U.S. patent application number 09/983598 was filed with the patent office on 2002-05-02 for novel spiro compounds.
Invention is credited to Fukami, Takehiro, Haga, Yuji, Ishihara, Akane, Ishii, Yasuyuki, Itoh, Takahiro, Kanatani, Akio, Sakamoto, Toshihiro, Takahashi, Toshiyuki.
Application Number | 20020052371 09/983598 |
Document ID | / |
Family ID | 26531087 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020052371 |
Kind Code |
A1 |
Fukami, Takehiro ; et
al. |
May 2, 2002 |
NOVEL SPIRO COMPOUNDS
Abstract
Compounds of the general formula (I): 1 (wherein Ar.sup.1
represents optionally substituted aryl or heteroaryl; n represents
0 or 1; T, U, V and W represent independently nitrogen atom or
optionally substituted methine group, where at least two of them
represent the said methine group; X represents methine or nitrogen;
Y represents optionally substituted imino or oxygen atom) exhibit
NPY antagonistic activities and are useful as agents for the
treatment of various diseases related to NPY, for example,
cardiovascular disorders such as hypertension, nephropathy, heart
disease, vasospasm, arteriosclerosis and the like, central nervous
system disorders such as bulimia, depression, anxiety, seizure,
epilepsy, dementia, pain, alcoholism, drug withdrawal and the like,
metabolic diseases such as obesity, diabetes, hormone abnormality,
hypercholesterolemia, hyperlipidemia and the like, sexual and
reproductive dysfunction, gastro-intestinal disorder, respiratory
disorder, inflammation or glaucoma, and the like.
Inventors: |
Fukami, Takehiro;
(Tsukuba-shi, JP) ; Kanatani, Akio; (Tsukuba-shi,
JP) ; Ishihara, Akane; (Tsukuba-shi, JP) ;
Ishii, Yasuyuki; (Tsukuba-shi, JP) ; Takahashi,
Toshiyuki; (Tsukuba-shi, JP) ; Haga, Yuji;
(Tsukuba-shi, JP) ; Sakamoto, Toshihiro;
(Tsukuba-shi, JP) ; Itoh, Takahiro; (Okazaki-shi,
JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
26531087 |
Appl. No.: |
09/983598 |
Filed: |
October 25, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09983598 |
Oct 25, 2001 |
|
|
|
09640784 |
Aug 18, 2000 |
|
|
|
Current U.S.
Class: |
514/243 ;
514/248; 514/260.1; 514/264.1; 514/278; 544/184; 544/231;
546/19 |
Current CPC
Class: |
A61P 3/04 20180101; C07D
307/94 20130101; C07D 491/10 20130101; A61P 9/00 20180101; A61P
15/00 20180101; C07D 471/10 20130101; A61P 3/10 20180101; A61P
25/00 20180101; C07D 405/12 20130101; C07D 213/61 20130101 |
Class at
Publication: |
514/243 ;
514/248; 514/264.1; 514/260.1; 514/278; 546/19; 544/231;
544/184 |
International
Class: |
A61K 031/519; A61K
031/4747; C07D 491/20; A61K 031/53 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 20, 1999 |
JP |
11-233573 |
May 10, 2000 |
JP |
2000-137692 |
Claims
What is claimed is:
1. A compound represented by the general formula (I): 21wherein
Ar.sup.1 represents aryl or heteroaryl which may be substituted,
the substituent being selected from the group consisting of
halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy,
lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl,
lower alkylene optionally substituted with oxo, and a group
represented by formula of --Q--Ar.sup.2; Ar.sup.2 represents aryl
or heteroaryl which may be substituted, the substituent being
selected from the group consisting of halogen, cyano, lower alkyl,
halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower
alkanoyl and aryl; n represents 0 or 1; Q represents a single bond
or carbonyl; T, U, V and W represent independently nitrogen atom or
methine group which may have a substituent selected from the group
consisting of halogen, lower alkyl, hydroxy and lower alkoxy, where
at least two of them represent the said methine group; X represents
methine or nitrogen; Y represents imino which may be substituted
with lower alkyl, or oxygen; a salt or ester thereof.
2. The compound of claim 1, wherein the aryl in Ar.sup.1 is
phenyl.
3. The compound of claim 1, wherein the heteroaryl in Ar.sup.1 is
pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,
1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl,
quinolyl or pyrido[3,2 -b]pyridyl.
4. The compound of claim 1, wherein T, U, V and W are independently
methine which may have a substituent selected from the group
consisting of halogen, lower alkyl, hydroxy and lower alkoxy.
5. The compound of claim 4, wherein T, U, V and W are independently
methine which may be substituted with halogen.
6. The compound of claim 1, wherein one of T, U, V and W is
nitrogen.
7. The compound of claim 1, wherein Y is unsubstituted imino or
oxygen.
8. The compound of claim 1, wherein Y is oxygen.
9. The compound of claim 1 which is represented by the general
formula (I-a): 22wherein Ar.sup.1 represents aryl or heteroaryl
which may be substituted, the substituent being selected from the
group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower
alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group represented by formula of
--Q--Ar.sup.2; Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q
represents a single bond or carbonyl; R.sup.1 represents hydrogen
or halogen.
10. The compound of claim 9, wherein the aryl in Ar.sup.1 is
phenyl.
11. The compound of claim 9, wherein the heteroaryl in Ar.sup.1 is
imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl,
pyrimidinyl, quinolyl or pyrido[3,2-b]pyridyl.
12. The compound of claim 1 which is represented by the general
formula (I-b): 23wherein Ar.sup.1 represents aryl or heteroaryl
which may be substituted, the substituent being selected from the
group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower
alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group represented by formula of
--Q--Ar.sup.2; Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q
represents a single bond or carbonyl; T, U, V and W represent
independently nitrogen atom or mothine group which may have a
substituent selected from tho group consisting of halogen, lower
alkyl, hydroxy and lower alkoxy, where at least two of them
represent the said methine group.
13. The compound of claim 12, wherein the aryl in Ar.sup.1 is
phenyl.
14. The compound of claim 12, wherein the heteroaryl in Ar.sup.1 is
pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,
1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl,
pyrimidinyl or 1,2,4-triazinyl.
15. The compound of claim 12, wherein one of T. U, V and W is
nitrogen.
16. The compound of claim 12, wherein V is nitrogen and each of T,
U and W is unsubstituted methine group.
17. The compound of claim 1, which is
N-(4-benzoylphenyl)-3-oxospiro[isoin-
doline-1,4'-piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)spir-
o[isoindoline-1,4'-piperidine]-1'-carboxamide,
N-(7-methyl-2-quinolyl)-3-o-
xospiro[isoindoline-1,4'-piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4'-piperidine]-1'-c-
arboxamide,
N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),-
4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)s-
piro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide
3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4'-pipe-
ridine]-1'-carboxamide,
N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquino-
line-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-[1-(2-quinol-
yl)-4-imidazolyl]spiro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoli-
ne-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-N-[5-(2-methyl-1-prope- nyl)-2-pyrazinyl]-3-oxospiro
isoquinoline-1(2H),4'-piperidine]-1'-carboxam- ide,
3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4-
'-piperidine]-1'-carboxamide,
N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-d-
ihydro-3-oxospiro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoqu-
inotine-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-[4-(2-pyr-
idylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide-
,
N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-pipe-
ridine]-1'-carboxamide,
N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3--
oxospiro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),4'-pip-
eridine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]sp-
iro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(2H),4-
'-piperidine]-1'-carboxamide,
N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-ox-
ospiro[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carb-
oxamide,
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4'-piper-
idine]-1'-carboxamide,
N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(-
3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[is-
obenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(7-trifluoromethy- lpyrido[3,2-b]pyridin-2-yl)spiro
isobenzofuran-1(3H),4'-piperidine)-1'-car- boxamide,
3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4'-pip-
eridine]-1'-carboxamide,
3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isoben-
zofuran-1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-3-pyrazolyl- )spiro[isobenzofuran-5
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4'-pipe-
ridine]-1'-carboxamide,
3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzo-
furan-1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(3-fluorophenyl)-2-pyrimid-
inyl]-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofuran-1(-
3H),4'-piparidine]-1'-carboxamide,
N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3--
oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1-
(3H),4'-piperidine]-1'-carboxamide,
3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-y-
l)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
N-(1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly)-3-oxospiro[isobenzofuran-1(3-
H),4'-piperidine]-1'-carboxamide,
N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxo- spiro
[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
N-[1-(3-methoxyphenyl)
-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4'-p-
iperidine]-1'-carboxamide,
6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[is-
obenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
6-fluoro-3-oxo-N-(5-pheny-
l-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4'-piper-
idine]-1'-carboxamide,
5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isob-
enzofuran-1(3H),4'-piperidine]-1'-carboxamide,
N-(4-benzoylphenyl)-3,4-dih-
ydro-3-oxospiro[1H-2-benzopyran-1,4'-piperidine]-1'-carboxamide,
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4'-pipe-
ridine]-1'-carboxamide,
N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1-
H-2-benzopyran-1,4'-piperidine]-1'-carboxamide,
trans-N-(4-benzoylphenyl)--
3'-oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1'(3'H)-isobenzo-
furan]-4-carboxamide,
trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohex-
ane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(5-phenyl-2-pyr-
imidinyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1,1-
'(3'H)-1sobenzofuran]-4-carboxamide,
trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)-
spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1,1'(3'-
H)-isobenzofuran]-4-carboxamide,
trans-N-(4-acetyl-3-trifluoromethylphenyl-
)-3'-oxospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1'(3'H)-i-
sobenzofuran]-4-carboxamide,
trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'-o-
xospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyclohex-
ane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-Prazinyl)spiro[4-azaisobenz-
ofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(3-phenyl-5-iso-
xazolyl)spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1'-c-
yclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisob-
enzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)--
3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4'-pip-
eridine]-1'-carboxamide,
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[is-
obenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
4-fluoro-3-oxo-N-(5-pheny-
l-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4'-pip-
eridine]-1'-carboxamide,
6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobe-
nzofuran-1(3H),4'-piperidine]-1'-carboxamide,
6-hydroxy-3-oxo-N-(5-phenyl--
2-pyrazinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H),1'-c-
yclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-o-
xospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran--
1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(4-phenyl-2-oxazolyl)s-
piro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran--
1(3H),.sub.1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-methylphenyl)-2-p-
yrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxa-
mide,
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azais-
obenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorometh-
ylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohxanc-
]-4'-carboxamide,
trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-o-
xospiro[5-azaisobenzofuran-1(3H),1'-cyclohexanc]-4'-carboxamide,
trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobe-
nzofuran-1(3H),1-cyclohexane]-4'-carboxamide,
trans-N-[4-(3-fluoromethoxyp-
henyl)-2-oxazolyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'--
carboxamide,
trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[-
5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-hydroxyphenyl1)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofura-
n-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrimidi-
nyl)spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzo-
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluoromethoxyphe-
nyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-
-carboxamide,
trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-azaisoben-
zofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-difluoromethox-
yphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]--
4'-carboxamide,
trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospi-
ro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(-
3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(4-fluorophenyl)-3-pyrazoly-
l]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1'-cyclohex-
ane]-4'-carboxamide,
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxosp-
iro[7-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),1'-cyclo-
hexane]-4'-carboxamide,
trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[7-azaiso-
benzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-
-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofuran-1(-
3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)sp-
iro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxamide,
trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxosp-
iro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxamide,
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxosp-
iro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(-
3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-1,2,4-thiadiaz-
ol-3-yl)spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1'-cy-
clohexane]-4'-carboxamide,
trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azais-
obenzofuran-1(3H),1'-cyclohoxane]-4'-carboxamide,
trans-3-oxo-N-(2-phenyl--
3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide
or
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(-
3H),1'-cyclohexane]-4'-carboxamide.
18. The compound of claim 1, which is
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro-
[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide.
19. The compound of claim 1, which is
3-oxo-N-(7-trifluoromethylpyrido[3,2-
-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide.
20. The compound of claim 1, which is
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-
-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide.
21. The compound of claim 1, which is
trans-3'-oxo-N-(5-phenyl-2-pyrimidin-
yl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide.
22. The compound of claim 1, which is
trans-3'-oxo-N-[1-(3-quinolyl)-4-imi-
dazolyl]spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-carboxamide.
23. The compound of claim 1, which is
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)-
spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
24. The compound of claim 1, which is
trans-N-[5-(3-fluorophcnyl)-2-pyrimi-
dinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
25. The compound of claim 1, which is
trans-N-[5-(2-fluorophenyl)-2-pyrimi-
dinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
26. The compound of claim 1, which is
trans-N-[1-(3,5-difluorophenyl)-4-im-
idazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxami-
de.
27. The compound of claim 1, which is
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)-
spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
28. The compound of claim 1, which is
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)-
spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
29. The compound of claim 1, which is
trans-3-oxo-N-(2-phenyl-1,2,3-triazo-
l-4-yl)spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide.
30. A process for producing a compound of the general formula
(I-1): 24wherein Ar.sup.1 represents aryl or heteroaryl which may
be substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo (lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower
alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group represented by formula of
--Q--Ar.sup.2; Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q
represents a single bond or carbonyl; T, U, V and W represent
independently nitrogen atom or methine group which may have a
substituent selected from the group consisting of halogen, lower
alkyl, hydroxy and lower alkoxy, where at least two of them
represent the said methine group; n and Y have the same meanings as
described hereinafter; a salt or ester thereof, which comprises
reacting a compound of the general formula (II): 25wherein
Ar.sup.1p represents aryl or heteroaryl which may be substituted,
the substituent being selected from the group consisting of
halogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl,
lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,
lower alkanoyl, lower alkoxycarbonyl, a group of formula:
--Q.sup.p--Ar.sup.2p, and an optionally protected, lower alkylene
optionally substituted with oxo, hydroxy(lower)alkyl or carboxyl
group; Ar.sup.2p represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower
alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,
aryl, and an optionally protected, hydroxy(lower)alkyl, hydroxy or
lower alkyl amino group; Ar.sup.3 represents phenyl which may be
substituted by halogen or nitro; Q.sup.p represents a single bond
or optionally protected carbonyl; with a compound of formula (III):
26wherein n represents 0 or 1; t, u, v and w represent
independently nitrogen atom or methine group which may have a
substituent selected from the group consisting of halogen, lower
alkyl, lower alkoxy and optionally protected hydroxy, where at
least two of them represent the said methine group; Y represents
imino which may be substituted with lower alkyl, or oxygen atom; to
provide a compound of formula (IV-1): 27wherein Ar.sup.1p, n, t, u,
v, w and Y have the same meanings as described above; optionally
followed by elimination of a protecting group.
31. A process for producing a compound of the general formula
(I-2): 28wherein Ar.sup.1 represents aryl or heteroaryl which may
be substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower
alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group represented by formula of
--Q--Ar; Ar.sup.2, represents aryl or heteroaryl which may be
substituted, the substituent being select,ed from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; Q
represents a single bond or carbonyl; T, U, V and W represent
independently nitrogen atom or methine group which may have a
substituent selected from the group consisting of halogen, lower
alkyl, hydroxy and lower alkoxy, where at least two of them
represent the said methine group; n and Y have the same meanings as
described hereinafter; a salt or ester thereof, which comprises
reacting a compound of formula (V):Ar.sup.1p---NH.sub.2 (V)wherein
Ar.sup.1p represents aryl or heteroaryl which may be substituted,
the substituent being selected from the group consisting of
halogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl,
lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,
lower alkanoyl, lower alkoxycarbonyl, a group of formula:
--Q.sup.p-Ar.sup.2p, and an optionally protected, lower alkylene
optionally substituted with oxo, hydroxy(lower)alkyl or carboxyl
group; Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower
alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,
aryl, and an optionally protected, hydroxy(lower)alkyl, hydroxy or
lower alkyl amine group; Q.sup.p represents a single bond or
optionally protected carbonyl; with a carboxylic acid of the
general formula (VI): 29wherein n represents 0 or 1; t, u, v and w
represent independently nitrogen atom or methine group which may
have a substituent selected from the group consisting of halogen,
lower alkyl, lower alkoxy and optionally protected hydroxy, where
at least two of them represent the said methino group; Y represents
imino which may be substituted with lower alkyl, or oxygen atom; or
a reactive derivative thereof to provide a compound of the general
formula (IV-2): 30wherein Ar.sup.1p, n, t, u, v, w and Y have the
same meanings as described-above; optionally followed by
elimination of a protecting group.
32. Neuropeptide Y receptor antagonist which contains a compound of
the general formula (I): 31wherein Ar.sup.1 represents aryl or
heteroaryl which may be substituted, the substituent being selected
from the group consisting of halogen, nitro, lower alkyl,
halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower
alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,
carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene
optionally substituted with oxo, and a group represented by formula
of --Q--Ar.sup.2; Ar.sup.2 represents aryl or heteroaryl which may
be substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl; n
represents 0 or 1; Q represents a single bond or carbonyl; T, U, V
and W represent independently nitrogen atom or methine group which
may have a substituent selected from the group consisting of
halogen, lower alkyl, hydroxy and lower alkoxy, where at least two
of them represent the said methine group; X represents methine or
nitrogen; Y represents imino which may be substituted with lower
alkyl, or oxygen; a salt or ester thereof as an active
ingredient.
33. An agent for the treatment of bulimia, obesity or diabetes
which contains a compound of the general formula 32wherein Ar.sup.1
represents aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen,
nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy,
lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl,
lower alkylene optionally substituted with oxo, and a group
represented by formula of --Q--Ar.sup.2; Ar.sup.2 represents aryl
or heteroaryl which may be substituted, the substituent being
selected from the group consisting of halogen, cyano, lower alkyl,
halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,
halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower
alkanoyl and aryl; n represents 0 or1; Q represents a single bond
or carbonyl; T, U, V and W represent independently nitrogen atom or
methine group which may have a substituent selected from the group
consisting of halogen, lower alkyl, hydroxy or lower alkoxy, where
at least two of them represent the said methine group; X represents
methine or nitrogen; Y represents imino which may be substituted
with lower alkyl, or oxygen; a salt or ester thereof as an active
ingredient.
34. A compound of the general formula (VI-1): 33wherein t, u, v and
w represent independently nitrogen atom or methine group which may
have a substituent selected from the group consisting of halogen,
lower alkyl, lower alkoxy and optionally protected hydroxy, where
at least two of them represent the said methine group.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is useful in medical fields. In more
detail, novel spiro compounds of this invention are useful as
neuropeptide Y receptor antagonists and as agents for the treatment
of various kinds of cardiovascular disorders, central nervous
system disorders, metabolic diseases, and the like.
[0003] 2. Description of the Prior Art
[0004] Neuropeptide Y (hereinafter referred to as NPY), a peptide
consisting of 36 amino acids, was first isolated from porcine brain
by Tatemoto et al. in 1982 [Nature, 296: 659 (1982)]. NPY is widely
distributed in central nervous system and peripheral nervous system
and plays various roles as one of the most abundant peptide in the
nervous system. That is, NPY acts as an orexigenic substance in the
central nervous system and markedly promotes fat accumulation via
the mediation of the secretion of various hormones or the action of
the nervous system. It is known that the continuous
intracerebroventricular administration of NPY induces obesity and
insulin resistance based on these actions (International Journal of
Obesity, vol. 19: 517 (1995); Endocrinology, vol. 133: 1753
(1993)). It is also known that NPY has central effects, such as
depression, anxiety, schizophrenia, pain, dementia and the like
(Drugs, vol. 52, 371(1996). Further, in the periphery, NPY coexists
with norepinephrine in sympathetic ending and is involved in the
tonicity of the sympathetic nervous system. It is known that
peripheral administration of NPY causes vasoconstriction and
enhances the activities of other vasoconstrictive substances such
as norepinephrine (British Journal of Pharmacology, vol. 95: 419
(1988)). It is also reported that NPY could participate in the
development of cardiac hypertrophy as a result of the sympathic
stimulation (Proceeding National Academic Science USA, Vol. 97,
1595(2000)).
[0005] On the other hand, it is reported that NPY is also involved
in the secretory function of sexual hormones and growth hormone,
sexual behavior and reproductive function, gastrointestinal
motility, bronchoconstriction, inflammation and alcohol preference
(Life Science, vol. 55, 551(1994); The Journal of Allergy and
Immunology, vol. 101, S345(1998); Nature, vol. 396, 366(1998)).
[0006] NPY has a variety of pharmacological effects which result
from NPY binding to the NPY receptors. Other NPY related peptides,
including peptide YY and pancreatic polypeptide also bind to the
NPY receptors. It is known that these pharmacological effects are
mediated by the action of, at least, five receptor subtypes with or
without synergistic interactions. (Trends in Neuroscience, vol. 20,
294(1997)).
[0007] Y1: It is reported that the central effect mediated by NPY
Y1 receptor includes the remarkable orexigenic effect
(Endocrinology, vol. 137, 3177(1996); Endocrinology, vol. 141,
1011(2000)). Further, the Y1 receptor is reported to be involved in
anxietyandpain (Nature, vol. 259, 528(1993); Brain Research, vol.
859, 361(2000)). In addition, the pressor effects mediated by the
strong action of vasoconstriction in the periphery by NPY is also
reported to be mediated by Y1 (FEBS Letters, vol. 362, 192(1995);
Nature Medicine, vol. 4, 722(1998)).
[0008] Y2: It is known that the inhibitory effect on the release of
various neurotransmitters in the sympathetic nerve endings is
mediated by the NPY Y2 receptor (British Journal of Pharmacology,
vol. 102, 41(1991); Synapse, vol. 2, 299(1988)). In periphery, NPY
causes constriction of blood vessel or vas deferens directly or via
the control of release of various neurotransmitters (The Journal of
Pharmacology and Experimental Therapeutics, vol. 261, 863(1992);
British Journal of Pharmacology, vol. 100, 190(1990)). In addition,
inhibition of lipolysis in adipose tissues is known (Endocrinology,
vol. 131, 1970(1992)). Further, the inhibition of ion secretion in
the gastro-intestinal tract is reported (British Journal of
Pharmacology, vol. 101 247(1990)).
