DC-89 DERIVATIVE

DERIVE DC-89

English Abstract

A DC-89 derivative represented by general formula (1) or (2) or a
pharmacologically acceptable salt thereof, having an excellent antitumor
activity and useful as an antitumor drug, wherein X represents Cl or Br; R
represents hydrogen or COR1; and W represents a group of general formula (3)
or (4).

French Abstract

Dérivé DC-89 représenté par la formule générale (1) ou (2), ou sel pharmaceutiquement acceptable de ce dérivé, présentant une excellente activité antitumorale et utile comme médicament antitumoral, formule dans laquelle X représente Cl ou Br; R représente l'hydrogène ou COR?1¿; et W représente un groupe de la formule générale (3) ou (4).

Claims

CLAIMS
1. A DC-89 derivative represented by the formula:
<IMG>
wherein <IMG> represents
<IMG> or <IMG>
in which X represents Cl or Br, R represents hydrogen or
COR1 in which R1 represents hydrogen, substituted or
unsubstituted lower alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heterocyclic group, NR2R3
(in which R2 and R3 independently represent hydrogen or
substituted or unsubstituted lower alkyl, amino, or mono- or
di(lower alkyl)amino),
<IMG>
in which R4 represents oxygen, N-R5 (in which R5 represents
hydrogen or lower alkyl), CH2 or <IMG> ,
<IMG>
(in which R4 and R5 are the same meanings as defined above),
or OR6 (in which R6 represents substituted or unsubstituted
lower alkyl, or substituted or unsubstituted aryl); and
- 100 -

W represents
<IMG>
in which Y1, Y2 and Y3 independently represent CH or N, Q1
and Q2 independently represent hydrogen, OR7 (in which R7
represents hydrogen or substituted or unsubstituted lower
alkyl), NR2aR3a (in which R2a and R3a are the same meanings as
R2 and R3 defined above), NHCO2R6a (in which R6a is the same
meaning as R6 defined above), or O(CH2)nR8 in which n
represents an integer of 1 to 4, and R8 represents CO2R7a (in
which R7a is the same meaning as R7 defined above), N3, or
NR2bR3b (in which R2b and R3b are the same meanings as R2 and
R3 defined above), provided that when Q1 is OCH3 and Y1, Y2
and Y3 are CH, Q2 is a group other than hydrogen, or
<IMG>
(in which Y4 represents oxygen, sulfur or NH, and R7b is the
same meaning as R7 defined above), and pharmaceutically
acceptable salts thereof.
2. A DC-89 derivative represented by the formula:
<IMG>
wherein X represents Cl or Br, R represents COR1 in which R1
represents substituted or unsubstituted lower alkyl, NR2R3
(in which R2 and R3 independently represent substituted or
unsubstituted lower alkyl or amino) or
<IMG>
(in which R5 represents lower alkyl); and
- 101 -

W represents
<IMG> or <IMG> ,
and a pharmaceutically acceptable salt thereof.
3. A DC-89 derivative represented by the formula:
<IMG>
wherein X represents Br, R5 represents lower alkyl; and W
represents
<IMG>
,
and a pharmaceutically acceptable salt thereof.
- 102 -

Description

~ 2i6~0
SPECIFICATION
DC-89 DERIVATIVES
Technical Field
The present invention relates to DC-89 derivatives.
The compounds of the present invention exhibit excellent
anti-tumor activity and are useful as anti-tumor agents.
Background Art
As DC-89 derivatives, DC-89A1, DC-89A2, DC-89B1 and
DC-89B2 represented by the following structural formula are
known, and these compounds exhibit antibacterial activity
against various bacteria and also antitumor activity against
melanoma B-16, etc.
CO2CH3
H3C~4O
Ho)b~N~--
O ~OCH3
H OCH3
OCH3
DC-89Al:X = -CH2-, Y = Cl
DC-89A2:X = single bond, Y = CH2Cl
DC-89Bl:X = -CH2-, Y = Br
DC-89B2:X = single bond, Y = CH2Br
DC-89A1 is disclosed in W087/06265, and DC-89A2, DC-
30 89B1 and DC-89B2 are disclosed in JP,A,2-119787. SF2582A
and SF2582B, which are the same compounds as DC-89A2 and DC-
89A1, are disclosed in JP,A,1-139590. In relation to the
compounds of the present invention, DC-88A and DC113 having
the following structural formulae are disclosed in
35 W087/06265 and JP,A,2-177890, respectively. These compounds
exhibit not only antibacterial activity against various
bacteria but also anti-tumor activity against melanoma B-16,
etc.
_

21 6~'89Q
c02CH3 H3C02C~
~ ~`OCH ~OCH
DC-88A DC11 3
DC-88A derivatives and DC-89 derivatives are disclosed
in JP,A,2-288879, JP,A,3-7287, JP,A,3-128379, JP,A,4-226988,
JP,A,4-356485, JP,A,5-51384 and JP,A,5-178858.
Derivatives of SF2582C are disclosed in JP,A,1-278881.
CC-1065 and derivatives thereof are disclosed in JP,A,54-
64695, JP,A,60-193989, W088/04659, EP-359454 and JP,A,3-
14581. Related derivatives are disclosed in JP,A,6-116269.
JP,A,5-178858 discloses Compounds (A~, (B) and (C)
represented by the following formulae. However, Compounds
(B) and (C) lack satisfactory water-solubility when these
compounds are used as injections.
H3C~ =~C02CH3
HN~3
~ l_
O `~Y N
(A)
H3C~C02CH3 H3C~C02CH3
IHN~ ~OCH3 ~ ~,OCH3
o N~J RO N~J
(B) (~)
It is an object of this invention to provide DC-89
derivatives which have excellent anti-tumor activity and
excellent water-solubility.

21638;~i~
Disclosure of the Invention
The present invention provides DC-89 derivatives
represented by formula (I):
CH3
)~CO2CH3
HNa ~ (I)
W
~
wherein ( ) represents
~C
W
~ R ~ -X
W W
in which X represents Cl or Br, R represents hydrogen or
CORl in which R1 represents hydrogen, substituted or
unsubstituted lower alkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heterocyclic group, NR2R3
(in which R2 and R3 independently represent hydrogen or
substituted or unsubstituted lower alkyl, amino, or mono- or
di(lower alkyl)amino),
\
in which R4 represents oxygen, N-R5 (in which R5 represents
hydrogen or lower alkyl), CH2 or ~~~\
CHN~
NN R4
R5
(in which R9 and R5 are the same meanings as defined above),
or oR6 (in which R6 represents substituted or unsubstituted
lower alkyl, or substituted or unsubstitut:ed aryl); and
- 3 -

~ ~ 2~L6389(~
W represents
yZ Q1
o ~ ~Q2
in which Ylr y2 and Y3 independently represent CH or N,
and Q2 independently represent hydrogen, GR7 (in which R7
represents hydrogen or substituted or unsubstituted lower
alkyl), NR2aR3a (in which R2a and R3a are the same meanings as
R2 and R3 defined above), NHCO2R6a (in which R6a is the same
meaning as R6 defined above), or o(CH2)nR3 in which n
represents an integer of 1 to 4, and R3 represents CO2R7a (in
which R7a is the same mean~ng as R7 defined above), N3, or
NR2bR3b (in which R2b and R3b are the same meanings as R2 and
R3 defined above), provided that when Q1 is OCH3 and yl~ y2
and Y3 are CH, Q2 is a group other than hydrogen, or
oR7b
~ y4 ~
(in which Y4 represents oxygen, sulfur or NH, and R7b is the
same meaning as R7 defined above), and pharmaceutically
acceptable salts thereof.
The compounds represented by formula (I) are
hereinafter referred to as Compounds (I). Similarly, the
compounds represented by formulae (I) to ~IV) are referred
to as Compounds (I) to (IV). Compounds (I:)a, (I)b and the
like are intended to be included in Compounds (I).
In the definition of the above-mentioned formula (I),
lower alkyl and the alkyl moiety of mono- or di(lower
alkyl)amino include linear or branched alkyl groups having 1
to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
hexyl, isohexyl, heptyl, octyl and iso-octyl. Examples of

21638~)
aryl include phenyl and naphthyl. Examples of the
heterocyclic group include pyridine, pyrazine and
pyrimidine. The substituted lower alkyl has 1 to 3
independently-selected substituents such as lower alkoxy,
lower alkylthio optionally substituted by carboxy, carboxy,
lower alkoxycarbonyl, amino, mono- or di(Lower alkyl)amino,
cyclic amino optionally substituted by lower alkyl or cyclic
amino, halogen and phenyl. Examples of the cyclic amino
include pyrrolidinyl, piperidino, piperazinyl and
morpholino. Lower alkyl and the alkyl moiety of lower
alkoxy, lower alkylthio, lower alkoxycarbonyl and mono- or
di(lower alkyl)amino has the same definition as that of the
above-mentioned lower alkyl. Examples of halogen include
fluorine, chlorine, bromine and iodine atoms. The
substituted aryl and the substituted heterocyclic group each
has 1 to 3 independently selected substituents such as
substituted or unsubstituted lower alkyl, lower alkoxy,
lower alkoxycarbonyl, amino, mono- or di(lower alkyl)amino
and halogen, in which lower alkyl and the alkyl moiety of
lower alkoxy, lower alkoxycarbonyl and mono- or di(lower
alkyl)amino has the same definition as that of the above-
mentioned lower alkyl, and the substituents and halogen of
substituted lower alkyl are the same meanings as defined
above.
Examples of the pharmaceutically acceptable salts of
Compounds (I) include inorganic acid-addition salts such as
hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate
and nitrate, and organic acid-addition salts such as
acetate, benzoate, maleate, fumarate, succinate, tartrate,
citrate, oxalate, glyoxylate, aspartate and
methanesulfonate.
The processes for preparing Compounds (I) are
described below.
When the defined group changes under reaction
conditions or are inappropriate for conducting the
processes, the processes can be easily carried out by using
-- 5 --

2163~9~
protection/deprotection method for functional groups
conventionally employed in the organic synthetic chemistry
including oxidation, reduction and hydrolysis.
Process 1
Among Compounds (I), Compound (I)a wherein
'10 ~ is ~
W , W
can be prepared by reacting Compound (A) c~isclosed in
JP,A,5-178858 with a reactive derivative of the
corresponding carboxylic acid in an inert solvent in the
presence of a base.
H3C CO2CH3 H3C\ ~ CO2CH3
H ~ HN
(A) (I)a
In the formulae, W is the same meanings as defined above.
Examples of the base include sodium hydride, lithium
diisopropylamide, potassium tert-butoxide, triethylamine, 4-
dimethylaminopyridine. The base is usually used in an
amount of 1 to 3 equivalents based on Compound (A). As the
inert solvent, dimethylformamide, tetrahydrofuran, toluene,
dimethylsulfoxide, etc. may be used singly or in
combination. Examples of the reactive derivative of the
carboxylic acid include acid halides such as acid chlorides
and acid bromides, and activated esters such as p-
nitrophenyl esters, 2,4,5-trichlorophenyl esters,
pentafluorophenyl esters and N-oxysuccinimide esters. The
reactive derivative is usually used in an amount of 1 to 3
equivalents based on Compound (A). The reaction is
conducted at -80 C to 30 C for 30 minutes to 1 day.
- 6 -

,~ 216389~
Process 2
Among Compounds (I), Compound (I)b wherein
R
W W
and R is hydrogen can be prepared by reacting Compound (I)a
with hydrochloric acid or hydrobromic acid in an inert
solvent.
H3C~C02CH3 H3~ CO2CH3
HN~ HN~
In the formulae, W and X are the same meanings as defined
above.
Hydrochloric acid or hydrobromic acid is usually used
in an amount of 1 to 20 equivalents based on Compound (I)a.
As the inert solvent, water, dimethylformamide,
tetrahydrofuran, toluene, dioxane, acetonitrile, etc. may be
used singly or in combination. The reaction is usually
conducted at -30~C to 50 C and for 10 minutes to 1 hour.
Process 3-1
Among Compounds (I), Compound (I)c wherein
i s
W W
and R is COR1 in which R1 is hydrogen, substituted or
unsubstituted lower alkyl, substituted or unsubstituted aryl
or a substituted or unsubstituted heterocyclic group can be
prepared by reacting Compound (I)b with a condensation agent
such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-(3-

~ 211~3~9~
dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine
and R1aCO2H (in which R1a represents hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted aryl or a
substituted or unsubstituted heterocyclic ring in the
definition of R1) in an inert solvent.
IH3C CO2CH3 HN =~ X
HN~ RlaC02H
HOJ~ ~ Rl~C2~b~--W
(I)bW (I) c
In the formulae, R1a, W and X are the same meanings as
defined above.
R1aCO2H, DCC and 4-dimethylaminopyridine are usually
used in amounts of l to 10 equivalents based on Compound
(I)b. As the inert solvent, methylene ch:Loride, chloroform,
dimethylformamide, tetrahydrofuran, toluene, dioxane,
acetonitrile, etc. may be used singly or in combination.
The reaction is usually conducted at -50 C to 50 C for 10
minutes to 2 days.
Process 3-2
Compound (I)c can be prepared by reacting Compound
(I)b with an acid anhydride such as (R1aCO)2O or an acid
chloride such as R1aCOCl in an inert solvent in the presence
of a base.
~3C ~ CO2CH3 H3C~ ~CO2CH3
- HN~ (RlDCO)20HN~
HO~N RlaCOaRl~CO2~J--N
(I)bW (I) C
In the formulae, R1a, W and X are the same meanings as
defined above.

21~3~
The acid anhydride or the acid chloride is usually
used in an amount of 1 to 10 equivalents based on Compound
(I)b. As the base, potassium tert-butoxide, triethylamine,
pyridine, 4-dimethylaminopyridine, etc. m~y be usually used
in an amount of 1 to 10 equivalents based on Compound (I)b.
However, when this base serves also as a solvent, it is used
in large excess. As the inert solvent, methylene chloride,
chloroform, dimethylformamide tetrahydrofuran, toluene,
dioxane, acetonitrile, etc. may be used singly or in
combination. The reaction is usually conducted at -20 C to
50 C for 10 minutes to 10 hours.
Process 4
Among Compounds (I), compound (I)d wherein
~ R~
W W
and R is COR1 in which R1 is NR2R3 (in which R2 and R3 are
the same meanings as defined above),
N R~
(in which R4 is the same meaning as defined above), or
A
INN~JR4
R
(in which R4 and R5 are the same meanings as defined above)
can be prepared according to the following steps.
(Step 1)
Compound (III) can be prepared by reacting Compound
(I)b with p-nitrophenyl chloroformate in an inert solvent in
the presence of a base.

21~i3~90
H3C CO2CH3 H3C CO2CH3
HN~_~ 02N ~ OCOCI HN~ X
5 HO N O2N~oco2 W
(I)b (III)
In the formulae, W and X are the same meanings as defined
above.0
p-Nitrophenyl chloroformate is usually used in an
amount of 1 to 5 equivalents based on Compound (I)b.
Examples of the base include potassium t-butoxide,
triethylamine, pyridine and 4-dimethylaminopyridine. The
15 base is usually used in an amount of 1 to 5 equivalents
based on Compound (I)b. However, when the base serves also
as a solvent, it is used in large excess. As the inert
solvent, methylene chloride, chloroform, pyridine,
dimethylformamide, tetrahydrofuran, toluene, dioxane, etc.
may be used singly or in combination. The reaction is
usually conducted at -80 C to 50 - C for 10 minutes to 20
hours.
(Step 2)
Compound (I)d can be prepared by reacting Compound
(III) with Compound (IV) represented by the formula
R2R3NH (IV)a
wherein R2 and R3 are the same meanings as defined above,
HN R4 (IV) b
wherein R4 is the same meanings as defined above, or
~\ 4
HNN~ R ( IV) c
R
wherein Rq and R5 are the same meanings as defined above,
in an inert solvent and in the presence of a base.
-- 10 --

21~i3~0
H3C CO2CH3 H3C CO2CH3
5O2N ~ HN~ RlbCo2~X
W W
(III) (I)d
..
wherein Rlb is NR2R3,
r~~R4
in which R4 is the same meaning as defined above, or
~_~ 4
Rs \~
in which R4 and R5 are the same meanings as defined above,
and W and X are the same meanings as defined above.
Examples of the base include triethylamine, pyridine
and 4-dimethylaminopyridine. The base is usually used in an
amount of 1 to 5 equivalents based on Compound (III).
However, when the base serves also as a solvent, it is used
in large excess. As the inert solvent, methylene chloride,
chloroform, dimethylformamide, tetrahydrofuran, toluene,
dioxane, etc. may be used singly or in combination. The
reaction is usually conducted at -80 C to 50 C for 10
minutes to 1 day.
Process 5
Among Compounds (I), Compound (I)e wherein
i s R~N -
V~ W
and R is CORl in which Rl is oR6 (in which R6 is the same
meaning as defined above) can be prepared by reacting
Compound (I)b with ClCO2R6 (in which R6 is the same meaning
as defined above) in an inert solvent in the presence of a
base.
-- 11 --

2~.~3~90
C CO2CH3 H3C>=~COzCH3
HN~ R60CO~
(I)b ~I) e
In the formulae, R6, W and X are the same meanings as
defined above.
ClCO2R6 is usually used in an amount of 1 to 10
equivalents based on Compound (I)b. Examples of the base
include potassium tert-butoxide, triethylamine, pyridine and
4-dimethylaminopyridine. The base is usually used in an
amount of 1 to 5 equivalents based on Compound (I)b.
However, when the base serves also as a solvent, it is used
in large excess. As the inert solvent, methylene chloride,
chloroform, dimethylformamide, tetrahydrofuran, toluene,
dioxane, etc. may be used singly or in combination. The
reaction is usually conducted at -40 C to 50 C for 10
minutes to 10 hours.
After the completion of the reaction of each step,
water, acid, buffer, an aqueous solution of sodium hydrogen
carbonate, etc. is added to the reaction mixture, if
necessary, and the mixture is extracted with an organic
solvent such as ethyl acetate, chloroform and ether. The
extract is washed with water, an aqueous solution of sodium
hydrogen carbonate, an aqueous solution of sodium chloride,
etc., and is then dried over anhydrous sodium sulfate, etc.
After the solvent is evaporated, the resulting residue is
purified by silica-gel column chromatography, thin-layer
chromatography, high-performance preparative liquid
chromatography, recrystallization, etc.
In the case where a salt of Compound (I) is desired
and it is obtained in the form of the desired salt, it can
be subjected to purification as such. In the case where
Compound (I) is obtained in the free state and its salt is
- 12 -

~ 21638~
desired, the desired salt can be obtained by dissolving or
suspending Compound (I) in a suitable solvent and adding a
suitable acid to the solution or suspension.
The reaction intermediates may be directly used in the
subsequent step without isolation or purification.
Compounds (I) and its pharmaceutically acceptable salts may
be in the form of adducts with water or various solvents,
which are also within the scope of the present invention.
Further, all possible isomers of Compounds (I) including
optical isomers and mixtures thereof also fall within the
scope of the present invention.
The structures and the compound numbers of
representative compounds which fall under Compounds (I) are
shown in Table 1.
- 13 -

~163~9~
Tab le
H3C~ C02CH3H3C~ =~C02C;H3
O ~ N ~ Z~o ~ N ~ Z
O O
A type B type
Compound z Type X R
N OCH3
~ A - -
N OCH3
2 ~ B Br CON~_~NCH3
N~OCH3
3 ~ B Br CON~_~NCH3. HCI
~N~ OCH3
4 ~ B Br CO2CH3
N~OCH3
~ B Br CONHCH2C02H
~N ~ OCH3
6 ~ A
~N ~ OCH3
7 ~ N B Br CON NCH3
N ~ OCH3
8 ~ N B Br CON NCH3.HCI
~N ~ OCH3 ~-~
g ~ N B Br CO2CH3
~N~ OCH3
~ N B Br CONHCH2CO2H
- 14 -

21~i3~gQ
~`
Tab l e 1 ( cont inued )
H3C~ C02CH3 H3Ck~COzCH3
O~N>~Z RO~S~Z
A type B type
Compound Z Type X R
,OCH3 B Br COCH3
12 ~OCH3 A
13 ~ ~OCH3 B Br CON~NCH3
14 ~OCH3 B Br CON\NCH3. HCI
2 0 15 ~OCH3 A -
16 ~OCH3 B ~3r CON~NCH3
17 ~OCH3 B E3r CON~NCH3. HCI
-o~OCH3 A
19 -~OCH3 B Br CON~NCH3
OJ~ocH3 B E3r CON\NCH3. HCI
3 5 21 ,~OCH2cH2cH3 A
,~O(CH2)4CH3 A
-- 15 --

21 G3890
Table 1 (continued)
H3C~=~C02CH3 H3C~=~C02CH3
o~N~Z HN~
O O
A type B type
Compound Z Type ~ R
~,OCF3
23 o~J A
~,OCF3
24 0~ B E3r CON~ NCH3
,~OCF3
~oJ~ B E3r CON~ NCH3. HCI
2 0 ~,NHCO2C(CH3)3
26 ~ A
~,N(CH3)2
27 ~ A
2 5 ~,NH2
28 ~ A
~s~,OCH3
29~o(cH2)3N3 A
3 o ~OCH3
30~O(CH2)3NH2 A
~,OCH3
31~o(cH2j3NH2 B E3r CON~ NCH3
3 5 ~,OCH3
32~O(CH2)3NH2. HCI B E3r CON~ NCH3. HCI
~,OCH3
33~O(CH2)3N(CH3)2 A
-- 16 --

21163~0
~'
Table 1 (continued)
H3C~C02CH3 H3C~ C02CH3
o~N~Z ~o~N~Z
O O
A type B type
Compound Z Type X
OCH3
~OCH2CO2CH3
~ OCH3
~OCH2CO2C(CH3)3
~ OCH3
36 ~ B IBr CON(CH3)2
~ OCH2CO2H
i~NH2 A
2 0 ~,OCH3
38 ~W`NH2 B E3r CO2CH3
,~OCH3
~NH2 B E3r CON,NCH3
~NH2. HCI B E3r CON,NCH3. HCI
41 ~~N(CCHH2)2 A
,~,OCH3
3 0 42 ~W`N(CH3)2 B E3r CON,NCH3
,o~OCH3
~N(CH3)2. HCI Br CON~NCH3. HCI
OCH3
~N(cH3)2 B Br COCH3
- 17 --

