4
OH
COOEt
Ph
COPh


5
OMe
COOEt
CN
COPh


6
OH
OQOEt
H
SO2Ph


7
OMe
OQOEt
H
SO2Ph


8
OH
COOEt
Me
SO2Ph


9
OMe
COOEt
nPr
SO2Ph


10
OH
COOEt
CN
SO2Ph


11
OMe
COOEt
Br
SO2Ph


12
OH
COOEt
Ph
SO2Ph


13
OMe
COOEt
Ph
SO2Ph


14
OH
CN
H
H


15
OMe
CN
CN
H


16
OH
CN
Me
H


17
OMe
CN
Et
H


18
OH
CN
Br
H


19
OMe
CN
CN
H


20
OH
CN
Ph
H


21
OMe
CN
Ph
H


22
OH
CN
H
Me


23
OMe
CN
H
Me


24
OH
CN
CN
Me


25
OMe
CN
Me
Me


26
OH
CN
Br
Me


27
OMe
CN
Br
Me


28
OH
CN
Ph
Me


29
OMe
CN
CN
Me


30
OH
CN
H
COPh


31
OMe
CN
H
COPh


32
OH
CN
CN
COPh


33
OMe
CN
Et
COPh


34
OH
CN
Br
COPh


35
OMe
CN
Br
COPh


36
OH
CN
Ph
COPh


37
OMe
CN
CN
COPh


38
OH
CN
H
SO2Ph


39
OMe
CN
H
SO2Ph


40
OH
CN
nPr
SO2Ph


41
OMe
CN
nPr
SO2Ph




















TABLE 42





Comp






No
R4
R6
R7
R8



















1
OH
CN
Br
SO2Ph


2
OMe
CN
Br
SO2Ph


3
OH
CN
CN
SO2Ph


4
OMe
CN
Ph
SO2Ph


5
OH
CH2NH2
H
H


6
OMe
CH2NH2
H
H


7
OH
CH2NH2
nPr
H


8
OMe
CH2NH2
Me
H


9
OH
CH2NH2
Br
H


10
OMe
CH2NH2
CN
H


11
OH
CH2NH2
Ph
H


12
OMe
CH2NH2
Ph
H


13
OH
CH2NH2
CN
Me


14
OMe
CH2NH2
H
Me


15
OH
CH2NH2
Et
Me


16
OMe
CH2NH2
CN
Me


17
OH
CH2NH2
Br
Me


18
OMe
CH2NH2
Br
Me


19
OH
CH2NH2
Ph
Me


20
OMe
CH2NH2
CN
Me


21
OH
CH2NH2
H
COPh


22
OMe
CH2NH2
H
COPh


23
OH
CH2NH2
nPr
COPh


24
OMe
CH2NH2
nPr
COPh


25
OH
CH2NH2
Br
COPh


26
OMe
CH2NH2
Br
COPh


27
OH
CH2NH2
Ph
COPh


28
OMe
CH2NH2
Ph
COPh


29
OH
CH2NH2
H
SO2Ph


30
OMe
CH2NH2
H
SO2Ph


31
OH
CH2NH2
Me
SO2Ph


32
OMe
CH2NH2
Me
SO2Ph


33
OH
CH2NH2
CN
SO2Ph


34
OMe
CH2NH2
Br
SO2Ph


35
OH
CH2NH2
CN
SO2Ph


36
OMe
CH2NH2
Ph
SO2Ph









EXPERIMENTALS
A mixture of radioactive ligands and some cardinal numbers of test compounds was incubated with a sample of cell membrane, which was prepared from brain of rats or HEK293 cells, which expressed the receptor, under the following conditions. Then, the sample was filtered by suction on a Whatman GF/C. Radioactivity on the filter was encountered by the use of a liquid scintillation counter. 50% Inhibitory concentration values (IC50 values) of each selective binding were calculated for test compounds and the Ki value was obtained by applying an equation of Cheng-Prusoff [Biochem. Pharmacol. 22 (1973) 3099-3108] Ki=IC50/(1+[L]/Kd). [L] represents a concentration of the radio ligand used and Kd shows dissociation constant.