[0009] On the other hand, the inhibitory effect on the central
nervous system functions such as memory and anxiety is also
reported (Brain Research, vol. 503, 73(1989); Peptides, vol. 19,
359(1998)).
[0010] Y3: It is reported that NPY Y3 receptor is mainly located at
brainstem and in the heart and is related to regulation of blood
pressure and heart rate (The Journal of Pharmacology and
Experimental Therapeutics, vol. 258, 633(1991); Peptides, vol. 11,
545(1990)). Further, it is known that the Y3 receptor is involved
in the control of catecholamine secretion in adrenal gland ((The
Journal of Pharmacology and Experimental Therapeutics, vol. 244,
468(1988); Life Science, vol. 50, PL7(1992)).
[0011] Y4: NPY Y4 receptor has high affinity for pancreatic
polypeptide. The related pharmacological effects reported to be
mediated by the Y4 receptor include the inhibition of pancreatic
secretion and the gastro-intestinal motility (Gastroenterology,
vol. 85, 1411(1983)). Further, it is reported that NPY enhances the
secretion of the sexual hormone in the central nervous system
(Endocrinology, vol. 140, 5171(1999)).
[0012] Y5: The effect mediated by NPY Y5 receptor includes feeding
stimulation and accumulation of fat (Nature, vol. 382, 168(1996));
American Journal of Physiology, vol. 277, R1428(1999)). It is
reported that the NPY Y5 receptor also mediates some CNS effects,
such as seizure and epilepsy, or pain and the morphine withdrawal
symptoms (Natural Medicine, vol. 3, 761(1997); ProceedingAcademic
Science USA, vol. 96, 13518(1999); The Journal of Pharmacology and
Experimental Therapetics, vol. 284, 633(1998)). In the periphery,
the Y5 receptor is reported to be involved in diuresis and
hypoglicemic effect caused by NPY (British Journal of Pharmacology,
vol. 120, 1335(1998); Endocrinology, vol. 139, 3018(1998)). NPY is
also reported to enhance cardiac hypertrophy as a result of the
sympathic accentuation (Proceeding National Academic Science USA,
Vol. 97, 1595(2000)).
[0013] The effects of NPY occur by binding to the NPY receptors in
the central or peripheral nervous system. Therefore, the action of
NPY can be prevented by blocking the binding to NPY receptors.
Substances antagonize NPY binding to NPY receptors may be useful
for the prophylaxis or treatment of various diseases related to
NPY, such as cardiovascular disorders (for example hypertension,
nephropathy, heart disease, vasospasm), central nervous system
disorders (for example bulimia, depression, anxiety, seizure,
epilepsy, dementia, pain, alcoholism, drug withdrawal), metabolic
diseases (for example obesity, diabetes, hormone abnormality),
sexual and reproductive dysfunction, gastrointestinal motility
disorder, respiratory disorder, inflammation or glaucoma and the
like (Trends in Pharmacological Sciences, 15: 153 (1994); Life
Science, 55, 551(1994); Drugs, vol. 52, 371(1996); The Journal of
Allergy and Immunology, vol. 101, S345(1998); Nature, vol. 396,
366(1998); The Journal of Pharmacology and Experimental
Therapeutics, vol. 284, 633(1998); Trends in Pharmacological
Science, vol. 20, 104(1999); Proceeding National Academic Science
USA, vol. 97, 1595(2000)).
[0014] Recently, according to the investigation of the present
inventors, it has been found that some kind of NPY receptor
antagonist is useful in the prophylaxis or treatment of
hypercholesterolemia, hyperlipidemia and arteriosclerosis
[International application publication WO99/27965].
SUMMARY OF THE INVENTION
[0015] The object of the present invention is to provide novel
medicines which exhibit NPY antagonistic activities.
[0016] The present inventors have discovered that the compounds of
the general formula (I): 2
[0017] wherein Ar.sup.1 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower
alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkylene optionally
substituted with oxo, and a group represented by formula of
--Q--Ar.sup.2;
[0018] Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hydroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl;
[0019] n represents 0 or 1;
[0020] Q represents a single bond or carbonyl;
[0021] T, U, V and W represent independently nitrogen atom or
methine group which may have a substituent selected from the group
consisting of halogen, lower alkyl, hydroxy and lower alkoxy, where
at least two of them represent the said methine group;
[0022] X represents methine group or nitrogen; Y represents imino
which may be substituted with lower alkyl, or oxygen;
[0023] exhibit NPY antagonistic activities and is useful as a
therapeutic agent for treatment of various diseases associated with
NPY, thereby completing the present invention.
[0024] Compounds of the present invention (I) are useful as agents
for the treatment of various diseases related to NPY, that is, for
example cardiovascular disorders (for example hypertension,
nephropathy, heart disease, vasospasm, arteriosclerosis), central
nervous system disorders (for example bulimia, depression, anxiety,
seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal),
metabolic diseases (for example obesity, diabetes, hormone
abnormality, hypercholesterolemia, hyperlipidemia), sexual and
reproductive dysfunction, gastrointestinal disorder, respiratory
disorder, inflammation, or glaucoma, and the like.
[0025] More particulary, compounds of this invention (I) is useful
as agents for the treatment of bulimia, obesity, diabetes, and the
like.
[0026] The present invention refers to compounds of the general
formula (I), the salts or esters thereof, and the process for
production and use.
[0027] In another embodiment, the present invention is related to
the intermediate for producing the compound represented by the
general formula (I). Specifically, it is related to the compound
represented by the general formula (VI-1): 3
[0028] wherein t, u, v and w represent independently nitrogen atom
or methine group which may have a substituent selected from the
group consisting of halogen, lower alkyl, lower alkoxy and
optionally protected hydroxy, where at least two of them represent
the said methine group.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The means of terms used in the present specification are
defined and more detailed description of this invention is shown in
the following.
[0030] "Halogen atom" refers to fluorine atom, chlorine atom,
bromine atom and iodine atom.
[0031] "Lower alkyl" refers to a straight- or branched-chain alkyl
group of C1 to C6, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
isohexyl, and the like.
[0032] "Halo(lower)alkyl" refers to the aforesaid lower alkyl
substituted with 1 or more than 2, preferably 1 to 3 aforesaid
halogen atoms identically or differently at the substitutable,
arbitrary positions, for example, fluoromethyl, difluoromethyl,
trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl,
2-chloroethyl, 1,2-dichloroethyl, bromomethyl, iodomethyl, and the
like.
[0033] "Hydroxy(lower)alkylo" refers to the aforesaid lower alkyl
substituted with 1 or more than 2, preferably 1 or 2 hydroxy groups
at the substitutable, arbitrary positions, for example,
hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl,
1,2-dihydroxyethyl, 3-hydroxypropyl, and the like.
[0034] "Cyclo(lower)alkyl" refers to a cycloalkyl group of C3 to
C6, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and the like.
[0035] "Lower alkenyl" refers to a straight- or branched-chain
alkenyl group of C2 to C6, for example, vinyl, 1-propenyl,
2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl,
1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl,
2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl,
4-pentenyl, and the like.
[0036] "Lower alkoxy" refer to a straight- or branched-chain alkoxy
group of C1-ethyl-1-ethenyl, to C6, for example, methoxy, ethoxy,
propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy,
pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, and the like.
[0037] "Halo(lower)alkoxy" refers to the aforesaid lower alkoxy
substituted with 1 or more than 2, preferably 1 to 3 aforesaid
halogen atoms identically or differently at the substitutable,
arbitrary positions, for example, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy,
chloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy,
iodomethoxy, and the like.
[0038] "Lower alkylthio" refers to a straight- or branched-chain
alkylthio group of C1 to C6, for example, methylthio, ethylthio,
propylthio, isopropylthio, butylthio, sec-butylthio, isobutylthio,
tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio,
and the like.
[0039] "Lower alkanoyl" refers to an alkanoyl group containing the
aforesaid lower alkyl, that is, an alkanoyl group of C2 to C7, for
example acetyl, propionyl, butyryl, isobutyryl, valeryl,
isovaleryl, pivaloyl, and the like.
[0040] "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group
containing the aforesaid lower alkoxy, that is, an alkoxycarbonyl
group of C2 to C7, for example, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and the
like.
[0041] "Lower alkylene optionally substituted with oxo" refers to a
straight- or branched-chain alkylene group of C2 to C6 which may be
substituted with 1 or more than 2, preferably 1 oxo group at a
substitutable, arbitrary position, for example, ethylene,
trimethylene, tetramethylene, pentamethylene, hexamethylene,
1-oxoethylene, 1-oxotrimethylene, 2-oxotrimethylene,
1-oxotetramethylene, 2-oxotetramethylene, and the like.
[0042] "Arylo" includes phenyl, naphthyl, and the like.
[0043] "Heteroaryl" refers to 5- or 6-membered monocylic
heteroaromatic group which contains 1 or more than 2, preferably 1
to 3 hetero atoms identically or differently selected from the
group of oxygen atom, nitrogen atom and sulfur atom; or condensed
heteroaromatic group, where the aforesaid monocylic heteroaromatic
group is condensed with the aforesaid aryl group, or with the
identified or different aforesaid monocylic heteroaromatic group
each other, for example, pyrrolyl, furyl, thienyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl,
1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, indazolyl, purinyl, quinolyl, isoquinolyl,
phthalazyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
pteridinyl, pyrido[3,2-b]pyridyl, and the like.
[0044] "Lower alkylamino" refers to an amino group mono-substituted
with the aforesaid lower alkyl, for example, methylamino,
ethylamino, propylamino, isopropylamino, butylamino,
sec-butylamino, tert-butylamino, and the like.
[0045] "Di-lower alkylamino" refers to an amino group
di-substituted with identical or different aforesaid lower alkyl,
for example, dimethylamino, diethylamino, ethylmethylamino,
dipropylamino, methylpropylamino, diisopropylamino, and the
like.
[0046] The salts of compounds of formula (I) refer to the
pharmaceutically acceptable and common salts, for example, base
addition salt to carboxyl group when the compound has a carboxyl
group, or acid addition salt to amino or basic heterocyclyl when
the compound has an amino or basic heterocyclyl group, and the
like.
[0047] Aforesaid base addition salts include salts with alkali
metals (for example sodium, potassium); alkaline earth metals (for
example calcium, magnesium); ammonium or organic amines (for
example trimethylamine, triethylamine, dicyclohexylamine,
ethanolamine, diethanolamine, triethanolamine, procaine,
N,N'-dibenzylethylenediamine), and the like.
[0048] Aforesaid acid addition salts include salts with inorganic
acids (for example hydrochloric acid, sulfuric acid, nitric acid,
phosphoric acid, perchloric acid), organic acids (for example
maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic
acid, trifluoroacetic acid), sulfonic acids (for example
methanesulfonic acid, isethionic acid, benzenesulfonic acid,
p-toluenesulfonic acid), and the like.
[0049] The esters of compounds of formula (I) refer to, for
example, the pharmaceutically acceptable, common esters on carboxyl
group when the compound has a carboxyl group, for example, esters
with lower alkyls (for example methyl, ethyl, propyl, isopropyl,
butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
cyclopropyl, cyclobutyl, cyclopentyl), aralkyls (for example
benzyl, phenethyl), lower alkenyls (for example allyl, 2-butenyl),
lower alkoxy (lower) alkyls (for example methoxymethyl,
2-methoxyethyl, 2-ethoxyethyl), lower alkanoyloxy(lower)alkyls (for
example acetoxymethyl, pivaloyloxy-methyl, 1-pivaloyloxyethyl),
lower alkoxycarbonyl(lower)alkyls (for example
methoxycarbonylmethyl, isopropoxycarbonylmethyl),
carboxy-(lower)alkyls (for example carboxymethyl), lower
alkoxycarbonyloxy-(lower)alkyls (for example
1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyl-oxycarbonyloxy)ethyl),
carbamoyloxy(lower)alkyls (for example carbamoyloxymethyl),
phthalidyl group, (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl (for
example (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), and the like.
[0050] "An agent for treatment" refers to a medicament which is
employed for the treatment and/or prophylaxis of various
diseases.
[0051] In order to disclose the aforesaid compounds of the general
formula (I) more detailed, the various symbols used in the formula
(I) are explained in more detail by the use of preferred
embodiments.
[0052] Ar.sup.1 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, loweralkoxy,
halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower
alkoxycarbonyl, lower alkylene optionally substituted with oxo, and
a group represented by formula of --Q--Ar.sup.2.
[0053] "Aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen,
nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy,
lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl,
lower alkylene optionally substituted with oxo, and a group
represented by formula of --Q--Ar.sup.2" refers to unsubstituted
aforesaid aryl or aforesaid heteroaryl, or the aforesaid aryl or
aforesaid heteroaryl which has substituent(s) at the substitutable,
arbitrary position(s). The aforesaid substituent can be,
identically or differently, one or more than 2, preferably 1 or 2
selected from the group consisting of halogen, nitro, lower alkyl,
halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower
alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,
carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene
optionally substituted with oxo, and a group of formula:
--Q--Ar.sup.2.
[0054] Halogen atom as the aforesaid substituent includes fluorine
atom, chlorine atom, and the like preferably.
[0055] Lower alkyl as the aforesaid substituent includes methyl,
ethyl, propyl, isopropyl, and the like preferably.
[0056] Halo(lower)alkyl as the aforesaid substituent includes
difluoromethyl, trifluoromethyl, and the like preferably.
[0057] Hydroxy(lower)alkyl as the aforesaid substituent includes
hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, and the
like preferably.
[0058] Cyclo(lower)alkyl as the aforesaid substituent includes
cyclopropyl, cyclobutyl, and the like preferably.
[0059] Lower alkenyl as the aforesaid substituent includes vinyl,
1-propenyl, 2-methyl-1-propenyl, and the like preferably.
[0060] Lower alkoxy as the aforesaid substituent includes methoxy,
ethoxy, and the like preferably.
[0061] Halo(lower)alkoxy as the aforesaid substituents includes
fluoromethoxy, difluoromethoxy, trifluoromethoxy, and the like
preferably.
[0062] Lower alkylthio as the aforesaid substituent includes
methylthio, ethylthio, and the like preferably.
[0063] Lower alkanoyl as the aforesaid substituent includes acetyl,
propionyl, and the like preferably.
[0064] Lower alkoxycarbonyl as the aforesaid substituent includes
methoxycarbonyl, ethoxycarbonyl, and the like preferably.
[0065] Lower alkylene optionally substituted with oxo as the
aforesaid substituent includes 1-oxotetramethylene, and the like
preferably.
[0066] In a group of formula: --Q--Ar.sup.2 as the aforesaid
substituent, Ar.sup.2 represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
hydroxy(lower)alkyl, hidroxy, lower alkoxy, halo(lower)alkoxy,
lower alkylamino, di-lower alkylamino, lower alkanoyl and aryl;
[0067] Q represents a single bond or carbonyl.
[0068] "Aryl or heteroaryl which may be substituted, the
substituent being selected from the group consisting of halogen,
cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy,
lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower
alkylamino, lower alkanoyl and aryl" refers to unsubstituted
aforesaid aryl or aforesaid heteroaryl, or the aforesaid aryl or
aforesaid heteroaryl which has substituent(s) at the substitutable,
arbitrary position(s). The aforesaid substituent can be,
identically or differently, one or not less than 2, preferably 1 or
2 selected from the group consisting of halogen, cyano, lower
alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower
alkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino,
lower alkanoyl and aryl.
[0069] Halogen atom as the aforesaid substituent includes,
preferably, fluorine atom, chlorine atom, and the like.
[0070] Lower alkyl as the aforesaid substituent includes,
preferably, methyl, ethyl, propyl, isopropyl, and the like.
[0071] Halo(lower)alkyl as the aforesaid substituent includes,
preferably, difluoromethyl, trifluoromethyl, and the like.
[0072] Hydroxy(lower)alkyl as the aforesaid substituent includes,
preferably, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl,
and the like.
[0073] Lower alkoxy as the aforesaid substituent includes,
preferably, methoxy, ethoxy, and the like.
[0074] Halo(lower)alkoxy as the aforesaid substituent includes,
preferably, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and
the like.
[0075] Lower alkylamino as the aforesaid substituent includes,
preferably, methylamino, ethylamino, and the like.
[0076] Di-lower alkylamino as the aforesaid substituent includes,
preferably, dimethylamino, diethylamino, and the like.
[0077] Lower alkanoyl as the aforesaid substituent includes,
preferably, acetyl, propionyl, and the like.
[0078] Aryl as the aforesaid substituent includes, preferably,
phenyl, and the like.
[0079] The substituent(s) of Ar.sup.2 include, preferably, halogen,
cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy,
halo(lower)alkoxy, and the like.
[0080] Aryl in Ar.sup.2 includes, preferably, phenyl, and the like
and heteroaryl includes imidazolyl, pyridyl, benzofuranyl,
quinolyl, and the like.
[0081] Consequently, a group of formula: --Q--Ar.sup.2 includes,
for example, phenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,
3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-fluoro-5-methylphenyl,
3-fluoromethylphenyl, 2-trifluoromethylphenyl,
3trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-fluoro-5-methoxyphenyl,
3-fluoromethoxyphenyl, 3-difluoromethoxyphenyl,
3-(2-hydroxyethyl)phenyl, 3-hydroxymethylphenyl,
3-(l-hydroxy-1-methyleth- yl)phenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl,
1,2,4-thiadiazol-5-yl, 1,3,4-thiadiaol-2-yl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,
4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-benzo[b]furanyl,
2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
8-quinolyl, benzoyl, 2-pyridylcarbonyl, and the like, and
preferably, phenyl, 2-fluorophenyl, 3-fluorophenyl,
3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl,
3-trifluoromethylphenyl, 3-difluoromethoxyphenyl,
3-(2-hydroxyethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo[b]furanyl, 2-quinolyl,
3-quinolyl, benzoyl, 2-pyridylcarbonyl, and the like.
[0082] The substituent of Ar.sup.1 includes, preferably, halogen,
lower alkyl, halo(lower)alkyl, lower alkenyl, lower alkanoyl, lower
alkylene optionally substituted with oxo, and a group of formula:
--Q--Ar.sup.2, and the like.
[0083] Aryl in Ar.sup.1 includes, preferably, phenyl, and the like
and heteroaryl of Ar.sup.1 includes pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,
1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl,
pyrido[3,2-b]pyridyl, and the like.