2163890
.
Table 1 (continued)
H3C~C02CH3 H3C~(,02CH3
~N Z Ro~XN~z
O O
A type B l:ype
o Compound Z Type :X R
,~,OCH3
r 1~ B E3r COCH3
~ N(CH3)2. HCI
46 ~N(cH~cH3)2 A
~ OCH3
47 , Ir B E3r CO2CH3
~--N(cH2cH3)2
2 0 48 ~OCH3 B E3r CON NCH3
N(CH2CH3)2
~ OCH3
49 1 ll B ~r CON NCH3. HCI
~-N(CH2CH3)2. HCI ~~
2 5 50 ~OCH3 B Cl COCH3
N(CH3)2
~ OCH3
51 ~ B C:l COCH3
~ N(CH3)2. HCI
3 52 ~r~OCH3 B Br CON(CH3)NH2
N(CH3)2
OCH3
53 1~ B Br CON(CH3)NH2
--N(CH3)2. HBr
i~ B Br co~
N(CH3k N
~OCH3 B Br ~NHs
- 18 -

~ 21638~
Table 1 (continued)
H3C~ cOzCH3 H3C~=~C0`2CH3
~N Z ~o)~`N~Z
O O
Atype Btype
Compound z Type X R
56 ~T[ N(CCHH33)2 B Br CO~N(CH3)2
~OCH3 B Br Co
58 ~OCH3 HBr H2N
~N(cH3)2 B Br CONHN\ NCH3
60 ~OCH3 B Br CONHN NCH3. HBr
N(CH3)2. HBr \~
OCH3
61 ~N(CH3)2 B Br CONHN(CH3)2
,~,OCH3
62 ~N(CH3)2. HBr B Br CONHN(CH3)2
63 ~ o(ccHH33)2 B Br CON(CH3)NHCH3
~,OCH3
64 ~ N(CH3)2. HBr B Br CON(CH3)NHCH3
-- 19 --

21~389~
Table 1 (continued)
H3C CO2CH3 H3C~ C02CH3
~N~Z ~o~ N~Z
O O
A type B type
Compound Z Type X R
~OCH3 B Br CO~CH2 N~JNCH3
66 ~OCH3 B Br CO~CH2 N~ NCH3. HBr
67 ~,~,OCH3 B B r Co~;~
2 o N OCH3 ~
68 ~,~ B Cl CONHN\ NCH3
N~OCH3 ~
69 ~,N B Cl CONHN /NCH3. HCI
2 5 _N OCH3
~ ,~ B Br CONHN~ NCH3
,N OCH3 A
71 ~,~ B Br CONHN~ NCH3. HCI
72 ~,~OCH3 B Br CONHN NCH3. HBr
73 ,~,~f B Br COCH2SCH2CO2H
N OCH3
74 ,~,~ B Br CON(CH3)NH2
- 20 -

~ 21G3~90
Table 1 (continued)
H3C~= ~CO2CH3 H3C~= Co2cH3
o~N~Z HN~
O O
A type B type
Compound Z Type X R
75 ~,~OCH3 B Br CO~CH2 N~ NCH3
76 ~,~OCH3 ~ B Br CO~CH2 N NCH3. HBr
77 ~N(CH3)2 B Br CO~
78 ~N(CH3)2 B Br CON NCH3
N(CH3)2. HBr ~--~
79 ~ B Br CON ~NCH3. HBr
~ OCH3~
~`N(CH3)2. HCI B Cl H
. ,~[ OCH, B Br H
~ OCH3
82 ~W N(CH3)2 HBr B Br COCH2N~ NCH3.2HBr
3 5 83 ~OCH3 B Br CoCH2N3N~> 2HBr

2163~gO
^ The pharmacological activity and water-solubility of
representative Compounds (I) are shown in Test Examples.
Test Example
1. Growth Inhibitory Effect against HeLaS3 cells
HeLaS3 cells were suspended in MEM medium containing
10% calf serum and 2 mM glutamine to a concentration of 2.67
x 104 cells/ml. The cell suspension thus prepared was put
into wells of a 24-well culture plate in an amount of 0.75
ml per well. After the cells were incubated in a CO2
incubator overnight at 37 C, Compound (I) which had been
appropriately diluted with a culture medium was added to
each well in an amount of 0.25 ml.
The cells were further incubated in the CO2 incubator
for 72 hours, and the culture supernatant was removed.
Then, the cells were dispersed in a solution of trypsin and
EDTA and recovered. The number of cells was counted using a
cell counter. The concentration (IC50) of Compound (I) at
which the growth of the cells is inhibited by 50% was
calculated by comparing the number of untreated cells with
the number of the cells treated with Compound (I) at known
concentrations.
The result is shown in Table 2.
2. Therapeutic Effect against Sarcoma 180 Tumor
Five male ddY-strain mice each weighing 18-20 g were
used for each group as test animals, and 5 x 105 Sarcoma 180
tumor cells were implanted at the axilla subcutaneously.
One day after the implantation, 0.2 ml of a physiological
saline containing Compound (I) at the concentration shown in
Table 2 was intravenously administered to each mouse. T/C
[T: average tumor volume (mm3) of the group treated with the
test compound, C: average tumor volume (mm3) of the control
group (to which 0.2 ml of a physiological saline was
intravenously administered)] was determined seven days after
the implantation.
The result is shown in Table 2.
- 22 -

~ 21~3~9~
Tab le 2
Compound I C50(nM)Dose l`/C
(mg/kg)
1 0.42
3 110 1.0 0.36
4 0.70 0.50 0.35
6 0.90
8 170 2.0 0.26
11 0.92 1.0 0.17
12 0.28
14 90 1.0 0.31
18 0.19
94 0.50 0.20
23 1.6
1100 2.0 0.12
26 0.56
27 1.6
28 2.6
1.4
34 0.86
37 0.53
38 0.67
41 0.92
43 52 2.0 0.13
0.54 1.0 0.20
49 280 8.0 0.20
51 0.46 4.0 0.14
53 1.2 2.0 0.07
0.43 1.0 0.28
56 2.2 1.0 0.36
0.94 4.0 0.15
62 0.62 2.0 0.19
64 1.1 1.3 0.26
66 1.1 2.0 0.21
67 1.2 1.0 0.26
69 1.4 4.0 0.40
71 1.5 2.0 0.30
72 1.6 4.0 0.15
73 1 2 1.0 0.36
- 74 2 4 1.0 0.37
76 1.3 1.0 0.25
77 0.45 4.0 0.19
79 52 8.0 0.22
0.44
81 0.50
82 0.50
83 0.59
- 23 --

2~63890
.
3. Acute toxicity
Compound (I) was intravenously administered to ddY-
strain male mice each weighing 20 + 1 g. MLD (minimum
lethal dose) was determined by observing the mortality at 14
days after administration. The result is shown in Table 3.
Table 3
Compound M L D (mg/kg)
o 3 1.0
4 0.50
8 4.0
11 1.0
14 0.50
0.50
4 0
43 4 0
l.0
49 >8. 0
51 4.0
53 2.0
1.0
56 l.0
>8. 0
62 2.0
64 2.0
66 2.0
67 l.0
69 4.0
72 4.0
77 4.0
82 2.0
4. Test for solubility in water
A sample tube was charged with 0.7 mg of Compound (I),
and 30 ~l of water were added thereto at room temperature.
The mixture was stirred, and the solubilit:y in water was
measured. When the compound was not dissolved, 30 ~l of
water was added thereto successively, and the mixture was
stirred. The solubility in water was measured when the
compound was dissolved. The result is shown in Table 4.
- 24 -

21~3~0
`
Table 4
Compound Solubility (mg/ml)
3 >20
8 >20
14 >20
17 >20
0.2
32 >20
>20
43 <0- 5
>20
49 >20
51 >10
>18
58 >20
>20
62 >20
64 >15
66 >20
69 >10
71 >10
72 >10
73 <0.1
76 >10
79 >20
>15
81 2.5
82 >10
83 >20
Compounds (I) and pharmaceutically acceptable salts
thereof can be used as anti-tumor compositions singly or in
combination with at least one pharmaceutically acceptable
auxiliary. For example, Compounds (I) or salts thereof are
dissolved in a physiological saline or in an aqueous
solution of glucose, lactose, mannitol, etc. to prepare a
pharmaceutical composition suitable for injection.
Alternatively, Compounds (I) or salts thereof are freeze-
dried in a conventional manner and mixed with sodium
chloride to prepare a powder injection. ]:f necessary,the
pharmaceutical composition of the present invention may
- 25 -

21~'~89~
`
contain additives which are known in the art of medical
preparation, for example, pharmaceutically acceptable salts.
Although the dose of the composition of the present
invention varies depending on the age, condition etc. of the
patient, Compound (I) is administered to mammals including
human beings at a dose of 0.01 to 60 mg/kg/day.
Administration may be conducted, for example, once a day
(single administration or consecutive administrations) or
intermittently l to 3 times a week or once every 2 to 3
weeks, intravenously. If desired, intraarterial
administration, intraperitoneal administration,
intrathoracial administration, etc. are also possible at a
similar dose and in a similar manner. Further, if desired,
the composition may also be administered orally, at a
similar dose and in a similar manner. Forms for oral
administration include tablets, capsules, powders, granules
and ampoules, which contain pharmaceutical auxiliaries well
known in the art of medical preparation.
The present invention is illustrated by referring to
the following Examples. The physicochemical properties of
the compounds shown in the following Examples were
determined with the following equipments.
NMR JEOL, Ltd. FX-100 (100 MHz)
JNM-GX270 (270 MHz)
JNM-EX270 (270 MNz)
Bluker AM-400 (400 MHz)
MS Hitachi Ltd. M-80B
JEOL, Ltd. JMS-D300
JMS-SX102
IR Japan Spectral Co., Ltd. IR-810
HORIBA FT200
In thin-layer chromatography, a silica-gel plate
(Silica gel 60F254s 0.5 mm 20 x 20 cm) manufactured by Merck
Co. was used. As the silica gel for column chromatography,
Wakogel C-200 manufactured by Wako Pure Chemical Industries,
Ltd. was used.
- 26 -

216~90
~`
Best Mode for Carrying Out the Invention
Example 1 Synthesis of Compound 1
N,N-dimethylformamide (0.38 ml) was added to 4.7 mg
(0.118 mmol) of 60% sodium hydride. An N/N-
dimethylformamide solution (0.5 ml) containing Compound (A)
prepared according to the method described in JP,A,5-178858
was added thereto, and the mixture was stirred at -20 C for
2 hours and 20 minutes in an argon atmosphere. To the
reaction mixture was added 0.5 ml of an NJN-
dimethylformamide solution containing 32.1 mg (0.107 mmol)
of p-nitrophenyl (E)-3-(6-methoxy-3-pyridinyl)acrylate
[prepared according to the method described in J. Med.
Chem., 32, 583 - 593 (1989)]. The mixture was stirred for
80 minutes. To the reaction mixture was added 0.01 M
phosphate buffer of pH 7, and the solution was extracted
with ethyl acetate. The ethyl acetate layer was washed with
a saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography [30 ml of silica gel,
chloroform:methanol=100:1 to 70:1) to give 31.8 mg of
Compound 1 (yield: 78%).
The physicochemical properties of Compound 1 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 11.52(lH,br),
8.32(lH,d,J=2.0Hz), 7.81(lH,dd,J=2.3,8.6Hz),
7.77(lH,d,J=15.2Hz), 6.77(lH,d,J=15.5Hz),
6.77(lH,d,J=8.9Hz), 6.74(lH,br), 4.24(lH,d,J=10.9Hz),
4.16(lH,dd,J=10.9, 4.6Hz), 3.98(3H,s), 3.81(3H,s), 3.55-
3.61(1H,m), 2.62(3H,s), 2.40(1H, dd,J=7.4~3.5Hz),
1.31(lH,dd,J=4.6,3.6Hz)
FABMS(m/z);420(M+H) +
IR(KBr)V(cml; 1701, 1668, 1614, 1601, 1495, 1462, 1389,
1292, 1244, 1219, 1111
- 27 -

~163~g~
-
Example 2 Synthesis of Compound 2
To 21.2 mg (0.051 mmol) of Compound 1 obtained in
Example 1 were added 1.27 ml of acetonitrile and 11.5 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 1.07 ml of
methylene chloride and 0.42 ml of toluene, and 29.6 mg
(0.158 mmol) of p-nitrophenyl chloroformate and 21.1 ~l
(0.153 mmol) of triethylamine were then added thereto at
-78 C. The mixture was stirred for 30 minutes.
Subsequently, to the mixture was added 19.6 ~l (0.179 mmol)
of N-methylpiperazine, and the mixture was stirred at -78 C
to O C for 20 minutes. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The obtained crude product was purified by thin-layer
chromatography (chloroform:methanol=9:1) to give 25 mg of
Compound 2 (yield: 78%).
The physicochemical properties of Compound 2 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.20(lH,brs),
8.34(lH,d,J=2.3Hz), 8.21(lH,br s),
7.89(lH,dd,J=8.6,2.3Hz), 7.79(1H,d,J=15.2Hz),
6.82(lH,d,J=15.2Hz), 6.81(lH,d,J=8.6Hz),
4.49-4.60(lH,m), 4.45(lH,d,J=10.2Hz),
4.30(lH,dd,J=9.6,8.9Hz), 3.98(3H,s), 3.95(3H,s),
3.79(lH,dd,J=9.6,9.6Hz), 3.76(2H,br), 3.63(2H,br),
3.21(lH,dd,J=10.2,9.9Hz), 2.53(3H,s), 2.49(4H,br),
2.36(3H,s)
FABMS(m/z); 628, 626(M+H) +
IR(KBr)~(cm~l); 1701, 1697, 1649, 1495, 1435, 1410,
1381, 1290, 1217, 1153, 1095
- 28 -

2~S38g~
Example 3 Synthesis of Compound 3
To 20.9 mg (0.0334 mmol) of Compound 2 obtained in
Example 2 were added 0.91 ml of ethanol and 0.46 ml of
methanol, and then 14.6 ~1 of 6.86 N hydrogen chloride in
ethanol was added thereto. The mixture was stirred at room
temperature for 4 hours. The reaction mixture was
concentrated under reduced pressure to give 22.1 mg of
Compound 3.
The physicochemical properties of CGmpound 3 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.12(lH,s),. 10.70(lH,br),
8.50(lH,d,J=2.3Hz), 7.35(lH,dd,J=8.6,2.3Hz),
8.10(lH,br), 7.61(lH,d,J=15.5Hz),7.19(lH,d,J=15.2Hz),
6.92(1H,d,J=8.9Hz), 4.36-4.51(4H,m), 4.12-4.18(2H,br),
3.91 (3H,s), 3.85(3H,s), 3.79 (lH,brd,J=8.3Hz),
2.85(3H,s), 2.68(3H,s)
IR(KBr)V(cm~l); 1714, 1695, 1657, 1651, 1435, 1414, 1219,
1173, 1095
Example 4 Synthesis of Compound 4
To 18.3 mg (0.0436 mmol) of Compound 1 obtained in
Example 1 were added l.1 ml of acetonitrile and 9.85 ~l of
48% hydrobromic acid. The mixture was stirred at room
temperature for 35 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 0.92 ml of
methylene chloride and 0.37 ml of toluene, and 10.4 ~l
(0.135 mmol) of methyl chloroformate and 18.2 ~l (0.131
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred at -78 C to room temperature for 40
minutes. To the reaction mixture was added a saturated
aqueous solution of sodium hydrogen carbonate, and the
resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by thin-layer
- 29 -

~ 3 ~ 9 Q
chromatography (chloroform:methanol=9:1) to give 22 mg of
Compound 4 (yield: 90%).
The physicochemical properties of Cornpound 4 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 8.79(lH,s), 8.40(lH,brs),
8.34(lH,d,J=2.3Hz), 7.88 (lH,dd,J=8.6,2.3Hz),
7.79(lH,d,J=15.2Hz), 6.82(lH,d,J=15.2Hz),
6.80(lH,d,J=8.6Hz), 4.50-4.60 (lH,m),
4.46(1H,d,J=9.9Hz), 4.30(1H,dd,J=9.2,9.2Hz), 3.98(3H,s),
3.96(3H,s), 3.94(3H,s), 3.80(lH,dd,J=9.6,2.6Hz),
3.22(lH,dd,J=10.2,9.9Hz), 2.68(3H,s)
FABMS(m/z);560, 558(M+H) +
IR(KBr)~(cm~l); 1768, 1697, 1647, 1498, 1437, 1416, 1408,
1290, 1246, 1215, 1196
Example 5 Synthesis of Compound 5
To 38.9 mg (0.0925 mmol) of Compound 1 obtained in
Example 1 were added 2 ml of acetonitrile and 21 ~l of 48%
hydrobromic acid, and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 1.95 ml of
methylene chloride and 0.78 ml of toluener and 57.8 mg
(0.287 mmol) of p-nitrophenyl chloroformale and 52 ~l (0.37
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred for 20 minutes. Subsequently, 54.5 mg
(0.324 mmol) of glycine tert-butyl ester hydrochloride and
45 ~1 (0.324 mmol) of triethylamine were added thereto. The
mixture was stirred at -78 C to room temperature for 16
hours. To the reaction mixture were further added 27.3 mg
(0.162 rnmol) of glycine tert-butyl ester hydrochloride and
22.5 ~1 (0.162 mmol) triethylamine, and the mixture was
stirred for 3 hours. To the reaction mixture was added a
0.01 M phosphate buffer of pH7, and the solution was
extracted with chloroform. The chloroforrn layer was washed
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
- 30 -

2163~9Q
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=20:1) to
give 62.3 mg of a tert-butyl ester of Compound 5.
To 46.8 mg of the tert-butyl ester of Compound 5 were
added 5 ml of 1,2-dichloroethane and 0.22 ml of
trifluoroacetic acid, and the mixture was stirred at 80 C
for 2 hours and 20 minutes. To the reaction mixture was
added water, and the solution was extracted with ethyl
acetate. The ethyl acetate layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=2:1) to
give 14.6 mg of Compound 5 (yield: 34%).
The physicochemical properties of Compound 5 are as
follows.
1H-NMR(270MHz,CD30D)~(ppm); 8.31(1H,d,J=2.0Hz),
8.10(lH,dd,J=8.9,2.6Hz), 8.09(lH,s),
7.63(lH,d,J=15.5Hz), 7.03(lH,d,J=15.2Hz),
6.85(lH,d,J=8.9Hz), 4.42-4.70(2H,m), 4.28-4.40(lH,m),
3.95(3H,s), 3.91(3H,s), 3.81-3.87(1H,m), 3.79(2H,s),
3.55-3.63(lH,m), 2.67(3H,s)
FABMS(m/z); 603, 601(M+H) +
IR(KBr)~(cm~1); 1701, 1697, 1686, 1601, 1497, 1439,
1419, 1211, 1190, 1138
Example 6 Synthesis of Compound 6
To 970 mg (8.47 mmol) of 2-chloropyrimidine were added
7 ml of methanol and 3.4 g (16.94 mmol) of 28 wt% of sodium
methylate in methanol, and the mixture wa.s stirred at room
temperature for 30 minutes.
Water was added to the reaction mixture, and the
solution was extracted with chloroform. The chloroform
layer was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. To 2-methoxypyrimidine
obtained were added 14 ml of trifluoroacetic acid, 3 ml of

21~i3~0
trifluoroacetic anhydride and 3.96 g (16.94 mmol) of N-
iodosuccinimide, and the mixture was stirred under reflux
(bath temperature:80 C) for 11 hours. Water was added to
the reaction mixture, and the solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate, an
aqueous solution of 5% sodium thiosulfate and a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The obtained crude product was purified by silica-gel column
chromatography (250 ml of silica gel, hexane:ethyl acetate=
3:1) to give 523 mg (2.22 mmol) of 2-methoxy-5-
iodopyrimidine (yield: 26%).
2-Methoxy-5-iodopyrimidine (1.736 g, 7.36 mmol) was
dissolved in 36 ml of N,N-dimethylformamide, and 99 mg of
palladium acetate, 2.54 g (18.4 mmol) of potassium
carbonate, 2.05 g (7.36 mmol) of tetrabutylammonium chloride
and 3.168 g (36.8 mmol) of methyl acrylate were added
thereto. The mixture was stirred in an argon atmosphere at
80 C for 1 hour. Water was added to the reaction mixture,
and the solution was extracted with ethyl acetate. The
ethyl acetate layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by silica-gel column
chromatography (250 ml of silica gel, hexane:ethyl
acetate=2:1 to 1:1) to give 1.26 g (6.49 mmol) of methyl
(E)-3-(2-methoxy-5-pyrimidinyl)acrylate (yield: 88%).
To 1.26 g of methyl (E)-3-(2-methoxy-5-
pyrimidinyl)acrylate were added 40 ml of methanol and 3.25
ml of a 4 N potassium hydroxide aqueous solution, and the
mixture was stirred at 50 C for 2 hours. To the reaction
mixture was added 0.5 N hydrochloric acid, and the solution
was extracted with ethyl acetate. The ethyl acetate layer
was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure to give 1.12 g (6.22
mmol) of (E)-3-(2-methoxy-5-pyrimidinyl)acrylic acid.
- 32 -

