Note: Descriptions are shown in the official language in which they were submitted.
') 94/01113 2 1 1 6 3 ~ ~ PCr/JPg3/0~3~
D E S C R I P T I O N
OXYTOCIN ANTAGONIST
Technical Field
This invention relates to a novel oxytocin
antagonist, which has excellent pharmacological activities,
ror example, inhibitory effect on uterin smooth muscle
c~nstriction, inhibitory effect on milk secretion,
inhibitory efîect on synthesis and e~reation of
prostaglandin, and vasodilation activity, and hence, are
useful in the protection or treatment of oxytocin relating
diseases, e.g. premature dellvery, dysmenorrhea,
endometritis, or in stopping labour~preparatory to Caesarian
delivery.
Backqround Art
The carb~xytril derlvatives of the followins
~formula (1) and ~he benzohetrocyclic compounds of the
.
rollowing formula ~2), whlch are actl~ve i~gredients of the `;
~present oxytocin antagonist, are known to hsve~vasopress;in~ -
antagonistic activity (cf. Japanese Patent Plrst Publication
(Kokai) NQ. 173870/1991, and European Patent No. ~0097,
respectively).
It is known that some heterocyclic compounds~have ;
oxytocin antagonistic activity. For example, EP-0421802-A2
discloses that 3-substituted-1,4-benzodlazepines of tne ;~`~
following ~ormula are antagonists sf oxytocin and are useful
in the treatment of pre~erm labour and dysmenorrhea and fo
''~'';"~
,' '
WO94~01~13 PCT/JP93~
211~33ll
stoppa~e of labour preparatory to Caesarian delivery~
R
l X7 :
5~N <R3
(R )p R2~ 3)p
:.. ~ ,.....
wherein Rl is H, Cl-C~ alkyl, lower alkenyl, lower alkynyl,
-Xl-COORD, -Xll-cyclo(lower)alkyl, -Xl2NR4R5, -Xl2CoN~4R5,~
-'Xl2CN or -XllCXlO; R2 is H, lower alkyl, subst`ituted~or
unsubstituted pAenyl, etc,; R3 is~ H, -XllNR18XllR7, etc.; R9 .
and RlO are each H, OH or CH3; Rl3 is H, lower alkyl, acyl,
O, cyclo~lower)alkyl~ -XllCoXgXllR7 or -XllCoXllR7 Xl H
NO2, CF3, CN, OH, lower alkyl, halo, etc.; X7 1S O,~S, NH or
NRlS; Xll is Cl-C4 alkylidene; and Xl is Cl-C4 alkyl, ~`;
:These~ compoun~s hav:e a~l,4-benzodi.azepine nucleus~wh`ich~ i~9 .,. -
inclusive within the active compounds of the ~ormula (2) cf
the :p~resent inventior, but~are dirferent ln the~substi~uen~
at l-position.
Some other European paten~ applications:d1sclose ``
also various oxytoci~n ~ntagon1sts, such a~s spiro(1nden~e~
piperidine) compounds and analogues thereof: (cf. EP-0:444945
A2, EP-0450761~ l, and EP-0~86280:-A2), but :these compounds.-~
are different from the active compounds or the formulae (l)
and (2) of the present invention in the chemical :~ :
structure. ~:-
', ..
~, .
Disclosur2 o th~ Invention
The presenc ir,ven~ors have intensively stud1e~d the
carDostyril deriva~ives of the formula (l) and the
: .
211633il
'.0~4/01113 3 P~TtJP93/~835
benzohetrocyclic compounds of the formula (2), and have
found that these compounds and pharmaceutically acceptable -:~
salts thereof have excellent oxytocin antagonistic activity
and have accomplished the present invention. ;~-~
The carbostyril derivatives, which are one of ~.
active ingredients of the oxytocin antagonist of the present
invention, have the following formula (l)~
R1~q ~ (1) .....
~N~O
R ::~
wherein Rl is hydrogen atom; nitro; a lower alkoxy; a lower .. ~,
alkoxycarbonyl; a lower alkyl; a halogen atom~, an amlno
having optionally one or two substituents~selected~from a
lo~Jer alkanoyl, a lower aIkyl, benozyl and a phenyl(lo~7er)~
.
alkoxycarbonyl; hydroxy; cyano; carboxy; a l:ower alkanoyl~
oxy; or hydrazinocarbonyl,
,;
q is an in~eger o~ 1 to 3, and -~:
R is a group of the formula: ~ -
H2)n ~ ~ ~Rl
R or ~3
wherein R' is hydroger~ atom; a lower alkoxycarbony1; a
pheno~ycarbonyl whereln the phenyl ring may optionally be
substituted by one to three substituents selected from nitro
,i,.
and an amino having optionally one or two substituents
selected from a lower alkanoyl, a lo~7er alkyl and benzoyl; a
phenyl(lower)alkenylcarbonyl; a ~henyl(lower)alkanoyl --~
wherein the 1Ower alkanoyl moiety may optionally be
, ".
.'~
.
-- 4
W094/~1113 PCT/JP93
21~633~
substitu~ed by an amino having optionally a lower
alkoxycarbonyl subs~ituen~; an alkanoyli an alkenylcarbonyl
2 phenylsulfonyl where.~n the phenyl ring may optionally be
substituted by a lower alkoxy; a group of the formula~
-C~NR8R9 (wherein R8 and R9 are th2 same or different and
are each hydrogen a~om orJ a phenyl which may optionally have
one ~o three substitu2nts selected from a ~ower alkoxy, a ;
lo~er alkyl, a halogen atom, an 3mino having optionally one
or two substituents selec~ed from a lower alkyl and a lo~,~er
alkanoyl, and ni~ro); a he~erocyclic group-substituted
carbonyl wherein the heterocyclic group may optionally have
one to three substituents selected from a phenyl(lower)- ;-
alkoxycarbonyl, a phenyl~lower)alkoxy, oxo, a lower alkyl,
d â lower alkyleneaioxy; a group of the formula~
-CO CH3 `
,>< ~
naphthylcarbonyl; a tn` enyl(lower)alkanoyl; a tricyclo~
[3.~1.1]decanyl(10wer)clkanoyl; ~ricyclo~3.~.1.1]-
decanylcarbonyl; or a group of the formula:
(~13) ~ :~
- CO ~ (wherein p is 0 or an integer of 1 to 3, and
R13 is hydroxy; an alkoxy; an alkoxy which has one or two -:~
suDstituents selectec from hydroxy, 2 lower alkanoyloxy, a ~::
tri~lower)al~.ylammoniu~, a lower alkoxy, and a group of ~he
formula: -NRl~RiS [wh2r2in R14 and R15 are the sam~ or
difr2r~nt and are each nydrogèn atom, a low~r alkyl, a
~,"
',';'
~4/~1113 5 2 l 1 ;3 3 3 `I1 PCT/JP~3/~3~ ~
hydroxy-substituted lower alkyl, a lower alkanoyl, a
tetrahydropyranyl(lower)alkyl, phenyl, a phenyl~lower)alkyl
(wherein the alkyl moiety may optionally be substituted by
hydroxy and the phenyl ring may optionally be substituted by
a lower alkoxy), or a pyridyl(lower)alkyl; or R14 and R15
may bind with the nitrogen atom to which they bond to form a
5- or 6-membered, saturated heterocyclic group which may be
intervened or not with nitrogen, oxygen or sulfur atom ~`~
(wherein the heterocyclic group may optionally be
substituted by a member selected from carbamoyl, a lower
alkyl, a phenyl(lower)~lkyl, phenyl and a hydroxy- -
substituted lower alkyl)~; a carboxy-substituted alkoxy; a
halogen-substituted lower alkoxy; a lower alkoxycarbonyl-
substituted alkoxy; a lower alkanoyloxy-substituted lower
alkoxy; a lower alkenyloxy-substituted lower alkoxy; a lower
alkoxy(lo~7er)alkoxy; a low2r alkylsulfonyloxy-substituted ;~
~
lower alkoxy; a benzo-~lo~y substituted lower alko~y; ;~
tricyclo~3.3.1.1]decanyl-substituted lower alkoxy, a lower ;~;
- ..
alkoxy(lower)alkoxy which is substituted by one or two
substituents selected from hydroxy and an amino being
..~ . .,
optionally substitute~ by a lower alkyl~; a morpholinyl-
substituted lower alko~y which may optionally be substituted
by a lower alkyl or oxo; a benzimidazolylthio-substituted ~`
lower al~oxy; a benzimidazolylsulfinyl-substituted lower -
alkoxy; a group of the formula: -o-A-(E)~-NR4RS (wherein A --
is an alkylene, ~ is an integer of 0 or 1, E is a group of
the formula: -C0- or -OC0-, R4 and R5 are the same or
difrerent and are each hydrogen atom; a lower alkyl which
.'' ;~"
,,.~.,.
W094/01~13 ~ P~IJPg3~
~11633~
may optionally De subs~itu~ed by hydroxy or cyano; a lower
alkenyl; a low2r alkynyl; a phenyl(lower)alkyl; a lower
alkanoyl which may op~ionally have one to three substituents
of a halos~en atom; a benzoyl wherein the phenyl ring may ~ :
optionally be substituted by a member selected from nitro
and an amino having option211y one or tWO substituents
selec~ed from a lower alkyl, a lower alkanoyl and a
phenyl(lower)alkoxycarbonyl; phenyl; a lower alkoxycarbonyl;
a lower alkoxycarbonyl~lower)alkyl wherein the lower alkyl :
moiety may option~lly be substituted by hydroxy or an amino
having optionally a phenyl(lower)alkoxycarbonyl substituenti
an 2mido havina op~ion211y a lower alkyl substituent; 2
pyrrolidinyl-subs~itu~ed c~rbonyl wherein the pyrrolidinyl
ring may op~iona'l~y be subs~ituted by a phenyl(lower)alkoxy-
carbonyl; an amino-subs~ituted lower alkanoyl wherein tn2 ~ ~
lower alkanoyl moiety may optiona:Lly be substitu~2d by a ~;.
memb2r select2~ rrom ?heny'(lower)alkoxycarbonylamino,
hys~roxy, a phenyl h~ving optionally â hydroxy substltu~e~
carbamoyl, imidazolyl and a lower alkylthio, and ~he 2~.i no ~
group ~.ay cptionally have a substituent selected from a :.
lower alkyl having optionally a hydroxy substitut~nt, a
lower alkenyl, a phenyl(lower)alkyl having optionally a
lower alkoxy 5ubstituent on the phenyl rin~, a lower -;
alkylsulfonyl, a lower alkanoyl, and a phenyl(lower)clk.o~.y~
carbonyl; a hya oxy-substi~uted lower alkanoyl; a lower i-,
alkanoyloxy(lower)~lkanoyl; a lower alkylsulronyl; a
phenylsulfon~l wnerein che ph~nyl ring may option~lly be
substituted by a lower 21kyl, nitro or an amino havins ;~
`~94/01113 2 1 1 ~ 3 3 ~ P~T/JP93/~835
option_lly one or two substituents selected from a lower ~.
alkvl and a lower alkanoyl; an amido-substituted lower alkyl --
wherein the lower alkyl moiety have optionally a substituent
selec~ed rrom a phenyl having optionally a hydroxy substi- :~
tuent, imidazolyl, carbamoyl and a lower al~ylthio, and the ~:
amido group m~y optionally have a lower al~.yl substituent
an amino-substi~uted lower ~lkyl which may optionally
substituted by a lower alkyl or a lower alkanoyl; anilino-
carbonyl; a piperidinyl which may optionally be substituted
by ~ phenyl(lower)clkyl; a cycloalkyl, a cycloalkenyl-
carbonyl; a cycloalkvlcarbonyl which may optionally have one
to three substituents selected ~rom hydrox~ and a lower ~;.
alkanoyloxy; a tetrahydropyranyl-substituted lower alkyl
wherein the tetrahydropyranyl ring may optionally have one
to four substituents selected from hydroxy and a lower
âl~o~y; a lower al~anoyl whicn is substituted by a 5- or 6-
memb2red s~ur_~ed heterocyclic group selected from
Dyrrolidinyl, pipera7inyl, piperidinyl and morpholinyl ~ ;
. -.
wherein the heterocyclic group ~ave option_lly a substi~uent ~`
selected from a lower alkyl and phenyl; a piperidinyl- `.
substituted carbonyl which may optionally b~ substituted by
a lower alkanoyl; 2 lower alkanoyloxy(lower)alkyl; a
pyridyl-substitu~ed lower alkyl; or an arnino acid residue
which can form an amido group with its amino group, or R~ -.
and R5 may bind tog2ther with the nitrogen atom to ~Jhich
they bond to form a 5- or 6-membered, saturated or -.
unsaturated heterocycl c group ~hich may be intervened or
not ~7ith ni~rogen, oxygen or sulfur atom, wherein the
., :,.
''.''',',;
W094/0II~3 P~T/JP93~
211~331 -
,
heterocyclic group may optionally be substituted by a member
selected from a phenyl having optionally a subsituent
selected from a lower alkoxy and a halogen atom, oxo,
hydroxy, a lower alkenyl, carboxy, a phenyl(lower)alkyl
having optionally a hydroxy substituent on the lower alkyl
moiety, a lower alkanoyl, a lower alkyl having optionally a
hydroxy substituent, benzoyl, an amido having optionally a
lower alkyl substituent, anilinocarbonyl, a benzoyI(lower)-
alkyl, a lower alkylsulfonyl, piperidinyl, pyrimidinyl, ;~
pyridyl, and a lower alkoxycarbonyl); a carbamoyl:oxy- :
subs~ituted lower alkoxy; a lower alkylthio-substituted ~-
lower alkoxy; a lower alkylsulfonyl-substituted lower :~
alkoxy; a lower alkylsulfinyl-substituted lower alkoxy; an -~
alkenyloxy; phenoxy; a.lower alkanoyloxyi a lower alkyl~ -
sulfonyloxy; a lower alkynyloxy; a phenyl(Iower)alkoxy; a -~
cyclOal~yl; a cycloal~yloxy; a cycloalkenyloxy; imidazo~
[4,5-c]pyridyl~carbonyl(lower)alkoxy; a gFOUp of the~
formula: -(B)~NR~R7 ~wherein Q is as defined above, B is:a ~:
lower alkylene or a group of -CO , and R6 and R7 are the
same or different and are each hydrogen atom, a lower alkyl,
a lower alkanoyl having optionally one to three halogen : -
su~stituents, a carboxy(lower)alkyl, a lower alkoxycarbonyl,
a lower alkoxycarbonyl(lower)alkyl, a lower alkenyl, an :-;
amido-substituted lower alkyl having optionally a lower
alkyl substituent, or a phenyl(lower)alkoxycarbonyl, or R6
and R7 may bind together with nitroqen atom to which they .. -~
bond to form a 5- or 6-membered, saturated or unsaturated
heterocyclic group which may be intervened or not with
`~94/01113 2 1 ~ ~ 3 3 ~ PCT/~P~3/~35
nitrogen, oxvgen or sulfur atom, wherein the heterocyclic ~:
group may optionally have a substituent selected from a
lower alkoxycarbonyl, a lower alkyl, a lower alkylthio, and
oxo); nitro; a hal~gen atom; a lower alkylsulfonyl; a lower
alkyl which may optionally have one to three substituents ~ ;
selected from a halogen atom, hydroxy, phenyl and a lower
alkoxy; a cyano-substitutPd lower alkoxy; an oxlranyl- ~
substituted lower alkoxy; a phthalimi.do~substituted alkoxy; ~ .
an amidino-substitu~ed lower alkoxy, a pyrrolyl-substituted ~:.
lowPr alkoxy; cyano; a lower aIkoxycarbonyli amldino; .:~
carbamoyl; carboxy; a lower alkanoyl; benzoyli a lower
alkoxycarbonyl~low2r)alkyl; a carboxy(lowèr)alkyl; a lower .-
alkoxy~lower)alkyl; a lower alkanoyloxy(lower)alkyl;
, . .;:
hydroxyimino-substitu~ed lower alkyl; phenyl; a l:ower ~
: -1k~rlthio; a lower alkvlsulfinyl; a lower alkenyl having
; ~ cptionally a hydroxy substituent; a lower alkylene~io~y, a u~
lower alkylsilyl; a pyrimidylthio-substituted lower alkoxy; .. :
~.......
a pyrimidylsul~inyl-subs~ituted low2r alkoxy; a pyrmidyl~
sufo~yl-substituted lower alkoxy; an imidazoly1thio-
~ -
substiiuted lower alkoxy which may optionally have a lower -`
alkyl substituent; an imidazo1yl~sulfon~ substituted lower~
alko,:y which may opt~onally have a lowe~ alkyl substituent;
. ~ " .
an ammonium-lower alkoxy having three substituents selected ~ -;
from lower alkyl, lower alkenyl and oxo; a phenylthio~
. . .
substituted lower alkoxy wherein the phenyl ring may .
: optionally have a substituent selected from nitro and amino; `--
a phenylsulronyl-substitut2d lower alkoxy wherein the phenyl
ring may optionally have a substituent selected from nitro
.., ~
WO 94/~ 3 PCr/JP~3/0~'
211~33~
and an amino having optionally one or two substituents
selected f rom a lower alkanoyl and lower al~;yl; a
pyridylthio-substituted lower alkoxy; or a pyridylsuflonyl- ~;
substituted lower alkoxy wherein the pyridyl ring may
optionally be substituted by oxo), n is an integer of 1 or
2, m is O or an integer of 1 to 3, R3 is a lower alkyl, R10
is a group of the formula: -(CO)~-NRllR12 (wherein ~ is as ;
defined above and Rll and R12 are the same or different and
are each hydrogen atom, a lower alkyl, a phenyl(lower)alkyl,
a lower alkenyl, a benzoyl which may optionally have a lower
alkoxy substituent, tricyclo[3.3.1.13decanyl, a phenyl which
may optionally have a lower alkoxy substituent, or a
cycloalkyl, or Rll and R12 may bind together with the
nitrogen atom to which they bond to form a saturated or
unsaturated heterocyclic group which may '~e intervened or
not with nitrogen, oxygen or sulfur atom, wherein the
heterocyclic group may optionally have a substituent
selected from a benzoyl, a lower alkanoyl, a phenyl(lower~
alkyl and a phenyl which may optionally be substituted by a
lower alkoxy or a lower alkanoyl), the bond between 3- and
4-positions of the carbostyril rin~ is single bond or double ~-~
bond, provided that when Rl is hydrogen atom and the Q in --
the formula -(CO)Q-NRllR12 is O and Rll R12 ar t
simlltaneously hydrog2n atom.
The benzoheterocyclic compounds, which are also one
of the active ingredien~ of the present oxytocin antagonist,
have the following formula (2)~
3 4
D94/0111~ ~ PCT/JP~3/~83~
R16 ~W) "`: :'
N
C~O (?)
~R~
wherein R16 is hydro~en atomi a halogen atom, a lower alkyl, ;.~:~
an amino having optionally a lower alkyl substituent, or a ;
lower alkoxy
17 ;.
R is hydrogen~atom, a halogen atom, a;lower
alkoxy, a phenyl~Iower)alkoxy, hydroxy, a lower alkyl, an ~:
amino having optionally a lower alkyl subs~tituent, a
carbamoyl-substituted lower alkoxyv:~an amlno-substituted
Iower alkoxy having~ optionally a lower alk:yl s:ubstituent, or
- .
a benzoyloxy which has optionally a halogen su~bstituent~on
the~phenyl ring,
~ R18 is a gr~oup of the ~formula: -NR19R20~or a group
:~ of:the formula -CoNR26~27, :
Rl9 is hy~drogen atom, a:benzoyl~which~has
optionally a halosen substituent on ~the:phenyl ring,~`or a
:~ : low~er alkyl,
R20 is a g-oup of the fo-mula: C
[wherein R31 is a halogen atomi a lower alkyl which has
optionally a substituent selected from a halogen~a~tom and~
; . .,
: hydroxy; hydroxy; a~lower alkoxy; a~lower alkanoyloxy; a : .
lower alkylthio; a: lower alkanoyl; carboxy; a lower
.: .
alkoxycarbonyl; cyano; nîtro; an amino which has optionally .
a substituent selected from a lower alkyl and a lower
~:
'
.
W~9~/01113 - 12 -
211633~
alkanoyl; phenyl; a cycloalkyl; a lower alkanoyloxy-
substituted lower alkoxy; a carboxy-substituted lower
alkoxy; a halogen-substituted lower alk~xy; a carbamoyl-
substituted lower alkoxy; a hydroxy-substi~uted lower ~:
alkoxy; a low~r alkoxycarbonyl-substituted lower alkoxy; a
phthalimido-substituted lower alkoxy; an aminocarbonyl-lower :~
alkoxy having a lower alkyl substituent; or a group of the ~:
formula: -O-F-N21R22 (F is a lower alkylene~ and R21 and R22
are the same or different and are each hydrogen atom, a
lower alkyl having optionally a hydroxy substituent r a lower
alkanoyl, or benz~yl, or R21 and R22 may bind to~ether with
,~ - "~,~
the nitrogen atom to which they bond to fo~m a 5- or 6- - '
membered saturated heterocyclic group with or without being
intervened with nitrogen or oxygen atom wherein the hetero-
cyclic group has optionally a substituent selected from
piperidinyl and a lower alkyl); and r is an integer of 0 to
3], a phenyl-lower alkoxycarbonyl, a lower alkanoyl, a ;~:
phenyl-lower alkanoyl, a cycloalkyl-lower alkanoyl, a
cycloalkylcarbonyl, tricyclo[3.3.1.1~decanylcarbonyl, ~ :~
naphthylcarbonyl, pyridylcarbonyl, f~royl, thenoyl, a
phenoxy-lower alkanoyl wherein the phenyl rlng has
optionally 1 to 3 substituents selected rom a lower alkyl, ~;
a lower alkoxy and an amino having optionally a lower
alkanoyl substituent, a phthalimido-substituted lower `~
alkanoyl, a lower alkoxycarbonyl-lower alkanoyl, a carboxy-
lower alkanoyl, a naphthyloxy-lower alkanoyl, a halogen~
substituted lower alkanoyl, a group of the formula:
~ CO ~ N_R23 (wherein R23 is hydrogen atom, a lower
- 13 2~1~33~
'~9~/01113 PCT
alkyl, a phenyl-lower alkoxycarbonyl, a carbamoyl-lower
alkyl, an amino-lower alkanoyl having optionally a lower -
alkyl substituent, or a lower alkanoyl), an anilinocarbonyl
which has optionally a lower alkyl substituent on the phenyl
ring~ phenoxycarbonyl, a phenylsulfonyl which has optionally -; ;
a substituent selected from a halogen atom and a lower alkyl
on the phenyl ring, quinolylsulfonyl, or a group of the .
formula -Co-G-(Co)S-NR24R25 (wherein G is a lower alkylene,
~ . .
s is an integer of 0 or 1, and R~4 and R25 are the same or
~ifferent and are each hydro~en atom, a lower alkyl having
optionally a hydroxy substituent, a cycloalkyl, a phenyl-
lower alkyl, a lower alkanoyl, a lower alkenyl, a phenoxy- ~:
lower alkyl, a phenyl which has optionally 1 to 3 .-
substituents selec~ed rrom an amino-lower alkyl having `
optionally a lower alkanoyl substltuent, a lower alkyl, a
lower alkoxy and a halogen atom, a phthalimido-substituted
lower alkyl, an amino-lower alkyl having optionally a lower
alkanoyl substituent, 2 lower alkynyl, or an amino-lower
alkyl having optionally a lower alkyl substituent, or:R24 .
and R25 may bind together with the nitroyen atom to which
they bond to form a 5- or 6-membered saturated heterocyclic
group with or withou~ being intervened wlth nitrogen or .`~
oxygen atom wherein the heterocylic group has optionally ~
substituent selected from a lower alkyl, a lower ~;
alkoxycarboyl and piperidinyl),
R26 is hydrogen atom or a lower alkyl, -~;
R~7 is a cycloalkyl/ or a phenyl which has
optionally 1 to 3 substituents selected from a lower alkoxy,
WO g'll~ pFrlJ'Pg31~8'
~11633~
a lower alkyl and a halogen atom,
W is a group of the formula: -(CH2)t- (t is an
integer of 3 to 5), or a ~roup of the formula~
-CH=CH-(CH2)V- (v is an integer of 1 to 3), the carbon atom
of these groups: -(CH2)t- and -CH=CH-(CH2)V- being
optionally replaced by oxygen atom, sulfur atom, sulinyl,
sulfonyl r or a group of the formula: -NR28- (R28 is hydrogen
atom, a cycloalkyl, or a lower alkyl), and further said
-(CH2)t- and -CH=CH-(CH~)V- groups having optionally 1 to 3
substituents selected from a lower alkyl having optionally a
hydroxy substituent, a lower alkoxycarbonyl, carboxy,
hydroxy, oxo, a lower alkanoyloxy having optionally a :~
halogen substituent, an amino-lower alkyl having optionally
a substituent selected from a lower alkyl and a lower
alkanoyl, a lower alkanoyloxy-substituted lower alkyl, a
lower alkyl sulfonyloxy-lower alkyl, an azido-lower alkyl, a
group of the formula: -OCH2-, an aminocarbonyloxy having ~
optionally a lower alkyl substituent, a lower alkoxy, a :-
lower alkoxycarbonyl-substituted lower alkoxy, a carboxy~
substituted lower alkoxyj an aminocarbonyl-lower alkoxy
having optionally a lower alkyl substituent, an amino-lower
alkoxy having optionally a substituent selected frorn a lower ~-
alkyl and a lower alkanoyl, a phthalimido-substituted lower
alkoxy, hydroxyimino, a lower alkanoyloxy-imino, a lower
alkylidene, a halogen atom, azido, sulfoxyimino, a group of
the formula R32-N~o (R32 is hydrogen atom or a lower
/o ::
alkyl~, hydrazino, pyrrolyl, an amino-lower alkanoyloxy
- 15 - 211S33-1
`l094/01113 pCTlJP93/~835 :
having optionally a lower alkyl substituent, a group of the
~ormula: -o-F-Co-NR33R34 (F is as defined above, and R33 and ~ .
R34 are the same or different aind are each hydrogen atom, a
lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-
substituted lower alkyl, or a pyridyl-lower alkyl, or R33 ~.. ;
and R34 may bind together with nitrogen atom to which they
bond to form a 5- or 6-membered saturated heterocyclic group
with or without being intervened with nitrogen, oxygen or .:
sulfur atom wherein the heterocyclic group has optionally a
substituent selected rrom oxo, a lower alkyl, a lower
alkanoyl, and carbamoyl), or a group of the formula: ~.
-(Co)S-NR29N30 (wherein s is as defined above, and R29 and
R30 are the same or dirferent and are each hydrogen atom, a
lower alkyl, a lower alkenyl, a lower alkanoyl, a
,-., .~ ..
cycloalkyl, an oxiranyi-substituted lower alkyl, a lower
alkyl having option-lly 1 to 2 substituents selected from a -~
lower alkoxy, hydroxy and an amino having optionally c low~r
alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower ~:;
alkyl~ a lower alkylsulfonyl, benzoyl, a lower alkoxy~
carbonyi, anilinocarbonyl, an aminocarbonyl having
optionally a lower alkyl substituent, a cyano-substltuled ~.
lower alkyl, a 10~7er alkoxycarbonyl-substituted lo~Jer alkyl,
2 carbamoyl-substituted lower alkyl, a carbo~y-substituted -::
lower alkyl, 3i te~rahydropyranyloxy-substituted lower ~lkyl,
a 10~7er alkanoyloxy-su~stituted lower alkyl, a piperi~inyl
having optionally a phenyl-lower alkyl substituent on the ~
piperidine ring, a halogen-substituted low~r alkanoyl, an ~-
imidazolyl-substituted lo~Jer alkanoyl, an amino-lower
. ~:
'''','
- 16 -
WO94101113 ~TIJP93/~
2~1633~ ~
alkanoyl having optionally a substituent selected from a .
l~wer alkyl and a lower alkoxycarbonyl, an aminocarbonyl~
lower alkyl having optionally a lower alkyI substituent, or
a phenyl-lower alkoxycarbonyl, or R29 and R30 may bind
together with nitrogen atom to which they bond to form a 5
or 6-membered saturated heterocyclic group with or without ~-~
being intervened with nitrogen or oxygen, wherein the ~-
heterocyclic group may optionally have a substituent
~elected from a lo~,7er alkyl, a phenyl-lower alkyl and a .
lo.wer alkanoyl).
The carbostyril derivatives of the formula ll) and
their sal~s, and the benzoheterocyclic compounds of the
formula (~) and their salts have excellent inhibitory effect :~
on uterin smooth muscle constriction, inhibitory e~fect on ;;;~
milk secreticn, inhibitory effect on synthesis and
secrection of prostaglandin, and vasodilation activity, and ;.
hence, they are useful in the protection or treâtment ~r
oxytocin relating ù1seases, expecially, for treatment or
premature delivery, dysmenorrhea, endometri~is, or for ;~
s~opping labour preparâtory to Caearian delivery.
Each group in the above formulae (l) and (2)
includes spec1fically the following groups.
The "alkoxy" includes a straight chain or branched
chain alko~y ~roup having l to l2 carbon atoms, for ex~mple,~
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, ~;
pentyloxy, hexyloxy, hep~yloxy, octyloxy, nonyloxy,
decyloxy, undecyloxy, ~odecyloxy, and the like.
The "lower al~yl" includes a straight chain or
2116:33~
~-~94/01113 - 17 - PCT/JP93/~835
~'',:'; '''~
branched chain alkyl group having l to 6 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, butyl, tert-
butyl, pentyl, hexyl, _nd the like.
The "halogen atom" includes fluorine atom, chlorine
atom, bromine atom and iodine atome.
The "amino having optionally one or two --
substituents selected from a lower alkanoyl, a lower alkyl
and benzoyl" includes an amino having optionally one or two
substituents selected from a straight chain or branched
chain alkyl group having l to 6 carbon atoms, a strai~ht
chain or branched chair. alkanoyl group having 1 to 6 carbon
atoms and benzoyl group, or~example, amino, methylamino, :~
ethylamino, propylamino, 1sopropylamino, butylamino~ t~ert- :
butylamino, pentylamino, hexylamino, dimethylam1no, d~iethyl-
.::
amino,~dipropylamino, dibutylamino,~di~entylamino, dihex:yl-
amino, N-methyl-N-eth~/lamino, N-ethyl-N-propylamino, N-
methyl:-N-butylaminoj N-me~hyl-N-h2x:ylamin~0, N-methyl~N~
~ .
a~etylamino, N-acetylamino, N-~ormylamino, N-propionylamino,:
N-butyrylamino, N-isobu~yrylamino, N-pentanoylamino~ N-tert-
~ .
butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylami~no,
: ~ ben7.oylamino, N-me~h l-N-benzoylamino, N-ethyl-N-benzoyl-
amlno, and the like.
~ ';
The "amino having optionally one or two ~.
1'1 ~
substituents selected rrom a lower alkanoyl and a Iower alkyl"~ :
- includes an amino having optionally one or two substituents
selected from a straignt cha1n or branched chain alkyl group
:-"~
having l to 6 carbon atoms and a straight chain or branched
chain alkanoyl grouD h-ving l to 6 carbon a~oms, for
.. .. '.
'' ~ ',
~.
W~94~0~13 - 18 - PCT/JP93~
211633~
example, amino, methylamino, ethylamino, propylamino, ~
isopropylamino, butylamino, tert-butylamino, pentylamino, ~-
hexylamino, dime~hylaminol diethylamino, dipropylamino, ~ -~
dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethyl-
amino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N
methyl-N-hexylamino, N-methyl-N-acetylamino, N-acetylamino r
N-formylamino, N-propionylamino, N-butyrylamino, N-
isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonyl-
amino, N-hexanoylamino, N-ethyl-N-acetylamino, and the like. :`
The "phenyl(lower)alkyl" includes a phenylalkyl
group wherein the alkyl moiety is a straight chain or
branched chain alkyl group having 1 to 6 carbon atoms, for
example, benzyl, 2~phenylethyl, l-phenylethyl, 3-phenyl-
propyl, 4-phenylbutyl, S-phenylpentyl, 6-phenylhexyl, 1,1- :
dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, and ;he
like.
The "amino having optionally one or two :;~
substi~uents selected from a lower alkyl, phenyl and a
phenyl(lower)alkyl" includes an amino having optionally one :~:
or tWG substituents seiected from a straight chain or branched
chain alkyl group having 1 to 6 carbon atoms, phenyl and a ~:~
phenylalkyl wherein the alkyl moiety is a straight chain or
branched chain alkyl group having 1 to 6 carbon atoms, for
example, amino, phenylamino, diphenylamino, methylamino,
ethylamino, propylamino, isopropylamino, butylamino, tert~
butylamino, pentylamino, hexylamino, dimethylamino, diethyl-
amino, dipropylamino, dibutylamino, dipentylamino, dihexyl~
amino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-
- 19 _ 2~l633~l
`~O 94/01113 p~rJPg3~00835
methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl~N-
phenylamino, N-ethyl-N-phenylamino, N-benzylamino, N-(2-
phenylethyl~amino, N-(l-phenylethyl)amino, ~-(3-phenyl- :
propyl)amino, N-(4-phenylbutyl)amino, N-(5-phenylpentyl)~
amino, N-(6-phenylhexyl)amino, N-(l,l-dimethyl-2~phenyl~
ethyl)amino, N-(2-methyl-3-phenylpropyl)amino, N-methyl-N- :~:
benzylamino, N~ethyl-N-benzylamino, N-phenyl-N-ben~ylamino, :;
and the like. .;
The "alkoxy which has one or two substltuent:s
selected from hydroxy, a lower alkanoyloxy, a tri(lower)-
alkylammonium, a lower alkoxy, and a group of the formula~
-NR14R15" includes an alkoxy group having 1 to 10 carbon
,
atoms which has one or two substituents selected from
hyd~roxy, a straight chain or branched chain alkanoyloxy
havlng 1 to 6 carbon atoms, a trialkylammonlum group:wherein ;~
the alkyl moiety is a straight chaln or bra~ched chain alkyl ;-
group having 1 to 6 carbon atoms, a straight chain or
~ .:
branched chain alkoxy group having 1 to 6 carbo~n atoms, and ;~:
a group o~ the formula: -NR14R15 [wherein R14 and R15 are ~-~
the same or different and are each hydrogen atom, a straight .-~
chain or branched chain alkyl group havlng 1 to 6 carbon :
atoms r a straight chain or branched chain alkanoyl~group ..
hav ?,9 1 to 6 carbon atoms, a hydroxy-substituted alkyl
group wherein the alkyl moiety is a strainght chai~n or
branched chain alkyl group having 1 to 6 carbon atoms, a
~,~
tetrahydropyranylalkyl group wherein the alkyl moiety is
strai~ht chain or branched chain alkyl group having 1 to 6
carbon atoms, phenyl, a phenylalkyl (wherein the alkyl '~
'''~".'
''' ~"`'.
~''''''`"~'`'
- 20 -
WO94~0~113 PCT/JP93/~
211633~
moiety is straight chain or branched chain alkyl group
having 1 to 6 carbon atoms which may optionally be -~
substituted by hydroxy and the phenyl rin~ may optionally be
substituted by one to three of straight chain or branched
chain alkoxy group having 1 to 6 carbon atoms), or a
pyridylalkyl wherein the alkyl moiety is straiqht chain or
branched chain alkyl group having 1 to 6 carbon atoms, or
R14 and R15 may bind wi~h the nitrogen atom to which they
bond to form a 5- or 6-membered, saturated heterocyclic
~group which may be intervened or not with nitrog2nr oxygen :~ .
or sulfur atom (wherein the heterocyclic group may
optionally be suhstituted by one to three substituents ~
selected from carbamoyl, a straight chain or branched chain ~-:
alkyl group having 1 to 6 carbon atoms, a phenylalkyl group
wherein the alkyl moiety is a straight chain or branched ~;:
chain alkyl ~roup having 1 to 6 carbon atoms, phenyl and a
hydroxy-substituted alkyl group wherein the alkyl moiety is
a straight chain or branched chaln alkyl group having 1 to 6
: carbon atoms)], for example, hydroxymethoxy, 2-hydroxy-
ethoxy, l-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxy~
ethoxy, 4-hydroxybutoxy, 3,4-dihydroxybutoxy,~l,l-dimethyl~
2-hydroxyethoxy, 5,6-dihydroxyhexyloxy, 5-hydroxypentyloxy, ~ ;~
6-hydroxyhexyloxy, 7-hydroxyheptyloxy, 8-hydroxyoctyloxy, 9- - :~
hydroxynonyloxy, 10-hydroxydecyloxy, 6-(3,4-dimethoxybenzyl-
amino)-5-hydroxyhexyloxy, 6-(3-methoxybenzylamino)-5- :~
hydroxyhexyloxy, 6-[2-(2-pyridyl)ethylamino]-5-hydroxy- :
hexyloxy, 6-[N-methyl-N-~2-pyridylethyl)amino]-5-hydroxy~
hexyloxy, 6-{N-ethyl-N-2-(2-pyridylethyl)amino}-5-hydroxy-
- 21 - 2 1 1633il
'094/01113 PCr/JP93/0083~ :
hexyloxy, 6-[N-ethyl-N-(4-pyridylmethyl)amino]-5-hydroxy-
hexyloxy, 6-~3-pyridylmethylamino)-5-hydroxyhexyloxy, 6-(2- :;
pyridylmethylamino)-5-hydroxyhexyloxy, 6-(diethyl,methyl
ammonium)-5-methoxyhexyloxy, 4-(trimethylammonium)-3
hydroxyhexyloxy, 5-(dipropyl,ethylammonium)-4-acetyloxy-
pentyloxy, 7-~2-ethoxybenzylamino)-6-acetyloxyheptyloxyl 8
~3,4,5-trimethoxybenzylamino)-7-ethoxyoctyloxy, 5-~3-(2- ~:
pyrldyl)propyl]-4-acetyloxypentyloxy, 7-[4-(3-pyridyl)~
butyl]-6-propoxyheptyloxy, 2-methyl-3-hydroxypropoxy,
aminomethoxy, l-aminoethoxy, 2-aminoethoxy, 3-aminopropoxy~ :
4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1- ;~
dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methyl~
aminomethoxy, ethylaminomethoxy, propylaminom2thoxy, :~
isopropylaminomethoxy, butylaminomethoxy, tert-butyl- ;~
aminomethoxy, pentylaminomethoxy, hexyla~inomethoxy, -.
dimethylaminomethoxyi diethylaminomethoxy, dipropylamino-
methoxy, dibutylaminomethoxy, dipentylaminomethoxy,
dihexylaminomethoxy, N-methyl-N~ethylaminomethoxy, N-methyl- ~;~
N-propylaminomethoxy, N-methyl-N-butylaminomethoxy, N~
methyl-N-hexylami~omethoxy, l-methylaminoethoxy, 2-ethyl-
aminoethoxy, 3-propylaminopropoxy, 4-butylaminobutoxy, 1,1
dimethyl-2-pentylaminoethoxy, 5-hexylaminopentyloxy, 6- .
dimethylaminohexyloxy, 7-methylaminoheptyloxy, 8-dimethyl-
aminooctyloxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, ;;`:;
l-(N-methyl-N-hexylamino)ethoxy, 3-dihexylaminopropoxy, 6
diethylaminohexyloxy, 4-dibutylaminobutoxy, 9-(N-methyl-N~
propylamino)nonyloxy, 2-(N-methyl-N-pentylamino)ethoxy, 7- ;.
hydroxy-8-dimethylaminooctyloxy, 2-hydroxy-3-diethylamino~
, ~:
WO94/01113 - 22 - P~T/JP93/~
2116334
propoxy, 7-hydroxy-8-diethylaminooctyloxy, 2-hydroxy-3-(N-
phenyl-N-benzylamino)propoxy, 7-hydroxy-8-ethylamino-
octyloxy, 3-hydroxy-4-methylaminobutoxy, 5-hydroxy-6-
diethylaminohexyloxy, 3-hydroxy-4-phenylaminobutoxy, 8- ~:
hydroxy-9-dimethylaminononyloxy, 4-hydroxy-5-dimethylamino-
pentyloxy, 9-hydroxy-10-diethylaminodecyloxy, 4-hydroxy-5-
methylaminopentyloxy, 4-hydroxy-5-diethylaminopentyloxy,
phenylaminomethoxy, diphenylaminomethoxy, benzylamino-
methoxy, 5-hydroxy-6-benzylaminohexyloxy, 5-hydroxy-6-[N-
methyl-N-(2-phenylethyl)amino]hexyloxy, 5-hydroxy-6-ethyl~
aminohexyloxy, 5-hydroxy-6-isopropylaminohexyloxy, 5-
hydroxy-6-(N-methyl-N-ben~ylamino~hexyloxy, 5-hydroxy-6-
aminohexyloxy, IN-methyl-N-benzylamino)methoxy, (N-ethyl-N- ;~
benzylamino)methoxy, (M phenyl-N-benzylamino)methoxy, 2-
(phenylamino)ethoxy, 3-(2--phentylethylamino)propoxy, 4-(3-
phenylpropylamino)butoxy, l,l-dimethyl-2-(4--phenylbutyl- ;~
amino)ethoxy, 5-(5~phenylpentylamino)pentyloxy, 6-(6-
phenylhexylamino)hexyloxy, 7-hydroxy-8-(N-phenyl-N-benzyl- ~
amino)octyloxy, 8-hydroxy-9-[N-~2-phenylethyl)amino]- ~ -
nonyloxy, 9-hydroxy-10-(N-ethyl-~-benzylamino)decyloxy, -
acetyloxymethoxy, 2-propionyloxyethoxy, l-butyryloxyethoxy,
3-acetyloxypropoxy, 4-isobutyryloxybutoxy, 5-pentanoyloxy- --~
pentyloxy, 6-tert-butylcarbonyloxyhexyloxy, 1,1-dimethyl-2- ~
hexanoylo~yethoxy, 2-methyl-3-acetyloxypropoxy, 7-acetyloxy- ~-
heptyloxy, 8-acetyloxyoctyloxy, 9-acetyloxynonyloxy, 10-
acetyloxydecyloxy, (hydroxymethyl)aminomethoxy, l-[N,N~di-
(2-hydroxyethyl)amlno]ethoxy, 2-(3-hydroxypropyl)amino-
ethoxy, 3-(4~hydroxybutyl)aminopropoxy, 4-(5-hydroxypentyl)- :~
21 16334
"094/01113 - 23 ~ P~T/JP93~0~83
aminobutoxy, 5-(6-hydroxyhe~yl)aminopentyloxy, 6- L N-(2-
hydroxyethyl)-N-me~hylamino]hexyloxy, 5-hydroxy-6-[N-(2-
hydroxyethyl)-N-methylamino]hexyloxy, 5-hydroxy-6-~N,N-di(2- ;~
hydroxyethyl)amino]hexyloxy, 6~hydroxy-7-[N-t2-hydroxy-
ethyl)-N-benzylamino]heptyloxy, 7-hdroxy-8~N-(3-hydroxy-
propyl)-N-phenylamino]octyloxy, 7-hydroxy-9-{N-(4-hydroxy- -~
butyl)-N-[(tetrahydropyranyl-2-yl)methyl]amino}nonyloxy, 8-
hydroxy-10-[N-(2-hydroxyethyl)-N-acetylamino]decyloxy,
acetylaminomethoxy, 2-(formylamino)ethoxy, l-(propionyl~
amino)ethoxy, 3-~butyrylamino)propoxy, ~-(isobutyrylamino)-; -~
butyloxy, 5-~pentanoylamino)pentyloxy, 6-(hexanoylamino)-
hexyloxy, 5-acetyloxy-6-acetylaminohexyloxy, 5-hydroxy-6-
acetylaminohexyloxy, 6-hydroxy-7-(N-methyl-N-acetylamino)- --
heptyloxy, 7-hydroxy-8-(N-benzyl-N-acetylamino)octyloxy, 8- ``~
hydroxy-9-(~-phenyl-N-~cetylamino)nonyloxy, 9-acetyloxy-10-
-(tetrahydro-2-pyranylmethyl)-N-acetylamino]decyloxy~
ttetrahydro-2-pyranyl~methylaminomethoxy, 2-~tetrahydro-3-,`5,',1
pyranylmethylamino)ethoxy, l-(tetrahydro-4-pyranylmethyl- ;~
amino)ethoxy, 3-[2-(tetrahydro-2-pyranyl3ethylamino~propoxy,
4-~3-[tetrahydro-2-pyranyl)propylamino]butoxy, 5-[4- :~
(tetrahydro-2-pyranyl)butylam~ino]pentyloxy, 5-hydroxy-6-[N~
ethyl-N-tetrahydro-2-pyranylmethylamino]hexyloxy, 6-hydroxy- .