[0084] Consequently, Arl includes, for example, 3-fluorophenyl,
4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3,4-dichlorophenyl, 4-acetylphenyl,
5-oxo-5,6,7,8-tetrahydro-2-naphthyl,
4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,
3-(2-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl,
4-(3-pyridyl)phenyl, 4-(2-ethyl-4-pyridyl)phenyl,
4-(4-pyrimidinyl)phenyl- , 4-benzoylphenyl,
4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-pyrrolyl,
1-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl,
1-(3-fluorophenyl)-4-imidazolyl, 1-(4-fluorophenyl)-4-imidazolyl,
1-(2,3-difluorophenyl)-4-imidazolyl,
1-(2,4-difluorophenyl)-4-imidazolyl,
1-(3,5-difluorophenyl)-4-imidazolyl,
1-(3-chlorophenyl)-4-imidazolyl, 1-(2-cyanophenyl)-4-imidazolyl,
1-(3-cyanophenyl)-4-imidazolyl, 1-(4-cyanophenyl)-4-imidazolyl,
1-(3-trifluoromethylphenyl)-4-imidazolyl,
1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl,
1-[3-(1-hydroxy-1-methylethyl)- phenyl]-4-imidazolyl,
1-(3-methoxyphenyl)-4-imidazolyl,
1-(2-difluoromethoxyphenyl)=-4-imidazolyl,
difluoromethoxyphenyl)-4-imida- zolyl,
1-(4-difluoromethoxy-phenyl)-4-imidazolyl,
1-(2-pyridyl)-4-imidazol- yl, 1-(4-benzo[b]furanyl)-4-imidazolyl,
1-(5-benzo[b]furanyl)-4-imidazolyl- ,
1-(7-benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl,
1-(3-quinolyl)-4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl,
1-(5-quinolyl)-4-imidazolyl, 1-96-quinolyl)-4-imidazolyl,
1-(8-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl,
5-phenyl-3-pyrazolyl, 1-phenyl-4-pyrazolyl,
1-(2-fluorophenyl)-3-pyrazolyl, 5-(2-fluorophenyl)-3-pyrazolyl,
5-(3-fluorophenyl)-3-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl,
1-(4-fluorophenyl)-3-pyrazolyl, 5-(4-fluorophenyl)-3-pyrazolyl,
5-(2-chlorophenyl)-3-pyrazolyl, 5-(3-chlorophenyl)-3-pyrazolyl,
5-(4-chlorophenyl)-3-pyrazolyl,
5-(3-difluoromethoxyphenyl)-3-pyrazolyl,
2-methyl-5-phenyl-3-pyrazolyl, 5-(2-pyridyl)-3-pyrazolyl,
5-(2-quinolyl)-3-pyrazolyl, 5-(3-quinolyl)-3-pyrazolyl,
4-phenyl-2-thiazolyl, 5-phenyl-2-thiazolyl,
5-(3-chlorophenyl)-2-thiazolyl, 5-(4-chlorophanyl)-2-thiazolyl,
5-(4-methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl,
2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl,
4-(2-fluoromethoxyphenyl)-2-oxazolyl,
4-(3-fluoromethoxyphenyl)-2-oxazoly- l, 5-phenyl-3-isoxazolyl,
3-phenyl-5-isoxazolyl, 3-(2-chorophenyl)-5-isoxa- zolyl,
3-(3-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5-isoxazolyl,
3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-1,2,3-triazol-4-yl,
5-phenyl-1,2,4-thiadiazol-3-yl, 5-phenyl-1,3,4-thiadiazol-2-yl,
5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl, 5-(2-pyridyl)-1,
3,4-thiadiazol-2-yl, 5-(2-ethyl-4-pyridyl)-1,3,4-thiadiazol-2-yl,
5-phenyl-2-pyridyl, 6-ph enyl-3-pyridyl, 2-phenyl-4-pyridyl,
5-(2-pyridyl)-2-pyridyl, 5-benzoyl-2-pyridyl, 6-benzoyl-3-pyridyl,
5-chloro-2-pyrazinyl, 5-(2-methyl-1-propenyl)-2-pyrazinyl,
5-acetyl-2-pyrazinyl, 5-propionyl-2-pyrazinyl,
5-phenyl-2-pyrazinyl, 5-(3-hydroxyphenyl)-2-pyrazinyl,
5-(4-hydroxyphenyl)-2-pyrazinyl,
5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl,
5-(1,3,4-thiadiazol-2-yl)-2-pyrazi- nyl, 5-(2-pyridyl)-2-pyrazinyl,
5-(3-pyridyl)-2-pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl,
5-(3-quinolyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,
5-(2-pyridylcarbonyl)-2-pyrazinyl, 5-acetyl-2-pyrimidinyl,
5-acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl,
5-phenyl-2-pyrimidinyl, 6-phenyl-4-pyrimidinyl,
2-phenyl-5-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,
5-(3-fluorophenyl)-2-pyrimidinyl, 5-(4-fluorophenyl)-2-pyrimidinyl,
5-(2-chlorophenyl)-2-pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl,
5-(4-chlorophenyl)-2-pyrimidinyl, 5-(2-methylphenyl)-2-pyrimidinyl,
5-(3-methylphenyl)-2-pyrimidinyl,
5-(2-fluoromethylphenyl)-2-pyrimidinyl,
5-(3-fluoromethylphenyl)-2-pyrimidinyl,
5-(2-trifluoromethylphenyl)-2-pyr- imidinyl,
5-(3-trifluoro-ethyphenyl)-2-pyrimidinyl 5(4-trifluoromethylphen-
yl)-2-pyrimidinyl, 5-(2-hydroxyrnethylphenyl)-2-pyrimidinyl,
5-(3-hydroxymethylphenyl)-2-pyrimidinyl,
5-(2-hydroxyphenyl)-2-pyrimidiny- l, 5-(3-hydroxyphenyl)
-2-pyrirnidinyl, 5-(2-methoxyphenyl)-2-pyrimidinyl,
5-(3-methoxyphenyl)-2-pyrimidinyl,
5-(4-rethoxyphenyl)-2-pyrimidinyl,
5-(2-fluororethoxyphenyl)-2-pyrimidinyl,
5-(3-fluoromethoxyphenyl)-2-pyri- midinyl,
5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl,
5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl, 6-phenyl-3-pyridazinyl,
6-phenyl-1,2,4-triazin-3-yl, 15-chloro-2-benzoxazolyl,
5-fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl,
2-methyl-5-benzothiazolyl, 4-methoxy-2-benzothiazolyl, 3-quinolyl,
6-quinolyl, 7-methyl-2-quinolyl, 2-methyl-6-quinolyl,
6-chloro-2-quinoxalinyl, pyrido[3,2-b]pyridin-2-yl,
7-chloropyrido[3,2-b]pyridin-2-yl,
7-methylpyrido[3,2-b]pyridin-2-yl,
7-trifluoromethylpyrido[3,2-b]pyridin-2-yl,
7-difluoromethoxypyrido[3,2-b- ]pyridin-2-yl,
7-acetylpyrido[3,2-b]pyridin-2-yl, and the like, preferably
3,4-dichlorophenyl, 4-acetylphenyl,
5-oxo-5,6,7,8-tetrahydro-2-naphthyl,
4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,
4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, I-phenyl-3-pyrrolyl,
1-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl,
1-(3,5-difluorophenyl)-4-imidazolyl,
1-(3-chlorophenyl)-4-imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl,
1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl- ,
1-(3-difluoromethoxyphenyl)-4-imidazolyl,
1-(7-benzo[b]furanyl)-4-imidaz- olyl, 1-(2-quinolyl)-4-imidazolyl,
1-(3-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl,
5-phenyl-3-pyrazolyl, 1-phenyl-4-pyrazolyl,
1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-pyrazolyl,
5-(4-chlorophenyl)-3-pyrazolyl, 5-(3-quinolyl)-3-pyrazolyl,
5-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl,
5-(2-methyl-1-propenyl)-2-py- razinyl, 5-phenyl-2-pyrazinyl,
5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,
5-(2-pyridyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,
5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrim- idinyl,
5-(3-fluorophenyl)-2-pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl-
, 5-(3-trifluoromethyl-phenyl)-2-pyrimidinyl,
5-chloro-2-benzoxazolyl, 4-methyl-2-benzothia-zolyl,
7-methyl-2-quinolyl, 7-trifluoromethylpyrido[- 3,2-b]pyridin-2-yl,
and the like, especially 1-phenyl-3-pyrazolyl,
5-phenyl-3-pyrazolyl, 5-phenyl-2-pyrazinyl,
5-(3-hydroxyphenyl)-2-pyrazin- yl, 5-(4-hydroxyphenyl)-2-pyrazinyl,
5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,
5-(3-fluorophenyl)-2-pyrimidinyl,
7-trifluoro-methylpyrido[3,2-b]pyridin-2-yl, and the like.
[0085] n represents 0 or 1, 0 is preferable.
[0086] T, U, V and W represent independently nitrogen atom or
methine which may have a substituent selected from the group
consisting of halogen, lower alkyl, hydroxy and lower alkoxy, where
at least two of them represent the said methine group.
[0087] "Methine which may have a substituent selected from the
group consisting of halogen, lower alkyl, hydroxy and lower alkoxy"
refers to unsubstituted methine or methine having a substituent
which can be selected from the group consisting of halogen, lower
alkyl, hydroxy and lower alkoxy.
[0088] Halogen atom as the aforesaid substituent includes
preferably fluorine atom, chlorine atom, and the like.
[0089] Lower alkyl as the aforesaid substituent includes preferably
methyl, ethyl, and the like.
[0090] Lower alkoxy as the aforesaid substituent includes
preferably methoxy, ethoxy, and the like.
[0091] The aforesaid substituent include preferably halogen, and
the like.
[0092] The preferred mode of T, U, V and W includes, for example,
T, U, V and W are independently methine optionally having the
aforesaid substituent, preferably halogen; or one of T, U, V and W
is nitrogen atom.
[0093] X represents methine or nitrogen.
[0094] Y represents imino which may be substituted with lower
alkyl, or oxygen.
[0095] "Imino which may be substituted with lower alkyl" refers to
unsubstituted imino or imino substituted with lower alkyl.
[0096] The aforesaid lower alkyl includes, preferably, methyl,
ethyl, and the like.
[0097] Y is preferably unsubstituted imino or oxygen, especially
oxygen.
[0098] In more detail, a group of formula (15): 4
[0099] includes a group of formula (16): 5
[0100] and the like.
[0101] Preferred compounds of the general formula (I) are, for
example, compounds of the general formula (I-a): 6
[0102] wherein R.sup.1 represents hydrogen atom or halogen,
Ar.sup.1 has the aforesaid meaning;
[0103] or compounds of the general formula (I-b): 7
[0104] wherein Ar.sup.1, T, U, V and W have the aforesaid
meanings.
[0105] With regard to the compound represented by the general
formula (I-a), the preferred compounds are, for example, the
compounds, wherein the aryl group in Ar.sup.1 is phenyl, or the
heteroaryl group in Ar.sup.1 is imidazolyl, pyrazolyl, isoxazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl or
pyrido[3,2-b]pyridyl.
[0106] With regard to the compound represented by the general
formula (I-b), the preferred compounds are, for example, the
compounds, wherein the aryl group in Ar.sup.1 is phenyl, or the
heteroaryl group in Ar.sup.1 is pyrrolyl, imidazolyl, pyrazolyl,
thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,
1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or
1,2,4-triazinyl.
[0107] Further, with regard to the compound represented by the
general formula (I-b), the preferred compounds are, for example,
the compounds, wherein one of T, U, V and W is a nitrogen atom and
the more preferred compounds are, for example, the compounds
wherein V is a nitrogen atom and T,U as well as W are an
unsubstituted methine group.
[0108] Compounds of this invention may include stereoisomers such
as optical isomers, diastereoisomers and geometrical isomers, or
tautomers depending upon the mode of substituents. Compounds of
this invention include all the stereoisomers, tautomers and their
mixtures.
[0109] For example, compounds of the general formula (I-b) include
stereoisomers such as trans-form compound of the general formula
(I-1b): 8
[0110] and cis-form compound of the general formula (I-2b): 9
[0111] trans form is preferable.
[0112] Also included within the scope of the invention are
polymorphs, hydrates and solvates of the compounds of the instant
invention.
[0113] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds of this invention which are
readily convertible in vivo into the required compound. Thus, in
the methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
conditions described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985,
which is incorporated by reference herein in its entirety.
Metabolites of these compounds include active species produced upon
introduction of compounds of this invention into the biological
milieu.
[0114] The specific compound represented by the general formula (I)
is, for example,
[0115]
N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4'-piperidine]-1'-carb-
oxamide,
[0116]
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4'-piperidine]-1'-
-carboxamide,
[0117]
N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4'-piperidine]-1'--
carboxamide,
[0118]
N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4'-piperidine-
]-1'-carboxamide,
[0119]
N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-pi-
peridine]-1'-carboxamide,
[0120]
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),-
4'-piperidine]-1'-carboxamide,
[0121]
3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4-
'-piperidine]-1'-carboxamide,
[0122]
N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-pip-
eridine]-1'-carboxamide,
[0123] 3,4-dihydro-3-oxo-N-[1-(2-quinolyl)
-4-imidazolyl]spiro[isoquinolin-
e-1(2H),4'-piperidine]-1'-carboxamide,
[0124]
3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoq-
uinoline-1(2H),4'-piperidine]-1'-carboxamide,
[0125]
3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoq-
uinoline-1(2H),4'-piperidine]-1'-carboxamide,
[0126]
3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H)-
,4'-piperidine]-1'-carboxamide,
[0127]
N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoqu-
inoline-1(2H),4'-piperidine]-1'-carboxamide,
[0128]
N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro-
[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide,
[0129]
3,4-dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-
-1(2H),4'-piperidine]-1'-carboxamide,
[0130]
N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-
-piperidine]-1'-carboxamide,
[0131]
N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquino-
line-1(2H),4'-piperidine]-1'-carboxamide,
[0132]
3,4-dihydro-3-oxo-N-(5-phenz1-2-thiazolyl)spiro[isoquinoline-1(2H),-
4'-piperidine]-1'-carboxamide,
[0133]
3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1-
(2H),4'-piperidine]-1'-carboxamide,
[0134]
3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1-
(2H),4'-piperidine]-1'-carboxamide,
[0135]
N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2-
H),4'-piperidine]-1'-carboxamide,
[0136]
N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-l-
'-carboxamide,
[0137]
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4'-piperid-
ine]-1'-carboxamide,
[0138]
N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4'-piperidin-
e]-1'-carboxamide,
[0139]
3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-1(3H),4'-piperid-
ine]-1'-carboxamide,
[0140]
3-oxo-N-(7-trifluoromethylpyrido[3,2-blpyridin-2-yl)spiro[isobenzof-
uran-1(3H),4'-piperidine]-1'-carboxamide,
[0141]
3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4'-piperi-
dine]-1'-carboxamide,
[0142]
3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4'-p-
iperidine]-1'-carboxamide,
[0143]
3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4'-piperidi-
ne]-1'-carlboxamide,
[0144]
N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4-
'-piperidine]-1'-carboxamide,
[0145]
3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4'-pi-
peridine]-1'-carboxamide,
[0146]
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H)-
,4'-piperidine]-1'-carboxamide,
[0147]
3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofu-
ran-1(3H),4'-piperidine]-1'-carboxamide,
[0148]
N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H)-
,4'-piperidine]-1'-carboxamide,
[0149]
N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzof-
uran-1(3H),4'-piperidine)-1'-carboxamide,
[0150] 3-oxo-N-(5-phenyl-1, 2, 4-thiadiazol-3-yl) spiro
[isobenzofuran-1(3H)4'4,-piperidine]-1'-carboxamide,
[0151]
N-(1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly)-3-oxospiro[isobenzofur-
an-1(3H),4'-piperidine]-l'-carboxamide,
[0152]
N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4-
'-piperidine]-1'-carboxamnide,
[0153] N-[1-(3-methoxyphenyl)
-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H- )
.sub.14'-piperidine]-1'-carboxamide,
[0154]
6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4'-
-piperidine]-1'-carboxamide,
[0155]
6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),-
4'-piperidine]-1'-carboxamide,
[0156]
5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4'-
-piperidine]-1'-carboxamide,
[0157]
5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),-
4'-piperidine]-1'-carboxamide,
[0158]
N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4'-pip-
eridine]-1'-carboxamide,
[0159]
3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4-
'-piperidine]-1'-carboxamide,
[0160]
N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,-
4'-piperidine]-1'-carboxamide,
[0161]
trans-N-(4-benzoylphenyl)-3'-oxospiro[cyclohexane-1,1'(3'H)-isobenz-
ofuran]-4-carboxamide,
[0162]
trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1'(3'H)-is-
obenzofuran]-4-carboxamide,
[0163]
trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1'(3'H)-i-
sobenzofuran]-4-carboxamide,
[0164]
trans-3'-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1'(3'H)--
isobenzofuran]-4-carboxamide,
[0165]
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexa-
ne-1,1'(3.sup.1'H)-isobenzofuran]-4-carboxamide,
[0166]
trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1'(3'H)-is-
obenzofuran]-4-carboxamide,
[0167]
trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1-
,1'(3'H)-isobenzofuran]-4-carboxamide,
[0168]
trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'-oxospiro[cyclohexane--
1,1'(3'H)-isobenzofuran]-4-carboxamide,
[0169]
trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1'(-
3'H)-isobenzofuran]-4-carboxamide,
[0170]
trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1,-
1'(3'H)-isobenzofuran]-4-carboxamide,
[0171]
trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),l'-cy-
clohexane]-4'-carboxamide,
[0172]
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),-
l'-cyclohexane]-4'-carboxamide,
[0173]
trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-azaisobenzofuran-1(3H)-
,1'-cyclohexane]-4'-carboxamide,
[0174]
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H-
),l'-cyclohexane]-4'-carboxamide,
[0175]
trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cy-
clohexane]-4'-carboxamide,
[0176]
trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cy-
clohexane]-4'-carboxamide,
[0177]
N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3HI)-
,4'-piperidine]-1'-carboxamide,
[0178]
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),-
4'-piperidine]-1'-carboxamide,
[0179]
4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),-
4'-piperidine]-1'-carboxamide,
[0180]
7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),-
4'-piperidine]-1'-carboxamide,
[0181]
6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4'--
piperidine]-1'-carboxamide,
[0182]
6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4-
'-piperidine]-1'-carboxamide,
[0183]
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H-
),1'-cyclohexane]-4'-carboxamide,
[0184]
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
[0185]
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
[0186]
trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1(3H),l-
'-cyclohexane]-4'-carboxamide,
[0187]
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
[0188]
trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),l'-cyclohexane]-4'-carboxamide,
[0189]
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azai-
sobenzofuran-1(3H),l'-cyclohexane]-4'-carboxamide,
[0190]
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azais-
obenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0191]
trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-a-
zaisobenzofuran-1(3H),l'-cyclohexane]-4'-carboxamide,
[0192]
trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-az-
aisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0193]
trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl]-3-oxospiro[5-azaisob-
enzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0194]
trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azai-
sobenzofuran-1(3H),l'-cyclohexane]-4'-carboxamide,
[0195]
trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenz-
ofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0196]
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1(3H-
),l'-cyclohexane]-4'-carboxamide,
[0197]
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azais-
obenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0198]
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azai-
sobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0199] trans-3-oxo-N-(6-phenyl-1,2
4-triazin-3-yl)spiro[6-azaisobenzofuran-
-1(3H),l'-cyclohexane]-4'-carboxamide,
[0200]
trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azai-
sobenzofuran-1(3H),l'-cyclohexane]-4'-carboxamide,
[0201]
trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azai-
sobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0202]
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0203]
trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0204]
trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1'-cy-
clohexane]-4'-carboxamide,
[0205]
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobe-
nzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0206]
trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),l'-
-cyclohexane]-4'-carboxamide,
[0207]
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),-
l'-cyclohexane]-4'-carboxamide,
[0208]
trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),l-
'-cyclohexane]-4'-carboxamide,
[0209]
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofu-
ran-1(3H),l'-cyclohexane]-4'-carboxamide,
[0210]
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),-
l'-cyclohexane]-4'-carboxamide,
[0211]
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),-
l'-cyclohexane]-4'-carboxamide,
[0212]
trans-N-[l-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0213]
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),-
l'-cyclohexane]-4'-carboxamide,
[0214]
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0215]
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0216]
trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0217]
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H)-
,l'-cyclohexane]-4'-carboxamide,
[0218]
trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(3H),l'-
-cyclohexane]-4'-carboxamide,
[0219]
trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide or
[0220]
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-
-1(3H),1'-cyclohexane]-4'-carboxamide.
[0221] Among these compounds, the preferable compound is, for
example,
[0222]
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4'-piperid-
ine]-1'-carboxamide,
[0223]
3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzof-
uran-1(3H),4'-piperidine]-1'-carboxamide,
[0224]
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H)-
,4'-piperidine]-1'-carboxamide,
[0225]
trans-3'-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1'(3'H)--
isobenzofuran]-4-carboxamide,
[0226]
trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1'(-
3'H)-isobenzofuran]-4-carboxamide,
[0227]
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide,
[0228]
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),l'-cyclohexane]-4'-carboxamide,
[0229]
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1(3H),1'-cyclohexane]-4'-carboxamide,
[0230]
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobe-
nzofuran-1(3H),1'-cyclohexane]-4'-carboxamide,
[0231]
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide,
[0232]
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide or
[0233]
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-
-1(3H),1'-cyclohexane]-4'-carboxamide.
[0234] The process for producing compounds of this invention is
illustrated as follows.
[0235] Compounds of this invention (I) can be synthesized, for
example, by the following processes for production or the processes
shown in examples, but these embodiments are not intended to
restrict the process for producing compounds of this invention
(I).
[0236] Production Process 1
[0237] A compound of the general formula (II): 10
[0238] wherein Ar.sup.1p represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, nitro, lower alkyl, halo(lower)alkyl,
cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy,
lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, a group of
formula: --Q.sup.P--Ar.sup.2p, and an optionally protected, lower
alkylene optionally substituted with oxo, hydroxy(lower)alkyl or
carboxyl group;
[0239] Ar.sup.2p represents aryl or heteroaryl which may be
substituted, the substituent being selected from the group
consisting of halogen, cyano, lower alkyl, halo(lower)alkyl, lower
alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,
aryl, and an optionally protected hydroxy(lower)alkyl, hydroxy or
lower alkyl amino group;
[0240] Ar.sup.3 represents phenyl which may be substituted by
halogen or nitro;
[0241] Q.sup.P represents a single bond or optionally protected
carbonyl; is reacted with a compound of the general formula (III):
11
[0242] wherein n, t, u, v, w and Y have the same meanings as
mentioned above;
[0243] to provide a compound of the general formula (IV-1): 12
[0244] wherein Ar.sup.1p, n, t, u, v, w and Y have the same
meanings as mentioned above;
[0245] optionally followed by elimination of a protective group to
give a compound of the general formula (I-1): 13
[0246] wherein Ar.sup.1, n, T, U, V, W and Y have the same meanings
as mentioned above.
[0247] This production process refers to the process for producing
a compound of the general formula (I), wherein X is nitrogen, that
is, a compound of the general formula (I-1).
[0248] When a reactant has an amino, hydroxy, carboxyl, oxo,
carbonyl, or the like group which does not participate in the
reaction, the reaction may be carried out after protecting the
amino, hydroxy, carboxyl, oxo, carbonyl, or the like group with an
amino protecting group, hydroxy protecting group, carboxyl
protecting group, or oxo- or carbonyl-protecting group, followed by
deprotection after completion of the reaction.
[0249] "Amino protecting group" includes aralkyl (for example
benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,
p-nitrobenzyl, benzhydryl, trityl); lower alkanoyl (for example
formyl, acetyl, propionyl, butyryl, pivaloyl); benzoyl;
arylalkanoyl (for example phenylacetyl, phenoxyacetyl); lower
alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl,
propyloxycarbonyl, tert-butoxycarbonyl); aralkyloxycarbonyl (for
example benzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
phenethyloxycarbonyl); lower alkylsilyl (for example
trimethylsilyl, tert-butyldimethylsilyl); and the like, especially
acetyl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, and
the like.
[0250] "Hydroxy protectuing group" includes lower alkyl (for
example methyl, ethyl, propyl, isopropyl, tert-butyl); lower
alkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl);
lowerl alkoxymethyl (for example methoxymethyl,
2-methoxyethoxymethyl); tetrahydropyranyl;
trimethylsilylethoxymethyl; aralkyl (for example benzyl,
p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
trityl); acyl (for example formyl, acetyl), and the like,
especially methyl, methoxymethyl, tetrahydropyranyl, trityl,
trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl, and
the like.