2~13~0
.
N,N-dimethylformamide (0.3 ml) was added to 3.7 mg
(0.0936 mmol) of 60% sodium hydride, and 0.4 ml of an N,N-
dimethylformamide solution containing 20 mg of Compound (A)
were added thereto. The mixture was stirred in an argon
atmosphere at -20 C for 2.5 hours. To the reaction mixture
was added 0.4 ml of an N,N-dimethylformamide solution
containing 25.8 mg (0.86 mmol) of p-nitrophenyl (E)-3-(2-
methoxy-5-pyrimidinyl)acrylate, and the resulting mixture
was stirred for 110 minutes. To the reaction mixture was
added a 0.01 M phosphate buffer of pH7, and the resulting
mixture was extracted with ethyl acetate and with
chloroform. The ethyl acetate layer and the chloroform
layer were separately washed with a saturated aqueous
solution of sodium chloride, and dried over anhydrous sodium
sulfate. The combined organic layer was concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (30 ml of silica gel,
chloroform:methanol=100:1 to 70:1) to give 24.1 mg of
Compound 6 (yield: 74%).
The physicochemical properties of Compound 6 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.39(lH,brs), 9.04(2H,s),
7.65(1H,d,J=15.8Hz), 7.21(1H,d,J=15.8Hz), 6.91(1H,br),
4.38(1H,d,J=10.9Hz),4.21(1H,dd,J=10.9,4.6Hz),
3.97(3H,s), 3.74(3H,s), 3.46-3.52(lH,m), 2.47(3H,s),
2.11(lH,dd,J=7.6,3.0Hz), 1.32(lH,dd,J=4.0,4.0Hz)
FABMS(m/z); 423(M+3) + ,421(M+H) +
IR(KBr)~(cm-1); 1701, 1676, 1624, 1618, 1595, 1477, 1400,
1340, 1250, 1111
Example 7 Synthesis of Compound 7
To 20.9 mg (0.0497 mmol) of Compound 6 obtained in
Example 6 were added 1.25 ml of acetonitrile and 17.7 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 50 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent vf 1.05 ml of
- 33 -

2163~0
methylene chloride and 0.41 ml of toluene, and 31 mg (0.154
mmol) of p-nitrophenyl chloroformate and 20.8 ~l (0.149
mmol) of triethylamine were added thereto at 78 C. The
mixture was stirred for 30 minutes, and 31 mg (0.154 mmol)
of p-nitrophenyl chloroformate and 20.8 ~l (0.149 mmol) of
triethylamine were further added thereto at -20 C. The
solution was stirred for 20 minutes. Subsequently, 38.6 ~l
(0.348 mmol) of N-methylpiperazine was added to the
solution, and the mixture was stirred at -20 C to O C for 60
minutes. A saturated aqueous solution of sodium hydrogen
carbonate was added to the reaction mixture, and the
resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol=10:1) to give 20.4
mg of Compound 7 (yield: 65%).
The physicochemical properties of Compound 7 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.01(lH,s), 8.75(2H,s),
8.21(lH,s), 7.71(lH,d,J=15.5Hz), 6.93(lH,d,J=15.5Hz),
4.53-4.63(lH,m), 4.45(lH,d,J=10.2Hz),
4.31(lH,dd,J=9.6,9.6Hz), 4.07(3H,s), 3.95(3H,s),
3.80(lH,dd,J=7.3,2.6Hz), 3.74(2H,br), 3.64(2H,br),
3.23(lH,dd,J=10.2,9.9Hz), 2.61(3H,s), 2.50(4H,brs),
2.37(3H,s)
FABMS(m/z); 629, 627(M+H) +
IR(KBr)~(cm~l); 1714, 1701, 1653, 1473, 1935, 1412, 1338,
1219, 1153, 1095
Example 8 Synthesis of Compound 8
To 20.4 mg (0.0325 mmol) of Compound 7 obtained in
Example 7 were added 1.33 ml of ethanol and 0.67 ml of
methanol, and then 19 ~l of 6.86 N hydrogen chloride in
ethanol was added thereto. The mixture was stirred at room
- 34 -

~ 2163~
temperature for 3.5 hours. The reaction mixture was
concentrated under reduced pressure to give 20.2 mg of
Compound 8.
The physicochemical properties of Compound 8 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.06(1H,s), 10.44(lH,br),
9.08(2H,s), 8.11(lH,s), 7.59(lH,d,J=15.8Hz),
7.36(1H,d,J=15.8Hz), 4.40-4.49(3H,m), 4.10-4.24(lH,br),
3.98(3H,s), 3.85(3H,s), 3.76-3.84(lH,m), 2.86(3H,s),
2.68(3H,s)
IR(KBr)~(cm~l); 1705, 1701, 1659, 1477, 1433, 1412, 1336,
1215, 1186, 1095
Fxample 9 Synthesis of Compound 9
To 18.2 mg (0.0433 mmol) of Compound 6 obtained in
Example 6 were added 1.1 ml of acetonitrile and 19.6 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 0.91 ml of
methylene chloride and 0.36 ml of toluene. Then, 20.6 ~l
(0.267 mmol) of methyl chloroformate and 36.1 ~l (0.259
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred at -78 C to room temperature for 2 hours
and 40 minutes. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by thin-layer
chromatography (chloroform:methanol=20:1) to give 15.3 mg of
Compound 9 (yield: 63%).
The physicochemical properties of Compound 9 are as
follows.

21~3~
H-NMR~270MHz,CDCl3)~(ppm); 8.82(lH,s), 8.74(2H,s),
8.39(lH,brs), 7.71(lH,d,J=15.5Hz), 6.92(1H,d,J=15.2Hz),
4.51-4.65(1H,m), 4.46(1H,d,J=9.9Hz),
4.32(1~I,dd,J=9.9,8.6Hz), 4.08(3H,s), 3.96(3H,s),
3.94(3H,s), 3.80(lH,dd,J=9.9,2.3Hz),
3.25(lEI,dd,J=9.9,9.6Hz), 2.70(3H,s)
FABMS(m/z); 561, 559(M+H) +
IR(KBr)~(cm~l); 1763, 1697, 1653, 1593, 1475, 1414, 1338,
1271, 1217, 1095
~xam~le 10 Synthesis of Compound 10
To 28.8 mg of Compound 6 obtained in Example 6 were
added 1.5 ml of acetonitrile and 23.2 ~l of 48% hydrobromic
acid, and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under reduced
pressure. The obtained crude product was dissolved in a
mixed solvent of 1.44 ml of methylene chloride and 0.58 ml
of toluene, and 42.8 mg (0.212 mmol) of p-nitrophenyl
chloroformate and 47.7 ~l (0.343 mmol) of triethylamine were
added thereto at -78 C. The mixture was stirred for 40
minutes. Then, to the solution were added 40.4 mg (0.240
mmol) of glycine tert-butyl ester hydrochloride and 33.4 ~l
(0.240 mmol) of triethylamine, and the mixture was stirred
at -78 C to room temperature for 3 hours. To the reaction
mixture was added a 0.01 M phosphate buffer of pH7, and the
solution was extracted with chloroform. The chloroform
layer was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by thin-layer chromatography
(chloroform:methanol=9:1) to give 47.7 mg of a tert-butyl
ester of Compound 6.
To 35.7 mg of the tert-butyl ester of Compound 6 were
added 3.5 ml of 1,2-dichloroethane and 0.168 ml of
trifluoroacetic acid, and the mixture was stirred at 80 C
for 2 hours and 10 minutes. Water was added to this
reaction mixture, and the solution was extracted with ethyl
acetate. The ethyl acetate layer was washed with a
- 36 -

21~3~90
saturated aqueous solutlon of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reducecl pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=3:1) to
give 18.9 mg (0.0314 mmol) of Compound 6 (yield: 60%).
The physicochemical properties of Compound 10 are as
follows.
lH-NMR(270 MHz, acetone-d6+trifluoroacetic: acid-d)
~(ppm); 8.97(2H,s), 8.20 (lH,brs), 7.65(1H,d,J=15.5Hz),
7.37(1H,d,J=15.5Hz), 4.51(1H,d,J=9.6Hz),
4.48-4.60(1H,br), 4.34-4.45(1H,m), 4.00(3H,s),
3.99(2H,s), 3.84(3H,s), 3.74-3.80(lH,m),
3.35(lH,dd,J=9.9,6.9Hz), 2.61(3H,s)
FABMS(m/z); 604, 602(M+H) +
IR(KBr)~(cm~l); 1684, 1655, 1595, 1479, 1435, 1414,
1275, 1211, 1138
~xample 11 Synthesis of Compound 11
To 14.3 mg (0.0340 mmol) of Compound 6 obtained in
Example 6 were added 1.43 ml of acetonitrile and 11.5 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 40 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 1.45 ml of
methylene chloride and 0.57 ml of toluene, and 9.94 ~l
(0.105 mmol) of acetic anhydride and 13.3 mg (0.109 mmol) of
4-dimethylaminopyridine were added thereto. The mixture was
stirred for 1.5 hours. To the reaction mixture was added a
0.01 M phosphate buffer of pH7, and the solution was
extracted with chloroform. The chloroform layer was washed
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=9:1) to
give 17 mg of Compound 11 (yield: 91%).
The physicochemical properties of Cc~mpound 11 are as
follows.
- 37 -

21~389~
H-NMR(270MHz,CDCl3)~(ppm); 8.74(2H,s), 8.66(1H,brs),
8.27(lH,s), 7.70(lH,d,J=15.5Hz), 6.92(lH,d,J=15.5Hz),
4.53-4.65(lH,m), 4.45(lH,d,J=9.6Hz),
4.32(lH,dd,J=10.2,8.9Hz), 4.08(3H,s), 3.96(3H,s),
3.82(1H,brd,J=9.2Hz), 3.25(1H,dd,J=9.9,9.9Hz),
2.67(3H,s), 2.39(3H,s)
FABMS(m/z); 545, 543(M+H) +
IR(KBr)~(cm~1); 1761, 1697, 1655, 1593, 1475, 1435,
1412, 1338, 1201, 1188, 1088
~xam~le 12 Synthesis of Compound 12
To 2 g of 3,6-dichloropyridazine were added 60 ml of
acetone and 20.12 g (268.4 mmol) of sodium iodide, and the
mixture was stirred under reflux (bath temperature:70 C) for
2 hours. Water was added to the reaction mixture, and the
solution was extracted with ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium thiosulfate and with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure to give 2.73 g
(8.23 mmol) of 3,6-diiodopyridazine (yield: 61%).
To 2.73 g (8.23 mmol) of 3,6-diiodopyridazine were
added 80 ml of methanol and 3.17 g (16.46 mmol) of 28 wt% of
sodium methylate in methanol, and the mixture was stirred at
room temperature for 13 hours. Water was added to the
reaction mixture, and the solution was extracted with ethyl
acetate. The ethyl acetate layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (200 ml of silica gel,
hexane:ethyl acetate=8:1) to give 1.661 g (7.04 mmol) of 3-
methoxy-6-iodopyridazine (yield: 86%).
3-Methoxy-6-iodopyridazine (1.661 g, 7.04 mmol) was
dissolved in 34 ml of N,N-dimethylformamide, and 99 mg of
palladium acetate, 1.06 g (7.67 mmol) of potassium
carbonate, 1.96 g (7.05 mmol) of tetrabutylammonium chloride
and 12.12 g (141 mmol) of methyl acrylate were added
- 38 -

21~3~9~
thereto. The mixture was stirred in an argon atmosphere at
80 C for 4.5 hours. Water was added to the reaction
mixture, and the solution was extracted with ethyl acetate.
The ethyl acetate layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by silica-gel column
chromatography (300 ml of silica gel, hexane:ethyl acetate
=3:1 to 2:1) to give 818 mg (4.21 mmol) of methyl (E)-3-(3-
methoxy-6-pyridazinyl) acrylate (yield: 60%).
To 818 mg (4.21 mmol) of methyl (E)--3-(3-methoxy-6-
pyridazinyl) acrylate were added 25 ml of methanol and 4.22
ml of 4 N aqueous potassium hydroxide, and the mixture was
stirred at room temperature for 8 hours. To the reaction
mixture was added 0.5 N hydrochloric acid, and the solution
was extracted with ethyl acetate and with chloroform. The
ethyl acetate layer and the chloroform layer were separately
washed with a saturated aqueous solution of sodium chloride,
dried together over anhydrous sodium chloride. The combined
organic layer was concentrated urLder reduced pressure to
give 668 mg (3.71 mmol) of (E)-3-(3-methoxy-6-
pyridazinyl)acrylic acid (yield: 88%).
To 3.7 mg (0.0936 mmol) of 60% sodium hydride was
added 0.4 ml of N,N-dimethylformamide, and then 0.4 ml of an
N,N-dimethylformamide solution containing 20 mg of Compound
(A) was added thereto. The mixture was stirred in an argon
atmosphere at -20 C for 2.5 hours. To the reaction mixture
was added 0.41 ml of an N,N-dimethylformamide solution
containing 25.8 mg (0.86 mmol) of p-nitrophenyl (E)-3-(3-
methoxy-6-pyridazinyl)acrylate, and the mixture was stirred
for 80 minutes. To the reaction mixture was added a 0.01 M
phosphate buffer of pH7, and the solution was extracted with
ethyl acetate. The ethyl acetate layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (30 ml of silica gel,
chloroform:methanol=100:1 to 70:1) to give 24 ml of Compound
- 39 -

' 2163~3~0
12 (yield: 73%).
The physicochemical properties of Compound 12 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 11.48(lH,brs),
7.84(lH,d,J=15.2Hz), 7.52(lH,d,J=9.2Hz),
7.44(lH,d,J=15.2Hz), 7.00(lH,d,J=9.2Hz), 6.93(lH,br),
4.29(lH,d,J=10.9Hz), 4.20(lH,dd,J=10.9,4.6Hz~,
4.19(3H,s), 3.81(3H,s), 3.54-3.66(lH,m), 2.62(3H,s),
2.39(lH,dd,J=7.6,3.6Hz), 1.31(lH,dd,J=5.0,3.6Hz)
FABMS(m/z); 423(M+3) + , 421(M+H) +
IR(KBr)~(cm~l); 1701, 1610, 1466, 1411, 1396, 1294, 1248,
1217, 1109, 1072
Compound 13 Synthesis of Compound 13
To 20.3 mg (0.0482 mmol) of Compound 12 obtained in
Example 12 were added 1.23 ml of acetonitrile and 17.2 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 1.02 ml of
methylene chloride and 0.40 ml of toluene, and 30.1 mg
(0.149 mmol) of p-nitrophenyl chloroformat:e and 20.2 ~l
(0.145 mmol) of triethylamine were added thereto at -78 C.
The mixture was stirred for 50 minutes. l'hen, 30.1 mg
(0.149 mmol) of p-nitrophenyl chloroformat:e and 20.2 ~l
(0.145 mmol) of triethylamine were further added thereto at
-20 C. The solution was stirred for 60 minutes.
Subsequently, to the solution were added 37.4 ~l (0.337
mmol) of N-methylpiperazine, and the mixture was stirred at
-20 C to O C for 2 hours. To the reaction mixture was added
a saturated aqueous solution of sodium hydrogen carbonate,
and the resulting mixture was extracted with chloroform.
The chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with an aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by thin-layer
- 40 -

~ 2 1 ~
chromatography (chloroform:methanol=10:1) to give 21.1 mg of
Compound 13 (yield: 70%).
The physicochemical properties of Compound 13 are
as follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.15(lH,brs), 8.24(1H,s),
7.84 (lH,d,J=15.2Hz), 7.57(lH,d,J=15.2Hz),
7.54(lH,d,J=8.9Hz), 7.01(lH,d,J=8.9Hz),4.53-4.60(lH,m),
4.52(lH,d,J=9.9Hz), 4.33(lH,dd,J=9.6,9.6Hz), 4.20(3H,s),
3.95(3H,s), 3.79(lH,dd,J=10.2,2.6Hz), 3.75(2H,br), 3.61
(2H,br), 3.21(1H,dd,J=10.2,9.9Hz), 2.57(3H,s),
2.49(4H,br), 2.36(3H,s)
FABMS(m/z); 627, 629(M+H)+
IR(KBr)~(cm~l); 1714, 1705, 1699, 1653, 1466, 1412,
15 1294, 1217 ,1153, 1093, 1005
Example 14 Synthesis of Compound 14
To 21.1 mg (0.0336 mmol) of Compound 13 obtained in
Example 13 were added 1.38 ml of ethanol and 0.69 ml of
20 methanol, and 19.6 ~l of 6.86 N hydrogen chloride in ethanol
was added thereto. The mixture was stirred at room
temperature for 3.5 hours. The reaction mixture was
concentrated under reduced pressure to give 23.3 mg of
Compound 8.
The physicochemical properties of Compound 14 are as
follows.
H-NMR(270MHz,DMS0-d6)~(ppm); 12.12(1H,s), 10.54(1H,br),
8.31(lH,d,J=8.9Hz), 7.74(lH,d,J=15.2Hz),
30 7.54(lH,d,J=15.2Hz), 7.34(lH,d,J=8.6Hz),
4.34-4.60(4H,m), 4.02-4.24(lH,br), 4.09(3H,s),
3.85(3H,s), 3.76-3.82(1H,m), 2.85(3H,br), 2.69(3H,s)
IR(KBr)~(cm~l); 1716, 1705, 1699, 1417, 1435, 1414, 1252,
1219, 1093
Example 15 Synthesis of Compound 15
To 3 g (31.5 mmol) of 3-hydroxypyridine were added 80
ml of methanol, 4.72 g (31.5 mmol) of sodium iodide and 1.26
- 41 -

216~890
g (31.5 mmol) of sodium hydroxide, and then 58.5 g of a 4%
sodium hypochlorite aqueous solution was added thereto
dropwise at O C in a period of 100 minutes. The mixture was
then stirred for 3 hours. To the reaction mixture were
added 10 ml of a 5% sodium thiosulfate aqueous solution and
0.1 N hydrochloric acid. The mixture was extracted with
ethyl acetate. The ethyl acetate layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (350 ml of silica gel,
hexane:ethyl acetate=4:1 to 1:1) to give ~.38 g of 3-
hydroxy-6-iodopyridine (yield: 34%).
To 647 mg (16.2 mmol) of 60% sodium hydride was added
20 ml of N,N-dimethylformamide, and then 20 ml of an N,N-
dimethylformamide solution containing 2.3~ g (10.8 mmol) of
3-hydroxy-6-iodopyridine was added thereto. The mixture was
stirred in an argon atmosphere at room temperature for 2
hours. To the reaction mixture were added 2.14 g (15.12
mmol) of methyl iodide, and the mixture was stirred for 1
hour. To the reaction mixture was added a 0.01 M phosphate
buffer of pH7, and the solution was extracted with ethyl
acetate. The ethyl acetate layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (20 ml of silica gel,
hexane:ethyl acetate=5:1 to 4:1) to give 2.57 g of 3-
methoxy-6-iodopyridine (yield: 100%).
3-Methoxy-6-iodopyridine (500 mg, 2.:L3 mmol) was
dissolved in 6 ml of N,N-dimethylformamide, and 29 mg of
palladium acetate, 736 mg (5.33 mmol) of potassium
carbonate, 592 mg (2.13 mmol) of tetra-n-butylammonium
chloride and 917 mg (10.65 mmol) of methyl acrylate were
added thereto. The mixture was stirred at 120 C for 12
hours in a sealed tube. To the reaction mixture was added a
0.01 M phosphate buffer of pH7, and the solution was
extracted with ethyl acetate. The ethyl acetate layer was
- 42 -

21~5,~90
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. The obtained crude product was
purified by silica-gel column chromatography (200 ml of
silica gel, hexane:ethyl acetate=4:1 to 3~1) to give 168 mg
(0.87 mmol) of methyl (E)-3-(3-methoxy-6-pyridyl)acrylate
(yield: 41%).
To 429 mg (2.22 mmol) of methyl (E)-3-(3-methoxy-6-
pyridyl)acrylate were added 12 ml of methanol and 1.11 ml of
a 4 N potassium hydroxide aqueous solution, and the mixture
was stirred at room temperature for 20 hours. To the
reaction mixture was added 1 N hydrochloric acid, and the
solution was extracted with ethyl acetate and with
chloroform. The ethyl acetate layer and t:he chloroform
layer were separately washed with a saturated aqueous
solution of sodium chloride. The combined organic layer was
dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to give 277 mg (1.55 mmol) of (E)-3-(3-
methoxy-6-pyridyl)acrylic acid (yield: 701;).
To 3.7 mg (0.0936 mmol) of 60% sodiurn hydride was
added 0.3 ml of N,N-dimethylformamide, ancl then 0.4 ml of an
N,N-dimethylformamide solution containing 20 mg of Compound
(A) was added thereto. The mixture was stirred in an argon
atmosphere at -20 C for 2 hours and 20 minutes. To the
reaction mixture was added 0.4 ml of an N,N-
dimethylformamide solution containing 25.8 mg (0.86 mmol) of
p-nitrophenyl (E)-3-(3-methoxy-6-pyridyl)acrylate, and the
mixture was stirred for 1.5 hours. To the reaction mixture
was added a 0.01 M phosphate buffer of pH7, and the solution
was extracted with ethyl acetate. The ethyl acetate layer
was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (30
ml of silica gel, chloroform:methanol= 100:1 to 50:1) to
give 27.1 mg of Compound 15 (yield: 83~).
The physicochemical properties of Cornpound 15 are as
follows.
- 43 -