TABLE 43








Condition of


Receptor
Origin
Radioactive Ligand
Incubation







5-HT1A
Rat
1 nM [3H] 8-OH-
25° C. 30 min



hippocampus
DPAT


5-HT2
Rat cerebral
1 nM [3H] Ketanserin
37° C. 30 min



cortex


5-HT6
rat5-HT6
8 nM [3H] 5HT
25° C. 120 min



(HEK293)
4 nM [3H] LSD
37° C. 60 min


5-HT7
Human 5-HT7
0.5 nM [3H] 5CT
25° C. 120 min



(HEK293)


















TABLE 44









Ki value (nM) ±SE











Example
Compd. No.
5-HT1A
5-HT6
5-HT7














5
8-1
36




12
19-1 
81


12
19-2 
23
97


12
19-3 
5.7

46


12
19-5 
10


12
19-7 
19


12
19-10
2.5


12
19-15
7.7
4.6
16


12
19-16
58
62
86


12
19-18

2.7


12
19-19
3.8


13
20-1 

1.7


13
20-5 

0.49


13
20-6 

2.7


13
20-9 
86
78


13
20-10
95
45


13
20-11

5.7


13
20-12

2.7


13
20-13

3.9


13
20-14

22


13
20-15

29


13
20-16

22


13
20-17

29


13
20-18

22


13
20-19

12


13
20-20

11


13
20-21

2.7


13
20-22

26


13
20-23

9.9


13
20-24

3.2


13
20-25

36


14
21
14


24
36-1 
29
65


24
36-2 

8.5


24
36-3 
58
4.2


24
36-4 


26
38
83

22


27
39
27

73


28
40
15
32
74


29
41
57


34
46-2 


34
46-3 
18


34
46-1 

28


35
47

78


36
48

1









INDUSTRIAL APPLICABILITY
Having an affinity against serotonin receptors, compounds described in this invention are useful as medicines such as therapeutic agents of diseases for central nervous systems thereof. Furthermore, these compounds are useful as synthetic intermediates thereof.

## Claims

1. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof of the formula: 




wherein
R1 is hydrogen; 
R2 is hydrogen or lower alkyl; 
R3 is hydrogen; 
R4 is —COOR13 wherein R13 is hydrogen or ester moiety; 
R5 is hydrogen, or R3 and R5 taken together may form a bond; 
R6 is hydrogen; 
R7 is hydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, or cycloalkyl(lower)alkyl; 
R8 is hydrogen, optionally substituted lower alkyl, cycloalkyl, or cycloalkyl(lower)alkyl; and 
R9, R10 and R11 are each independently hydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, or cycloalkyl(lower)alkyl.

2. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R2 is hydrogen.

3. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R3 is hydrogen.

4. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R5 is hydrogen.

5. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R3 and R5 taken together may form a bond.

6. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R4 represents —COOR13 wherein R13 is hydrogen or lower alkyl.

7. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R4 is —COOR13 wherein R13 is hydrogen or methyl.

8. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R7 is hydrogen, lower alkyl, or halogen.

9. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R7 is hydrogen, methyl, ethyl, or halogen.

10. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R8 is hydrogen, or optionally substituted lower alkyl.

11. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R8 is hydrogen.

12. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein all of R9, R10 and R11 are hydrogen.

13. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R2 is hydrogen, R3 and R5 are hydrogen or taken together may form a bond.

14. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein all of R9, R10 and R11 are hydrogen; wherein R2 is hydrogen; wherein R3 and R5 are hydrogen or together form a bond; wherein R6 is hydrogen; R7 is hydrogen, lower alkyl, or halogen and R8 is hydrogen, or lower alkyl.

15. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R9 is hydrogen or halogen.

16. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R9 is hydrogen.

17. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R10 is hydrogen.

18. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R11 is hydrogen, halogen, or lower alkyl.

19. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R11 is hydrogen, halogen, or methyl.

20. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R1, R2, R3, R5, R6, R9, and R10 is hydrogen; R7 is hydrogen, halogen, or lower alkyl, R8 is hydrogen and R11 is hydrogen, halogen, or lower alkyl.

21. A pharmaceutical composition comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to claim 1, together with a pharmaceutically acceptable additive thereof.

22. A method for preparing a therapeutic or prophylactic medicament for a serotonin receptor mediated disease, which comprises mixing a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to claim 1, together with a pharmaceutically acceptable additive thereof.