[0251] "Carboxyl protecting group" includes lower alkyl (for
example methyl, ethyl, propyl, isopropyl, tert-butyl); lower
haloalkyl (for example 2,2,2-trichloroethyl); lower alkenyl (for
example 2-propenyl); aralkyl (for example benzyl, p-methoxybenzyl,
p-nitrobenzyl, benzhydryl, trityl); and the like, especiallymethyl,
ethyl, tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl, benzhydryl,
and the like.
[0252] "Oxo- or carbonyl-protecting group" includes acetal or ketal
(for example ethylene ketal, trimethylene ketal, dimethyl ketal),
and the like.
[0253] The reaction between a compound of the general formula (II)
and a compound of the general formula (III) is usually carried out
by employing an equivalent to excessive mole, preferably an
equivalent to 1.5 moles of compound (III) based on 1 mole of
compound (II).
[0254] The reaction is usually carried out in an inert solvent, and
as the inert solvent, made is use of, for example, methylene
chloride, chloroform, tetrahydrofuran, dimethylformamide, dimethyl
sulfoxide or the mixture, and the like, preferably.
[0255] The aforesaid reaction may be preferably carried out in the
presence of base, including organic bases (for example
triethylamine, diisopropylethylamine, pyridine,
4-dimethylaminopyridine) or inorganic bases (for example sodium
hydroxide, potassium hydroxide), and the like.
[0256] The amount of the aforesaid base employed is usually an
equivalent to excessive mole, preferably 1 to 5 moles based on 1
mole of a compound of the general formula (II).
[0257] Reaction temperature is usually -30.degree. C. to
200.degree. C. preferably 20.degree. C. to 100.degree. C.
[0258] Reaction time is usually 5 minutes to 7 days, preferably 30
minutes to 24 hours.
[0259] At the conclusion of the reaction, the crude product of a
compound of the general formula (IV-1) can be obtained by usual
treatment. Thus obtained compound (IV-1) is purified by the
conventional method, or not purified, if necessary followed by
optional combination of elimination reaction of amino-, hydroxy-,
carboxyl-, oxo- and carbonyl-protecting group to give a compound of
the general formula (I-1).
[0260] The elimination of protecting groups may be carried out
depending upon the kinds of the aforesaid protecting groups, the
stability of a desired compound (I-1) and so on, for example, by
the manner described in the literature [Protective Groups in
Organic Synthesis, T. W. Greene, John Wiley & Sons, (1981)] or
its similar manner, for example, solvolysis using acid or base,
that is, for example 0.01 mole to a large excess of acid,
preferably trifluoroacetic acid, formic acid, hydrochloric acid, or
the like, or an equivalent mole to a large excess of base,
preferably potassium hydroxide, calcium hydroxide, or the like;
chemical reduction using metallic complex hydride, or the like; or
catalytic reduction using palladium-carbon catalyst, Raney nickel
catalyst, or the like.
[0261] Production Process 2
[0262] A compound of the general formula (V):
Ar.sup.1p--NH.sub.2 (V)
[0263] wherein Ar.sup.1p has the same meaning as mentioned
above;
[0264] is reacted with a carboxylic acid of the general formula
(VI): 14
[0265] wherein n, t, u, v, w and Y have the same meanings as
mentioned above;
[0266] or its reactive derivative to provide a compound of the
general formula (IV-2): 15
[0267] wherein Ar.sup.1p, n, t, u, v, w and Y have the same
meanings as mentioned above;
[0268] optionally followed by elimination of a protecting group to
give a compound of the general formula (I-2): 16
[0269] wherein Ar.sup.1, n, T, U, V, W and Y have the same meanings
as mentioned above.
[0270] This production process refers to the process for producing
compounds of the general formula (I), wherein X is methine, that
is, a compound of the general formula (I-2).
[0271] Reaction between a compound of the general formula (V) and a
carboxylic acid of the general formula (VI) is usually carried out
by employing 0.5 mole to excessive moles, preferably 1 mole to 1.5
mole of carboxylic acid (VI) based on 1 mole of compound (V).
[0272] The reaction is usually carried out in an inert solvent, and
preferable examples of the inert solvent include methylene
chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine
or a mixture thereof, and the like.
[0273] The aforesaid reaction is preferably carried out in the
presence of condensing agents, for example N,
N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodilmi- de,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium
hexafluorophosphate,
benzotriazol-1-yloxy-tris-pyrrolidinophosphonium
hexafluorophosphate, bromotris-(dimethylamino)phosphonium
hexafluorophosphate, diphenylphosphoryl azide,
1,1'-carbonyldiimidazole, or the like.
[0274] The aforesaid condensing agent is usually employed at 1 mole
to excessive mole, preferably.1 mole to 1.5 moles based on 1 mole
of compound (VI).
[0275] Reaction temperature is usually -50.degree. C. to
100.degree. C. preferably -20.degree. C. to 50.degree. C.
[0276] Reaction time is usually 30 minutes to 7 days, preferably 1
hour to 24 hours.
[0277] A compound of formula (I-2) is also produced by reacting a
compound of the general formula (V) with a reactive derivative of
the carboxylic acid (VI) instead of the carboxylic acid (VI).
[0278] The reactive derivatives of carboxylic acid of the general
formula (VI) include acid halides, mixed acid anhydrides, activated
esters, activated amides, and the like.
[0279] The acid halides of carboxylic acid of the general formula
(VI) may be obtained by reacting a carboxylic acid of the general
formula (VI) with a halogenating agent according to the
conventional method. Halogenating agent includes thionyl chloride,
phosphorus trichloride, phosphorus pentachloride, phosphorus
oxychloride, phosphorus tribromide, oxalyl chloride, phosgene, and
the like.
[0280] The mixed acid anhydrides of carboxylic acid of the general
formula (VI) may be obtained by reacting a carboxylic acid of the
general formula (VI) with alkyl chlorocarbonate (for example ethyl
chlorocarbonate); aliphatic carboxylic acid chloride (for example
pivaloyl chloride), and the like according to the conventional
method.
[0281] The activated esters of carboxylic acid of the general
formula (VI) may be obtained by reacting a carboxylic acid of the
general formula (VI) with N-hydroxy compound (for example
N-hydroxysuccinimide, N-hydroxyphthalimide,
1-hydroxybenzotriazole); phenol compound (for example
4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol,
pentachlorophenol), or the like in the presence of a condensing
agent (for example N, N'-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-- ethylcarbodi-imide) according to the
conventional method.
[0282] The activated amides of carboxylic acid of the general
formula (VI) may be obtained by reacting a carboxylic acid of the
general formula (VI) with for example 1,1'-carbonyldiimidazole,
1'-carbonylbis(2-methylimidazo- le), or the like according to the
conventional method.
[0283] Reaction between a compound of the general formula (V) and a
reactive derivative of the carboxylic acid of the general formula
(VI) is usually carried out by employing 0.5 mole to excessive
mole, preferably 1 mole to 1.5 moles of the reactive derivative of
carboxylic acid (VI) based on 1 mole of compound (V).
[0284] The reaction is usually carried out in an inert solvent, and
preferable examples of the inert solvent include methylene
chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine
or a mixture thereof, and the like.
[0285] The aforesaid reaction proceeds in the absence of bases, but
it is preferable to carry out the reaction in the presence of bases
to promote the reaction smoothly.
[0286] The aforesaid bases include organic bases (for example
triethylamine, diisopropylethylamine, pyridine,
4-dimethylaminopyridine) or inorganic bases (for example sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, sodium hydrogen carbonate), and the like.
[0287] It is preferable to employ 1 mole to excessive mole of the
aforesaid base to 1 mole of a compound of the general formula (V).
When the aforesaid base is liquid, the aforesaid base can also be
used as a solvent.
[0288] Reaction temperature is usually -50.degree. C. to
100.degree. C. preferably -20.degree. C. to 50.degree. C.
[0289] Reaction time is usually 5 minutes to 7 days, preferably 30
minutes to 24 hours.
[0290] A compound of the general formula (I-2) can be produced by
treating a reaction mixture in the usual way after deprotection if
the product has a protecting group at the conclusion of the
reaction, or by treating the mixture directly in the usual way if
the protective group is absent.
[0291] Elimination of the protecting groups and post-treatment, and
the like can be carried out according to the method described in
the aforesaid production process 1.
[0292] Compounds of the general formula (I-1) or (I-2) may readily
be isolated and purified by the conventional separation technique,
for example, solvent extraction, recrystallization, column
chromatography, preparative thin layer chromatography, or/and the
like.
[0293] These compounds may be converted into the pharmaceutically
acceptable salts or esters by the conventional method, on the
contrary, the conversion of the salts or esters into free compounds
may also be carried out according to the conventional method.
[0294] Compounds of the general formula (II), (III), (V) or (VI)
are commercially available, or are prepared according to the
methods described in the literature [Japanese Patent Unexamined
Publication No. 94/263737-A, U.S. Pat. No. 3,301,857, J. Org. Chem,
40: 1427 (1975), International Patent Publication WO95/28389 or the
like], or analogous methods thereto or the methods shown below or
in Examples, optionally in combination. 17
[0295] wherein L.sup.1 represents halogen; Ar.sup.1p and Ar.sup.3
have the same meanings as given above;
[0296] This process refers to a process for producing a compound of
the general formula (II). Compound (II) is prepared by reacting a
compound of the general formula (V) with a compound of the general
formula 1 according to this process.
[0297] The reaction between a compound (V) and a compound 1 is
usually carried out by employing 0.5 mole to excessive mole,
preferably an equivalent to 1.5 moles of compound 1 based on 1 mole
of compound (V).
[0298] The reaction is usually carried out in an inert solvent, and
the preferable examples of the inert solvent include methylene
chloride, chloroform, tetrahydrofuran, ethyl ether, benzene,
toluene, dimethylformamide or a mixture thereof, and the like.
[0299] It is preferable to carry out the reaction in the presence
of bases. The aforesaid bases include organic bases (for example
triethylamine, diisopropylethylamine, pyridine,
4-dimethylaminopyridine) or inorganic bases (for example sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, sodium hydrogen carbonate), and the like.
[0300] It is preferable to employ an equivalent to excessive mole
of the aforesaid base to 1 mole of a compound (V). When the
aforesaid base is liquid, the aforesaid base can be used also as a
solvent.
[0301] Reaction temperature is usually -78.degree. C. to
100.degree. C. preferably -20.degree. C. to 50.degree. C.
[0302] Reaction time is usually 5 minutes to 7 days, preferably 30
minutes to 24 hours.
[0303] Compounds of formula I are commercially available, or are
prepared according to the conventional method, the methods
described in Examples, or the like methods, optionally in
combination. 18
[0304] wherein P.sup.1 represents an amino protecting group;
[0305] R.sup.10 represents hydrogen, nitro, lower alkyl or lower
alkoxy;
[0306] L.sup.1, t, u, v and w have the same meanings as given
above.
[0307] This process refers to a process for producing compounds of
the general formula (III-1). Compound (III-1) may so be prepared by
the present process that a compound of the general formula X is
subjected to dehydrogenated condensation with a compound of the
general formula 3 to give a compound of the general formula 4,
which is subjected to reaction with a compound of the general
formula 5 in the presence of a base to yield a compound of the
general formula 6 and then the compound 6 is cyclized by an
intra-molecular Heck reaction to give a compound of the general
formula 7, and then the compound 7is subjected to reduction,
optionally followed by elimination of amino protecting group
P.sup.1.
[0308] Amino protecting group p1 includes the amino protecting
groups described in the aforesaid production process 1.
[0309] A step for preparing compound 4 by dehydrogenated
condensation of compound 2 with compound 3 is usually carried out
in an inert solvent, for example benzene, toluene, or the like.
[0310] Reaction temperature is preferably from room temperature to
the boiling point of a solvent used and reaction time is preferably
from 30 minutes to 24 hours.
[0311] A step for preparing compound 6 from compound 4 is usually
carried out in an inert solvent (for example benzene, toluene,
methylene chloride, chloroform, acetonitrile, dimethylformamide) in
the presence of base (for example triethylamine,
diisopropylethylamine, pyridine, 4-dimethylaminopyridine).
[0312] Reaction temperature is preferably from 0.degree. C. to the
boiling point of a solvent used and reaction time is preferably
from 30 minutes to 24 hours.
[0313] So-called intramolecular Heck reaction well known in the
field of organic chemistry can be applied to the step for preparing
compound 7 from compound 6.
[0314] The aforesaid step is usually carried out in an inert
solvent (for example benzene, toluene, tetrahydrofuran,
acetonitrile, dimethylformamide, N-methylpyrrolidone) in the
presence of palladium catalyst (for example palladium acetate,
palladium chloride), phosphine ligand (for example
triphenylphosphine, tri-2-furylphosphine) and base (for example
potassium carbonate, triethylamine), optionally additives (for
example tetraethylammonium chloride).
[0315] Reaction temperature is preferably from room temperature to
the boiling point of a solvent used in reaction and reaction time
is preferably from 30 minutes to 24 hours.
[0316] As a method for reduction in the step for preparing compound
(III-1) from compound 7, for example catalytic reduction is
preferable.
[0317] The catalytic reduction is usually carried out in an inert
solvent (for example methanol, ethanol, methylene chloride,
chloroform, tetrahydrofuran, dimethylformamide, acetic acid) in the
presence of a catalyst such as palladium-carbon at 1 to 50
atmospheric pressure of hydrogen.
[0318] Reaction temperature is preferably from room temperature to
the boiling point of a solvent used and reaction time is preferably
from 30 minutes to 24 hours.
[0319] At the conclusion of the reaction, if a reaction product has
a protecting group, compound (III-1) can be prepared by elimination
of the protecting group.
[0320] Elimination of a protecting group can be carried out
according to the method described in the aforesaid production
process 1.
[0321] This step may also be carried out by elimination of the
protecting group of compound 7, followed by reduction of the
resulting compound.
[0322] Compounds of the general formula 2, 3 or 5 are commercially
available, or may be prepared according to the conventional method,
the methods shown in Examples, or the like methods, optionally in
combination. 19
[0323] wherein L.sup.2 represents hydrogen or halogen;
[0324] Ph represents phenyl;
[0325] y.sup.1 represents oxygen or imino substituted with lower
alkyl or aryl;
[0326] t, u, v and w have the same meanings as given above.
[0327] This production process refers to the process for preparing
compound of the general formula (VI-1). The compound represented by
the general formula of (VI-1) is novel compound, which is not
disclosed in the literature. The compound can be produced according
to the present production process, that is, a compound of the
general formula 8 is subjected to lithiation, reaction with
compound 9 and lactonization with an acid, followed by deketalation
to yield a compound of the general formula 10; and 1) methylene
group is introduced to the compound 10, which is followed by
hydroboration to give a compound of the general formula 11, and the
compound is subjected to oxidation reaction, or 2) the compound 10
is reduced to give a compound of the general formula 12, which is
subjected to introduction of a leaving group and then cyanization
to give a compound of the general formula 13, followed by
hydrolysis of the compound 13 at the cyano group.
[0328] Lithiation in the step preparing compound 10 from compound 8
is usually carried out by allowing compound 8 to be acted on by an
organic lithium reagent (for example n-butyllithium, lithium
2,2,6,6-tetramethyl-piperidide) in an inert solvent (for example
tetrahydrofuran, diethyl ether).
[0329] Reaction temperature is usually from -120.degree. C. to
0.degree. C., preferably from -100.degree. C. to -50.degree. C. and
reaction time is preferably from 1 hour to 4 hours.
[0330] Reaction between the resulting lithio type and a ketone of
the general formula 9 is usually carried out in an inert solvent
(for example tetrahydrofuran, diethyl ether).
[0331] Reaction temperature is preferably from -100.degree. C. to
room temperature and reaction time is preferably from 10 minutes to
2 hours.
[0332] The resulting compound can be lactonized by treating with an
acid (for example hydrochloric acid, sulfuric acid).
[0333] Reaction temperature is preferably from 0.degree. C. to the
boiling point of a solvent used and reaction time is preferably
from 30 minutes to 8 hours.
[0334] Compound 10 can be prepared by subjecting the resulting
lactone type to deketalation according to the conventional
method.
[0335] Reaction temperature is preferably from 50.degree. C. to the
boiling point of a solvent used and reaction time is preferably
from 1 hour to 24 hours.
[0336] The method used for converting oxo group to hydroxymethyl
group, which As well known in the field of organic chemistry, can
be applied to the step for preparing compound 11 from compound 10
and the step is usually carried out by reacting compound 10 with
for example methylenetriphenylphosphorane to introduce a methylene
group, followed by hydroboration in an inert solvent (for example
benzene, toluene, methylene chloride, chloroform, acetonitrile,
tetrahydrofuran, dimethylformamide).
[0337] In both steps for introducing methylene group and for
hydroboration, reaction temperature is preferably from 0.degree. C.
to the boiling point of a solvent used and reaction time is
preferably from 30 minutes to 8 hours.
[0338] The method used for oxidizing hydroxymethyl group to
carboxyl group, which is well known in the field of organic
chemistry, can be applied to the step for preparing compound (VI-1)
from compound 11 and the step is usually carried out by using an
oxidizing agent such as sodium periodate and a catalytic amount of
ruthenium chloride, in an inert solvent (for example benzene,
toluene, methylene chloride, chloroform, acetonitrile,
dimethylformamide).
[0339] Reaction temperature is preferably from 0.degree. C. to the
boiling point of a solvent used and reaction time is preferably
from 30 minutes to 8 hours.
[0340] The method used for reducing oxo group to hydroxyl group,
which is well known in the field of organic chemistry, can be
applied to the step for preparing compound 12 from compound 10 and
the step is usually carried out by using a reducing agent (for
example sodium borohydride, lithium borohydride), in an inert
solvent (for example water, methanol, ethanol, tetrahydrofuran or a
mixture thereof).
[0341] Reaction temperature is preferably from -20.degree. C. to
50.degree. C. and reaction time is preferably from 10 minutes to 4
hours.
[0342] The method used for converting hydroxy group to cyano group,
which is well known in the field of organic chemistry, can be
applied to the step for preparing compound 13 from compound 12 and
the step is usually carried out by reacting compound 12 with for
example methanesulfonyl chloride, p-toluenesulfonyl chloride, or
the like to convert hydroxy group to a leaving group in the
presence of base (for example triethylamine, pyridine), followed by
reacting the resulting compound with a cyanide (for example sodium
cyanide, potassium cyanide, tetraethylammonium cyanide,
tetrabutylammonium cyanide).
[0343] The step for converting hydroxy group to a leaving group is
usually carried out in an inert solvent (for example
methylenechloride, chloroform, ethylacetate, acetonitrile,
tetrahydrofuran, dimethylformamide). Reaction temperature is
preferably from -20.degree. C. to room temperature and reaction
time is preferably from 10 minutes to 8 hours.
[0344] The step for reacting with a cyanide is usually carried out
in an inert solvent (for example tetrahydrofuran, dioxane,
dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide).
Reaction temperature is preferably from 50 to 120.degree. C. and
reaction time is preferably from 2 to 24 hours.
[0345] Hydrolysis of cyano group, which is well known in the field
of organic chemistry, can be applied to the step for preparing
compound (VI-1) by hydrolysis of the cyano group of compound 13 and
the step is usually carried out by using an acid (for example
hydrochloric acid, sulfuric acid) or a base (for example sodium
hydroxide, potassium hydroxide, calcium hydroxide), in a solvent
(for example methanol, ethanol, tetrahydrofuran, dioxane, water or
a mixture thereof).
[0346] Reaction temperature is preferably from 50.degree. C. to the
boiling point of a solvent used and reaction time is preferably
from 1 to 48 hours.
[0347] Compounds of the general formula (VI-1) have two kinds of
stereoisomers represented by the general formula (VI-1-a) or
(VI-1-b): 20
[0348] wherein t, u, v and w have the same meanings as given
above.
[0349] These stereoisomers can be separated from the mixture by the
conventional method such as chromatography, fractional
recrystallization, and the like.
[0350] Compounds of the general formula (VI-1-a) or (VI-1-b) can be
prepared by using an intermediate product which is obtained by
separation of the stereoisomers of the general compound 11, 12 or
13.
[0351] Compounds of the general formula 8 or 9 are commercially
available, or are prepared according to the conventional method,
the methods described in Examples, or the like methods, optionally
in combination.
[0352] The utility of compounds of the present invention as a
medicament is proved by describing NPY antagonistic activity, for
example, in the following pharmacological tests.
[0353] Pharmacological Test 1 (NPY binding inhibition test) CDNA
sequence encoding human NPY Y5 receptor [International patent
publication number WO96/16542] was cloned into expression vectors
pcDNA3, pRc/RSV (made by Invitrogen Inc.) and pCI-neo (made by
Promega Inc.). This obtained expression vectors were transfected to
host cells COS-7, CHO and LM(tk-) (American Type Culture
Collection) by cationic lipid method [Proceedings of the National
Academy of Sciences of the United States of America, 84:
7413(1987)] to give NPY Y5 receptor expression cells.
[0354] A membrane sample prepared from the cells which expressed
NPY Y5 receptor was incubated together with a test compound and
[.sup.125I]peptideYY (NEN) (20,000 cpm) in an assay buffer (25mM
Tris buffer, pH7.4, containing 10 mM magnesium chloride, 1 mM
phenylmethylsulfonyl fluoride, 0.1% bacitracin and 0.5% bovine
serum albumin) at 25.degree. C. for 2 hours, then filtered through
a glass filter GF/C and washed with 5mM Tris buffer (pH7.4)
containing 0.3% BSA. The radioactivity of the cake on the glass
filter was measured. Nonspecific binding was measured in the
presence of 1 .mu.M peptideYY and a 50% Inhibitory Concentration
(IC50) of the test compound against specific peptideYY binding was
determined [Endocrinology, 131: 2090(1992)]. The results are
summarized in Table 1.