21G3~90
H-NMR(270MHz,CDCl3)~(ppm); 11.80(lH,br),
8.23(lH,d,J=15.2Hz), 8.22(1H,dd,J=4.1,1.5Hz),
7.46(lH,d,J=15.2Hz), 7.21-7.30(2H,m), 6.92(lH,br),
4.31(1H,d,J=10.9Hz), 4.20(1H,dd,J=10.6,4.6Hz),
3.90(3H,s), 3.81(3H,s), 3.55-3.62(lH,m), 2.62(3H,s),
2.36(lH,dd,J=7.6,3.3Hz), 1.29(lH,dd,J=4.6r3.6Hz)
FABMS(m/z); 422(M+3) + ,420(M+H) +
IR(KBr)~(cm~1); 1701, 1672, 1618, 1578, 1450, 1390, 1296,
1252, 1217, 1113
Fxample 16 Synthesis of Compound 16
To 17.7 mg (0.0422 mmol) of Compound 15 obtained in
Example 15 were added 1.06 ml of acetonitrile and 9.6 ~l of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in a mixed solvent of 0.89 ml of
methylene chloride and 0.35 ml of toluene, and 24.7 mg
(0.131 mmol) of p-nitrophenyl chloroformate and 17.6 ~l
(0.127 mmol) of triethylamine were added t:hereto at -78 C.
The mixture was stirred for 50 minutes. Subsequently, to
the solution was added 16.4 ~ll (0.148 mmo]) of N-
methylpiperazine, and the mixture was stirred at -78 C to
O C for 30 minutes. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol=-9:1) to give 15.2
mg of Compound 16 (yield: 58%).
The physicochemical properties of Compound 16 are as
follows.
1H-NMR(270MHz,CDCl3)~(ppm); 9.47(lH,brs),
8.28(1Hrd,J=15.2Hz), 8.27(1H,dd,J=4.0,1.3Hz),
- 44 -

2163~90
7.55(1H,d,J=14.9Hz), 7.21-7.30(2H,m), 4.54(lH,br),
4.52(lH,d,J=9.6Hz), 4.33(lH,dd,J=9.9,9.2Hz), 3.93(3H,s),
3.89(3H,s), 3.76(1H,dd,J=9.9,2.6Hz), 3.74(2H,br),
3.60(2H,br), 3.21(lH,dd,J=9.9,9.9Hz), 2.51(3H,s),
2.46(4H,br), 2.34(3H,s)
FABMS(m/z); 628, 626(M+H) +
IR(KBr)~(cm~l); 1722, 1701, 1697, 1433, 1408, 1292, 1259,
1217, 1153, 1093
Example 17 Synthesis of Compound 17
To 14.4 mg (0.0230 mmol) of Compound 16 obtained in
Example 16 were added 0.55 ml of ethanol and 0.28 ml of
methanol, and then lO.l ~l of 6.86 N hydrogen chloride in
ethanol was added thereto. The mixture was stirred at room
temperature for 3 hours. The reaction mixture was
concentrated under reduced pressure to give 16 mg of
Compound 17.
The physicochemical properties of Compound 17 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.15(lH,s),
10.75(1H,br), 8.28(1H,d,J=3.6Hz), 8.11(1H,s),
7.96(lH,d,J=15.2Hz), 7.62(lH,d,J=8.6Hz),
7.54(lH,d,J=15.5Hz), 7.45-7.50(lH,m), 4.30-4.58(4H,m),
4.08-4.24(lH,br), 3.94(3H,s), 3.85(3H,s), 3.81(lH,br),
2.85(3H,br), 2.69(3H,s)
IR(KBr)~(cm~l); 1722, 1699, 1655, 1614, 1437, 1416, 1255,
1219
~xample 18 Synthesis of Compound 18
To 9.3 mg (0.23 mmol) of 60% sodium hydride was added
0.3 ml of N,N-dimethylformamide, and then 1 ml of an N,N-
dimethylformamide solution containing 50 rng (0.194 mmol) of
compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 3 hours. To the reaction
mixture was added 1 ml of an N,N-dimethylformamide solution
containing 70 mg (0.23 mol) of p-nitrophenyl 4-
methoxyphenoxyacetate, and the mixture was stirred at from
- 45 -

~ 21g;3~390
-20 C to O C for 2 hours. To the reaction mixture was added
a 0.2 M phosphate buffer of pH7, and the solution was
extracted with ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. The obtained crude product was
purified by silica-gel column chromatography (30 ml of
silica gel, chloroform:methanol=100:1) to give 71 mg of
Compound 18 (yield: 73%).
The physicochemical properties of Compound 18 are as
follows.
H-NMR(400MHz,CDCl3)~(ppm); 10.65(lH,br), 7.25(lH,br),
6.89(2H,d,J=9.2Hz), 6.83(2H,d,J=9.2Hz), 4.73(2H,s),
4.20(1H,br d,J=10.6Hz), 4.11(1H,m), 3.81(3H,s),
3.76(3H,s), 3.56(lH,m), 2.60(3H,s),
2.31(lH,dd,J=7.5,3.4Hz), 1.17(lH,m)
IR(KBr)~(cm-l); 1701, 1606, 1507, 1409, 1217, 1109, 1027
SIMS(m/z); 423(M+H) +
Fxample 19 Synthesis of Compound 19
Compound 18 (20 mg, 0.047 mmol) obtained in Example 18
was dissolved in a mixed solvent of 1 ml of N, N-
dimethylformamide and 1 ml of acetonitrile, and 1 ml of 48%
hydrobromic acid was added thereto. The rnixture was stirred
at room temperature for 1 hour. To the reaction mixture was
added 1 N hydrobromic acid, and the solution was extracted
with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate, and concentrated under reduced
pressure. The resulting crude product was dissolved in 1 ml
of methylene chloride, and 29 mg (0.144 mrnol) of p-
nitrophenyl chloroformate and then 0.020 ml (0.144 mmol) of
triethylamine were added thereto at -78 C The mixture was
stirred for 1 hour. To the reaction mixture was added 0.019
ml (0.17 mmol) of N-methylpiperazine, and the mixture was
stirred at -78 C to O C for 2 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with chloroform. The chloroform
- 46 -

` 21~S389~
layer was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (20
ml of silica gel, chloroform:methanol=30:1) to give 12 mg of
Compound 19 (yield: 41%).
The physicochemical properties of Compound 19 are as
follows.
lH-NMR(400MHz,CDCl3)~(ppm); 8.75(1H,br), 8.10 (lH,br),
6.97(2H,d,J=9.lHz), 6.84(2H,d,J=9.lHz), 4.78 (2H,s),
4.54(lH,m), 4.41(lH,d,J=ll.OHz),
4.19(lH,dd,J=10.2,8.5Hz), 3.94(3H,s), 3.77(lH, br),
3.76(2H,br), 3.76(3H,s), 3.62(2H,br),
3.20(lH,dd,J=lO.O,lO.OHz), 2.68(3H,s), 2.50(4H,br),
2.37(3H,s)
IR(KBr)V(cm~l); 1688, 1589, 1506, 1412, 1292, 1216,
1149, 1096, 1004
SIMS(m/z); 631, 629(M+H) +
Fxample 20 Synthesis of Compound 20
To 11 mg (0.017 mmol) of Compound 19 obtained in
Example 19 were added 0.5 ml of methanol and 0.5 ml of
ethanol, and then 0.005 ml of 5.3 N hydrogen chloride in
ethanol was added thereto. The mixture was stirred at O C
for 2 hours. The reaction mixture was concentrated under
reduced pressure to give 13 mg of Compound 20.
The physicochemical properties of Compound 20 are as
follows.
H-NMR(400MHz,DMSO-d6)~(ppm); 12.08(1H,br), 10.56(1H,br),
7.92(lH,s), 6.93(2H,d,J=9.lHz), 6.84(2H,d,J=9.2Hz),
4.92(lH,d,J=15.2Hz), 4.83(1H,d,J=15.2Hz), 4.49(lH,br),
4.35(2H,br), 4.30(lH,dd,J=10.5,10.5Hz),
35 4.19(1H,br d,J=11.2Hz), 3.85(3H,s),
3.79(lH,dd,J=9.0,2.4Hz), 3.69(3H,s), 3.41(7H,br),
2.83(3H,s), 2.67(3H,s)
IR(KBr)V(cm-l); 1649, 1559, 1507, 1437, 1219, 1091
- 47 -

~ ` 216~
Example 21 Synthesis of Compound 21
To 3.7 mg (0.092 mmol) of 60% sodium hydride was added
0.1 ml of N,N-dimethylformamide, and then 0.4 ml of an N,N-
dimethylformamide solution containing 20 mg (0.078 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 3 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 31 mg (0.094 mmol) of p-nitrophenyl 4-n-
propyloxyphenoxyacetate, and the mixture was stirred at
-20 C to O C for 2 hours. To the reaction mixture was added
a 0.2 M phosphate buffer of pH7, and the solution was
extracted with ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and t:hen concentrated
under reduced pressure. The obtained crude product was
puriied by silica-gel column chromatography (20 ml of
silica gel, chloroform:methanol=100:1) to give 18 mg of
Compound 21 (yield: 50%).
The physicochemical properties of Cornpound 21 are as
follows.
H-NMR(400MHz,CDCl3)~(ppm); 10.30(lH,br), 7.25(lH,br),
6.87(2H,d,J=9.2Hz), 6.83(2H,d,J=9.3Hz), 4 73(2H,s),
4.21(lH,br d,J=10.8Hz), 4.11(lH,m), 3.86(2H,t,J=6.6Hz),
3.81(3H,s), 3.56(lH,m), 2.60(3H,s),
2.30(1H,dd,J=7.5,3.4Hz), 1.77(2H,m), 1.17~1H,m),
1.02(3Hrt,J=7.4Hz)
IR(KBr)~(cm~l); 1701, 1606, 1506, 1457, 1293, 1213
SIMS(m/z); 451(M+H) +
Example 22 Synthesis of Compound 22
To 3.7 mg (0.092 mmol) of 60% sodium hydride was added
0.1 ml of N,N-dimethylformamide, and 0.4 ml of an N,N-
dimethylformamide solution containing 20 mg (0.078 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 3 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 34 mg (0.095 mmol) of p-nitrophenyl 4-n-
- 48 -

~ ` 21~)90
pentyloxyphenoxyacetate, and the mixture was stirred at
-20 C to O C for 2 hours. To the reaction mixture was added
a 0.2 M phosphate buffer of pH7, and the solution was
extracted with ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. The obtained crude product was
purified by silica-gel column chromatography (20 ml of
silica gel, chloroform:methanol=100:1) to give 18 mg of
Compound 22 (yield: 48%).
The physicochemical properties of Cornpound 22 are as
follows.
lH-NMR(400MHz,CDCl3)~(ppm); 10.28(lH,br), 7.25(lH,br),
6.87(2H,d,J=9.2Hz), 6.82(2H,d,J=9.3Hz), 4 72(2H,s),
4.21(1H,br d,J=10.7Hz), 4.10(1H,m), 3.90(2H,t,J=6.6Hz),
3.81(3H,s), 3.56(lH,m), 2.60(3H,s),
2.30(1H,dd,J=7.6,3.6Hz), 1.77(2H,m), 1.43~4H,m),
1.17(lH,m), 0.92(3H,t,J=7.2Hz)
IR(KBr)~(cm~1); 1703, 1604, 1507, 1400, 1293, 1261, 1215
SIMS(m/z); 479(M+H) +
Fxample 23 Synthesis of Compound 23
To 6.3 mg (0.0158 mmol) of 60% sodium hydride was
added 0.3 ml of N,N-dimethylformamide, ancl 0.5 ml of an N,N-
dimethylformamide solution containing 30 mg of Compound (A)
was added thereto. The mixture was stirred in an argon
atmosphere at from -20 C for 2.5 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 49.7 mg (0.139 mmol) of p-nitrophenyl 4-
n-(trifluoromethoxy)phenoxyacetate, and the mixture was
stirred for 1.25 hours. To the reaction mixture was added a
0.01 M phosphate buffer of pH7, and the solution was
extracted with ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and t:hen concentrated
under reduced pressure. The obtained crude product was
purified by silica-gel column chromatography (30 ml of
- 49 -

~ ` 2~38~
silica gel, chloroform:methanol=100:1) to give 39.6 mg of
Compound 23 (yield: 72%).
The physicochemical properties of Cornpound 23 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); ll.90(lH,brs),
7.15(2H,d,J=8.6Hz), 7.00(lH,br), 6.93(2H,d,J=8.9Hz),
4.77(2H,s), 4.15 (2H,brs), 3.80(3H,s),3.63(lH,brs),
2.60(3H,s), 2.33~1H,dd,J=7.3,3.0Hz), 1.18~1H,brs)
FABMS(m/z); 479(M+3) + , 477(M+H) +
IR(KBr)~(cm~l); 1730, 1697, 1647, 1601, 1512, 1410,
1252, 1217, 1174, 1138, 1096
Example ~4 Synthesis of Compound 24
To 19.9 mg (0.0418 mmol) of Compound 23 obtained in
Example 23 were added 1.06 ml of acetonitrile and 14.19 ~l
of 48% hydrobromic acid. After the solution was stirred at
room temperature for 60 minutes, the reaction mixture was
concentrated under reduced pressure. The obtained crude
product was dissolved in 1.06 ml of methy]ene chloride, and
25.3 mg (0.125 mmol) of p-nitrophenyl chloroformate and 17.5
~l (0.125 mmol) of triethylamine were added thereto at
-78 C. The mixture was stirred for 35 minutes. Then, to
this solution was added 24.3 ~l (0.219 mmol) of N-
methylpiperazine, and the mixture was stirred at -78 C to
O C for 2 hours. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the solution was extracted with chloroform. The chloroform
layer was washed with a saturated aqueous solution of sodium
hydrogen carbonate and with a saturated aqueous solution of
sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by thin-layer chromatography
(chloroform:methanol=10:1) to give 25.7 mg of Compound 24
(yield: 90%).
The physicochemical properties of Compound 24 are as
follows.
- 50 -

~ ~ 21~8'~0
lH-NMR(270MHz,CDCl3)~(ppm); 9.18(lH,brs), 8.04(1H,s),
7.16(2H,d,J=8.9Hz), 7.01~2H,d,J=9.2Hz),
4.86(lH,d,J=14.9Hz), 4.80(lH,d,J=14.9Hz),
4.51(lH,brt,J=7.6Hz), 4.35(lH,d,J=10.6Hz),
4.17(lH,dd,J=10.6,8.6Hz), 3.92(3H,s),
3.76(lH,brd,J=10.2Hz), 3.63-3.72(4H,m),
3.19(lH,dd,J=9.9,9.9Hz), 2.47(7H,brs), 2.35(3H,s)
FABMS(m/z); 685, 683(M+H) +
IR(KBr)~(cm~l); 1701, 1670, 1506, 1439, 1417, 1261, 1238,
1220, 1196, 1159, 1005
Fxample 25 Synthesis of Compound 25
To 19.5 mg (0.0285 mmol) of Compound 24 obtained in
Example 24 were added 0.92 ml of ethanol and 0.46 ml of
methanol, and 8.3 ~l of 6.86 N hydrogen chloride in ethanol
was added thereto. The mixture was stirred at room
temperature for 3.5 hours. The reaction mixture was
concentrated under reduced pressure to gi~7e 20.4 mg of
Compound 25.
The physicochemical properties of Compound 25 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.13(1H,s), 10.62(1H,br),
7.91(lH,s), 7.29(2H,d,J=8.6Hz), 7.09(2H,d,J=9.2Hz),
5.10(lH,d,J=15.8Hz), 4.97(lH,d,J=15.5Hz), 4.50-
4.52(lH,m), 4.32(lH,dd,J=10.2,8.9Hz),
4.17(lH,d,J=10.6Hz), 3.85(3H,s),
3.79(1H,dd,J=9.6,2.0Hz), 2.82(3H,s), 2.67(3H,s)
FABMS(m/z); (M+H) +
IR(KBr)~(cm~l); 1716, 1695, 1506, 1439, 1417, 1248, 1232,
1194, 1171, 1097
~xample 26 Synthesis of Compound 26
To 1.9 mg (0.048 mmol) of 60% sodium hydride was added
0.1 ml of N,N-dimethylformamide, and 0.2 ml of an N,N-
dimethylformamide solution containing 10 mg (0.04 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 1 hours. To the reaction
- 51 -

3 ~ 9 ~
mixture was added 0.2 ml of an N,N-dimethylformamide
solution containing 19 mg (0.149 mmol) of p-nitrophenyl 4-
tert-butoxycarbonylaminocinnamate, and the mixture was
stirred at -20 C to O C for 3 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with ethyl acetate The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by silica-gel column
chromatography (20 ml of silica gel, chloroform:methanol=
80:1) to give 13 mg of Compound 26 (yield: 65%).
The physicochemical properties of Compound 26 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 11.32(lH,br),
7.76(1Hrd,J=15.5Hz), 7.51(2H,d,J=8.8Hz),
7.41(2H~d,J=8.9Hz), 6.80(1H,d,J=15.5Hz), 6.62(1H,br),
4.23(lH,d,J=11.2Hz), 4.12(lH,dd,J=11.2,7.3Hz),
3.82(3H,s), 3.59(lH,m), 2.62(3H,s),
2.40(1H,dd,J=7.6,3.3Hz), 2.05(1H,s), 1.54~9H,s),
1.30(lH,dd,J=4.3,4.0Hz)
IR(KBr)V(cm-1); 1707, 1620, 1587, 1525, 1520, 1394,
1294, 1240, 1159
SIMS(m/z); 504(M+H) +
Example 27 Synthesis of Compound 27
To 1.9 mg (0.048 mmol) of 60% sodium hydride was added
0.1 ml of N,N-dimethylformamide, and 0.2 ml of an N,N-
dimethylformamide solution containing 10 mg (0.04 mmol) ofCompound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 0.2 ml of an N,N-dimethylformamide
solution containing 10 mg (0.052 mmol) of p-nitrophenyl 4-
dimethyLaminocinnamate, and the mixture was stirred at -20 C
to O C for 1 hour. To the reaction mixture was added a 0.2
M phosphate buffer of pH7, and the solution was extracted
with ethyl acetate. The ethyl acetate layer was washed with
- 52 -

~ 6389~
a saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (20 ml of silica gel,
chloroform:methanol=50:1) to give 11 mg of Compound 27
(yield: 64%).
The physicochemical properties of Compound 27 are as
follows.
1H-NMR(270MHz,CDCl3)~(ppm); 10.73(lH,br),
7.77(lH,d,J=15.2Hz), 7.46(2H,d,J=8.9Hz),
6.59(2H,d,J=8.9Hz), 6.64 (lH,d,J=15.5Hz), 6.63 (lH,br),
4.21(1H,d,J=10.9Hz), 4.14(lH,dd,J=10.9,4.6Hz),
3.82(3H,s), 3.53(lH,m), 3.04(6H,s), 2.61(3H,s),
2.36(lH,dd,J=7.3,3.6Hz), 1.30(lH,dd,J=4.9,3.3Hz)
IR(KBr)~(cm-1); 1701, 1593, 1525, 1389, 1360, 1242,
1217, 1169
SIMS(m/z); 432(M+H) +
~xample 28 Synthesis of Compound 28
Compound 26 (8 mg, 0.016 mmol) obtained in Example 26
was dissolved in 1 ml of acetonitrile, and then 0.5 ml of 1
N hydrobromic acid and 0.2 ml of trifluoroacetic acid were
added thereto. After the solution was stirred at room
temperature for 4 hours, the reaction mixture was
concentrated under reduced pressure. To the obtained crude
product were added 1 ml of acetonitrile, ().2 ml of water and
0.2 ml of triethylamine, and the mixture was stirred for 24
hours. To the reaction mixture was added a 0.2 M phosphate
buffer of pH7, and the solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude procluct was purified
by thin-layer silica-gel chromatography (cleveloping solvent,
chloroform:methanol=10:1) to give 3 mg of Compound 28
(yield: 47%).
The physicochemical properties of Compound 28 are as
- 53 -

~ ` 2163890
follows.
H-NMR(270MHz,CDCl3)~(ppm); 10.28(lH,br),
7.74(lH,d,J=15.5Hz), 7.39(2H,d,J=8.6Hz),
6.68(1H,d,J=15.5Hz), 6.65(2H,d,J=8.5Hz), 6.62(1H,br),
4.21(lH,d,J=11.2Hz), 4.11(lH,dd,J=11.2,6.3Hz),
3.82(3H,s), 3.56(lH,m), 2.60(3H,s),
2.36(lH,dd,J=7.6,3.3Hz), 1.32(lH,dd,J=4.5,3.4Hz)
IR(KBr)~(cm~1); 1697, 1595, 1518, 1443, 1392, 1242,
1219, 1174
SIMS(m/z); 404(M+H) +
Example 29 Synthesis of Compound 29
To 12 mg (0.3 mmol) of 60% sodium hydride was added
0.6 ml of N,N-dimethylformamide, and 1.5 ml of an N,N-
dimethylformamide solution containing 60 mg (0.23 mmol) of
Compound (A) was added thereto. The react:ion mixture was
cooled to -20 C, and 1.5 ml of an N,N-dimethylformamide
solution containing 124 mg (0.31 mmol) of p-nitrophenyl 3-
(3-azidopropyloxy)-4-methoxycinnamate was added thereto.
The mixture was stirred at -20 C to O C for 2 hours. To the
reaction mixture was added a 0.2 M phosphate buffer of pH7,
and the solution was extracted with ethyl acetate. The
ethyl acetate layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfater and then concentrated under reduced pressure. The
obtained crude product was purified by silica-gel column
chromatography (30 ml of silica gel,
chloroform:methanol=50:1) to give 77 mg of Compound 29
(yield: 65%).
The physicochemical properties of Compound 29 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.81(lH,br),
7.68(1Hrd,J=15.5Hz), 7.11(1H,dd,J=8.3,2.0Hz),
7.01(lH,d,J=2.0Hz), 6.81(lH,d,J=8.2Hz),
6.66(1Hrd,J=15.5Hz), 6.56(1H,br), 4.15(lH,d,J=11.2Hz),
4.07(2H,t,J=5.9Hz),4.06(lH,m), 3.84(3H,s), 3.76(3H,s),
- 54 -