7-{N-phenyl-N-t5-(tetrahydro-2-pyranyl)pentylamino}-
heptyloxy, 7-hydroxy-8-{N-benzyl-N-[6-~tetrahydro2-pyranyl)- .
. hexylamino}octyloxy, (2-hydroxy-2-phenylethyl)aminomethoxy,
2-- L ( 3-hydroxy-3-phenylpropyl)amino]ethoxy, 3-[(2-hydroxy-4-; :
phenylbutyl)amino]propoxy, 4-[(6-hydroxy-6-phenylhexyl)-
amino]butoxy, 5-~(2-hydroxy~2-pheny~ethyl)amino]pentyloxy,
WO9~J~1113 - 24 - PCT/JP93/~8~
~116 33 ~
5-hydroxy-6-[(2-hydroxy-2-phenylethyl)amino)hexyloxy, 6-
hydroxy-7-[N-(2-hydroxy-2-phenylethyl)-N-methylamino]-
heptyloxy, 7-hydroxy-8-[N-(2-hydroxy-2-phenylethyl)-N-
phenylamino]octyloxy, 8-hydroxy-9-[N-(2-hydroxy-~-phenyl-
ethyl)-N-benzylamino]nonyloxy, 9~hydroxy-10-[N-(2-hydroxy-2-
phenylethyl)-N-acetylamino]decyloxy, (piperazin-l-yl)-
methoxy, 2-(pyrrolidin-1-yl)ethoxy, 3~(piperidin-1-yl)-
propoxy, 4-morpholinobutoxy, 5-thiomorpholinopentyloxy, 6
(piperazin l-yl)hexyloxy, 5-hydroxy-6-(4-benzyl-1-
piperazinyl)hexyloxy, 5-hydroxy-6-~1-piperazinyl)hexyloxy,
5-hydroxy-6-(4-methyl-1-piperazinyl~hexyloxy, 4-hydroxy-5-
(l-pyrrolidinyl)pentyloxy, 4-hydroxy-5-(1-piperidinyl)-
pentyloxy, 4-hydroxy-5-morpholinopentyloxy, 5-hydroxy-6-(1-
pyrrolidinyl)hexyloxy, 5-hydroxy-6~ piperidinyl)hexyloxy,
5-hydroxy-6-(4-phenyl-1-piperazinyl)hexyloxy, 5-hydroxy-6- --~
(2-carbamoyl-1-pyrrolidinyl)hexyloxy, 7-hvdroxy-8~
pyrrolidinyl)octyloxy, 5-hydroxy-6-(2-hydroxymethyl-1 ~.
pyrrolidinyl)hexyloxy, 7--(2-carbamoylmorpholino)-6-
hydroxyheptyloxy, 8-hydroxy-9-~4-benzyl-l-piperazinyl)-
nonyloxy, 4-(3-carbamoyl-1-piperidinyl)-3-hydroxybu~oxy, 9-
hydroxy-10-~4-ethyl-1-Di.perazinyl)decyloxy, 6-(4-carbamoyl-
l-piperazinyl)-5-hydroxyhexyloxy, and the like. : ;~
The "car-boxy-substituted alkoxy" includes a
carboxy-substituted al~oxy group wherein the alkoxy moiety
is a straight chain or branched chain alkoxy group having 1
to 12 carbon atoms, f~r example, carboxymethoxy, 2-carboxy-
ethoxy, l~carboxyethoxy, 3-carboxypropoxy, ~-carboxybutoxy,
5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-
21:~33ll -
'~94/0~113 - 25 - P~T/JP~3/~83
carboxyethoxy, 2-~etnyl-3-carboxypropoxy, 7-carboxyheptyl-
oxy, 8-carboxyoctyloxy, 9-carboxynonyloxy, 10-carboxydecyl-
oxy, ll-carboxyundecyloxy, 12-carboxydodecyloxy, and the
like. ;~
The "lower alkoxycarbonyl-substituted alkoxy"
includes an alkoxycarbonyl-substituted straight chain or :~
branched chain alkoxy group having 1 to 12 carbon atoms
wherein the alkoxycarbonyl moiety is a straight chain or : :
branched chain alkoxycarbonyl group having 1 to 6 carbon ~:
~atoms, for example, methoxycarbonylmethoxy, 3-methoxy-
oarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonyl-
propoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonyl~
pentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxy- -
carbonylethoxy, 2-me~hyl 3-tert-butoxycarbonylpropoxy,~2-
pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, 7-methoxy-
carbonylheptyloxy, 8-ethoxycarbonyloctyloxy, 9-propoxy-
c~rbonylnonyloxy, 10 butoxycarbonyldecyloxy, ll-methoxy-
c2rbonylundecyloxy, 12-ethoxycarbonyldodecyloxy, and the .
like.
; The "lower al~anoyloxy-substituted lower alkoxy" ~.
includes a straight ch~in or branched chaln~alkoxy group:
having 1 to 6 carbon a~oms which is substituted by a .'
straight chain or brar.ched chain alkanoyloxy group having ~
to 6 carbon atom~, f or example / acetyloxymethoxy, 2- ~.
`- propionyloxyethoxy, l--butyryloxyethoxy, 4-acetyloxybutoxy,
3-acettyloxypropoxy, ~-lsobutyryloxybutoxy, 5-pentanoyl~
oxypentyloxy, 6-acetyloxyhexyloxy, 6-tert-butylcarbonyloxy- `
hexyloxy, l,l-dimethyl-?-hexanoyloxyethoxy, 2-methyl-3
- 26 -
W~94/01~3 PC~/JP93
211633'il
acPtyloxypropoxy, and the like.
The "lower alkenyloxy-substituted lower alkoxy"
includes a straight chain or branched chain alkoxy group ;~
having 1 to 6 carbon a~oms which is substituted by a
straight chain or branched chain alkenyloxy group having 2
to 6 carbon atoms, ror example, vinyloxymethoxy, -allyloxy-
ethoxy, l-(2-but2nyloxy)ethoxy, 3-allyloxypropoxy, 4-(3-
butenyloxy~utoxy, 5~ methylallyloxy~pentyloxy, 6~(2-
pentenyloxy)hexyloxy, l,l-dimethyl-2-(2-hexenyloxy)ethoxy,
2-methyl-3-allyloxypropoxy, and the like. `~::
The "lower alkoxy~lower)alkoxy" includes a straight .;
chain or branched chaln alkoxy group having 1 to 6 ccrbon ~;~
atoms whlch is substituted by a straight chain or branched
chain alkoxy group h~ving 1 to 6 carbon atoms, for ex~mple, ~.
m~thoxymethoxy, 3-methoxypropoxy, 4 ethoxybutoxy, 6~propoxy- .
hexyloxy, 5-isopropoxip2ntyloxy, 1,1-dimethyl-2-butox~
elhoxy, 2-methyl-~-tert-butoxypropoxy, 2-pentyloxyethoxy,
hexyloxymethoxy, cnd ~ne like.
The "lo~er alkylsulfonyloxy-substituted lower ~'
.:
alkoxy" includes a s~r~ight chain or branFhed chain alkoxy ::
group having 1 to 6 ccrbon atoms which is substituted by a
straight chain or branched chain alkylsulfonyloxy group
having 1 to 6 carbon atoms, for example, methylsulronyloxy- :~
methoxy, 3-methylsulfonyloxypropoxy, 4-ethylsulfonyloxy- :
butoxy, 2-methylsulfo~loxyethoxy, 6-propylsulfonyloxyhexyl- .:
oxy, 5-isopropylsulronyloxypentyloxy, 1,1-dimethyl-2-butyl-
sulfony~oxyethoxy, ~ thyl-3-methlsulfonyloxypropoxy, and
the like.
-~4~ 3 - 27 - 2 ~ 1 6 3 3 '1 PCT/JP93~35
The "benzoyloxy-substituted lower alkoxy" includes
a benzoyloxyalkoxy group wherein the alkoxy moiety is a ~ -
straight chain or branched chain alkoxy group having 1 to 6 ;
carbon atomsr for example~ benzoyloxymethoxy, 2-benzoyloxy-
ethoxy, l-benzoyloxyethoxy, 3-benzoyloxypropoxy, 4-benzoyl- ~
oxybutoxy, 6-benzoyloxyhexyloxy, 5-benzoyloxypentyloxy, 1,1- ;;;
dirnethyl-2-benzoyloxyethoxy, 2-methyl-3-benzoyloxypropoxy,
and the like. ~ -
The "tricyclo[3.3.1.1]decanyl-substituted lower
alkoxy" includes a tricyclo[3.3.1~1]decanyl-substituted
straight chain or branched chain alkoxy ~roup having 1 to 6 -~
carbon atoms, for example, tricyclo[3.3.1.1]decan~1methoxy,
2-tricyclo~3.3.1.1]decanylethoxy, 1-tricyclo~3.3.1.1
decanylethoxy, 3-tricyclo[3.3.1.1~decanylpropoxy, 4-
- tricyclo[3.3.1.1]decanylbutoxy, 5-tricyclo[3.3.1.1]decanyl-
p2n~yloxy, 6-tricyclo[3.3.1.1]decanylhexyloxy, l,l-dimethyl-
2-tricyclo~3.3.1.1]decanylethoxy, 2-methyl-3-tricyclo-
[~.3.1.1]decanylpropoxy, and the like.
The "lower alkylene" includes a straight chain or
branched chain alkylen~ group having 1 to 6 carbon atoms,
~ . :
for example, methylene, ethylene, trimethylene, ~'-methyltri~
methvlene, 2,2-dimethyltrimethylene, l-methyltrimethylene,
methylmethylene, ethylmethylene, tetramethylene, penta~
methylene, hexamethylene, and the like.
~ The "lower alkanoyl" includes a straight chain or
branched chain alkanoyl group having 1 to 6 carbon atoms,
for example, formyl, acetyl, propionyl, butyryl, isobutyryl,
pentanoyl, tert-b~tylcarbonyl, hexanolyl, and the like.
W~94/~1113 - 28 - PCTJ3P~3/~B~
~116~3~
The "amino having optionally one or two substi~
tuents selected from a lower alkyl, a lower aikanoyl and a ~-~
phenyl(lower)al~oxycarbonyl" includes an amino having ~:~
optionally one or two substituents selected ~rom a straigh~
chain or branched chain alkyl group having 1 to 6 carbon
atoms~ a straight chain or branched chain alkanoyl group
having 1 to 6 carbon atoms and a phenylalkoxycarbonyl group
wherein the alkoxy moiety is a straight chain or branched
chain alkoxy group having 1 to 6 carbon atoms, for example,
amino, methylamino, ethylamin~, propylamino, isopropylamino,
butylamino, tert-butylamino, pentylamino, hexylamino,
dimethylamino, diethylamino, dipropylamino~ dibutylamino,
dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl~
N-propylamino, N-methyl-N-butylamino, N-melhyl-N-hexylamino, ;~
N-benzyloxycarbonylamino, N-(2-phenylethoxycarbonyl)amino,
N-(l-phenylethoxycarbonyl)amino, N-(3-phenylpropoxy-
carbonyl)amino, N-(4-phenylbutoxycarbonyl)amino, N-(5-
phenylpentyloxycarbonyl)amino, N-(6-phenylhexyloxy-
carbonyl)amino, N--(l,l-dimethyl-2-phenylethoxycarbonyl)~
amino, N-(2-methyl-3-phenylpropoxycarbonyl~amino, N-methyl-
N-benzyloxycarbonylamino, N-ethyl-N-benzyloxycarbonyl~mino,
acetylamino, formylamino, propionylamino, butyrylamino, ~.
isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, ~-
hexanoylamino, N-methyl-N-acetylamino, N-ethyl-N-acetyl- :~
amino, N-benzyloxycarbonyl-N-acetylamino, and the like. ~.
The "benzoyl wherein the phenyl ring may optionally :~
has a substituent selected from nitro and an amino having
optionally one or two substituents selected from 2 lower
2~1 633 1 ~ :
09~/~1113 29 PCT/~P93l00835 ~
alkyl, a lower alkanoyl and a phenyl(lower)~lkoxycarbonyl " ; ~ ~;
includes a benzoyl group wherein the phenyl ring may
optionally have one to three substituents selected from
nitro and an amino op~ionally having one or two substituents
selected from a straight chain or branched chain alkyl group -- `~
having 1 to 6 carbon atoms, a straight chain or branched b-
chain alkanoyl group having 1 to 6 carbon atoms and a ~;
phenylalkoxycarbonyl group wherein the alkoxy moiety is a ..
straight chain or branched chain alkoxy group having 1 to 6 ~:
carbon atoms, for example, benzoyl, 2-aminobenzoyl, 4-amino~
benzoyl, 4-methylaminobenzoyl, 3-ethylaminobenzoyl, 2-(N- ~ ;~
methyl-N-ethylamino)benzoyl, 3-(N-methyl-N-hexylamlno)-
benzoyl, 4-dimethylaminobenzoyl, 4-dipentylaminobenzoyl, 2-
~.
isopropylaminobenzoyl, 3-butylaminobenzoyl, 4-(N-methyl-N- :~
benzyloxycarbonylamino)benzoyl, 2-[N-(2-phenylethoxy-
carbonyl)amino)benzoyl, 2,3-bis(dimethylamino)benzoyl, 3,4~
bis(methylamino)benzoyl, 3,4,5-tri(methylamino)benzoyl, 2,6- ~;
: di(N-methyl-N-benzyloxycarbonylamlno)benzoyl, 3-[N-(3-
phenylpropoxycarbonyl)amino]benzoyl, 4-1N-~5-phenylpentyl-
oxycarbonyl)amino]benzoyl, 2-[N-(6-phenylhexyloxycarbonyl)-
amino]benzoyl, 3-[N-(4-phenylbutoxycarbonyl)amino)benzoyl,
4-acetylaminobenzoyl, 3-(N-methyl-N-acetylamino)benzoyl, 2- `;~
(N-benzyloxycarbonyl-N-ac~tylamino~benzoyl, 4-nitrobenzoyl,
4-nitro-3-methylaminobenzoyl, 2,4-dinitrobenzoyl, 2,4,6- ~:
trinitrobenzoyl, and the like.
The "lower alkoxycarbonyl" includes a straight
chain or branched ch2in alkoxycarbonyl group having 1 to
carbon atoms in the alkoxy moiety, for example, metho~:y-
:,
W~94/01113 P~IJP~3l~ .
2~1~33ll ~
carbonyl, ethoxycarbonyl J propoxycarbonyl, isopropoxy-
carbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxy~
carbonyl, hexyloxycarbonyl, and the like.
The "lower alkoxycarbonyl(lower)alkyl" includes a ::~
straight chain or brar.ched chain alkoxycarbonylalkyl yroup
having l to 6 carbon atoms in the alkoxy moiety wherein the
alkyl moiety is a straight chain or branched chain alkyl ;
~roup having l to 6 carbon atoms, for example, methoxy~
carbonylmethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonyl- :~;
~propyl, ethoxycarbonylmethyl, 4-ethoxycarbonylbutyl, l-
ethoxycarbonylethyl/ 1-methoxycarbonylethyl, 6-propoxy-
~arbonylhexyl, 5-isopropoxycarbonylpentyl, 1,l-dimethyl-2
butoY.ycarbonylethyl, 7-methyl-3-tert-bu~oxycarbonylpropyl,
2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, and the
li~e.
The "amido h_~ing optionally a lower alkyl
substituent" includes ~n amido having optiGnally one or two
substituents or a straight chain or branched chain aIkyl
group having l ~o o carbon atoms, for example, carbamoyl,
methylamido, ethylamido, propylamido, isopropylamido, butyl-
amido, tert-bu~vlamido, penty1amido, hexylamido, dimethyl~
~miao, diethylamido, dipropylamido, dibutylamido, dipentyl-
amido, dihexylamidc, N-methyl-N-ethylamido, N-ethyl-N-
propylamido, N-methyl-N-butylamido, N-methyl-N-hexylamido,
and Ihe like. -
The "low~r alkylsulfonyl" includPs a straight chain ~. .
or branched chain al~ylsulfonyl group having l to 6 carbon
aioms, for example, methylsulfonyl, ethylsulfonyl, propyl- `
211~33-l
094/~1113 - 31 - P~T/JP93/~3~ :
sulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butyl~
sulfonyl, pentylsulfonyl, hexylsulfonyl, and the like. ~-
The "5- or 6-membered, saturated or unsaturated
heterocyclic group which is formed by binding the groups R4
and R5 together with the nitrogen atom to which they bond
and may be intervened or not with nitrogen, oxygen or sulfur
atom" includes, for example, pyrrolidinyl, piperi~inyl, ~;~
piperazinyl, morpholino, thiomorpholino, pyrrolyl,
pyrazolyl, imidazolyl, imidazolidlnyl, 1,2,4-triazolylj -
1,2,3,4-tetrazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl~
pyrazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl~
isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl,
isothiazolidinyl, and the like. -~
~ .
The "phenyl which may optionally have a substltuent
selected from a lower alkoxy and a halogen atom" includes a
phenyl group which may optionally have one to three
substituents selected rrom a straight chain or branched
ch~in alkoxy group havin~ 1 to 6 carbon atoms and a h210gen
atom, for example, phenyl, 2-methoxyphenyl, ~-methoxyphenyl, ~ ;~
4-methoxyphenyl, 2-ethoxyphenvl, 3 ethoxyphenyl, 4-ethoxy-
phenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 2,4-
dimethoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-
ethoxy-4-methoxyphenyl, 2,3--dimethoxyphenyl, 3,4-diethoxy-
~.
phenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5- ;.
dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3 ! 4,5-trimethoxy-
phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2
fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, ;~
3-bromophenyl, 4-bromophenyl, 2-1odophenyl, 3-iodophenyl, 4
- 32 -
W094/0~113 pCT/JP93/~8
211~33~ -:
iodophenyl, 3,~-dichlorophenyl, 3,5-dichlorophenyl, 2~6- ;
dichlorophenyl, 2,3~dichlorophenyl, 2,4-dicnloropnenyl, 3,4
difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlor_Dhenyl, 2
methoxy-3-chlorophenyl, and the like.
The "heterocyclic group which is substit~te~ by a
member selected rrom ~. phenyl having optionally
subsitutent selected rrom a lower alkoxy and a halogen a~om,
oxo, hydroxy, a lower alkenyl, carboxy, a phenyl(lowe~)alkyl
having optionally a hydroxy substituent on the 10~72r _l~vl ~:
~moiety, a lower alkanoyl, a lower alkyl having option~lly a .
hydroxy substituent, benzoyl, an amido having option2l1y a
lower alkyl substituent, anilinocarbonyl, a benzoyl(l~wer)~
alkyl, a lower alkylsulfonyl, piperidinyl, pyrimidiny~,
pyridyl, and 2 lowzr al~oxycarbonyl" lncludes the abo-Je~
mentioned heterocyclic groups wh.ich is substitlted by one to
three substituents selected from a phenyl having opticnally
one tc three subsitutents selected from 2 straight ch~in or
branched chain al~oxy group having 1 to 6 carbon a~oms and 2
halogen atom, an oxo group, a hydroxy group, a straiS--
chain or branched chain alkenyl group having 2 to 6 c2rbon :.
atoms, carboxy, a phenylalkyl wherein the alkyl moie~ is
s~raight chain or branched chain alkyl group having 1 ~o 6
carbon atoms and having optlonally a hydroxy substit~2nt, a
straight chain or branched chain alkanoyl group h2vins 1 to ;~
6 carbon atoms, a straight chain or branched chain al!;vl
group having 1 to ~ carbon atoms and having optionall-. one .-.
to three hydro~y subs~ituents, benzoylr an amido crou
having optionally onz or t~o substituents of a St! ig:,r
211633'1
`1094/01113 - 33 - P~T/JP9~0~835 :
chain or branched chain alkyl ~roup havinq 1 to 6 carbon
~toms, anilinocarbonyl, a benzoylalkyl group wherein the
alkyl moiety is a straight chain or branched chain alkyl
group having 1 to o carbon atoms, a straight chain or
branched chain alkylsulfonyl g~oup having 1 to 6 carbon
atoms in the al~yl moiety, piperidinyl, pyrimidinyl,
pyridyl, and a s~raight chain or branched chain alkoxy-
carbonyl group having 1 to 6 carbon atoms, for example~ 4~
phenylpiperazinyl, 4-~4-methoxyphenyl)piperazinyl, 4-(4- :
chlorophenyl)piperazinyl, 3-(2-ethoxyphenyl)pyrrolidinyl, 2-
(4-isopropoxyphenyl)pyrrolidinyl, 4-(~-pentyloxyphenyl)-
piperidinyl, 3-(4 hexyloxyphenyl)piperidinyl, 3-(2,3-
dimethoxyphenyl)morpholino, 2-~2-methoxyphenyl)morpholino,
3-(3-etnoxyphenyl)thiomorpholino, 2-(3,4,5-trimethoxy~
~henyl)thiomorpholino, 4-(3,4-dimethoxyphenyl)piperazinyl,
4-(3,4,5-trimethoxyphenyl)piperazinyl, 3-t2-fluorophenyl)-
pyrrolidinyl, 2-(3-bromophenyl)pyrrolidinyl, 4-(3-iodo~
phenyl)piperidinyl, 3-(4-bromophenyl)piperidinyl, 2-(3,4-
.. . i
aichlorophenyl)morpholino, 3-(3-chlorophenyl)morpholino, 3- -- ~;
~2-bro~ophenyl)thiomorpholino, 2-(4-fluorophenyl)thio~
morpholino, 4-(3,4,5-trichlorophenyl)piperazinyl, 4-(2j6
dichlorophenyl)piper~zinyl, 4-benzylpiperazinyl, 3-(2- :.
phenylethyl)pyrrolidinyl, 2-(3-phenylpropyl)pyrrolidinyl, ~-
~4-phenylbutyl)piperidinyl, 3-(5-phenylpentyl)morpholino, 2-
, ;~ ~ . . .
(6-phenylhexyl)thiomorpholino, 4-(2-phenyl-2-hydroxyethyl)
~iperazinyl, 3~ hydroxy-1-phenylmethyl)pyrrolldinyl, 2-(3
hydroxy-3-phenylpropyl)pyrrolidinyl, 4-(2 hydroxy-4-phenyl-
butyl)piperidinyl, 2-(5-hydroxy-S-phenylpentyl)thio-
';`~'.'
WO94~01113 PCT~JP93/~8
211633'1
morpholino, 3-(6-hydroxy-6-phenylhexyl)morpholino, 4-
acetylpiperazinyl, 3-formylpyrrolidinyl, 2~propionyl-
pyrrolidinyl, 4-butyrylpiperidinyl, 3-pentanoylthio-
morpholino, 2-hexanoylmorpholino, 4-methylpiperazinyl, 3,4-
dimethylpiperazinyl, ~-ethylpyrrolidinyl, 2-propyl-
pyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butyl- :~
piperidinyl, 3-pentylmorpholino, 2-hexylthiomorpholino~ 4-
benzoylpiperazi.nyl, 3-benzoylpyrrolldinyl, 3-benzoyl-
morpholino, 2-benzoylthiomorpholino, 3-benzoylpiperidinyl,
4-anilinocarbonylpiper~zinyl, 2-anilinoca~bonylpyrrolidinyl,
3-anilinocarbonylpiperidinyl, 2-anilinocarbonylmorpholino, .
3-anilinocarbonylthiomorpholino, 4-(benzoylmethyl)-
piperazinyl, 3-ll-benzoylethyl)pyrrolidinyl, 2-(3-benzoyl- ~
propyl)pyrrolidinyl, 4-(4-benzoylbutyl)piperidinyl, 3-(5- .;;
benzoylpent.yl)morpholino, 2-(6-benzoylhexyl)thiomorpholino, :~
3-methyl-4-benzoylpiperazinyl, 3-ethyl-4-acetylpiperi~diny~
3-methyl-4-benzylpvrrolidinyl, 3-propyl-4-anilinocarbonyl- :.
pyrrolidinyl, 3-methyl-5-(benzoylmethyl)morphollno, 3-
methyl-5-(2-phenyl-2-hydrcxyethyl)thiomorpholino, 4-methyl- .
sulfonylpiperazinyl, 4-methoxycarbonylpiperazlnr~l, 3-ethyl-
sulronylpyrrolidinyl, 3-ethoxycarbonylpyrrolidinyl, 4- -
propylsulfonylpiperidinyl, 3-propoxycarbonylpiperidinyl, 3- .
butylsulfonylmorpholino, 2-pentyloxycarbonylmorpholino, 2- ~ :
hexylsullonylthiomorpholino, 3-hexyloxycarbonylthio-
morpholino, 4-allylpiperazinyl, 4-ethoxycarbonylpiperidinyl, . .
4-carboxypiperidinyl, 4-dimethylamidopiperidinyl, 4-
carbamoylpiperidinyl, 4-(1-piperidinyl)piperidinyl, 3-
hydroxypiperidinyl, 2-carbamoylpyrrolidinyl, ~-hydroxy-
_ 35 _ 211~334
'094/011~3 PCr/JP93/~835
methylpiperidinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxy- ~
methylpiperidinyl, 3-hydroxypyrrolidinyl, 4-(2-hydroxy- ;--
ethyl)piperidinyl, 2-methoxycarbonylpyrrolidinyl, 2-(2- :
hydroxyethyl)piperidinvl, (2-pyrimidyl)piperazinyl, (2- ~.
pyridyl)piperazinyl, 4-oxothiomorpholino, ~ dioxothio-
morpholino, 2-methylimidazolyl, 3-methyl-1,2,4-triazolyl, 5-
methyl-1,2,3,4-tetrazolyl, 4-hydroxymethylimidazolyl, 3-
allyl-1,2,4-tria~olyl, S-phenyl-1,2,3,4-tetrazolyl, 3
carboxypyrrolyl, 2-hydroxyoxa~olidinyl, 2-carbamoyl-
''thiazolidinyl, and the like.
The "phenyl(lower)alkyl having optionally a ~-
hydroxy-substituent on the alkyl moiety and having
optionally a lower alkoxy substituent on the phenyl ring"
includes a phenylalkyl group whereln the alkyl moiety is a
straigh~ chain or branched chain al,;yl group having 1 to 6 ;~
carbon atoms and having optionally a hydroxy-subs~ituent ana
~. .
the phenyl ring has optionally one to three substituents of
,
a: straight chain or branched chain alkoxy group having 1 to '.`-
6 carbon atoms, for example, in addition to the abov~
mentioned phenyl(lower)alkyl groups, l-hydroxy-l-phenyl~
methyl, l-phenyl-2-hydroxyethyl, 2-phenyl-2-hydrcxyethyl, 3- ' ~
hydroxv-3-phenylpropyl, 2-hydroxy-4-phenylbutyl, 6-hydroxy- '` ''
6-phenylhexy', 3,4-dimethoxybenzyl, 3-methoxybenzyl, 1-(2-
methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 3-(2-ethoxy- '~
phenyl)propyl, 4-(3-ethoxyphenyl)butyl, 5-(4-ethoxyphe~nyl)-
pentyl, 6-(4-isopropoxyphenyl)hexyl, 1,1-dimethyl-2-(4- i
pentyloxyphenyl)ethyl, 2-methyl-3-l4-hexyloxyphenyl)propyl/
3-ethox~-4-methoxyben~yl, 2,3-dimethoxybenzyl, 3,4-diethoxy-
~ :'
W09~/01113 - 36 - PCT/JP93/~g
211633~
benzyl, 3,4,5-trimethoxyben~yl, l--hydroxy-l-(3-methoxy-
phenyl)methyl, l-(2,5-dimethoxyphenyl)-2-hydroxyethyl, 2-
(2,6-dimethoxyphenyl)-2-hydroxyethyl, 5-hydroxy-5-~3,4-
dipentyloxyphenyl)pentyl, and the like.
The "benzoyl(lower)alkyl" includes a ben~oylalkyl
group ~herein the alkyl moiety is a straight chain or
branched chain alkyl group having l to 6 carbon atoms, for
example, benzoylmethyl, l-benzoylethyl, 2-ben~oylethy1, 3-
benzoylpropyl, 4-ben70ylbutyl, 5-benzoylpentyl, 6~benzoyl~
hexyl, l,l-dimethyl-2 benzoylethyl, 2-methyl-3-benzoyl-
propyl, and the like.
The "carbamoyloxy-substituted lower alkoxy"
includes a carbamoyloxy-subst1tuted alkoxy group wherein the
alkoxy moiety is a straight chain or branched chain alkoxy
group having l to 6 carbon atoms, for example, carbamoyloxy-
methoxy, ~-carbamoyloxyethoxy/ 1-carbamoyloxyethoxy, 3- -
carbamoyloxypropoxy, ~-carbamoyIoxybutoxy r 5-carbamovloxy-
pentyloxy, 6-carbamoyloxyhexyloxy, l,l-dime~hyl-2-carbamoyl-
oxyethoxy, 2-methyl-3-carbamoyloxypropoxy, and the like.
The "lower alkylthio-substituted alkoxy" includes a
alkylthio-substituted s~raight chain or branched chain `~
alkoxy group having l to 6 carbon atoms wherein the -~
alkylthio moiety is a straight chain or branched chain `~
alkylthio group having l to 6 carbon atoms, for example,
methylthiomethoxy, 3-ethylthiopropoxy, 4-methylthiobutoxy, --
2-methylthioethoxy, 6-propylthiohexyloxy, 5-isopropylthio~
pentylsxy, l,l-dimethy~-2-butylthioethoxy, 2-methyl-3-
methylthiopropoxy, and the like.
_ 37 _ 211633~
'094/01113 PCT~3P93~00835
The "lo~er alkylsulfonyl-substituted lower alkoxy"
includes a straight chain or branched chain alkoxy group
having 1 to 6 carbon atoms which is substituted bv a
straight chain or branched chain alkylsulfonyl group having ~ .
1 to 6 carbon atoms, for example, methylsulfonylmethoxyj 3-
ethylsulfonylpropoxy, 4 methylsulfonylbutoxy, 2-methyl- :;
sulronylethoxy, 6-propylsulfonylhexyloxy, 5-isopropyl-
sulfonylpentyloxy, l,l-dimethyl-2-butylsulfonylethoxy, 2- ~:
methyl-3-methylsulfonylpropoxy, and the like.
The "lower alkylsulfinyl-substituted lower alkoxy" -
includes a straight chain or branched chain alkoxy group
having 1 to 6 carbon atoms which is substituted by a `~
straight chain or branched chain alkylsulfin:yl group having
1 to 6 carbon atoms, for example, methylsulrinylmethoxy, 3
ethylsulfinylpropoxy, 4-methylsulfinylbutoxy, :2-m~thyl- `
sulfinylethoxy, 6-propylsulrinylhexyloxy, 5-isopropyl- ~.
sulinylpentyloxy, 1,1-dimethyl-2-butylsulfinylethoxy, 2-
: ~ methyl-3-methylsu~lfinylpropoxy, and the like.
The "alkenyloxy"-includes a straight chain or
branched chain alkenyl group having 2 to 12 carbon atoms and
containin~ one to three double bonds, for example, vlnyloxy~
allyloxy, 3-methyl-2-butenyloxy, 2-butenyloxy, 3-butenyloxy, -
l-methylallyloxy, 2-pentenyloxy, 2-hexenylcxy, l-heptenyl~
o~y, l-o~tenyloxy, l-nonenyloxy, l-decenyloxy, l-undecenyl-
oxy, l-dodecenyloxy, 2-heptenyloxy, 3-heptenyloxy, 2-~e~hyl-
4-heptenyloxy, 2-methyl-S-heptenyloxy, 4-methyl-2-heptenyl- ;;.:
oxy, 3-methyl-1-heptenyloxy, 1,3-heptadienyloxy, ,4-:nepta-
dienyloxy, l,S-heptadienyloxy, ~,6-heptadienyloxy, 2,'-
WO94/01113 - 38 - PCT/JP93/~
211633~
heptadienyloxy, 2-methyl-2,4-heptadienyloxy, 2,6-dimethyl-
2,4-heptadienyloxy, 2,5-dimethyl-1,3-heptadienyloxy, 2,4,6-
trimethyl-2,4-heptadienyloxy, 2-octenyloxy, 3-octenyloxy, 4-
octenyloxy, 2-me~hyl-5-octenyloxy, 2-methyl-6-octenyloxy, 2- -
methyl-7-octenyloxy, 1,3-octadienyloxy, 1,4-o~tadienyloxy,
1/5-octadienyloxy, 1,6 octadienyloxy, 1,7-octadienyloxy, ~ ~
2,4-octadienyloxy, 3,7-octadienyloxy, 4,8-dimethyl-3,7- ~ .
octadienyloxy, 2,4,6-trimethyl-3,7-octadienyloxy, 3,4~
:...
dimethyl-2,5-octadienyloxy, 3,7-dimethyl-2,6-octadienyloxy, .~ .
4,8-dimethyl-2,6-octadienyloxy, 2 nonenyloxy, 3-nonenyloxy, .;
4-nonenyloxy, 2-methyl-5-nonenyloxy, 2-methyl-6-nonenyloxy, . :~
2-methyl-7-nonenyloxy, 2-methyl-8-nonenyloxy, 1,3-non~
dienyloxy, 1,4-nonadienyloxy, 1,5-nonadienyloxy, 1,6-nona-
dienyloxy, 1,7-nonadienyloxy, 1,8-nonadienyloxy, 2,4-nona- :
dienyloxy, 3,7-nonadienyloxy, 4,8-dimethyl-3,7-nonad~enyl- ;
oxy, 2,4,6-trimethyl-3,7-nonadienyloxy, 3,4-dimethyl-2,5- -
nonadienyloxy, 4,8-dimethyl-2,6-nona~ienyloxy, 2-dec~nyloxy, : `
' :.`, ~ '.
3-decenyloxy, 4 decenyloxy, 5-decenyloxy, 2-methyl-6~
.:~ ' '.
decenyloxy~ 3-methyl-7-decenyloxy, 4-methyl-8-decenyloxy, 5-
:.:
methyl-9-decenyloxy r 1/ 3-decadienyloxy, 1,4-decadienyloxy,
1,5-dec~dienyloxy, 1,6-decadienyloxy, 1,7:-decadienyloxy,
1,8-decadienyloxy, l,9-decadlenyloxy, 2-methyl-2,~-deca~
dienyloxy r 3~methyl-~,5-decadienyloxy, 4,8-dimethyl-2,6-
decadienyloxy, 2,4,6-trimethyl-3,7-decadienyloxy, 2,9- -
dimethyl-3,7-decadienyloxy, 2-undecenyloxy, 3-undecenyloxy,
4-undecenyloxy, 5-undec~nyloxy, 2-methyl-6-undecenyloxy, 3~
methyl-7-undecenyloxy, 4-methyl-8-undecenyloxy, 5-met:~yl-9-
undecenyloxy, 2-methyl-10-undecenyloxy, 1,3-undecadienyloxy, ~
. .
: .
" ~'
211~33'1
'094/011~3 ~T~JP~3/~83
1,4-undecadienyloxy~ 1,5-undecadienyloxy, 1,6-undecadienyl~
oxy, 1,7-undecadienyloxy, 1,8-undecadienyloxy, 1,9-undeca-
dienyloxy, l,10-undecadienyloxy, 2-methyl-2,4-undecadienyl-
oxy, 3-me~hyl-~,5-undec~dienyloxy, 4,8-dimethyl-2,6-undeca-
dienyloxy, 2,4,6-trimethyl-3,8-undecadienyloxy, 2,9-
dimethyl-3,8-undecadienyloxy, 2-dodecenyloxy, 3-dodecenyl-
oxy, 4-dodecenyloxy, 5-dodecenyloxy, 6-dodecenyloxy, 2-
m~thyl-7-dodecenyloxy, 3-methyl-8-dodecenyloxy, 4-methyl-9
dodecenyloxy, S-methyl-10-dodecenyloxy, 6-methyl~
dodecenyloxy, 2-methyl-2,4-dodecadienyloxy, 3-methyl-2,5- ~.-
dodecadienyloxy, 4,8-dimethyl-2,6-dodecadienyloxy, 2 9 4,6-
trimethyl-2,7-dodecadienyloxy, 2,10-dimethyl-2,8-dodeca- -
dienyloxy, ~,5-dimethyl-3,7~dodecadienylox~, 4,8,12~
trimethyl-3,7,11-dodecatrienyloxy, 1,3j5-heptatrienyloxy,
: 2,4,6-octatrienyloxy, 1,3,6-nonatrienyloxy, 2,6,8-dodeca-
trienyloxy, l,5,7-undecatrienyloxy, and the like. -`
The "lo~er alkanoyloxy" includes a s~raight chain~:~
or branched chain alkanoyloxy group having 1 to 6 carbon ~ -;
atoms, for example, ormyloxy, acetyloxy, propionyloxy,~
-:.
butvryloxy, isobutyryloxy, pentanoyloxy, ter~-~utyl~
carbonyloxy, hexanoyloxy, and the like.
The "lower alkylsulfonyloxy" includes a str2ight ~:
ch~in or branched chain al~ylsulronylo~y group having ~ to 6
carbon atomsl for example, methylsulfonyloxy, ethylsulfonyloxy, -~
isopropylsulfonyloxy, butylsulfonyloxy, tert-butylsulfonyloxy, :~
pentylsulfonyloxy, hexylsulfonyloxy, and the like.
The "lower alkynyloxy" includes a straight chain or
branched chain alkynyloxy group having 2 to 6 carbon ~toms,
WO9~/011~3 p~T/JP93/~8
21163~
for example, ethynyloxy, 2-propynyloxy, 2-bu~ynyloxy, 3- ~:
butynyloxy, l-methyl-2-propynyloxy, 2-pentynyloxy, 2-
hexynyloxy, and the like.
The "phenyl(lower)alkoxy" includes a phenylalko~y ~. .
group wherein the alkoxy moiety is a straight chain or
branched chain alkoxy ~roup having l to 6 carbon atoms, for :
example, ben~yloxy, 2-phenylethoxy, l-phenylethoxy,
phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6- -
phenylhexyloxy, l,l-dimethyl-2-phenylethoxy, 2-methyl-3~
phenylpropoxy, and the like. ~.
The "cycloalkyloxy" includes a cycloalkyloxy group ~:~
having 3 to 8 carbon ~toms, for example, cyclopropyloxy,
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy t cyclooctyl-
oxy, and the like.
The "cycloalken~yloxy" includes a cycloal~enyloxy
group having 3 to ~ carbon atoms, for exampler cyclo- :~
propenyloxy, cyclobutenyloxy, cyclopentenvloxy, cyclo- `~:~
h~xenyloxy, cycloheptenyloxy, cyclooctenyloxy, and tne like.
The "lower al~anoyl which may optionally have on~
to three substituents of a halogen atom" includes a straight -~;
chain or branched chain alkanoyl ~roup having l to 6 carbon :~
atoms which may optionally have one to three substituents of
a halogen atom, for e~ample, in addition to the above
mentioned lower alkanoyl groups, 2,2,2-trifluoroacetyl,
2,2,2-trichloroacetyl, 2-chloroacetyl, 2-bromoacetyl, 2
fluoroacetyl, 2-iodoacetyI, 2,2-dirluoroacetyl, 2,2-dibromo-
acetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl,
3 chloropropionyl, 2,3-dichlopropionyl, 4,4,4-trichloro-
:
211~334 ~
'~4/011~3 - 41 - p~T~JP93/~835
butyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-
methylpropionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl, and
the like. : :
The "lower alkenyl" includes a straight chain or
branched chain alkenyl group having 2 to 6 carbon atoms, for
example, vinyl, allyl, 2-butenyl, 3-butenyl, l-methylallyl~
2-pentenyl, 2-hexenyl, and the like. ;:
The "lower alkylthio" includes a straight chain or
branched chain alkylthio group having l to 6 carbon atoms,
for example, methylthio, ethylthio, propylthio, isopropyl-
thio, butylthio, tert-butylthio, pentylthio, hexylthio, and
the like.
The "5- or 6-membered~ saturated or unsaturated
heterocyclic group ~hich is formed by binding p6 and R7
together ~7ith '-he nitrogen atom to which they bond and may
be intervened or not with nitrogen, oxygen or sulfur atom"
includes/ for example, pyrrolidinyl, piperidinyl, piperazinyl, ~.
morpholino, thiomorpholino, pyrrolyl, pyrazoIyl, imidazolyl, .
imidazolidinyl, pyrrolyl, imidazolinyl, pyrazolinyl,
pyrazolidinyl, oxazolinyl, oxaæolidinyl, isoxazolinyl,
. ~
isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl,
isothiazolidinyl, and the like. .
The "heterocyclic group having a substituent .:~.
selected from a lower alkoxycarbonyl, lower alkyl, lower ~.
alkylthio and oxo" includes the above heterocyclic groups ;.
which have a substituent select~d from a straight chain or -:
branched chain alkoxycarbonyl group having l to 6 carbon
atoms, a straight chein or branched chain alkyl group having
'~
, .
WO94~01113 - 42 -- PC~/JP93/~8?
211633~
1 to 6 carbon atoms, a straight chain or branched chain :~
alkylthio group having 1 to 6 car~on atoms, and an oxo
group, for example, 4-tert-butoxycarbonylpiperazinyl, 4-
methylpiperazinyl, 2-ethylthioimida~olyl, 2-oxopyrrolidinyl,
2-oxo-oxazolidinyl, 3-oxopiperazinyl, 4-methoxycarbonyl- :
piperazinyl, 3--ethoxycarbonylpiperidinyl, 2-propoxycarbonyl-
pyrrolidinyl, 3-pentyloxycarbonylthiomorpholino, 2-hexyloxy-
carbonylthiomorpholino, 3--ethoxycarbonylpyrrolyl, 3-methoxy-
carbonylimidazolyl, 3-ethylpiperidinyl, 3-propylpyrrolidin- `
yl, 3-butylpyrrolyl, 2-pentylimidazolyl, 3-hexylmorpholino,
2-methylthiomorpholino, 2-methyloxazolidinyl, 2-ethyl- .
thiazolinyl, 3-methylisoxazolinyl, 2-methylthioimidazolyl,
2-propylthioimidazolinyl, 2-butylthioimidazolidinyl, 3-
pentylthiopyrrolyl, 3-hexylthiopyrrolinyl, 3-methylthio- ;~
pyrrolidinyl, 3-ethylthiomorpholino, 2-methylthiomorpholino, :~
2-methylthioisoxazolidinyl, and the like.
The "lower alkyl which may optionally have one to :-~
three substituents selected from a halogen atom, hydroY.y,
phenyl and a lower alkoxy" includes a straight chain o~ -~
branched chain alkyl sroup having 1 to 6 carbon atoms which
,.~.~. ." ~.
may optionally have one to three substituents selected from
-.
a halogen atom, hydroxy, phenyl and a straight chain or
branched chain alkoxy group having 1 to 6 earbon atoms, ror .~-
example, in addition to the above-mentioned lower alkyl :~
c-,
groups, hydroxymethyl, 2-hydroxyethyl, l-hydroxyethyl, 3- ;
hydroxypropyl, 2,3-dihyroxypropyl, 4-hydroxybutyl, 1,1 : :~
dimethyl-2-hydroxyethyl, 5,5,4-trrhydroxypentyl, 5-hydroxy~
pentyl~ 6-hydroxyhexyl, l-hydroxyisopropyl, 2-methyl-3
,'"' ':.