[0355] [Table 1]
[0356] Inhibitory activities on NPY receptor binding
1 Compounds IC50 (nM) Example 1 1.2 Example 9 0.72 Example 23 1.9
Example 26 2.5 Example 32 0.91 Example 44 1.5 Example 50 0.48
Example 55 0.59
[0357] As shown above, compounds of this invention potently
inhibited peptideYY (NPY homologue) binding to NPY Y5
receptors.
[0358] Pharmacological Test 2 (Antagonistic effect on bPP-induced
feeding behavior)
[0359] A guide cannula (external diameter 0.8 mm, internal diameter
0.5 mm, length 10 mm) was inserted stereotaxicly into the right
lateral ventricle of male SD rats (7-8 weeks old, 200-300 g)
anesthetized with pentobarbital (single intraperitoneal
administration of 50 mg/kg) and fixed by dental resin. The top of
the cannula was located 0.9 mm behind bregma, 1.2 mm to the right
of median line and 1.5 mm depth from the brain surface so that,
when injection needle is inserted into the guide cannula, the
needle extends 2 mm beyond the tip of the guide cannula and reaches
the lateral ventricle. After about 1-week recovery period, bovine
pancreatic polypeptide (bPP, 5 .mu.g/10 .mu.L/head, 0.01 M, pH7.4
phosphate buffered saline solution containing 0.05% bovine serum
albumin) was injected into the lateral ventricle. A test compound
suspended in aqueous 0.5% methylcellulose was administered orally 2
hours before the administration of bPP and the food consumption was
measured 2 hours after administration of bPP.
[0360] Compounds of this invention significantly inhibited the
increase in food consumption induced by bPP (NPY homologue) which
was administered to the lateral ventricle.
[0361] Compounds of the general formula (I) can be administered
orally or parenterally and may be formulated in the form suitable
for administration to provide an agent for treatment of various
diseases related to NPY, which include, for example, cardiovascular
disorders (for example hypertension, nephropathy, heart disease,
vasospasm, arteriosclerosis), central nervous system disorders (for
example bulimia, depression, anxiety, seizure, epilepsy, dementia,
pain, alcoholism, drug withdrawal), metabolic diseases (for example
obesity, diabetes, hormone abnormality, hypercholesterolemia,
hyperlipidemia), sexual and reproductive dysfunction,
gastrointestinal motility disorder, respiratory disorder,
inflammation or glaucoma and the like, preferably, bulimia,
obesity, diabetes and the like. In clinical use, compounds of this
invention can be administered after being formulated, together with
pharmaceutically acceptable additives, into an appropriate
preparation according to the mode of administration. For said
additives, those which are usually used in the field of
pharmaceutical formulation may be used, for example, gelatin,
lactose, sucrose, titanium oxide, starch, crystalline cellulose,
hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch,
microcrystalline wax, white petrolatum, magnesium methasilicate
aluminate, anhydrous calcium phosphate, citric acid, sodium
citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid
ester, polysorbate, sucrose fatty acid ester, polyoxyethylene,
hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate,
light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum
arabic, propylene glycol, polyalkylene glycol, cyclodextrin or
hydroxypropyl cyclodextrin.
[0362] A mixture with said additives may be formulated in the form
of solid preparations (for example tablets, capsules, granules,
powder, suppositories); or liquid preparations (for example syrups,
elixirs, injections). Such preparations may be formulated according
to techniques well-known in the art of pharmaceutical formulation.
Liquid preparations may be in the form of preparations which are
dissolved or suspended in water or other appropriate media when
used and especially injectable preparations may be dissolved or
suspended in physiological saline or glucose solution if necessary,
optionally together with a buffer and preservative.
[0363] Such preparations may contain 0.1 to 100 wt. %, preferably
1.0 to 60 wt. % of compounds of this invention and may also contain
therapeutically effective other compounds.
[0364] The compounds of the present invention can be used in
combination with other agents useful for treating metabolic and/or
feeding disorders. The individual components of such combinations
can be administered separately at different times during the course
of therapy or concurrently in divided or single combination forms.
The instant invention is therefore to be understood as embracing
all such regimes of simultaneous or alternating treatment and the
term "administering" is to be interpreted accordingly. It will be
understood that the scope of combinations of the compounds of this
invention with other agents useful for treating metabolic and/or
feeding disorders includes in principle any combination with any
pharmaceutical composition useful for treating metabolic and/or
feeding disorders.
[0365] When compounds of this invention are used clinically, the
dose and frequency of dosage may be varied depending upon the sex,
age, body weight, the degree of symptoms and the kind and range of
the desired treatment effects. A daily dose for an adult is
0.01-100 mg/kg, preferably 0.03-3 mg/kg orally, or 0.001-10 mg/kg,
preferably 0.001-0.1 mg/kg parenterally, preferably in a single
dose or in divided doses.
[0366] An ordinarily skilled physician, veterinarian or clinician
can readily determine and prescribe the effective amount of the
drug required to prevent, counter or arrest the progress of the
condition.
EXAMPLES
[0367] The following examples are provided so that the present
invention may be more concretely illustrated but they should not be
construed as limiting the invention in any way.
[0368] Unless otherwise noted, melting point was measured by MP-S3
Model (manufactured by Yanagimoto Seisakusho) and disclosed in this
specification without correction.
Example 1
[0369] Preparation of
N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1.4'-pipe-
ridine]-1'-carboxamide
[0370] (1) Preparation of
N-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-2-iodobenzamide
[0371] A mixture of N-tert-butoxycarbonyl-4-piperidone (1.11 g) and
benzylamine (597 mg) dissolved in toluene (20 mL) was stirred at
100.degree. C. for 3 hours and then concentrated. Toluene (30 mL),
o-iodobenzoyl chloride (1.13 g) and triethylamine (0.70 g) were
added to the residue and the mixture was stirred at 80.degree. C.
for 2 hours. The reaction mixture was poured into water and
extracted with ethyl acetate. The ethyl acetate layer was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate=4/1 to 1/2) to give the subject compound (2.44 g).
[0372] (2) Preparation of 2-benzyl-1'-tert-butoxycarbonyl-1',
6'-dihydro-spiro[1H-isoindole-1,4'(5'H)-pyridine]-3(2H)-one
[0373] To
N-benzyl-N-(1-tert,-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-y-
l)-2-iodobenzamide (2.4 g) dissolved in acetonitrile, palladium
acetate (80 mg), triphenylphosphine (187 mg), anhydrous
K.sub.2CO.sub.3 (987 mg) and tetraethylammonium chloride (591 mg)
were added and stirred at 80.degree. C. for 6 hours. The reaction
mixture was poured into water and extracted with ethyl acetate. The
ethyl acetate layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography on
silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject
compound (1.64 g).
[0374] (3) Preparation of
2-benzyl-1'-tert-butoxycarbonylspiro[1H-isoindol-
e-1,4'-piperidine]-3(2H)-one
[0375] To a solution of 2-benzyl-1'-tert-butoxycarbonyl-1',
6'-dihydrospiro[1H-isoindole-1,4'(5'H)-pyridine]-3(2H)-one (1.0 g)
in chloroform (20 mL), trifluoroacetic acid (20 mL) was added and
the mixture was stirred for 1 hour. The reaction mixture was
concentrated. The residue was dissolved in methanol and
hydrogenated with 4M hydrogen chloride/ethyl acetate in the
presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours.
The catalyst was removed by filtration and the filtrate was
concentrated. To the residue, aqueous 1N sodium hydroxide (5 mL),
di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added
and the mixture was stirred at room temperature for 4 hours. The
reaction mixture was poured into water and extracted with ethyl
acetate. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=4/1 to
1/2) to give the subject compound (200 mg).
[0376] (4) Preparation of
spiro[1H-isoindole-1,4'-piperidine]-3(2H)-one hydrochloride
[0377]
2-Benzyl-1'-tert-butoxycarbonylspiro[1H-isoindole-1,4'-piperidine]--
3(2H)-one (200 mg) was added to metallic sodium (235 mg) in liquid
ammonia (10 mL) and the mixture was stirred for 30 minutes. To the
reaction mixture was added methanol, neutralized with a saturated
ammonium chloride aqueous solution and extracted with ethyl
acetate. The organic layer was dried over anhydrous Na.sub.2SO4 and
concentrated. The residue dissolved in methanol was stirred
together with 4M hydrogen chloride/ethyl acetate at 50.degree. C.
for 1 hour. The reaction solution was concentrated to give the
subject compound (591 mg).
[0378] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.ppm): 1.70-1.90
(2H, m), 2.00-2.20 (2H,m), 3.00-3.20 (2H,m), 4.20-4.40 (2H, m),
7.40 (1H, d, J=7.5Hz), 7.51 (1H, t, J=7.5Hz), 7.59 (1H, t,
J=7.5Hz), 7.84 (1H, d, J=7.5Hz).
[0379] (5) Preparation of phenyl N-(4-benzoylphenyl)carbamate
[0380] To 4-aminobenzophenone (1.97 g) dissolved in pyridine (50
mL), phenyl chlorocarbonate (1.38 g) was added at 0.degree. C. and
the mixture was stirred at room temperature for 1 hour. The
reaction mixture was poured into water and extracted with ethyl
acetate. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to
give the subject compound (3.1 g).
[0381] (6) Preparation of
N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4'--
piperidine]-1'-carboxamide
[0382] A mixture of spiro[1H-isoindole-1,4'-piperidine]-3(2H)-one
hydrochloride (48 mg), triethylamine (0. 14 mL) and phenyl
N-(4-benzoylphenyl)carbamate (58 mg) was stirred in chloroform at
80.degree. C. for 2 hours. The reaction mixture was poured into
water and extracted with chloroform. The organic layer was dried
over anhydrous Na.sub.2SO4 and concentrated. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate=4/1 to 1/2) and crystallized from ethyl ether-hexane to
give the subject compound (49 mg) as colorless crystals (melting
point 253.degree. C.).
[0383] Compounds of Example 2 and 3 were obtained in the similar
manner as Example 1-(6) by replacing phenyl
N-(4-benzoylphenyl)carbamate used in Example 1-(6) by the
corresponding materials, respectively.
Example 2
[0384]
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1.4'-piperidine]-1'-
-carboxamide
[0385] melting point 286-287.degree. C.
Example 3
[0386]
N-(7-methyl-2-quinoly)-3-oxospiro[isoindoline-1.4'-piperidine]-1'-c-
arboxamide
[0387] melting point 194-196.degree. C.
Example 4
[0388] Preparation of
N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline--
1.4'-piperidine]-1'-carboxamide
[0389] The subject compound was obtained in the similar manner as
Example 1-(6) by replacing
spiro[1H-isoindole-1,4'-piperidine]-3(2H)-one hydrochloride by
2-methylspiro[1H-isoindole-1,4'-piperidine]-3(2H)-one
hydrochloride.
[0390] melting point 154-156.degree. C.
Example 5
[0391] Preparation of
N-(4-benzoylphenyl)-3.4-dihydro-3-oxosqiro[iso-quino-
line-1(2H),4'-piperidine]-1'-carboxamide
[0392] Spiro[isoquinoline-1(2H),4'-piperidine]-3(4H)-one
hydrochloride (30 mg) and phenyl N-(4-benzoylphenyl)carbamate (37
mg) were dissolved in dimethyl sulfoxide (2 mL) and stirred
together with aqueous 10 N sodium hydroxide (12 .mu.L) at room
temperature for 30 minutes. The reaction mixture was poured into
water and extracted with ethyl acetate (20 mL). The organic layer
was washed with water (20 mL) and saturated saline solution (20
mL), then dried over anhydrous Na.sub.2SO.sub.4 and concentrated.
The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/1 to 1/2) and recrystallized from
chloroform-acetone (1:3) to give the subject compound (81 mg) as
colorless crystals (melting point 241-243.degree. C.).
[0393] Compounds of Example 6 to 21 were obtained in the similar
manner as Example 1-(6) or Example 5 by using
spiro[isoquinoline-1(2H),4'-piperidin- e]-3(4H)-one hydrochloride
and phenyl carbamate derivatives corresponding to the desired
compounds.
Example 6
[0394]
3.4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoauinoline-1(2H),-
4'-piperidine]-1'-carboxamide
[0395] melting point 237-239.degree. C.
Example 7
[0396]
3.4-Dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4-
'-piperidine]-1'-carboxamide
[0397] melting point 216-218.degree. C.
Example 8
[0398]
N-(4-acetylphenyl)-3.4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-pip-
eridine]-1'-carboxamide
[0399] melting point>300.degree. C.
Example 9
[0400]
3.4-Dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-
-1(2H),4'-piperidine]-l'-carboxamide
[0401] melting point 264-266.degree. C.
Example 10
[0402]
3.4-Dihydro-3-oxo-N-(5-oxo-5.6.7.8-tetrahydro-2-naphthyl)spiro[isoq-
uinoline-l(2H),4'-piperidine]-1'-carboxamide
[0403] melting point 220.5-222.2.degree. C.
Example 11
[0404]
3.4-Dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoq-
uinoline-1(2H),4'-piperidine]-1'-carboxamide
[0405] melting point 232.9-236.5.degree. C.
Example 12
[0406]
3.4-Dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H)-
,4'-piperidine]-1'-carboxamide
[0407] melting point 239-241.degree. C.
Example 13
[0408]
N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3.4-dihydro-3-oxospiro[isoqu-
inoline-1(2H),4'-piperidine]-1'-carboxamide
[0409] melting point 192-194.degree. C.
Example 14
[0410]
N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3.4-dihydro-3-oxospiro-
[isoquinoline-1(2H),4'-piperidine]-1'-carboxamide
[0411] melting point 161-163.degree. C.
Example 15
[0412]
3.4-Dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-
-1(2H),4'-piperidine]-l'-carboxamide
[0413] melting point 162-164.degree. C.
Example 16
[0414]
N-(3.4-dichlorophenyl)-3.4-dihydro-3-oxospiro[isoquinoline-1(2H),4'-
-piperidine]-1'-carboxamide
[0415] melting point>300.degree. C.
Example 17
[0416]
N-[1-(3-chlorophenyl)-4-imidazolyl]-3.4-dihydro-3-oxospiro[isoquino-
line-1(2H),4'-piperidine]-1'-carboxamide
[0417] melting point 255-258.degree. C.
Example 18
[0418]
3.4-Dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),
4'-piperidine]-1'-carboxamide
[0419] melting point>300.degree. C.
Example 19
[0420]
3.4-Dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1-
(2H),4'-piperidine]-1'-carboxamide
[0421] melting point 223-225.degree. C.
Example 20
[0422]
3.4-Dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxosipiro[isoquinoline--
1(2H),4'-2piperidine]-1'-carboxamide
[0423] melting point 144-146.degree. C.
Example 21
[0424]
N-(5-chloro-2-benzoxazolyl)-3.4-dihydro-3-oxospiro[isoquinoline-1(2-
H), 4'-piperidine]-1'-carboxamide
[0425] melting point 256-258.degree. C.
Example 22
[0426] Preparation of
N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0427] A mixture of spiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (48 mg), phenyl N-(4-benzoylphenyl)carbamate (58 mg)
and triethylamine (0.14 mL) in chloroform (5 mL) was stirred at
80.degree. C. for 2 hours. The reaction mixture was poured into
water and extracted with chloroform (20 mL). The organic layer was
washed with saturated saline solution (20 mL), then dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to
give the subject compound (81 mg) as colorless crystals (melting
point 161-163.degree. C.).
Example 23
[0428] Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1-
(3H),4'-piperidine]-1'-carboxamide
[0429] (1)Preparation of phenyl N-(5-phenyl-2-pyrazinyl
)carbamate
[0430] Phenyl chlorocarbonate (15.05 mL) was added at 0.degree. C.
to a solution of 2-amino-5-phenylpyrazine (17.12 g) in pyridine
(200 mL). The mixture was stirred at room temperature for 2 hours.
To the reaction mixture was added water (200 mL) and ethyl ether
(200 mL). The whole was stirred to provide a suspension containing
the subject compound as a crystal. The crystal was collected by
filtration and further washed with ethyl ether (50 mL) and then
dried under reduced pressure to provide the subject compound (24.57
g) as colorless crystals (melting point 192-198.degree. C.
decomposed).
[0431] (2)Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofura-
n-1(3H),4'-piperidine]-1'-carboxamide
[0432] (Crystal Form A)
[0433] A mixture of spiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (6.24 g, 26.6 mmol), phenyl
N-(5-phenyl-2-pyrazinyl)carbama- te(7.59 g, 26.0 mmol) and
triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was stirred
at 80.degree. C. for 3 hours. The reaction mixture was washed with
saturated aqueous sodium bicarbonate (100 mL). After the organic
layer was washed with 10% citric acid aqueous solution (100 mL), 1N
aqueous sodium hydroxide (100 mL) and then saturated saline
solution (100 mL), the organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and then concentrated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=1/2) to
provide the subject compound as a colorless solid. The solid was
washed with diethyl ether (30 mL) to provide the subject compound
(8.23 g) as a crude crystal. The crystal was dissolved in hot ethyl
acetate (300 mL). After removal of about 100 mL of ethyl acetate by
distillation, the white suspension began to occur. At this point
the distillation was stopped and the whole was cooled and then kept
at room temperature for 14 hours. The colorless prisms formed was
collected by filtration, which was washed with heptane (20 mL). The
obtained crystal was dried at 50.degree. C. in vacuo for 6 hours to
provide the subject compound (Crystal Form A) (5.17 g) as colorless
prisms (melting point 210-211.degree. C.).
2 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps)
8.160 4135 9.600 2607 11.680 1372 14.620 194 15.320 1505 15.620
1321 15.880 2687 16.080 1711 16.420 3174 17.940 1036 19.100 6232
19.600 878 20.280 206 20.860 813 21.300 3360 22.020 328 22.740 1498
23.460 3782 23.820 549 24.420 1915 24.880 474 25.840 1329 26.360
515 28.480 433 29.260 248 30.860 692 32.140 246 34.300 112 39.160
163
[0434] Above powder X-ray diffraction analysis data were measured
by RINT1100 (manufactured by Rigaku International Corporation) and
analysis methods were as follows:
[0435] X-ray radiation source:Cu,
[0436] tube voltage:40 kV,
[0437] tube current:30 mA,
[0438] monochromater:automatic monochromater,
[0439] monoreceiving slit:0.60 mm,
[0440] goniometer:Wide angle goniometer,
[0441] scan step:0.02 deg.,
[0442] scan speed:2.00 deg./min.,
[0443] divergence slit(DS):1 deg.,
[0444] scattering slit:1 deg.,
[0445] receiving slit (RS):0.15 mm,
[0446] measured temperature:ambient temperature.
[0447] (3) Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofura-
n-1(3H),4'-piperidine]-1'-carboxamide (Crystal Form A)--an
alternative method for preparation--
[0448] Crude crystals (2 g) prepared by the above procedure (2) was
dissolved under heating into tetrahydrofuran (20 mL). After
confirming complete dissolution, the mixture was cooled to the room
temperature by standing it at room temperature. Heptane (27 mL) was
dropwise added to the tetrahydrofuran solution, followed by
stirring at room temperature for 15 hours. The yielded colorless
crystals were collected by filtration, washed with heptane (5 mL)
and dried in vacuum at 30.degree. C. for 15 hours to obtain the
above-identified compound in crystal form A (1.82 g).
[0449] (4) Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofura-
n-1(3H),4'-piperidine]-1'-carboxamide (Crystal Form B)
[0450] Crude crystals (2 g) prepared by the above procedure (2) was
dissolved under heating into dimethylformamide (6 mL). After
confirming complete dissolution, water (13 mL) was dropwise added
at 80.degree. C. and the resultant mixture was cooled to room
temperature, followed by stirring for 15 hours. The yielded
colorless crystals were collected by filtration at room
temperature, washed with heptane (5 mL) and dried in vacuum for 15
hours at room temperature to obtain 1.78 g of the above-identified
compound in the crystal form B as colorless prisms (melting point;
208.degree. C. measured without correction by the use of Melting
Point B-545 distributed by Buchi Company).
3 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps)
7.300 211 9.540 555 13.340 619 14.320 848 14.680 2435 15.620 7792
15.980 2307 16.400 6800 19.280 781 19.620 3137 19.920 1954 20.280
2234 20.900 4008 23.000 2311 24.060 3362 24.760 3598 25.300 953
25.880 3117 26.160 632 26.620 461 26.900 426 27.540 584 28.920 312
31.400 546 31.780 247 33.320 270 38.440 357 39.140 307 39.660
103
[0451] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
[0452] (5) Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofura- n-1(3H),
4'-piperidine]-1'-carboxamide (Crystal Form C)
[0453] Crude crystals (2 g) prepared by the above procedure (2) was
dissolved under heating: into tetrahydrofuran (20 mL). After
confirming complete dissolution, the solution was cooled to
-30.degree. C. Heptane (30 mL) was dropwise added to the
tetrahydrofuran solution, followed by stirring at -30.degree. C.
for one hour. The yielded colorless crystals were collected by
filtration, washed with heptane (5 mL) and dried in vacuum at room
temperature for 15 hours to obtain 1.90 g of the above-identified
product (monotetrahydrofuran solvate, the crystal form C) as
colorless fine granules.
4 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps)
5.940 1209 7.680 7150 11.420 1480 13.180 2032 14.240 1859 14.840
623 15.460 2629 16.580 2244 16.800 4076 17.960 706 18.640 2479
20.340 296 21.260 699 21.680 839 22.220 642 23.040 2515 24.000 1355
25.220 467 26.500 850 27.160 840 27.640 1078 28.780 389 30.940 283
34.200 267
[0454] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
[0455] (6) Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofura-
n-1(3H),4'-piperidine]-1'-carboxamide (Crystal Form D)
[0456] Spiro[isobenzofuran-1(3H), 4'-piperidine]-3-one
hydrochloride (515 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate
(583 mg) were dissolved into dimethyl sulfoxide (2.6 mL), followed
by dropwise addition of dimethylbenzylamine (0.33 mL). The
temperature of the resultant mixture was raised up to 50.degree.