~t 216389~
3.50(2H,t,J=6.6Hz), 3.46(lH,m), 2.52(3H,s),
2.31(lH,dd,J=7.6,3.3Hz), 2.05(2H,m),
1.25(lH,dd,J=5.3,3.4Hz)
IR(KBr)~(cm~l); 2098, 1697, 1622, 1608, 1516, 1392,
1263, 1217
SIMS(m/z); 518(M+H) +
Example 30 Synthesis of Compound 30
Compound 29 (15 mg, 0.029 mmol) obtained in Example 29
was dissolved in 1.5 ml of tetrahydrofuran, and then 23 mg
(0.088 mmol) of triphenylphosphine was added thereto. The
mixture was stirred at room temperature for 30 minutes. To
the reaction mixture was added 1.5 ml of water, and the
mixture was stirred at room temperature for 24 hours. To
the reaction mixture was added an aqueous solution of sodium
hydrogen carbonate, and the resulting mixture was extracted
with chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and concentrated under reduced
pressure. The obtained crude product was purified by
silica-gel column chromatography (30 ml of silica gel,
chloroform:methanol:triethylamine at=200:~0:1) to give 4 mg
of Compound 30 (yield: 28%).
The physicochemical properties of Compound 30 are as
follows.
1H-NMR(270MHz,DMSO-d6)~(ppm); 7.75(lH,d,J=15.2Hz),
7.54(1H,br s), 7.49(1H,br d,J=8.6Hz),
7.18(1H"d,J=8.6Hz), 7.09(1H,d,J=15.2Hz), 7.03(1H,br),
4.15 (lH,br d,J=11.2Hz), 4.39 (lH,m),
4.27(2Hrt,J=6.3Hz),3.96(3H,s), 3.87(3H,s), 3.61(lH,m),
3.12(2H,t,J=7.2Hz), 2.61(3H,s),2.23(1H,m), 2.16(2H,m),
1.46(lH,m)
IR(KBr)~(cm~l); 1647, 1610, 1512, 1458, 1394, 1385,
1294, 1219
SIMS(m/z); 492(M+H) +

~ 2~53890
Example 31 Synthesis of Compound 31
Compound 29 (50 mg, 0.096 mmol) obtained in Example 29
was dissolved in 5 ml of acetonitrile, and 1 ml of 48%
hydrobromic acid was added thereto. The mixture was stirred
at room temperature for 1 hour. To the reaction mixture was
added 1 N hydrobromic acid, and the solution was extracted
with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was dissolved
in 5 ml of methylene chloride. Then, 58 mg (0.29 mmol) of
p-nitrophenyl chloroformate and succesively 0.04 ml (0.29
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred for 30 minutes. To the reaction mixture
was added 0.038 ml (0.34 mmol) of N-methylpiperazine, and
the mixture was stirred at from -78 C to O C for 2 hours.
To this reaction mixture was added a 0.2 M phosphate buffer
of pH7, and the solution was extracted with chloroform. The
chloroform layer was washed with a satura-ted aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The
obtained crude product was purified by silica-gel column
chromatography (30 ml of silica gel,
chloroform:methanol=20:1) to give 51 mg of an azido compound
(yield: 73%). To 35 mg (0.049 mmol) of the azido compound
were added 5 ml of methanol, 1 ml of acetone and 22 mg of a
mixture of 10% lead/barium sulfate. The resulting mixture
was stirred in a hydrogen atmosphere at room temperature for
4 hours. The reaction mixture was filtered, and then
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (30
ml of silica gel, chloroform:methanol:ammonia=10:1:1) to
give 12 mg of Compound 31 (yield: 35%).
The physicochemical properties of Compound 31 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 8.09(lH, br s), 7.96(lH,s),
7.90(2H,br), 7.58(1H, d,J=15.2Hz), 7.44(lH,s),
7.35(1H,br d,J=8.2Hz), 7.07(lH,d,J=15.5Hz),
- 56 -

~ 216~890
7.05(1H,d,J=8.6Hz), 4.53(1H,m), 4.42(2H,m),
4.18(2H,t,J=5.9Hz), 3.85(3H, s), 3.84(3H, s),
3.79(lH,m), 3.45(lH,m), 3.00(2H,br), 2.75(2H,br),
2.74(3H,s), 2.69(3H,s), 2.06(2H,m)
IR(KBr)~(cm~l); 3547, 1718, 1697, 1637, 1511, 1436,
1409, 1263, 1219
FABMS(m/z); 698, 700(M+H) +
Fxample 32 Synthesis of Compound 32
To 16 mg (0.023 mmol) of Compound 31 obtained in
Example 31 was added 2 ml of methanol, and then 0.0084 ml of
6.86 N hydrogen chloride in ethanol was added thereto. The
mixture was stirred at O C for 1 hour. The reaction mixture
was concentrated under reduced pressure to give 16.4 mg of
Compound 32.
The physicochemical properties of Compound 32 are as
follows.
1H-NMR(270MHz,DMSO-d6)~(ppm); 12.18(lH,br),
10.93(1H,br), 8.09 (lH,br s), 7.89 (2H,br),
7.56(lH,d,J=15.2Hz), 7.43(lH,br s), 7.33(:LH,d,J=8.2Hz),
7.06(1H,d,J=15.3Hz), 7.03(1H,d,J=8.3Hz), 4.50(1H,m),
4.40(2H,m), 4.15(2H,t,J=5.6Hz), 3.85(3H,s}, 3.83(3H,s),
3.46(6H,br), 3.26(4H,br), 2.99(2H,m), 2.84(3H,s),
2.68(3H,s), 2.05(2H,m)
IR(KBr)~(cm~l); 1716, 1647, 1509, 1437, 1408, 1263, 1140
FABMS(m/z); 700, 698(M+H) +
Example 33 Synthesis of Compound 33
To 3.7 mg (0.093 mmol) of 60% sodium hydride was added
0.2 ml of N,N-dimethylformamide, and 0.5 ml of an N,N-
dimethylformamide solution containing 20 mg (0.078 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 41 mg (0.10 mmol) of p-nitrophenyl 3-(3-
dimethylaminopropyloxy)-4-methoxycinnamate, and the mixture
was stirred at -20 C to O C for 2 hours. To the reaction

~ 2163~90
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by silica-gel column
chromatography (20 ml of silica gel,
chloroform:methanol=5:1) to give 21 mg of Compound 33
(yield: 52%).
The physicochemical properties of Compound 33 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.38 (lH,br),
7.59(lH,d,J=15.5Hz), 7.39(lH,br s),
7.28(lH,br d,J=8.5Hz), 7.00(lH,d,J=8.6Hz),
6.94(lH,d,J=15.6Hz), 6.90(lH,br s),
4.34(lH,br d,J=10.8Hz), 4.27(lH,m), 4.06(1H,t,J=6.2Hz),
3.81(3H,s), 3.76(lH,m), 3.73(3H,s), 3.12(2H,m),
2.59(3H,s), 2.23(1H,m), 2.16(2H,m), 1.46(1H,m)
IR(KBr)~(cm~1); 1684, 1601, 1443, 1437, 1385, 1263
FABMS(m/z); 520(M+H) +
~xample 34 Synthesis of Compound 34
Compound 35 (5 mg, 0.009 mmol) obtained in Example 35
was dissolved in 0.5 ml of ethylene dichloride, and 0.2 ml
of 48% hydrobromic acid was added thereto The mixture was
stirred at 50 C for 2 hours. To the reaction mixture was
added methanol, and the solution was concentrated under
reduced pressure. Acetonitrile (lml) and 4 ml of a 0.2 M
phosphate buffer of pH7 were added thereto, and the mixture
was stirred at room temperature for 2 hours. To the
reaction mixture was added an acetate buffer of pH4, and the
solution was extracted with chloroform. The chloroform
layer was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (20
ml of silica gel, chloroform:methanol=10:1) to give 4 mg of
- 58 -

~ 21~3~0
Compound 34 (yield: 88%).
The physicochemical properties of Compound 34 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 10.69(lH,br),
7.65(lH,d,J=15.5Hz), 7.15(1H,dd,J=8.2,1.7Hz),
6.96(lH,d,J=2.0Hz), 6.83(lH,d,J=8.6Hz),
6.63(lH,d,J=15.5Hz), 6.60 (lH,br), 4.66(2H,s),
4.14(lH,dd,J=10.9, 10.9Hz),4.07(lH,m), 3.86(3H,s),
3.76(3H,s), 3.74(3H,s), 3.48(lH,m), 2.52(3H,s),
2.31(lH,dd,J=7.6,3.3Hz), 1.25(lH,dd,J=5.0,3.4Hz)
IR(KBr)~(cm~l); 1699, 1653, 1616, 1516, 1458, 1396, 1219
SIMS(m/z); 507(M+H) +
~xample 35 Synthesis of Compound 35
To 4.0 mg (0.1 mmol) of 60% sodium hydride was added
0.2 ml of N,N-dimethylformamide, and then 0.5 ml of an N,N-
dimethylformamide solution containing 20 mg (0.078 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 41 mg (0.096 mmol) of p-nitrophenyl 3-
tert-butoxycarbonylmethoxy-4-methoxycinnamate, and the
mixture was stirred at -20 C to O C for 2 hours. To the
reaction mixture was added a 0.2 M phosphate buffer of pH7,
and the solution was extracted with ethyl acetate. The
ethyl acetate layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purlfied by si]ica-gel column
chromatography (20 ml of silica gel, chloroform:methanol=
50:1) to give 35 mg of Compound 35 (yield 82%).
The physicochemical properties of Compound 35 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 10.61(1H,br),
7.65(lH,d,J=15.2Hz), 7.15(1H,dd,J=8.2,1.6Hz),
6.92(lH,d,J=2.0Hz), 6.83(lH,d,J=8.5Hz),
- 59 -

~ ` 2 1 6 ~
6.60(1H,d,J=15.5Hz), 6.58(1H,br), 4.52(2H,s),
4.14(lH,d,J=10.9Hz), 4.09(lH,m), 3.86(3H,s), 3.75(3H,s),
3.49(lH,m), 2.54(3H,s), 2.31(lH,dd,J=7.6,3.3Hz),
1.55(9H,s), 1.25(lH,dd,J=4.6,3.4Hz)
IR(KBr)~(cm~l); 1751, 1701, 1616, 1512, 1458, 1392,
1294, 1142
FABMS(m/z); 549(M+H) +
Fxample 36 Synthesls of Compound 36
To 99 mg (0.18 mmol) of Compound 35 obtained in
Example 35 were added 5 ml of acetonitrile and 0.155 ml of
48% hydrobromic acid. The mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added 1
N hydrobromic acid, and the solution was extracted with
chloroform. The chloroform layer was dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was dissolved in 5 ml
of methylene chloride. Then, 109 mg (0.51 mmol) of p-
nitrophenyl chloroformate and 0.076 ml (0.54 mmol) of
triethylamine were added thereto at -78 C. The mixture was
stirred for 1 hour. To the reaction mixture was added 0.162
ml (1.8 mmol) of a 50% dimethylamine aqueous solution, and
the mixture was stirred at -78 C to O C for 2 hours. To the
reaction mixture was added a 0.2 M phosphate buffer of pH7,
and the solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by si:Lica-gel column
chromatography (30 ml of silica gel, chloroform:methanol=
20:1) to give 44 mg of an ester of Compound 36 (yield: 35%).
To 30 mg (0.043 mmol) of the ester were added 1 ml of
ethylene dichloride and 0.051 ml of trifluoroacetic acid,
and the mixture was stirred at 80 C for 24 hours. To the
reaction mixture was added 1 N hydrobromic acid, and the
solution was extracted with chloroform. The chloroform layer
was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium suliate, and then
- 60 -

~ 2163~
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (30
ml of silica gel, chloroform:methanol:acet:ic acid=100:10:1)
to give 23 mg of Compound 36 (yield: 83%)~
The physicochemical properties of Compound 36 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.01(lH,br),
8.02(lH,br), 7.51(lH,d,J=15.lHz), 7.26(lH,br d,J=8.5Hz),
7.17(lH,br s), 6.97(lH,d,J=15.lHz),
6.96(1H~d,J=8.5Hz), 4.50(1H,m), 4.38(2H,m), 4.30(2H,s),
3.84(3H/s), 3.81(3H,s), 3.78(2H,br), 3.15~3H,s),
2.96(3H,s), 2.65(3H,s)
IR(KBr)~(cm~l); 1701, 1585, 1437, 1416, 1317, 1267, 1169
FABMS(m/z); 645, 643(M+H) +
Example 37 Synthesis of Compound 37
To 10 mg (0.25 mmol) of 60% sodium hydride was added
0.5 ml of N,N-dimethyl~ormamide, and 1.5 ml of an N,N-
dimethylformamide solution containing 50 mg (0.19 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 2.0 ml of an N,N-dimethylformamide
solution containing 103 mg (0.25 mmol) of p-nitrophenyl 3-
tert-butoxycarbonylamino-4-methoxycinnamate, and the mixture
was stirred at -20 C to O C for 2 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by silica-gel column
chromatography (30 ml of silica gel, chloroform:methanol=
80:1) to give 98 mg of tert-butoxycarbonyl (Boc) compound of
Compound 37 (yield: 97%).
The physicochemical properties of Boc compound of
Compound 37 are as follows.
- 61 -

2163~!~0
.
lH-NMR(270MHz,CDCl3)~(ppm); 10.76(lH,br), 8.37(lH,br),
7.78(lH,d,J=15.5Hz), 7.17(1H,dd,J=8.6,2.3Hz),
7.11(1H,br s), 6.84(1H,d,J=8.6Hz), 6.79(11I,br),
6.74(lH,d,J=15.5Hz), 4.24(lH,d,J=10.5Hz),
4.16(1H,dd,J=10.4,3.9Hz), 3.92(3H,s), 3.82(3H,s),
3.54(1H,m), 2.60(3H,s), 2.36(1H,dd,J=7.5,3.3Hz),
1.54(9H,s), 1.32(lH,dd,J=4.0,3.3Hz)
IR(KBr)U(cm~l); 1705, 1614, 1531, 1390, 1261, 1219, 1157
FABMS(m/z); 534(M+H) +
Boc compound of Compound 37 (30 mg, 0.056 mmol) was
dissolved in 3 ml of ethylene dichloride, and 0.1 ml of 48~
hydrobromic acid was added thereto. The mixture was stirred
at 50 C for 2 hours. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by si:Lica-gel column
chromatography (30 ml of silica gel, chloroform:methanol=
40:1) to give 12 mg of Compound 37 (yield: 49%).
The physicochemical properties of Compound 37 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.40(lH,br),
7.53(lH,d,J=15.5Hz), 7.03(lH,d,J=1.7Hz),
6.96(1H,dd,J=8.3, 1.8Hz), 6.88(1H,d,J=8.31Iz),
6.83(lH,br), 6.76(lH,d,J=15.5Hz), 4.88(2H,s),
30 4.30(1H,d,J=10.5Hz), 4.22(1H,dd,J=10.4, 4.9Hz),
3.85(3H,s), 3.76(3H,s), 3.48(1H,m), 2.50(3H,s),
2.11(lH,dd,J-7.3,4.OHz), 1.35(lH,dd,J=4.6,3.3Hz)
IR(KBr)~(cm-l); 1703, 1612, 1514, 1446, 1390, 1271,
1217, 1111
FABMS(m/z); 434(M+H) +
- 62 -

~ 21~38~30
~xample 38 Synthesis of Compound 38
Boc compound of Compound 37 (30 mg, 0.056 mmol)
obtained in Example 37 was dissolved in 3 ml of
acetonitrile, and then 0.015 ml of 48% hydrobromic acid was
added thereto. The mixture was stirred at O C for 1 hour.
To the reaction mixture was added an acetate buffer of pH4,
and the resulting solution was extracted with chloroform.
The chloroform layer was dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was dissolved in 3 ml of methyLene
chloride. Then, 0.013 mg (0.17 mmol) of methyl
chloroformate and 0.024 ml (0.17 mmol) of triethylamine were
added thereto at -78 C. The mixture was stirred for 1 hour.
To this reaction mixture was added an acetate buffer of pH4,
and the resulting solution was extracted with chloroform.
The chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by th:in-layer
chromatography (chloroform:methanol=80:1) to give 32 mg of
Boc compound of Compound 38 (yield: 85%). To 25 mg (0.037
mmol) of this Boc compound were added 2 m:L of ethylene
dichloride and 0.065 ml of 48% hydrobromic acid, and the
mixture was stirred at 80 C for 1 hour. To the mixture was
added a phosphate buffer of pH7, and the resulting solution
was extracted with chloroform. The chloroform layer was
washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. The obtained crude product was
purified by thin-layer chromatography (chloroform:methanol=
10:1) to give 13 mg of Compound 38 (yield: 61%).
The physicochemical properties of Compound 38 are as
follows.
1H-NMR(270MHz,CDCl3)~(ppm); 8.58 (lH,br), 8.42(lH,br),
7.73(lH,d,J=15.2Hz), 7.71(lH,t,J=4.5Hz), 7.01(2H, br),
6.98(1H,dd,J=8.4,2.0Hz), 6.80(1H,d,J=8.3Hz),
6.75(lH,d,J=15.2Hz), 4.56(lH,m), 4.47(1H,br d,J=10.6Hz),
- 63 -

21~3890
4.30(lH,dd,J=8.6,8.6Hz), 3.97(3H,s), 3.95(3H,s),
3.90(3H,s), 3.80(lH,dd,J=9.5,2.3Hz),
3.23(lH,dd,J=9.6,9.6Hz), 2.71(3H,s)
IR(KBr)V(cm~1); 1767, 1647, 1514, 1439, 1282, 1221, 1115
FABMS(m/z); 574, 572(M+H) +
~xample 39 Synthesis of Compound 39
To 29 mg (0.054 mmol) of Boc compound of Compound 37
obtained in Example 37 were added 3 ml of acetonitrile and
0.02 ml of 48% hydrobromic acid, and the mixture was stirred
at room temperature for 1 hour. To the reaction mixture was
added 1 N hydrobromic acid, and the solut:ion was extracted
with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was dissolved
in 3 ml of methylene chloride. Then, 33 rng (0.16 mmol) of
p-nitrophenyl chloroformate and 0.023 ml (0.16 mmol) of
triethylamine were added thereto at -78 C. The mixture was
stirred for 1 hour. To the reaction mixture was added 0.021
ml (0.19 mmol) of N-methylpiperazine, and the mixture was
stirred at -78 C to O C for 2 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with chloroform. The chloroform
layer was washed with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by silica-gel column chromatography (30
ml of silica gel, chloroform:methanol=20:1) to give 20 mg of
Boc compound of Compound 39 (yield: 50%). To 20 mg (0.027
mmol) of the Boc compound were added 2 ml of ethylene
dichloride and 0.025 ml of 48% hydrobromic acid, and the
mixture was stirred at 50 C for 2 hours. To the reaction
mixture was added a saturated aqueous solution of sodium
hydrogen carbonate, and the mixture was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude procluct was purified
- 64 -

216~90
by silica-gel column chromatography (30 ml of silica gel,
chloroform:methanol=20:1) to give 15 mg of Compound 39
(yield: 87%).
The physicochemical properties of Compound 39 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 8.80(lH, s), 8.25(lH, br),
7.73(1H, d,J=15.2Hz), 7.02(1H, br s), 6.80(1H, d,J=8.3Hz),
6.75(lH, d, J=15.8Hz), 4.57(lH, m),
4.47(1H, br d, J=10.2Hz), 4.30(1H, m), 3.96(3H, s),
3.90(3H, s), 3.81(1H, dd, J=9.6, 2.3Hz), 3.76(2H, br),
3.63(2H, br), 2.68(3H, s), 2.50(4H, br), 2.37(3H, s)
IR(KBr)V(cm~l); 1699, 1646, 1589, 1514, 1437, 1408,
1284, 1257, 1219, 1151, 1095
FABMS(m/z); 642, 640(M+H) +
Example 40 Synthesis of Compound 40
Methanol (lml) was added to 15 mg (0.023 mmol) of
Compound 39 obtained in Example 39, and 0.005 ml of 6.86 N
hydrogen chloride in ethanol was added thereto. The solution
was stirred at O C for 2 hours. The reaction mixture was
concentrated under reduced pressure to give 16 mg of
Compound 40.
The physicochemical properties of Compound 40 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.09(1H,br), 10.64(lH,br),
8.10(lH,br), 7.49(lH,d,J=15.2Hz), 7.22(lH,br s),
7.16(lH,d,J=8.6Hz), 6.95(lH,d,J=2.9Hz),
30 6.90(lH,d,J=15.lHz), 4.42(2H,m), 4.19(lH,m), 3.86(3H,s),
3.85(3H,s), 3.79(1H,br), 3.49(9H,br), 2.89(3H,s),
2.68(3H,s)
IR(KBr)V(cm~l); 1699, 1645, 1514, 1439, 1412, 1281, 1219
FABMS(m/z); 642, 640(M+H) +
Example 41 Synthesis of Compound 41
To 7.5 mg (0.19 mmol) of 60% sodium hydride was added
0.2 ml of N,N-dimethylformamide, and 1.0 ml of an N,N-
- 65 -

21~3~9û
dimethylformamide solution containing 40 mg (0.155 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 1.0 ml of an N,N-dimethylformamide
solution containing 64 mg (0.19 mmol) of p-nitrophenyl 3-
dimethylamino-4-methoxycinnamate, and the mixture was
stirred at -20 C to O C for 2 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by silica-gel column
chromatography (20 ml of silica gel, chloroform:methanol=
50:1) to give 46 mg of Compound 41 (yield: 64%).
The physicochemical properties of Compound 41 are as
follows.
1H-NMR(270MHz,CDCl3)~(ppm); 10.73(lH,br),
7.77(1H,d,J=15.5Hz), 7.22(lH,dd,J=8.6,2.OHz),
7.11(1H,d,J=2.1Hz), 6.87(1H,d,J=8.5Hz),
6.73(lH,d,J=15.5Hz), 4.23(lH,d,J=10.9Hz),
4.15(lH,dd,J=11.0,4.6Hz), 3.94(3H,s), 3.82(3H,s),
3.55(lH,m), 2.82(6H,s), 2.61(3H,s),
2.11(lH,dd,J=7.6,3.2Hz), 1.32(lH,dd,J=4.9~3.3Hz)
IR(KBr)~(cm~l); 1705, 1614, 1576, 1387, 1240, 1219, 1109
FABMS(m/z); 462(M+H) +
Example 42 Synthesis of Compound 42
To 24 mg (0.052 mmol) of Compound 41 obtained in
Example 41 were added 1 ml of acetonltrile and 0.018 ml of
48% hydrobromic acid, and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was
concentrated under reduced pressure, and the resulting crude
product was dissolved in a mixed solvent of 1 ml of
methylene chloride and 0.5 ml of toluene. Then, 32 mg (0.16
mmol) of p-nitrophenyl chloroformate and 0.029 ml (0.21
mmol) of triethylamine were added thereto at -78 C. The
- 66 -