;: .'.~
211~331 ~ :
'l094/01113 ~ 43 - pCTlJP93/~835
hydroxypropyl, trifluoromethyl, trichloromethyl, chloro-
methyl, bromomethyl, fluoromethyl, iodomethyl, difluoro~
methyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, ;~
2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, -~
4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-
chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl, ~.
ben~yl~ l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-
phenylbutyl, l,l-dimethyl-2-phenylethyl, 5-phenylpentyl, 6
phenylhexyl, 2-methyl-3-phenylpropyl, methoxymethyl, 3-
~. ,
methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl, 5-isopropoxy-
pentyl, l,l-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxy ;~
propyl, 2-pentyloxyethyl, hexyloxymethyl, di~ethoxymethyl,
2,3-dimethoxyethyl, o,oj5-trlmethoxyhexyl, l-hydroxy-l- ;
phenylmethyl, l-hydroxy-2-phenylethyl, 1-hydroxy-3-phenyl-
propyl, l-methoxy-l-phenylmethyl, and the like.
The "cyano-substituted lower alkoxy" includes a
straight chain or branched chain alkoxy group having 1 to 6
carbon atoms ~7hlch is substituted by cyano group, for : :
example, cyanomethoxy, 2-cyanoethoxy, l-cyanoethoxy, 3- ~ ~
cyanopropoxy, 4-cyanobutoxy, 5-cyanopentyloxy, 6-cyanohexyl- ;.
oxy, l,l-dimethyl-2-cyanoethoxy, 2-methyl-3--cyanopropoxy~
and the like.
' ' ' ',','; ~`~
The "oxiranyl-substituted lower alkoxy" includes a :`~
straight chain or branched chain al~oxy group having 1 to ~
carbon atoms which i5 substituted by oxiranyl group, for .`:.
example, glycidoxy, 2-oxiranylethoxy, l-oxiranylethoxy, 3-
oxiranylpropoxy, 4-oxiranylbutoxy, 5-oxiranylpentyloxy, 6~ `~
~ ~.":.
oxiranylhexyloxy, l,l-dimethyl-2-oxiranylethoxy, 2-methyl-3-
'',''~"'.
'.:
W094/01~l3 - 44 - PCr/JP93/~8'
2116334
oxiranylpropoxy, and ~he like.
The "phthalimido substituted alkoxy" includes a
straight chain or .branched chain alkoxy group having 1 to 12 ~;~
carbon atoms which is substituted by phthalimido group, for
example, phthalimidomethoxy, 2-phthalimidoethoxy, l-phthal- ;~.
imidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxyr 5-
phthalimidopentyloxy, D-phthalimidohexyloxy, 1,1-dimethyl-2-
phthalimidoethoxy, 2-methyl-3-phthalimidopropo~y, 7-phthal-
imidoheptyloxy, 8-phthalimidooctyloxy, 9-phthalimidononyl- `::~
oxy, 10-phthalimidodecyloxyr ll-phthalimidoundecyloxy, 12-
phthalimidododecyloxy, and the like.
The "pyrrolyl-substituted lower alkoxy" includes a
straight chain or branched chain alkoxy group having 1 to 6`.
. ~
carbon atorns which is substituted by pyrrolyl group, for --
example, ~l-pyrrolyl)methoxy, 2-~2-pyrrolyl)ethoxy, 1-(3- .;
pyrrslyl)ethoxy, 3~ pyrrolyl)propoxy, 4~ pyrr~lyl)~
bu~oxy, 5-~2-pyrrolyl)pentyloxy, 6-(3-pyrrolyl)he~yloxy,
1,1-dimethyl-2-(1-pyrrol~l)ethoxy, 2-methyl-3-ll-pyrrolyl)-
propo~y, and the like. ;~
The "ami~ino-substituted lower alkoxy" :incluaes~a~
straight chain or branched chain alkoxy group having 1 to 6.--~
carbon atoms whlch is substituted by amidino group, for
eY.ample, amidinomethoxy, 2-amidinoethoxy, l-amidlnoethoxy, ~-
3-amidinopropoxy, 2-amidlnobutoxy, 5-amidinopentyloxy, 6- .-
amidinohexyloxy, l,l-dimethyl 2-amidinoethoxy, 2-methyl-3-
~midinopropoxy, and the like.
The "lower alkanoyloxy(lower)alkyl" includes a
straight chain or branched chain alkyl group having 1 ~o 6
211633'1
- 45
~4/011~3 PCT/JP93J0083
carbon atoms which is substituted by a straight chain or
branched chain alkanoyloxy group having 2 to 6 carbon atoms,
for example, acetyloxymethyl, 2 propionyloxyethyl, l~
butyryloxyethyl, 3-acetyloxypropyl, 4-isobutyryloxybutyl, 5-
pentanoyloxypentyl, 6-tert~butylcarbonyloxyhexyl, l r 1-
dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, and
the like. -~
The "lower alkylsulfinyl" includes a straight chain
or branched chain alkylsulfinyl group having l to 6 carbo~
atoms, for example, methylsulfinyl, ethylsulfinyl,
isopropylsulfinyl, butylsulfiyl, tert-butylsulfinyl,
penkylsulfinyl, hexylsul~inyl, and the like.
The "lower alkenyl having optionally a hydroxy- -
substituent" include a straight chain or branched cha1n ;
:~ aIkenyl group having 2 to 6 carbon atoms and havlng
optionally a hydroxy-substituent, for example, in addition
.,~ , ,.
to the above mentioned lower alkenyl groups, l-hydroxya:llyl, - -
...... ...
4-hydroxy-l-butenyl, 4-hyd~oxy-2-buteny1,:2-hydroxy-3-buteny1,
5-hydro~y-2-pentenyl, 6~hydroxy-2-hexenyl, and the li~P.
The "lo~er alkylenedioxy" includes a straight chain ` .
or branched chain alkylenedioxy group having 1 to~4 carbon ~;~
atoms, for exa~ple, methylenedioxy, ethylenedioxy, -~
~: .
trimethylenedioxy, tetramethylenedioxy, and the llke.
The "lower alkylsilyl" includes a silyl group .. ~ .
having one to three substituents of a straight chain or .;
branched chain alkyl group having l to 6 carbon atoms, for
example, methylsilyl, ethylsilyl, propylsilyl,
isopropylsilyl, butylsilyl, tert-butylsilyl, pentylsilyl, ~-
"
WO94/01113 - 46 - P~TIJP93~00~
211~33~
hexylsilyl, dimethylsilyl, trimethylsilyl, dimethyl-tert- -~
butylsilyl, and the like. -~
The "amino which may optionally be substituted by a ~ ;~
lower alkanoyl" includes an amino which may optionally be
substituted by a straight c~lain or branched chain alkanoyl ~:
group having 1 ~o 6 carbon atoms, for example, amino,
formylamino, acetylamino, propionylamino, butyrylamino, -~
isobutyr~lamino, pent~noylamino, ~ert-butylcarbonylamino,
hexanoylamino, and the llke.
The '`phenoxycarbonyl which may optionally have one :~
to three substituen~s selected from nitro and an amino
having optionally one or two substituents selected from a
lower alkanoyl, lower alkyl and benzoyl" includes a -.
phenoxycarbonyl group which may optionally have one to three ; -
substituents selected from nitro group and an amino group .
having optionally one or two substituents selected from a
straight chain or branched chain alkanoyl group having l to .:
6 carbon atoms, a straight châin or brancned chain alkyl
group having 1 to 6 carbon atoms:and benzoyl group, for
:. ~
example, phenoxycarbonyl, 2-nitrophenoxycarbonyl, 3-nltro-
phenoxycarbonyl, 4-nitrophenoxycarbonyl, 3,4-dinltrophenoxy~
carbonyl, 2,5-dinitrophenoxycarbonyl, 2,6-dinitrophenoxy-
carbonyl, 3,4,5-trinitrophenoxycarbonyl, 2-amlnophenoxy-
carbonyl, 3-aminophenoxycarbonyl, 4-aminophenoxycarbonyl, 3-
acetylaminophenoxycarbonyl, 4-formylaminophenoxycarbonyl,~ 4~
isobutyrylaminophenoxycarbonyl, 2-pentanoylaminophenoxy- .;
carbony1, 3-hexanoylaminophenoxycarbonyl, 3,4-diacetylamino-
phenoxycarbonyl, 3,4-diaminophenoxycarbonyl, 2,6-diaminophe~ ::
211S33~
- 47 -
`'094/011~3 PCT/JP93~3
noxycarbonyl, 2,5-diaminophenoxycarbonyl, ~,4,6-triamino-
phenoxycarbonyl, 4-acetylaminophenoxycarbonyl, 4-dimethyl- :;
aminophenoxycarbonyl, 4-benzoylaminophenoxycarbonyl, 3-(N-
methyl-N-benzoylamino)phenoxycarbonyl, 2-(N-ethyl-N-acetyl-
amino)phenoxycarbonyl, and the like.
The "phenyl(lower)alkenylcarbonyl" includes a
phenylalkenylcarbonyl group wherein the alkenylcarbonyl ~
moiety is a straight chain or branched chain alkenylcarbonyl: ~:
group having 3 to 6 carbon atoms, for example, cinnamoyl, 4~
. . .
phenyl-3-butenoyl, 4-phenyl-2-butenoyll 5-phenyl-4~
pentenoyl, 5-phenyl-3 pentenoyl, S~phenyl-2-pentenoyl, 6-
phenyl-5--hexenoyl, 6-phenyl-4-hexenoyl, 6-phenyl-3-hexenoyl,
6-phenyl-2-hexenoyl, 2-methyl-4-phenyl-3-butenoyl r and the -~
like.
The "amino having optionally a lower alkoxycarbonyl
substituentl' includes an amino being optionally substituted ;
by a straight chain or branched chain alkoxycarbonyl group
having 1 to 6 carbon atoms, for example, amino, rnethoxy-
carbonylamino, ethoxycarbonylamino, propoxycarbonylamino,
isopropoxycarbonylamino, butoxycarbonylamlno, tert-butoxy~
. ~ .
carbonylamino, pentyloxycarbonylamino, hexyloxycarbonyl~
amino, and the like. - ~:
The "phenyl~lower)alkanoyl wherein the lower
alkanoyl moiety may optionally be substituted by an amino
having optionally a lower alkoxycarbonyl substituent" ~
includes a phenylalkanoyl wherein the alkanoyl moiety is a :~:
straight chain or branched chain alkanoyl group having 2 to ;~
6 carbon atoms and may optlonally be substituted by an amino
'
~ ~8 -
W094J0~113 PCT/JP93/~
211633~1
group which may optionally be substituted by a straight
chain or branched chain alkoxycarbonyl group having l to 6
carbon atoms, for example, phenylacetyl, 3-phenylpropionyl,
2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenyl- .
propionyl, 5-phenylpentanoyl, 6-p~lenylhexanoyl, 3-methyl-4- :-;
phenylbutyryl, 2-amino-4-phenylacetyl, 2-tert-butoxy-
carbonylamino-2-phenylacetyl, 2-methoxycarbonylamino-2- ;-
phenylacetyl, 2-ethoxycarbonylamino-3-phenylpropionyl, 2- ~ ~
propoxycarbonylamino-4-phenylbutyryl, 2-pentyloxycarbonyl- ~-.
amino-5-phenylpentanoyll 2-hexyloxycarbonylamino-6-phenyl- ~
hexanoyl, and the like. ~-
The "alkanoyl" includes a straight chain or -.
branched chain alkanoyl group having l to 12 carbon atoms, -
for example, in addition to the above-mentioned lower .. :
alkanoyl groups, heptanoyl, octanoyl, nonanoyl, decanoyl,
undecanoyl, dodecanoyl, neopentanoyl, and the like. ~:
The "alkenylcarbonyl" lncludes a straight chain or ` .
branched chain alkenylcarbonyl group having 2 to 12 carbon
. . ~ .
atoms and having one to three double bonds, for example, :-;
vinylcarbonyl, aorylcarbonyl, 3-methyl-2~-butenylcarbonyl, 2-
butenylcarbonyl, l-methylallylcarbonyl, 2 pentenylcarbony~
2-hexenylcarbonyl, l-heptenylcarbonyl, 1-octenylcarbonyl, l-
nonenylcarbonyl, l-decenylcarbonyl, l-undecenylcarbonyl, l-
dodecenylcarbonyl, 2-heptenylcarbonyl, 3-heptenylcarbonyl,
2-methyl-4-heptenylcarbonyl, 2-methyl-5-heptenylcarbonyl, 4-
methyl-2 heptenylcarbonyl, 3-methyl-l-heptenylcarbonyl, l,3- ~
heptadienylcarbonyl, l,4-heptadienylcarbonyl, l,5-hepta- .
dienylcarbonyl, l,6-heptadienylcarbonyl, 2,4-heptadienyl-
211S33~1
- 49 -
'094/01113 PCT~JP93/~g3
carbonyl, 2-methyl-2,4-heptadienylcarbonyl, 2,6-dimethyl-
2,4-heptadienylcarbonyl, 2,6-dimethyl-l,5-heptadienyl-
carbonyl, 2,5-dimethyl-l,3-heptadienyl~arbonyl, 2,4,6-
trimethyl-2,4-heptadienylcarbonyl, 2 octenylcarbonyl, 3- - :
octenylcarbonyl, 4-octenylcarbonyl, 2-methyl-5-octenyl- ~
carbonyl, 2-methyl-6-octenylcarbonyl~ 2-methyl-7-octenyl- :.
carbonyl, l~3-octadienylcarbonyl, l,4-octadienylcarbonyl,
l,5-octadienylcarbonyl, l,6-octadienylcarbonyl, l,7-
octadienylcarbonyl, 2,4-octadienylcarbonyl, 3,7-octadienyl-
carbonyl, 4,8-dimethyl-3,7-octadienylcarbonyl, 2,4,6- .
trimethyl-3,7-octadienylcarbonyl, 3,4-dimethyl-2J5-
octadienylcarbonyl, 4,8-dimethyl-2,6-octadlenylcarbonyl, 2
nonenylcarbonyl, 3-nonenylcarbonyl, 4-nonenylcarbonyl, 2-
methyl-5-nonenylcarbonyl, 2-methyl-6-nonenylcarbonyl, 2-
methyl-7-nonenylcarbonyl, 2-methyl-8-nonenylcarbonyl, l,3- ;
nonadienylcarbonyl, l,4-nonadienylcarbonyl, l,5-nonadien~
carbonyl, l,6-nonadienylcarbonyl~ l,7-nonadienylcarbonyl,
l,8-nonadienylcarbonyl, 2,4-nonadienylcarbony1, 3,7
nonadienylcarbonyl, 4,8-dimethyI-3,7~nonadienylcarbonyl, '~
2,4,6-trimethyl-3,7-nonadienylcarbonyl, 3,4-dimethyl-2,5
nonadienylcarbonyl, 4,8-dimethyI-2,6-nonadienylcarbonvl, 2~
decenylcarbonyl, 3-decenylcarbonyl, 4-decenylcarbonyl, 5- ~-
decenylcarbonyl, 2-methyl-6-decenylcarbonyl, 3-methyl-7-
decenylcarbonyl, 4-methyl-8-decenylcarbonyl, 5-methyl-9- :~
decenylcarbonyl, l,3-decadienylcarbonyl, l,4-decadienyl-
carbonyl, l,5-decadienylcarbonyl, l,6-decadienylcarbonyl,
l,7-decadienylcarbonyl, l,8-decadienylcarbonyl, l,9-
decadienylcarbonyl, 2-methyl-2,4-decadienylcarbonyl, 3-
- so -
WO9~/01113 P~T/JP93/~$~
211633~ ;
methyl-2,5-decadienylcarbonyl, ~,8-dimethyl 2,6-decadienyl~
carbonyl, 2,4,6-trimethyl-3,7-decadienylcarbonyl, 2,9-
dimethyl-3,7-decadienylcarbonyl, 2-undecPnylcarbonyl, 3-
undecenylcarbonyl, 4-undecenylc~rbon~l, 5-un~ecenylcarbonyl,
2-methyl-6-undecenylcarbonyl, 3-methyl-7 undecenylcarbonyi, . ;~
4-methyl-8-undecenylcarbonyl, 5-methyl-9-undecenylcarbony;, :-~
2-methyl-10-undecenylcarbonyl, 1,3-undecadienylcarbonyl, -
1,4-undecadienylcarbonyl, 1,5-undecadienylcarbonyl, 1,6
undecadienylcarbonyl, 1,7-undecadienylcarbonyl, 1,8-
undecadienylcarbonyl, l,9-undecadienylcarbonyl, 1,10 -:
undecadienylcarbonyl, 2-methyl-2,4-undecadienylcarbonyl, -
3-methyl-2,5~undecadienylcarbonyl r 4,8-dimethyl-2,6~
undecadienylcarbonyl, 2,4,6-trimethyl-3,8-undecadienyl-
carbonyl, 2,9-dimethyl-3,8-undecadienylcarbonyl, 2- ~:~
dodecenylcarbonyl, 3-dodecenylcarbonyl, 4-dodecenylcarbonyl, :~
5-dodecenylcarbonyl, 6-dodecenylcarbonyl, 2-methyl-7- :
dodecenylcarbonyl, 3-methyl-8-dodecenylcarborlyl, A-methyl-9-
dodecenylcarbonyl, S-methyl-10-dodecenylcarbonyl, 6-me~hyl- ~:
ll-dodecenylcarbonyl, 2-methy'-2,~-dodecadienylcarbonyl, '~ ~-
methyl-2,5-dodecadienylcarbonyl, 4,8-dimethyl-2,6- :-
dodecadienylcarbonyl, 2,4,6-trime~hvl-2,7-dodecadienyl- :~
carbonyl, 2,10-dimethyl-2,8-dodecaalerylcarbonyl, 2,5-
dimethyl-3,7-dodecadienylcarbonyl, 4,8,12-trimethyl-3,7,11-
dodecatrienylcarbonyl, 1,3,5-heptatrienylcarbonyl, 2,4,6-
octatrienylcarbonyl, 1,3,6-nonatrienylcarbonyl, 2,6,8- ;:
dodecatrienylcarbonyl, 1,5,7-undec-~rienylcarbonyl, and th~
lik~
The "phenylsul~onyl wherein ~ne phenyl ring may :
~:~
'094~01113 - 51 ~ 2 1 1 ~ 3 3 'I PcT/Jp93/~o~3~ ~
optionally have a lower alkoxy substituent" includes a
phenylsulfonyl group wherein the phenyl ring may optionally
have one to three substituents of a straiyht chain or
branched chain alkoxy group having l to 6 carbon atoms, for
example, phenylsulfonyl, 2-methoxyphenylsulfonyl, 3-methoxy- ^
phenylsulfonyl, 4-methoxyphenylsulfonyl, 2-ethoxyphenyl~
sulfonyl, 3-ethoxyphenylsulfonyl, 4-ethoxyphenylsulfonyl, 4
isopropoxyphenylsulfonyl, 4-pentyloxyphenylsulfonyl, 4-
hexyloxyph2nylsulfonyl, 3,4-dimethoxyphenylsulfonyl, 3- ` .
ethoxy-4-methoxyphenylsulfonyl, 2,3-dimethoxyphenylsulfonyl,
3,4-diethoxyphenylsulfonyl, 2,5-dimethoxyphenylsulfonyl,
..
2,6 dimethoxyphenylsu~fonyl, 3,5-dimethoxyphenylsulfonyl, ~=~
3,4-dipentyloxyphenylsulfonyl, 3,4,5-trimethoxyphenyl~
sulfonyl, and the like.
The "phenyl which may optionally have one to three --~
substituents selected from a lower alkoxy, a lower alkyl, a
halo~en atom, an amino having:optionally one or two
substituents selecte~d from a lower alkyl and a lower ~`~
alkanoyl, and nitro" includes a phenyl group which may
optionally have one to three substituents selected from a .
straight chain or branched chain al~o~y group`having l to 6
carbon atoms, a straight chain or branched cha1n alkyl group
having l to 6 carbon atoms, a halogen atom, an amino group ~;
having optionally one or two substituents selected from a : :
straight chain or branched chain alkyl group having l to 6
carbon atoms and a straight chain or branched chain alk.anoyl ~;
group having l to 6 carbon atoms, and a nitro group, for .
example, pheny1, 2-methoxyphenyl, 3-methoxyphenyI, 4~
- 52 -
WO94~011~3 PCT/JP93l~
211633~
methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxy-
phenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxy- - :~
phenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4- :~
methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4
diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimetho~yphenyl,
3,5-dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-tri-
methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methyl-
phenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-
isopropylphenyl, 3-butylphenyl, 4-pentylphenyl r 4~hexyl~
phenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,~-dimethyl-
phenyl, 2,6-dimethylphenyl, 3,4,5-trimPthylphenyl, 2-chloro- ;~: -
phenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- .
fluorophenyl, 4-fluorophenyl, 2-bromophenyl r 3-bromophenyl,
4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodoptlenyl, ~:
3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, -~
2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-di~luorophenyl, -
3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-nitrophenyl, 3-
nitrophenyl, 4-nitrophenyl, 3,4-dinitrophenyl, 2,~-dinitro~
phenyl, 2,6-dinitrophenyl, 3,4,5-trinitrophenyl, 2-amino- :~
phenyl, 3-aminophenyl, 4-aminophenyl, 3-(N-acetylamino)- ~-
phenyl, 4-(N-formylamino)phenyl, 4-(N-isobutyrylamino)-
phenyl, 2-(N-pentanoylamino)phenyl, 3,4-diaminophenyl, 3,4- ~
di(N acetylamino)phenyl, 3,4,5-triaminophenyl, 2,6-diamino- ~;
phenyl, 2,5 diaminophenyl, 3,5-di-t-butyl-4-hydroxyphenyl,
3-hydroxy-4-pentyloxyphenyl, 2-hydroxy-5-t-butylphenyl r 3 r 5~ - ~ ~
dichloro-4-aminophenyl, 3-amino-4-hydroxyphenyl, 3-acetyl- :~:
amino-4-methoxyphenyl, 3-nitro-4-acetylaminophenyl, 3~nitro-
4-chlorophenyl, 3-chloro-4-methylphenyl, 3-metho~:y-4-me,~hyl- ;~
2~1633'1
- 53 -
'094/01113 PCT/JP93~35
5-iodophenyl, 3,4-dimethoxy~5-bromophenyl,~3,5-diiodo~
methoxyphenyl, 4-dimethylaminophenyl, 3-methylaminophenyl,
2-butylaminophenyl, 4-diethylaminophenyl, 3-dipropylamino- ;.
phenyl, 2-~N-methyl-N-hexaylamino)phenyl r 4-(N-methyl-N~
acetylamino)phenyl, 2,4-dimethylaminophenyl, and the like.
The "heterocyclic group~substitu~ed carbonyl"
includes a carbonyl group which is substituted by a S- to `~
10-membered, monocyclic ~r dicyclic heterocyclic groups
containing one or two hetero atoms selected from nitrogen -.:
atom, oxygen atom and/or sulfur atom, for example, 2-
pyrrolidinylcarbonyl, 3-pyrrolidinylcarbonyl, l-piperidinyl~
carbonyl, l-piperazinylcarbonyl; morpholinocarbonyl,
thiomorpholinocarbonyl, 2-tetra~lydrofurylcarbonyl, 2-
thienylcarbonyl, 3-thienylcarbonyl, 2-pyrrolylcarbonyl, 3- :~
. .
pyrrolylcarbonyl, 2-furoyl, 3-furoyl, 2-pyridylcarbonyl, 3~
pyridylcarbonyl, 4-pyridylcarbonyl, 3-pyridazylcarbonyl, 2-
thiazolylcarbonyl, 2-oxazolylc~rbonyl, 2-imidazolylcarbonyl,
4-pyridazylcarbonyl, 5-pyridazylcarbonyl, 6-pyridazyl~
carbonyl, 2-pyrim~dylcarbonyl, 4-pyrimidylcarbonyl, 5- ;;;
pyrimidylcarbonyl, 6 pyrimidylcarbonyl, 2-pyradylcarbonyl,
3-pyradylcarbonyl, 6-quinolylcarbonyl, 5-indolylcarbonyl, 6
isoquinolylcarbonyl, 4-cinnolylcarbonyl, 3-quinoxalyl~
carbonyl, 4-phthalazylcarbonyl, 5-quinazolylcarbonyl/ 3-
benzo~b]furanylcarbonyl, 5-benzo[b]thiophenylcarbonyl r 2-
oxo-6-quinolylcarbonyl, 2-oxo-4-quinolylcarbonyl, and the
like~
The above "heterocyclic group-substituted carbonyl `~
which has one to three substitutents selected from a phenyl-.;
-- 54 --
W~ 94/01113 P~TIJP93/0
2116 3 3 Ll
(lower)alkoxycarbonyl, a phenyl~lower)alkoxy, oxo, a lower~ ~.
alkyl and a lower alkylenedioxy" includes the above-
mentioned heterocyclic group-substituted carbonyl groups
which have one to three substituents selected from a phenyl~
alkoxycarbonyl group wherein the alkoxycarbonyl moiety is a
straight chain or branched chain alkoxycarbonyl group having
1 to 6 carbon atoms, a phenylalkoxy group wherein the alkoxy
moiety is a straight chain or branched chain alkoxy group -
having 1 to 6 carbon atoms, an oxo group, a straight chain`~
or branched chain alkyl group havin~ 1 to 6 carbon atoms,
and a straight chain or branched chain alkylenedioxy group
having 1 to 4 carbon atoms, for example, I~benzyloxy~
carbonyl-2-pyrrolidinylcarbonyl, 3-benzyloxycarbonyl-4,5- ;~
~ .
(l,l-dimethylmethylene)-2-tetrahydrofurylcarbonyl, 4-(2
phenylethoxycarbonyl)-l-piperazi.nylcarbonyl, 3-methyl-2~
thienylcarbonyl, 3-ethyl-2-pyrrolylcarbonyl, 3-propyl-2- : ;
furoyl, 4-butyl-2-oxo-6-quinolylcarbonyl, 6-pentyl-2-oxo-4-
quinolylcarbonyl, 5-hexyl-2-pyrazylcarbonyl, 1,3-dioxo-2- ;~
methyl-6-quinazolylcarbonyl, 4,5-methylenedioxy-3-indolyl-
carbonyl, 3 (3-phenylpropoxy)morpholinocarbonyl, and the
like.
The "thienyl(lower)alkanoyl" includes a thienyl~
alkanoyl wherein the alkanoyl moiety is a straight chain or
branched chain alkanoyl group having 2 to 6 carbon atoms,
for example, 2-(2-thienyl)acetyl, 3-(3-thienyl)propionyl, 2- ~ -
(3-thienyl)propionyl, 4-~2-thienyl)butyryl, 2,2-dimethyl-3- ~;~
(3-thienyl)propionyl, 5-~2-thienyl)pentanoyl, 6-(3-thienyl)- :.`;
hexanoyl, 3-methyl-4-(2-thienyl)butyryl, and the like.
, ,'~.';
_ 55_ 2il~3~l
'~94/01113 P~T/JP~3/~35
The 1I tricyclo[3.3.1.1]decanyl(lower)alkanoyl"
includes a tricyclo[3.3.1.1ldecanylalkanoyl wherein the ~ ~
alkanoyl moiety is a straight chain or branched chain ~ :
alkanoyl group having 2 to 6 carbon atoms, for example, 2
tricyclo~3.3.1.1~decanylacetyll 3-tricy~10~3.3.1.1]decanyl-
propionyl, 2-tricyclo[3.3.1.1]decanylpropionyl, 4-tricyclo-
[3.3.1.1]decanylbutyryl, 2,2-dimethyl-3-tricyclo~3.3.1.1~-
decanylpropionyl, 5-tricyclo[3.3.1.1]decanylpentanoyl, 6-
tricyclo[3.301~1]decanylhexanoyl, 3-methyl-~-tri~yclo-
~3.3.1.1]decanylbutyryl, and the like. ;.
The "benzoyl wherein the phenyl ring may optionally
have a lower alkoxy substituent" includes a ben20yl which ~;
may optionally have one to three substi~tuents of a straight
chain o~ branched chaîn alkoxy group having 1 to 6 carbon .
atoms on the phenyl ring, for example, benzoyl, 2-methoxy~
benzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxy- -~
benzoyl, 3-ethoxybenzoyl, 4-butoxybenzoyl, 4-isopropoxy-
; benzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4~
dlmethoxybenzoyl, 3-ethoxy-4~methoxybenzoyl, ~,3-dimethoxy- ~.
benzoyl, 3,4-diethoxybenzoylj 2,5-dimethoxybenzoyl, 2,6-
dimethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,4,6-trimethoxy- :
benzoyl, 3,5-dimethoxybenzoyl, 3,4-dipe~tyloxybenzoyl,
3,4,5-trimethoxybenzoyl, and the like.
The "phenyl which may optionally have a lower
alkoxy substituent" includes a phenyl group whi,ch may ~-~
optional~y have one to three substituents of a straight -~
chain or branched chain alkoxy gro~p having 1 to 6 carbon ; ~
atoms, for example, phenyl, 2-methoxyphenyl, 3-methoxy ~`:
- 56 -- :
W094/01113 PCT/JP93/~8?
2116334 :~
~ .
phenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-
ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-
pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3- :
ethoxy-4-methoxyphenyl, 2,3-dimethoxypheIIyl, 3,4-diethoxy-
phenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5~
dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxy-
phenyl, and the like.
The "cycloalkyl" includes a cycloalkyl havlng 3 to
8 carbon atoms, ~or example, cyclopropyl, cyclobutyl, cyclo-
pentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The "saturated or unsaturated heterocyclic groupwhich is ormed by binding the groups Rll and R12 together
with the nitrogen atom to which they bond and ma~ be .~
intervened or not with nitrogen, oxygen or sulfur atom" ~:
includes, a 5- to 10-membered, saturated or unsaturated,
monocyclic or dicyclic heterocyclic group, for example,
pyrrolidinyl, piperidinyl, piperazinyl, morphollno,
thiomorpholino, pyrrolyl, imidazol~l, pyrazolyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, oxazolinyl,
o~azolidinyl, isoxazolinyl, isoxazolidlnyl, thiazolinyl,
thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2,3,4
tetrahydro~uinolyl, 1,2-dihydroquinolyl, indolyl, `~
isoindolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydro-
isoquinolyl, lH-indazolyl, 1,2-dihyroauinazolyl, 1,2-
dihydrocinnolyl, 1,2-dihydroquinoxalyl, 1,2,3,4-tetrahydro-
quinazolyl, 1,2,3,4-tetrahydrocinnolyl, 1,2,3,4-tetrahydro- -~
quinoxalyl, and the like.
The "phenyl ~7hich may optionally have a substituent
~ .
211~33 1
-v0~4/01113 p~T/JP93/~835
selected from a lower alkoxy and a lower alkanoyl" includes
a phenyl group which may optionally have one to three
substituents selected from a straight chain or branched
chain alkoxy group having l to 6 carbon atoms and a straight ~ ;:
chain or branched chain alkanoyl group having 1 to 6 carbon
atoms, for examplet phenyl, 2-methoxyphenyl, 3-methoxy- -
phenyl, 4-metho~yphenyl, 2 ethoxyphenyl, 3-ethoxyphenyl, 4
ethoxyphenyl, 4-isoproDoxyphenyl, 3-bu~oxyphenyl, 4-pentyl-
oxyphenyl, 4-he~yloY.yphenyl, 3,4-dimethoxyphenyl, 3 ethoxy-
4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, ;:~
2,5-dimethoxyphenyl~ 2,6 dimethoxyphenyl, 3,5-dimethoxy-
phenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 3-
methoxy-4-acetylphenyl, 2 acetylphenyl, 3-acetylphenyl, 4
acety~phenyl, 2-formylphenyl, 3-propionylphenyl, 4- ~.~
isobutyrylphenyl, 2-pentanoylphenyl, 3-hexanoylphenyl, 3,4- ~-
:
diacetylphenyl, ~,5-diacetylphenyl, 3,4,5-triacetylphenyl, ~:~
and the like.
The "heterocyclic group which is substituted by a
member sel2cted from benzoyl, a lower aI~anoyl, a phenyl~
(lower)alkyl, and a phenyl having optionally a substituent ;-~
selected from a lower alkoxy and a lower alkanoyl" i:ncludes ~ -
the above heterocyclic groups which have a substituent
~ ~,
selected from benzoyl group, a straight chain or branched .~
- '':~:
chain a.lkanoyl group having l to 6 carbon atoms, a phenyl~
". -~.
alkyl group wherein the alkyl moiety i~ a straight chain or
branched chain alkyl group having l to 6 carbon atoms, and a
phenyi group having optionally one to three substituents ~-
selected from a straight chain or branched chain alkoxy -;
W094~01113 - 58 - PCTJ3P93~8?~
2 1 1 ~i 3 3 ~
group having 1 to 6 carbon atoms and a straight chain or .
branched chain alkanoyl. group having 1 to 6 carbon atoms r
for example, 3-benzoyl-1-pyrrolidinyll 4-benzoyl~
piperidinyl, 4-benzoyl-1-pipera~inyl, 4-benzyl-1-
piperazinyl, 3-(2-phenyl2thyl)morpholino, 3-(3-phenyl
propyl~thiomorpholino, 3-(4-phenylbutyl)-1-pyrrolyl, 4-
ace~yl-l-piperidinyl, 4-acetyl-1-piperazinyl, 4-formyl-1-
piperazinyl, 2-(5-phenylpentyl)-1-imidazolyl, 3-(6-phenyl-
pentyl)-l-pyra~olyl~ 4-(4-methoxyphenyl)-1-piperazinyl, 4-
~4-acetylphenyl)-1-piperazinyl, 4 (3-ethoxyphenyl)-1-
piperazinyl, 4-(3-propionylphenyl~-1-piperazinyl, 5-benzyl-
1,2,3,4-tetrahydroquinolin-1-yl, 6-(4-butyrylphenyl)~
1,2,3,4-tetrahydroisoquinolin-2-yl, 4-(2-propoxyphenyl)-1
indolyl, ~-(3-pentanoylphenyl)-lH--indazol-l-yl, 6-(3- :~
butoxyphenyl)-l,~-dihydroquirazolin-l-yl, 7-(4-hexanoy~
phenyl)-1,2-dihydrocinnolin-2-yl, 6-(4-hexyloxyphenyl)- ;~
1,2,~,4-tetrahydroquinoxalin-1-yl, and the like.
The "al~ylene" includes a straight chain or ~-
branched chain alkylene group having 1 to 12 carbon atoms,
for example, in addition to the above-mentioned lower
alkylene groups, heptamethylene, octamethylene, nona- ~`
methylene, decamethylene, undecamethylene, dodecamethylene, ~;-
and the like.
The "low2r al~oxycarbonyl(lower)alkyl wherein the;;~;
alkyl moiety may optionally be substituted by hydroxy or an
amino naving optionally a phenyl~lower)alkoxycarbonyl
substituent" includes a straight chain or branched chain
alkoxycarbonylalkyl group having 1 to 6 carbon atoms in the~:
59 211~33~
'~9~101113 pCTJ3P93/~835
al~oxy moiety, wherein the alkyl moiety is straight chain or
branched chain alkyl group having 1 to 6 carbon atoms and ~ ;~
has opt~onaly a substituent selected from a hydroxy group -
and an amino group having optionally a substituent of a
phenylalkoxycarbonyl group wherein the alkoxycarbonyl moiety ~.
is a straight chain or branched chain alkoxycarbonyl group
having 1 to 6 carbon atoms, for example, l-hydroxy~
methoxycarbonylmethyl, l-methoxycarbonyl-2-hydroxyethyl, 3- ~ ;~
hydroxy-3-methoxycarbonylpropyl, 2-hydroxy-~-ethoxycarbonyl~
butyl, 2-hydroxy-6-propoxycarbonylhexyl, 2-hydroxy-2~
pentyloxycarbonylethyl, l-hydroxy-l hexyloxycarbonylmethyl,
S-benzyloxycarbonylamino-l-methoxycarbonylpentyl, 5-amlno-1- ~`.
methoxycarbonylp2ntyl, 3-(2-phenylethoxycarbonylamino)~
ethoxycarbonylpropyl, 4-amino-1-butyloxycarbonylbutyl, and
, -
the like.
The "amino-substi~uted lower alk~noyl whereln the
lower alkanoyl molety may optionally be subs~tituted by a
member selected from a phenyl(lo~er)alkoxycarbonylamino, -
hydroxy, a phenyl having optionally a hydroxy substitutent, -~
carbamoyl, imidazolyl and a lower alkylth~lo, and the amino
g~roup may optionally have a substîtuent selected from a :~
lower alkyl having optionally a hydroxy substitutent, a ~.
lower alkenyl, a phenyl(lower~alkyl having optionally 2 . ~;
lower zlkoxy substituent on the phenyl ring, a lower
alkylsulfonyl, a lower alkanoyl, and a phenyl~lower)alkoxy~
carbonyl" includes an amino-substituted straight chain or
branched chain alkanoyl group haviny 2 to 6 carbon atoms, ;~
wherein the alkanoyl moiety may optionally be substituted by ~;
WO94~0~113 - 60 - PCT/JP93/~8'`
211633~ ~
.
a member selected from phenylalkoxycarbonylamino wherein the ~ -~
alkoxycarbonyl moiety is a s~raight chain or branched chain
alkoxycarbonyl group havin~ 1 to 6 carbon atoms, a hydroxy
group, a phenyl group having optionally one to three :~
hydroxy-substitutents, a carbamoyl group, an imidazolyl:~
group and a straight chain or branched chain alkylthio group ~ ~-
having 1 to 6 carbon atoms, and the amino group may .
optionally have a substituent selected from a straight chain ;~
or branched chain alkyl group having 1 to 6 carbon atoms and
having optionally one to three hydroxy-substitutents, a
straight chain or branched chain alkenyl group having 2 to 6
carbon atoms, a phenylalkyl ~roup wherein the al~yl moiety
is a straight chain or branched chain alkyl group havin~
to 6 carbon atoms and the phenyl ring has optionally one to :~
three substituents of a straight chain or branched chain
alkoxy group having 1 to 6 carbon atoms, a straight chain or ~:
branched chain alkylsulfonyl group having 1 to 6 carbon
atoms, a straight chain or branched chain alkanoyl group
having 1 to 6 carbon atoms, and a phenylal~oxycarbonyl
wherein the alkoxycarbonyl moiety is a straight chain or
branched chain alkoxycarbonyl group having 1 to 6 carbon
atoms, for example, amlnoacetyl, 3-formylaminopropionyl~
ace~ylaminoacetyl, 2-propionylaminopropionyl, 4-butyryl- :
aminobutyryl, 2,2-dimethyl-3-isobutyrylaminopropionyl, 5-
pentanoylaminopentanoyl, 6-tert-butylcarbonylaminohexanoyl,
3-methyl-4-hexanoylaminobutyryl, 4-methylthio-2-acetylamino-
butyryl, 3-~imidazol-~-yl)-2-acetylaminopropionyl, 2-
acetylaminopropionyl, 3-(4-hydroxyphenyl)-2-benzyloxy- :
211633ll ,
'094/01113 - 61 -
carbonylaminopropionyl, 4-carbamoyl-2-acetylaminobutyryl, 2-
acetylaminoisopentanoyl, 5-ethylthio-2-acetylaminopentanoyl,
4-(imidazol-2-yl)-~-propionylaminobutyryl, ~-(2-hydroxy- ~
phenyl)-2-butyrylaminohexanoyl, 3-carbamoyl-2-benzyloxy- -:
carbonylaminopropionyl, 5-carbamoyl-2-(2-phenylethoxy-
carbonylamino)pentanoyl, 3-(2,4-dihydroxyphenyl)-2-(3- ~:~
phenylpropoxycarbonylamino)propionyl, 2,5-dibenzyloxy-
carbonylaminohexanoyl, 3-(4-hydroxyphenyl)-2-aminopropionyl, ~:
dimethylaminoacetyl, 3-hydroxy-2-benzyloxycarbonylamino-
propionyl, 2-benzyloxycarbonylaminopropionyl, 2-amino-
propionyl, 2-aminoisopentanoyl, 2-aminobutyryl, 4-benzyloxy~
carbonylaminobutyryl, diethylaminoacetyl, 4-acetylamino- ;-
butyryl, 4-dimethylaminobutyryli 2-hydroxyacetyl, ethyl~
aminoacetyl, allylaminoacetyl, benzylaminoacetyl, isopropyl~
aminoacetyl, (N-methyl-N-ben7ylamino)acetyl, [N-methyl-N (2-
hydro~yethyl)amino]acetyl, ~N-methyl-N-(4-ethoxyben~yl)-
amino~acetyl, 2-benzyloxycarbonylaminoacetyl, methyl- ~:~
sulronylaminoacetyl., ~3-methoxybenzyl)aminoacetyl, (N- :.:
methyl-~-acetylamlno)acetyl, 5 (N-methyl-N-allylamlno)- :~
pentanoyl, 6-[N-allyl-N-(3,4-dimethoxy~enzyl)amino~hexanoyl,
and the like.
The "amido-substituted lower alkyl wherein the
lower alkyl moiety has optionally a substituent selected
from a phenyl having optionally a hydroxy substituent, :~
imidazolyl, carbamoyl and a lower alkylthio, and the amido
group may optionally have a lower alkyl substituent"
includes an amido-substituted straight chain or branched
chain alkyl group having 1 to 6 carbon atoms wherein the
' .
W~94/01113 - 62 - P~T/JP931~
211~33'1
alkyl moiety have optionally a substituent selected from a
phenyl having optionally one to three hydroxy-substituents,
an imidazolyl group, a carbamoyl group and a straight chain ~:~
or branched ch~in alkylthio group having 1 to 6 carbon
atoms, and the amido group may optionally have one or two :~
substituents of a straight chain or branched chain alkyl -
group having 1 to 6 carbon atoms, for example, carbamoyl~
methyl, 2-carbamoylethyl, l-carb~moylethyl, 3-carbamoyl-
propyl, 4-carbamoyIbutyl, 5-carbamoylpentyl, 6-carbamoyl- ~ :~
hexyl, l,l-dimethyl-2-carbamoylethyl, 2-methyl-3-carbamoyl- ~,
propyl, methylamidomethyl, l-ethylamidoethyl, 2-propylamido- ;;
ethyl, 3-isopropylamidopropyl, 4--butylamidobutyl, 5-pen~yl- ~-.
amidopentyl, 6-hexylamidohexyl, dimethylamidomethyl, (N- - :
ethyl-N-propylamido)methyl, 2-lN--methyl-N-hexylamido)ethyl, :` .
2-(4-hydroxyphenyl)carbamoylethyl, l-carbamoylisobutyl, 2
(imlda~ol-4-yl)-1-carbamoylethyl, 1,3-dicarbamoylpropyl, 3-
methylthio-l-carbamoylpropyl, 3-(2-hydroxyphenyl)-1-methyl-
amidopropyl, 4-(2,6-d]hydroxyphenyl)-1-(N-metbyl-~-hexyl-
amido)butyl, 3-(imidazol-2-yl)-1-propylamidopropyl, 1,4- ^
dicarbamoylbutyl, ~-ethylthio-l~butylamidobutyl, 4-pentyl- : -
thio-l-hexylamidobutyl, and the like.
The "carboxy~lower)alkyl" includes a carboxyalkyl - :
group wherein the alkyl moietyl is a straight chain or
~ranched chain alkyl group having 1 to 6 carbon atoms, for ~ :
example, car~oxymethyl, 2-carboxyethy~ carboxyethyl, 3-
carboxypropyl, 4-carbo~ybutyl, 5-carboxypentyl, 6-carboxy~
hexyl, l,l-di~ethyl-2-carboxyethyl, 2-methyl-3 carboxy~
propyl, and the like. .
- 63- 2116331
'0~4/01113 PCT/JP93/~3~
The 'llower alkoxy(lower)~lkyl~ includes a straight
chain or branched chain alkoxyalkyl ~roup having 1 to 6
carbon atoms in the alkoxy mo.iety wherein the alkyl moiety
is a straight chain or branched chain alkyl group having 1
to 6 carbon atoms, for example, methoxymethyl, 2-ethoxy~
ethyl, l-methoxyethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-
propoxyhexyl, 5-isopropoxypentyl, 1,1-dimethyl-2-butoxy- :~
ethyl~ 2-~ethyl-3-tert-butoxypropyl, 2-pen~yloxyethyl, ;.
hexyloxymethyl, and the like~
The "amino acid residue which is able to form an
amido bond with the amino group to which R4 and R5 bind" ~: ~
includes, for example, alanine residue, N2-arginine residue, ~;
N5-arginine residue, N6 arginine residue, N4-asparagine -~
res:idue, aspartic acid residue, N5-glutamlne residue,
cysteine residue, glutamic acid residue, glycine residue, :~
histidine residue, isoleucine residue, leucine residue, N~
lysine residue, ~6 lysine residu;e, methionine residue
phenylalanine residue, proline resldue, serlne residue, ~;~
threonine residuP, tryptophane residue, tyrosine residue,~
valine residue, and the like.
