U.S. patent application number 11/872408 was filed with the patent office on 2008-05-01 for methods for treating depression, neurodegeneration, inhibiting amyloid beta deposition, delaying senescence, and extending life spans with heterocyclic compounds.
This patent application is currently assigned to ZENYAKU KOGYO KABUSHIKI KAISHA. Invention is credited to Toshiyuki Matsuno, Hitoshi Miyashita, Takeshi Nagata, Kenichi Saitoh, Yoshimasa Yamaguchi, Ryogo Yui.
Application Number | 20080103157 11/872408 |
Document ID | / |
Family ID | 39069373 |
Filed Date | 2008-05-01 |
United States Patent
Application |
20080103157 |
Kind Code |
A1 |
Yamaguchi; Yoshimasa ; et
al. |
May 1, 2008 |
METHODS FOR TREATING DEPRESSION, NEURODEGENERATION, INHIBITING
AMYLOID BETA DEPOSITION, DELAYING SENESCENCE, AND EXTENDING LIFE
SPANS WITH HETEROCYCLIC COMPOUNDS
Abstract
Disclosed is an antidepressant, neuroprotectant, amyloid .beta.
deposition inhibitor, or age retardant composition containing a
heterocyclic compound having the general formula (I): ##STR1##
Inventors: |
Yamaguchi; Yoshimasa;
(Tokyo, JP) ; Yui; Ryogo; (Tokyo, JP) ;
Matsuno; Toshiyuki; (Tokyo, JP) ; Saitoh;
Kenichi; (Tokyo, JP) ; Miyashita; Hitoshi;
(Tokyo, JP) ; Nagata; Takeshi; (Tokyo,
JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
ZENYAKU KOGYO KABUSHIKI
KAISHA
Chuo-ku
JP
|
Family ID: |
39069373 |
Appl. No.: |
11/872408 |
Filed: |
October 15, 2007 |
Current U.S.
Class: |
514/259.1 ;
514/278; 514/300 |
Current CPC
Class: |
C07D 513/20 20130101;
A61K 31/438 20130101; A61K 31/495 20130101; A61P 17/00 20180101;
A61P 9/10 20180101; A61P 39/06 20180101; A61P 9/12 20180101; A61P
25/00 20180101; A61P 25/28 20180101; A61K 31/444 20130101; A61P
29/00 20180101; A61P 19/10 20180101; A61K 31/425 20130101; A61P
25/24 20180101; C07D 487/04 20130101; A61P 7/04 20180101; C07D
471/04 20130101; A61P 9/04 20180101; A61P 19/02 20180101; C07D
471/10 20130101; C07D 487/10 20130101; A61P 17/14 20180101; A61K
31/437 20130101; A61K 31/40 20130101; A61K 31/429 20130101; A61K
31/519 20130101; A61P 27/12 20180101; C07D 513/04 20130101; A61K
31/4745 20130101; A61K 31/426 20130101; A61P 39/00 20180101; A61K
31/4015 20130101 |
Class at
Publication: |
514/259.1 ;
514/278; 514/300 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/438 20060101 A61K031/438; A61K 31/519 20060101
A61K031/519; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 13, 2006 |
JP |
2006-280768 |
Claims
1. A method of treating or preventing depression, manic depressive
psychoses, obsessive-compulsive disorder, panic disorder, or
anxiety disorder in a mammal in need thereof, comprising
administering to the mammal an effective amount of a heterocyclic
compound having the general formula (I): ##STR91## or a
pharmaceutically acceptable salt or hydrate thereof, wherein: in
the general formula (I), the structural unit having the general
formula (II): ##STR92## is one or more structural units selected
from multiple types of structural units having the general formula
(III): ##STR93## in the general formula (I), R.sub.1 and R.sub.2
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, amino group, acetylamino group, benzylamino group,
trifluoromethyl group, C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, and --O--(CH.sub.2).sub.n--R.sub.5, wherein R.sub.5
is a vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or phenyl
group, and n is 0 or 1; R.sub.3 and R.sub.4 each are one or more
functional groups independently selected from the group consisting
of a hydrogen atom, C.sub.1-C.sub.6 alkyl group, C.sub.3-C.sub.8
cycloalkyl group, and --CH(R.sub.7)--R.sub.6; alternatively,
R.sub.3 and R.sub.4 together forms a spiro ring having the general
formula (IV): ##STR94## said R.sub.6 is one or more functional
groups selected from the group consisting of a vinyl group; ethinyl
group; phenyl optionally substituted by a C.sub.1-C.sub.6 alkyl
group, C.sub.1-C.sub.6 alkoxy group, hydroxy group, 1 or 2 halogen
atoms, di C.sub.1-C.sub.6 alkylamino group, cyano group, nitro
group, carboxy group, or phenyl group; phenethyl group; pyridyl
group; thienyl group; and furyl group; said R.sub.7 is a hydrogen
atom or C.sub.1-C.sub.6 alkyl group; in the general formula (IV),