216:~9~
mixture was stirred for 1 hour. To the reaction mixture was
added 0.021 ml (0.19 mmol) of N-methylpiperazine, and the
mixture was stirred at -78 C to O C for 2 hours. To the
reaction mixture was added a 0.2 M phosphate buffer of pH7,
and the solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by silica-gel column
chromatography (30 ml of silica gel, chloroform:methanol=
10:1) to give 22 mg of Compound 42 (yield: 63%).
The physicochemical properties of Compound 42 are as
follows.
1H-NMR(270MHz, CDCl3)~(ppm); 8.80(lH, s),
8.25(1Hr br s), 7.79(1H, d, J=15.2Hz), 7.26(1H, m),
7.17(1Hr d, J=2.0Hz), 6.88(lH, d, J=8.3Hz),
6.77(1Hr d, J=15.5Hz), 4.45-4.57(2H, m), 4.32(1H, m),
3.96(3Hrs), 3.94(3H, s), 3.80(lH, m), 3.79(2H, br),
3.63(2H, br), 3.23(lH,dd, J=10.2, 9.9Hz), 2.85(6H, s),
2.68(3Hr s), 2.50(4H, br), 2.37(3H,s)
FABMS(m/z); 670, 668(M+H) +
IR(KBr)V(cm~l); 1726, 1697, 1646, 1408, 1240, 1215,
1149, 1093
Example 43 Synthesis of Compound 43
To 22 mg (0.033 mmol) of Compound 42 obtained in
Example 42 was added 1 ml of methanol, and 0.006 ml of 6.86
N hydrogen chloride in ethanol was added thereto. The
mixture was stirred at O C for 2 hours. The reaction
mixture was concentrated under reduced pressure to give 21
mg of Compound 43.
The physicochemical properties of Compound 43 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.09(lH,br),
10.55(lH,br), 8.10(lH,br s),7.58(lH,d,J=15.2Hz),
7.46(2H,br), 7.04(lH,d,J=15.2Hz), 7.03(lH,br),
- 67 -

~ 21~;3~
.
4.49(4H,m), 4.18(1H,m), 3.86(3H,s), 3.85(3H,s),
3.79(lH,br d,J=9.9Hz), 3.48(3H,br), 2.85(10H,s),
2.68(3H,s), 2.50(3H,s)
IR(KBr)~(cm~1); 1716, 1697, 1647, 1510, 1434, 1414,
1246, 1217, 1095
Example 44 Synthesis of Compound 44
To 20.4 mg (0.0442 mmol) of Compound 41 obtained in
Example 41 were added 1.86 ml of acetonitrile and 15 ~l of
48% hydrobromic acid. The mixture was stirred at roo~
temperature for 60 minutes, and the reaction mixture was
then concentrated under reduced pressure. The resulting
crude product was dissolved in 1.86 ml of methylene
chloride. Then, 12.9 ~l (0.137 mmol) of acetic anhydride
and 17.3 mg (0.141 mmol) of 4-dimethylaminopyridine were
added thereto at O C. The mixture was stirred for 1 hour.
To this reaction mixture was added a 0.01 M phosphate buffer
of pH7, and the mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by thin-layer
chromatography (chloroform:methanol=15:1) to give 23.8 mg of
Compound 44 (yield: 92%).
The physicochemical properties of Compound 44 are as
follows.
1H-NMR(270MHz,CDCl3)~(ppm); 9.33(lH,brs), 8.29(lH,brs),
7.80(lH,d,J=15.2Hz), 7.24(lH,d,J=9.2Hz), 7.16(1H,s),
6.87(1H,d,J=8.6Hz), 6.78(1H,d,J=15.5Hz), 4.54(1H,br),
4.48(lH,d,J=11.2Hz), 4.33(lH,brt,J=8.9Hz)~ 3.95(3H,s),
3.93(3H,s), 3.80(lH,brd,J=7.6Hz),
3.23(1H,dd,J=10.2,9.9Hz), 2.84(6H,s), 2.56(3H,s),
2.34(3H,s)
FABMS(m/z); 586, 584(M+H)+
IR(KBr)~(cm~1); 1767, 1697, 1645, 1508, 1435, 1414,
1321, 1246, 1190, 1088, 1028
- 68 -

2163~9~
> ~xample 45 Synthesis of Compound 45
To 20.4 mg (0.0349 mmol) of Compound 44 obtained in
Example 44 was added 1.7 ml of anhydrous ethyl acetate, and
10.17 ~l of 6.86 N hydrogen chloride in ethanol was added
thereto. The mixture was stirred at room temperature for 3
hours. The reaction mixture was concentrated under reduced
pressure to obtain 24.6 mg of Compound 45.
The physicochemical properties of Compound 45 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.07(1H,s), 8.06(1H,brs),
7.95(lH,br), 7.80-7.83(lH,br), 7.63(lH,d,J=15.5Hz),
7.27(lH,d,J=8.6Hz), 7.15(lH,d,J=15.2Hz),
4.43-4.53(3H,br), 3.98(3H,s), 3.85(3H,s), 3.79(1H,br),
3.09(6H,s), 2.66(3H,s), 2.39(3H,s)
IR(KBr)U(cm~1); 1759, 1693, 1651, 1514, 1437, 1414,
1277, 1203, 1090, 1014
Example 46 Synthesis of Compound 46
To 6.4 mg (0.16 mmol) of 60% sodium hydride was added
0.3 ml of N,N-dimethylformamide, and 0.9 ml of an N,N-
dimethylformamide solution containing 34 mg (0.13 mmol) of
Compound (A) was added thereto. The mixture was stirred in
an argon atmosphere at -20 C for 2 hours. To the reaction
mixture was added 0.5 ml of an N,N-dimethylformamide
solution containing 58 mg (0.16 mmol) of p-nitrophenyl 3-
dimethylamino-4-methoxycinnamate, and the mixture was
stirred at -20 C to O C for 2 hours. To the reaction
mixture was added a 0.2 M phosphate buffer of pH7, and the
solution was extracted with ethyl acetate. The ethyl
acetate layer was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The obtained
crude product was purified by silica-gel column
chromatography (30 ml of silica gel, chloroform:methanol=
50:1) to give 55 mg of Compound 46 (yield: 87%).
The physicochemical properties of Compound 46 are as
follows.
- 69 -

21G3~3Q
lH-NMR(270MHz,CDCl3)~(ppm); 10.39(lH,br),
7.76(1H,d,J=15.5Hz), 7.25(1H,dd,J=8.6,1.9Hz),
7.11(lH,d,J=2.0Hz), 6.86(lH,d,J=8.6Hz),
6.70(lH,d,J=15.5Hz), 6.67(lH,br s), 4.22(lH,d,J=10.9Hz),
4.15(lH,dd,J=10.9,4.6Hz), 3.90(3H,s), 3.82(3H,s),
3.54(1H,m), 3.19(4H,q,J=7.3Hz), 2.60(3H,s),
2.36(lH,dd,J=7.6,3.6Hz), 1.32(1H,dd,J=5.3,3.5Hz),
1.05(6H,t,J=7.0Hz)
IR(KBr)~(cm~l); 1701, 1616, 1508, 1389, 1255, 1109
FABMS(m/z); 490(M+H) +
Example 47 Synthesis of Compound 47
To 16 mg (0.033 mmol) of Compound 46 obtained in
Example 46 were added 1.5 ml of acetonitrile and 0.06 ml of
48% hydrobromic acid. The mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added 1
N hydrobromic acid, and the solution was extracted with
chloroform. The chloroform layer was dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The resulting crude product was dissolved in 1.5
ml of methylene chloride. Then, 0.008 ml (0.10 mmol) of
methyl chloroformate and 0.014 ml (0.10 mmol) of
triethylamine were added thereto at -78 C. The mixture was
stirred for 1 hour. To the reaction mixture was added a 0.2
M phosphate buffer of pH7, and the solution was extracted
with chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (20 ml of silica gel,
chloroform:methanol=80:1) to give 17 mg of Compound 47
(yield: 82%).
The physicochemical properties of Compound 47 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 8.63(lH,br), 8.43(lH,br),
7.78(lH,d,J=15.6Hz), 7.29 (lH,dd,J=8.9,2.0Hz),
7.17(lH,d,J=2.0Hz), 6.88(lH,d,J=8.6Hz),
- 70 -

2 1 6 ~
6.75(1H,d,J=15.5Hz), 6.74(1H,br s), 4.56(1H,m),
4.50(1H,dd,J=10.5,1.7Hz), 4.34(lH,dd,J=10.4, 10.4Hz),
3.97(3H,s), 3.95(3H,s), 3.91(3H,s),
3.81(lH,dd,J=6.7, 2.3Hz), 3.25(lH,dd,J=6.7,6.7Hz),
3.21(4H,q,J=6.9Hz), 2.71(3H,s), 1.06(6H,t,J=7.0Hz)
IR(KBr)~(cm~l); 1699, 1653, 1645, 1591, 1506, 1412, 1257
FABMS(m/z); 629, 627(M) +
Example 48 Synthesis of Compound 48
To 20 mg (0.041 mmol) of Compound 46 obtained in
Example 46 were added 2 ml of acetonitrile and 0.1 ml of 48%
hydrobromic acid. The mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added 1
N hydrobromic acid, and the solution was extracted with
chloroform. The chloroform layer was dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The resulting crude product was dissolved in 2 ml
of methylene chloride. Then, 38 mg (0.125 mmol) of bis(p-
nitrophenyl) carbonate and 0.018 ml (0.13 mmol) of
triethylamine were added thereto at O C. The mixture was
stirred for 2 hours. To the reaction mixture was added
0.023 ml (0.17 mmol) of N-methylpiperazine, and the mixture
was stirred at O C for 2 hours. To the reaction mixture was
added a 0.2 M phosphate buffer of pH7, and the solution was
extracted with chloroform. The chloroform layer was washed
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by silica-gel column chromatography (30 ml of silica gel,
chloroform:methanol= 20:1) to give 14 mg of Compound 48
(yield: 50%).
The physicochemical properties of Compound 48 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 8.78(lH,s),
8.25(1H, br s), 7.79(1H,d, J=15.2Hz), 7.2~ (lH, m),
7.17(lH, d, J=2.0Hz), 6.89 (lH, d, J=8.6Hz),
6.76(lH, d, J=15.5Hz), 4.58(lH, m),
- 71 -

2~63~go
4.47(lH, br d, J=10.6Hz),4.31 (lH, m), 3.96(3H, s),
3.91(3H, s), 3.82(1H, m), 3.79(2H, br),3.63(2H, br),
3.21(4H, q, J=6.9Hz), 2.69(3H, s), 2.51(4H, br),
2.37(3H, s), 1.07(6H, t, J=6.9Hz)
IR(KBr)V(cm~l); 1697, 1652, 1591, 1506, 1408, 1292,
1259, 1217, 1093
Ex~mple 49 Synthesis of Compound 49
To 11 mg (0.016 mmol) of Compound 48 obtained in
Example 48 was added 1 ml of ethanol, and 0.004 ml of 6.86 N
hydrogen chloride in ethanol was added thereto. The mixture
was stirred at O C for 1 hour. The react:ion mixture was
concentrated under reduced pressure to give 13 mg of
Compound 49.
The physicochemical properties of Compound 49 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.19(lH,br),
10.88(lH,br), 8.10(2H,br), 7.60 (lH,br d,J=8.6Hz),
7.40(lH,br s), 7.24(lH,br s), 7.00(lH,br), 4.58(3H,m),
3.85(6H,s), 3.81-3.26(6H,m), 3.21(4H,q,J=7.2Hz),
2.88(4H,br), 2.69(3H,s), 2.51(4H,br), 2.37(3H,s),
1.07(6H,t,J=7.0Hz)
IR(KBr)~(cm~l); 1714, 1645, 1435, 1417, 1410, 1255, 1219
FABMS(m/z); 698, 696(M+H) +
Example 50 Synthesis of Compound 50
To 32.2 mg (0.0689 mmol) of Compound 41 obtained in
Example 41 were added 2.94 ml of acetonitrile and 18.2 ~l of
35% hydrochloric acid. The mixture was stirred at room
temperature for 60 minutes, and concentrated under reduced
pressure. The resulting crude product was dissolved in 2.94
ml of methylene chloride. Then, 20.4 ~l ~0.216 mmol) of
acetic anhydride and 27.2 mg (0.223 mmol) of 4-
dimethylaminopyridine were added thereto. The mixture wasstirred for 2 hours. To the reaction mixture was added a
0.01 M phosphate buffer of pH7, and the solution was
extracted with chloroform. The chloroform layer was washed
- 72 -

216~95
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=15:1) to
give 26.3 mg of Compound 50 (yield: 70%).
The physicochemical properties of Compound 50 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.62(lH,brs), 8.29(1H,brs),
7.79(1H,d,J=15.5Hz), 7.23(1H,d,J=9.6Hz), 7.15(1H,s),
6.86(1H,d,J=8.6Hz), 6.78(1H,d,J=15.2Hz),
4.41-4.54(lH,br), 4.50(lH,d,J=9.9Hz),
4.32(1H,dd,J=9.2,8.2Hz), 3.92(6H,s), 3.85--3.90(1H,m),
3.35(1H,dd,J=10.2,10.2Hz), 2.83(6H,s), 2.53(3H,s),
2.32(3H,s)
FABMS(m/z); 542, 540(M+H) +
IR(KBr)~(cm~l); 1697, 1643, 1591, 1510, 1437, 1414,
1242, 1190, 1115, 1090
Fxample 51 Synthesis of Compound 51
To 18.3 mg (0.0339 mmol) of Compound 50 obtained in
Example 50 was added 1.52 ml of anhydrous ethyl acetate, and
then 9.9 ~l of 6.86 N hydrogen chloride in ethanol was added
thereto. The mixture was stirred at room temperature for 2
hours and 50 minutes. The reaction mixture was concentrated
under reduced pressure to give 20.0 mg of Compound 51.
The physicochemical properties of Compound 51 are as
follows.
30 lH-NMR(270MHz,DMSO-d6)~(ppm); 12.09(lH,brs~,
8.07(lH,brs), 8.03(lH,brs), 7.85(lH,d,J=7.9Hz),
7.63(1Hrd,J=15.5Hz), 7.30(lH,d,J=8.6Hz),
7.17(1H,d,J=15.5Hz), 4.38-4.52(3H,m), 3.99(3H,s),
3.91(1Hrbrd,J=9.2Hz), 3.84 (3H,s), 3.56(1H,dd,J=9.9,
35 9.3Hz), 3.12(6H,s), 2.66(3H,s), 2.39(3H,s)
IR(KBr)~(cm~l); 1693, 1651, 1516, 1470, 1435, 1414,
1277, 1203, 1190, 1090
- 73 -

` 21~389~
Example 52 Synthesis of Compound 52
To 28.5 mg (0.0618 mmol) of Compound 41 was added 1.5
ml of acetonitrile, and 300 mg of 5% hydrobromic acid in
methanol was added thereto. The mixture was stirred at room
temperature for 50 minutes. The reaction mixture was
concentrated under reduced pressure. The resulting crude
product was dissolved in 1.48 ml of methylene chloride.
Then, 37.4 mg (0.185 mmol) of p-nitrophenyl chloroformate
and 25.8 ~l (0.185 mmol) of triethylamine were added thereto
at -78C. The mixture was stirred for 40 minutes. To the
reaction mixture was then added 16.4 ~l (0.309 mmol) of 1-
methylhydrazine, and the mixture was stirred at -78 C to O C
for 1.5 hours. To the reaction mixture was added a
saturated aqueous solution of sodium hydragen carbonate, and
the resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude praduct was purified by thin-
layer chromatography (chloroform:methanol=15:1) to give 28.0
mg of Compound 52 (yield: 74%).
The physicochemical properties of Compound 52 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 9.92-10.16(lH,br),
8.24(lH,brs), 7.80(lH,d,J=15.2Hz), 7.24(1H,d,J=8.3Hz),
7.16 (lH,s), 6.87(lH,d,J=8.6Hz), 6.79(lH,d,J=15.2Hz),
4.45-4.54(lH,br), 4.47(lH,d,J=9.6Hz),
4.40(lH,dd,J=10.2,9.2Hz), 3.94(3H,s), 3.93(3H,s),
3.77(lH,dd,J=9.5, 1.9Hz), 3.28(3H,br),
3.20(1H,dd,J=9.9,9.9Hz), 2.84(6H,s), 2.30(3H,s)
FABMS(m/z); 616, 614(M+H) +
IR(KBr)V(cm~l); 1697, 1686, 1647, 1508, 1437, 1414,
1246, 1~19, 1188, 1159, 1111
- 74 -

` 21B3~9~
Example 53 Synthesis of Compound 53
To 18.0 mg (0.0293 mmol) of Compound 52 obtained in
Example 52 was added 2.0 ml of ahnydrous ethyl acetate, and
142 mg of 5% hydrobromic acid in methanol was added thereto.
The mixture was stirred at -20 C for 1 hour. The reaction
mixture was concentrated under reduced pressure to give 20.7
mg of Compound 53.
The physicochemical properties of Compound 53 are as
follows.
1H-NMR(270MHz,DMSO-d6)~(ppm); 12.02(lH,brs),
8.12(lH,brs), 7.97(lH,brs), 7.83 (lH,d,J=8.2Hz),
7.63(1H,d,J=14.8Hz), 7.29(1H,d,J=8.6Hz),
7.17(lH,d,J=15.2Hz), 4.40-4.58(3H,br), 3.99(3H,s),
3.85(3H,s), 3.81(lH,brd,J=lO.OHz), 3.11(6H,s),
2.67(3H,s)
IR(KBr)~(cm~1); 1650, 1645, 1516, 1464, 1435, 1416,
1279, 1219, 1190, 1159, 1107, 1092
Example 54 Synthesis of Compound 54
To 40.0 mg (0.0867 mmol) of Compound 41 were added
2.10 ml of acetonitrile and 421 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 2.10 ml of methylene chloride. Then, 32.0 mg (0.260
mmol) of nicotinic acid and 53.7 mg (0.260 mmol) of
dicyclohexylcarbodiimide were added thereto at -20 C. The
mixture was stirred for 5 minutes. To the reaction mixture
was added 31.8 mg (0.260 mmol) of 4-dimethylaminopyridine,
and the mixture was stirred at -20 C to O C for 3 hours. To
the reaction mixture was added a saturated aqueous solution
of sodium hydrogen carbonate, and the resulting solution was
extracted with chloroform. The chloroform layer was washed
with a saturated aqueous solution of sodium hydrogen
carbonate and with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude

~ 21~90
product was purified by thin-layer chromatography
tchloroform:methanol=25:1) to give 47.4 mg of Compound 54
(yield: 84%).
The physicochemical properties of Compound 54 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 11.79(lH,brs), 9.27(lH,s),
8.67(1H,brs), 8.29(lH,s), 8.17(lH,d,J=7.9Hz),
7.73(lH,d,J=15.2Hz), 7.26(lH,br),
7.23(lH,d,J=8.6Hz), 7.13(lH,s), 6.86(lH,d,J=8.3Hz),
6.73(lH,d,J=15.2Hz), 4.57-4.68(lH,m),
4.46(1H,d,J=9.9Hz), 4.31(1H,dd,J=10.2,9.2Hz),
3.97(3H,s), 3.92(3H,s), 3.85(lH,dd,J=9.9, 2.4Hz),
3.26(1H,dd,J=9.9,9.9Hz), 2.83(6H,s), 2.71(3H,s)
FABMS(m/z); 649, 647(M+H) +
IR(KBr)~(cm~l); 1697, 1647, 1591, 1508, 1437, 1410,
1267, 1246, 1217, 1192, 1093
Example 55 Synthesis of Compound 55
To 47.4 mg (0.0732 mmol) of Compound 54 obtained in
Example 54 was added 2.6 ml of anhydrous ethyl acetate, and
355 mg of 5 % hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under
reduced pressure to give 51.8 mg of Compound 55.
The physicochemical properties of Compound 55 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.16(lH,s), 9.37(lH,s),
30 8.96 (lH,d,J=4.3Hz), 8.57(lH,dt,J=7.9,2.0lIz),
8.23(lH,brs), 8.12(lH,brs), 7.93(lH,d,J=8.3Hz),
7.73(1H,dd,J=7.9,5.0Hz), 7.65(1H,d,J=15.2]Iz),
7.35(lH,d,J=8.9Hz), 7.22(lH, d,J=15.2Hz),
4.47-4.60(3H,br), 4.02(3H,s), 3.86(3H,s),
35 3.84(lH,dd,J=10.6,2.6Hz), 3.51(1H,dd,J=9.6,8.6Hz),
3.18(6H,s), 2.64(3H,s)
IR(KBr)~(cm~l); 1686, 1647, 1516, 1466, 1458, 1437,
1414, 1279, 1219, 1097
- 76 -