- The "hydroxyimino-substituted lower alkyl" includes
a hydroxyimino-substituted straight chain or branched chain
alkyl group having 1 to 6 carbon atoms, for example,
hydroxyiminomethyl, l-hydroxyiminoethyl, 2-hydroxyimino- :
ethyll 3-hydroxyiminopropyl, 4-hydroxyiminobutyl, 5- ~;
hydroxyiminopentyl, 6~hydroxyiminohexyl, 1,1-dimethyl-2-
hydroxyiminoethyl, 2-methyl-3-hydroxyiminopropyl, and the :~
like. .
- 64 -
W0~4J011~3 P~TIJP~31
211633~
The "halogen-substituted lower alkoxy" includes a ~.~
straight chain or br~nched chain alkoxy group having l to 6~;
carbon atoms which is substitu~ed by one to three h~logen :.~
atoms, for example, trifluoromethoxy, trichloromethoxy, :;.
chl.oromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, ~ :~
difluoromethoxy, dibromome~hoxy, 2-chloroethoxy, 2,2,2~
trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy,
2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fIuorobutoxy,
5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyl~
oxy, 5,6-dichlorohexyloxy, and the like. .:.
The '~phenyl(lower)alkoxycarbonyl" includes a
phenylalkoxycarbonyl wherein the alkoxycarbonyl moietyl is a ;:
straight chain or branched chain alkoxycarbonyl group having
l to ~ carbon atoms, ~or example, benzyloxycarb~nyl, 2-
phenylethoxycarbonyl, l-phenylethoxyca.rbonyl, 3-phenyl~
propoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxy~
carbonyl, 6-phenylhexyloxycarbonyl, l,l-d1methyl-2-phenyl~
ethoxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl, and the .
like.
The "lower alkoxy(lower)alkoxy which lS SUbStltUted ;~
by one or two substituents selected from hydroxy and an
amino being optionally substi.tuted by a lower alkyl" ~:~
includes an alkoxy-alkoxy group wherein both alkoxy moieties-;;
are each a straight chain or branched chain alkoxy group ~`
having l to 6 carbon atoms which is substituted by one or .
two substituents selected from hydroxy and an amino being ~.
optionally substituted by a straight chain or branched chain !~
alkyl group having l to 6 carbon atoms, for example,
3 ~
- 65 -
~0~4/0~113 pCT~JP93/00835
hydroxymethoxymethoxy, 3-(2-hydroxyethoxy)propoxy, 4-(1-
hydroxyethoxy)butoxy, 6-(3-hydroxypropoxy)hexyloxy, 5-(2j3-
dihydroxypropoxy)pentyloxy, l,l-dimethyl-2-(4-hydroxy~
butoxy3ethoxy, 2-methyl-3-(3,4-dihydroxybutoxy)propoxy, 2- ~ ~
~ dimethyl-2-hydroxyethoxy)ethoxyr (5-hydrox~pentyloxy)- .~:
methoxy, ~6-hydroxyhexyloxy)methoxy, (2-methyl-3-hydroxy-
propoxy)methoxy, aminomethoxymethoxy, 2-(1-aminoethoxy)- .
ethoxy, 1-(2-aminoethoxy)ethoxy, 3-~3-aminopropoxy)propoxy,
4-(4-aminobutoxy)butoxy, 5-(5-aminopentyloxy)pentyloxy, 6- ~:
(6-aminohexyloxy)hexyloxy, ~l,l-dimethyl-~-aminoethoxy)- ~
methoxy, (2-methyl-3-aminopropoxy)methoxy t 1,1-dimethyl-2- ~ ~;
~methylaminomethoxy)ethoxy, 2-methyl-3-(ethylaminomethoxy)- :~
propoxy, propylaminomethoxymethoxy, 1 (isopropylamino- ~;~
methoxy)ethoxy, 2-(butylaminomethoxy)ethoxy, 3-(tert-butyl- ~::
- aminomethoxy)propoxy, 4-~pentylaminomethoxy)butoxy, 5- ;
(hexylaminomethoxy)pentyloxy, 6-(dimethylarninomethoxy)-
hexyloxy, l,l-dimethyl-2-(diethylaminomethoxy)ethoxy, 2-
methyl-3-(dipropylaminomethoxy)propoxy, dibutylamlnomethoxy~
methoxy, 1-(dipentylaminomethoxy~ethoxy, 2-(dihexylamino~
methoxy)ethoxy,.3-(~-methyl-N-ethylaminomethoxy)propoxy, 4-
~N-methyl-N-propylaminomethoxy)butoxy, S~(N-methyl-N-butyl-
aminomethoxy)pentyloxy, 6-~N-methyl-N-hexylaminomethoxy)- ~
hexyloxy, (l-methylaminoethoxy)methoxy, l-(2-ethylamino- .
ethoxy3ethoxy, 2-(3-propylaminopropoxy)ethoxy, 3-(~-butyl-
aminobutoxy)propoxy, 4-(1,1-dimethyl-2-pentylaminoethoxy)~
butoxy, 5-(5-hexylaminopentyloxy)pentyloxy, 6-(6-dimethyl-
aminohexyloxy)hexyloxy, 3-(2-diethyl.aminoethoxy3propoxy, 4-
[l-(N-methyl-N-hexylamino)ethoxy]butoxy, 5-(3-di-hexylamino
~'.',''.';
.
W094/01113 - 66 -
211633i ; ~
propoxy)pentyloxy, 6-(4-dibutylaminobutoxy)hexyloxy, 3-[2- ;
(N-methyl-N-pentylamino)ethoxy]propoxy, 5~(2-hydroxy-3-
dimethylaminopropoxy)pentyloxy, 5-(2-hydroxy-3-diethyla~ino-
propoxy)pentyloxy, 3-(2-hydroxy-3-diethylaminopropoxy)- :~
propoxy, 4-(3-hydroxy-4-methylaminobutoxy)butoxy, 5-(4-
hydroxy-5-dimethylaminopentyloxy)pentyloxy, 6-(4-hydroxy-5-
methylaminopentyloxy)hexyloxy, and the like.
The "morpholinyl-substituted lower alkoxy which may
optionally have a substituent selected from a lower alkyl "
and oxo" includes a morpholinyl-substituted straight chain ~
or branched chain alkoxy group having 1 to 6 carbon atoms ~ ;
which may optionally have one or two substituents selected
from a straight chain or branched chain alkyl group having 1 ~:
to 6 carbon atoms, and an oxo group, for example, 12~
morpholinyl)methoxy, 2-(3-morpholinyl)~thoxy, 1-(3- - :
morpholinyl)ethoxy, 3-~2-morpholinyl)propoxy, 4-(3-
morpholinyl)butoxy, 5-(2-morpho1lnyl3penty:10xy, 6-(3-
morpholinyl)hexyloxy, l,l-dimethyl-2-(3-morpholinyl)ethoxy,
2-methyl-3-~2-morpholinyl)propoxy, v-(1-methyl-S-oxo-3~
morpholinyl)hexyloxy, (l-ethyl-2-morpholinyl)methoxy, 2-(2-
oxo-3-morpholinyl)ethoxy, 1-(2-propyl-3-morpholinyl~ethoxy, :
3-(3-butyl-2-morpholinyl)propoxy, 4-~5-pentyl-3- .
morpholinyl)butoxy, 5-(6-hexyl-2-morpholinyl)pentyloxy, 3-
(5-oxo-1-propyl-2-morpholinyl)propoxy, 4-(2-oxo-1-butyl-3-
morpho~inyl)butoxy, 5-(3-oxo-1-pentyl-6-morpholinyl)-
pentyloxy, 6-(2-o:xo-1-hexyl-5-morpholinyl)hexyloxy, and the :
like.
The "benzimidazolylthio-substituted lower alkoxy"
''~
211~33 1
-- 67 --
0 ~4/0l1l3 PCT/JP93/00335
includes a benzimidazolylthio-substituted straight chain or
branched chain alkoxy group having 1 to 6 carbon atoms, for
example, (benzimidazol-2-yl)thiomethoxy, 1-(benzimidazol-4-
yl~thioethoxy, 2-(benzimidazol-5-yl)thioethoxy, 3 :~:
~benzimidazol-6-y~)thiopropoxy, 4-(benzimidazol-2-yl)thio~
butoxy, 5-(benzimidazol-7-yl)thiopen~yloxy, 6-(benzimidazol-
2-yl)thiohexyloxy r 1~1-dimethyl-2-(ben~imidazol-2-yl)thio-
ethoxy, 2-methyl-3-(benzimidazol-2-yl~thiopropoxy, and the
like.
The "benzimidazolylsulfinyl-substituted lower
alkoxy" includes a benzimidazolylsulfinyl substituted
strai~ht chair. or branched chain alkoxy group having 1 to 6 ..
carbon atoms, for example, (benzimidazol-2-yl)sulfinyl-
methoxy, l-~benzimidazol-4-yl)sulfinylethoxy, 3
(benzimidazol--6-yl)sulinylpropoxy, 4-~benzimidazol 2-yl)- ..
su1finylbutoxy, 5-(benzimidazol-7-yl)sulfinylpentyloxy, 6-
(benzimidazol-2-yl)sulfinylhexyloxy, 1~1-dimethyl-2~
(benzimidazol-2-yl)sul~inylethoxy, 2-methyl-3-(benzimidazol-
2~yl)sulfinylpropoxy, and the like.
The "tetrahydropyranyl-substituted lower alkyl"
includes a tetrahydropyranyl-substituted straight chain or
~ranched chain alkyl group having 1 to 6 carbon atoms, ~or
example, (2-, 3- or 4 tetrahydropyranyl)methyl, 2-(2-, 3- or :::
4 tetrahydropyranyl)ethyl, 1-(2-, 3- or 4-tetrahydro-
pyranyl)ethyl, 3-(2-, 3- or 4-tetrahydropyranyl)propyl, 4~
~2-, 3- or 4-tetrahydropyranyl)butyl, 5-(2-, 3- or 4-tetra~ :
hydropyranyl)pentyl, 6-(2-, 3- or 4-tetrahydropyranyl)hexyl,
1,1-dimethyl-2-(2-, 3- or 4-tetrahydropyranyl)ethyl, 2-
'''' ~
......
- 68 -
W~94/~1113 P~T/~P93/OD~
211633~
methyl-3-(2-, 3- or 4-tetrahydropyranyl)propyl, and the
like.
The "5- or 6-membered saturated hetero~yclic group
which is formed by binding Rl4 and Rl5 together with the
nitrogen atom to which they bond with being intervened or
not with nitrogen, oxygen or sulfur a~om" includes, for :~
example, pyrrolid1nyl, piperidinyll piperazinyl, morpholino, ;-~:
thiomorpholino, and the like. : .
The "heterocyclic group hav1ng a substituent :~
~elected from carbamoyl, a lower alkyl, a phenyl(lower)~
alkyl, phenyl and a hydroxy-substituted lower alkyl"
includes the above-mentioned heterocyclic groups which hav~
one to three substituents selected from a carbamoyl group, a
straight chain or branched chain alkyl group having l to 6
carbon atoms, a phenylalkyl group wherein the alkyl moiety
iS 2 straight chain or branched chain alkyl group having l ~;
to 6 carbon atoms, a phenyl group and a hydroxy substituted
straight chain or branched chain alkyl group having 1 to 6
carbon atoms, for exampIe, 4-phenylpiperazinyl, 2-phenyl~
pyrrolidinyl, 4-pheny1piperidinyl, 3-phenylmorpholino, 3- :
phenylthiomorpholino, ~-benzylpiperazinyl, 3-l2-phenyl- -~
ethyl)pyrrolidin~l, 2-(3-phenylpropyl)pyrrolidinyl, 4-(4~
phenylbutyl)piperidinyl, 3-(5-phenylpentyl)morpholino, 2-(6- -
phenylhexyl)thiomorpholino, 4-methvlpiperazinyl,: 3,4-di- :~:
methylpiperazinyl, 3-ethylpyrroli.dinyl, 2-propyl-
pyrrolidinyl, 3,4,5-trimethylp1peridinyl, 4-butyl- ;`
piperidinyl, 3-pentylmorpholino, 2-hexylthiomorpholino, 4- : `
ethylpiperazinyl, 3-methyl-4-phenylpiperazinyl, 3-ethyl-4~ ~
- 69 _ 2 1 1 6 3 3`
0941~113 P~T/JP93lOD~3~
' '
benzylpiperidinyl, 3-methyl-~-benzylpyrrolidinyl, 3-methyl~
5-phenylmorpholino, 3-methyl-5-12-hydroxyethyl~thio- ~
morpholino, 4-(2-hydroxyethyl)piperazinyl, 2-(hydxoxy- ;~:
methyl)pyrrolidinylr 4-(4-hydroxybutyl)piperidinyl, 2-~5
hydroxypentyl)thiomorpholino, 3-~6-hydroxyhexyl~morpholino~
2-methyl-4-(2-hydroxyethyl)pyrroIidinyl, 2-carbamoyl-
pyrrolidinyl, 3-carbamoylpyrrolidinyl, 4-carbamoyl-
piperazinyl, 3-carbamoylpiperazinyl, 2-carbamoylpiperazinyl, ::
4-carbamoylpiperidinyl, 3-carbamoylpiperidinyl, 2-carbamoyl~
piperidinyl, 3-carbamoylmorpholino, 2-carbamoyl-
thiomorpholino, 2-methyl-~-carbamoylpyrrolidinyl, 3-me~hyl~
4-carbamoylpiperidinyl, 2,6-dimethyl-4-carbamoylp~perazinyl,
and the like.
I'he "amino having optionally a phenyl(lower)alkoxy- ~
carbonyl substituent" includes an amino group which may ~: .
optionally have a~substituent of a phenylalkoxycarbonyl
gro~p wherein the alkoxycarbonyl moiety is a straight chain -~
or branched chain alkoxycarbonyl group having l to 6 carbon
atoms, for example, amino, benzyloxycarbonylamino, ~2-
phenylethoxycarbonyl)amino, (l-phenylethoxycarbonyl)amino,
l3-phenylpropoxycarbonyl)amino, (4-phenylbutoxycarbonyl)~
amino, (5-phenylpentyloxycarbonyl~amino, (6-phenylhexyloxy- ;
carbanyl)amino, (l,l-dimethyl-2-phenylethoxycarbonyl)aminoj :
(2-methyl-3-phenylpropoxycarbonyl)amino, and the like. f~
- The "phenyl having op~ionally hydroxy substituent"
includes a phPnyl group having optionally one to three
.. ~
hydroxy-substituentsr for example, phenyl, 9-hydroxyphenyl
3-hydroxyphenyl, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-
~ .
,.,,~,
WO94~ pCT/3P93~8-
211~331 `
dihydroxyphenyl, 2,3,4-trihydroxyphenyl, and the like .
The "phenylsulfonyl wherein the phenyl ring may
optionally have a substituent selec~ed from a lower alkyl,
nitro, and an amino having optionally one cr two substi-
tuents selected from a lower alkanoyl and lower alkyl" .:
includes a phenylsulfonyl group wherein the phenyl:r_ng may ;`~
optionally have one to three substitutents selected rom a ~ .
straight chain or branched chain alkyl group having 1 to 6
carbon atoms, a nitro group, and:an amlno group having ~ .
optionally one or two substituents selected from 2 strai~ht ~`
chain or branched chain alkanoyl group having 1 to 6 carbon ; -
atoms and a straight chaln or~branched chain alkyl group ~.`
~having 1 to 6 carbon atoms,: for example, phenylsulfonyl, 2
methylphenylsulfonyl, 3~methylphenylsulfonyl, 4-me~;hyl~
phenylsulfonyl, 2-ethylphenylsulfonyl, 3-e~hylphenyl~
sul~onyl, 4-ethylphenylsulfonyl, 4-isopropylphenylsulfonyl,
4-butylphenylsulfonyl, 2-pentylphenylsulfonyl, 3-hexyl~
phenylsulfonyl, 2,4-dimethylphenylsulfonyl, 3,4-dietnyl~
phenylsulfonyl, 3,4,5-trlmethylphenylsulfonyl, 4-amino~
phenylsulfonyl, 3-aminophenylsulfonyl, 2-aminophenyl~
sulfonyl, 3,4-diaminophenylsul~fonyl) 2i5-diamlnophenyl-
sulfonyl1 2,4,6-~riaminophenylsulfonyl;. 4-nitropheny~
sulronyl, 3-nitrophenylsulfonyl, 2-nitrophenylsulfonylj 2,3-
dinitrophenylsulfonyl, 2,6-dinitrophenylsulfonyl, 2,~,6 `:
trinitrophenylsulfonyl, 4-acetylaminophenylsulfonyl, 4-
dimethylaminophenylsulronyl, ~-lN-methyl-N-ace~ylamino)
phenylsulfonyl, 2-methyl-4-aminophenylsulfonyl, 3-ni_ro-4
methyl~henylsulfonyl, 2-ethylaminophenylsulfonyl, 2-methyl- :~
- 71 - 2 1 1 S~ 3ll
:Og4/01113 PCTIJP93/WB35 ..
3-diethylaminophenylsulfonyl, and the likeO
The "amino-substituted lower alkyl which may ~ :~
optionally have a substituent selected from a lower alkyl
and a lower alkanoyl" includes a straight chain or branched
chain alkyl group having 1 to 6 carbon atoms which is
substituted by an amino group having optionally one or two :~-
substituents selected from a straight chain or branched . -
chain alkyl group having 1 to 6 carbon atoms and a straight ~ ~:
chain or branched chain alkanoyl group having 1 to 6 carbon :
atoms, f~r example, aminomethyl, 2 aminoethyl, l-aminoethyl,
3-aminopropyl~ 4-aminobutyl, 5-aminopentyl, 6-aminohexyl,
1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, me~hyl-
aminomethyl, l-ethylaminoethyl, 2-propylaminoethyl, 3
isopropylaminopropyl, 4-butylaminobutyl, 5-pentylamino~
pentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-et:hyl-N- ~ :
propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, 2-
(acetylamino)ethyl, 3-(acetylamino)propyl, formylamlno- ~:~
methyl, l-(propionylamino)ethyl, 4-(butyrylamino)butyl, 5-
(pentanoylamino)pentyl, 5-lhexanoylamino)hexyl, 2-(N-methy1~
: N-acetylamino)ethyl, l-(N-ethyl-N-acetylamino)ethyl, and t~he .~;
like.
The "piperidinyl havin~ optionally a phenyl(lower) -
alkyl su~stituent" includes a piperidinyl which has -~
. ~ ..
optionally a substituent of a phenylalkyl group wherein the~
alkyl moiety is a stralght chain or branched chain alkyl
group having 1 to 6 carbon atoms, for example, 4-piperidin~
yl, 3-piperidinyl, 2-piperidinyl, 1-benzyl-4-piperidinyl, 1
~2-phenylethyl) 3-piperidinyl, 2-(3-phenylpropyl)-5~
.:.'. ...
W0~4/~1113 - 72 - PCT/JP93~0U8~ ~
211633~1 ~
piperidinyl, 3-(4-phenylbutyl)-6-piperidinyl, 4-(5-phenyl-
pentyl)-3-piperidinyl, 5-(6-phenylhexyl)-4-piperidinyl, 2-
benzyl-4-piperidinyl, l-(3-phenylpropyl)-4-piperidinyl, and
the like.
The "imidazo[4,5-c]pyridylcarbonyl(lower3alkoxy"
includes an imidazo~4,5-c]pyridylcarbonylalkoxy group `
wherein the alkoxy moiety is a straight chain or branched
chain alkoxy group having 1 to 6 carbon atoms, for ex;ample, -:;
(imidazo[4,5-c]pyridln-2-yl)carbonylmethoxy, 2-(1midazo[4,5- ~:
c]pyridin-2-yl)carbonylethoxy, l-(imidazo[4,5-c1pyridin-4
yl)carbonylethoxy, 3-(imidazo~4,5-c]pyridin-5-yl~carbonyl~
propoxy, 4-(imidazo[4,5-c~pyridin-7-yl)carbonylbutoxy, 5-
(imidazo~4,5-c~pyridin-2-yl)carbonylpentyloxy, 6-(1midazo-
[~,5-c]pyridin 2~yl)carbonylhexyloxy, l,l-dimethyl-2~
(imidazo[4,5-c~pyridin-2-yl~carbonylethoxy, 2-methyl-3- ~ ;
~irnidazo~4,5-c~pyr1din-2-yl)carbonylprop~xy, and the like.
The "tri(lower aIkyl)ammonium" includes an ammonium
group having three of a straight chain or branched chain
alkyl group having l to 6 carbon atoms, for example,
trimethylammonlum, triethylammonium, tripropylammonium
triisopropylammonium, tributylammonium, tri(tert-butyl)~
ammonium, tripentylammonium, trihexylammonium, dimethyl- ~ .
ethylammonium, diethylpropylammonium, dimethylbutylammonium,
diethylmethylammonium, dimethylhexylammonium, dipropyl~
methylammonium, dibutylethylammonium, methylethylpropyl~
ammonium, methylbutylpentylammonium, and the li~e.
The "pyridyl(lower)alkyl" include a pyridylalkyl
group wherein the alkyl moiety is a straight chain or
- 73 - 211633''1 :
'094/~1113 PC~/JP~3/0~83
branched chain alkyl group having 1 to 6 carbon atoms, for ;~;~
example, (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)~
methyl, 2-~2-pyridyl)ethyl, 1-(3-pyridyl)ethyl, 3-(4- :'
pyridyl)propyl, ~-(2-pyridyl)butyl, 5-(3-pyridyl)pentyl, 6- .
(4-pyridyl)hexyl, 1,1 dimethyl-2-(2-pyridyl~ethyl, 2-methyl- .
3-(3-pyridyl)propyl, and the like. ~
The "lower alkyl which may optionally have a ~;
substituent selected from hydroxy and cyano" includes a ~::
straight chain or branched chain alkyl group having 1 to 6 ;~
carbon atoms which may optionally have one to three substi- ~:
tuents selected from a hydroxy group and a cyano group, for
example, hydroxymethyl, 2-hydroxyethyl, l-hydroxyethyl, 3-
hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1- ;-
.:
dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl/ 5-hydroxy~
pentyl~ 6-hydroxyhexyl, l-hydroxyisopropyl, 2-methyl-3-
hydroxypropyl, 2,3-dihydroxyethyl, 3,4~dihydroxybutyl, 5 r 6
. -
: dihydroxyhexyl, cyanomethyl, 2-cyanoethyl, l-cyanoethyl, 3-
cyanopropy7, 4-cyanobutyl, 5-cyanopentyl, 5-cyanohexyl, 1,1-
dimethyl-2-cyanoethyl, 2-methyl-3-cyanopropyl, and the like. ~
: The "lower alkynyl" include~ a straight chain or -~:
branched chain alkynyl group having 2 to 6 carbon atoms, or ~ :~
example, ethynyl, 2-propynyl, 2-butynyl, 3-~utynyl, 1-
methyl-2-propynyl, 2-pentynyl, 2-hexynyl, a-~ the like. ;~~
The "pyrrolidinylcarbonyl which may optionally be
substituted by a phenyl(lower)alkoxycarbonyl on the ~ :
pyrrolidine ring" includes a pyrrolidinylcarbonyl which may
optionally be substituted by a phenylalkoxycarbonyl group on
the pyrrolidine ring wherein the alkoxy moiety is a straight -~
': ","
WO94/01113 74 PCTJJP93~
~11633~
chain or branched chain alkoxy group having 1 to 6 carbon
atoms, for example, l-benzyloxycarbonyl-2-pyrrolidinyl-
carbonyl, 2-pyrrolidinylcarbonyl, l~pyrrolidinylcarbonylf 3-
pyrrolidinylcarbonyl, l-~2-phenylethoxycarbonyl)-2- .~:
pyrrolidinylcarbonyl, 2-(1-phenylethoxycarbonyl)~
pyrrolidinylcarbonyl, 3-(3-phenylpropoxycarbonyl)-2-
pyrrolidinylcarbonyl, l-(4-phenylbutoxycarbonyl)-2-
pyrrolidinylcarbonyl, 2-(5-phenylpentyloxycarbonyl)-1~
pyrrolidinylcarbonyl, 2-(6-phenylhexyloxycarbonyl)-3- . :
pyrrolidinylcarbonyl, and the like.
The "phenyl(lower)alkoxycarbonylamino" includes a ~ .
phenylalkoxycarbonylamino where:Ln the alkoxycarbonyl moiety
is a straight chaln or branched chain alkoxycarbonyl group ;~
having 1 to 6 carbon atoms, for example, N-benzyloxy-
carbonylamino~ ~-(2-phenylethoxycarbonyl)amino, N~ phenyl :
ethoxycarbonyl)amino, N- ( 3-phenylpropoxycarbonyl)aminor N~
(4-phenylbutoxycarbonyl)amino, N-~5-phenylpentyloxy-
carbonyl)amino, N-(6-phenylhexyloxycarbonyl)amino, N~
dimethyl-2-phenylethoxycarbonyl)amino, N-~2-methyl-3-phenyl~
propoxycarbonyl)amino, and the like.
The "lower alkyl having optionally a hydroxy-
substituent" includes a straight chain or branched chain
alkyl group having 1 to 6 carbon atoms which has optlonally~
one to three hydroxy-substituents, for example, in addition -
to the above-mentioned lower alkyl groups, hydroxymethyl, 2- .
hydroxyethyl, l-hydroxyethyl, 3-hydroxypropyl, 2,3- :
dihydroxypropyl, 4-hydroxybutyl, l,l-dimethyl-2-hydroxy-
ethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxy-
~11633'1
`'094/01113 pCTlJP93/~835
hexyl, l-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, 2,3-
dihydroxybutyl, 3,4-dihydroxyhexyl, 5,6-dihydroxyhexyl, ~-
2,3,4-trihydroxybutyl, and the like. ~ :~
The "hydroxy-subs~ituted lower alkanoyl" includes a ~
hydroxy-substituted straight chain or branched chain ~:
alkanoyl group having 2 to 6 carbon atoms, for example, 2~
hydroxyacetyl, 3-hydroxypropionyl, 2-hydroxypropionyl, 4- ~:
hydroxybutyryl, 2,2-dimethyl-3-hydroxypropionyl, 5-hydroxy-
pentanoyl, 6-hydroxyhexanoyl, 3-methyl-4-hydroxybutyryl, and
the like. ;
The "lower alkanoyloxy(lower)alkanoyl" includes an
alkanoyloxy-substituted alkanoyl wherein both alkanoyl ~;
moieties are a straight chain or branched chain alkanoyl
group having 2 to 6 carbon~atoms, for example, 2-acetyloxy~
acetyl, 3-pro~ionyloxyproplonyl, 2-butyryloxyproplonyl, 4-
pentanoyloxybutyryl, 2,2-dimethyl-3-hexanoyloxypropionyl, 5
acetyloxypentanoyl, 6-propionyloxyhexanoyl ! and the like. -
. .~
The "phenyl/lower)alkyl wherein the phenyl ring may :;:
optionally has a lower alkoxy substituent" includes a
phenylalkyl group wherein the alkyl moiety is a straight
chain or branched chain alkyl group having 1 to 6 carbon
atoms and the phenyl ring has optionally one to three
substituents of a straight chain or branched chain alkoxy
group having 1 to 6 carbon atoms, for example, in additlon ~;;
to the above-mentioned phenyl(lower)alkyl groups, 2-methoxy~
benzyl, 3-methoxybenzyl, 2-(4-methoxyphenyl)ethyl/ 1-(2~
ethoxyphenyl)ethyl, 3-(4-isopropoxyphenyl)propyl, 4-(3- ~:
pentyloxyphenyl)butyl, 5-(4-hexyloxyphenyl)pentyl, 6-(2-
.....
`''` "''',
W09~/~1113 - 76 - PCr/JP93~
211~3~'!1
butyloxyphenyl)hexyl, 3,4-dimethoxybenzyl, 3-ethoxy 4
_ methoxybenzyl, 2,3-dimethoxybenzyl, 2,6-dimethoxybenzyl~ ;~
3,4,5-trimethoxybenzyl, and the like.
The "cycloalkenylcarbonyl" includes a cycloalkenyl- -
carbonyl group having 3 to 8 carbon atoms, for example,
cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenyl-
carbonyl, cyclohexenylcarbonyl, cycloheptenylcarbonyl,
cyclooctenylcarbonyl, and the like.
The "pyrimidylthio-substituted lower alkoxy"
includes a pyrimidylthio-substituted straight chain or
branched chain alkoxy group having 1 to 6 carbon atoms, for
example, (2-pyrimidyl)thiomethoxy, 2-t4~pyrimidyl)thio- ~:
ethoxy, 1 (5-pyrimidyl~thioethoxy, 3-(6-pyrimidyl)thio-
propoxy, 4-(4-pyrimidyl)thiobutoxy, 5-(2-pyrimidyl)thio-
pentyloxy, 6-(5-pyrimidyl)thiohexyloxy, 1,1-dimethyl-2-(2- ~
pyrimidyl)thioethoxy, 2-methyl-3-(2-pyrimidyl)thiopropoxy, ~.
and the like. ~:
: The "pyrimidylsulflnyl-substltuted lower alkoxy" ;~
includes a pyrimldylsulfinyl-substituted straight chain or
branched chain alkoxy group having 1 to 6 carbon atoms, for
example, (2-pyrimidyl)sulfinylmethoxy, 2-(4-pyrimidyl)- :
sulfinylethoxy, l-(5-pyrimidyl)sulfinylethoxy, 3-(6- :~:
pyrimidyl)sulfinylpropoxy, 4-(4-pyrimidyl)sulfinylbutoxy, 5- :-;
(2-pyrimidyl)sulfinylpentyloxy, 6-(S-pyrimidyl)sulfinyl- ~
hexyloxy, l,l-dimethyl-2-~2 pyrimi~yl)sulfinylethoxy, 2- :
methyl-3-(2-pyrimldyl)sulfinylpropoxy, and the like.
The "pyrimidylsulfonyl-substituted lower alkoxy"
includes a pyrimidylsulfonyl-substituted straight chain or
~il633'1
- 77 - :
'0~4/0~113 PCr/JPg3/00835
branched chain alkoxy group having 1 to 6 carbon atoms, for
example, (2-pyrimidyl)sulfonylmethoxy, 2-(4-pyrimidyl)- ;~
sulfonylethoxy, l-(5-pyrimidyl)sulfonylethoxy, 3-(6- :
pyrimidyl)sulfonylpropoxy, 4-[4-pyrimidyl)sulfonylbutoxy, 5-
(2-pyrimidyl)sulfonylpentyloxyf 6-(5-pyrimidyl)sulfonyl-
hexyloxy, l,l-dimethyl-2-~2-pyrimidyl)sulfonylethoxy, 2-
methyl-3-(2-pyrimidyl)sulfonylpropoxy, and the like.
The "imidazolylthio-substitu~ed lower alkoxy which
may optionally have a lower alkyl substituent" includes a
.. imidaæolylthio-substituted straight chain or branched chain
alkoxy group having 1 to 6 carbon atoms which may optionall~
have a substituent of a straight chain or ~ranched chain
alkyl group havin~ 1 to 6 carbon atoms on the imidazolyl
group, for example, (2-imidazolyl)thiomethoxy, 2-(4
imidazolyl)thioethoxy, l-(5-imidazolyl)thioethoxy, 3-(2~
imidazolyl)thiopropoxy, 4-(4-imidaæolyl)thiobutox~ 5-(2-
imidazolyl)thiopentyloxy, 6-(5-imidazolyl)thiohexyloxy, 1,1- -
dimethyl-2-(2-imidazolyl)thioethoxy, 2-methyl-3-(2 imidazol~
yl)thiopropoxy, (4-methyl-2-imidaæolyl)thiomethoxy, 2-(5- -:
ethyl-4-imidazolyl)thioethoxy, 1-(4-propyl-5-imidazolyl)- ~`
..~
thioethoxy, 3~ butyl-2-imi.dazolyl)thiopropoxy, 4-(2-
pentyl-4-imidazolyl)thiobutoxy, 5-(1-methyl-2-imidazolyl)~
thiopentyloxy, 6~ hexyl~5-imidazolyl)thiohexyloxy, 1,1-
dimethyl-2-(1-ethyl-2-imidazolyl~thioethoxy, 2-methyl-3
propyl-2-imidazolyl)thiopropoxy, and the like.
The "imidazolylsulfonyl-substituted lower alkoxy ;~
which may optionally have a lower alkyl substituent" ~- ;
includes a imidazolylsulfonyl-substituted straight chain or ~
- 78 -
WOg4/01113 PCT/JP93~008'
2116334
branched chain alkoxy group having 1 to 6 carbon atoms which :
may optionally have a substituent of a straight chain or
branched chain alkyl group having 1 to 6 carbon atoms on the
imidazolyl group, for example, (2-imidazolyl)sulfonyl-
methoxy, 2-(4-imidazolyl)sulfonylethoxy, 1-(5-imidazolyl)- :
sulfonylethoxy, 3~2-imidazolyl)sulfonylpropoxy, 4-(4-
imidazolyl)sulfonylbu~oxy, 5-(2-imidazolyl)sulfonylpentyl-
oxy, 6-(5-imidazolyI)sulfonylhexyloxy, 1,1-dimethyl-2-~2- :~
imidazolyl)sulfonylethoxy, 2-methyl-3-(2-imidazolyl)-
sulfonylpropoxy, (4-methyl-2-1midazolyl)sulfonylme~hoxy, 2
(5-ethyl-4-imidazolyl~sulfonylethoxy, 1-(4-propyl-5-
imidazolyl)sulfonylethoxy, 3-(1-butyl-2-1midazolyl)sulfonyl-
propoxy, 4-(2-pentyl-4-imidazolyl)sulfonylbutoxy, 5-(1-
methyl-2-imidazolyl)sulfonylpentyloxy, 6-(1-hexyl-5-
imidazolyl)sulfonyIhexyloxy, 1,1-dimethyl-2-(1-ethyl-2-
imidazolyl)sulfonylethoxy, 2-methyl-3~(1-propyl-2-
imidazolyl)sulfonylpropoxy, and the like. ~ -
The "ammonium-substituted lower alkoxy having:three .
substituents selected from a lower alkyl, a lower alkenyl
and oxo" includes an ammonium-substituted straight chaln or
branched chain alkoxy group having 1 to 6 carbon atoms,
which have three substituents selected from a stralght chain
or branched chain alkyl group having 1 to 6 carbon atoms, a
straight chain or branched chain alkenyl group having 2 to 6 -:
carbon atoms! and an oxo group, for example, trlmethyl-
ammoniummethoxy, ~-(triethylammonium)ethoxy, l-(tripropyl
ammonium)ethoxy, 3-(tributylammonium)propoxy, 4-(tripentyl- :
ammonium)butoxy, 5-(triethylammonium)pentyloxy, 6-(trihexyl- ~
094/01113 2 1 1 6 3 3 1 p~T/Jp93~83~
ammonium~hexyloxy, l,l-dimethyl-2-~triallylammonium)ethoxy,
2-methyl-3-(tributenylammonium)propoxy, tri(l-methylallyl)-
ammonium-methoxy, 2-[tri(2-pentenyl)ammonium]ethoxy, l-~tri-
(2-hexenyl)ammonium~ethoxy, 3-(N-allyl-N,N-dimethyl-
ammonium)propoxy, 4-~N,N-diallyl-N methylammonium)butoxy, 5
(N-allyl-N methylamino)pentyloxy ~-oxide, 6 1N-allyl-N-
ethylamino)hexyloxy N-oxide, 5-tN-allyl-N-methyl-N-ethyl-
ammonium)pentyloxy, and the like.
The "phenylthio(lower)alkoxy wherein the phenyl
rin~ may optionally have a substituent selected from nitro
and an amino" includes a phenylthioalkoxy wherein the alkoxy
moiety is a straight chain or branched chain alkoxy group .. ~.
hav ng 1 to 6 carbon atoms, and the phenyl ring may -~
optlonally have one to three subs:tituents selected from a
nitro group and an amino group~ for example, phenylthio-
methoxy, 2-phenylthioethoxy, l-phenylthioethoxy, 3-phenyl- -
thiopropoxy, 4-phenylthiobutoxy, 5-phenylthiopentyloxy, 6- ;~
:
phenylthiohexyloxy, l,l-dimethyl-2-phenylthioethoxy, 2- ;
methyl-3-phenylthioprQpoxy, (2-nitrophenyl)thiomethoxy, 2- ~ `
(3-nitrophenyl)thioethoxy, 1-(4-nitrophenyl)thioethoxy, 3- v
(2,3-dinitrophenyl)thiopropoxy, 4-(3,4-dinltrophenyl)thio-
butoxy, 5-(4-nitrophenyl)thiopentyloxy, 6-(2,6-dinitro-
phenyl)thiohexyloxy, l,l-dimethyl-2-(2,4,6-trinitrophenyl)- -~
thioethoxy, 2-methyl-3-(4-nitrophenyl)thiopropoxy, (2-
aminophenyl)thiomethoxy, 2-(3-aminophenyl)thioethoxy, 1-(4-
aminophenyl)thioethoxy, 3-(2,3-diaminophenyl)thiopropoxy, 4
(3,4-diaminophenyl)thiobutoxy, 5-(4-aminophenyl)tniopentyl-
oxy, 6-(2,6-diaminophenyl)thiohexyloxy, 1,1-dimethyl-2~
- 80 -
WO94/01113 PCTJ3Pg31~8
211~33~
(2,4,6-triaminophenyl)thioethoxy, 2-methyl-3-(4-amino-
phenyl)thiopropoxy, and the like.
The "phenylsulfonyl(lower)alkoxy wherein the phenyl
ring may optionally have a substituent selected from nitro
and an amino having optionally one or two substituents
selected from a lower alkanoyl and a lower alkyl" includes a
phenylsulfonylalkoxy wherein the alkoxy moiety is a straight ::-
chain or branched chain alkoxy group havin~ 1 to 6 carbon
atoms, and the phenyl ring may optionally have one to`three `~:
substituents selected from a nitro group and an amino ~roup
having opitonally one or two substituents selected from a
straight chain or branched chain alkyl group havin~ 1 to 6 ~:-
carbon at~ms and a straight chain or branched chain alkanoyl
group havin~ 1 to 6 carbon atoms, for example, phenyl~
sulfonylmethoxy, 2-phenylsulfonylethoYy, l-phenylsulfonyl~
ethoxy, 3-phenylsulfonylpropoxy, 4-phenylsulfonylbutoxy, 5
phenylsulfonylpentyloxy, 6-phenylsulfonylhexyloxy, 1,1
dimethyl-2-phenylsulfonylethoxy, 2-methyl-3-phenylsulfonyl-
propoxy, (2-aminophenyl)sulfonylmethoxy, 5-(4-aminophenyl)- :
sulfonylpentyloxy, 2-(4-methylaminophenyl)sulfonylethoxy, 1-
(3-ethylaminophenyl)sulfonylethoxy, 3-[2-(N-methyl-N-ethyl-
amino)phenyl]sulfonylpropoxy, 4-~3-(N-methyl-N-hexylamino)-
phenyl]sulfonylbutoxy, 5-14-dimethylaminophenyl)sulfonyl-
pentyloxy, 4-dipentylaminophenylsulfonylmethoxy, 2-(2- ;
isopropylaminophenyl)sulfonylethoxy, l-(3-butylaminophenyl)-
sulfonylethoxy, 5-(2,4-diaminophenyl)sulfonylpentyloxy, 3~
[2,3-bis(dimethylamino)phenyl]sulfonylpropoxy, 4-t3,4~bis- ~;
(methylamino)phenyl]sulfonylbutoxy, 5-(2,4,6-triamino- ::
- 81 _ 2 ~ 1 6 3 3 ~
'Og4/01113 PCT/JP93/0~83~ :
phenyl)sulfonylpen~yloxy, 6-[3,4,5-tri(methylamino)phenyl]-
sulfonylhexyloxy, 5-(4-acetylaminophenyl)sulfonylpentyloxy,
3-[4-(N-methyl-N acetylamino)phenyl]sulfonylpropoxy, 5-(4- :~
nitrophenyl)sulfonylpentyloxy, 2 ~4-nitro-3-methylamino
phenyl)sulfonylethoxy, 3-(2,4-dinitrophenyl)sulfonylpropoxy, ~;
4-(2,4,6-trinitrophenyl)sulfonylbutoxy, and the like. -~
The "pyridylthio-substituted lower alkoxy" i.ncludes
a pyridylthio-substituted straight chain or branched chain
alkoxy group having 1 to 6 carbon atoms, for example, (2~
pyridyl)thiomethoxy, 2-~3-pyridyl)thioethoxy, 1-(4-pyridyl)-
thioethoxy, 3-(3-pyridyl)thiopropoxy, ~-(4-pyridyl~thio-
butoxy, 5-(2-pyridyl)thiopentyloxy, 5-(4-pyridyl)thiopentyl~
oxy, 6-(3-pyridyl)thiohexyloxy, 1,1-dimethyl-2-(2-pyridyl)- `~
thioethoxy, 2-methyl-3-(4~pyridyl)thiopropoxy, and the like. ~.
The "pyridylsulfonyl-substituted lower alkoxy which ~:
may optionally have an oxo subsituent on the pyridine ring" ~;
includes a pyridylsulfonyl-substituted straight chain or
branched chain alkoxy group having 1 to 6 carbon atoms wnlch
may optionally have an oxo substituent:on the pyridine ring,
for example, (2-pyridyl)sulfonylmethoxy, 2-(3-pyridyl)- .
sulfonylethoxy, 1-(4 pyridyllsulfonylethoxy, 3-(3-pyridylj~
sulfonylpropoxy, 4-(4-pyridyl)sulfonylbutoxy, 5-(2-pyridyl)-
sulfonylpentyloxy, 5-(4-pyridyl)sulfonylpentyloxy, 6-(3- ~
pyridyl)sulfonylhexyloxy, l,l-dlmethyl-2-(2-pyridyl)- .~.
sulfonylethoxy, 2-methyl-3-(4-pyridyl)sulfonylpropoxy, 5
oxido-4-pyridyl)sulfonylpentyloxy, (4-oxo-2-pyridyl)- ~ ;~
sulfonylmethoxy, 2-(1-oxo-3-pyridyl)sulfonylethoxy, 1 (2-
oxo-4-pyridyl)sulfonylethoxy, 3-(2-oxo-3-pyridyl)sulfonyl-
- 82
WOg4/01113 PCT~JP93/~
2111~33~
propoxy, 4-13-oxo-4-pyridyl)sulfonylbutoxy, 5-(1-oxido-2-
pyridyl)sulfonylpentyloxy, 6~ oxido-3-pyridyl~sulfonyl- ~;
hexyloxy, and the like.
The '1cycloalkylcarbonyl having optionally one to :
three substituents selected from hydroxy and a lower ~-~
alkanoyloxy" includes a cycloalkylcarbonyl having 3 to 8
carbon atoms which has optionally one to three substituents
selected from a hydroxy group and a straight chain or
branched chain alkanoyloxy group having 2 to 6 carbon atoms,
for example, cyclopropylcarbonyl, cyclobutylcarbonyl, .--~
cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptyl~
carbonyl, cyclooctylcarbonyl, 2-hydroxycyclopropylcarbonyl, ~ ~
3-hydroxycyclobutylcarbonyl, 2-hydroxycyclopentylcarbonyl, - .