the structural unit B is one or more structural units selected from
multiple types of structural units having the general formula (V):
##STR95## said structural unit B binds at a position marked by * in
the general formula (V) to form a spiro ring; and R.sub.8 is one or
more functional groups selected from the group consisting of a
hydrogen atom, halogen atom, hydroxy group, C.sub.1-C.sub.6 alkoxy
group, cyano group, and trifluoromethyl group.
2. The method according to claim 1 wherein said heterocyclic
compound is one or more heterocyclic compounds selected from the
group consisting of: 3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one,
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one,
3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one,
5,5-dibenzylimidazo[2,1-b]thiazol-6(5H)-one,
3,3-dibenzylimidazo[1,2-a]pyrimidin-2(3H)-one,
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-fluoroindan)],
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-methoxyindan)],
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-cyanoindan)],
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-indan],
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-((1,2,5-thiadiazo)[4,5-c]indan-
)], spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-indan],
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,4'-(1'-cyclopentene)],
3,3-bis(4-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
8-cyclopropylmethyloxy-3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one,
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-hydroxyindan)],
spiro[8-hydroxy-imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
spiro[8-methoxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cyclopentene)],
and
spiro[8-cyclopropylmethyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-
-cyclopentene)].
3. The method according to claim 1 or 2 wherein said administration
is oral.
4. The method according to claim 1 or 2 wherein said method is for
treating depression.
5. A method of reducing or preventing neurodegeneration in a mammal
in need thereof, comprising administering to the mammal an
effective amount of a compound having the general formula (I):
##STR96## or a pharmaceutically acceptable salt or hydrate thereof,
wherein: in the general formula (I), the structural unit having the
general formula (II): ##STR97## is one or more structural units
selected from multiple types of structural units having the general
formula (III): ##STR98## in the general formula (I), R.sub.1 and
R.sub.2 each are one or more functional groups independently
selected from the group consisting of a hydrogen atom, halogen
atom, hydroxy group, amino group, acetylamino group, benzylamino
group, trifluoromethyl group, C.sub.1-C.sub.6 alkyl group,
C.sub.1-C.sub.6 alkoxy group, and --O--(CH.sub.2)n-R.sub.5, wherein
R.sub.5 is a vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or
phenyl group, and n is 0 or 1; R.sub.3 and R.sub.4 each are one or
more functional groups independently selected from the group
consisting of a hydrogen atom, C.sub.1-C.sub.6 alkyl group,
C.sub.3-C.sub.8 cycloalkyl group, and --CH(R.sub.7)--R.sub.6;
alternatively, R.sub.3 and R.sub.4 together form a spiro ring
having the general formula (IV): ##STR99## said R.sub.6 is one or
more functional groups selected from the group consisting of a
vinyl group; ethinyl group; phenyl optionally substituted by a
C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6 alkoxy group, hydroxy
group, 1 or 2 halogen atoms, di C.sub.1-C.sub.6 alkylamino group,
cyano group, nitro group, carboxy group, or phenyl group; phenethyl
group; pyridyl group; thienyl group; and furyl group; said R.sub.7
is a hydrogen atom or C.sub.1-C.sub.6 alkyl group; in general
formula (IV), the structural unit B is one or more structural units
selected from multiple types of structural units having the general
formula (V): ##STR100## said structural unit B binds at a position
marked by * in the general formula (V) to form a spiro ring; and
R.sub.8 is one or more functional groups selected from the group
consisting of a hydrogen atom, halogen atom, hydroxy group,
C.sub.1-C.sub.6 alkoxy group, cyano group, and trifluoromethyl
group.