` 21~3890
Example 56 Synthesis of Compound 56
To 30.0 mg (0.065 mmol) of Compound 41 were added 1.58
ml of acetonitrile and 316 mg of 5 % hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.58 ml of methylene chloride. Then, 32.2 mg (0.195
mmol) of 4-dimethylaminobenzoic acid and 40.2 mg (0.195
mmol) of dicyclohexylcarbodiimide were added thereto at
-20 C. The mixture was stirred for 5 minutes. To the
mixture was added 23.8 mg (0.195 mmol) of 4-
dimethylaminopyridine, and the mixture was stirred at -20 C
to room temperature for 5 hours. To the reaction mixture
- was added a saturated aqueous solution of sodium hydrogen
carbonate, and the resulting solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=40:1) to
give 57.8 mg of the crude product. Subsequently, the crude
product was purified by preparative high-performance liquid
chromatography (acetonitrile:water=90:10) to give 27.2 mg of
Compound 56 (yield: 61%).
The physicochemical properties of Compound 56 are as
follows.
1H-NMR(270MHz,CDCl3)tS(ppm); 9.50(lH,brs), 8.27(lH,brs),
7.90(2H,d,J=9.2Hz), 7.73(lH,d,J=15.2Hz),
7.23(lH,d,J=8.6Hz), 7.15(lH,s), 6.86(lH,d,J=8.6Hz),
6.74(lH,d,J=15.2Hz), 6.50(2H,d,J=8.9Hz), 4.48-4.58(lH,m),
4.44(lH,d,J=10.2Hz), 4.27(1H,dd,J=10.6,8.4Hz),
3.94(3H,s), 3.92(3H,s), 3.81(lH,dd,J=9.6,2.3Hz),
3.20(1H,dd,J=10.2,9.9Hz), 3.00(6H,s), 2.83(6H,s),
2.48(3H,s)
FABMS(m/z); 691, 689(M+H) +
IR(KBr)~(cm-1); 1697, 1686, 1647, 1606, 1508, 1437,

` ~163~0
1412, 1269, 1182, 1090
Example 57 Synthesis of Compound 57
To 30.0 mg (0.065 mmol) of Compound 41 were added 1.58
ml of acetonitrile and 316 mg of 5 % hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.58 ml of methylene chloride. Then, 27.1 mg (0.195
mmol) of 3-aminopyrazine-2-carboxylic acid and 40.2 mg
(0.195 mmol) of dicyclohexylcarbodiimide were added thereto
at -20 C. The mixture was stirred for 5 minutes. To the
reaction mixture was added 23.8 mg (0.195 mmol) of 4-
dimethylaminopyridine, and the mixture was stirred at -20 C
to room temperature for 4.5 hours. To the reaction mixture
was added a saturated aqueous solution of sodium hydrogen
carbonate, and the resulting solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=25:1) to
give 36.2 mg of Compound 57 tyield: 84%).
The physicochemical properties of Compound 57 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 11.47(lH,s), 8.32(lH,brs),
8.18(lH,d,J=2.3Hz), 7.79(lH,d,J=2.3Hz),
7.75(1H,d,J=16.8Hz), 7.21 (lH,dd,J=7.3,1.7Hz),
7.14(lH,d,J=2.0Hz), 6.86(lH,d,J=8.3Hz),
6.73(1H,d,J=15.2Hz), 6.10-6.70(2H,br), 4.48-4.59(1H,m),
4.45(lH,d,J=10.9Hz), 4.29(lH,dd,J=9.6,9.211z),
3.92(3H,s), 3.89(3H,s), 3.79(1H,dd,J=9.6,2.0Hz),
3.22(lH,dd,J=10.2,10.2Hz), 2.83(6H,s), 2.59(3H,s)
FABMS(m/z); 665, 663(M+H) +
IR(KBr)~(cm-1); 1647, 1637, 1595, 1508, 1437, 1410,
1298, 1246, 1221, 1192, 1092
- 78 -

~ 216389~
Example 58 Synthesis of Compound 58
To 23.8 mg (0.0359 mmol) of Compound 57 obtained in
Example 57 was added 1.65 ml of anhydrous ethyl acetate, and
the 177 mg of 5 % hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under
reduced pressure to give 26.4 mg of Compound 58.
The physicochemical properties of Compound 58 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.13(lH,s),
8.41(1H,d,J=2.3Hz), 8.14(2H,brs), 8.07 (lH,d,J=2.0Hz),
7.94 (lH,d,J=8.6Hz), 7.66(lH,d,J=15.2Hz), 7.43(3H,br),
7.35(lH,d,J=15.2Hz), 7.21(lH,d,J=15.2Hz),
4.13-4.41(3H,m), 4.02(3H,s), 3.86(3H,s),
3.84(lH,brd,J=11.2Hz), 3.18 (6H,s), 2.62(3H,s)
IR(KBr)U(cm~1); 1689, 1645, 1601, 1516, 1437, 1414,
1279, 1219, ll90, 1095
Example 59 Synthesis of Compound 59
To 40.0 mg (0.0867 mmol) of Compound 41 were added
2.11 ml of acetonitrile and 421 mg of 5 % hydrobromic acid
in methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 2.11 ml of methylene chloride. Then, 52.0 mg (0.258
mmol) of p-nitrophenyl chloroformate and 36.0 ~l (0.258
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred for 30 minutes. To the reaction mixture
was added 51.8 ~l (0.430 mmol) of 1-amino-4-
methylpiperazine, and the mixture was stirred at O C to room
temperature for 7.5 hours. To the reaction mixture was
added a saturated aqueous solution of sod:ium hydrogen
carbonate, and the resulting solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
- 79 -

216~9~
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=5:1) to
give 27.7 mg of Compound 59 (yield: 47%).
The physicochemical properties of Compound 59 are as
follows.
lH-NMR(270MHz,CDC13)~(ppm); 10.08(lH,brs), 8.24(lH,s),
7.77(lH,d,J=15.2Hz), 7.25 (lH,dd,J=8.7,1.7Hz),
7.15 (lH,d,J-1.7Hz), 6.86(lH,d,J=8.6Hz),
10 6.75(1H,d,J=15.2Hz), 4.45-4.55(1H,m),
4.42 (lH,d,J=11.2Hz),4.26(lH,dd,J=10.2,8.9Hz),
3.92(3H,s), 3.89(3H,s), 3.74 (lH,dd,J=8.9~1.9Hz),
3.17(lH,dd,J=9.9,9.9Hz), 2.96(4H,br), 2.83(6H,s),
2.56(3H,s), 2.49(4H,br), 2.23(3H,s)
15 FABMS(m/z); 685, 683(M+H) +
IR(KBr)~(cm~l); 1697, 1645, 1591, 1508, 1446, 1414,
1246, 1215, 1190, 1088
Example 60 Synthesis of Compound 60
To 27.7 mg (0.0405 mmol) of Compound 59 obtained in
Example 59 was added 1.82 ml of anhydrous ethyl acetate, and
then 262 mg of 5 % hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 60
minutes. The reaction mixture was concent:rated under
25 reduced pressure to give 31.3 mg of Compound 60.
The physicochemical properties of Compound 60 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.09(lH,s), 9.53(lH,br),
30 9.48(lH,s), 8.03(2H,brs), 7.85(lH,d,J=7.9Hz),
7.63(lH,d,J=15.2Hz), 7.31 (lH,d,J=8.3Hz),
7.18(lH~d,J=15.2Hz), 4.39-4.58(3H,m), 4.00(3H,s),
3.85(3H,s), 3.80(1H,dd,J=9.4,2.8Hz), 3.45~4H,br),
3.14(6H,s), 3.08-3.25(5H,br), 2.82(3H,d,J-4.3Hz),
35 2.66(3H~s)
IR(KBr)~(cm~l); 1743, 1689, 1649, 1516, 1464, 1435,
1416, 1279, 1219, 1190, 1094
- 80 -

~ 2 1 ~
Example 61 Synthesis of Compound 61
To 30.0 mg (0.065 mmol) of Compound 41 were added 1.58
ml of acetonitrile and 316 mg of 5 % hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.58 ml of methylene chloride. Then, 39.3 mg (0.195
mmol) of p-nitrophenyl chloroformate and 27.2 ~l (0.195
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred for 40 minutes. To the reaction mixture
was then added 24.7 ~l (0.325 mmol) of 1,1-
dimethylhydrazine, and the mixture was stirred at -20 C to
room temperature for 3 hours and 40 minutes. To the
reaction mixture was added a saturated aqueous solution of
sodium hydrogen carbonate, and the resulting solution was
extracted with chloroform. The chloroform layer was washed
with a saturated aqueous solution of sodium hydrogen
carbonate and with a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by thin-layer chroma~ography
(chloroform:methanol=20:1) to give 21.9 mg of Compound 61
(yield: 54%).
The physicochemical properties of Compound 61 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.78(lH,brs), 8.23(lH,brs),
7.80(lH,d,J=15.2Hz), 7.25(lH,dd,J=6.3, 2.0Hz),
7.16(lH,d,J=2.0Hz), 7.13 (lH,br), 6.87(lH,d,J=8.6Hz),
6.77(lH,d,J=15.2Hz), 4.42-4.52(lH,m),
4.41(lH,d,J=9.6Hz), 4.26(lH,dd,J=9.9, 8.9Hz),
3.93(3H,s), 3.87(3H,s), 3.72(1H,brd,J=6.6Hz),
3.16(lH,dd,J=9.2,8.lHz), 2.84(6H,s), 2.64(6H,s),
2.48(3H,s)
FABMS(m/z); 630, 628(M+H) +
IR(KBr)~(cm-l); 1734, 1697, 1645, 1591, 1508, 1458,
1437, 1414, 1246, 1217, 1190, 1098
- 81 -

~ 2 1 ~
Example 62 Synthesis of Compound 62
To lS.8 mg (0.0251 mmols) of Compound 61 obtained in
Example 61 was added 1.13 ml of anhydrous ethyl acetate, and
then 122 mg of 5% hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under
reduced pressure to give 18.2 mg of Compound 62.
The physicochemical properties of Compound 62 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.08(lH,s),
9.17 (lH,brs), 8.02 (2H,brs), 7.87(1H,d,J=8.9Hz),
7.64(lH,d,J=15.2Hz), 7.32(lH,d,J=8.9Hz),
7.18(lH,d,J=15.5Hz), 4.39-4.58(3H,m), 4.01(3H,s),
3.84 (3H,s), 3.80(lH,dd,J=9.9,2.6Hz), 3.15(6H,s),
2.65(6H,s), 2.61(3H,s)
IR(KBr)~(cm~1); 1749, 1695, 1684, 1647, 1516, 1471,
1437, 1414, 1277, 1219, 1095
Example 63 Synthesis of Compound 63
To 30.0 mg (0.065 mmol) of Compound 41 were added 1.58
ml of acetonitrile and 316 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.40 ml of methylene chloride. Then, 39.3 mg (0.195
mmol) of p-nitrophenyl chloroformate and 27.2 ~l (0.195
mmol) of triethylamine were added thereto at -78 C. The
mixture was stirred for 40 minutes. To the mixture were
added 43.2 mg (0.325 mmol) of 1,2-dimethylhydrazine
dihydrochloride and 90.6 ~l (0.65 mmol) of triethylamine
dissolved in 0.2 ml of chloroform, and the mixture was
stirred at -20 C for 2 hours and 50 minutes. To the
reaction mixture was added a saturated aqueous solution of
sodium hydrogen carbonate, and the resulting solution was
extracted with chloroform. The chloroform layer was washed
with a saturated aqueous solution of sodium hydrogen
carbonate and with a saturated aqueous solution of sodium
- 82 -

- ~ 2163~0
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The obtained crude
product was purified by thin-layer chromatography
(chloroform:methanol=30:1) to give 35.0 mg of Compound 63
(yield: 86%).
The physicochemical properties of Compound 63 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.87(lH,brs), 9.63(lH,brs),
8.22(lH,s), 7.79(lH,d,J=15.5Hz),
7.26(1H,dd,J=8.3, 2.0Hz), 7.17 (lH,d,J=1.7Hz),
6.88(lH,d,J=8.6Hz), 6.78(lH,d,J=15.2Hz), 4.42-
4.55(lH,br), 4.47(lH,d,J=10.2Hz),
4.34(lH,dd,J=9.2,9.2Hz), 3.94(3H,s), 3.93(3H,s),
3.77(lH,dd,J=9.6,2.0Hz), 3.26(3H,brs),
3.19(lH,dd,J=10.2,9.9Hz), 2.85(6H,s), 2.69(3H,s),
2.36(3H,brs)
FABMS(m/z); 630, 628(M+H) +
IR(KBr)~(cm~l); 1697, 1647, 1591, 1508, 1458, 1435,
20 1414, 1246, 1219, 1190, 1157, 1109
Example 64 Synthesis of Compound 64
To 25.8 mg (0.0410 mmol) of Compound 63 obtained in
Example 63 was added 1.85 ml of anhydrous ethyl acetate, and
then 199 mg of 5% hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under
reduced pressure to give 28.2 mg of Compound 64.
The physicochemical properties of Compound 64 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.04(lH,s), 8.12(2H,brs),
7.92(lH,d,J=8.6Hz), 7.64(lH,d,J=15.2Hz),
7.35(lH,d,J=8.6Hz), 7.20 (lH,d,J=15.5Hz), 4.39-
4.60(3H,m), 4.02(3H,s), 3.85(3H,s),
3.81(lH,brd,J=10.7Hz), 3.19(6H,s), 2.67(3E~,s),
2.50(3H,s)
IR(KBr)~(cm~l); 1695, 1651, 1645, 1516, 1471, 1441, 1435,
- 83 -

2~63~0
1416, 1279, 1219, 1107
Example 65 Synthesis of Compound 65
To 25.0 mg (0.0542 mmol) of Compound 41 were added
1.32 ml of acetonitrile and 351 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 30 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.32 ml of methylene chloride. Then, 38.1 mg (0.163
mmol) of 4-(4-methylpiperazinylmethyl)benzoic acid and 31.2
mg (0.163 mmol) of N-ethyl-N'-3-dimethylaminopropyl
carbodiimide hydrochloride were added thereto at -20 C. The
mixture was stirred for 5 minutes. To the mixture was then
added 19.9 mg (0.163 mmol) of 4-dimethylaminopyridine, and
the mixture was stirred at -20 C to room temperature for 6
hours. To the reaction mixture was added a saturated
aqueous solution of sodium hydrogen carbonate, and the
resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol=10:1) to give 25.0
mg of Compound 65 (yield: 61%).
The physicochemical properties of Compound 65 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.27(lH,brs), 8.32(lH,brs),
8.07(2H,d,J=8.3Hz), 7.73 (lH,d,J=15.2Hz),
7.38(2H,d,J=8.2Hz), 7.22(lH,dd,J=8.2,2.OHz),
7.13(lH,d,J=2.0Hz), 6.86(lH,d,J=8.6Hz),
6.73(lH,d,J=15.2Hz), 4.48-4.60(lH,m),
4.45(lH,d,J=10.6Hz), 4.29(1H,dd,J=9.5,8.9r~z),
3.95(3H,s), 3.92(3H,s), 3.80(lH,dd,J=9.6,2.3Hz),
3.53(2H,s), 3.21(1H,dd,J=10.2,9.9Hz), 2.83(6H,s),
2.60(3H,s), 2.48(8H,br), 2.30(3H,s)
FABMS(m/z); 760, 758(M+H) +
- 84 -

6~9~
IR(KBr)~(cm~1); 1740, 1697, 1647, 1508, 1446, 1412, 1248,
1217, 1192, 1140, 1090
~xample 66 Synthesis of Compound 66
To 18.0 mg (0.0237 mmol) of Compound 65 obtained in
Example 65 was added 1 ml of anhydrous ethyl acetate, and
then 153 mg of 5% hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under
reduced pressure to give 22.9 mg of Compound 66.
The physicochemical properties of Compound 66 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.14(1H,s), 9.51(1H,br),
8.21(2H,d,J=8.3Hz), 8.19 (lH,d,J=15.2Hz),
7.75-7.89 (2H,br), 7.63 (2H,d,J=8.9Hz),
7.60 (lH,d,J=5.9Hz), 7.24 (lH,d,J=8.6Hz),
7.16(lH,d,J=15.5Hz), 4.45-4.58(3H,br), 3.97(3H,s),
3.86(3H,s), 3.83 (lH,brd,J=9.7Hz), 3.06(8H,br),
2.81(3H,s), 2.63(3H,s)
IR(KBr)U(cm-1); 1734, 1695, 1647, 1616, 1516, 1437,
1412, 1263, 1217, 1092, 1018
Fxample 67 Synthesis of Compound 67
To 10.0 mg (0.0238 mmol) of Compound 6 were added 0.4
ml of acetonitrile and 5.6 ~l of 48% hydrobromic acid, and
the mixture was stirred at room temperature for 50 minutes.
The reaction mixture was concentrated under reduced
pressure. The resulting crude product was dissolved in 0.26
ml of methylene chloride. Then, 6.1 mg (0.0495 mmol) of
nicotinic acid and 0.10 ml of methylene chloride containing
20.4 mg (0.099 mmol) of dicyclohexylcarbodiimide were added
thereto at -20 C. The mixture was stirred for 5 minutes.
To the reaction mixture was then added 6.1 mg (0.0495 mmol)
of 4-dimethylaminopyridine, and the mixture was stirred at
-20 C to room temperature for 18 hours. 'rO the reaction
mixture was added a saturated aqueous solution of sodium
hydrogen carbonate, and the resulting solution was extracted
- 85 -

~ 21~389Q
with chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=25:1) to
give 10.9 mg of Compound 67 (yield: 76%).
The physicochemical properties of Compound 67 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 11.44(lH,brs), 9.32(lH,s),
8.73(1H,d,J=4.9Hz), 8.71(2H,s), 8.31(1H,s),
8.23(lH,d,J=8.3Hz), 7.64(lH,d,J=15.5Hz),
7.35(lH,dd,J=7.9,4.9Hz), 6.90(lH,d,J=15.5Hz),
4.59-4.69(lH,m),4.46(lH,d,J=10.6Hz),
4.34(lH,dd,J=10.6,8.9Hz), 4.06(3H,s), 3.97(3H,s),
3.86(lH,dd,J=9.5,2.6Hz), 3.31(lH,dd,J=10.2,9.9Hz),
2.71(3H,s)
FABMS(m/z); 608, 606(M+H) +
IR(KBr)~(cm~1); 1697, 1653, 1593, 1475, 1435, 1412,
1335, 1271, 1219, 1093
~xample 68 Synthesis of Compound 68
To 40.0 mg (0.0951 mmol) of Compound 6 were added 2.32
ml of acetonitrile and 41.6 ~l of 6.86 N hydrogen chloride
in ethanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 2.32 ml of methylene chloride. Then, 57.5 mg (0.285
mmol) of p-nitrophenyl chloroformate and 53 ~l (0.380 mmol)
of triethylamine were added thereto at -78 C. The mixture
was stirred for 50 minutes. To the reaction mixture was
then added 57.2 ~l (0.476 mmol) of 1-amino-4-
methylpiperazine, and the mixture was stirred at -78 C to
O C for 24 hours. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
- 86 -

2163~90
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol=6:1) to give 19.5mg of Compound 68 (yield: 34~).
The physicochemical properties of Compound 68 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.67(1H,brs), 8.73(2H,s),
8.20(lH,brs), 7.66(lH,d,J=15.2Hz), 7.12(lH,br),
6.90(lH,d,J=15.5Hz), 4.40-4.47(lH,br),
4.39(1H,d,J=10.2Hz), 4.21(1H,dd,J=9.4,8.9Hz),
4.06(3H,s), 3.88(3H,s), 3.85(lH,br),
3.35(1H,dd,J=10.9,9.4Hz), 2.95(4H,br), 2.51(7H,br),
2.26(3H,s)
FABMS(m/z); 600, 598(M+H) +
IR(KBr)~(cm~l); 1743, 1697, 1653, 1593, 1475, 1437,
1412, 1338, 1215, 1090
Example 69 Synthesis of Compound 69
To 16.2 mg (0.0271 mmol) of Compound 68 obtained in
Example 68 was added 1.22 ml of anhydrous ethyl acetate, and
then 7.9 ~l of 6.86 N hydrogen chloride in ethanol was added
thereto. The mixture was stirred at -20 C for 20 minutes.
The reaction mixture was concentrated under reduced pressure
to give 15.5 mg of Compound 69.
The physicochemical properties of Compound 69 are as
follows.
H-NMR(27OMHz,DMSO-d6)~(ppm); 12.15 (lH,brs),
10.21-10.28 (lH,br),9.51(lH,s), 9.09(2H,s), 8.04(lH,s),
7.60(lH,d,J=15.5Hz), 7.38(lH,d,J=15.2Hz),
4.52(lH,d,J=10.9Hz), 4.31-4.49(2H,m), 3.97(3H,s),
3.85(lH,brd,J=10.9Hz), 3.83(3H,s),
3.53(lH,dd,J=10.4,9.9Hz), 3.05-3.29(8H,m),
2.78(3H,brd,J=3.3Hz), 2.66(3H,s)
IR(KBr)~(cm~l); 1691, 1686, 1653, 1649, 1595, 1475,
- 87 -

2.~638~
t
1458, 1437, 1414, 1215, 1190
~xample 7Q Synthesis of Compound 70
To 80 mg (0.190 mmol) of Compound 6 were added 4.0 ml
of acetonitrile and 922 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in a mixed solvent of 3.0 ml of methylene chloride and 1.13
ml of toluene. Then, 115 ml (0.570 mmol) of p-nitrophenyl
chloroformate and 106 ~l (0.760 mmol) of triethylamine were
added thereto at -78 C. The mixture was stirred for 100
minutes. To the reaction mixture was then added 114 ~l
(0.95 mmol) of 1-amino-4-methylpiperazine, and the mixture
was stirred at -20 C to room temperature for 17 hours and 40
minutes. To the reaction mixture was added a saturated
aqueous solution of sodium hydrogen carbonate, and the
resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform: methanol:triethylamine-
9:1:0.2) to give 45 mg of a crude product. The crudeproduct was then purified by column chromatography
(chloroform:methanol:triethylamine=150:15:1) to give 33.9 mg
of Compound 70 (yield: 28%).
The physicochemical properties of Compound 70 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 9.37(lH,brs), 8.74(2H,s),
8.23(lH,brs), 7.69(lH,d,J=15.5Hz), 6.91(lH,d,J=15.5Hz),
6.70(1H,br), 4.50-4.60(1H,m), 4.41(1H,d,J=10.6Hz),
4.27(lH,dd,J=9.6,9.2Hz), 4.07(3H,s), 3.93(3H,s),
3.78(lH,dd,J=9.9, 2.3Hz), 3.22(lH,dd,J=9.9,9.2Hz),
2.97(4H,br), 2.61(3H,s), 2.58(4H,br), 2.30(3H,s)
FABMS(m/z); 644, 642(M+H) +
- 88 -