C., and the mixture was stirred for one hour. The reaction mixture
was cooled to room temperature, and acetonitrile/water (1:2)
mixture solution (7.8 mL) was dropwise added. At the time when 0.2
mL of the mixture solution was added, seed crystal was added. The
resultant mixture was stirred at room temperature for 6 hours. The
yielded colorless crystals were collected by filtration, washed
with acetonitrile/water (1:1) and dried in vacuum at room
temperature for 15 hours to obtain the above-identified compound
(793 mg) as crude colorless crystals. Crude crystals (26 g)
prepared by the repetition of the above procedure were suspended in
water-saturated isopropyl acetate (143 mL). The mixture was seeded
with seed crystal and stirred at room temperature for 18 hours. The
yielded crystals were collected by filtration, washed with
isopropyl acetate (20 mL) and dried in vacuum at 30.degree. C. for
15 hours to obtain the above-identified compound in the crystal
form D (25.2 g) as colorless crystals (melting point; 206.degree.
C. measured without correction by the use of Melting Point B-545
distributed by Buchi Company).
5 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps)
9.680 337 10.260 1796 11.480 1921 11.800 2608 12.580 2119 13.160
5843 13.900 1413 15.440 4091 15.660 4780 16.520 1853 17.520 298
19.320 1748 20.220 4858 20.660 2115 21.020 1063 21.480 493 21.820
856 22.280 947 22.700 2126 23.140 13619 23.640 502 24.460 3174
25.400 1919 26.060 1306 26.580 860 26.960 337 28.040 1036 28.620
188 29.080 852 30.160 328 30.880 617 31.820 728 37.460 315
[0457] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 23(2).
[0458] (7) Preparation of
3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofura-
n-1(3H),4'-piperidine]-1'-carboxamide (Crystal Form B) --an
alternative method for preparation--
[0459] Crude crystals (26 g) prepared by the above procedure
[0460] (6) was suspended in acetonitrile (260 mL). The mixture was
seeded with the seed crystal prepared by the above procedure (4)
and stirred at room temperature for 24 hours. The yielded crystals
were collected by filtration, washed with acetonitrile (50 mL) and
dried in vacuum at 30.degree. C. for 15 hours to obtain the
above-identified product in the crystal form B (25.5 g).
[0461] Compounds of Example 24 to 39 were obtained in the similar
manner as Example 22 by replacing phenyl
N-(4-benzoylphenyl)carbamate used in Example 22 by the
corresponding materials, respectively.
Example 24
[0462] N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0463] melting point 178-180.degree. C.
Example 25
[0464] 3-Oxo-N-(3-phenyl-5-isoxazolyl)-spiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0465] melting point 239-242.degree. C.
Example 26
[0466]
3-Oxo-N-(7-trifluoromethylpyrido[3.2-b]pyridin-2-yl)-spiro[isobenzo-
furan-1(3H),4'-piperidine]-1'-carboxamide
[0467] melting point 246-248.degree. C.
Example 27
[0468] 3-Oxo-N-(5-phenyl-2-pyrimidinyl)-spiro[isobenzofuran-1(3H)
4'-piperidine]-1'-carboxamide
[0469] melting point 211-214.degree. C.
Example 28
[0470]
3-Oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0471] melting point 251-254.degree. C.
Example 29
[0472] 3-Oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0473] melting point 160-165.degree. C.
Example 30
[0474]
N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4-
'-piperidine]-1'-carboxamide
[0475] melting point 255-258.degree. C.
Example 31
3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0476] melting point 253-257.degree. C.
Example 32
[0477]
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H)-
,4'-piperidine]-1'-carboxamide
[0478] melting point 122-125.degree. C.
6 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps) 4.96
5335 9.94 2512 13.82 1020 14.56 555 14.64 565 14.94 1705 16.14 1067
16.66 2260 17.12 1668 17.60 1420 17.92 590 19.40 447 19.80 788
19.94 627 20.42 1057 21.00 963 21.80 1698 22.06 2397 22.36 1235
23.96 555 24.16 632 24.32 402 25.08 1603 25.38 538 26.82 647 27.06
1345 27.84 1073 28.80 465 28.86 493 29.42 752 30.30 1015 30.74 850
34.16 422 38.12 918 42.36 625 43.88 528
[0479] Above powder X-ray diffraction analysis data were measured
by RINT2100 Ultima+ System(2 KW) (manufactured by Rigaku
International Corporation) and analysis methods were as
follows:
[0480] X-ray radiation source:Cu,
[0481] tube voltage:40 kV,
[0482] tube current:30 mA,
[0483] monochromater:automatic monochromater,
[0484] monoreceiving slit:0.15 mm,
[0485] goniometer:Horizontal goniometer I,
[0486] scan step:0.02 deg.,
[0487] scan speed:2.00 deg./min.,
[0488] divergence slit(DS):1 deg.,
[0489] scattering slit:1 deg.,
[0490] receiving slit (RS):0.15 mm,
[0491] measured temperature:ambient temperature.
Example 33
[0492] 3-Oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl
spiro[isobenzofuran-1(3H), 4'-piperidine]-1'-carboxamide
[0493] melting point 190-192.degree. C.
Example 34
[0494]
N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H
), 4'-piperidine]-l'-carboxamide
[0495] melting point 126-128.degree. C.
Example 35
N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobe-
nzofuran-1(3H), 4'-piperidine]-1'-carboxamide
[0496] melting point 193.degree. C.
Example 36
[0497]
3-Oxo-N-(5-phenyl-1.2.4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),
4'-piperidine]-1'-carboxamide
[0498] melting point 239-241.degree. C.
Example 37
[0499]
N-{1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl}-3-oxospiro[isobenzofu-
ran-1(3H), 4'-piperidine-]'-carboxamide
[0500] melting point 99-100.degree. C.
Example 38
[0501]
N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(34),
4'-piperidine]-1'-carboxamide
[0502] melting point 221-223.degree. C.
Example 39
[0503]
N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H)-
,4'-piperidine]-1'-carboxamide
[0504] melting point 208-210.degree. C.
Example 40
[0505] Preparation of
6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro-[isoben-
zofuran-1(3H), 4'-piperidine]-1'-carboxamide
[0506] A mixture of 6-fluorospiro[isobenzofuran-1(3H),
4'-piperidine]-3-one hydrochloride (64 mg), phenyl
N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174
.mu.L) in chloroform (5 mL) was stirred at 80.degree. C. for 2
hours. The reaction mixture was poured into water and extracted
with chloroform (20 mL). The organic layer was washed with
saturated saline solution (20 mL), then dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=4/1 to
1/2) and recrystallized from ethyl ether-hexane to give the subject
compound (101 mg) as colorless crystals (melting point
222-224.degree. C.).
Example 41
[0507] Preparation of
6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[iso-b-
enzofuran-1(3H), 4'-piperidine]-1'-carboxamide
[0508] The subject compound was obtained in the similar manner as
Example 40 by replacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate
used in Example 40 by phenyl
N-(5-phenyl-2-pyrimidinyl)carbamate.
[0509] melting point 176-178.degree. C.
Example 42
[0510] Preparation of
5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenz-
o-furan-1(3H), 4'-piperidine]-1'-carboxamide
[0511] A mixture of 5-fluorospiro[isobenzofuran-1(3H),
4'-piperidine]-3-one hydrochloride (64 mg), phenyl
N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174
.mu.L) in chloroform (5 mL) was stirred at 80.degree. C. for 2
hours. The reaction mixture was poured into water and extracted
with chloroform (20 mL). The organic layer was washed with
saturated saline solution (20 mL), then dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=4/1 to
1/2) and recrystallized from ethyl ether-hexane to give the subject
compound (100 mg) as colorless crystals (melting point
236-238.degree. C.).
Example 43
[0512] Preparation of
5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[iso-b-
enzofuran-1(3H), 4'-piperidine]-1'-carboxamide
[0513] The subject compound was obtained in the similar manner as
Example 42 by replacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate
used in Example 42 by phenyl
N-(5-phenyl-2-pyrimidinyl)carbamate.
[0514] melting point 255-257.degree. C.
Example 44
[0515] Preparation of N-(4-benzoylphenyl)-3,
4-dihydro-3-oxospiro[1H-2-ben- zopyran-1
4'-piperidine]-1'-carboxamide
[0516] Spiro[1H-2-benzopyran-1,4'-piperidine]-3(4H)-one
hydrochloride (50.6 mg) and phenyl N-(4-benzoylphenyl)carbamate
(63.4 mg) were suspended in dimethyl sulfoxide (1.0 mL) and the
suspension was vigorously stirred together with aqueous 10M sodium
hydroxide (30 .mu.L) for 5 minutes. The reaction mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with saturated saline solution, then dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
crystallized from methanol-diisopropyl ether to give the subject
compound (68.0 mg) as colorless crystals (melting point
138-146.degree. C.).
[0517] Compounds of Example 45 and 46 were obtained in the similar
manner as Example 44 by replacing phenyl
N-(4-benzoylphenyl)carbamate used in Example 44 by the
corresponding materials, respectively.
Example 45
[0518]
3,4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4-
'-piperidine]-1'-carboxamide
[0519] melting point 221.degree. C.
Example 46
[0520]
N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,-
4'-piperidine]-1'-carboxamide
[0521] melting point 128-131.degree. C.
Example 47
[0522] Preparation of
trans-N-(4-benzoylphenyl)-3'-oxospiro[cyclohexane-1,-
1'(3'H)-isobenzofuran]-4-carboxamide
[0523] (1) Preparation of
spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3',4-- dione
[0524] A solution of 2-bromobenzoic acid (4.77 g) in anhydrous
tetrahydrofuran (100 mL) was cooled to -78.degree. C. under an
atmosphere of nitrogen, to which n-butyllithium (1.53M solution in
hexane, 31 mL) was dropwise added while being kept the internal
temperature below -55.degree. C. After being stirred for 1 hour, a
solution of 1,4-cyclohexanedione monoethylene ketal (5.18 g) in
anhydrous tetrahydrofuran (10 mL) was added dropwise to the mixture
while being kept the internal temperature below -67.degree. C.
After the temperature was raised to room temperature, the reaction
solution was partitioned between water (150 mL) and hexane (100
mL). The aqueous layer was acidified with concentrated hydrochloric
acid and refluxed together with acetone (10 mL) for 2 hours. After
cooling, thus obtained mixture was neutralized with potassium
carbonate and extracted with ethyl acetate. The organic layer was
washed with saturated saline solution, then dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was crystallized from
ethyl acetate-hexane to give the subject compound (2.42 g).
[0525] (2) Preparation of
4-methylenespiro[cyclohexane-1,1'(3'H)-isobenzof- uran]-3-one
[0526] A suspension of methyltriphenylphosphonium bromide (715 mg)
in anhydrous tetrahydrofuran (7.0 mL) was cooled to 0.degree. C.
under an atmosphere of nitrogen, to which n-butyllithium (1.53M
solution in hexane, 1.3 mL) was added, stirred at that temperature
for 20 minutes and then cooled to -78.degree. C. A solution of
spiro[cyclohexane-1,1'(3'H)-i- sobenzofuran]-3', 4-dione (216 mg)
in anhydrous tetrahydrofuran (3 mL) was added to the reaction
mixture and the temperature was raised to 0.degree. C. After
stirring for 20 minutes, aqueous ammonium chloride was added to
thus obtained mixture and the resulting crude product was extracted
with ethyl acetate. The organic layer was washed with saturated
saline solution, then dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography on
silica gel (hexane/ethyl acetate=4/1) to give the subject compound
(196 mg).
[0527] (3) Preparation of
4-hydroxymethylspiro[cyclohexane-1,1'(3'H)-isobe-
nzofuran]-3'-one
[0528] A solution of
4-methylenespiro[cyclohexane-1,1'(3'H)-isobenzofuran]- -3-one (196
mg) in anhydrous tetrahydrofuran (5.0 mL) was cooled to 0.degree.
C., to which borane-dimethyl sulfide complex (2M tetrahydrofuran
solution, 690 .mu.L) was added and the mixture was stirred at that
temperature for 1.5 hours, then additional 20 minutes together with
aqueous 2M sodium hydroxide (5.0 mL) and aqueous 30% hydroperoxide
(5.0 mL). The reaction mixture was diluted with water, extracted
with ethyl acetate, washed with saturated saline solution, then
dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The residue
was purified by column chromatography on silica gel (hexane/ethyl
acetate=2/1) to give the subject compound (190 mg) as
diastereomers.
[0529] (4) Preparation of
trans-3'-oxospiro[cyclohexane-1,1'(3'H)-isobenzo-
furan]-4-carboxylic acid
[0530] A mixture of
4-hydroxymethylspiro[cyclohexane-1,1'(3'H)-isobenzofur- an]-3'-one
(190 mg), chloroform (2.0 mL), acetonitrile (2.0 mL) and sodium
phosphate buffer (pH6.5, 2.0 mL) was cooled to 0.degree. C. to
which sodium periodate (612 mg) and ruthenium(III) chloride
n-hydrate (10 mg) were added and the mixture was stirred for 30
minutes. The reaction mixture was stirred together with 1N
hydrochloric acid (2.0 mL) for 30 minutes and partitioned between
water (50 mL) and ethyl acetate (50 mL). The organic layer was
washed with saturated saline solution, dried over anhydrous
Na.sub.2SO.sub.4 and then concentrated. The residue was purified by
column chromatography on silica gel (chloroform/methanol=100/- 1)l
to give the subject compound (98.6 mg).
[0531] (5) Preparation of
trans-N-(4-benzoylphenyl)-3'-oxospiro[cyclohexan-
e-,1'(3'H)-isobenzofuran]-4-carboxamide
[0532] To a solution of
trans-3'-oxospiro[cyclohexane-1,1'(3'H)-isobenzofu-
ran]-4-carboxylic acid (24.6 mg) in pyridine (500 .mu.L),
4-aminobenzophenone (19.8 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbod- iimide hydrochloride (57.5
mg) were added and the mixture was stirred at 50.degree. C. for 2
hours. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with aqueous potassium
hydrogen sulfate, aqueous sodium hydrogen carbonate, and saturated
saline solution and then dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was crystallized from ethyl acetate-hexane
to give the subject compound (31.2 mg) as colorless crystals
(melting point 194.degree. C.).
[0533] Compounds of Example 48 to 56 were obtained in the similar
manner as Example 47-(5) by replacing 4-aminobenzophenone used in
Example 47-(5) by the corresponding materials, respectively.
Example 48
[0534]
Trans-3'-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1'(3'H)-is-
obenzofuran]-4-carboxamide
[0535] melting point 223.degree. C.
Example 49
[0536]
Trans-3'-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1'(3'H)-i-
sobenzofuran]-4-carboxamide
[0537] melting point 264.degree. C.
Example 50
[0538]
Trans-3'-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1'(3'H)--
isobenzofuran]-4-carboxamide
[0539] melting point 184.degree. C.
Example 51
[0540]
Trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexa-
ne-1,1'(3'H)-isobenzofuran]-4-carboxamide
[0541] melting point 294.degree. C.
Example 52
[0542]
Trans-3'-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1'(3'H)-is-
obenzofuran]-4-carboxamide
[0543] melting point 238.degree. C.
Example 53
[0544]
Trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1-
,1'(3'H)-isobenzofuran]-4-carboxamide
[0545] melting point 258.degree. C.
Example 54
[0546]
Trans-N-(4-acetyl-3-trifluoromethylphenyl)-3'-oxospiro[cyclohexane--
1,1' (3'H)-isobenzofuran]-4-carboxamide
[0547] melting point 274-275.degree. C.
EXAMPLE 55
[0548] Trans-3'-oxo-N-[1-(3-quinolyl)-4
-imidazolyl]spiro[cyclohexane-1,1'
(3'H)-isobenzofuran]-4-carboxamide
[0549] melting point>300.degree. C.
Example 56
[0550]
Trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3'-oxospiro[cyclohexane-1,-
1' (3'H)-isobenzofuran]-4-carboxamide
[0551] melting point 268-270.degree. C.
Example 57
[0552] Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofu-
ran-1(3H),1'-cyclohexanel-4'-carboxamide
[0553] (1) Preparation of
dispiro[4-azaisobenzofuran-1(3H),1'-cyclohexane--
4',2"-1",3"-dioxolane]-3-one
[0554] A solution of N-methyl-2-pyridinecarboxamide (9.53 g) in
anhydrous tetrahydrofuran (400 mL) was cooled to -78.degree. C.
under an atmosphere of nitrogen, to which n-butyllithium (1.54M
solution in hexane, 100 mL) was dropwise added. After being stirred
for 1.5 hours at the some temperature, a solution of
1,4-cyclohexanedione monoethylene ketal (10.93 g) in anhydrous
tetrahydrofuran (100 mL) was added dropwise to the mixture. After
the temperature was raised to room temperature, the reaction
mixture was partitioned between water (300 mL) and ethyl ether (100
mL). The aqueous layer was acidified with 2N hydrochloric acid,
stirred for 30 minutes, neutralized with potassium carbonate and
then left overnight. The resulting precipitate was collected by
filtration and dried to give the subject compound (6.84 g).
[0555] (2) Preparation of
spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-3- ,4'-dione
[0556] A mixture of dispiro[4-azaisobenzofuran
1(3H),1'-cyclohexane-4',2 "-1",3" dioxolane]3one (6.8 g), 2N
hydrochloric acid (20 mL) and acetone (5 mL) was heated under ref
lux for 13 hours. After cooling, the mixture was neutralized with
potassium carbonate and stirred together with isopropyl ether (5
mL) for 3 hours. The resulting precipitate was collected by
filtration, washed with water and isopropyl ether and then dried to
give the subject compound (3.39 g).
[0557] (3) Preparation of
cis-4'-hydroxyspiro[4-azaisobenzofuran-1(3H),1'--
cyclohexane]-3-one
[0558] Spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane ]-3,4'-dione
(5.7 g) was dissolved in tetrahydrofuran (50 mL) and water (10 mL)
and cooled to. The solution was stirred together with sodium
borohydride (993 mg) for 20 minutes, acidified with 10% sulfuric
acid, adjusted to pH7.4 with saturated sodium hydrogen carbonate
aqueous solution and extracted with chloroform-ethanol and
chloroform-tetrahydrofuran. The organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
crystallized from ethyl acetate-isopropyl ether to give the subject
compound (2.02 g).
[0559] (4) Preparation of
trans-3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carbonitrile
[0560] To a solution of
cis-4'-hydroxyspiro[4-azaisobenzofuran-1(3H),1'-cy-
clohexane]-3-one (2.02 g) in anhydrous tetrahydrofuran (60 mL),
triethylamine (3.08 mL) was added and cooled to 0.degree. C.
Methanesulfonyl chloride (1.3 mL) was added dropwise to the mixture
and stirred at that temperature for 1 hour. The reaction mixture
was diluted with water and extracted with chloroform. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was crystallized from ethyl acetate-isopropyl ether to give
mesylate (2.47 g). Thus obtained mesylate was dissolved in
dimethylformamide (25 mL) and stirred together with
tetraethylammonium cyanide (3.25 g) at 100.degree. C. for 3 hours.
After cooling, the reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was washed with
water and saturated saline solution, dried over anhydrous
Na.sub.2SO.sub.4 and then concentrated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate=2/3) to
give the subject compound (1.0 g).
[0561] (5) Preparation of
trans-3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxylic acid
[0562] A solution of
trans-3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyclohex-
ane]-4'-carbonitrile (1.0 g) in 30% sulfuric acid was heated under
reflux for 11 hours. After cooling, the reaction mixture was
diluted with water and adjusted to pH6 with potassium carbonate.
The resulting precipitate was collected by filtration, washed with
water and air-dried to give the subject compound (974 mg).
[0563] (6) Preparation of trans-N-(4-benzoylphenyl)
3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyclohexane)-4'-carboxamide
[0564] To a solution of
trans-3-oxospiro[4-azaisobenzofuran-1(3H),1'-cyclo-
hexane]-4'-carboxylic acid (66 mg) in pyridine (1 mL),
4-aminobenzophenone (52.6 mg) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153
mg) were added and the mixture was stirred at 40.degree. C. for 2
hours. The reaction mixture was concentrated and the residue was
partitioned between water and ethyl acetate. The organic layer was
washed with saturated saline solution, dried over anhydrous
Na.sub.2SO.sub.4 and then concentrated. The residue was
crystallized from ethyl acetate-hexane to give the subject compound
(94.4 mg) as colorless crystals (melting point 237.degree. C.).
[0565] Compounds of Example 58 to 60 were obtained in the similar
manner as Example 57-(6) by replacing 4-aminobenzophenone used ie
Example 57-(6) by the corresponding materials, respectively.
Example 58
[0566]
Trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide
[0567] melting point 203.degree. C.
Example 59
[0568]
Trans-3-oxo-N-(3-phenyl-5-isoxazolylspiro[4-azaisobenzofuran-1(3H),-
1'-cyclohexane]-4'-carboxamide melting point 217.degree. C.
Example 60
[0569]
Trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H-
),1'-cyclohexane]-4'-carboxamide melting point 237.degree. C.
Example 61
[0570] Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide
[0571] (1) Preparation of
dispiro[5-azaisobenzofuran-1(3H),1'-cyclohexane--
4',2"-1",3"-dioxolane]-3-one
[0572] 2,2,6,6-Tetramethylpiperidine (41,1 mL) was dissolved in
anhydrous tetrahydrofuran (400 mL) and cooled to -50.degree. C., to
which n-butyllithium (1.50 M solution in hexane, 217 mL) and
nicotinic acid (10.0 g) were added successively. After being
stirred at -50.degree. C. for 1 hour, a solution of
1,4-cyclohexanedione monoethylene ketal (13.9 g) in anhydrous
tetrahydrofuran (25 mL) was added and then the mixture was stirred
at -50.degree. C. for 1 hour. After the temperature was raised to
room temperature, the reaction mixture was poured into water (800
mL) and extracted with hexane-ether (1:1, 500 mL). The aqueous
layer was adjusted to pH3 with 6N hydrochloric acid and stirred at
room temperature for 2 hours. The resulting precipitate was
collected by filtration and washed with water. Thus obtained solid
was dissolved in chloroform (300 mL), washed with saturated sodium
bicarbonate aqueous solution (150 mL), dried and then concentrated.