6. The method according to claim 5 wherein said heterocyclic
compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan].
7. The method according to claim 5 or 6 wherein said administration
is oral.
8. The method according to claim 5, wherein said neurodegeneration
is the result of one or more cerebrovascular disorders selected
from the group consisting of transient ischemic attack, cerebral
hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage,
cerebral infarct, and hypertensive encephalopathy.
9. A method of inhibiting amyloid .beta. deposition in an mammal in
need thereof, comprising administering to the mammal an effective
amount of a compound having the general formula (I): ##STR101## or
a pharmaceutically acceptable salt or hydrate thereof, wherein: in
the general formula (I), the structural unit having the general
formula (II): ##STR102## is one or more structural units selected
from multiple types of structural units having the general formula
(III): ##STR103## in the general formula (I), R.sub.1 and R.sub.2
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, amino group, acetylamino group, benzylamino group,
trifluoromethyl group, C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, and --O--(CH.sub.2)n-R.sub.5, wherein R.sub.5 is a
vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or phenyl group, and
n is 0 or 1; R.sub.3 and R.sub.4 each are one or more functional
groups independently selected from the group consisting of a
hydrogen atom, C.sub.1-C.sub.6 alkyl group, C.sub.3-C.sub.8
cycloalkyl group, and --CH(R.sub.7)--R.sub.6; alternatively,
R.sub.3 and R.sub.4 together form a spiro ring having the general
formula (IV): ##STR104## said R.sub.6 is one or more functional
groups selected from the group consisting of a vinyl group; ethinyl
group; phenyl optionally substituted by a C.sub.1-C.sub.6 alkyl
group, C.sub.1-C.sub.6 alkoxy group, hydroxy group, 1 or 2 halogen
atoms, di C.sub.1-C.sub.6 alkylamino group, cyano group, nitro
group, carboxy group, or phenyl group; phenethyl group; pyridyl
group; thienyl group; and furyl group; said R.sub.7 is a hydrogen
atom or C.sub.1-C.sub.6 alkyl group; in the general formula (IV),
the structural unit B is one or more structural units selected from
multiple types of structural units having the general formula (V):
##STR105## said structural unit B binds at a position marked by *
in the general formula (V) to form a spiro ring; and R.sub.8 is one
or more functional groups selected from the group consisting of a
hydrogen atom, halogen atom, hydroxy group, C.sub.1-C.sub.6 alkoxy
group, cyano group, and trifluoromethyl group.
10. The method according to claim 9 wherein said heterocyclic
compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan].
11. The method according to claim 9 or 10 wherein said
administration is oral.
12. The method according to claim 9 or 10 wherein said amyloid
.beta. deposition is associated with one or more amyloid-related
pathologies selected from the group consisting of amyloidosis,
cerebral amyloid angiopathy, cataract, glaucoma, the progression of
glaucoma, age-related macular degeneration, rheumatism,
osteoporosis, metabolic syndrome, wrinkles, and hair loss.