~ 21638~
IR(KBr)~(cm-l); 1703, 1695, 1651, 1593, 1473, 1456, 1435,
1412, 1338, 1271, 1215, 1190, 1090
Fxample 71 Synthesis of Compound 71
To 14.0 mg (0.0218 mmol) of Compound 70 obtained in
Example 70 was added 0.98 ml of anhydrous ethyl acetate, and
then 6.4 ~l of 6.86 N hydrogen chloride in ethanol was added
thereto. The mixture was stirred at -20 C for 20 minutes.
To the reaction mixture was added diethyl ether, and the
mixture was concentrated under reduced pressure to give 14.4
mg of Compound 71.
The physicochemical properties of Compound 71 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.13(lH,brs),
10.04(lH,br), 9.50(lH,s), 9.09(2H,s), 8.04(lH,s),
7.60(lH,d,J=15.2Hz), 7.37(lH,d,J=15.5Hz),
4.37-4.57(2H,m), 4.47(lH,d,J=10.2Hz), 3.97(3H,s),
3.85(3H,s), 3.80(lH,brd,J=10.8Hz),
3.43(lH,dd,J=9.2,8.6Hz), 3.00-3.30(8H,m), 2.80(3H,s),
2.66(3H,s)
IR(KBr)~(cm~l); 1736, 1697, 1653, 1595, 1473, 1458, 1411,
1340, 1219, 1092
~xample 72 Synthesis of Compound 72
To 33.9 mg (0.0528 mmol) of Compound 70 obtained in
Example 70 was added 2.0 ml of anhydrous ethyl acetate, and
then 171 mg of 5% hydrobromic acid in methanol was added
thereto. The mixture was stirred at -20 C for 20 minutes.
To the reaction mixture was added diethyl ether, and the
mixture was concentrated under reduced pressure to give 36.8
mg of Compound 72.
The physicochemical properties of Compound 72 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 12.09(lH,brs),
9.58(lH,brs), 9.48(lH,brs), 9.08(2H,s), 8.04(lH,s),
7.60(lH,d,J=15.8Hz), 7.37(lH,d,J=15.5Hz),
- 89 -

2163~9~
4.37-4.57(2H,m), 4.47 (lH,d,J=10.2Hz), 3.97(3H,s),
3.85(3H,s), 3.79(lH,brd,J=9.6Hz), 3.00-3.30(7H,br),
2.80(3H,s), 2.66(3H,s)
IR(KBr)~(cm-l); 1747, 1697, 1653, 1595, 1475, 1437,
1414, 1340, 1219, 1093
Fxample 73 Synthesis of Compound 73
To 29.6 mg (0.0704 mmol) of Compound 6 were added 1.27
ml of acetonitrile and 342 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 45 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.7 ml of methylene chloride. Then, 28.8 ml (0.218 mmol)
of thiodiglycolic anhydride and 27.5 mg (0.225 mmol) of 4-
dimethylaminopyridine were added thereto at O C. Themixture was stirred at O C for 3 hours. 'ro the reaction
mixture was added a 0.01 M phosphate buffer of pH7, and the
resulting solution was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The
obtained crude product was purified by thin-layer
chromatography (chloroform:methanol:acetic acid=8:1:0.1) to
give 23.6 mg of Compound 73 (yield: 53%).
The physicochemical properties of Compound 73 are as
follows.
1H-NMR(270MHz,CDCl3+CD3OD)~(ppm); 8.49(2H,s),
8.06(1H,s), 7.24(lH,d,J=13.2Hz), 6.64(lH,d,J=15.5Hz),
4.37-4.47(lH,m), 4.23(lH,d,J=10.4Hz),
4.17(lH,dd,J=10.9,8.3Hz), 3.98(3H,s), 3.85(3H,s),
3.69(lH,dd,J=9.6,2.3Hz), 3.64(2H,s), 3.34(2H,s),
3.24(lH,dd,J=10.2,8.9Hz), 2.47(3H,s)
FABMS(m/z); 635, 633(M+H) +
IR(KBr)~(cm~l); 1697, 1657, 1597, 1477, 1435, 1414, 1338,
1273, 1219, 1109
- 90 -

~ 21S3~
.
Example 74 Synthesis of Compound 74
To 25.2 mg (0.0599 mmol) of Compound 6 were added 1.45
ml of acetonitrile and 291 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 50 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in a mixed solvent of 1.0 ml of methylene chloride and 0.45
ml of toluene. Then, 36.2 ml (0.180 mmol) of p-nitrophenyl
chloroformate and 25 ~l (0.180 mmol) of triethylamine were
added thereto at -78 C. The mixture was stirred for 35
minutes. To the mixture was then added 15.9 ~l (0.3 mmol)
of 1-methylhydrazone, and the mixture was stirred at -78 C
to O C for 2 hours. To the reaction mixture was added a
saturated aqueous solution of sodium hydrogen carbonate, and
the resulting mixture was extracted with chloroform. The
chloroform layer was washed with a satura-ted aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol= 9:1) to give 22.5
mg of Compound 74 (yield: 66%).
The physicochemical properties of Compound 74 are as
follows.
lH-NMR(270MHz,CDC13+CD30D)~(ppm); 8.62(2H,s),
8.11(lH,s), 7.45(lH,d,J=15.5Hz), 6.82(lH,d,J=15.5Hz),
4.39-4.51(lH,m), 4.34(lH,d,J=10.2Hz),
4.21(lH,dd,J=9.9, 9.2Hz), 4.01(3H,s), 3.89(3H,s),
3.74(lH,dd,J=9.7,2.5Hz), 3.24(lH,dd,J=10.2,9.9Hz),
3.11(3H,s), 2.54(3H,s)
FABMS(m/z); 575, 573(M+H) +
IR(KBr)~(cm~1); 1697, 1653, 1593, 1475, 1433, 1412,
1338, 1271, 1219, 1161, 1111, 1090
Example 75 Synthesis of Compound 75
To 30.0 mg (0.0714 mmol) of Compound 6 were added 1.73
ml of acetonitrile and 347 mg of 5% hydrobromic acid in
-- 91 -

` 21~33~G
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in a mixed solvent of 1.3 ml of methylene chloride and 0.43
ml of toluene. Then, 50.2 ml (0.214 mmol) of 4-(4-
methylpiperazinylmethyl) benzoate and 44.2 mg (0.214 mmol)
of dicyclohexylcarbodiimide were added thereto at -20 C.
The mixture was stirred for 5 minutes. To the mixture was
then added 26.2 ml (0.214 mmol) of 4-dimethylaminopyridine,
10 and the mixture was stirred at from -20 C to room
temperature for 21 hours. To the reaction mixture was added
a saturated aqueous solution of sodium hydrogen carbonate,
and the resulting mixture was extracted with chloroform.
The chloroform layer was washed with a saturated aqueous
15 solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced
pressure. The obtained crude product was purified by thin-
layer chromatography (chloroform:methanol=6:1) to give 25.7
20 mg of Compound 75 (yield: 50%).
The physicochemical properties of Compound 75 are as
follows.
lH-NMR(270MHz,CDCl3)~(ppm); 9.33(lH,brs), 8.68(2H,s),
8.30(lH,brs), 8.07(2H,d,J=8.3Hz), 7.61(lH,d,J=15.5Hz),
7.40(2H,d,J=8.3Hz), 6.88(lH,d,J=15.2Hz),
4.48-4.61(1H,m), 4.42(1H,d,J=9.9Hz),
4.27(lH,dd,J=9.6,8.9Hz), 4.04(3H,s), 3.95(3H,s),
3.81(lH,dd,J=9.6,2.6Hz), 3.54(2H,s),
3.25(lH,dd,J=10.2,9.6Hz), 2.60(3H,s), 2.43(8H,br),
2.30(3H,s)
FABMS(m/z); 719, 717(M+H) +
IR(KBr)U(cm~1); 1738, 1697, 1657, 1593, 1475, 1435, 1412,
1336, 1265, 1217, 1090
Example 76 Synthesis of Compound 76 r
To 24.2 mg (0.0337 mmol) of Compound 75 obtained in
Example 75 was added 2.46 ml of anhydrous ethyl acetate, and
- 92 -

~'~6~8~0
then 136 mg of 5% hydrobromic acid in methanol was added
thereto. The mixture was stirred at room temperature for 15
minutes. To the reaction mixture was added diethyl ether,
and the mixture was concentrated under reduced pressure to
give 26.6 mg of Compound 76.
The physicochemical properties of Compound 76 are as
follows.
1H-NMR(270MHz,DMSO-d6)~(ppm);12.15(1H,brs), 9.49(1H,br),
9.08(2H,s), 8.22 (2H,d,J=8.3Hz), 8.16(lH,s),
7.63(2H,d,J=8.3Hz), 7.60 (lH,d,J=15.2Hz),
7.37(lH,d,J=15.8Hz), 4.41-4.50(3H,m), 3.97(3H,s),
3.86(3H,s), 3.82(lH,brd,J=9.4Hz), 2.95-3.20(3H,br),
2.82(3H,s), 2.63(3H,s)
IR(KBr)~(cm-1); 1736, 1697, 1653, 1593, 1475, 1435, 1412,
1338, 1265, 1219, 1092
Fxample 77 Synthesls of Compound 77
To 32.8 mg (0.0760 mmol) of Compound 27 were added
1.28 ml of acetonitrile and 25.8 ~l of 48% hydrobromic acid,
and the mixture was stirred at room temperature for 40
minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.15 ml of methylene chloride. Then, 28.1 mg (0.228
mmol) of nicotinic acid and 94.1 mg (0.456 mmol) of
dicyclohexylcarbodiimide were added thereto at -20 C. The
mixture was stirred for 5 minutes. Subsequently, to the
mixture was added 27.9 mg (0.228 mmol) of 4-
dimethylaminopyridine, and the mixture was stirred at -20 C
to room temperature for 15 hours. To the reaction mixture
was added a saturated aqueous solution of sodium hydrogen
carbonate, and the resulting solution was extracted with
chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=20:1) to
- 93 -

21~38!~0
give 28.5 mg of a crude product. The crude product was
purified by preparative high-performance liquid
chromatography [acetonitrile:0.05-M phosphate buffer (pH
5.9)=70:30] to give 22.1 mg of Compound 77 (yield: 47%).
The physicochemical properties of Compound 77 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 11.54(lH,brs),
9.29(lH,d,J=1.7Hz), 8.68(lH,dd,J=5.0,1.7Hz),
8.31(lH,brs), 8.20(lH,dt,J=7.9,2.OHz),
7.74(lH,d,J=15.2Hz), 7.49(2H,d,J=8.9Hz),
7.28(lH,dd,J=7.9,5.0Hz), 6.69(2H,d,J=8.6Hz),
6.68(lH,d,J=15.5Hz), 4.56-4.66(lH,m),
4.46(1H,d,J=10.6Hz), 4.29(1H,dd,J=9.6,8.9Hz),
3.98(3H,s), 3.85(lH,dd,J=9.6,2.3Hz),
3.26(lH,dd,J=10.2,9.9Hz), 3.03(6H,s), 2.72(3H,s)
FABMS(m/z); 619, 617(M+H) +
IR(KBr)V(cm~l); 1699, 1645, 1589, 1524, 1935, 1408,
1352, 1267, 1217, 1184, 1093
Example 78 Synthesis of Compound 78
To 42.4 mg (0.0983 mmol) of Compound 27 were added
2.39 ml of acetonitrile and 33.4 ~l of 48% hydrobromic acid,
and the mixture was stirred at room temperature for 50
minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in a mixed solvent of 2.09 ml of methylene chloride and 0.82
ml of toluene. Then, 59.4 mg (0.295 mmol) of p-nitrophenyl
chloroformate and 41.1 ~1 (0.295 mmol) of triethylamine were
added thereto at -78 C. The mixture was stirred for 80
minutes. Subsequently, to the mixture was added 38.2 ~l
(0.344 mmol) of N-methylpiperazine, and the mixture was
stirred at -78 C to O C for 40 minutes. To the reaction
mixture was added a saturated aqueous solution of sodium
hydrogen carbonate, and the resulting solution was extracted
with chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, dried
- 94 -

~ 2163~0
over anhydrous sodium sulfate, and then concentrated under
reduced pressure. The obtained crude product was purified
by thin-layer chromatography (chloroform:methanol=20:1) to
give 14.8 mg of a crude product of Compound 78. The crude
product was purified by preparative high-performance liquid
chromatography [acetonitrile:0.05-M phosphate buffer (pH
5.9)=70:30] to give 14.0 mg of Compound 78 (yield: 22%).
The physicochemical properties of Compound 78 are as
follows.
H-NMR(270MHz,CDCl3)~(ppm); 9.25(lH,s), 8.23(lH,brs),
7.79(lH,d,J=15.2Hz), 7.51(2H,d,J=8.6Hz),
6.71(lH,d,J=14.2Hz), 6.70(2H,d,J=9.2Hz), 4.53(lH,m),
4.46(1H,d,J=10.9Hz), 4.30(1H,dd,J=9.6,9.2Hz),
3.95(3H,s), 3.80(lH,dd,J=9.9, 2.3Hz), 3.75(2H,br),
3.62(2H,br), 3.21(1H,dd,J=10.2,10.2Hz), 3.03(6H,s),
2.52(3H,s), 2.49(4H,br), 2.35(3H,s)
FABMS(m/z); 640, 638(M+H) +
IR(KBr)~(cm~l); 1716, 1699, 1591, 1524, 1431, 1406, 1354,
1215, 1093
Fxample 79 Synthesis of Compound 79
To 16.0 mg (0.025 mmol) of Compound 78 obtained in
Example 78 were added 0.76 ml of ethanol and 0.38 ml of
methanol, and then 10.9 ~l of 6.86 N hydrogen chloride in
ethanol was added thereto. The mixture was stirred at room
temperature for 2 hours. The reaction mixture was
concentrated under reduced pressure to gi~e 16.9 mg of
Compound 79.
The physicochemical properties of Compound 79 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.19(lH,s), 11.05tlH,br),
8.09(lH,s), 7.63(2H,d,J=8.6Hz), 7.54(lH,d,J=15.2Hz),
6.91(lH,d,J=15.2Hz), 6.80(2H,d,J=7.9Hz),
4.33-4.55(4H,br), 4.13-4.17(lH,br), 3.78(3H,s),
3.25-3.62(5H,m), 3.00(6H,s), 2.83(3H,brd,J=3.6Hz),
2.68(3H,s)
- 95 -

~ 21~i3890
IR(KBr)~(cm~l); 1716, 1699, 1647, 1589, 1'iO8, 1437,
1217, 1093
Example 80 Synthesis of Compound 80
To 24.7 mg (0.0535 mmol) of Compound 41 were added
1.35 ml of ethyl acetate and 39.0 ~1 of 6.86 N hydrogen
chloride in ethanol. The mixture was stirred at room
temperature for 50 minutes. The reaction mixture was
concentrated under reduced pressure to give 26.1 mg of
Compound 80.
The physicochemical properties of Compound 80 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 11.92(lH,s),
10.13(lH,brs), 8.07(lH,brs), 7.91(lH,s),
7.86(lH,d,J=8.3Hz), 7.62(lH,d,J=15.5Hz),
7.30(lH,d,J=8.6Hz), 7.18(lH,d,J=15.5Hz),
4.28-4.47(3H,br), 3.99(3H,s), 3.86(1H,brd,J=10.6Hz),
3.80(3H,s), 3.13(6H,s), 2.60(3H,s)
IR(KBr)~(cm~l); 1693, 1651, 1591, 1516, 1462, 1435, 1416,
1352, 1277, 1213, 1093
~xample 81 Synthesis of Compound 81
To 25.5 mg (0.0553 mmol) of Compound 41 was added 1.39
ml of ethyl acetate, and then 447 mg of 5% hydrobromic acid
in methanol were added thereto. The mixture was stirred at
room temperature for 40 minutes. The reaction mixture was
concentrated under reduced pressure to give 32.6 mg of
Compound 81.
The physicochemical properties of Compound 81 are as
follows.
H-NMR(270MHz,DMSO-d6)~(ppm); 11.88(lH,s), 10.12(lH,brs),
8.10(lH,s), 7.88-7.90(2H,m), 7.64(lH,d,J=15.2Hz),
7.34(lH,d,J=8.9Hz), 7.18(lH,d,J=15.5Hz),
4.32-4.46(3H,br), 4.02(3H,s), 3.81(3H,s),
3.76(1H,brd,J=7.6Hz), 3.33(1H,dd,J=9.2,8.3Hz),
3.18(6H,s), 2.60(3H,s)
- 96 -

21~38~
IR(KBr)~(cm~1); 1684, 1635, 1516, 1458, 1437, 1417,
1358, 1277, 1217, 1092
Fxample 82 Synthesis of Compound 82
To 30.0 mg (0.0650 mmol) of Compound 41 were added
1.58 ml of acetonitrile and 316 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.58 ml of methylene chloride. Then, 45.1 ml (0.195
mmol) of 2-(4-methylpiperazinyl)acetic acid dihydrochloride
and 37.3 mg (0.195 mmol) of N-ethyl-N'-3-
dimethylaminopropylcarbodiimide hydrochloride were added
thereto at -20 C. The mixture was stirred for 5 minutes.
To the mixture was then added 47.6 mg (0.390 mmol) of 4-
dimethylaminopyridine, and the mixture was stirred at -20 C
for 4 hours. To the reaction mixture was added a saturated
aqueous solution of sodium hydrogen carbonate, and the
resulting mixture was extracted with chloroform. The
chloroform layer was washed with a saturated aqueous
solution of sodium hydrogen carbonate and with a saturated
aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. Trifluoroacetic acid was then
added thereto, and the mixture was concentrated under
reduced pressure. To the resulting crude product were added
2.00 ml of anhydrous ethyl acetate and 526 mg of 5%
hydrobromic acid in methanol, and the mixture was stirred at
room temperature for 1 hour. To the reaction mixture were
added 1.5 ml of diethyl ether and 0.5 ml of diisopropyl
ether, and the precipitated crystals were collected by
filtration. These crystals were washed with ethyl acetate,
and dried under reduced pressure to give 31.0 mg of Compound
82 (yield: 52%).
The physicochemical properties of Compound 82 are as
follows.
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.11(lH,s), 9.55(lH,brs),
8.17(lH,s), 8.10 (lH,s), 7.94 (lH,d,J=8.9Hz),
- 97 -

2~3~90
7.63(lH,d,J=15.2Hz), 7.36(lH,d,J=8.9Hz),
7.22(1H,d,J=15.5Hz), 3.85-4.60(3H,m), 4.03(3H,s),
3.94(2H,s), 3.85(3H,s), 3.79-3.81(lH,m),
3.40-3.53(3H,m), 3.20(6H,s), 3.05-3.25(4H,br),
2.76-2.89(5H,br), 2.67(3H,s)
IR(KBr)~(cm~1); 1695, 1684, 1653, 1516, 1446, 1412,
1358, 1279, 1221, 1188, 1107
~xample 83 Synthesis of Compound 83
To 30.0 mg (0.0650 mmol) of Compound 41 were added
1.58 ml of acetonitrile and 316 mg of 5% hydrobromic acid in
methanol, and the mixture was stirred at room temperature
for 40 minutes. The reaction mixture was concentrated under
reduced pressure. The resulting crude product was dissolved
in 1.58 ml of methylene chloride. Then, 58.4 mg (0.195
mmol) of 2-(4-piperidinopiperidino)acetic acid
dihydrochloride and 37.3 mg (0.195 mmol) of N-ethyl-N'-3-
dimethylaminopropylcarbodiimide hydrochloride were added
thereto at -20 C. The mixture was stirred for 5 minutes.
To the mixture was then added 47.6 mg (0.390 mmol) of 4-
dimethylaminopyridine, and the mixture was stirred at from
-20 C to room temperature for 4.5 hours. To the reaction
mixture was added a saturated aqueous solution of sodium
hydrogen carbonate, and the resulting mixture was extracted
with chloroform. The chloroform layer was washed with a
saturated aqueous solution of sodium hydrogen carbonate and
with a saturated aqueous solution of sodium chloride, and
dried over anhydrous sodium sulfate. Trifluoroacetic acid
was then added thereto, and the mixture was concentrated
under reduced pressure. To the resulting crude product were
added 2.00 ml of anhydrous ethyl acetate and 526 mg of 5%
hydrobromic acid in methanol, and the mixture was stirred at
-20 C for 2 hours and 10 minutes. The precipitated crystals
were collected by filtration, washed with ethyl acetate, and
dried under reduced pressure to give 56.7 mg of Compound 83
(yield: 88%).
The physicochemical properties of Compound 83 are as
follows.
- 98 -

~- 2~S38913
lH-NMR(270MHz,DMSO-d6)~(ppm); 12.23(1H,s)~ 9.46(1H,brs),
8.20(lH,s), 7.91(lH,br), 7.77(lH,br),
7.62(lH,d,J=15.2Hz), 7.26 (lH,d,J=9.2Hz),
7.16(1H,d,J=15.8Hz), 4.38-4.62(3H,m), 3.98(3H,s),
3.85(3H,s), 3.80(1H,m), 3.43-3.70 (5H,m), 3.08(6H,s),
2.90-3.20(4H,br), 2.69(3H,s),2.19-2.37(2H,m),
1.67-2.12(7H,m), 1.41-1.49(lH,m)
IR(KBr)V(cm~l); 1767, 1684, 1645, 1516, 1439, 1412, 1354,
1279, 1182, 1138, 1107
Industrial Avail~hillty
According to the present invention, provided are
Compounds (I) and pharmaceutically acceptable salts thereof
which have excellent anti-tumor activity, and are useful as
anti-tumor agents.
_ 99 _

Representative Drawing