The residue was recrystallized from ethyl acetate-hexane to give
the subject compound (4.29 g).
[0573] (2) Preparation of
spiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-3- ,4'-dione
[0574]
Dispiro[5-azaisobenzofuran-1(3H),1'-cyclohexane-4',2"-1",3"-dioxola-
ne]-3-one (4.29 g) and p-toluenesulfonic acid monohydrate (3.74 g)
were dissolved in acetone (80 mL) and water (8 mL) and the solution
was heated under reflux for 3 hours. After cooling, acetone was
evaporated off and chloroform (100 mL) was added to the residue.
The mixture was washed with saturated sodium bicarbonate aqueous
solution (50 mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
then evaporated. The resulting crystals were recrystallized from
ethyl acetate-hexane to give the subject compound (2.68 g).
[0575] (3) Preparation of
cis-4'-hydroxyspiro[5-azaisobenzofuran-1(3H),1'--
cyclohexane]-3-one
[0576] A suspension of
spiro[5-azaisobenzofuran-1(3H),1'-cyclohexane]-3,4'- -dione (167
mg) in tetrahydrofuran-water (10:1, 4 mL) was cooled to 0.degree.
C. and stirred together with sodium borohydride (32 mg) at
0.degree. C. for 30 minutes. The reaction mixture was poured into
water (5 mL), stirred at room temperature for 30 minutes and then
extracted with chloroform (20 mL.times.3). The extract was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
recrystallized from ethyl acetate-hexane to give the subject
compound (77.7 mg).
[0577] (4) Preparation of
trans-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carbonitrile
[0578] A solution of
cis-4'-hydroxyspiro[5-azaisobenzofuran-1(3H),1'-cyclo-
hexane]-3-one (1.31 g) and triethylamine (1.17 mL) in anhydrous
tetrahydrofuran (20 mL) was cooled to 0.degree. C. and stirred
together with methanesulfonyl chloride (0.555 mL) at 0.degree. C.
for 1 hour. The reaction mixture was poured into water (50 mL),
extracted with ethyl acetate (100 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give crude mesylate (1.87 g).
The mesylate was dissolved in anhydous dimethylformamide (30 mL)
and stirred together with triethylammonium cyanide (2.98 g) at
100.degree. C. for 5 hours. The reaction mixture was poured into
water (100 mL) and extracted with ether (150 mL.times.3), and
ether-ethyl acetate (2:1, 200 mL). The combined extracts were dried
over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting
oily residue was purified by column chromatography on silica gel
(hexane/ethyl acetate/methanol=2/1/0 to 1/1/0 to 30/30/1) and the
obtained solid was recrystallized from ethyl acetate-hexane to give
the subject compound (631 mg).
[0579] (5) Preparation of
trans-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxylic acid
[0580] A mixture of trans-3-oxospiro[5
-azaisobenzofuran-1(3H),1'-cyclohex- ane]-4'-carbonitrile (100 mg),
water (0.7 mL) and concentrated sulfuric acid (0.3 mL) was ref
luxed for 11 hours. The reaction mixture was cooled to room
temperature and adjusted to pH4 with aqueous 4N sodium hydroxide.
The resulting precipitate was collected by filtration, washed
successively with water, ethanol and diisopropyl ether and then
dried to give the subject compound (78 mg).
[0581] .sup.1H-NMR (200MHz, DMSO-d.sub.6, .delta. ppm): 1.63-1.87
(2H, m), 1.88-2.20 (6H, m), 2.70 (1H, m), 7.76 (1H, dd, J=5.2, 1.1
Hz), 8.86 (1H, d, J=5.2 Hz), 9.06 (1H, d, J=1.1 Hz).
[0582] (6) Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisoben-
zofuran-1(3H),1'-cyclohexane]-4'-carboxamide
[0583] A solution of
trans-3-oxospiro[5-azaisobenzofuran-1(3H),1'-cyclohex-
ane]-4'-carboxylic acid (20 mg) and 4-aminobenzophenone (16 mg) in
anhydrous pyridine (0.5 mL) was stirred together with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg)
at 60.degree. C. for 2 hours. The reaction mixture was poured into
water (10 mL) and extracted with ethyl acetate (30 mL .times.2).
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting oily residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate =1/1 to 1/2) and the obtained solid was recrystallized from
ethyl acetate-hexane to give the subject compound (10 mg) as
colorless crystals (melting point 256-257.degree. C.).
[0584] Example 62
[0585] Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiror6-azaisobenzofu-
ran-1(3H),1'-cyclohexane]-4'-carboxamide
[0586] (1) Preparation of dispiro[6-azaisobenzofuran-1(3H),
1'-cyclohexane-4',2"-1",3"-dioxolane]-3-one
2,2,6,6-Tetramethylpiperidine (50 mL) was dissolved in anhydrous
tetrahydrofuran (500 mL) and the solution was cooled to -50.degree.
C., to which n-butyllithium (1.50 M solution in hexane, 270.7 mL)
and isonicotinic acid (12.5 g) were added successively. The
reaction mixture was stirred at -50.degree. C. for minutes and the
temperature was raised to 25.degree. C. over 30 minutes. The
reaction mixture was further stirred at 25.degree. C. for 10
minutes and then cooled to -65.degree. C. 1, 4-Cyclohexanedione
monoethylene ketal (19 g) was added and the reaction mixture was
stirred at -65.degree. C. for 10 minutes. The temperature of the
reaction mixture was raised to -15.degree. C. over 1 hour, then to
0.degree. C. over 30 minutes. Then the mixture was poured into
water (300 mL), from which the aqueous layer was separated. The
organic layer was extracted with aqueous 2N sodium hydroxide. The
combined aqueous layers were adjusted to pH3 with concentrated
hydrochloric acid and extracted with ethyl acetate 500 mL). The
organic layer was washed with saturated aqueous sodium bicarbonate
(200 mL), and saturated saline solution, then dried over anhydrous
MgSO.sub.4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate =1/0 to 4/1 to
3/2) and recrystallized from ethyl acetate-hexane to give the
subject compound (7.20 g).
[0587] (2) Preparation of
spiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-3- ,4'-dione
[0588]
Dispiro[6-azaisobenzofuran-1(3H),1'-cyclohexane-4',2"-1",3"-dioxola-
ne]-3-one (7.20 g) and p-toluenesulfonic acid monohydrate (5.80 g)
were dissolved in acetone (150 mL) and water (15 mL) and the
solution was heated under reflux for 5.5 hours. After cooling,
acetone was evaporated off and the residue was extracted with ethyl
acetate (100 mL.times.3). The combined organic layers were washed
with saturated saline solution (50 mL), dried over anhydrous
MgSO.sub.4 and then evaporated. The resulting crystals were
recrystallized from ethyl acetate-diisopropyl ether to give the
subject compound (1.96 g).
[0589] (3) Preparation of
cis-4'-hydroxyspiro[6-azaisobenzofuran-1(3H),1'--
cyclohexane]-3-one
[0590] A solution of spiro[6
-azaisobenzofuran-1(3H),1'-cyclohexane]-3,4'-- dione (1.0 g) in
ethanol (100 mL) was cooled to 0.degree. C. and stirred together
with sodium borohydride (174 mg) at0.degree. C. for hour. The
reaction mixture was adjusted to pH4 with 10% sulfuric acid,
rendered basic with aqueous saturated sodium bicarbonate and then
extracted with chloroform (200 mL.times.2). The extract was dried
over anhydrous MgSO.sub.4 and concentrated. The residue was
recrystallized from ethyl acetate-hexane to give the subject
compound (954.5 mg).
[0591] (4) Preparation of
trans-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carbonitrile
[0592] A solution of
cis-4'-hydroxyspiro[6-azaisobenzofuran-1(3H),1'-cyclo-
hexane]-3-one (954 mg) and triethylamine (0.91 mL) in
dimethylformamide (10 mL) was cooled to 0.degree. C. and stirred
together with methanesulfonyl chloride (0.40 mL) at 0.degree. C.
for 1 hour. The reaction mixture was diluted with ethyl acetate
(100 mL), washed with aqueous saturated sodium bicarbonate (50
mL.times.2), and saturated saline solution (50 mL), then dried over
anhydrous MgSO.sub.4 and concentrated. The residue was
recrystallized from ethyl acetate-diisopropyl ether to give
mesylate (995 mg). This mesylate was dissolved in anhydrous
dimethylformamide (30 mL) and stirred together with
triethylammonium cyanide (1.57 g) at 100.degree. C. for 1.5 hours.
The reaction mixture was diluted with ethyl acetate (200 mL) and
washed successively with water (200 mL), aqueous saturated sodium
bicarbonate (200 mL), and saturated saline solution (100 mL). The
organic layer was dried over anhydrous MgSO.sub.4 and concentrated.
The residue was recrystallized from ethyl acetate-diisopropyl ether
to give the subject compound (447 mg).
[0593] (5) Preparation of
trans-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxylic acid
[0594] A mixture of trans-3-oxospiro[6
-azaisobenzofuran-1(3H),1'-cyclohex- ane]-4'-carbonitrile (445 mg),
water (3.5 mL) and concentrated sulfuric acid (1.5 mL) was refluxed
for 6 hours. The reaction mixture was cooled to room temperature
and adjusted to pH8 with aqueous 5N sodium hydroxide, then to pH4
with concentrated hydrochloric acid. The resulting crystals were
collected by filtration, washed with water and dried to give the
subject compound (416 mg) as colorless crystals (melting point
222-223.degree. C.). .sup.1H-NMR (300 MHz, DMSO-d.sub.6,
.delta.ppm): 1.7-2.2 (6H, m), 2.65-2.75 (1H, m), 7.83 (1H, dd,
J=1.2 Hz, 4.9 Hz), 8.86 (1H, d, J=4.9 Hz), 9.05 (1H, d, J=1.2 Hz),
12.3 (1H, brs).
[0595] (6) Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisoben-
zofuran-1(3H),1'-cyclohexane]-4'-carboxamide
[0596] A solution of trans-3-oxospiro[6
-azaisobenzofuran-1(3H),1'-cyclohe- xane]-4'-carboxylic acid (50
mg) and 4-aminobenzophenone (51.6 mg) in anhydrous pyridine (1 mL)
was stirred together with
1-(3-dimethylaminopropyl)-3-ethylcarboduimide hydrochloride (48.7
mg) at 60.degree. C. for 2 hours. The reaction mixture was diluted
with ethyl acetate (20 mL) and washed successively with water (20
mL), 10% citric acid aqueous solution (20 mL.times.2), aqueous
saturated sodium bicarbonate, and saturated saline solution. The
organic layer was dried over anhydrous MgSO.sub.4 and concentrated.
The resulting oily residue was purified by column chromatography on
silica gel (hexane/ethyl acetate =3/2 to 1/4) and the obtained
solid was recrystallized from ethyl acetate-hexane to give the
subject compound (62.7 mg) as colorless crystals (melting point
147-149.degree. C.).
Example 63
[0597] Preparation of N-[5-(4-hydroxyphenyl)-2
-pyrazinyl]-3-oxospiro[isob-
enzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0598] (1) Preparation of 2-amino-5-(4-hydroxyphenyl)pyrazine To a
solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20
mL) was added 4-hydroxyphenylboronic acid (320 mL), 1.5N sodium
carbonate aqueous solution (2.5 mL) and tetrakis
(triphenylphosphine) palladium (0) (54 mg). The mixture was stirred
at 80.degree. C. for 3 hours. To the reaction mixture was added
water (20 mL) and the whole was extracted with ethyl acetate (50
mL.times.3). The extract was washed with saturated saline solution,
then dried over anhydrous Na.sub.2SO.sub.4. The removal of the
solvent provided crystal residue, which was washed with diethyl
ether (10 mL) to give the subject compound (305 mg).
[0599] (2) Preparation of phenyl
N-[5-(4-hydroxyphenyl)-2-pyrazinyl]carbam- ate
[0600] To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283
mg) in pyridine (20 mL) was added under ice-cooling phenyl
chloroformate (199 .mu.L) and the mixture was stirred for 1 hour.
The reaction mixture was poured into water (30 mL) and extracted
with ethyl acetate (20 mL.times.3). The organic layer was washed
with saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4 The concentration of the solvent left a crystal
residue, which was washed with diethyl ether (10 mL) to give the
subject compound (314 mg).
[0601] (3) Preparation of N-[5-(4-hydroxyphenyl)-2-pyrazinyl
]-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0602] A mixture of spiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (96 mg), phenyl
N-5-[(4-hydroxyphenyl)-2-pyrazinyl]carbamat- e (128 mg) and
triethylamine (279 .mu.L) in chloroform (5 mL) was stirred at
80.degree. C. for 2 hours.
[0603] The reaction mixture was poured into water and extracted
with chloroform (20 mL). The organic layer was washed with
saturated saline solution (20 mL) and then dried over anhydrous
Na.sub.2SO.sub.4
[0604] The concentration of the solvent left a residue, which was
purified by column chromatography on silica gel (hexane/ethyl
acetate=4/1 to 1/2) followed by recrystallization from ethyl
ether-hexane to give the subject compound (114 mg) as colorless
crystals (melting point 263-265.degree. C.).
Example 64
[0605] Preparation of N-[5-(3-hydroxyphenyl)-2-pyrazinyl
]-3-oxospiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0606] (1) Preparation of 2-amino-5-(3-methoxyphenyl)pyrazine
[0607] To a solution of 2-amino-5-bromopyrazine (642 mg) in
dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560
mg), 1.5N aqueous sodium carbonate solution (4 mL) and
tetrakis(triphenylphosp- hine) palladium (0) (86 mg). The mixture
was stirred at 80.degree. C. for6 hours. To the reaction mixture
was added water (20 mL) and the whole was extracted with ethyl
acetate (50 mL.times.3). The extract was washed with saturated
saline solution and then dried over anhydrous Na.sub.2SO.sub.4. The
concentration of the solvent left a crystal residue, which was
washed with ethyl ether (10 mL) to give the subject compound (760
mg).
[0608] (2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine
2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in
methylene chloride (10 mL). To this mixture was added under
ice-cooling boron tribromide (530 .mu.L) and the whole was stirred
at room temperature for 14 hours. To the reaction mixture was added
1N aqueous sodium hydroxide. The whole was extracted with ethyl
acetate (30 mL.times.2). The organic layer was washed with
saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the solvent provides the
subject compound (94 mg) as a yellow solid.
[0609] (3) Preparation of Phenyl
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbam- ate
[0610] To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg)
in pyridine (10 mL) was added under ice-cooling phenyl
chloroformate (63 .mu.L). The mixture was stirred for 1 hour and
then poured into water (30 mL) and extracted with ethyl acetate (20
mL.times.3). The extract was washed with saturated saline solution
and then dried over anhydrous Na.sub.2SO.sub.4. The concentration
of the solvent left a crystal residue, which was washed with ethyl
ether (10 mL) to give the subject compound (51 mg).
[0611] (4) Preparation of
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[i-
sobetzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0612] A mixture of spiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (40 mg), phenyl
N-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamat- e (51 mg) and
triethylamine (119 .mu.L) in chloroform (5 mL) was stirred at
80.degree. C. for 2 hours. The reaction mixture was poured into
water and extracted with chloroform (20 mL). The organic layer was
washed with saturated saline solution (20 mL) and then dried over
anhydrous Na.sub.2SO.sub.4. The concentration of the solvent left a
residue, which was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/1 to 1/2) followed by recrystallization
from ethyl ether-hexane to give the subject compound (24 mg) as
colorless crystals (melting point 257-259.degree. C.).
Example 65
[0613] Preparation of
4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobe-
nzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0614] A mixture of
4-fluorospiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (150 mg), phenyl N-(5 -phenyl-2-pyrimidinyl)carbamate
(170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was
stirred at 60.degree. C. for 3 hours. The concentration of the
reaction mixture left a residue, which was purified by column
chromatography on silica gel (hexane/ethyl
acetate/methanol=1/1/0.about.8/8/1.about.6/6/1) followed by
recrystallization from ethyl acetate-hexane to give the subject
compound (190 mg) as colorless crystals (melting point
247-249.degree. C.).
Example 66
[0615] Preparation of 7-fluoro-3-oxo-N-(5-phenyl-2
-pyrimidinyl)spiro[isob-
enzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0616] A mixture of
7-fluorospiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride (150 mg), phenyl N-(5 -phenyl-2-pyrimidinyl)carbamate
(170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was
stirred at 60.degree. C. for 2 hours. The reaction mixture was
diluted with ethyl acetate. The whole was washed with 10% citric
acid aqueous solution, saturated aqueous sodium bicarbonate and
saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the reaction mixture left a
residue, which was recrystallized from ethyl acetate to give the
subject compound (202 mg) as colorless crystals (melting point
244-246.degree. C.)
Example 67
[0617] Preparation of
6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzo-
furan-1(3H),4'-piperidine]-1'-carboxamide
[0618] (1) Preparation of 2-(4-ethylphenyl)-4,4-dimethyl-2
-oxazoline
[0619] To a solution of 4-ethylbenzoic acid (3.80 g) in anhydrous
acetonitrile (100 pL) was added under a nitrogen atmosphere,
triphenylphosphine (20 g), 2-amino-2 -methyl-1-propanol (2.74 mL)
and triethylamine (28.2 mL). The mixture was cooled on an ice bath
and then tetrachloromethane (5.36 mL) was added. The reaction
mixture was allowed to stand at room temperature and stirred for 18
hours. To the reaction mixture was added ethyl acetate and hexane
and the precipitate was removed by filtration. The concentration of
the filtrate left a residue, which was purified by column
chromatography on silica gel (hexane/ethyl acetate/=9/1/to 6/1) to
give the subject compound (1.15 g).
[0620] (2) Preparation of
1'-benzyl-6-ethylspiro[isobenzofuran-1(3H),4'-pi- peridine]-3-one
hydrochloride
[0621] Under a nitrogen atmosphere, a solution of
2-(4-ethylphenyl)-4,4-di- methyl-2-oxazoline (1.15 g) in anhydrous
tetrahydrofuran (100 mL) was cooled to -78.degree. C. To this
solution was added 1.5 M butyl lithium hexane solution (4.53 mL).
After being stirred for 1 hour, 1-benzyl-4 -piperidone (1.05 mL)
was added dropwise. After the reaction temperature was allowed to
rise up to room temperature, 2N hydrochloric acid was added to the
reaction mixture to make the mixture acidic. The whole was refluxed
for 2 hours. After cooling, sodium hydroxide aqueous solution was
added to make the reaction mixture basic. The mixture was extracted
with ethyl ether. The organic layer was washed with saturated
saline solution and then dried over anhydrous Na.sub.2SO.sub.4. The
concentration of the organic solvent left a residue, which was
purified by column chromatography on silica gel (hexane/ethyl
acetate/=3/2) to give the subject compound (409 mg).
[0622] (3) Preparation of
6-ethylspiro[isobenzofuran-1(3H),4'-piperidine]-- 3-one
hydrochloride
[0623]
1'-benzyl-6-ethylspiro[isobenzofuran-1(3H),4'-piperidine]-3-one
hydrochloride(400 mg) was dissolved in methanol (10 mL) and 10%
palladium carbon was added. The mixture was stirred under a
hydrogen atmosphere for 1.5 hours.
[0624] After the palladium carbon was removed by filtration, the
filtrate was concentrated to give a residue, which was subjected to
crystallization with methanol-ethyl ether to give the subject
compound (222 mg).
[0625] (4) Prepartation of 6-ethyl-3-oxo-N-(5-phenyl-2
-pyrazinyl)spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide
[0626] To a suspension of
6-ethylspiro[isobenzofuran-1(3H),4'-piperidine]-- 3-one
hydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate
(58 mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium
hydroxide aqueous solution (0.02 mL). The mixture was vigorously
stirred for 5 minutes followed by partition between water and ethyl
acetate. The organic layer was separated and then washed with
saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4 The concentration of the organic solvent left a
residue, which was subjected to the crystallization from ethyl
acetate to give the subject compound (46 mg) as crystals (melting
point 176-178.degree. C.).
Example 68
[0627] Preparation of
6-hydroxy-3-oxo-N-(5-phenyl-2-ryrazinyl)spiro[isoben-
zofuran-1(3H),4'-piperidine]-1'-carboxamide
[0628] (1) Preparation of
2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline
[0629] To a solution of 2-amino-2-methyl-1-propanol (14.4 g) and
triethylamine (23 mL) in dried THF (200 mL) was added dropwise
under ice-cooling a solution of 4-methoxybenzoyl chloride (25 g) in
dried THF (20 mL). The mixture was stirred at room temperature for
1 hour and then water (200 mL) was added. The reaction mixture was
extracted with ethyl acetate (100 mL) twice. The organic layer was
washed with saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the organic solvent provided
the subject compound (29.5 g) as a white solid. Thionyl chloride
(25 mL) was added to the above white solid compound, and the
reaction was carried out at room temperature for one hour. The
reaction mixture was made alkaline by the addition of 5N sodium
hydroxide aqueous solution and was extracted twice each with ethyl
acetate (100 mL). The combined organic layer was washed with
saturated sodium chloride aqueous solution and dried with anhydrous
sodium sulfate. The solvent was evaporated off to give the
above-identified compound (22 g) as colorless oil.