3-hydroxycyclopentylcarbonyl, 2,4-dihydroxycyclopentyl~
carbonyl, 2-hydroxycyclohexylcarbonyl, 3-hydroxycyclohexyl- `~.
carbonyl, 4-hydroxycyclohexylcarbonyl, 3,4-dihydroxy-
cyclohexylcarbonyl, 2,4-dihydroxycyclohexylcarbonyl, 2,5
dihydroxycyclohexylcarbonyl, 3,4,5-trihydroxycyclohexyl-
carbonyl, 3-hydroxycycloheptylcarbonyl, 3,4-dihydroxycyclo-
heptylcarbonyl, 2,3,4-trihydroxycycloheptylcarbonyl, 4~
hydroxycyclooctylcarbonyl, 4,5-dihydroxycyclooctylcarbonyl, ~-
4,5,6-trihydroxycyclooctylcarbonyl, 2-acetyloxycvclopropyl-
carbonyl, 3-propionyloxycyclobutylcarbonyl, 2-butyryloxy~
cyclopentylcarbonyl, 3-pentanoyloxycyclopentylc~rbonyl, 2,4
dihexanoyloxycyclopentylcarbonyl, 2-acetyloxycyclohexyl-
carbonyl, 3-propionyloxycyclohexylcarbonyl, 4-butyryloxy-
cyclohexylcarbonyl, 3,4-diacetyloxycyclohexylcarbonyl, 2,4- ~;~
diacetyloxycyclohexylcarbonyl, 2,5-diacetyloxycyclohexyl~
- 83 - 211633~
- ~g~/01113 PCr/JP~3/~3~ ~
` ', ~: '
carbonyl, 3,4,5-triacetyloxycyclohexylcarbonyl, 3,4-
diacetyloxy-5-hyroxycyclohexylcarbonyl, 3-pentanoyloxycyclo-
heptylcarbonyl, 3,4-diacetyloxycycloheptylcarbonyl, 2,3,4- -~;
tripropionyloxycycloheptylcarbonyl, 4-hexanoyloxycyclooctyl-.~ -
carbonyl, 4,5-dibutyryloxycyclooctylcarbonyl, 4,5,6- :~
triacetyloxycyclooctylcarbonyl~ and the like. ~ .
The "tetrahydroypyranyl(lower)alkyl wherein the
tetrahydroxypyranyl ring may optionally have one to four
substituents selected from hydroxy and a lower alkoxy"
includes a tetrahydropyranylalkyl wherein the alkyl moiety ;~
is a straight chain or branched chain alkyl group having 1~:`
to 6 carbon atoms, and the tetrahydropyranyl ring may :
optionally have one to four substituents selected from a ;~
hydroxy group and a straight chain or branched chain alkoxy
group having 1 to 6 carbon atoms, for example, (2-tetra~
.:;
hydropyranyl)methyl, 2-(3-tetrahydropyranyl)ethyl~ 4-
tetrahydropyranyl)ethyl, 3-(2-tetrahydropyranyl)propyl, 4- ~;
(3-tetrahydropyranyl)butyl, 5-(4-tetr;ahydropyranyl)pentyl,: :~
6-(2-tetrahydropyranyl)hexyl, 1,1-dimethyl-2-(3-tetrahydro~
pyranyl)ethyl, 2-methyl-3-(4~tetrahydropyranyl)propyl, (3- -.
: ., .
hydroxy-2-tetrahydropyranyl~methyl, 2-(2,4-dihydroxy-3-
tetrahydropyranyl~ethyl, l-(2,3,5-trihydroxy-4-tetrahydro-
pyranyl)ethyl, 3-(6-methoxy-2-tetrahydropyranyl)propyl, 4- ~
(4-ethoxy-3-tetrahydropyranyl)butyl, 5-(4,6-dimethoxy-4- ...
tetrahydropyranyl)pentyl, 6-(4,5,6-trimethoxy-2 tetrahydro~
pyranyl)hexyl, l,l-dimethyl-2-(2-propoxy-3-tetrahydro- -~
pyranyl)ethyl, 2-methyl-3-(6-butoxy-4-tetrahydropyranyl)~
propyl, (6-pentyloxy-2-tetrahydropyranyl)methyl, 2-(4- ~ ~
.::
- ~4 - . -
W20~04/01113 Pcl~/JPo3/n~ls~
hexyloxy-3-tetrahydropyranyl3ethyl, 2-(3,4,S-trihydroxy-6-
methoxy-2-tetrahydropyranyl)methyl, 1-(3,4,5,6 tetrahydroxy- -
~-tetrahydropyranyl)ethyl, 3-(3,4,5,6-tetramethoxy-2-tetra-
hydropyranyl)propyl, and the like.
The "lower alkanoyl substituted by a 5- or 6-
membered saturated heterocyclic group selected from pyrrol-
idinyl, piperazinyl, piperidinyl, and morpholinyl" includes
a straight chain or branched chain alkanoyl group having 2
to 6 carbon atoms which is substituted by a S- or 6-membered
saturated heterocyclic group selected from pyrrolidinyl,
piperazinyl, piperidinyl, and morpholinyl, for example, 2- -~
(l-pyrrolidinyl)acetyl, 3-(2-pyrrolidinyl)propionyl, 2-(3- ~;~
pyrrolidinyl)propionyl, 4-(1-pyrrolidinyl)butyryl, 2,2~ ~.
dimethyl-3-(2-pyrrolidinyl~propionyl, 5-(3-pyrrolidinyl~
pentanoyl, 6~ pyrrolidinyl)hexanoyl, 2-(1-piperazinyl)~
acetyl r 3-(2-piperazinyl)proplonyl, 2-(3-piperazinyl)-
propionyl, 4-(1-piperazinyl)butyryl, ~,2-dimethyl-3-(2~
piperazinyl)propionyl, 5-(3-piperazinyl)pentanoyl, 6-(1- ..
piperazinyl)hexanoyl, 2~(1-piperidinyl)acetyl, 3-~2-
piperidinyl)propionyl, 2-(3-piperidinyl)propionyl, 4-(4-
piperidinyl)butyryl, 2,2-dimethyl-3-(1-piperidinyl)-
propionyl, 5-(2-piperidinyl)pentanoyl, 6~(3-piperidinyl)-
hexanoyl, 2-~4-morpholinyl)acetyl, 3-(2-morpholinyl)- ;~
propionyl, 2-(3-morpholinyl)propionyl, 4-(4-morpholinyl)-
butyryl, 2,2-dimethyl-3-(2-morpholinyl)propionyl, 5-(3- ~
morpholinyl)pentanoyl, 6-(4-morpholinyl~hexanoyl, and the .
like.
The above "heterocyclic group-substituted lowe
~9~/01113 - 85 ~ 2 ~ ~ ~ 3 3 4 pCr/JPg3/~835
alkanoyl which has a substituent selected from a lower alkyl
and phenyl" includes the above heterocyclic group-substi-
tuted straight chain or branched chain alkanoyl group havin~
2 to 6 carbon atoms, which has one to three substituents ~
selected from a straight chain or branched chain alkyl group ;~:
having 1 to 6 carbon atoms, and a phenyl group, for example,
2-(2-methyl-1-pyrrolidinyl)acetyl, 3-(1-ethyl-2 pyrrolidîn-
yl)propionyl, 2-(1-propyl-3-pyrrolidinyl)propionyl, 4-(3-
butyl-l-pyrrolidinyl)butyryl, 2,2-dimethyl-3-(4-pentyl-2-
pyrrolidinyl)propionyl, 5-(1-hexyl-3-pyrrolidinyl)pentanoyl,
6-(2,3 dimethyl-l-pyrrolidinyl)hexanoyl/ 2-(2,3,4-trimethyl-
l~pyrrolidinyl)acetyl, 3-(l~phenyl-2-pyrrolidinyl)propionyl, ;~
2 (1-methyl-2-phenyl-3-pyrrolidinyl)propionyl, 2-(4-methyl-
piperazinyl)acetyl, 2-(4-pheny].-1-piperazinyl)acetyl, 3-
(4-ethyl-2-piperazinyl)propionyl, 2-(4-propyl-3-piperazin-
yl)propionyl, 4-(4-butyl-1-piperazinyl~utyryl, 2,2
~dimethyl-3-(4-pentyl-2-piperazinyl:)propionyl~ 5-(4-hexyl-3- :
piperazinyl)pentanoyl, 6-(2,4-dimethyl-1-p~perazinyl)- .
hexanoyl, 2-(3,4,5-trimethyl-1-piperazinyl)acetyl, 2-(4-
."::,
phenyl-3-methyl-1-piperazlnyl)acetyl, 2-(4-methyl-1-piperi-
dlnyl)acetyl, 3-(1-ethyl-2-piperidinyl)propionyl, 2~
propyl-3-piperidinyl)propionyl, ~-(1-butyl-4-piperidinyl)- ~.
butyryl, 2,2-dimethyl-3-(4-pentyl-1-piperidinyl)propionyl,
5-(1-hexyl-2-piperidinyl)pentanoyl, 6-(1-phenyl-3-piperi-
dinyl)hexanoyl, 2-~2,5-dimethyl-4-phenyl-1-piperldlnyl)-
acetyl, 2-(2,3r4-trimethyl-1-piperldinyl)acetyl, 2-(1,2-
dimethyl-4-piperidinyl)acetyl, 2-(3-methyl-1-morpholinyl)-
acetyl, 3-(1-ethyl-2-mQrpholinyl)propionyl, 2-(1-propyl-3-
"'
- 86 -
WOg4/~1113 PCT~JP93/~
2 ~ 3 3 '1
morpholinyl)propionyl~ 4-(2-butyl-4-morpholinyl)butyryl,
2,7-dimethyl-3-(l-pentyl-~-morpholinyl)propionyl, 5-(2- ~
hexyl-3-morpholinyl~pentanoyl, 6-~3,5-dimethyl-4- ~ .
morpholinyl)hexanoyl, 2-~2,3,5-trimethyl-4-morpholinyl)-
acetyl, 2-(3-phenyl-4-morpholinyl)acetyl, 2-(2-methyl-3-
phenyl-4-morpholinyl)acetyl, and the like.
The "piperidinylcarbonyl which may optionally h~ve
a lower alkanoyl substituent" includes a piperidinylcarbonyl ~:~
which may optionally have a substituent of a straight chain :~
or branched chain alkanoyl group having 1 to 6 carbon atoms,
for example, ~l-piperidinyl)carbonyl, ~2-piperidinyl)- .
carbonyl, (3-piperidinyl)carbonyl, (4-piperidinyl)carbonyl,
(l-acetyl-4-piperidinyl)ca~bonyl, (4-formyl-1 piperidinyl)~ . ;.
carbonyl, (~-propionyl-2-piperidinyl)carbonyl, (1-butyryl-4- -
plperidinyl)ca-bonyl, (I-pentanoyl-4-piperidinyl)carbonyl,
hexanoyl-4-piperidinvl)carbonyl, and the like. ~.
The "lower al'~oxy" includes a straight chaln or :.
branched chain al~oxy group having 1 to 6 carbon atoms, for
~.. ..
exampl2, methoxy, etho~y, propoxy, isopropoxy, butoxy, tert- :
butoxy, pentyloxy, hexyloxy, and the like.
The "amino having optionally a lower alkyl .
. .. : . ~
su~s~ituent" includes an amino optionally having one ~o two .~
.: .
straiqht chain or br2nched chain alkyl group having~l to 6 .. :
carbon atoms, for exam~le, amino, methylamino, ethylamino,
propyl amino, isopropylamino, butylamino, tert-butyIamino,
pentylamino, hexylamino, dimethylamino, diethylamino, ;
di~ropylamino, dibutylamino, dipentylamino, dihexylamino, N- ~.
me~hyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-
, ~:
- 87 ~ 211633'1
0g4~0~113 p~T/JP93~0835
butylamino, N-methyl-N-hexylamino, and the like.
The "lower alkyl which has optionally a substituent
selected f~om a halogen atom and hydroxy" includes a
straight chain or branched chain alkyl group having 1 to 6 ~.
carbon atoms which may optionally have 1 to 3 substituents
selected from a halogen atom and hydroxy, for example, in
addition to the above mentioned lower alkyl qroups, hydroxy~
methyl, 2-hydroxyethyl, l-hydroxyethyl, 3-hydroxypropyl, ~:
2,3-dihyroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxy-
ethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxy- ~
hexyl, l-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, ~:.
trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, ~;
fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-
chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichlor~ethyl, 3- ;
chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-
~luorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5- ;
bromohexyl, 5,6-dichlorohexyl, and the like.
The "amino having optionally a substituent selected
from a lower alkyl and a lower alkanoyl" includes an amino
, . .; :.. ~
having optionally one or two substituents:selected from a
straight chain or branched chain alkyl group having I to 6
carbon atoms and a straiyht chain or branched chain alkanoyl
group having 1 to 6 carbon atoms, for example, amino,
methylamino, ethylamino, propylamino, isopropylamino,
butylamino, tert-butylamino, pentylamino, hexylamino,
dimethylaminol diethylamino, dipropylamino, dibutylamino, ~:.
dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl~
N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino,
- 88 -
W094/~1113 ~CTJJP931008
211633'1
N-methyl-N-acetylamino, N-acetylamino, N-formylamino, N- :
propionylamino, ~-butyrylamino, N-isobutyrylamino, N- ~:
pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino,
N-ethyl-N-acetylamino, and the like.
The "carbamoyl-substituted lower alkoxy" includes a
carbamoyl-substituted straight chain or branched chain
alkoxy group having 1 to 6 carbon atomst for example,
carbamoylmethoxy, 2-carbamoylethoxy, l-carbamoylethoxy, 3-
carbamoylpropoxy, 4-carbamoylbutoxy, 5-carbamoylpentyloxy, ~ ;
6-carbamoylhexyloxy, 1,1-dimethyl-2-carbamoylethoxy, 2-
methyl-3-carbamoylpropoxy, and the like. .
The "hydroxy-substituted lower alkoxy" includes a
straight chain or branched chain alkoxy group having 1 to 6 ~:
carbon atoms and having 1 to 3 hydroxy-substltutents, for :-
example, hydroxymethoxy, 2-hydroxyethoxy, l-hydroxyethoxy,
3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, ~-.
3,4-dihydroxybutoxy, 1,1-dlmethyl-2-hydroxyethoxy, 5-
hydroxypentyloxy, 6-hydroxyhexyloxy, 2-metnyl-3-hydroxy~
..... .
propoxy, 2,3,4-trihydroxybutoxy, and the like.
The "lo~er alkoxycarbonyl-substituted lower alkoxy'` ..
includes an alkoxycarbonyl-substituted straight chain or
branched chain alkoxy group having 1 to 6 carbon atoms
wherein the alkoxycarbonyl molety is a straight chain or `.
branched chain alkoxycarbonyl group having 1 to 6 carbon `-.
atorns, for example, methoxycarbonylmethoxy, 3-methoxy- ~-~
carbonylpropoxy, ethoxycarboxymethoxy, 3-ethoxycarbonyl~
propoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonyl-
pentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxy-
- 89 _ 211~33'~
'Og4/01113 P~T/JP~3/~83
carbonylethoxy, 2-me~hyl-3-tert~butoxycarbonylpropoxy, 2-
pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, and the
like.
The "carboxy substituted lower alkoxy" includes a
carboxy-substituted strai~ht chain or branc'héd chain alkoxy;'-;;
group having 1 to 6 carbon atoms, for example, carboxy-
methoxy) 2-carboxyethoxy, l-carboxyethoxy, 3-carboxypropoxy,
4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1~
dimethyl-2-carboxyethoxy, 2-methyl-3~carboxypropoxy, and the -'"'
like.
The "phthalimido-substituted lower alkoxy" includes
a strai~ht chain or branched chain alkoxy group having 1 to
6 carbon atoms which is substitu~ed by phthalimido group
for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1~
phthalimidoethoxy, 3-phthalimidopropoxy, 4-phthalimido- ;;
butoxy, 5-phthalimidope~ntyloxy, 6-phthalimidohexyloxy, 1,1- ;
dimethyl-2-phthalimidoethoxy, 2~methyl-3-phthalimidopropoxy, ~'~
.~, .
and the like. ' '
The "5- or 6-membered satur~ted heterocycllc group '~'
which is formed by binding the groups R21 and R22 together '~
with the nitrogen atom to which they bond with or without
being intervened'with nitro~en or oxygen atom" includes, for'~'
example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino,
and the like.
- The above-mentioned "he'terocyclic group havlng a ;;;
substituent selected from piperidinyl and a lower alkyl"
includes the above-mentioned he~erocyclic groups having 1 to
3 substituents selected from piperidinyl and a straight
9o
WOg4/01113 PCT/JP93J~
2 ll633'1
chain or branched chain alkyl group having 1 to 6 carbon
atoms, for example, 4 methylpiperazinyl, 3,4-dimethyl- -~
piperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl,
3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentyl-
morpholino, 4-hexylpiperazinyl, 4~ piperidinyl)- .-
piperidinyl, 3-(1-piperidinyl)pyrrolidinyl, 3-(1-
: .;,
piperidinyl)-4-methylpiperazinyl, 3-(1-piperidinyl)- ~
morpholino, and the like. .:
-. -
The "phenyl(lower)alkanoyl" includes a phenyl~alkanoyl wherein the alkanoyl moiety is a straight chain or
branched chain alkanoyl group having 2 to 6 carbon atoms,
for example, phenylacetyl, 3-phenylpropionyl, 2-phenyl~
propionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl~ .
5-phenylpentanoyl, 6-phenylhexanoyl, and the like. :
The "cycloalkyl-lower alkanoyl" includes C3-C8
cycloalkyl-alkanoyl group wherein the alkanoyl moiety is a `-
straight chain or branched chain alkanoyl having 2 to 6
carbon atoms, for example, cyclohexylacetyl, 3-cyclopropyl-
propionyl, 2-cyclopentylpropionyl, 4-cyclohexylbutyryl~ 2,2~
dimethyl-3-cycloheptylpropionyl, 5-cyclooctylpentanoyl, 6- ;~-
cyclohexylhexanoyl, and the like.
The 'Icycloalkylcarbonyl'l includes a cycloalkyl- ':
carbonyl having 3 to 8 carbon atoms, for example, ;~
cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl-
carbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, :~
cyclooctylcarbonyl, and the like.
The "phenoxy-lower alkanoyl wherein the phenyl ring
has optionally 1 to 3 substituents selected from a lower
.~
Q94/01113 ~ 91 ~ 2 1 1 6 3 3 ll P~T/~P93/Q~835
alkyl, a lower alkoxy and an amino having optonally a lower ::
alkanoyl substituent" includes a phenoxyalkanoyl group
wherein the alkanoyl moiety is a straight chain or branched
chain alkanoyl having 2 to 6 carbon atoms and the phenyl
ring has optionally 1 to 3 substituents selected from a
straight chain or branched chain alkyl having 1 to 6 carbon `
atoms, a straight chain or branched chain alkoxy having 1 to; ~:
6 carbon atoms and an amino having optionally a straight
chain or branched chain alkanoyl havin~ 1 to 6 carbon atoms, :~
for example, phenoxyacetyl, 3-phenoxypropionyl, 2-phenoxy~
propionyl, 4-phenoxybutyryl, 2,2-dimethyl-3-phenoxy~
propionyl, 5-phenoxypentanoyl, 6-phenoxyhexanoyl~ ~2-amino~
phenQxy)acetyl, 3-(4~aminophenoxy)propionyl, (2-methyl-
phenoxy)acetyl, ~4-methylphenoxy)acetyl, (3-methylphenoxy)-
acetyl, (3-me~hoxyphenoxy)acetyl, ~3-acetylaminophenoxy)~
acetyl, 4-(2-propionylaminophenoxy)butyryl, 2,2-dimethyl-3
~4-butyrylaminophenoxy)propionyl, 5-(2-pentanoylamino-
phenoxy)pentanoyl, 6-~4-hexanoylaminophenoxy)hexanoyl, 3-(2-
ethylphenoxy)propionyl, 2-(4-propylphenoxy)propionyl, 4-~4
butylphenoxy)butyryl, 5-(3-pentylphenoxy)pentanoyl, 6-(4-
hexylphenoxy)hexanoyl, t2,3-dimethylphenoxy)acetyl, (2,5~
dimethylphenoxy)acetyl, (3,4-dimethylphenoxy)acetyl, (3,4,5-
trimethylphenoxy)acetyl, 3-(4-ethoxyphenoxy~propionyl, 2-~2- ~:
propoxyphenoxy)propionyl, 4-(3-butoxyphenoxy)butyryl, 5-(4- ~;~
pentyloxyphenoxy)pentanoyl, 6-(4-hexyloxyphenoxy)hexanoyl,
(3,4-dimethoxyphenoxy)acetyl, (3,5-dimethoxyphenoxy)acetyl,
(2,4-dimethoxyphenoxy)acetyl, (3,4,5-trimethoxyphenoxy)- -~
acetyl, (2-acetylamino-4-methylphenoxy)acetyl, (4-acetyl-
- 92 - :
WO94/01113 PCTJJP93/~ : .
2i1~33~1 ;;
amino-3-methoxyphenoxy)acetyl, and the like. ~.
The "phthalimido-substituted lower alkanoyl" -~
includes a straight chain or branched chain alkanoyl group
having 2 to 6 carbon atoms which is substituted by
phthalimido group, for example, 2-phthalimidoacetyl, 3- -
phthalimidopropionyl, 2-phthalimidopropionyl, 4-phthalimido-
butyryl, 2,2 dimethyl-3-phthalimidopropionyl, 5-phthalimido- :~
pentanoyl, 6-phthalimidohexanoyl, 3-methyl-4-phthalimido-
butyryl, and the like.
The "lower alkoxycarbony1-lower alkanoyl" includes
an alkoxycarbonyl-alkanoyl group ~herein the alkoxy moiety
is a straight chain or branched chain alkoxy having l to 6
carbon atoms and the alkanoyl moiety is a straight chain or
branched chain alkanoyl having 2 to 6 car:bon atoms, for .-:~-
example, methoxycar~onylacetyl, 3-methoxycarbonylpropionyl,
~ .
ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxy~
carbonylbutyryl, 3-propoxycarbonylproplonyl, 2-methoxy~
carbonylpropionyl, 6-propoxycarbonyIhexanoyl, 5-isopropoxy~
carbonylpentanoyl, 2,2-dimethyl-3-butoxycarbonylpropionyl, :~
2-methyl-3-tert-b~toxycarbonylpropionyl, penty1Oxycarbonyl- :
acetyl, hexyloxycarbonylacetyl, and the like.
The "carboxy-1Ower alkanoyl" includes a carboxy-
alkanoyl group wherein the alkanoyl moiety is a straight -~
chain or branched chain ai.kanoyl having 2 to 6 carbon atoms, :;~
for example, carboxyacetyl, 3-carboxypropionyl, 2-carboxy- ~`
propionyl, 4-carboxybutyryl, 2,2-dimethyl-3-carDoxy-
propionyl, 5-carboxypentanoyI, 6-carboxyhexanoyl, and the
like. ::.
_ g3 21 l 6 3 3 1
~94/01113 P~/JP93/~835
The "naphthyloxy-lower alkanoyl" includes a .
naphthyloxy-alkanoyl group wherein the alkanoyl moiety is a ~-
strai~ht chain or branched chain alkanoyl having 2 to 6 ~:
carbon atoms, for example, naphtyloxyacetyl, 3-naphtyloxy~
propionyl, 2-naphtyloxypropionyl, 4-naphthyloxybutyryl, 2,~
dimethyl-3-naphthyloxypropionyl, 5-naphthyloxypentanoyl, 6-
naphthyloxyhexanoyl, and the like. :~
The "phenyl-lower alkoxycarbonyl" includes a -~
phenylalkoxycarbonyl wherein the alkoxycarbonyl mc~ety is a :~
straight chain or branched chain alkoxycarbonyl group having ~;;
1 to 6 carbon atoms, for example, benzyloxycarbonyl, 2-
phenylethoxycarbonyl, l-phPnylethoxycarbonyl, 3-phenyl-
propoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxy-
carbonyl, 6-phenylhexyloxycarbQnyl, 1,1-d-imethyl-2-phenyl~
ethoxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl, and the
like. ;~
The "phenoxy-lower alkyl" includes a phenoxyalkyl
group wherein the al.kyl moiety is a straight chain or
branched chain alkyl group having 1 to 6 carbon atoms, for
example, phenoxymethyl, l-phenoxyethyl, 2-phenoxyethyl, 3
phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 6-phenoxy-
hexyl, l,l-dimethyl-2-phenoxyethyl, 2-methyl-3-phenoxy-
propyl, and the like.
The "phenyl which has optionally 1 to 3
substituents selected from a lower alkyl, a lower alko~y and ~
a halogen atom" includes a phenyl group which has optionally ~;
1 to 3 substituents selected from a s~raight chain or
~ranched chain alkyl group having 1 to 6 carbon a oms, a
_ gg _ ' .
WO94/01~13 P~T/JPg3Jo~ 7
2116~3'1 ~:
straight chain or branched chain al~oxy group having 1 ~o 6 ;
carbon atoms and a halogen atom, for example, phenyl, 2-
methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxy~
phenyl, 3-ethoxyphenyl, 4~ethoxyphenyl, 4-isopropoxyphenyl, .~
4-pentyloxyphenyl, 2,4-dimethoxyphenyl, 4-hexyloxyphenyl, ~;
3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-
dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl,
2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxy~
phenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chloro~
phenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4
fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,
2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichloro- ~:
phenyl, 3,5-dichlorophenyl, 2,6-clichlorophenyl, 2,3- .
dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-
dibromophenyl, 3,4,5-trichlorophen~l, 2-methoxy-3-chloro-
phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- ~
ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropyl- ;
phenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-
dimethylphenyl, 3,4-dlethylphenyl, 2,4-dimethylphenyl r 2 ~ 5~
dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, `:~-
.. ~
3-chloro-4-methylphenyl, 3-methoY~y-4-methyl-5-iodophenyl,
3~4-dimethoxy-5-bromophenyl, 3,5-diiodo-4-methoxyphenyl, and ~:~
the like.
The "amino lower alkyl having optionally a lower
alkyl substituent" includes a straight chain or branched :~
chain alkyl group having 1 to 6 carbon atoms which is
substituted by an amino group having optionally 1 to 2 ;
substituents of a straight chain or branched chain alkyl
3 3 !~
_ 95 _ ~:
`!O 94/01113
group having 1 to ~ carbon atoms, for example, a.~inomethyl, :~
2-aminoethyl, l-aminoethyl, 3-aminopropyl, 4-amir.obutyl, 5-
aminopentyl, 6-aminohexyl, l,l-dimethyl-2-aminoet:~yl r 2- ; ` -
methyl-3-aminopropyl, methylaminomethyl, l-ethyl2~inoethyl,
2-propylaminoethyl, 3-isopropylaminopropyl, 4-buty1amino-
butyl, 5-pentylaminopentyl, 6-hexylaminohexyl, di~eth~
aminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N-~eth~ N-
hexylamino)ethyl, and the like.
The "5- or 6-membered satur2ted heterocyclic yroup
which is ~ormed by binding the groups R24 and R25 together
with the nitrogen atom to which they bond with or wit;-out
being intervened with nitrogen or oxygen atom" ir.clud_s, for
examDle, pyrrolidinyl, piperidinyl, piperazinyl, ~orph.olino,
and the like.
The above-mentioned "heterocyclic group navirg a :~
substituent selected rrom a lower al~yl, a lower a1ko~y~
carbonyl and piperLdinYl" includes the above-men~-one~
heterocyclic groups:having 1 to 3 subst1tuents selecte~d from ~-
a straight chain or ~ranched chain alkyl group h~Jin~ l to 6
carbon ~toms, a stra1~ht cha1n or branched chain a1ko:-y;- ~;~
carbonyl having l to 6 carbon atoms and ~iperidir.~ or
example, in addition to the above-mentioned heter~cyc~ lC
groups having a subst1tuent selected from 2 lower alk~:' and - :~
piperidinyl, 4-methoxyc~rbonylpiperazinyl, ~-ethc:~c2r~0nyl-
pip ridinyl, 3-propoxycarbonylpyrrolidinyl, 2-per. yloxy- ~ -
carbonylmorpholino~, 4-he~yloxycarbonvlp1peridinyl, 4-~thoxy~
carbonyl-3-methy1piperid1nyl, 3-methyl-~-ethoxyc_-bon~
pi~erazinyl, and the Iike. :~
~;",','':~;
~ 96 -
W~94/011~3 PCT/~P93/~&
211633~ ~
The "5- or 6-membered saturated heterocyclic group
which is formed by binding the groups R29 and R30 together
with the nitrogen atom to which they bond with or without
. , .
being intervened with nitrogen or oxygen atom" includes, for
example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, ~.
and the like.
The above-mentioned "heterocyclic group having a ~;~
lower a~kyl substituent" includes the above-mentioned - :
heterocyclic groups having l to 3 substituents of a straight ~;
chain or branched chain alkyl group having 1 to 6 carbon
atoms, for example, 4-methylpiperazinyl, 3,4-dimethyl~
pipera~inyl, 2-ethylpyrro11dinyl~ 2-propylpyrrolidinyl,
3,4,5-trimethylpiperidlnyl, 4-bu~yIpiperidinyl, 3-pentyl-
morpho1ino, 4-hexy1piperazinyl, and the like.
The heterocyclic ring in the formula (2) includes
tetrahydroquinolyl, 2,3,4,5-tetrahydro-lH-benzazepinyl,
l,2,3,4,5,6-hexahydrobenzazocinyl, l,2-dihydroquinolyl, 2,3-
dlhydro-lH benzazepinyl, I,~,3,4-tetrahydrobenzazocinyl, and;~-
the like.
The heterocyclic ring in the formula (23 wherein
.~
the carbon atom in the group of the formula: -(C:H2)t- or
CH=CH-(CH2)~- for W is replaced by oxygen atom, sulfur .::~
atom, sulfinyl group, sulfonyl group, or a group of the
formula: -NRZ8- (R28 is hydroyen atom or a lower alkyl)
includes a heterocylic group wherein the carbon atom in the~-~
yroup of the formula: -(CH2)t- or -CH=CH-(CH2)v- for W is
replaced by oxygen atom, sulfur atom, sulfinyl group, `~:-
sulfonyl group, or a group of the formula: -NR~8- (R2~ is
.''''''
97 211~331
~94tO1~13 PCTIJP93/~0~35
hydrogen atom or a straight chain or branched chain alkyl ;~
having 1 to 6 carbon atoms), for example, 3,4-dihydro-2H-
1,4~benzoxazinyl, 1,2,3,5-tetrahydro 4,1-benzoxazepinyl,
1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4,5,6-hexahydro-1,5- -~
benzodiazocinyl, 5-methyl-1,2,3,4,5,6-hexahydro-l,S-benzo-
diazocinyl, 4-methyl-1,2,3,4-tetrahydroquinoxalînyl,
1~2,3,4-tetrahydro-5,1-benzoxazepinyl, 3,4-dihydro-2H-1,4-
benzothiazinyl, 2,3,4,5-tetrahydro-1,5-benzothiazepinyl,
1,2,3,5-tetrahydro-4,1-benzothiazepinyl, 4-ethyl-1,~,3,4-
tetrahydroquinoxalinyl, 4-propyl-1,2,3,4-tetrahydro- -
quinox~linyl, 4-butyl-1,2,3,4-tetrahydroquinoxalinyl, 4-
pentyl-1,2,3,4-tetrahydroquinoxalinyl, 4-hexyl-1,2,3,4- ;~
tetrahydroquinoxalinyl, 2,3,4,5-tetrahydro-lH-1~4-benzo-
diazepinyl, 4-methyl 2,3,4,5-tetrahydro-lH-1,4-benzo-
diazepinyl, 4-ethyl-2,3,4,5-tetrahydro-lH-1,4-benzo-
: ~iazepinyl, 4-propyl-2,3,4,5-tetrahydro-lH-1,4-benzo~
diazepinyl, 4-butyl-2,3,4,5-tetrahydro-lH-1,4-benzo-
diazepinyl, 4-pentyl-2,3,4,5-tetrahydro-lH-1,4-benzo-
diazepinyl, 4-hexyl-2,3,4,5-tetrahydro-lH-1,4-benzo-
diazepinyl, 2,3,4,~-tetrahydro-lH-1,5-benzodiazepinyl, 5- ~
methyl-2,3,4,5-tetrahydro-lH-1,5-benzodiazepinyl, S-ethyl- ~ ;
2,3,4,5-tetrahydro-lH-1,5-benzodiazepinyl, 5-propyl-2,3,4,5-
tetrahydro-lH-1,5-benzodiazepinyl, 5-butyl-2,3,4,5-
tetrahydro-lH-1,5~-benzodiazepinyl, 5-pentyl-~,3j4,S- ;
tetrahydro-lH-1,5-benzodiazepinyl, 5-hexyl-2,3,4,5-
tetrahydro-lH-1,5-benzodiazepinyl, 3,4-dihydro-1-oxo-2H-1,4-
benzothiazepinyl, ~,4-dihydro-1,1-dioxo-2H-1,4-benzo-
thiazepinyl, l-oxo-2,3,4,5-tetrahydro-1 r 5 benzothiazepinyl, .
':". '.:
: ~
- 98
WOg4/Q1~13 P~T/JP93/~
211633'1
1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazepinyl, 4-oxo-
1,2,3,5-tetrahydro-4,1-benzothiazepinyl, 4,4-dioxo-1/2,3,5-~ :
tetrahydro-4,1-benzothiazepinyl, and ~he like.
The "halo~en-substituted lower alkanoyl" includes a :
straight chain or branched chain alkanoyl group havin~ 1 to
6 carbon atoms which has 1 to 3 substituents of a halogen
atom, for example, 2,2,~-trifluoroacetyl, 2,2/2-trichloro-
acetyl, 2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-~;
iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-
trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloro-
propionyl, 2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4
fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-methyl-
propionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl, and the
like.
The "aminocarbonyl-lower alkoxy having a lo~er~ ;
~lkyl substituenl" includes a straight chain or branchec
~hain alkoxy group having 1 to 6 carbon atoms which i5 ~.
substituted by an aminocarbonyl group naving 1 to 2 ~`:
~substituents of a straight chain or branched chain alkyl
group having 1 to 6 carbon atoms, for example, methylamino~
carbonylmethoxy, l-ethylaminocarbonylethoxy, 2~propylamino~
car~onylethoxy, ~ isopropylaminocar~onylpropoxy, 4-~uty'-
aminoc~rbonylbutoxy, S-pentylaminocarbonylpentyloxy, 6- `
hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethoxy, 3- -
diethylarninocarbonylpropoxy, diethylaminocarbonylmethoxy, ~
(N-ethyl-N-propylamino)carbonylmethoxy, 2-(N-methyl-N-hexyl-
amino)carbonylethoxy, and th~ like.
The "carbamoyl-l~wer alkyl" includes a carbamoyl-
gg 211~33'1
'094J011~3 PCT~JP93/~835
substituted straight chain or branched chain alkyl group
having 1 to 6 carbon atoms, for example, carbamoylmethyl, 2- :
carbamoylethyl, l-carbamoylethyl, 3-carbamoylpropyl, 4-
carbamoylbutyl, 5-carbamoylpentyl, 6-carbamoylhexyl, l,l~
dimethyl-2-carbamoylethyl, 2-methyl-3-carbamoylpropyl, and ~
the like. ~-
The "amino-lower alkanoyl having optionally a lower
alkyl substituent" includes a straight chain or branched
chain alkanoyl having 2 to 6 carbon atoms which is ~-
.. substituted by an amino group having optionally l to 2 ~:
substituents of a straight chain or branched chain alkyl
g~oup having l to 6 carbon atoms, for example, 2-amino-
acetyl, 3-aminopropionyl, 2-aminopropionyl, 4-aminobutyryl,
5-aminopentanoyl, 6-aminohexanoyl., 2,2-dimethyl-3-amino- ;~
propionyl, 2-methyl-3-aminopropionyl, 2-methylaminoacetyl,
2-ethylaminopropionyl, 3~propylaminopropionyl, 3-isopropyl~
aminopropionyl/ 4-butylaminobutyryl, 5-pentylaminopentanoyl, :-
6-hexylaminohexanoyl, 2-dimethylaminoacetyl, 2-diethylamlno- `
acetyl, 2-(N-ethyl N-propylamino~acetyl, 3-(N-methyl-N-
hexylamino)propionyl, and the like. :~
The "amino-lower alkyl having optionally a lower ~ :
alkanoyl substituent" includes a straight chain or branched
chain alkyl having l to 6 carbon atoms which is substituted ; :~
by an amino group having optionally a substituent of a
straight chain or branched chain alkanoyl group havlng l to ;~:
6 carbon atoms, for example, aminomethyl, 2-aminoethyl, l~
~minoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-
a~inohexyl, l,l-dimethyl-2-aminoethyl, 2-methyl-3-amino- ;:
-- 100 --
WO g4/01113 PCT`/JP93/00~, ~
21163~
propyl, acetylaminomethyl, l-acetylaminoethyl, 2-propionyl-
aminoethyl, 3-isopropionylaminopropyl, 4-butyrylaminobutyl,
S-pentanoylaminopentyl, 6~hexanoylaminohexyl, formylamino-
.; ..: ~,methyl, and the like.
The "anilinocarbonyl having optionally a lower ;.
alkyl substituent on the phenyl ring" includes an
anilinocarbonyl group having optionally 1 to 3 substituents
of a straight chain or branched chain alkyl group having 1
to 6 carbon atoms on the phenyl rin~, for example, anilino- ;
carbonyl, 2-methylanilinocarbonyl, 3-methylanllinocarbonyl, --:
4-methylanilinocarbonyl, 2-ethylanilinocarbonyl, 3-ethyl- `-:
anilinocarbonyl, 4-ethylanilinocarbonyl, 4-isopropylanilino~
. -~ ~.,
- carbonyl, 3-butylanilinocarbonyI, 4-pentylanilinocarbonyl, ~:-
-~:
. .~ .
4-hexylanilinocarbonyl, 3,4-dimethylanilinocarbonyl, 3,4-
diethylanilinocarbonyl, 2,4-dimethylanilinocarbonyl, 2,5-
dim2thylanilinocarbonyl, 2,6-dimethylanilinocarbonyl, 3,4,5-
trimethylanilinocarbonyl, and the like.
The "phenylsulfonyl which has optionally a
substituent selected from a halogen and a lower alkyl on the .
phenyl ring" includes a phenylsulfonyl group ~ihich has
optionally 1 to 3 substitutents selected~from a straight ~
chain or branched chain alkyl group having 1 to 6 carbon ~ .
atoms and a halogen atom, for exampler phenylsulfonyl, 2-
chlorophenylsulfonyl, 3-chlorophenylsulfonyl, 4-chloro~
phenylsulfonvl, 2-fluorophenylsuIfonyl; 3-fluorophenyl- -~
sulfonyl, 4-fluorophenylsulfonyl, 2-bromophenylsulfonyl, 3
bromophenylsulronyl, 4 bromophenylsulfonyl, 2-iodophenyl-
sulfonyl, ~-iodophenylsulfonyl, 4-iodophenylsulfonyl, 3,4
~ lo~- 211~33~
'094/01113 PCT/JP93/~83~
dichlorophenylsulfonyl, 3,5-dichlorophenylsulfony;, 2,6-di-
chlorophenylsulfonyl, 2~3-dichlorophenylsulfonyl, 2,4
dichlorophenylsulfonyl, 3,4-difluorophenylsulfonyl, 3,5-
dibromophenylsulfonyl, 3,4,5-trichlorophenylsulfonyl, 2- -`
ethyl-3-chlorophenylsulfonyl, 2-methylphenylsulforyl, 3
methylphenylsulfonyl, 4-methylphenylsulfonyl, 2-e :~yl~henyl~
sulfonyl, 3-ethylphenylsulfonyl, 4-ethylphenylsul-onyl, 4-
isopropylphenylsulfonyl, 3--butylphenylsul~onyl, 4-?en~yl
phenylsulfonyl, 4-hexylphenylsulfonyl, 3/4-dimeth:lphenyl- ~ ;
sulronyl, 3,4-diethylphenylsulfonyl, 2,4-dimethyl~hen7.~
sulfonyl, 2,5-dimethylphenylsulfonyl, 2,6-dimethy`~heryl-
sulfonyl 7 2~4,6-trimethylphenylsulfonyl, 3,4~5-tr_metr.yl- ~-
phenylsulfonyl, 3-chloro-4-methylphenylsulfonyl, -me-.;nyl-5-
iodophenylsulfonyl, 3,4-dimethyl-5-bromophenylsul~ony~, 3,5
diiodo-4-methylphenylsulfonyl, and the like.
The "phthalimido-substituted lower alkyl" includes
a straight chain or brancAed chain alkyl group hc~ing 1 to 6 `;~
carbon atoms which is substituted by 3hthalimido ~ro~?, for
e~arnple, phthalimldomethyl, 2-phthalimidoe`thyl, '-~ht~.al-
imidoethyl, 3-phthalimidopropyl, 4~phthalimidobut~
phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimeth~ 2~
phthalimidoethyl, 2-methyl-3-phthali~idopropyl, cnd t~e ~ .:
like. ~ :;~
The !'lower alkynyl" includes a stralght chai~. or ~-~
branched chain alkynyl having 2 to 6 carbon atom~, fo-
example, ethynyl, 2-propynyl, 2-butynyl, 3-butyn~y~
methyl-2-propynyl, 2-pentynyl, 2-hexynyl, and th~ lik~
The "benzoyl ~hich has optionally a halc en
1 0 2 ~ ' ~
WC~ 9~t/013113 PC~JP93/009~'"""'` . ' ~-'' .
211633~
substituent on the phenyl ring" includes a benzoyl grou? -- -
which has optionally 1 to 3 substituents of a halogen atom
on the phenyl ring, for example, benzoyl, 2-chlorobenzoyl,
3-chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 3-fluoro- ~
benzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4- ~ -
bromobenzcyl, 2-iodobenzoyl, 3-iodobenzoyl, 4-iodobenzoyl, ;~
3~4-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichloro- ~ ~-
benzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 3,4-
difluorobenzoyl, 3,5-dibromobenzoyl, 3,4,5-trichlorobenzoyl, -
and the like.
The "amino-lower alkoxy having optionally a
substituent selected from a lower alkyl and a lower
alkanoyl" include Q straight chain or branched chain al!;oxy
group having 1 to 6 carbon atoms which is substituted by an
amino group having optionally 1 to 2 substituents selecred
from a straight chain or branched chain alkyl group having
to 6 carbon atoms and a straight chain or branched chain
alkanoyl group having 1 to 6 carbon atoms, for examDle, -~
aminomethoxy, 2-aminoethoxy, l-aminoethoxy, 3-amino~rowxy,
4-aminobutoxy, 5-aminopentyloxy, 6~aminohexyloxy, 1,1
dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, acetyl~
aminomethoxy, l-acetylaminoethoxy, 2-propionylaminoeth_xy,
3-isopropionylaminopropoxy, 4-butyrylaminobutoxy, 5-
pentanoylaminopentyloxy, 6-hexanoylaminohexyloxy, form~y'~
aminomethoxy, methylaminomethoxy, l-ethylaminoethoxy,
propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylamino- ;~
butoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy,
dimethylaminomethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-
- lo~ 2il633~1 ~
'~94/01113 pCT~3P93/~835 .
;,~
methyl-N-hexylamino)ethoxy, and the like.
The "benzoyloxy which has optionally a halogen
substituent on the phenyl rint3" includes a benzoy oxy group
which has optit~nally l to 3 substituents of a halogen atom -:
on the phenyl ring, ~or example, benzoyloxy, 2-chloro-
benzoyloxy, 3-chlorobenzoyloxy, 4-chlorobenzoy1Oxy, 2-
fluorobenzoyloxy, 3~fluorobenzoyloxy~ 4-fluorobenzoyloxy, 2-
bromobenzoyloxy, 3-bromobenzoyloxy, 4-bromobenzoyloxy, 2-
iodobenzoyloxy, 3-iodobenzoyloxy, 4~iodobenzoylo.Y~, 3,~
dichlorobenzoyloxy, 3,5-dithlorobenzoyloxy, 2,6-dichloro
benzoyloxy, 2,3-dirhlorobenzoyloxy, 2,4-dichlorob~nzoyloxy, ;~
3,4-difluorobenzoyloxy, 3,5-dibromt~benzoyloxy, 3,~,5
trichlorobenzoyloxy, and the like.
The "lowe~r alkanoyloxy-substituted lo~er:alky~
includes a straight chain or branched chain alkyl gro~ ~.. ;.
having l to 6 carbon atoms which is substituted by a
straight chain or branched chain alkanoyloxy grou~ having 2
to 6 carbon atoms, for example, acetyloxymethyl, 2-propion~
yloxyethyl, l-butyryloxyethyl, 3-acetyloxypropyl, 4;-acetyl~
oxybutyl, 4 isobutyryloxybutyl, 5-pentanoyloxypen-vl, 6
acetyIoxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl~
2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, 2nd tne :
like. ;~
The "lower alkylsulfonyloxy-lower alkyl" includes~a
straight chain or branched chain alkyl group havirg l to 6
carbon atoms ~hich ls substituted by a straight chain or :~
branched chain alkylsulfonyloxy group having l t~ 6 c2rbon
atoms, for example., methylsulfonyloxymethy~, l-e.hyl-
- 104 -
W~94~0~113 PCT/JP~3/~
211~33~ ;
sulfonyloxyethyl, ~-propylsulfonyloxyethyl, 3-isopropyl~
sulfonyloxypropyl, 4-butylsulfonyloxybutyl, 5-pentylsulfoyl- ;;~-.
oxypentyl, 6-hexylsulfonyloxyhexyl, 1,1-dimethyl-2-methyl~
sulfonyloxyethyl, 2-methyl-3-ethylsulfonyloxypropyl, and the ~:~
like. ~;~
The "azido-lower alkyl" includes a straight chain
or branched chain alkyl group having 1 to 6 carbon atoms
which is substituted by an azido group, for example,
azidomethyl, l-azidoethyl, 2-azidoethyl, 3-azidopropyl, 4
azidobutyl, 5~azidopentyl, 6 aæidohexyl, 1,1-dimethyl-2
azidoethyl, 2-methyl-3-azidopropyl, and the like~
The t~ lower alkanoyloxyirninol' in:cludes a straight
chain or branched chain alkanoyloxyimino group having 1 to 6 :~
carbon atoms, for example, ormy:Loxyimino, acetyloxyimino
propionyloxyimino, butyryloxyimino, isobutyryloxyimino, :~
pentanoyloxyimino, tert-butylcarbonyloxyimino, hexanoyl~
oxyimino, and the like.
The "lower alkylidene" includes a straight chain or
branched chain alkylidene group having 1 ~o 6 carbon atoms,
for example, methylidene, ethylidene, propylidene,
isopropylidene, butylidene, pentylidene, hexylidene, and the ~ -
like.
The "oxiranyl-substituted lower alkyl" includes a 'A;`~
straight chain or branched chain alkyl group having 1 to 6 : -
carbon atoms whlch is substituted by oxiranyl group, for ` -~
example, oxiranylmethyl, l-oxlranylethyl, 2-oxiranylethyl,
3-oxiranylpropyl, ~oxiranylbutyl, 5-oxiranylpentyl, 6- ;-~
oxiranylhexyl, l,l-dimethyl-2-oxiranylethyl, 2-methyl-3-
~116331
~094/011~3 - 105 - ~CT/JP~3/fla~3
oxiranylpropyl, and the like. -~
The "lower alkyl having 1 to 2 substituents
selected from a lower alkoxy, hydroxy and an amino having
optionally a lower alkyl substituent" includes a strai~ht
chain or branched chain alkyl group having 1 to 6 carbon
atoms and having 1 to 2 substituents selected from a
straight chain or branched chain alkoxy group having 1 to 6
carbon atoms, hyd~oxy and an amino having optionally a
straight chain or branched chain alkyl group having 1 to 6
carbon atoms, for examplP, methoxymethyl, l-ethoxyethyl, 2
propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl r 5-pentyl-
oxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl r 2- ;
methyl-3-ethoxypropyl~ 3-methoxy~2-hydroxypropyl, hydroxy~
,:
methyl, 2-hydroxyethyl, l~hydroxyethyl, 3-hydroxypropyl,
2 r 3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-
dimethyl-2-hydroxyethyl, 5,6-dihydroxyhexyl, 5-hydroxy~
pentyl, 6-hydroxyhexyl, 6-(N-ethyl~N-methylaminoj-5-methoxy-
hexyl, 2-methyl-3-hydroxypropyl, aminomethyl, l-aminoethyl, ~ -~
2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6
aminohexyl, 1,1-dimethyl-2-aminoethyl~ 2-methyl-3-amino~
propyl, methylaminomethyl, ethylaminomethyl, propylamino~
methyl, isopropylaminomethyl r butylaminomethyl, tert-
butylaminomethyl~ pentylaminomethyl, hexylaminomethyl,
., ~,,
dimethylaminomethyl, diethylaminomethyl, dipropylamino~
.
methyl, dibutylaminomethyl, dipentylaminomethyl, dihexyl-
aminomethyl, N-methyl-N-ethylaminomethyl, N-methyl-N-
propylaminomethyl, N-methyl-N~butylaminomethyl, N-methyl-N- ~.
hexylaminomethyl, l-methylaminoethyl, 2-ethylaminoethyl, 3- ~
~';'.:.'
- lQ6 -
W094/~ 3 pCTJJP93/~8
211(~3~
propylaminopropyl, 4-butylaminobutyl, 1,1-dimethyl-2 pentyl-
aminoethyl, 5-hexylaminopentyl, 6-dimethylaminohexyl~ 4-
dimethylaminobutyl, 2~diethylaminoethyl, l-(N-methyl-N-
hexylamino)ethyl, 3-dihexylaminopropyl, 6-diethylaminohexyl,
4-dibutylaminobutyl, 2-(N-methyl-N-pentylamino)ethyl~ 2- ;
hydroxy-3-diethylaminopropyl, 3-hydroxy-4-methylaminobutyl,
5-hydroxy-6-diethylaminohexyl, 4-hydroxy-5-dimethylamino-
pentyl, 4-hydroxy-5-methylaminopentyl, 4-hydroxy-5-diethyl~
aminopentyl, 5-hydroxy-6-ethylaminohexyl, 5-hydroxy-6~
isopropylaminohexyl, 5-hydroxy-6-aminohexyl, and the like.
The "aminocarbonyloxy having optionally a lower
alkyl substituent" includes an aminocarbonyloxy group having ~:
optionally 1 to 2 substituents of a straight chain or
branched chain alkyl group havinq 1 to 6 carbon atoms, for -~
example, aminocarbonyloxy, methylaminocarbonyloxy, ethyl~
aminocarbonyloxy, propylaminocarbonyloxy, isopropylamino- : :
carbonyloxy, butylamihocarbonyloxy, tert-butylaminocarbonyl-
. ~
oxy, pentylaminocarbonyloxy, hexylaminocarbonyloxy, ~.:
dimethylaminocarbonyloxy, diethylaminocarbonyloxy, dipropyl-:~
aminocarbonyloxy~ dibutylaminocarbonyloxy:, dipentylamino-
carbonyloxy, dihexylaminocarbonyloxy, N-methyl-N-ethylamino-
carbonyloxy, N-ethyl-N-propylaminocarbonyloxy, N-methyl-N-
butylaminocarbonyloxy, N-methyl-N-hexylaminocarbonyloxy, and ~;
the like. ~ :
The "lower alkanoyloxy having optionally a halogen
substituent" includes a straight chain or branched chain
alkanoyloxy group having 1 to 6 carbon atoms which has ~ -.
optionally 1 to 3 substituents of a halogen atom, for ~ -
- 107 ~ 2 11 ~ 3
094/01113 PCT/JP93l~3~
example, in addition to the above-mentioned lower alkanoyl-
oxy groups, 2,2,2-trifluoroacetyloxy, 2,2,2-trichloroacetyl-
oxy, 2-chloroacetyloxy r 2-bromoacetyloxy, 2-fluoroacetyloxy,
2-iodoacetyloxy, 2,2-difluoroacetyloxy, 2,2-dibromo-
acetyloxy, 3,3,3-trifluoropropionyloxy, 3,3,3-trichloro-
propionyloxy, 3-ch~oropropionyloxyJ 2,3-dichloro-
propionyloxy, 4,4,4-trichlorobutyryloxy, 4-fluorobutyryloxy,
5-chloropentanoyloxy, 3-chloro-2-methylpropionyloxy, 6-
bromohexanoyloxy, 5,6-dibromohexanoyloxy, and the like. -~
The "amino-lower alkyl having optionally a
substituent selected from a lower alkyl and a lower ~ :
alkanoyl" includes a straight chain or branched chain alkyl
group having 1 to 6 carbon atoms which is substituted by an ~-'
amino group having optionally 1 to 2 substituents selected -~
from a straight chain or branchecl chain alkyl group having 1
to 6 carbon atoms and a straight chain or branched chain
alkanoyl group having 1 to 6 carbon atoms, for example,
aminomethyl, 2-aminoethyl, l-aminoethyl, 3-amlnopropyl, 4- ~.
aminobutyl, 5-aminopentyl, 6 aminohexyl, 1,1-dimethyl~2- :
aminoethyl, 2-methyl-3-aminopropyl, acetylaminomethyl, 1
acetylaminoethyl, 2-propionylaminoethyl, 3-isopropionyl~
aminopropyl, 4-butyrylaminobutyl, 5-pentanoylaminopentyl, 6-
hexanoylaminohexyl, formylaminomethyl, methylaminomethyl, 1
ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl,
4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl,
dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2~(N~
mPthyl-N-hexylamino)ethyl, and the like. .
The t'amino-lower alkanoyloxy having optionally a ~:
- 108 -
2 1 1 6 3 3 !1 PCT/JP93/00~ ~
lower alkyl substituent" includes a straight chain or
branched chain alkanoyloxy having 2 to 6 carbon atoms which
is substituted by an amino group having optionally 1 to 2
substituents of a straight chain or branched chain alkyl
group having 1 to 6 carbon atoms, for example, 2-amino~
acetyloxy, 3-aminopropionyloxyl 2-aminopropionyloxy, 4-
aminobutyryloxy, S-aminopentanoyloxy, 6-aminohexanoyloxy,
2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-aminopropionyl-
oxy, 2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 3-
propylaminopropionyloxy, 3-isopropylaminopropionyloxy, 4- ;
butylaminobutyryloxy, 5-pentylaminopentanoyloxy, 6-hexyl-
aminohexanoyloxy, 2-dimethylaminoacetyloxy, 2-diethylamino-
acetyloxy, 2-(~-ethyl-N-propylamino)acetyloxy r 3-(N-methyl-
N-hexylamino)propionyloxy, and the like.
The "pyridyl-lower alkyl" includes a pyridylalkyl
group wherein the alkyl moiety is a straight chain or ~ `
branched chain alkyl group having 1 to 6 carbon atoms, for
example, (4-pyridyl)methyI, 1-(3-pyridyl)ethyl, 2-(2-
pyridyl)ethyl, 3-l2-pyridyl)propyl, 4 (3-pyridyl)butyl, 5
(4~pyridyl)pentyl, 6-(2-pyridyl)hexyl, 1,1-dimethyl-2-(3- `~
pyridyl)ethyl, 2-methyl-3-(4-pyridyl)propyI, and the like.
The "5- or 6-membered saturated heterocyclic group `;
which is formed by binding the groups R33 and R34 together
with the nitrogen atom to which they bond with or without
being intervened with nitrogen, oxygen or sulfur atom" ~-
includes, for example, pyrrolidinyl, piperidinyl,
piper~zinyl, morpholino, thiomorpholino, and the like.
The above "heterocyclic group which has a
-
,:
- 109- 2ll~33~l
`~94/01~13 PCT/JP~3/~835
substituent selected from oxo, a lower alkyl, a lower
alkanoyl and carbamoyl" includes the above heterocyclic
~roups which have 1 to 3 substituents selected from oxo, a ~ :
straight chain or branched chain alkyl group having 1 to 6
carbon atoms, a straight chain or branched chain alkanoyl
group having 1 ~o 6 carbon atoms, and carbamoyl group, for
example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-
ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-~rimethyl~
piperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino,
hexylpiperazinyl, 2-methylthiomorpholino, 4-acetyl- .;
piperazinyl, 2-propanoylmorpholino, 3-butyrylthiomorpholino,
3-pentanoylpyrrolidinyl, 4-hexanoylpiperidinyl, 3-methyl-4
acetylpiperazinyl; 2-carbamoylpyrrolidinyl, 4-carbamoyl-
piperazinyl, 3-carbamoylthiomorpholino, 2-carbamoyl
morpholino, 3 carbamoylpiperidinyl, l-ox~thiomorpholino,
l,l-dioxothiomorpholino, and the like.
The "aminocarbonyl having optionally a lower alkyl
substituent" includes an aminocarbonyl group having
optionally 1 to ~ substituents of a straight chain or
branched chain alkyl group having 1 to 6 carbon atoms, for
example, aminocarbonyl, methylaminocarbonyl, ethylamino~
carbonyl, propylaminocarbonyl, isopropylaminocarbonyl,
butylaminocarbonyl, tert-butylaminocarbonyl, pentylamino~
carbonyl, hexylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl, dipropylaminocarbonyl, dibutylamino- -
carbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-
methyl-N-ethylaminocarbonyl, N-ethyl-N-propylaminocarbonyl,
N-methyl-N-butylaminocarbonyl, N-methyl-N-hexylamino~
'';
-- 110 --
WOg4~01113 P~T/JP~3/~
211 b 33
carbonyl, and the like. ;
The "cyano-substituted lower alkyl~ includes a
straight chain or branched chain alkyl group having 1 to 6
carbon atoms which is substituted by cyano group, for
,
example, cyanomethyl, 2 cyanoethyl, l-cyanoethyl, 3-cyano~
propyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl r 1 t 1-
dimethyl-2-cyanoethyl, 2-methyl-3-cyanopropyl, and the like.
~ ~.
The 'llower alkoxycarbonyl-substituted lower alkyl"
includes an alkoxycarbonyl-substi~uted straight chain or :~
.. branched chain alkyl group havin~ 1 to 6 carbon atoms
. . .
wherein the alkoxycarbonyl ~oie~y is a straight chain or -` .
branched chaîn alkoxycarbonyl group having 1 to 6 carbon
atoms, for example, methoxycarbonylmethyl, 3~methoxy- :~
carbonylpropyl, ethoxycarboxymethyl, 3~ethoxycarbonylprvpyl,
4~ethoxycarbonylbu~tyl, 5-isopropoxycarbonylpentyl, 6-
propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, ~- :
methyl-3-tert-butoxycarbonylpropyI, 2-pentylo~ycarbonyl~
ethyl, hexyloxycarbonylmethyl, and ~he like. ;:.~
The "carboxy-substituted lower alkyl" includes a .. ;
carboxy-substituted alkyl group wherein the alkyl mo~lety lS
a straight chain or branched chain alkyl group having 1 to 6 ~:
carbon atoms, for example, carboxymethyl, 2-carboxyethyl, 1-
carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, S-carboxy~
pentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2- . :
methyl-3~carboxypropyl, and the like.
The "tetrahydropyranyloxy-substituted lower alkyl" ~ ~:
includes a tetrahydropyranyloxy-substituted straight chain
or branched chain alkyl group having 1 to 6 carbon atoms,
2 1 1 6 3 3 ~1
~4~01113 PC~JP93/~835
for example, (2-tetrahydropyranyl~oxymethyl, 2-(3-tetra-
hydropyranyl)oxyethyl, 1-(4-tetrahydropyranyl)oxyethyl, 3
(2-tetrahydropyranyl)oxypropyl, 4-(3-tetrahydropyranyl)oxy-
butyl, 5-(4-tetrahydropyranyl)oxypentyl, 6-(2-tetrahydro~
pyranyl)oxyhexyl, l,l-dimethyl-2-(3-tetrahydropyranyl)oxy-
ethyl, 2-methyl 3-(4-tetrahydropyranyl)oxypropyl, and the
like.
The "piperidinyl having optionally a phenyl-lower
alkyl substituent'l includes a piperidinyl ~hich has :
optionàlly a substituent of a phenylalkyl group wherein the
alkyl moiety is a straight chain or branched chain alkyl ~:
~roup having 1 to 6 earbon atoms~ for example, piperidinyl,
l-benzyl-4-piperidinyl, 1 (2-phe,nyl~thyl)-3-piperi~dinyl, 1-
(l-phenylethyl)-2-piperidinyl, 1-~3-phenylpropyl)-4
piperidlnyl, 1-(4-phenylbutyl)-4-piperi.dinyl, 1-(5 phenyl-
pentyl)-4-piperidinyl, 1-(6-phenylhexyl)-4-piperidinyl, 1-
(l,l-dimethyl-2-phenylethyl)-3-piperidinyl, 1-(2-methyl-3
- - :. .
phenylpropyl)-2-piperidinyl, and the like. :~
The "imidazolyl-substituted lower alkanoyl"
.~. .
includes an imidazolyl-substituted alkanoyl group wherein `~;
the alkanoyl moiety is a straight chain or branched chain
alkanoyl group having 2 to 6 carbon atoms, for: example, (1-
imidazolyl)acetyl, 3-(2-imidazolyl~propionyl, 2-~4- :
imidazolyl)propionyl, 4-(1-imidazolyl)butyryl, 2,2-di~ethyl-
3-(2-imidazolyl)propionyl, 5-(4-imidazolyl)pentanoyl, 6~
imidazolyl)hexanoyl, and the like. ~ ::
The "amino-lower alkanoyl having optionally 2 `: .
substituent selected from a lower alkyl and a lower alkoxy~
lI2 - :
WO94~01113 PCT/JW30~'
2 1 1 ~ 3 3 ~
carbonyl" includes a straight chain or branched chain
alkanoyl having 2 to 6 carbon atoms which îs substituted by
an amino group having optionally l to 2 substituents
selected from a straight chain or branched chain alkyl ~roup
haviny l to 6 carbon atoms and a strai~ht chain or branched
chain alkoxycarbonyl group having l to 6 carbon ~toms, for
example, 2-aminoacetyl, 3-aminopropionyl, 2-aminopropionyl,
4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-
dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl,
methylaminoacetyl, 2-ethylaminopropionyl, 3-propylamino-
propionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl,
, ,.
S-pentylaminopen~anoyl, 6-hexylaminvhexanoyl, 2-dime~hyl- :~
aminoacetyl, 2-diethylaminoacetyl, 2-(N ethyl-N-propyl~
amino)acetyl, 3-(N-mPthyl-N~hexylamino)propionyl, 2-methoxy~
carbonylaminoacetyl, 2-ekhoxycarbonylaminoacetyl, 3-propoxy-
carbonylaminopropionyl, 4-b~toxycarbonylaminobutyry1, 2-
tert-butoxycarbonylaminoacetyl, 5-pentyloxycarbonylamino-
pentanoyl, 6-hexyloxycarbonylaminohexanoyl, 2-(N-methyl-N~
tert-butoxycarbonylamino)acetyl, and the llke.
The "aminocarbonyl-lower alkyl having~a lowe:r alkyl :.:
substituent" includes a straight chain or branched chain ~
alkyl group havin~ l to 6 carbon atoms which is substituted :-
by an aminoc~rbonyl group havin~ l to 2 substltuents of a
straig~t chain or branched chain alkyl group havin~ l to 6
carbon atoms, for example, methylaminocarbonylmethyl, 1- .
ethylarninocarbonylethyl, 2-propylaminocarbonylethyl, 3- -
isopropylaminocarbonylpropyl, 4-butylaminocarbonylbutyl, 5~
pentylaminocarbonylpentyl, 6-hexylaminocarbonylhexyl, ;
,,,',: :',
,.~,'~''
~ 113 ~ 3 3 ~ `
'O 94~01113 P~IJ~3/~ 35
~ '
dimethylaminocarbonylmethyl, 3 diethylaminocarbonylpropyl,
die~hylaminocarbonylmethyl, (N-ethyl-N-propylamino)carbonyl-
methyl, 2-~N-methyl-N-hexylamino)carbonylethyl, and the
like.
The "amino-substituted lower alkoxy having :
optionally a lower alkyl substituent" includes an amino~ ;
substituted straight chain or branched chain alkoxy having 1
to 6 carbon atoms wherein the amino group has optionally 1
to 2 substituents of a straight chain or branched chain
alkyl having 1 to 6 carbon atoms, for example/ aminomethoxy,
2-aminoethoxy, l-aminoethoxy, 3-aminopropoxy, 4-aminobu~oxy,
5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-amino~
ethoxy, ~-methyl-3-aminopropoxy, methylaminomethoxy, 1
ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylamino~
propoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-
hexylaminohexyloxy, dimethylaminomethoxy, (N-methyl~N~
,, ~" ., ~
propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy, and .
the like.
:.,.,'
The active ingredients of the present oxytocin ~
antagonists of the present invention can be easily prepared
by a conventional method, for example, the carbostyril ..
derivatives of the formula (1) can be prepared, or example,
by the method dislcosed in Japanese Paten~ First Publication; .-
~Kokai) No. 173870/1991, and the benzohetrocyclic compounds
of the formula (2) can be prepared, for example, by the
method disclosed in European Patent No. 450097. .~.
Among the active compounds (13 and (2) of this : .
invention, the compounds having an acidic group can easily
~,~
- 114 -
W09~/~1113 PCT/JP9
211~33~
be converted into salts by treating with a pharmaceutically
acceptable basic compound. The basic compound includes, for
example, metal hydroxides such as sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide,
etc., alkali metal carbonates or hydrogen carbonates such as
sodium carbonate, sodium hydrogen carbonate, etc., alkali
metal alcohola~es such as sodium methylate, potassium
ethylate, etc. Besides, among the active compounds (l) and
(2) of this invention, the compounds having a basic ~roup
c~n easily be converted into acid addition salts thereof by -~
treating with a pharmaceutically acceptable acid. The acid
includes, for example, inorganic acids such as sulfuric ;:
~cid, nitric acid, hydrochloric acid, hydrobromic acid, .` .
etc., and organic acids such as acetic acid/ p-toluene- ~
sulfonic acid, ethanesulfonic acid, oxalic acid, maleic :~-
acid, citric acid, succinic acid, benzoic acid, etc. ~mong ~s
the active compounds (l) and (2) of the inventlon, the
compounds having an ammonium group can be converted into a
salt thereof with a pharmaceutically acceptable halogen
anion (e.~. chlorlne anion, bromine anion, fluorine anion,
or iodine anion). These salts are useful as an active
ingredient of the present oxytocin antagonist as like as the -~
compounds (l) and (2) in the free form. `
In addition, the active compounds (l) and (2~ of ~ -`
this invention include stereoisomers and optical isomers,
and these isomers are also useful as the active ingredient
in this invention.
The active compounds (2) of the present oxytocin
115 - 2 1 1 ~ 3 3 'I
`'09~ 113 P~T/JPg3/0083
antagonst obtained by the method disclosed in European
Patent No. 4~0097 can easily be isolated and puri^ied by a
conventional isolation method. The isolation methods are,
for example, distillation method, recrystallization method,
column chromato~raphy, ion exchange chromatography, gel
chromatography, affinity chromtography, preparatiYe thin ~-~
layer chroma~ography, extraction with a solvent, and the
like.
..:
The compoun~s of the formulae (l), (2) ar.d their ~
: - ~
salts are useful as an oxytocin antagonist and arc used in
the form of a conventional pharmaceutical preparation. The
preparation is prepared by using conventional dilutents or
carriers such as fillers, thicken1ng agents, binders,
wettin~ a~ents, d1sintegrators, surfactants, lubricants, and
the like. The pharmaceutical preparations may be selected
from various forms in accordance with the desired utilities, -~
and the representative forms are tablets, pills, Dowders,
solutions, suspensions, emulsions, granules, capsules, -~-
suppositories, injections Isolutions, suspensions, etc.),
and the like. In order to form in tablets, there are used
conventional carriers such as vehicles te.g. lact3se, white
sugar, sodium chloride, glucose, urea, starches, calc~um
carbonate, kaolin, crystalline cellulose, silicic acid, ~-
etc.), binders (e.g. water, ethanol, propanol, si ple syrup, -~
glucose solution, starch solution, gelatin solution, -
carboxymPthyl cellulose, shellac, methyl cellulos_,
potassium phosphate, polyvinylpyrrolidone, etc.),
disintegrators ~e.g. dry starch, sodium arginate, ag2- ~
:' ''.
.. ~
- 116 -
WO94~01113 P~Tr~P93l~8-
334
powder, laminaran powder, sodium hydrogen c~rbonate, calcium
carbonate, polyoxyethylene sorbitan fatty acid esters, ;~
sodium laurylsul~ate, stearic monoglyceride, starches,
lactose, etc.), disintegration inhibitors (e.g. white sugar,
stearin, cacao butter, hydrogenated oils, etc.~, absorption
promoters ~e.g. quaternary ammonium base~ sodium lauryl-
sulfate, etc.), wetting agents ~e.g. glycerin, starches,
etc.), adsorbents (e.g. starches, lactose, kaolin, bento-
nite, colloidal silicates, etc.), lubricants ~e.~. purified
- talc, stearates, boric acid powder, pclyethylene glycol, ~-
etc.), and the like. Moreover, the tablets may also be in ;~
the form of a conventional coate~d tablet/ such as sugar-
coated tablets, gelatin-coated tablets, enteric coated `~
tablets, film coating tablets, or double or multiple layer
tablets. In the preparation of pills, the carriers include
conventional vehicles ~e.g. glucose, lactose, starches,
cacao butter, hydrogenated vegetable oils~ kaolin, talc, ~;~
etc.), binders (e.g. gum arabic powder, tragacanth powder,
gelatin, ethanol, etc.)j disintegrators (e.g. laminaran, `-
agar, etc.), and the like. In the preparation of
suppositories, the carriers include conventional vehicles, -~
for example r polyethylene glycol, cacao oils, hi~her
alcohols, higher alcohol esters, gelatin, semi-synthetic
.
glycerides, and the like. Capsules can be prepared by
char~ing a mixture of the active compound of this invention
with the above carriers into hard gelatin capsules or soft
capsul~s in a usual manner. In the preparation of 1njec~
tions, the solutions, emulsions or suspendions are steri-
- 117 - 2 11 ~ 3 3il
'~94/01113 p~T/JP~3/~835
lized and are preferably made isotonic with the blood. In
the preparation of these solutions, emulsions and
suspensions~ there are used conventional diluents, such as :.
water, ethyl alcohol, macrogol, propylene glycol,
ethoxylated isostearyl alcohol, polyoxylated isostearyl ~:
alcohol, polyoxyethylene sorbitan fatty acid esters, and the~;
like. In this case, the pharmaceutical preparations may :-
a~lso be incorporated with sodium chloride, glucose, or ::
slycerin in an amo~nt sufficient to m~ke them isotcn,c, and~: -
may also be incorporated with conventional solubilizers,
buffers, anesthetizing agents. Besides, the pharmaceutical
preparations may optionally be incorporated with coloring
agents, preservatives, perfumes, flavors, sweeting agents,
and other me~icaments, if required. `.-
The amount of the active compounds of the formulae
(l~ and ~2~ of this invention (active ingredient) to be ~;
incorporated into the oxytocin antagonist of the present .~.;
invention is not specified but may be selected from a broad .:
range, but usually, it is preferably in the range of about l
to 70 % by weight, more preferably about 5 to 50 ~O by :
weight. : ;
The oxytocin antagonist of the present invention
may be administered in any method, and suitable method for
administration may be determined in accordance with types of
the preparations, ages, sexes and other conditions of the .
patients, the degree of severity of diseases, and the
like. For instance, tablets, pills, solutions, suspensions, :-
emulsions,-granules and capsules are administered orally. ~
118 -
W~94/~113 pCT/JP93~8'
2i~33 1
The injections are intraveneously administered alone or
together with a conventional auxiliary liquid (e.g. glucose~
amino acid solutions)~ and further are optionally administ-
ered alone in intramuscular, intracutaneous, subcutaneous,
or intraperitoneal route, if required. Suppositories are
administered in intrarectal route. : :
The dGsage of the oxytocin antagonist of the ;.
present invention may be selected in accordance with the ~;
usage, ages, sexes and other conditions of ~he patients, the
degree of severity of the diseases, and the like, but is
usually in the range of about about 0.6 to 50 mg of the
active compound (l) or (2~ per l k~ of body weight of the `~
patient per day. The active compound is prefera~ly
contained in an amount of about lO to lO00 mg per the dosage ~;-
unit.
Best Mode for Carrying Out the Invention
The present inven~ion is illustrated by the .--;
following Preparations of oxytocin antagnist, and
Experiments of the activities of the active compounds (l)
and (2) of the present invention.
Preparation 1
Film coated tablets are prepared from the following ~;~
components.
Com~onents Amount
l-[l-(4-Dimethylaminobenzoyl)-4-
piperidinyl]-3~4-dihydrocarbostyril 150 g
Avicel (tradename of microcrystalline cellulose,
manu~actured by Asahi Chemical Industry
Co., Ltd., Japan) 40 g
21i~3~ll
-- 119 --
'~94~ 13 PCT~JP~3/~3
Corn starch 30 g :-~
Magnesium stearate 2 g
Hydroxypropyl methylcellulose10 9
Polyethylene glycol-6000 3 g -; ~:
Castor oil 40 9
Ethanol 40 9
The active component of the present invention,
Avicel, corn starch and magnesium stearate are mixed and
kneaded and the mix~ure is tabletted using a conventional
pounder (R 1~ mm) for sugar coating. The ta~lets ~hus `~
obtained are coated with a film coating agent-consisting of ;~
hydroxypropyl methylcellulose, polyethylene glycol~6000,
castor oil and ethanol to give ~:ilm coated tablets.
~le~-~tio~
... ..
Tablets are prep~red from the following components,
Components ~mount
~ (2-Methoxy-4-ethoxybenzoyl)-4- .;~
piperidinyl]-3,4-dihydrocarbostyril 150 g ~;
Citric-acid 1~0 9
Lactose 33.5 9
Dicalcium phosphate 70.0 9
Pullonic F-68 30.0 9
Sodium laurylsulfate 15.0 g
Polyvinylpyrrolidone 15.0 g .~-
Polyethylene glycol ~Carbowax 1500) 4.5 g ~ ;
Polyethylene glycol ICarbowax 6000~ 45.0 g
Corn starch 30.0 g
Dry sodium stearate 3.0 g
';'
WO ~/0~113 - l20 - PCT/JP93/~B~
211633~
Dry magnesium stearate 3.0 g
Ethanol q.s.
The active compound of the present invention,
citric acid, lactose, dicalcium phosphate, Pullonic F-68 and
sodium laurylstearate are mixed. The mixture is screened
with No. 60 screen and is granulated with an alcohol
solution containing polyvinylpyrrolidone, carbowax 1500 and
6000. If required, an alcohol is added thereto so that the
powder mixture is made a paste-like mass. Corn starch is
added to the mixture and the mixtllre is continuously mixed
to form uniform particles. The resulting particles are
passed through No. lO screen and entered into a tray and
then dried in an oven at 100~C for 12 to 14 hours. The
dried particles are screened with No. 16 screen and thereto ~-
are added dry sodium laurylsulfate and dry magnesium
stearate, and the mixture is tabletted to form the desired
shape.
The core tablets thus prepared are vanished and ~-
dusted with talc in order to guard from wetting.
Undercoating is applied to the core tablets. In order to
administer the tablets orally, the core tablets are vanished
several times. In order to give round shape and smooth
surface to the tablets, further undercoating and coating
with lubricant are applied thereto. The tablets are further ~
coated with a coloring coating material until the desired ~-
colored tablets are obtained. After drying, the coated
tablets are polished to obtain the desired tablets having
uniform gloss.
211{i3~1
- 121 -
`V~4/01~13
: ;. ,~
Pre~aration 3 `
- .~
An injection preparation is prepared from the
following components. ~--
Com~onents ~mount :
7-Fluoro-l-ll t2,4-dimethoxybenzoyl)-4~
piperidinyl~-3,4-dihydrocarbostyril 5 9
Polyethylene glycol (molecular weight: 4000~ 0.3
Sodium chloride 0.9 g .
Polyoxyethylene sorbitan monooleate Q.4 g ~`~
Sodium metabisulfite 0.1 9
~ . ~, . :
Methyl-paraben Q.18 g -:
Propyl-paraben 0.02 g
Distilled water for injection 10.0 ml
The above parabens, sodium metabisulfite and sodium ~.
:chloride are dissolved in distilled water of halE volume of ~:
the above with stirring at 80~C. The solution thus obtained:: :
is cooled to 40C, and the actlve compound of this invention :
and furth r polyethylene glycol and polyoxyethylene sorbitan
monooleate are dissolved in the above solution. To the
~. .:,, ,~,,
solution is added distilled water f:or injection to adjust tQ ;`
the desired volume, and the solutlon is:sterllized by
filteri~ng with an appropriate filter paper to give an
injection preparation.
~L2~ n
Film coated tablets are prepared from the following :~
componentsO ~
Com~onents Amount : ::
4 Methylamino-1-[4-(3,5-dichlorobenzoyl
amino)benzoyl}-1,2,3,4 tetrahydroquinoline 150 g
-- 122 --
WO g4/~1113 PCI`/JP93J~08
~11633~ ~ ~
Avicel (tradename of microcrystalline cellulose,
manufactured by Asahi Chemical Industry :::
Co., Ltd., Japan) 40 g
Corn starch 30 g
Magnesium stearate 2 g
. ,,
Hydroxypropyl methylcellulose 10 g
Polyethylene glycol-6000 3 9 ;:~
Castor oil . 40 g
Ethanol 40 9
The active component o the present invention, .
Avicel~ corn starch and magnesium stearate are mixed and
kneaded and the mixture is tabletted using a conventional
pounder (R 10 mm) for sugar coating. The tablets thus ~
obtained are coated with a film coating agent conslsting of ~ :
hydroxypropyl methylcelluloser polyethylene glycol-6000,
castor oil and ethanol to give film coated tabIets.
Pre~aration 5
Tablets are prepared from the following components. :~
Com~onents ~ Amount
-[4-(N-Butylanilinoacetylamino)benzoyl]~
2~3,4,5-tetrahydroy-lH-benzazepine 150 9 ~;
Citric acid : ~1.0 g ~` :
LactosP 33 5 9
Dicalcium phosphate 70.0 g
Pullonic F-68 30.0 g
Sodium laurylsulfate 15.0 g
Polyvinylpyrrolidone 15O0 9 ;-;~
Polyethylene glycol (Carbowax 1500) 4.5 9
Polyethylene glycol (Carbowax 6000) 45.0 9 ~ ~;
~ 123 ~ 331 ~:
'~D4/01113 PCT/JP93/~835
Corn starch 30.0 9
Dry sodium stearate 3~ 9
Dry magnesium stearate 3.0 g
,Ethanol q.s. :
The active compound of the present invention, -~
citric acid, lactose, dicalcium phosphate, Pullonic F-68 and
sodium laury1stearate are ~ixed. The mixture is screened :;
with No. 60 screen and is granulated with an alcohol
solution containing polyvinylpyrrolidone, carbowax 1500 and `~
~000. If required, an alcohol is added thereto so that the ;-~
powder mixture is made a pastP-l.ike mass. Corn starch is .
added to the mixture and ~he mix~ure is continuously mixed ~ :
~to form uniform particles. The resulting particles are
passed through No. 10 screen and entered into a tray and
then dried in an oven at lO0C for 12 to 14 hours. The
dried particles~ar~e screened with No:. 16 screen and thereto ~;~
. - .
are added dry sodium laurylsulfate and dry magneslum ;~
stearate, and ~he m1xture is tabletted to form the desired .
shape.
The core tablets thus prepared are vanished and ~ :
~ .:
dusted with talc in ordPr to guard from wetting.
Undercoating is applied to the core tablets. In order to
administer the tablets orally, the core tablets are v2nished -~
several times. In order to give round shape and smooth
surface to the tablets, further undercoating and coating
with lubricant are applied thereto. The tablets are further
coated with a coloring coating material until the desired
~" .' '~'
- 124 -
WO ~01~13 PCT~JP93/OD~
2 ~ 3 '~
colored tablets are obtained. ~fter drying, the coated
tablets are polished to obtain the desired tablets having
uniform gloss.
Preparation 6
An injection preparation is prepared from the
following components.
ComPonents Amount ~:
. .
4-Methyl-l-[4-(2,3-dimethylbenzoyl- :
amino~enzoyl~-2,3,4,5-tetrahydro~ 5 9
lH-l,4-benzodiazepine
Polyethylene glycol (molecular weight: 4000)0~3 g
Sodium chloride 0.9 9 ;~
Polyoxyethylene sorbitan monooleate 0.4 9
Sodium metabisulfite O.l g
Methyl-paraben : 0.18 g
Propyl-paraben 0.02 g
Distilled water for injection ~ lO.O ml
The abvve parabens, sodium metabisulfite and sodium
chloride are dissolved in distilled water of half volume of
the above with stirring at 80C. The solution thus obtained
is cooled to 40C, and the active compound of this invention
and further polyethylene glycol and polyoxyethylene sorbltan;;~
monooleate are dissolved in the above solution. To the
solution is added dlstiIled water for injection to adjust to~;~
the desired volume, and the solution is sterilized by
filteriny with an appropriate filter papPr to give an ~:
injection preparation.
Pharmacological Test
..
Oxytocin RecePtor kindinq Assay
,'",;'`:
.', '~ ~
211633i~ :
- 1~5 -
`'O9q~1113 P~TIJP93/~835 ~
''~"
~terin muscle is taken out from a rat which has ~-:
previously been injected subcutaneously with diethyl~
stilbestrol the day beforel and homo~enized, which is us~d .
as a membrane preparation. The membrane preparation (0.2 -~
mg), [3~ oxytocin (lODOOO dpm, 10 9M), a test compound (10
9 - 10 5 M) are inclubated at 25C for one hour in 100
Tris-HCl buffer (pH=8.0, ~SO ~1) containing 5 mM MgC12, ' mM
MEDTA and 0.1 ~ BSA. The mixture is filtered through ~he
glass filter (GF/F) so as to separate the membrane
preparation combining with ~3H]-oxytocin, and then, wcshed
twice with the buffer (S mlj. This glass filter lS put into
a vial and mixted with A~uasole (liquid scintillation
cocktail). The amount of [3H]-oxytocin combining wit:~ the
membrane is measured by liquid scintillation coun~erO The
rate of the inhibitory effect of the test compound is
estimated according to the following equation. ~
Inhibitory Rate (%) = 100 - [(Cl-B)/(Co-3)] ~ 100 .-~.
: Cl: The amount of ~3~]-oxytocln combining ~~-h t~e .
membrane in the presence of a test compound ~known
amount).
CO: The amount of [3H]-oxytocin combining wi h t:~e
membxane in the absence of a test compound~
B: The amount of [3H]-oxytocin combining wl-h t~e ~-
membrane in the presence of the excess 2~our_ o_ `
oxytocin (5 x 10 6 M). --
The results are expressed as IC50 values, wr.ich is ~ ~-
.. . .
WO94101113 - 126 - PCTIJP93/~8
2-1 1 6 3 3 ~
the concentration of the test compound required to achieve
the inhibitory effect in the rate of 50 %. ~:
The results are shown in the following Tables 1 and --:-
Test com~ounds
The compounds of the formula (l~;
1-1. 1-{1-[4-(6-~minohexyloxy~benzoyl]-4-piperidinyl}-
3,4-dihydrocarbostyril
1-2: 1-{1-~4-(6-Acetylaminohexyloxy)benzoyl]-4-
piperidinyl}-3,4-dihydrocarbostyril
1-3: 1-{1-[4 (6-Methylsulfonylaminohexyloxy)benzoyl]-4- ~
piperidinyl}-3,4-dihydrocarbostyril ~ ~:
1-4: 1~{1-~4-(7-Hydroxy-8-diethylamlnooctyloxy)benzoyl~-
4-pi~eri~inyl}-3,4-dihydrocarbostyril :~
1-5: 1-{1-(4-[6-(4-Methyl-l-piperaz:.nyl)hexyloxy]- .
benzoyl)-q-piperidinyl}-3,4-dihydrocarbostyril ~;~
1-6~ 1-(4-[6-[N-Methyl-N-~2-(2-pyridyl)ethyl)amino)-
hexyloxy)benzoyl)-4-piperidinyl}-3,4-dihydro~
: carbostyril ~ ~
1-7: 1-{1-[4-(6-Di~ethylaminohexyloxy)benzoyl]-4- ~ -
piperidinyl}-3,4-dihydrocarbostyril
1-8~ 1-[4-(6-(1-Pyrrolidinyl)hexyloxy)benzoyl]-4
piperidinyl}-3,4-dihydrocarbostyril ;
1-9: 1-{1-[4-(7~ Pyrrolidlnyl)octyloxy~benzoyl] 4- '--"~
piperidinyl}-3,4-dihydrocarbostyril
1-10: 1-{1-~4-(7-(4-Methyl-l-piperazinyl)octyloxy)- -~
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-{1-~4-(4-Acetylaminobutyloxy)benzoyl]-4-
`;'';'' '
- 1~7 - 2116~3
'V ~4/01113 P~/JPg3/1~083
piperidinyl}-3,4-dihydrocarbostyril
1-12: 1-{1-[4-(6-Diethylamino-5-hydroxyhexyloxy)benzoyl}-
4-piperidinyl}-3,4-dihydrocarbostyril
1-13: 1-{1-[4-~6-Dimethylamino-5-hydroxyhexyloxy)-
, . .
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-14~ [4-(4-(4-Benzyl-l-piperazinyl~butoxy)benzoyl]- :-
4-piperidinyl}-3,4-dihydrocarbostyril . : .
1-15: 1-{1-[4-(4-(1-Piperazinyl)butoxy)benzoylJ-4-
piperidinyl}-3,4-dihydrocarbostyril
1-16: 1-{1-[4-[4-(1-Piperazinyl)carbonyloxybutoxy~-
benzoyl)-4-piperidinyl}--3,4-dihydrocarbostyril
7: 1-{ l- [ 4- E 5-~yd~oxy-6-~4-benzyl-1-piperazinyl)hexyl~
oxy)benzoyl]-4 piperidinyl~-3,4 dihyd~rocarbostyril .
1~18: 1-{1-[4-(5-Hydroxy~-6-[N-methyl-N-(2-hydroxy-2-
phenylethyl)amino]hexyloxy)benzoyl]-4-piperîdinyl~
3,4~dihydrocarbos~yril
` 1-19: 1-{1-~4-~(6[2(S)-Hydroxymethyl-l-pyrrolidinyl3-5-
, . . ~
hydroxy)hexyloxy)benzoyl]-4-piperldinyl)-3~,4
~;: dihydrocarbostyril
1-20: 1-~1- E 4-(S-Hydroxy-6-(3,4-dimethoxybenzylamino~
hexyloxy)benzoyl]-4-piperidinyl}-3,~4-dlhydro~
carbostyril -
1-21: 1-{1-[4-~5-Hydroxy-6-(4-benzyl-1-piperidlno)hexyl~
oxy)benzoyl~-4-piperidinyl}-3,4-dihydrocarbostyril
1-22~ -(4-[4-(4-piperidlnylcarbonylamino)butoxy)- ~ ~
benzoyl)-4-piperidinyl}-3,4-dihydrocarb~styril ~ -`
1-23: 1-{1-[4-~5-Methoxy-6-diethylmethylammoniumhexyl- `~
oxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril ~.