[0630] (2) Preparation of 1'-benzyl-6
-methoxyspiro[isobenzofuran-1(3H),4,- -piperidine]-3-one
[0631] Under a nitrogen atmosphere, to a solution of
2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in anhydrous
toluene (100 mL) was added dropwise under ice-cooling 1.5M butyl
lithium hexane solution (28 mL). After being stirred for 3 hours at
the same temperature, 1 -benzyl-4-piperidone (8 g) in anhydrous
toluene (20 mL) was added dropwise. After the reaction mixture was
stirred at room temperature for 14 hours, a saturated ammonium
chloride aqueous solution (50 mL) was added. The mixture was
extracted with ethyl acetate (100 mL) twice. The organic layer was
washed with saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the organic solvent provided
the compound (8.3 g) as a white solid. This compound was dissolved
in methanol (50 mL) and concentrated sulfuric acid (4 mL) was
added. The mixture was stirred at room temperature for 1 hour. To
the reaction mixture was added 1N sodium hydroxide aqueous solution
to make the reaction mixture basic. The mixture was extracted with
ethyl acetate (100 mL) twice. The organic layer was washed with
saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the organic solvent provided
the subject compound (6.6 g) as a yellow solid.
[0632] (3) Preparation of
6-hydroxyspiro[isobenzofuran-1(3H),4'-piperidine- ]-3-one
hydrochloride
[0633] 1'-benzyl-6-methoxyspiro[isobenzofuran-1
(3H),4'-piperidine]-3-one (1.8 g) was dissolved in methylene
chloride (20 mL). To this solution was added under ice-cooling
boron tribromide (1.3 mL). After the reaction mixture was stirred
at room temperature for 14 hours, 1 N sodium hydroxide aqueous
solution was added. The mixture was extracted with ethyl acetate
(30 mL) twice. The organic layer was washed with saturated saline
solution and then dried over anhydrous Na.sub.2SO.sub.4. The
concentration of the organic solvent provided the compound (1.2 g)
as a yellow solid, which was dissolved in methanol (30 mL). To this
solution was added 4 N hydrogen chloride-ethyl acetate (5 mL), 20%
palladium hydroxide-carbon (300 mg). The mixture was stirred under
a hydrogen atmosphere for 14 hours. After the catalyst was removed
by filtration, the filtrate was concentrated to give the subject
compound (891 mg) as a white solid.
[0634] (4) Prepartation of 6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)
spiro[isobenzofuran-1 (3H),4'-piperidine]-1'-carboxamide
[0635] A mixture of 6-hydroxyspiro[isobenzofuran-1(3H),
4'-piperidine]-3-one hydrochloride (51 mg), phenyl
N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) and triethylamine (119
.mu.L) in chloroform (5 mL) was stirred at 80.degree. C. for 2
hours. The reaction mixture was poured into water, and then
extracted with chloroform (20 mL). The organic layer was washed
with saturated saline solution (20 mL) and then dried over
anhydrous Na.sub.2SO.sub.4. The concentration of the organic
solvent left a residue, which was purified by column chromatography
on silica gel (hexane/ethyl acetate/=4/1 to 1/2) followed by the
recrystallization from ethyl etherhexane to give the subject
compound (29 mg) as colorless crystals (melting point
206-208.degree. C.).
[0636] The compounds from Example 69 to Example 79 were prepared,
according to the same preparation procedure described in Example 61
by using the corresponding starting material in place of
4-aminobenzophenon used in the Example 61.
[0637] Example 69
[0638]
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiror[5-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide.
[0639] melting point 215-217.degree. C.
Example 70
[0640]
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiror[5-azaisobenz-
ofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0641] melting point 205-207.degree. C.
Example 71
[0642]
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiror[5-azaisobenz-
ofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0643] melting point 226-228.degree. C.
7 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps)
11.14 970 14.62 1418 15.02 570 15.12 920 15.56 895 16.22 475 17.10
1873 19.22 1698 20.06 3202 20.54 542 20.78 1013 21.00 1063 21.78
2405 23.24 5557 24.12 555 24.90 888 25.98 487 26.30 500 27.52 2765
28.22 690 28.56 553 28.82 647 29.04 423 29.70 653 30.54 1102 32.84
362 36.46 408
[0644] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 32.
Example 72
[0645]
trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0646] melting point 273-275.degree. C.
Example 73
[0647]
trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzo-
furan-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0648] melting point 213-215.degree. C.
Example 74
[0649]
trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiror[5-azaisobenz-
ofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0650] melting point 145-147.degree. C.
Example 75
[0651] trans-N-[5-(3-fluoromethoxyphenyl
-2-pyrimidinyl]-3-oxospiro[5-azai- sobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0652] melting point 157-159.degree. C.
Example 76
[0653] trans-N-[5-(3-fluoromethylphenyl)
-2-pyrimidinyl]-3-oxospiro[5-azai- sobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0654] melting point 153-155.degree. C.
Example 77
[0655] trans-N-[5-(3-fluoro-5-methoxyphenyl)
-2-pyrimidinyl]-3-oxospiro]5-- azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0656] melting point 218-220.degree. C.
Example 78
[0657]
trans-N-[5-(2-fluoro-5-methyliphenyl)-2-pyrimidinyl]-3-oxospiro[5-a-
zaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0658] melting point 151-153.degree. C.
Example 79
[0659]
trans-N-[4-(3-fluoromethoxylphenyl)-2-oxazolyl]-3-oxospiro[5-azaiso-
benzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0660] melting point 214-217.degree. C.
Example 80
[0661] Preparation of
trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3--
oxospiro[5-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0662] To a solution of 2-chloro-1,3-dimethylimidazolium chloride
(613 mg) in chloroform (10 mL) was added pyridine (0.489 mL),
trans-3-oxospiro[5-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxylic acid (300 mg) and
2-amino-5-bromopyrimidine (211 mg). The mixture was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate.
[0663] The whole was washed with 10% citric acid aqueous solution,
saturated sodium bicarbonate aqueous solution, saturated saline
solution and then dried over anhydrous Na.sub.2SO.sub.4. The
concentration of the organic solvent left a residue, which was
purified by column chromatography on silica gel (hexane/ethyl
acetate=1/1 to 1/3 to 1/4 to 1/5) followed by the crystallization
from ethyl acetate to give the desired amide (210 mg). This amide
was suspended in ethyleneglycol dimethyl ether (3.5 mL), and water
(0.5 mL), 3-hydroxymethylphenylboronic acid (95 mg), 2 M sodium
carbonate aqueous solution (0.31 mL) and
tetrakistriphenylphosphinepalladium (30 mg) was added thereto.
[0664] The mixture was refluxed for 2 hours and then diluted with
water. The whole was extracted with ethyl acetate and then dried
over anhydrous Na.sub.2SO.sub.4. The concentration of the organic
solvent left a residue, which was purified by column chromatography
on silica gel (ethyl acetate/methanol=1/0 to 30/1 to 20/1 to 15/1)
to give the subject compound (151 mg) as light yellow crystals
(
[0665] melting point 207-209.degree. C.).
Example 81
[0666] Preparation of
trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospi-
ro[5-azaisobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0667] To a solution of 2-chloro-1,3-dimethylimidazolium chloride
(622 mg) in chloroform (7 mL) was added pyridine (0.50 mL),
trans-3-oxospiro[5-azaisobenzofuran-1(3H),
1'-cyclohexane]-4'-carboxylic acid (303 mg) and
2-amino-5-(3-benzyloxyphenyl) pyrimidine (340 mg). The mixture was
stirred at room temperature overnight. The reaction mixture was
diluted with ethyl acetate. The whole was washed with 10% citric
acid aqueous solution, saturated sodium bicarbonate aqueous
solution, saturated saline solution and then dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the organic solvent left a
residue, which was purified by column chromatography on silica gel
(hexane/ethyl acetate=1/1 to 1/2 to 1/4 to 1/5 to 1/6) followed by
the crystallization from ethyl acetate to give the desired amide
(210 mg). This amide was dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL), and 10% palladium-carbon (120 mg) was
added. The mixture was stirred at room temperature under a hydrogen
atmosphere overnight. The catalyst was removed by filtration. The
filtrate was concentrated to give a residue, which was purified by
column chromatography on silica gel (chloroform/methanol=50/1 to
30/1) to give a solid compound. The solid compound was washed with
ethanol and then recrystallized from ethyl acetate to give the
subject compound (95 mg) as light yellow crystals (melting point
260-262.degree. C.).
[0668] The compounds from Example 82 to Example 89 were prepared,
according to the same preparation procedure described in Example 62
by using the corresponding starting material in place of
4-aminobenzophenon used in the Example 62.
Example 82
[0669]
trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0670] melting point 189-191.degree. C.
Example 83
[0671]
trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azais-
obenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0672] melting point 199-200.degree. C.
Example 84
[0673]
trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azai-
sobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0674] melting point 198-200.degree. C.
Example 85
[0675] trans-3-oxo-N-(6-phenyl-1, 2,
4-triazin-3-yl)spiro[6-azaisobenzofur- an-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0676] melting point 272-275.degree. C.
Example 86
[0677]
trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azai-
sobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0678] melting point 239-240.degree. C.
Example 87
[0679]
trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azai-
sobenzofuran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0680] melting point 183-185.degree. C.
Example 88
[0681]
trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0682] melting point 182-184.degree. C.
Example 89
[0683]
trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0684] melting point 228-229.degree. C.
Example 90
[0685] Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofu- ran-1(3H),
1'-cyclohexane]-4'-carboxamide
[0686] (1) Preparation of 3-cyano-2-hydroxypyridine
[0687] To malonaldehyde bisdimethylacetal (16.4 g) was added 0.5 N
hydrochloric acid (40 mL). The mixture was stirred at 50.degree. C.
for 20 minutes and then cooled to room temperature. To the reaction
mixture was added triethylamine (16 mL) followed by
2-cyanoacetoamide (9 g). The whole was stirred at room temperature
for 30 minutes and further heated at 60.degree. C. for 90 minutes
as well as 100.degree. C. for 2 hours. After cooling, the reaction
mixture was concentrated to give a residue, which was
recrystallized from ethanol-ethyl ether to give the subject
compound (7.49 g).
[0688] (2) Preparation of 2-bromo-3-cyanopyridine
[0689] Tetrabutylammonium bromide (35.4 g) and diphosphorus
pentaoxide (15.58 g) was suspended in toluene (100 mL). After the
mixture was stirred at 70.degree. C. for 30 minutes,
3-cyano-2-hydroxypyridine (6.59 g) was added thereto. The mixture
was refluxed for 4 hours. The reaction mixture was poured into the
ice water (200 g) and extracted with ethyl acetate (200
mL.times.2). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4. The concentration of the solvent gave a oily
residue, which was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/1 to 3/1) to give a solid compound. The
solid compound was recrystallized from ethyl acetate-hexane to give
the subject compound (5.16 g).
[0690] (3) Preparation of spiro[7-azaisobenzofuran-1 (3H),
1'-cyclohexane]-3,4'-dione
[0691] 2-bromo-3-cyanopyridine (2.96 g) and 1,4-cyclohexanedione
monoethyleneketal (3.47 g) were dissolved in anhydrous
tetrahydrofuran (38 mL). After being cooled to -78.degree. C.,
n-butyl lithium (1.5 M hexane solution, 12.64 mL) was added and the
mixture was stirred at -78.degree. C. for 30 minutes. The reaction
temperature was allowed to rise up to the room temperature. The
reaction mixture was poured into water (40 mL) and extracted with
ethyl acetate (100 mL.times.3). The organic layer was dried over
anhydrous MgSO.sub.4. The concentration of the solvent gave a
residue, which was recrystallized from ethyl ether-hexane to give
iminoether compound (2.93 g). This compound was dissolved in
acetone (5 mL) and 2 N hydrochloric acid (30 mL). The solution was
refluxed for 2 hours. After cooling, 2 N sodium hydroxide aqueous
solution was added to the reaction mixture to adjust pH to 4. The
whole was extracted with ethyl acetate (100 mL.times.3). The
organic layer was dried over anhydrous MgSO.sub.4. The
concentration of the solvent gave a residue, which was
recrystallized from ether-hexane to give the subject compound (1.07
g).
[0692] (4)Preparation of cis-4'-hydroxyspiro[7-azaisobenzofuran-1
(3H), 1'-cyclohexane]-3-one
[0693] Spiro[7-azaisobenzofuran-1 (3H), 1'-cyclohexane]-3,4'-dione
(1.6 g) was suspended in tetrahydrofuran (37 mL). After being
cooled to 0.degree. C., lithium tert-butoxyaluminium hydride (1.0 M
tetrahydrofuran solution, 9.58 mL) was added dropwise to the
mixture. After the mixture was stirred at 0.degree. C. for 90
minutes, 1 N hydrochloric acid was added to adjust pH to 2. The
mixture was extracted with ethyl acetate (100 mL.times.4). The
organic layer was dried over anhydrous MgSO.sub.4. The
concentration of the solvent gave the subject compound (1.58
g).
[0694] (5) Preparation of
trans-3-oxospiro[7-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carbonitrile
[0695] Cis-4'-hydroxyspiro[7-azaisobenzofuran-1 (3H),
1'-cyclohexane]-3-one (1.58 g) and triethylamine (1.81 mL) were
dissolved in chloroform (28 mL). After being cooled to 0.degree.
C., methanesulfonyl chloride (0.67 mL) was added thereto. The
mixture was stirred at room temperature for 2 hours and then poured
into the saturated sodium bicarbonate aqueous solution (50 mL). The
whole was extracted with chloroform (100 mL.times.3). The organic
layer was dried over anhydrous MgSO.sub.4. The concentration of the
solvent gave a oily residue, which was purified by column
chromatography on silica gel (hexane/ethyl acetate=2/1 to 1/2) to
give a solid compound. The solid compound was recrystallized from
ethyl acetate-hexane to give the desired mesylate compound (2.03
g). This compound was dissolved in anhydrous dimethylformamide (30
mL), and triethylammonium cyanide (3.2 g) was added thereto. The
mixture was stirred at 100.degree. C. for 3 hours. After being
cooled, the reaction mixture was poured into water (100 mL). The
whole was extracted with ethyl acetate (100 mL.times.3). The
organic layer was dried over anhydrous MgSO.sub.4. The
concentration of the solvent gave a oily residue, which was
purified by column chromatography on silica gel (hexane/ethyl
acetate=3/1 to 2/1) to give a solid compound. The solid compound
was further recrystallized from ethyl ether-hexane to give the
subject compound (515 mg).
[0696] (6) Preparation of trans-3-oxospiro[7-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxylic acid
[0697] Water (6.6 mL) and concentrated sulfuric acid (2.2 mL) were
added to trans-3-oxospiro[7-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboni- trile (515 mg). The mixture was
refluxed for 13 hours. After the reaction mixture was cooled to
0.degree. C., 4 N sodium hydroxide aqueous solution was added to
adjust pH to 4. The crystal precipitated was collected by
filtration. The crystal was washed with water, ethanol as well as
diisopropyl ether and then dried. The subject compound (500 mg) was
obtained.
[0698] .sup.1H-NMR (300 MHz, DMSO-d.sub.6,.delta. ppm):
1.73-1.80(2H, m), 1.81-1.94(2H, m), 1.99-2.08(2H, m), 2.14-2.22(2H,
m), 2.64-2.68(1H, m), 7.63(1H, dd, J=7.8, 4.8 Hz), 8.28(1H, dd,
J=7.8, 1.5 Hz), 8.89(1H, dd, J=4.8, 1.5 Hz).
[0699] (7) Preparation of
trans-N-(4-benzoylphenyl)-3-oxospiro-[7-azaisobe- nzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0700] trans-3-oxospiro[7-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carb- oxylic acid (26 mg) and
4-aminobenzophenone (20 mg) were dissolved in anhydrous pyridine (1
mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(29 mg) was added thereto. The mixture was stirred at room
temperature for 18 hours.
[0701] The reaction mixture was poured into water (10 mL). The
whole was extracted with ethyl acetate (30 mL.times.3). The
combined organic layer was dried over anhydrous MgSO.sub.4. The
concentration of the solvent gave an oily residue, which was
purified by column chromatography on silica gel (hexane/ethyl
acetate=3/1 to 2/1) to give a solid compound. The solid compound
was further recrystallized from ethyl acetate-hexane to give the
subject compound (30 mg) as colorless crystals (melting point
214-216.degree. C.).
[0702] Employing the procedure substantially as described in
Example 90-(7), but substituting the appropriate amines for
4-aminobenzophenone used in Example 90-(7), compounds of Examples
91 to 95 were prepared.
Example 91
[0703] trans-N-[1-(3,
5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisob- enzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0704] melting point 269-271.degree. C.
8 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps) 6.68
338 7.62 288 13.42 1202 14.22 693 14.36 1880 15.48 965 16.40 652
16.92 1240 17.00 1232 18.82 1258 19.30 690 20.02 908 20.12 932
20.26 515 21.56 663 22.80 560 22.90 755 23.12 538 23.34 520 23.42
502 23.88 1342 25.10 2087 26.70 722 28.64 348 28.98 272 29.66 273
31.42 273 31.94 315 32.08 353 34.06 293 36.02 267
[0705] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 32.
Example 92
[0706] trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0707] melting point 221-223.degree. C.
Example 93
[0708]
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0709] melting point 240-242.degree. C.
Example 94
[0710]
trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0711] melting point 214-217.degree. C.
Example 95
[0712]
trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofu-
ran-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0713] melting point 210-212.degree. C.
[0714] Employing the procedure substantially as described in
Example 57-(6), but substituting the appropriate amines for
4-aminobenzophenone used in Example 57-(6), compounds of Examples
96 to 98 were prepared.
[0715] Example 96
[0716]
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0717] melting point 200-202.degree. C.
Example 97
[0718]
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0719] melting point 223-225.degree. C.
9 Powder X-ray diffraction 2 .theta. (degrees) Intensity (cps) 8.14
1612 11.58 613 11.86 4470 12.60 1472 13.20 1208 13.30 975 15.86
1913 16.32 1665 17.72 2347 18.66 1482 18.76 2192 19.38 647 19.42
805 19.68 4470 19.76 3805 20.60 2302 21.46 1698 22.26 1375 22.34
1550 23.10 1422 23.88 588 24.48 697 24.66 3807 24.76 6918 25.28 992
25.38 1390 26.14 447 26.74 1853 27.50 2855 28.62 943 28.70 975
30.58 1747 31.22 543 33.68 670 33.78 918
[0720] Above powder X-ray diffraction analysis data were measured
by the same conditions as Example 32.
Example 98
[0721]
trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro4-azaisobenzofur-
an-1 (3H), 1'-cyclohexane]-4'-carboxamide
[0722] melting point 176-178.degree. C.
[0723] Employing the procedure substantially as described in
Example 62-(6), but substituting the appropriate amines for
4-aminobenzophenone used in Example 62-(6), compounds of Examples
99 to 106 were prepared.
Example 99
[0724]
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0725] melting point 249-250.degree. C.
Example 100
[0726] trans-N-[1-(4-fluorophenyl)
-3-pyrazolyl]-3-oxospiro[6-azaisobenzof- uran-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0727] melting point 254-257.degree. C.
Example 101
[0728]
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofu-
ran-1 (3H),1'-cyclohexane]-4'-carboxamide
[0729] melting point 239-241.degree. C.
Example 102
[0730] trans-3-oxo-N-(5-phenyl-1, 2,
4-thiadiazol-3-yl)spiro[6-azaisobenzo- furan-1 (3H),
1'-cyclohexane]-4'-carboxamide
[0731] melting point 221-223.degree. C.
Example 103
[0732]
trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0733] melting point 259-261.degree. C.
Example 104
[0734] trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0735] melting point 249-251.degree. C.
Example 105
[0736]
trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1
(3H), 1'-cyclohexane]-4'-carboxamide
[0737] melting point 278-280.degree. C.
Example 106
[0738]
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-
-1(3H),1'-cyclohexane]-4 carboxamide melting point 232-233.degree.
C.
[0739] Formulation example 1
[0740] 20.0 grams of compound of Example 1, 417 grams of lactose,
80 grams of crystalline cellulose and 80 grams of partial
.alpha.-starch were blended with a V-cone blender. To the mixture
was added 3.0 grams of magnesium stearate and the whole was
blended. The blended powder was compressed into 3000 tablets by
conventional procedure so that each tablet has a weight of 150 mg
and 7.0 mm in diameter.
10 The content of one tablet with a weight of 150 mg the compound
of Example 1 5.0 mg lactose 104.25 mg crystalline cellulose 20.0 mg
partial .alpha.-starch 20.0 mg magnesium stearate 0.75 mg
Formulation example 2
[0741] 10.8 grams of hydroxypropylcellulose 2910 and 2.1 grams of
polyethylene glycol 6000 were dissolved in 172.5 grams of purified
water. To the solution was dispersed 2.1 grams of titanium oxide to
provide a coating liquid. 2500 tablets prepared in Formulation
example 1, was subjected to spray-coating with the coating liquid
using HICOATER-MINI to provide a film coated tablet with a weight
of 155 mg.
11 The content of one tablet (155 mg) the tablet prepared in the
Formulation example 1 150 mg hydroxypropylcellulose 2910 3.6 mg
Polyethylene glycol 6000 0.7 mg titanium dioxide 0.7 mg
[0742] Compounds of the present invention exhibit NPY antagonistic
activities and are useful as agents for the treatment of various
diseases related to NPY, for example, cardiovascular disorders such
as hypertension, nephropathy, heart disease, vasospasm,
arteriosclerosis and the like, central nervous system disorders
such as bulimia, depression, anxiety, seizure, epilepsy, dementia,
pain, alcoholism, drug withdrawal and the like, metabolic diseases
such as obesity, diabetes, hormone abnormality,
hypercholesterolemia, hyperlipidemia and the like, sexual and
reproductive dysfunction, gastrointestinal disorder, respiratory
disorder, inflammation or glaucoma, and the like.
* * * * *