- 128 -
WO94/~ 3 pcT/Jp93/~&~
211~33~
iodide :
1-24: 1-{1-[4-(Allylaminobutoxy~benzoyl]-4-piperidinyl}-
3,4~dihydrocarbostyril
1-25; 1-{1-[4-(5-Hydroxy-6 (allylaminohexyloxy)benzoyl]-
4-piperidinyl}-3,4-dihydrocarbostyril
1-26: 1-{1-[4-~3-(4-Benzoyl-l-piperazinyl~propoxy]-
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-27: 1-[1-~4-[3-(4-Anilinocarbonyl-l-piperazinyl)-
propoxy]benzoyl} 4 piperidinyl]-3,4-dihydro-
carbostyril
1-28: 1-{1-[4-(3-Phenylsulfonylaminopropo~y~benzoyl]-4- :~
piperidinyl}-3,4-dihydrocarbostyril -~
1-29: 1-{1-[4-(4-Hydroxy-5-(1-py~rrolidinyl)pentyloxy)-
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-30~ [4-(4-Hydroxy-S-(l-piperidlnyl)pentyloxy)-
benzoyl]-4-piper:idinyl}-3,4-dihydrocarbostyril
1-31: 1-{1-[4-(4-Hydroxy-5-(4-morphol~ino)pentyloxy)- -
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril ; ~
1-32: 1-{1-[4-(3-Diethylaminopropoxy)benzoyl]~-4- .
piperidinyl}-3,4-dihydrocarbostyril
1-33: 1 {1-14-(3-Hydroxy~4-diethylaminobutaxy)benzoyl]:-4
piperidinyl}-3,4-dihydrocarbostyril :~
1~34: 1-{1-[4-Anilinooxycarbonyl~-4-piperidinyl}-3,4- ;~
dihydrocarbostyril -~
1-35: 1-{1-[4-Benzoylaminophenoxycarbonyl~-piperidinyl}-
3,4-dihydrocarbostyril
1-36: 1-{1 [4-~5-Hydroxypentyloxy)benzoyl]-4- ;~
piperidinyl)-3,4-dihydrocarbostyril
~ l29 ~ 33~ :
'~94/01113 PCT1/Pg3/~B3
1-37~ 4-(4-Carbamoylmethylaminocarbonylbutoxy)-
benzoyl~-4-piperidinyl}-3,4-dihydrocarbostyril
1-38: 1-{1-~4-(5-Carbamoyloxypentyloxy~benzcyl]-4
piperidinyl]-3,4-dihydrocarbostyril
1-39: 5,7-Di1uoro-1-[1-(2-methoxy-4-ethoxybenzoyl)-4- -
piperidinyl]-3,4 dihydrocarbostyril
1-40~ 1-[4-(5-[(lS)-1,3~Dicarbamoyl]propylamino-
carbonylpentyloxy)benzoyl~-4-piperidinyl~-3,4- ~
dihydro~arbostyril :
1-41: 1-[1-(2-Hydroxy-4-ethoxybenzoyl)-4-piperidinyl]-7- ` `
fluoro-3,4-dihydrocarbostyril
1-42: 5-Methyl-1-[l-(2-me~hoxy-4-ethoxybenzoyl)-4- --
piperidinyl~-3,4-dihydrocarbostyril ::~
1-43: 1-{1-(4-[5~ Imidazolyl)pentyIoxy]benzoyl)-4-
piperidinyl}:-3 t 4-dihydrocarbostyril
1-44: 5-~ethyl-l-fl-[4-~3-acetylaminopropoxy)benzoyl]
piperidinyl}-3,4-dihydrocarbostyril
: 1-45: 1-{1-~4-(2-Propionyloxy)benzoyll-4-plperidinyl~-
3,4-dihydrocarbostyril
1-46: 1-{1-~4-(4-Carboxybutoxy)benzoyl1-4-piperidinyl}~
3,4~dihydrocarbostyril :
1-47: 1-{1-[4-(5-Carbamoylpentyloxy)benzoyl]-4- ~;
piperidinyl}-3,4-dihydrocarbostyril
~ .
1-48: 1-~1-[4-(3-Carbamoylpropylamlno)benzoyl~-4-
piperidinyl}-3,4-dihydrocarbostyril `~
1 49 1-{1-[4-(5-Hydroxypentyloxy)benzoyl~-4
piperidinyl}-3,4-dihydrocarbostyril
1-50: 1-{1-[4 (.5-Acetylaminopentyloxy)benzoyl) 4-
- 130 -
WOg4/~ 3 pCT/JP93/~8'
211~33'1
piperidinyl}-3,4-dihydrocarbostyril
1-51: 1-[1-(4-Methoxyanilinocarbonyl)-4-piperidinyl)-3,4-
dihydr~carbostyril
1-52: 1-[1-(4-Ethoxybenzoyl)-4-piperidinyl3carbostyril
1-53: 6,7-Difluoro-l- E 1- ( 2-methoxy-4-ethoxybenzoyl)-4-
piperidinyl]-3,4-dihydrocarbostyril
1-54: 1-[1-{4-[4-(1-Pyrrolyl)butoxy]benzoyl}-4- :;`
piperidinyl]-3,4-dihydrocarbostyril
1-550 1-[1-{4-E3-(4-Methyl-l-piperazinyl)propoxy]- ~:
benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril ~-~
dioxalate
1-56: 1-{1-~4-{5-[(lS)~l-Carbamoyl-2-(4-hydroxyphenyl~
ethylaminocarbonylpentyloxy}benzoyl]-4- ~:
piperidlnyl}-3,4-dihydro~arbostyr~
1-57: 7-E'luoro~ l-benzoyl-4-piperidinyl)carbostyril
1-58: 7-Fluoro-1-[1-(2,4-dimethoxybenzoyl)-4-piperidin-
yl]carbostyril
1-59: 1-{1-[4-{5-[(lS)-l-Carbamoyl-3-(methylthlo)]propyl-
aminocarbonylpentyloxy}benzoyl]-4-piper~dinyl}-3,4-
dihydrocarbostyril :~
1-60~ [4-(5-(2-Hydroxy-3-diethylaminopropoxy)- ~ :1
pentyloxy)benzoyl]-4-piperidinyl}-3,4
dihydrocarbostyril
1-61: 1-{1-[4-~5-(3-Dimethylaminopropyl)aminocarbonyl-
pentyloxy)benzoyl]-4-piperidinyl}-3,4- ~
dihydrocarbostyril :~:
1-62: 1 {1-~4-(5-(1-Benzyl-4-piperidinyl)aminocarbonyl-
pentyloxy)benzoyl]-4-piperidinyl}-3,4-
211633ll
'094/01113 - 131 -
dihydrocarbostyril
1-63: 1-{1-[4-(5-Hydroxy-6-~1-pyrrolidinyl)hexyloxy)~
benzoyl]-4-piperidinyl}-3y4-dihydrocarbostyril
1-64: 1-{1-[4-(5-l4-Piperidinyl)aminocarbonylpentyloxy~
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-65~ [4-(5-(1-Pyrrolidinyl)pentyloxy)benzoyl]-4~
piperidinyl}-3,4-dihydrocarbostyril ,~A"'~.'"
1-66: 1-{1-[4-(5,6-Dihydroxyhexyloxyjbenzoyl]-4
piperidinyl}-3,4-dihydrocarbostyril
1 67: 1-{1-(4-[5-Hydroxy-6-(3-methoxybenzylamino)hexyl- ~.'.7'',
~'.. ,' :, ~.
oxy]benzoyl)=4-piperidinyl}-3,4-dihydrocarbostyril
1-68: 1-{1-(4-[3 ((l~S3-1-Aminoethyl~arbonylamino~
prop~xy]benzoyl~-4-piperidinyl}-3,4-dihydro~
carbostyril
1-69: 5,7-Dimethyl-1-[1-~2-methoxy-4-ethoxybenzoyl)-4- ;~
piperidinyl]-3,4-dihydrocarbostyril
1-{1~ 5-~2-Imidazolylsulfonyl)pentyloxy]~
: benæoyl)-4-piperidinyl}-3,4-dihydrQcar:bostyril
71: 1-{1-~4-[5-~ydroxy-6-[N-methyl-N-(2-(2-pyridyl)~
~: ethyl~amlno~hexyloxy]~benzoyl)-4-piperidinyl}-3,4
dihydrocarbostyril
1-72: 1 {1-(4-~5-(2-(4-Methyl-l-piperazinyl)acetylamino)- .
pentyl~xy]benzoyl~-4-piperidinyl}-3,4-dihydro~
carbostyril . : :~
1-73: 1-{1-(4-[5-(~-Oxo-4-pyridylsulfonyl)pentyloxyJ~
benzoyl-4-pipe:ridlnyl}-3,4-dihydrocarbostyril
1-74: 1-{1-(4-~[5-~3-Hydroxy-l-piperidino)pentyloxy]-
benzoyl)-4-piperidinyl}-3,4-dihydrocarbostyril :
- 132 -
WO~4/01113 p~T/JP9~/~
211633'1
1-75: 1-{1-(4-[5-~4-Dimethylaminophenylsulfonyl)pentyl-
oxy]benzoyl)-4-piperidinyl}-3,4-dihydrocarbostyril ;~
1-76: 1-{1-[4-(5-(4-Dimethylaminobenzoylamino~pentyl
oxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-77: 1-{1-(4-[5-(2-(2-Hydroxyethyl)-l-piperazinyl)-
pentyloxy]benzoyl)-4-piperidinyl}-3,4-dihydro~
carbostyril
1-78: 1-{1-(4-[5-(N,N-(2-Hydroxyethyl)amino]pentyloxy~
benzoyl-4-piperidinyl}-3,4-dihydrocarbostyril ~-~
1-79: 1-{1-[4-(5-Hydroxy-6-(I-piperidinyl)hexyloxy~
benzoyl]-4-piperidinyl}-3/4-dihydrocarbostyril ~.
1-80: 5-~ydroxy~ 4-(3-acety1aminopropo~y)benzoyl3-4- ~
piperidinyl~-3,4-dihydroca~rbostyril ~.
1-81~ [2-Methoxy-4-(4-carbamoylbutoxy)benzoyl]-4- -
piperidiny1}-3,4-dihydrocarbostyril
1-82: 1-{1-L4-(5-(2-Methyl-l-piperidinyl)pentyloxy~
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1-83: 5-Acetoxy-1-[1-(2-methoxy-4-ethoxybenzoy1)-4-
piperidinyl]-3,4-dihydrocarbostyril
~ 1-84~ 1-[4-[(5-Isopropylamino)pentyloxy]benzoyl.~-4- :
- piperidiny1}-3,4-dihydrocarbostyr~
1-85: 1-{1-(4-[2,4-Di-(5-(1-pyrrolidinyl)pentyloxy)]-
benzoyl)-4-piperidinyl~-3,4-dihydrocarbostyril
1-86: 1-{1-[4-(5-Dimethylaminopentyloxylbenzoy1]-4-~
piperidinyl~-3,4-dihydrocarbostyril ~;
1-87: 1-{1-12-Methoxy-4-t4-thiomorpholinocarbonyIbutyl-
oxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril ~ :
1-88: 1-{1-(2-Methoxy-4-[4-(l~oxo-4-thiomorpholino)- `~
- 133 _ 2 1 1 ~ 3 3~1
"094/01113 P~T/JP93~35
carbonylbutyloxybenzoyl}-4-piperidinyl~-3,4
dihydrocarbostyril
1-89: 1-{1~ Methoxy-4-[1,1-dioxo~4-thiomorpholino)-
.. .
carbonylbutyloxybenzoyl)-4~piperidinyl}-3,4-
dihydrocarbostyril
1-90: 1-{1-[4-(5-tert-Butylaminopentyloxy)benzoyl]-4-
piperidinyl}-3,4-dihydrocarbostyril
1-91: 1-{1-[4-~5-(2-Propynylamino)pentyloxy)benzoyl]-4~
piperidinyl}-3,4-dihydrocarbostyril -~`
. 1-92: 1-{1-14-(6~-Hydroxy-7 die~hylamlno:)heptyloxy)-
benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril
1 93: 1-{1-[4-(5-Cyclopropylaminopentyloxy)benzoyl]-4-
piperidinyl~ 3,4-dihydrocarbostyril ``.-~
1-94: 1-{1-~4-(5-Tricyclot3.3.1.1]decanylmet~hylamino- ;~
pentyloxy)benzoyl]~4-pipe~ridinyl}-3,4-
: dihydrocarbostyril
1-95: 1-{1-[5-[3-(3-Azaspiro(5,~5~undecanyl)~]-(5-phenyl-
spiro-4-(1-piperidinyl)pentyloxy)ben:zoyl]-4
piperidinyl}-3~4-dihydrocarbostyril
1-96: 1-{1-[4-(:5-Butylaminopentyloxy:)benzoyl]-4
piperidinyl~-3,4-dihydrocarbostyril :~
1-97: 1-{1-[4-t5-Cyclohexylaminopentyloxy)benzoyl]-4-
piperidinyl}-3,4-dihydrocarbostyril
1-98: 1-{1-[4-(5-Tricyclot3.3.1.1]decanylaminopentyl-
oxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril ~ -~
1-99 1-{1-[4-(3-Acetylaminopropoxy)benzoyl]-4- ~ -
piperidinyl~-3,4-dihydrocarbostyril
: :~
- 134 -
W~94/~1113 PCT/JP93/~D~' :
211~33~ ~
The compounds of the formula (2);
2-1: 3-Methyl-1-[4-(2-methylbenzoylamino)benzoyl]~
1,2,3,4-tetrahydroquinoline
2-~: S-Methyl~ 4-~2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine ~
2-3: 5-Hydroxymethyl-7-ohloro-1-[4-(2~methylbenzoyl- ;.
amino)benzoyl]~2,3,4,5-tetrahydro-lH-benzazepine
2-4: 4-Hydroxy-1-~4-(2-methylbenzoylamino)benzoyl] ~.
1,2,3,4-tetrahydroquinoline
2-5: 4-~ydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine
2-6: 5-Hydroxy-1-[2-methoxy-4-~2-methylbenzoylamino)~
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-7: . 5-Hydroxy-6-methyl-1- E 2-chloro-4-(2-methylbenzoyl-
amino)benzoyl3-2,3,4,5-t~etrahydro-lH benzazepine
:2-8: 4-Methyl-5-hydroxy-1-14-~-methylbenz:oylamino)-
: benzoyl)-2,3,4,5-tetrahydro-lH-benza2epine :~
2-9: 5-Hydroxy-7-chloro-1- L 2-methoxy-4-(2-methylbenzoyl ~ ~:
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-10: 5-Hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-
amino)benzoyl]-2,3~4,5-tetrahydro-lH-benzazepine
2-11: 5-Hydroxy-7-chloro-1-~3-methoxy-4-(2-methylbenzoyl-
amino)benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-12: 5-Hydroxy-7-chloro-1-~4~[2-(2-methylphenyl~acetyl-
amino]b nzoyl}-2,3,4,5-tetrahydro-lH-benzazepine
2-13: 5-Hydroxy-7-chloro-1-[3-methoxy-4-(2-chlorobenzoyl- : ;
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine .
2-14: S-Hydroxy-1-[2-chloro-4-(2,4~dichlorobenzoylamino)~
,~ ',..:.
- 13~ 3 3~1
~/~94/011~3 PC~/JP93/~083S
benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine :~
2-15: 5-Oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,~
tetrahydro-lH-benzazepine
~-16: 4-Oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-17: 5-Oxo-1 ~-methoxy-~-~2-methylbenzoylamino)- -~
benzoyl]~2,3,4,5-tetrahydro~lH-benzazepine .-~
2-18: 5-Oxo-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine
2-19: 5-Hydroxy-6-methyl-1-[2-chloro-4-(2-methylbenzoyl~
amino~benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine ~.
2-~0: 5-Acetyloxy-1-[4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine
2-21: ~-Dimethylaminomethyl-1-[4-(2-methylbenzoylamino)- :
benzoyl]-1,2,3,4-tetrahydroquinoline
2-22: 5-Aminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]- ~;
- 2 1 3 r 4,5-tetrahydro-lH-be~nzazepine : :
2~3: 5-Formylaminomethyl-1-[4-(2-methylbenzoylamino)-
benæoyl]-2,3,4,5-tetrahydro-lH-benzazepine ; :~
2-24: 5-Acetyloxymethyl-1-[4-(2-methylbenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine ;~.
2--25: 5-~ethylsulfonyloxymethyl-1-~4-(2 methylbenzoyl-
amino)benzoyl3~2,3,4,5-tetrahydro-lH-benzazepine
2-26: 1-~2-Chloro-4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine-5-spiro-2'~
oxirane
2-27: 5-Methylamin~carbonyloxy-1-[4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine ~`
- 136 -
W094~ 3 PCT/3P93/~08
211633~ ~
-.
2-28: ~-Carbamoyloxy-1-[4-(2-methylbenzoylamino3benzoyl3-
2,3,4,5-tetrahydro~ benzazepine
2-29: 5-Dimethylaminocarbonyloxy-1-[4-(2-methylbenzoyl-
amino)benzoyl)-2,3,4,5-tetrahydro-lH-benæazepine
2-30: 5-Ca~boxymethoxy-1-[4-(2-methylbenzoylamino~-
benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-31: 5-(4-Dimethylaminobutoxyj-1-[4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-32: 5-(3-~minopropoxy)-1~[4-(2-methylbenzoylamino)-
benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-3~: 5-(2-Dimethylaminoethoxy)-7-fluoro-1-[3-methoxy-4-
(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- -~ :
. ~:
lH-benzazeplne hydrochloride
2-34: 5-(3-Phthalimidopropoxy~ 4-~2-methylbenzoyl- ::
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-35: 5-Hydroxyimino-1-[4-~(2-methylbenzoylamino)benzoyl]~
-~
~ 2,3,4,$-tetrahydro-:lH-benzazepine
, ~ .
2-36: 5-Acetyloxyimino-1-[4-(2-methylbenzoylamino)~
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine ~ -~
: 2-37: 5-Methylidene-1-[2-chloro-9-(2-methylbenzoylamino)-
benzoyl]-2,3,~,5-tetrahydro-lH-benzazeplne
2-38: 5-Methylidene-1-[4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine~
2-39: Potassium {1-[2-chloro-4-t2-methylbPnzoylamino)- :.^
: benzoyl3-2,3,4,5-tetrahydro--lH-benzazep1n-S-yl}- .- ; .
imino-O-sulfonate ~ .
2-40: 5-(2-Dimethylaminoacetyloxy)-1-[4-(2-methylbenzoyl- ~ :
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
',';;.' '
- 137 _ 211 ~ 3 3'1
~94/011~3 pC~JJp93/~835
~,, ~,.....
2 41: 5-(2-Dimethylaminoacetyloxy)-7-fluoro-1-[2-methoxy-
9-(2-methylbenzoylamino)benzoyl~-2,3,4,5
tetrahydro-lH-benzazepine
2-42: 5-(2-Dimethylaminoacetyloxy~-7-chloro-1-~4-(2
chlorobenzoylamino)-2-methoxybenzoyl]-2,3 t 4,5~
tetrahydro-lH-benzazepine hydrochloride ;~
2-43: S-t2-Dimethylaminoacetyloxy)-7-chloro-1-[3-methoxy-
4-~2-methylbenzoylamino)benzoyl]-2,3,4,5~
.;; ~
tetrahydro~lH-benzazepine hydrochloride .~
., .
2-44: 5-(2-Dimethylaminoacetyloxy)-7-chloro~ 3-chloro-
4-(2-methylbenzoylamino)benzoyl]-2,3 r 4 ~ 5~
tetrahydro-lH-benzazepine `~
2-45: 5-(2-Dimethylaminoacetyloxy)-7-chloro-1-{2-methoxy- .
4-[(2~methylphenyl)acetylamino~3benzoyl}-2,3,4,5
tetrahydro-lH-benzazepine hydrochloride
:2-46: 5-(4-Dimethylaminobutyryloxy)-7-chloro-1-~2
methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,~i5~
tetrahydro-lH-benzazepine:hydrochloride ~ ~ :
~ ~ 2-47: 5-(2-Dimethylaminoacetyloxy)-7-fluoro-l-t2-ch10ro-
:: ~ 4-~2-methylbenzoylamino)benzoyl3-2,3,4,5- ;~
tetrahydro-lH-benzazepine
2-48: 5-(2-Dimethylaminoacetyloxy~-7-chloro-1-[2-methyl- ~ ;
4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5- ~ ;~
tetrahydro-lH-benzazepine hydrochloride
~-49: 5-(2-Aminoacetyloxy3-7-chloro-1-[3 methoxy-4 (2- ~
chlorobenzoylamino)benzoyl3-2,3/4,5-tetrahyaro-lH- .-:
benzazepine hydrochloride
2-50: 5-(2-~minoacetyloxy)-7-chloro-1-[3-chloro-4-(2
.-.
,,`,, ~,
- 138
W~g4/011~3 P~T/JP93/00
2116~3~
¦ methylbenzoylamino)benzoyl]-2,3,4,~-tetrahydro-1
benzazepine hydrochloride
2-51: 5-(2-Aminoacetyloxy)-7-fluoro-1-[2-chloro-4-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzaæepine hydrochloride
2-52: 5~(2-Aminoacetyloxy)-7-chloro-1-[ 2-mPthyl~ 2-
chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine hydrochloride
2-53: 5-Carbamoylmethoxy-1-[4-~2-methylbenzoylamino)-
benæoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-54: 5-Dimethylaminocarbonylmethoxy-1-{4-(2-methyl-
~enzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-55: 5-Carbamoylmethylaminocarbonylmethoxy-7-chloro-1-
: [4-(2-chlorobenzoylamino)benzoyl3-2,3,4,5-
tetrahydro-lH-benzazepine
2-5~: 5-(4-Methyl-l-plperazinylcarbonylmethoxy3-1-t4-(2- :
methylbenzoylamlno)benzoyl]-2:,3,4,5-tetrahydro-lH-
benzazepine
~::2~-57~ Amino~ 4-(2-methyl~enzoylam~ino)benzoyl~
2t3,4,5-tetrahydro-lH-benzazepine
2-58: 3-Dimethylamino-1-[4-(3~5-dichlorob~nzoylami;no)-
benzoyl ]-17 2, 3,4-tetrahydroquinoline
~; 2-59: ~-Methylamino-1-[4-~2-m.ethylbenzoylamino)bPnzoyl]-
1,2,3,4-tetrahydroquinoline
: 2-60: 4-Dimethylamino-1-[3-methoxy-4-(2-methylbenzoyl-
amino)benzoyl]-1,2,3,4-tetrahydroquinoline
2-61: 3-Dimethylamino-1-[3-methoxy-4-(2-methylbenæoyl-
: . .
:
2~ 33~
`~94/~1113 - 139 - P~T~JY~3/~83
amino)benzoyl~-2~3,4,5-tetrahydro-lH-benzazepine
2-62: 5-(N-Methyl-N-ethylamino~ [4-(2-methylbenzoyl-
amino~benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-63: 5-Dimethylamino-1-[4-(2-methylbenzoylamino)-
benzoyl3-2,3,4,5~tetrahydro-lH-benzazepine
2-6~: 5-Dimethylamino~ 2-chloro-~-(2-methylbenzoyl~
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-65: 5-Dimethylamino~ 3-ethoxy-4-(2-methylbenzoyl-
amino)ben~oyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-66: S-~imethylamino-1-[3-hydroxy-4-(2-methylbenzoyl-
amino)benzoyl]-2~3,4,5-tetrahydro-lH~benzazepine ~:
2-67: 5-Dimethylamino-1-[3-benzyloxy-4-(2-methylbenzoyl- ~
,:
amino)benzoyl3-2,3,4,5-tetrahydro=lH-benzazepine ~
~2-68:: S-Dimethylamino-1-[2-ethoxy-4-(2-methylbenzoyl- ~ -
amino)benzoylJ-2~3~4l5-~etrahydro-lH-benzazepine
.
2-69O S-Dimethylamino-l-f3-methyl-4-(2-methylbenzoyl-
amino)benzoyll-2,3~4,5-tetrahydro~ benzazepine -~
2-70: 5-Dimethylamino-l- E 2-fluoro-4-(~-methylbenzoyl~
: ~ amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
~2--71: S-Dimethylamino-1-f3-fluoro-4-(2-methylbenzoyl- ~ ~ .
amino)benzoyl~-2,3,4,5-tetrahydro-lH-benzazeplne : -: ;
2-72: ~ 5-Dimethylamino-1-t3-methoxy-4-(2,3-dimethyl- `~`~
benzoylamino)benzoyl]-2,3,4,5-tetrahyd~ro-lH-
benzazepine
,. . ,~. .
2-73: S-Dimethylamino-1-[9-(2-methylanilinocarbonyl)-
benzoyl7-2,3,4,5-tetrahydro-1~-~enzazepine
2-74: 5-Dimethylamino-1-[3-hydroxy-4-(2-chlorobenzoyl-
amino)benzoyl)-2,3,4,5-tetrahydro-lH-benzazepine
`~,~,'`'
~ 140
W094/~1113 P~/~P93tQ~
2 1 1 ~
2-75: 3-Hydroxy-4-dimethylamino-1-[4-(2-methylbenzoyl-
amino)benzoyl]-1,2,3,4-tetrahydroquinoline
2-76: 4-Methyl-S-dimethylamino-1-[4-12-methylbenzoyl-
amino)benzoyl] 2,3,4,5~tetrahydro-lH ben2azepine
2-77: 5-Methylamino-1-[4-(2-rnethylbenzoylamino)benzoyl]-
~,3,4,5-tetrahydro-lH-benzazepine
2-78: 5-Methylamino-1-[2-methyl-4-(2-methylbenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-79: 5-Methylamino-1-[2-chloro-4-(2~methylbenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-80: 5-Propylamino-1-~4-(2-methylbenzoylamino)benzoyl3
2,3,4~5-tetrahydro-lH-benzazepine
2-81: 5-Ethylamino-1-~4-t2-methylbenzoylamino)benzoyl]-
2,3,4,5--tetrahydro-lH-benzazepine
: ~-82: 5-Allylamino-1-[2-chloro-4-(~-methylbenzoylamino)~
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-83: 5-Acetylamino-1-[4-t2-methylbenzoylamino)benzoyl]-
~; 2,3,4,5-tetrahydro-lH-benzazepine
2-84: 5~1~-Acetyl-N-methylamino)-1-[4-(2-methylbenzoyl-
: amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-85: 5-Cyclopropylamlno-1-~2-chloro-4-(2-methylbenzoyl-~
amino)ben~oyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-86: 5-(2-Dimethylaminoethylamino)-1-[2-chloro-4-~2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-87: 5-(3-Dimethyl-2-hydroxypropylamino~ 4-(2-chloro-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
- 141 ~ 3'1
394/~ 3 P~T/JP93~0~35
2-8B: 5-(2,3 Dihydroxypropylamino~ l4-~2-methylben20yl-
amino~benzoyl]-2,3,4,5-~etrahydro-lH-benzazepine
2-89: 5-lN-(3-Hydroxypropyl)-N-methylamino]~ 4-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lE-
benzazepine
2-90: 5-senzoylamino-l-[4-(2-methylbenzoylamino)benzoyl]
2,3,4,5-t~trahydro-lH-benzazepine
2-9l: 5-(N-Cyanomethyl-N-methylamino)-1-[4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzaz 2pi ne
2-92: 5-(N-Carbamoylmethyl-N-methylamino) l-[4-~2-methyl-
ben~oylamino~benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-93: 5-~N-(3-[l-Tetrahydropyranyloxy]propyl)-N-methyl]-
: amino-l-[4-(2-methylbenzoylamlno)benzoyl]-2,3,4,5-
tetrahydro-lH~benza2epine
2-94: 5-[N-(3-~cetyloxypropyl):-N-methyl]amino-l-E4-(2-
methylbenzoylamirlo)benzoyl]-2j3j4 J 5-tetrahydro~
:: benzazepine
~ ~ :
~: 2-9~: 5~ Benzyl-4-piperidinyl)amlno-1-[4-(2-methyl-
benzoylamino)ben~oyl]-2,3,4/5-tetrahydro-lH-
benzazepine
~-96: 3-(4-Methyl-l-piperazinyl)-1-[4-(2,3-d~imethyl-
benzoylamino)benzoyl~-l,2j3,4-tetrahydroquinoline
2-97: 3-~1-Pyrrolidinyl)-l-[4-(2,3-dimethylbenzoylamino)-
benzoyl]~l,2,3,4-tetrahydroquinoline
2-98: 5-Hydroxy-5-hydroxymethyl-l-[2-chloro-4-(2-methy~-
: benæoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
WO94/0~113 - 142 - PcT/Jp93/Qo~
211~33~1
benzazepine
2-99: 5-Hydroxy-5-hydroxymethyl-1 [4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benza2epine
2-100: 5-Hydroxymethyl-5-N-methylamino-1-14-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-101: 5-Hydroxy-5-(N-methylamino)methyl-1-[4-(2-methyl-
benzoylamino3benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-10~: 5-Hydroxy-5-methyl-1-[4-(2-methylbenzoylamino)-
benzoyl] 2,3,4,5-tetrahydro-lH-benzazepine
2-103: 5-(N-Ethoxycarbonylmethyl-N-methylamino3-1-[4-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
:2-104~ 4-~2-methylbenzoylaminojbenzoyl]-1,2~,3,5-
tetrahydro-4,1-benzoxazepine
2-105~ 4-~(2-Meehylbenzoylamino~benzoyl]-1,2,3,4-
tetranydro-S,I~benzoxazepine
: 2-106: 4-Methyl-1-l4-(2-methylbenzoylamino3benzoyl]-
1,2,3,4-tetrahydro~uinoxaline ~ :
~: ~ 2-107: 4-Methyl-1~ (3,5-dichlorobenzoyl~amLno)benzoyl]-
:j 2~3,9,5-tetr_hydro-lH-1,4-benzodiazepine
2-108: 5-Methyl-1-(4-bPnzoylaminobenzoyl]-2,3/4,5-
:; t~trahydro-1~-1,5-benzodiazepine
2-109: 5-Isopropyl-1-~4-(2,3-dimethylbenzoylamino)-
: benzoyl]-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine
2-110: 1-[4-(2-methvlbenzoylamino)benzoyl]-1,2-dihydro-
quinoline
.
.
2~1~33~1
- 143 -
~94~1113 PCTJ3P93/~83
2-111: 5-[2~4-Morpholino)acetyloxy]-7-chloro-1-[2-
methoxy-4-(2-methylben20ylamino)benzoyl]-2~3~4,5-
tetrahydro-lH-benzazepine hydrochloride
2-112: 5-(2-Isopropylaminoacetyloxy)-7-chloro-1-[2-
methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-lH~benzazepine hydrochloride
2-113: 5-(1,5-DiaminopentyIcarbonyloxy)-7-chloro-1-[2-
methoxy-4-(2-methylbenzoylamino3benzoyl]-2,3,4,5-
tetrahydro-lH benzazepine hydrochloride
2-114: 5-t3-Aminopropionyloxy3-7-chloro-1-[2-methoxy-4-(2-
methylbenzoylamino)benzoyl]-2,3,g,5-tetrahydro-lH-
benzazepine hydrochloride
2~115: 5-[4-Dimethylaminobutyryloxy)-7-chloro-1-[3-
methcxy~4~~2-methylbenzoylamino)benzoyl]-2,3,4p5-
:
te~rahydro-lH-ben~az~pine hydrochloride
~: 2-116: 5-[1,5-Diaminopentylcarbonyloxy~-7-chloro-1-[3-
methoxy-4-(2-methylbenzoylamino)benzoyl~-2,3,4,5-
tetrahydro-lE-benzazepine hydrochloride: :~
2-11?: 5-~3-Amlnopropionyloxy3-7-fluoro~ 2-chloro-4-(2-
~ethylbenzoylamino)benzoyl]-2,3,4,~5-tetrahydro-lH-
~:~ benz~zepine hydrochloride
2-118: S-Formyloxy-7-chloro-1-[4-(2-methylbenzoylamino)~
benzoyl]-2,3,4,5-tetrahydro-lH-benzazeplne :-
2-11~: 5-Dimethylaminocarbonylmethyl-7-chloro-1-[g~(2
methylben70ylamino)benzoyl]-2/3,4,5-tetrahydro~
benzazepine
2-120~ 4-[3-Methylphenylsulfonylamino)benzoyl~~2,3,4,5-
tetrahydro-lH-benzazepine
W094/01~13 PCT~3P93/~
211~33~
2-121: 1-[4-(2-Methylbenzoylamino~benzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-122: 1-[4-(4-Methylbenzoylamino)benzoyl]-2/3,4,5-
tetrahydro-lH-benzazepine
2-123: 1-[4-(2,3-Dimethylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-124~ 1-[4-~2-Chlorobenzoylamino~benzoyl]-2,3,4,5-
: tetr~hydro-lH-benzazepine
2-125: 1-[4-(2-Bromobenzoylamino)benzoyl]-2J3,9,5-
tetrahydro-lH-benzazepine
2-126: 1-[4-(2-Methoxybenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-127: 1-(4-Cyclohexylcarbonylaminobenzoyl)-2,3/4,5-
tetrahydro-lH-benzazepine
2-128~ 4-(2-Car~amoylmethoxybenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH benzazepine
2-129: 1-{4-[~2-(6-;Isopropylamlnohexyloxy)benzoylamlno)-
~enzoyl}-2j3,4,5-tetrahydro-:lH-benzazepine
2-13G~ 4-(2-(N-Phenyl-~-ethynylamino)acetylamlno)-
: benzoyl]-2~,3,~,5-tetrahydro-1~-benzazepi.ne : :
: ~ :
2-131: 1-[4-(2-(N-Phenyl-N-methylamino)acetylamino)- ~ :
benzoyl]-2,3, A ~ 5-tetrahydro-1~-benzazepine
~; 2-132: 1-[(2-(4-Phenylamino)acetylamlno)benzoyl]-2,3,q,5-
: tetrahydro-lH-benzazepine
133~ {4-(2-[N-Phenyl-N-t2-acetyloxy~ethoxy3amino)-
acetylamino}benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
~-134: 1-{[4-(2-(2-Acetylaminophenoxy) acetvlamino]-
~ 145 - 211 ~ 3 ~J i
`~94101113 ~CT/3P93J0~3
benzoyl}~2,3,4/5-tetrahydro-lH-benzazepine
2-135: 1-[4-(3-Fluorobenzoylamino)benzoyl]-1,2,3,4-
tetrahydrcquinoline
2-136: 1-[4-Tricyclo[3.3.1.1~decanylcarbonylaminobenzoyl]-
1,2,3,4-tetrahydroquinoline
2-137: 1-l4-Benzylcarbonylaminobenzoyl)-1,2,3,4-tetra-
hydroquinolin~
2-138: 1-[4-(2-~uroylamino)benzoyl]-1,2,3,4-tetrahydro-
quinoline
2-139: 1-[4-~3-Thenoylamino)benzoyl]-1,2,3,4-tetrahydro-
quinoline
2-14U: 1 ~4-(3-Ethoxybenzoylamino)benzoyl]-1,2,3,4-
tetrahydroquinoline
2-141~ 7-~hloro-1-[4-~3-hydroxybè:nzoylamino)benzoyl3-
2,3,4,5-tetrahydro-lH-benza2epine
2:-142: 7-Chloro-1-[4-(3-acetyloxybenzoylamino)benz:oyl3-
2,3,4,5-tetrahydro-lH-benzazepine
2-143: 7-Chloro-1-(4-~(2-carbamoylmethoxybenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
~: 2-144: 7-Chloro-1-{3-~2~-(2-d~imethylaminoet~hoxy)benzoyl-
: aminoJbenzoyl}-2,~3,4,5 tetrahydro-lH-benzazepine ~:
.i hydrochloride
: ~ 2-145: 7-Chloro-1-{4-[2-[4-isopropylaminobutoxy)benzo~
: amino~benzoyl}-2,3,4,5-tetrahydro-lH-benzaze~ine
2-146: 1-[4-(2-Methylbenzoylamino)benzoyl]-1,2,3,4,5,6-
: hexahydrobenzazocine
2-147: 1-[4-(2-Methoxybenzoylamino)benzoyl]-1,2,3,~,5,6-
hexahydrobenzoazocine
-- lg6 -- `
W094/01113 PCT/3P93/00~
211633~ -
2-148: 6-Methyl-1-[4-~3,4-dichlorobenzoylamino)benzoyl]-
1,2,3,4-tetrahydroquinoline
2-149: 1-[4-(3-Methylbenzoylamino)benzoyl]perhydro-
quinoline
2-150: 1-[4-(2-Methylbenzoylamino)benzoyl]-1,2,3,4-
tetrahydroquinoline
2-151: 1-~4-(4-Methoxycarbonylbenzoylamino)benzoyl]-
1,2,3,4-tetrahydroquinoline
2-152: 1-[4-(2-Nitrobenzoylamino~benzoyl~-1,2,3,4-
tetrahydroquinoline
2-153: 1-(4-Isobutyrylaminobenzoyl)-1,2,3l4-tetrahydro-
quinoline
2-154: 1-[4-t2,3-Dimethylbenzoylamino3benzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-155: 4-~ethyl-1-[4-cyclohexyIcarbonylaminobenzoyl3-
2,3,4,5-tetrahydro-lH-benzazepine
2-156: 3-Methyl-1-[4-(2-methylben20ylamino)benzoyl3-
1,2,3~4-tetrahydroquinoline
2-157: 2-Methyl-1-(4-benzoylaminobenzoyl)-1,2,3,4-
tetrahydroquinoline
2-158: 1-~4-[4-(6-(1-Piperidyljhexyloxy)benzoylamino]-
benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine
2-159: 1-[4-(2-Chloro-4-aminobenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepine
2-160: 3-~imethylaminocarbonyl-1-[4-(3,5-dichlorobenzoyl-
amino)benzoyl]-1,2,3,~-tetrahydroquinoline
2-161: 1-{4-[2-(4-Methoxyanilino)acetylamino]benzoyl}-
2,3,4,5-tetrahydro-lH-benzazepine
211~33~
~4/~113 - 147 - P~T/JPg3/0083
2-162: 1-{4-[2-(2-(4-Morpholino)ethoxy)benzoylamino]-
benzoyl}-2~3~4~5-tetrahydro-lH-benzazepine
2-163: 1-{4-[2-t4-Hydroxybutoxy)ben~oylamino]benzoyl}-
2,3,~,5-tetrahydro-lH-benzazepine
2-164: 1-{4-(2-Diethylaminocar~onylmethoxybenæoylamino)-
benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine
2-165: 1-{4-(2~[N-tl-(2-Propyl~), N-(phenyl)amlno]acetyl~
amino)benzoyl)-2,3,4,5-tetrahydro-lH benzazepine
2-166: 4-Isopropyl-1-{4-(2r3-dimethylbenzoylamino)-
,..
benzoyl}-2,3,4,5-tetrahydro-lH-1,4-ben20diazepine
2-167~ 4~[4-(2-Diethylamin~ace~yl-l-piperidinyl~
: carbonylamino]benz~yl}-2,3,4,5-tetrahydro-lH-
:
ben2azepine hydrochloride
2-168: 5-Methoxy-l-E4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro~ -benzaæepine
2-169: S-Ethoxycarbonylmethoxy-l-[s-(2-methylbenzoyl-
: am~ino)benzoyl~-2,3,4,5-tetrahydro-lH-ben2azepine
2-170: S-Hydroxymethyl-1-[4-(2-methylbenzoylamino)-
benzoyl~-2,3,4,5-tetrahydro lH-benzazepine
2-171: 1-[4-(2-Methylbenzoylamin:o)~enzoyl]-2,3,4,5-
tetrahydro-lE-benzazepine-5-spiro-2'-oxirane~ ;
, 2-172: 5-[~-Methyl,N-t2-hydroxy-3-diethylaminopropyl)]-
amin~o-1-[4-~2-methylbenzoylamirlo~ben~zoyl]-2,3,4,5-
tetrahydro-lH-benzazepine
2-173: 5-~N-ethyl,:N-n-propyl)amino-1-[4-~2-methylben~zoyl-
amino)benzoyl)-2,3,4,5-tetrahydro~ benzazepine
2-174: 5-(4-MorpholinocarbonyImethoxy)-l-[4-(2-methyl-
.
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
W~94~01113 - l48 - ~CTJJP93/ool
211633'1
benzazepine
2-175: 5~(4-Thiomorpholinocarbonylmethoxy3-l-[4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-176: 5-(Anilinocarbonylamino)-l-[4-(2-methylbenzoyl-
amin~)benzoyl~-2,3,4,5-tetrahydro-lH-benzaæepine
: 2-177: 5-Isobutylamino-l ~4-[2-methylbenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-178: 5-~ormylamino-l-[4-(2-methylbenzoylamino)benzoyl]-
., .
2,3,4,5-tetrahydro-lH-benzazepine
2-179: 5-~l-Oxoth1omorpholinocarbonylmethoxy)~ 4-(2-
methyl~benzoylamino)benzoyl]-2,3,4,5-tetrahydro l~-
benzazepine
2-180: 5-Methylaminocarbonylamino-l-[4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-l8l: 5-(l-Pyrrol)-l-[:4-(2-methylbenzoylamino)benzoy1]-
, ~ :
2~3~4J5-tetrahydro-lH-benzazeplne
2-182: 5-[(2S)-2-Carbamoyl-(l-pyrrolidinyl)]carbonyl-
methoxy~ 4-~2-methylbenzoylaminojbenzoyl3-
2,3,4,5-tetrahydro-lH-benzazepine~ :
2 1~3: 5-Carbamoy1methy1aminocarbonylmet:hoxy~ [4-(2-~
~,: methylbenzoylamino)benæoyl]-2,3,4,5-tet~rahydro-lH-
benzazepine
: 2-184: 5-[(l,1-Dioxothiomorpholino)carbonylmethoxy~
(?-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
lH-benzazepine
::
2-185: 5-[~4-Acetyl-l piperaæinyl)carbonylmethoxy]-l-[4-
(2-methylben~oylamino)benæoyl]-2~3l4r5-tetrahydr
~1163~1
_ ~,g_
~94/011~3 P~T/JP931~083
lH-benzazepine
2-186: 7-Chloro-5-dimethylamino~ 4 (2-methylbenzoyl-
amino)benzoyl]-2,3,4~5-tetrahydro-lH-benzazepine
2-187: 5-Ethoxycarbonylamino-1-[4-(2~methylbenzoylamino)-
benzoyl]-2,3,4,5 tetr~hydro-lH-benzazepine
2-188: 5-(2-~ethylamino)acetylamino 1-[4-(2~methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-189: 5e~N-~ethyl,N-(2-hydroxyethyl)aminocarbonyl-
methoxy~-1-[4-(2-methylbenzoylamino)benæoyl]-
2,3,4,5-tetrahydro-lH-benzazepine
2-190: S-Dimethylamino-1-[4-(2-methylbenzoyloxy)benzoyl3-
2,3,4,5-tetrahydro-lH-benzazepine
2-191: 2-[N-Methyl-N-{1-~4-(2-methylbenzoylamino)benzoyl]-
2,3,4,5-tetrahydro-lH-benzazepin-5-yl}amino]acetic
acld potassium salt
2-192: 5-l2~[N-Methyl,N-~l-imidazol)]acetylamino)-1-[4-(2-
methylaminobenzoylamino)benzoyl]-2,3,g,5-
tetrahydro~ benzazepine
:
2-193: 5-Dlmethylamlno-1-[4-(2-dimethylaminobenæoylamino)-
benzoyl]-2,3~4,5-tetrahydr:o-lH-benzazepine
2-194: 5-~2-AminoacetylamLno)-1-~4-(2-methylaminobenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-195: 5-[2-(1-Imidazol)acetylamino]-1-[4-(2-methylamino-
benzoylamino)benzoyl3-2,3,4,5-tetrahydro lH-
benzazepine
2-196: 8-Chloro-5-dimethylamino-1-[4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
: 2-197: 8-Chloro-5-methylamino-1-[~ (2-methylbenzoylamino)-
- 150 -
WOg4/01~13 PCT/JP93J0
211~33~1
benzoyl]-2l374~5-tetrahydro-lH-benzazepine
2-198: 5-(2-tert-Butoxycarbonylamino)ace~ylamino)-1-[4-(2
methylbenzoylamino)benzoyl~-2,3,4,5-tetrahydro-lH-
benzazepine
2-199: 6~Chloro-5-hydroxy-1-[4-(2-methylbenzoylamino)-
benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-200: 6-Chloro-5 dimethylamino-1-[4-(2-methylbenzoyl-
amino)benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-201: 7-Chloro-S~cyclopropylami~no-1-~4 (2-methylben20yl-
amino)benzoyl]-2,3,415-tetrahydro-IH-benzazepine
2-202. 9-Chloro-5-methylamino-1-~4-(2-methylbenzoylamino)-
benzoyl] 2,3,4,5-tetrahydro-lH-benzazepine
2-203: 9-Chloro-5-dimethylamino~ -(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH~-benzazepine
2-204: 5-Dimethlamino~ 4-(2-methylbenzylcarbonylamino)-
; ~ benzoyl]-2,3,4,5-tetrahydro-lH-benzazeplne
2 205 6-Methylamlno-l-[4-~2-methylbenzoylamino)benzoyl]-
l,2,3,`4,5,6-hexahydrobenæazocine ~
: : 2-206: 7-Chloro-5-methylamino-1-[3-methoxy~4-(2-methyl-~ ;
~; : benzoylamino)benzoyl]-2,3,4,5-tetrahydro-IH- ~;
benzazepine : ~ :
2-207: 7-Chloro-5-dime~hylamino-1-[3-methoxy-4-(2-methyl-
: benz~ylamino3benzoyl]-2,3,4,5-tetrahydro-lH- ~ : benzazepine
2-208: 7-Chloro-5-cyclopropylamino-l- E 3-methoxy-4-(2-
: methylbenzoylamiDojbenzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-209: 7-Methoxy-5-oxo-1-[4-(2-methylbenzoylamino)-
:
lSl- 211~33/1
~94/01~13 PCTJlP93~oQ83
benzoyl]-2,3,~ tetrahydro-lH-benzazepiRe
2-210: 7-~ethyl-5-methylamino-1-[4-(2-methylbenzoylamino)-
benzoyl]-2,3,4,5~tetrahydro-lH-benzazepine
2-~211: 7-Methyl-S-cyclopropylamino-1-[4-(2-methylbenzQyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-212: 7-Methyl-5~dimethylamino-1- E 4-(2-methylbenzoyl-
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-213: 7-Methoxy-5-oxo 1 [3-methoxy-4-(2-methylbenzoyl-
amino)benzoyl3-~,3,4,5-tetrahydro-lH-benzazepine
2-214: 7~Methoxy-5-methylamino-1~[2-chloro-4-(~ methyl-
~ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
; benzazepine
2-215: 7 Bromo-5-methylamino-1-[4-(2-methylbenz:oylamino)-
benzoyl]-2~3,4~5~tetrahydro-lH-benzazepine
2-216 0 7-Chloro-S-methylamino-1-[2-ohloro-4-~2-methyl-
benzoylamino)benzoyl~-2,3,4,5-tetrahydro-lH-
benzazepine
2-217: 7-Chloro-5-cyclopropylamino-1-~2-chloro-4-(2-
mçthylbenzoylamino)benzoyl]-2,3,4,5-~etrahydro-lH-
benzazepine
~ 2-218: 7-Chloro-S-dimethylamino 1-~2-chloro-4-(2-methyl-
¦~ ~ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
~ benzazeplne
¦;~ 2-219: 7-Methyl-5-~N-methyl,N-ethyl~amino-1-[4-(2-methyl-
1:
¦~ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
¦~ benzazepine
¦~ 2-220: 7-Bromo-5-dimethylamino-1-[4-(2-methylbenzoyl-
¦~; amino)benzoyl]-2,3,4,5-tetrahydro-lH-benæazepine
I .
- 152 -
W094/01113 P~T/JP93J~n8~``.
2116~3~
2-221: 7-Methoxy-5-methylamino-1-[4-(2-methylbenzoyl-
amino1benæoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-222: 7-Methoxy-5-methylamino-1-[3-methoxy-4-(2-methyl-
benzoylamino)ben~oyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-223: 7-~ethoxy-5-dlmethylamino~ 2-chloro-4-~2-methyl-
benzoylamino)ben20yl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-224: 7-Methyl-5-methylamino-1-[2-chloro-4-~2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
~-225: 7-~ethoxy-5~dimethylamino~ 4-(2-methylbenzoyl~
amino)benzoyl3-2,3,4,~-tetrahydro-lH-~enzazepine
2-226: 7-Methyl-5-cycloprQpylamino-1-[2-chloro-4-~2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
~en2azepine
2-227: 7-Chloro-S-allylamino-1-[2-chloro-4-(2-methyl- :
: benzoylamino)benzoyl3-2l3,4,~-tetrahydro 1~-
: ~ benzazepine
2 228: 7 Chloro-5-dimethylamino~ 2-methyl-4-(2-methyl-
benæoylamlno)benzoylJ-2,3,g,5-tetrahydro--lH-
benzazepine
2-229: 6-Methylamino-1-[2-chloro-4-(2-methylbenzoylamino)-
benzoyl]-1,2,3,4,5,6-hexahydrobenzazocine
2-230: 7 Methoxy-5-dimethylamino-1-13-methoxy-4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-231: 7-Methoxy-5-cyclopropylamino-1-[2-chloro-4-(2
j 3 ~
- 153 -
- `'~94/01113 PCTJJP93/~835
methylbenzoylamino)benæoyl]-2~3r4~5~tetrahydro-lH
benzazepine
2-232: 7-Chloro-5-ethylamino-1-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-~,3,4,5-tetrahydro-1~-
benzazepine
2-233: 7-Methoxy-5-cyclopropyl-1-[3-methoxy-4-(2-methyl-
benzoylamino)benzoyl~-2,3,4,5-tetrahydro-lH-
benzaæepine
2-234: 7-Dimethylamino-5-oxo-1-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1~-
benzazepine
~ 2-23~: 8-Chloro-6-methylamino-1 [2-chloro-4~(2-methyl-
: ben~oylamlno)benzoyl]-1,2,3,4~5,6-hexahydro-
benzazocine
2-236: 7-Methoxy-5-cyclopropylamino-1-[4-~2-methylbenzoyl-
; ~ aminojbenzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-237: 7-Methoxy-5-hydroxy-1-[2-c~loro-4-(2-methylbenzoyl-
: :
: amino)benzoyl~-2,3,4,5-tetrahydro-lH-benza~zepine
2-238: 6-Chloro-4-me~thylamino-1-[4-(2-methylbenzoylamino)-
benzoyl]-1,2,3,4-tetrahydroquinollne
2~239: 7-Dimethylamino-5-me~hylamino-1-[2-chloro-9-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazeplne
2-240: 7-Methyl-5-dimethylamino-1-~2-chloro-4-(2-methyl-
:: :
benzoylamino~enzoyl]-2,3,4,5-tetrahydro-1~-
: benzazepine
~ 2-241: 7-Dimethylamino-5-hydroxy-1-[2-chloro-4-(2-methyl-
: benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
-- 154;
~ 1 1 6 3 3 ~ PCr/JP93/oof
benzazepine
2-2~2: 6-Chloro-4-methylamino-1-[2 chloro-4 (2-methyl-
benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline
2-243: 7-Chloro-5-methylamino-1-[2 methoxy-4-(2-methyl-
benzoylamino)benzoyl~-2,3,4 f 5~tetrahydro~1H-
benzazepine
: 2-244: 7~Chloro-5-dimethylamino-1-[2~methoxy-4-(2-methyl-
benzoylamino)benzoyl]-2l3,4,5-tetrahydro-lH-
benzazepine
2-245: (+~-5-Dimethylamino-1-[4-~-methylbenzoylamîno)~
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
hydrochloride
2-246: (-3~5-Dimethylamino~ 4-(2-methylbenzoylamino~-
benzoyl~-2,3~4,5-tetrahydro-lH benzazepine
hydrochloride
2 247: 7-Chloro-S-cyclopropylamino-1-[ 2-mPthyl-4- ~ 2-
~:: methylbenzoylamino3benzoyl~-2,3,4,5-tetrahydro-lH-
ben:zazepine ~ :
2 248: 7-Methyl S-methylamino~ cbloro-4-(2-methyl-
:;: benzoyla~ino~benzoyl]-2~3,4,5-tetrahydro-lH-
benzazepine
~, 2-249: 8-Me~hoxy-6-methylamino-1-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-1,2,3~4,5~6-hexahydro-
benzazocine
2-250: 7-Methoxy-S-methylamino-1-[4-(2-methylbenzoyl- .
`~ amino)benzoyll-1,2,3,4-tet~ahydroquinoline
2-251: 6-Methoxy-4-methylamino-1-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline
:: ~
~llS33~1
- 155 -
~9~/01113 PCTIJP~3/~35
.
2-252: 7-Fluoro-5-cyclopropylamino-l-[4-(2-methylbenzoyl-
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-253: 7~Fluoro-5-cyclopropylamino-l-~2-chloro-4-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-254: 7-Fluoro-5-cyclopropyl-l-[3-methoxy~4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-255: 6-Methoxy-4-dimethylamino-1-[4-(2-methylbe~nzoyl-
amino)benzoyl]-1,2,3,4-tetrahydroquinoline
2-256: 7-Methoxy-4-dimethylamino-l-[2-chloro-4-(2-methyl-
benzoylamlno)benzoyl]--l/2,3,4-tetrahydroquinoline
: 2-257: 7-Methyl-5 methylamino-I-[3-methoxy-4-(2-methyl-
ben20ylamino3benzoyl3-2,3,4,5-tetrahydro-lH-
benzazepine :~
2-258: 7-Methyl-S-dlmethylamino-l-[3 methoxy-4-(2-methyl-
: benzoylamino~)benzoyl]-:2,3,4,5-tetrahydro~lH-
: : benzazepine :
2-259: 6-Chloro-4-methylamino l-[2-methyl-4-(2-methyl-
benæoylamiDo)benzoyl]-l,2,3/9-tetrahydroqu1nollne ~ ~:
60: 7-Chloro-5-dimethylamino~ 2-methyl-4-(2-methyl-
, benzoy;lamino)benzoyl3-l,2,3,4-tetrahydro~uinollne
: 2-261: 7-Fluoro-S-methylamino-l-~3-methoxy~4-(~2-methyl-
benzoylamino)~enzoyl]-2,3,4,5-tetrahydro-lH-
: benzazepine
2-262: 7-Fluoro-5-dimethylamino-l-[4-(2-methylbenzbyl-
: amino)ben~oyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-263: 7-Fluoro-5-dimethylamino-l-[2-chloro-4-(2-methyl-
W094/~1113 - 1S6 - PCT/3P~3~8' `
211G334
benzoylamino~benzoyl]~2,3,4,5-tetrahydro-l~-
benzazepine
2-264: 7-Chloro-5-allylamino-l-[4-(2-methylbenzoylamino3- -
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-265: 7-Chloro-5-(N-methyl,N-allyl)amino-l-[4-(2-methyl-
benzoylamino)benzoyl3-2,3,4,5~tetrahydro-lH-
benzazepine
2-266: 7-Fluoro-5-dimethylamino-l-[3-methoxy-4-(2-methyl-
benzoylamino)benzoyl]-2,3,9,5-tetrahydro-lH-
benzazepine
2-267: 7-~ethoxy-5-methyIamillo-l-[2-methyl-4~(2-methyl~
benzoylamino)benzoyl]--2,3,4,5-tetrahydro-lH-
benzazepine
2-268: 7-Methoxy-5-~imethylamino-1-[2-methyl~4-(2-methyl-
: benzoylamino~benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
; . , . j .
2-269: 6-Methyl-4-methylamino-1-[9-~2-methylbenzoylamino)-
benzoyl]-l,2,3,4-tetrahydroquinoline
~:~2-270: 6-Chloro-4-methylamino-3-methyl-1-[4-(2-methyl-
ben2oylamino~benzoyl]-l,2,374-tetrahydroquinQline~
2-271: 4-Methylamino-3-methyl-l-[9-(2-methylbeDzoylaminoj-
benzoyl)-l,2,3,4-tetrahydroquinoline
2-272: 6-Ch~loro-4-methylamino-l~[2-chloro-4-(2-methyl-
benzoylamino)benzoyl] l,2,3,4-tetrahydroquinoline
2-273: 6-Chloro-4-dimethylamino-l-14-(2-methy1benzoyl-
amino)benzoyl]-l,2,3,4-tetrahydroquinoline
2-274: 6-Chloro-4-dimethylamino-l-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline
~,r. ; ~ r.
~ 1 5 7 ~ 6~
94~01~3 ~ 1~W~I P~;13Pg3/0~1835
2-275: 6-Methyl-4-dimethylamino-1-[4-(2-methylbenzoyl-
amino)benzoyl~l,2,3,4-tetrahydroquinoline
- 2-276: 6-Methyl-4-dimethylamino~l-[2-chloro-4-(2-methyl-
benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline
2-277: 6-Chloro-4-dimethylamino-3--methyI-1-[2-chlor~-4-(2-
methylbenzoylamino)benzoyl~-1,2,3,4-tetrahydro-
qùinoline
2-278: 4-Dimethylamino-3-methyl-1- L 2~chloro-4-~2-methyl-
benæoylamino)benzoyl~-1,2,3,4-tetrahydroquinoline
2-279: 8-Chloro-6-methylamino-1-[4-(2-methylbenzoylamino~=
benzoyl]-1,2,3,4,5,6~hexahydrobenzazocine
:
2-280: 7-Chloro-5-allylami.no~ 3-me~hoxy-4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
:: :
benzazepine
2-281: 7~ hloro-5-(N methyl,N-ethyl)amino-1-[3-methoxy-4-
(2-methylbenzoylamino)benzoyl]~-2,3,4,5-tet~ahydro-
: lH-benzazepine
2-282: 7-~hloro-5-~N~methyl,N-allyl)amino-1-[3-methoxy-4-
(2 chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
lH-benzazeplne
~ 283: 7-Fluoro-S-hydroxy-1-[4-(2-meth~lbenzoylamLno:)-
:~ benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-284: 7-Fluoro-5-hydroxy~ 2-chloro-4-(2-methylbenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lX-benzazepine
2-285: 7-Fluoro-5-hydroxy-1-[3-methoxy-4-(2-methylbenzoyl-
amino)benzoyl)-2,3,4,5-tetrahydro-lH-benzazepine
2-286: 5-Dimethylamino-1-[4 t2-methylbenzoylamino)
benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
W~4/011~3 - 158 - PCTJJ~93l~
211~33-~1
2-287: 5-Chloro-1-[~-(2-methylbenzoylamino)benzoyl)-
2,3,4,5-tetr~nydro-lH-benzazepine
2-788: 7-Methoxy-5-methylidene-1-[2-chloro-4-(2 methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydrc-lH-
benzazepine
2-289: 7-Chloro-4-me~nyl-1-~4-(2-methylbenzoylamino)-
benzoyl)-2,3,4,5-te~rahydro-lH-1,4-benzodiazepine
2-290: 4-Methyl-1-[2-chloro-~-(2-methylbenzoylamino)-
benzoyl]-?,3,~,5-tetrahydro-lH-1,4-benzodiazepine
2-291: 7-Metho~y-5-h~droxymethyl-5-hydroxy-1- E 2-chloro-4-
~2-me~hylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
lH-benz~zepine
2-292: 7-Methoxy-5-m2~hylamino-i- E 2-methoxy~4-(2-methyl-
benzoylamino)Denzoyl~-2,3,4,5-tetrahydro-lH-
:
benzazGpine
~:: 2-253: 7-~etho~:y-5-hydroxy~ 2-m~thoxy-4-~2-methyl-
benzoyl~mlnv)benzoyl~-2,3,4,5-tetrahydrc-l a-
benzazepine
2-294: 7-Fluoro-5-E2-(4-methyl-1-piperazinyl)ethoxy]~ 2-
~:~ methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydFG-lH-b~nz~zepine
2-295: 7~Chloro-~-{2-methoxy-4-[2-(4-[4-methyl-1-
~iperazlnyl]butoxy)benzoylamino]benzoyl}-2,3,~,5-
tetrahydro-l~-benzazepin2
2-29~: 7-Chloro-5-(2-(isopropylarnino)2thoxy)-1-[2-methyl-
~-(2-me~hylbenzoylamino)b2nzoyl]-2,3,4,5-
tetrahydro-lH-benzazepine hydrochloride
2-297: 7-Chloro-5-(4-metnyl-1-piperazinyl)carbonylmethyl-
~g4/01ll3 - 159 - 2~163~ PC~/~P93~35
1-[2-chloro-4-(2-methylbenzoylamino)benzoyl3-
2,3,4,5-tetrahydro-lH-benzazepine hydrochloride
2-298: 7-Chloro-1-{3-methoxy-4-[2-(2-dimethylaminoethoxy~-
benzoylamino]benzoyl}-2,3,4,5-tetrahydro-lH-
benza2epine
2-299: 7~Chloro-5-~4-methyl-1-piperldinyl)carbonylmethyl-
1-[4-(2 methylbenzoylamino)benzoyl]-2,3,4,5
tetrahydro-lH-benzazepine hydrochloride
2-300: 7-Chloro-5-~2~dimethy}aminoethyl)~1-[2-methoxy-4-
(2-methylbenzoylamino3benzoyl)-2,3~4~5-tetrahydro-
lH-benzazepine hydrochloride
2-3~1: 7-Chloro-4-hy~roxy-1-[2-methoxy-4-(2-methylbenzoyl~
: amino)benzoyll-2,3~4,5-tetrahydro~lH-benzazepine
: 2-302: 7-Chloro-1-[2-chloro-4-(2-acetyloxybenzoylamino)-benzoyl~-2,3,4,5 tetrahydro-lH-benzazepine
2 303: 7-Chloro-1-[2-chloro-4-(2-hydroxybenzoylamino)-
benzoyl]-2,3~4,5-tetrahydro-lH-benzazepine
2-304: 7-Chloro-1-[2-methyl-4-(2-hydroxybenzoylamino)-
benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-305: 7-Fluoro-5-[~4-dimethylamino-1-piperidino~carbonyl-
~ ~ methyl~-1-[2-methoxy-4-(2-methylbenzoylamlno?-
; ben.zoyl~-2,3,4,5-tetrahydro-lH-benzazepine
2-306: 7-Fluoro-5-(1-piperidinocarbonylmethyl~ [2-
methoxy-4~(2-methyl~enzoylamino)benzoyl)-2,3,4,5-
'~ tetrahydro-lH-benzazepine
2-307: 7-Chloro-5-[(1-methyl-4-piperidinyl)aminocarbonyl-
methoxy]-1-[2-methyl-4 (2-methylbenzoylamino)-
benzoyl~-2,3,4,5-tetrahydro-lH-benzazepine
160
WO94~1113 P~T/JPg3/~
211~33~
hydrochloride
2-308: 7-Chloro-5~(2-acetylaminoethyl)-1-[2-methoxy-4-(2-
me~hylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2 309: 7-Chloro-5-dimethylamino arbonylmethyl~ 4-(2-
methylbenzoylamino~benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-310: 7-Chloro-S-carbamoylmethyl-1-[4-(2-meth~ylbenzoyl-
amino)benzoyl3-2,3/4,5-tetrahydro-1H-benzazepine
~- ~ 2-311: 7-Chloro-5-~(4-methyl-1-piperazinyljcarbonyl-
methoxy]-1-[4-(2-methylbenzoylzmino)benzoyl]-
; . 2, 3 r 4,5-t:etrahydro-lH-benzazepine
2-312: 7-Fluoro-5-:[(4-acetylamino-1-piperidino;)carbo~yl-
methyl~ [4-(2-methylbenzoylamlno)benzoyl]~
2,3,4,5-tetrahydro lH-benzazepine
2-313 7-Chloro-S-[(4-acetylamino-1-plperidlno)carbonyl-
me~thyl~ [2-methoxy-4-(2-methylbenzoylaminc)-
~:. ; benzoyl]:-2,3,4,5-tetrahydro-lH-benzazepine~
2-314: 5-[(4-~cetylamino-l-piperidino)carbonylme~thyl]-7-
~ fluoro-l-l2-methoxy-4-(2-bromomethyIbenzoylamino):~ ~ benzoyl]-2,3,4,5-tetrahydro-lH~benY.azepine ~ ~
2-315: 7-Chloro-1-[2-chloro-4-(2-carbamoylmethoxybe~zoyl-
amino)benæoyl]-2,3,4,5-tetrahydro-1~-benzazepine
2-316: 7-Chloro-1-{2-chloro-4-[2-(2-dimethylaminoethoxy)~-
benzoylamino]benzoyl}-2,3,4,5-tetrahydro-lH-
: benzazepine
2-317: 7-Chloro-1-{2-chloro-4-[2-(4-dimethylamillobutoxy)-
benzoylamino}benzoyl}-2,3,4,5-tetrahydro-lH-
.
:
- 161 2 11 63 3
~94/0~113 PCT/JPg3l00~3
benzazepine
2-318: 7-Chloro-1-{2-chloro-4-[2-(4-isopropylaminobutoxy)-
benzoylamino]ben2Oyl}-2,3~4,5-tetrahydro-lH
benzazepine
2-319: 7-Chloro-1-{2 methyl-4-(2-carbamoylmethoxy)benzoyl-
amino]benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine
2-320: 7-~hloro-5-~2-hydroxyethyl)-1-[4-(2-methylben~oyl-
amino)benzoyl]-2,3,4,5-tetrahydro~lH-benzazepine
2-321: 7-Chloro-5~(2-hydroxyethyl)-1-[4-(2-chlorobenzoyl-
amino)benzoyl]-2,3,4,5-tetrahydro-lH~benzazeplne
2-322: 7-Chloro-5-(2-hy~roxyethoxy)-1-[4-(2-methylbenzoy~-
amino)benzoyll-2,1,4 t 5-tetrahydro-l~-benzaz2pine
2-323: 7-Chloro-5-(~2-hydroxyethoxy)-1-[4-(2-chlorobenzoyl-
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2~3~4: 7-Chloro-5-~2-dimethylaminoethyl)-1-(4-(2-chloro-
benzoylamino)~enzoyl]-2,3,4jS-~tetrahydro-lH-
benzazepine
2-325: 7-Chloro-5-(2-chloroethyl)-1-~4-(2-chlorobenzoyl-
amino)benzoyl]~2,3,4,5-tetrahydro-lH-benzazepine
326: 7-Chloro-5-(2-dimethylaminoe~hyl)-1-~4-(2-methyl-
,
benæoylamlno)benzoyl]-2,3,4,5-tetrahydro~
benza 2 epine
2-327: 7-Chloro-5-(2-isopropylaminoethyl)-1~[4-:~2-chloro-
; benzoylamino)benzoyl3-2,3,~,5-tetrahydro-lH-
benzazepine
2-328: 7-Chloro-5-(2-isopropylaminoethyl)-1-[4 (2-methyl-
~::
benzoylamino)benzoyl3-2,~,4,5-tetrahydro-lH~
~': benzazeplne
- 162 -
WO94~1113 P~T/~P93/~
2116334
2-329: 7-Chloro-5-~2-tert butylaminoethyl)-1~[4-(2-chloro-
benzoylamino~benzoyl~-2,3,4,5-tetrahydro-1
benzazepine
2-330: 7-Chloro-5-~2-tert-butylaminoethyl)-1~[4-(2-methyl-
benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-331: 7-Chloro-5-(2-isopropylaminoethoxy)-1-[4-(2-chloro-
benzoylamino)benzoyl3-2,3~4,5-tetrahydro-1~-
ben~azeplne
. 2-332: 7-Chloro-5-(2-1sopropylaminoethoxy)-1-[4-(2-methyl-
benzoylamino~b~nzoyl]-2,3,4,5-tetrahydro-lH-
: benzazepine
2-333.~ 7-Chloro-S-~2-tert-butylaminoethoxy)~ 4-(2-
methylbenzoylamino)benzoyl~-2,3,4,5-tetrahydro-lH-
I :~
benzazepine
2-334: 7-Chloro-4-m~thylamino-1-[2-methoxy-4 (2-methyl-~
:~ benzoylamino)b nzoyl]-2,3,4,5-tetrahydro-lH-
: :
; benzazeplne ~
2-335: 7-Chloro-4-dimethylamino 1-[2-methoxy-4-(2-methyl-
:~
benzoylamino)benzoyl]-2,3,4,5-tetrahydro~
benzazepine
2-336: 7-Chloro-5-(2-dimethylaminoethyl)-1- E 2-methyl-4-(2-
chlorobenzoylamino)benzoyl)-2,3,4,5-tetrahydro-lH-
benzazepine
: 2-337: 7-Chloro-5-(2-diethylaminoethyl)-1-[2-methyl-4-(2-
~: : chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
:
; benzazepine
:;; Z-338: 7-Chloro-5-(2-isopropylaminoethyl)-1-[2-methyl-4-
~: ~
211~3'1
- 163 -
~94/01113 PCr/~P93/OOB35
(2-chlorobenzoylamino3ben~oyl]-2,3~4,5-tetrahydro;
lH-benzazepine
2-339: 7-Chloro-5-(2-tert-butylaminoethyl3-l-[2-methyl-4-
(2-chlorobenzoylamino3benzoyl]-2,3,4,5-tetrahydro~
lH-benzazepine
2-340: 7-Chloro-5-(2-dimethylaminoethoxy)-I-[3-methoxy-4-
(2-chlorobenzoylamino)benzoyl]-2 t 3,4,5-tetrahydro-
lH-benzazepine
2-341: 7-Chloro-5-(2-diethylaminoethoxy)~1-[3-methoxy-4-
(2-chlorobenzoyIamino)benzoyl~-2,3,4,5-tetrahydro-
lH benzazepine
2-342: 7-Chloro-5-(2-isopropylaminoethoxy)-l~3-methoxy~4-
~2-chlorobenzoyla~mino)benzoyl]-2,3,4,5-tetrahydro-
: lH-benzazepine
~: :
2-343: 7~Chloro-5-(2-diethylaminoethoxy)-l-~3-methoxy-4-
(2-methylbenzoylamino~benzoyl]-2,:3,4,5-tetrahydro-
1H-benzazepine
2-344: 7~Chloro-5-(2-isopropylaminoethoxy)-1- E 3-methoxy-4-
;: : : :
(2-methylbenzoylamino3benzoyl]-2,3~4~5-tetrahydro-
lH-benzazepine
2-345: 7-Chloro~5-(2-tert-butylethoxy)-l-l3~-methox:y-4-~2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine ~ ~ ~
2-346: 7-Chloro-5-(2-diethylaminoethyl)-1-[2-methoxy-4-(2-
methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-~-
benzazepine
2-347: 7-Chloro-5-(2-isopropylaminoethyl)-l-[2-methoxy-4-
(2-methylbenzoylamino)benzoyl~-2,3,4,5-tetrahydro-
-- 164 -
WO94/~113 P~r/3P~3~0
211~33~1
lH-benzazepine
2-348: 7-Chloro-5-t2-tert-butylaminoethyl)~1-[2-methoxy-4-
(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
lH-benzazepine
2-349: 7-Chloro-5-(2-diethylaminoethyl)-1 [2 methoxy-4-(2
chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-
benzazepine
2-350: 7-Chloro-5-(2-isopropylaminoethyl)-1-[2~methoxy-4-
~2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
.,
lH-benzazepine
2-351: 7-Chloro-5-(2-tert-butylaminoethyl)-1-~2-methoxy-4-
; (2-chlorobenzoylamino~benzoyl]-~,3,4,5-tetrahydro-
lH-benzazepine
~ 2-352: 7-Chloro~l-[2-methoxy-4-(3-hydroxybenzoylamino)-
;~ benzoyl]-2,3,4,5~tetrahydro-lH-benzazeplne
2-353: 7-Chloro-1-[3-methoxy-4-(2-hydroxybenzoylamino)-
benzoyl]-2,3r4,5-tetrahydro-lH-benzazeplne :~
:: 2-354: 7-Chloro-1-[3-methoxy 4-(2-carbamoylmethoxybenzoyl-
amino)benzoyl~]-2,3,4,5-tetrahydro~-lH-benzaze~ine
2-355: 7-Chloro-1-{3-methoxy-4-[2-(2-dlmethylaminoethoxy)-
benzoylamino]benzoyl}-2,3,4:,5-tetrahydro-lH-
, benzazeplne
:~ 2-356: 7-Chloro-1-{3-methoxy-4-[2-(2-isopropylamino-`
et:hoxy)benzoylamino]benzoyl)-2,3,4,5-tetrahydro-lH-
benzazepine
~:
~; 2-357: 7-Chloro-1-{3-methoxy-4-~2-l4-dimethylamlnobutoxy3-
benzoylamino]benzoyl}-2,3,~,5-tetrahydro-lH-
benzazepine
- 165-211~33~
Vg4~1113 PC~/JP93~ 5
2-35~3: 7-Chloro-1~{3-methoxy-4-~2-(4-isopropylamino-
butoxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-lH-
benzazepine
2-359: 7-Chloro-4-hydroxy-1-[2-~ethox~-4-(2-metn.ylbenzoyl
amino)benzoyl]-2,3,4,5-~etrahydro-lH-benzazepine
2-360: 7-Chloro-S-(2-aminoethyl)-1-[2-methoxy-4-(2-
methylbenzoylamino~benzoyl]-2,3,4,5-tetr2hydro-lH-
benzazepine nydrochlorid
2-361: 7-Chloro-4-hydroxy-1~[2-methyl-4-l2-methylbenzoyl-
amino)benzoyl3-2,3,4,5-tetrahydro-lH-benzazepine
2-362: 7-Chloro-1-[2-methyl-4-(2-acetyloxybenzoyl-
amino)benzoyl]-2,3r4,5-tetrahydro-lH-ben~azepine
-363: 7-Chloro-5-carbamoylmethoxy~ 2-methyl-4-(2-
chlorobenzoylamino)benzoyl]-2,3,4,5-tetr2:~ydro-lH-
: benzazepine
:2-~64: 7-Fluoro-5-(2-diethylam~noethyl)-1-L2-me~hyl-~-~2-
chlorobenzoyl.~mino)benzoyl}-2,3,4,5-tetr2hydro-lH-
benzazepine
2-365: 7-Fluoro-5-(2-isopropylaminoethyl)-1-l2-m~thy;1-4-
(2-chlorobenzoylamin:o)ben~oyl}-2,3,4,5-tetrahydro-
lH-b:enzazepine ; ~ :
2-366: 7 Fluoro-5-(2-cert-butylaminoethyl)-1-[2-methyl~4-
.
~2-chlorobenzoylamino1ben70yl]-2,3,4,5 tetrahydro-
: lH-benzazepine
' 2-367: 7-Chloro-5-(2-ethylaminoethoxy)-1-[2-meth~xy-4-(2-
chlorobenzoyl~mino~benzoyl)-2,3,4,5-tetrc.~ydro lH-
benzazepine
2-368: 7-Chloro-5-~2-acetylaminoethoxy)-1-~2-me~:~ox~y-4-(2-
: :
~ ~:
W~94/0~113 - 166 - P~TIJP~31~'
211633'1
chlorobenzoylamino)benzoyl~-2~3/4~5-tetrahydro-lH~
benzazepine
2-369: 7-Chloro-5-(2-isopropylaminoethoxy)-1-[2-methoxy-4-
(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
lH-benzazepine
2-370: 7-Chloro-5-methoxy-1-[2-methoxy-4-(2-methylbenzoyl~
amino3benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine
2-371: 7-Chloro-5-{N-methyl,N-[2-(~-pyridyl)ethyl]amino-
carbonylmethoxy-1-[2-trifluoromethyl-4-(2-methyl-
benzoylamino)benzoyl]-2,3,4~5-tetrahydro-lH-
benzazepine
2-372: 7-Chloro~5-[2-[N-ethyl,N-butylamino3ethoxy]-1 [2-
methoxy-4~(2-chloro~enzoylamino~3benzoyl]-2,3,4,5-
tetrahydro-lH-benza~epine
I ;~ ~
`~:
:~
:
~ ,
- 167 ~ 3~
'~94/01113 ~TIJ~3/~0~35
Table 1 (*): Inhibitory Rate ~%) at 10 5 ~
_ .
Test IC50 Test IC50
Comp. Comp.
No. (~M) No. t~M)
1-1 7.6~ 1-2 5.6~
1-3 4.37 1-4 3.96
1-5 8.38 1-6 4~57
1-7 7.66 1-8 ~.23
1-9 4.89 1-10 4.09
1-11 5.05 1-12 3.55
1-13 4.75 1 14 43.8 (*)
1-15 6.18 1-16 6.03
1-17 4.32 1-18 ~3.3 (*)
1-19 5.10 1-20 7.13
1-21 5.10 1-22 4.32
1-2~ 4.99 1-24 22.7 (*)
:
1-25 7.14 1-~6 24.2 (*)
` ~ 1-27 13.6 ~*) 1-28 5.55
1-29 7.24 1-30 2~.6 (*)
~:
1-31 33.8 (*~ 1-32 2~.~7 (*)
33 14.6 ~*) 1-3~ ~10.~ t*)
:~:
1-35 32.4 (*) ~-36 4.4
1-37 1.9l 1 38 4.3
1-39 0.85 1-40 2.92
1 7.70 1-42 4.54
1 43 4.14 1-44 8.28
1-45 9.24 1-46 40.1 (*)
1-47 3.28 1-48 ~4.5 ~(*~
49 7.85 1-50 8~59
1-51 40.1 ~*) 1-52 6.8~
3 72.7 1-54 47.4 (*)
:::
: :
- 1~8 -
WO94/01113 PCT/JP93/Q0
2 ~ 1~33~
Test IC5~ Test IC50
Comp. Comp.
No. (~M) No. t~M~
1-55 4~7 (*) 1-56 2.92
1-57 30.3 (*) 1-58 43.8 (*)
1-59 3.19 1-60 4.29
1-61 5.08 1-62 5.13
1-63 5.73 1-64 4.55
1-65 6.86 1-6~ 45.8 (*)
1-67 6.80 1-68 49.7 (*)
1-69 41.~ (*) 1~70 2.93
1-71 3.42 1-72 5.82
1-73 2.85 1 74 7~39
1-75 44~1~ (*3 1-76 43.3 ~*)
1-77 3.29 1-78 5.16
79 ~.74 1-~0 6.62
:~
1-81 1.89 1 82 4.69
1-83 1.91 1-84 5.54
1-85 15.7 (*) 1-8~ 8.~1
: l-B7 9.85 : 1-38 2.45
89 6.73 1-90 5~75
91 ?.05 ~ 1-92 2.32
93 5.13 1-9~ 7.44
1-95 4.02 1-96 3.10
: 1-97 3.87 ~ 1-98 7.13
1-99 4.6
~ '
- 169 _ 21 1 6~3 ~
'~ ~/01113 p~T/3P93/008~5
Table 2 ~*): Inhibitory Rate (%) at lO 5 M
(**): Inhibitory Rate (%) at lO 6 M
Test IC50 T st IC50
No. (~M) No. ~M)
_
2-l 4.0l 2-2 l.S5
2-3 0.22 2 4 21.3 (*)
2-5 l.57 2-6 l.26
2-7 25.0 (*) 2-8 0.52
2-9 0.23 2-lO 3.07
2-ll 0.34 2-12 ~.60
2-13 0.23 2-14 ~2.0 (*)
2-lS 15.3 (*) 2-16 5~30
2-17 43.2 (*) 2-18 37.g (*)
2-l9 14O8 (*) 2-20 5.20
2-21 27.2 (*) 2-22 3~89
2-23 0.72 2-24 2.49
2-25 2.82 2-26 8.89
2-27 7.25 2-28 7.61
2-29 37.l (*) 2-30 8.~lO
2-31 1.83 2-32 2.55
2-33 l.I2 2-34 4.04
2-35 41.1 (*) 2-36 35.~ (*)
2-37 6.6~ 2-38 l.50
2-39 27.9 (*) 2-40 1.38
2-~l 0.48 2-42 0.07
2-43 0.55 2-44 4.29
2-45 0.23 2-46 0.07
2 47 8~35 2-48 3.64
2-49 0.55 2-50 2.93
2-51 4.79 ~-52 2.70
2-53 5.~l 2-54 2.92
_ _ , _ _
~: ,
- 170 -
WO 9~/0~113 PCT/JP93J~8-
211633'1
Test IC50 Test I~50
Comp. Comp.
No. (~M) No. (~M)
2 55 0.38 2-56 1.83
~-57 8.79 2-58 3.8~
2-59 22.8 ( * ) 2-~0 S .01
2-61 22.7 ~*) 2-~37.9 ~*)
2-63 5.30 2-64 12.0 ( * )
2-65 33.g (*) 2-6616.8 (*)
2-67 28.5 (*) 2-6816.9 (*)
2 -69 31.2 ~ * ) 2-705.19
2-71 6.07 2-72 26.3 (*)
2-73 8.93 2-74 22.9 (*)
2-75 32.0 (*~ 2-761.55
2-77 6.10 2-78 10.3 ( * )
2-79 19.6 ( * ~ 2-808.39
2-81 22.4 (*) 2-8227.5 (*)
2-~3 30.1 ~ * ) 2-847.92
2-85 4~.3 (*) 2-8637.3 (*)
~-87 5.55 2-~ 2.37
2-89 ~.58 2-90 26.5 ~*)
:
2-91 8.62 2-92 2.47
2-93 5.38 2-94 3.19
2-~5 5.56 2-96 9.19
2-97 3.81 2-98 16.6 (*)
2-99 ~4.2 t*) 2-100 21.8 (*3
2-101 14.6 ( * ) 2-102 3.48
2-103 3.03 2-104 7.61
2-105 33,7 (*) 2-1~6 32.4 ~*)
2-107 3.57 2-108 5.84
2-109 8.75 2-110 36.9 ( * )
__ _ _ _ _ .
--17~_ 2~ 3~
~ g4/01113 P~T/J~93/$~3~
.
Test IC50 Test IC50
Comp. Comp.
No. (~M) No. (~M)
_
2-111 0.05 2-112 O . OS
2-113 0.11 2-1~4 0. ~3
2-115 0.4~ 2-116 1.26
2-117 6.02 ~ 3 0.55
2-119 0. ~2 2-120 3.33
2-121 1.18 2 122 g .61
2-123 1.24 2-12~ 1.2g
2-125 0.88 2 -126 7.3~
2-127 1.02 2-128 46.4 ~ * )
2-129 45.0 ( * ) 2-130 ~ .42
2-131 2.05 2-132 8. ~9
2-133 4.16 2-134 4~ .9 ~ * )
2-135 19.0 2-13~ 10. ~ ( * j
2-137 11.4 (*) 2-138 16.2 (*)
2-139 8.97 2-140 19.0 t*)
2-141 2.41 2-142 3.29
2-143 5.76 2-144 8.26
2-145 ~.54 2-146 3.1~
2-1~7 13 ~ 2 ( * ) 2-14~ 7.02
-14~ 4.83 2-150 3.3~
2-151 10.9 ~ * ) 2-152 21.7 ~ * )
2-153 8.96 2-154 7. g3
2-155 2.54 2-156 4.01
2-157 13.8 (*) 2-~58 23.7 (*)
2-159 6.73 2-160 ~ 49.3 ( * )
2-161 6.32 2-162 30.7 (*)
2-163 22.2 (*) 2-164 23.3 (*)
2-165 8.42 2 166 ~ .7~
2-167 25.2 ( * ) 2-168 1.60
I 172 -
W094/a1113 PCTIJP93l~-
211633~i
Test IC50 Test IC50
Comp. Comp.
No . ( ~M) N~ . ( ~M)
2-169 1.76 2-170 0.96
2-171 1.90 2-172 5.34
2-173 43.4 t * ) 2-174 1.78
2~175 1.24 2-176 21.1 ( * )
2-177 24.1 ( * ) 2-178 9.26
2-179 2.63 2-180 28.6 ( * )
2-1$1 14.2 ( * ) 2-182 1.3~
2-lB3 2.09 2-184 2.40
2-185 1.47 2-186 1.4~
2-187 10.1 (*) 2-188 41.7 (*)
2-1~9 2.36 2-190 34.2 ( *
2-191 15.6 ( * ) 2-192 7.71
2-193 7.60 2~194 26.7 ( * )
2-lg5 53.4 ~ * ) 2-196 8.93
2-197 44.1 ( * ) 2-lg8 46.0 ( * )
2-199 31.1 ( * ) ~-200 38 ~ 1 ~ * )
2-201 1.17 2-202 4.45
2-203 6.00 2-204 47.4 ( * )
2-205 38.2 ( * ) 2-206 1.5~
2-207 3. ~7 2-208 3.19
2-209 17.8 ( * ) 2-210 2.71
2-211 3.49 2-212 1.44
2-213 36.1 ( * ) 2-214 5. ~6
2-215 0.49 2-216 4.76
2-217 48.8 ( * ) 2-218 8.58
2-219 3.78 2-22~ 1.35
2-221 2.32 2-222 3.37
2-223 4.53 2-224 45.6 ( * )
. , _ ___ . __ _ _
3 ~1
~~O ~4/01113 - 173 ~ PCT/3P93~835
-
Test IC50 Test IC50
Comp. Comp.
No. (,JM) 2~o. (,IM)
~-2~5 1.76 2 226 9.19
2-227 47.4 ( * ) 2-228 40.4 ( * )
2-229 34.4 ( * ) 2-230 4.17
2-231 5.39 2-232 42.8 ~ * )
2-233 5,27 2-234 22.2 ( * )
2-235 2.86 2-236 3.05
2-237 2.40 2-238 2.47
2-239 15.8 ( * ) 2-240 7.83
2-241 18.1 ( * ) 2-24244 O 5 ~ * )
2-243 3.19 2-24416 O 4 t * )
2-245 20.2 ( * ) 2-246 2.60
2-247 9.78 2-248 43.1
2-249 1.76 ~-250 41.1 ( * )
2-251 11.6 ( * ) 2-252: 5.56
2-253 33.7 ( * ) 2-254~ .09
2-25~ 3.21 2-256 29.5 ( * 3
2-257 5.82 2-258 5.86
2-259 25.0 ( * ) 2-2602~ .8 ( * )
2-261 8.3~ 2-262 5.68
2-263 ~9.8 ( * ) 2-2640. ~3
2-265 7.32 ~-266 6.68
2-267 9.46 2-268 35.0 (*)
2-269 ~5.1 ( * ) 2~2700.2~
2-~ 71 2.17 2-272 9.46
2-273 3.20 2-27~ 10.5 ( * )
2-2?5 4.47 2-276 32.8 ( * ~
~ 277 26.0 (*) 2-278 18.8 (*)
2-279 1.18 2-280 3.9
- 17~ ~
WO ~0~113 P~T/JP931~ `
211~33~
.
Test IC5~ Test IC5
Comp. Comp.
No. (~M) N . (~M)
2-281 36 ~ 9 ~ * ) 2~282 35.9 ( * )
2 283 1.18 2-284 3.43
2-285 ` 0.94 2-286 1.81 ( * )
2-287 1.17 ~-288 3.62
2-28g 2.41 2-290 7.58
2-~gl 33. ~ ~ * ~ 2-292 46. Q t * )
~-~93 89 ~ 7 ( * ) 2-294 1.64
2-295 3.69 2-296 2.18
2~2~7 1.85 2-298 47.3 ( * )
2-29g 0.3~ 2-300 0.97
2-301 ~ .12 2-302 ~9 O ~ ( * )
2-303 14.4 ~ * ) 2-304 17.7 ( * )
2 3~5 0.22 2-30~ 0.09
2-307 1.94 2-308 0.09
2-309 0. ~5 2-310 0.28
2-311 0.1~ 2-312 1.2~
2-313 0.13 2-314 0.10
2-315 4.44 2-31~ 3.52
2-317 6~75 2-318 8.01
2-31~ 3.58 2-3~0 0.22
2-321 0.30 2-322 0.23
2-323 0.25 2-324 1.76
2-325 27.6 ( * ~ 2-326 0.61
~-327 0.37 2-328 0.35
2-32g 0.45 2-330 0.33
2-331 ;0 ~ 30 2-332 0.3~3
2-333 0.52 2-33~ 0.35
2-~35 0.14 2-336 7.54
:
2 ~ 3 ~
- 175 -
4/~1113 P~r~P93/0083
Test IC50 T~st IC50
Comp. Comp.
No . ( llM) No. ( ~IM)
__ .
2-337 4 . 23 ~-338 7 . 55
~-3~9 5 . 41 2-3~û 0 . 57
2-341 0 . 49 2-342 O . 62
2-343 0 . 6û 2-344 1 . 87
2-345 2 . 50 2-346 0 . 33
2-3D~7 o . 64 2-348 0 . 6
2~349 0 . 51 2-350 0 . 43
2-351 0 . 86 2-352 0 . 72
2-353 31 . 6 ( * ) 2-354 4 . 52
2-355 9 . 50 2-356 9 . Z3
2-357 0 . 57 2-~58 5 . 18
2-359 0 . OB 2 360 0 . 45
2-3~1 1.37 2-362 2402 (*~
2 3 ~ 3 4 . O 0 2 3 6 4 4 . 4 9
2--3 6 5 -1 . 4 0 2--3 6 6 9 . 2 g
2-367 0 .10 2-36a 0 . 21
2-369 88.~ (**) 2-:370 0.78
:: 2-371 1 ~ 93 2-372 0 . 88
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