13. An method of delaying senescence is an animal in need thereof,
comprising administering to the animal an effective amount of a
heterocyclic compound having the general formula (I): ##STR106## or
a pharmaceutically acceptable salt or hydrate thereof, wherein: in
the general formula (I), the structural unit having the general
formula (II): ##STR107## is one or more structural units selected
from multiple types of structural units having the general formula
(III): ##STR108## in the general formula (I), R.sub.1 and R.sub.2
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, amino group, acetylamino group, benzylamino group,
trifluoromethyl group, C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, and --O--(CH.sub.2)n-R.sub.5, wherein R.sub.5 is a
vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or phenyl group, and
n is 0 or 1; R.sub.1 and R.sub.4 each are one or more functional
groups independently selected from the group consisting of a
hydrogen atom, C.sub.1-C.sub.6 alkyl group, C.sub.3-C.sub.8
cycloalkyl group, and --C H(R.sub.7)--R.sub.6; alternatively,
R.sub.3 and R.sub.4 together form a spiro ring having the general
formula (IV): ##STR109## said R.sub.6 is one or more functional
groups selected from the group consisting of a vinyl group; ethinyl
group; phenyl optionally substituted by a C.sub.1-C.sub.6 alkyl
group, C.sub.1-C.sub.6 alkoxy group, hydroxy group, 1 or 2 halogen
atoms, di C.sub.1-C.sub.6 alkylamino group, cyano group, nitro
group, carboxy group, or phenyl group; phenethyl group; pyridyl
group; thienyl group; and furyl group; said R.sub.7 is a hydrogen
atom or C.sub.1-C.sub.6 alkyl group; in the general formula (IV),
the structural unit B is one or more structural units selected from
multiple types of structural units having the general formula (V):
##STR110## said structural unit B binds at a position marked by *
in the general formula (V) to form a spiro ring; and R.sub.8 is one
or more functional groups selected from the group consisting of a
hydrogen atom, halogen atom, hydroxy group, C.sub.1-C.sub.6 alkoxy
group, cyano group, and trifluoromethyl group.
14. The method according to claim 13 wherein said heterocyclic
compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan].
15. The method according to claim 13 or 14 wherein said
administration is oral.
16. A method of extending the life span of a mammal in need
thereof, comprising administering to the mammal an effective amount
of a compound having the general formula (I): ##STR111## or a
pharmaceutically acceptable salt or hydrate thereof, wherein: in
the general formula (I), the structural unit having the general
formula (II): ##STR112## is one or more structural units selected
from multiple types of structural units having the general formula
(III): ##STR113## in the general formula (I), R.sub.1 and R.sub.2
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, amino group, acetylamino group, benzylamino group,
trifluoromethyl group, C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, and --O--(CH.sub.2)n-R.sub.5, wherein R.sub.5 is a
vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or phenyl group, and
n is 0 or 1; R.sub.3 and R.sub.4 each are one or more functional
groups independently selected from the group consisting of a
hydrogen atom, C.sub.1-C.sub.6 alkyl group, C.sub.3-C.sub.8
cycloalkyl group, and --CH(R.sub.7)--R.sub.6; alternatively,
R.sub.3 and R.sub.4 together form a spiro ring having the general
formula (IV): ##STR114## said R.sub.6 is one or more functional
groups selected from the group consisting of a vinyl group; ethinyl
group; phenyl optionally substituted by a C.sub.1-C.sub.6 alkyl
group, C.sub.1-C.sub.6 alkoxy group, hydroxy group, 1 or 2 halogen
atoms, di C.sub.1-C.sub.6 alkylamino group, cyano group, nitro
group, carboxy group, or phenyl group; phenethyl group; pyridyl
group; thienyl group; and furyl group; said R.sub.7 is a hydrogen
atom or C.sub.1-C.sub.6 alkyl group; in the general formula (IV),
the structural unit B is one or more structural units selected from
multiple types of structural units having the general formula (V):
##STR115## said structural unit B binds at a position marked by *
in the general formula (V) to form a spiro ring; and R.sub.8 is one
or more functional groups selected from the group consisting of a
hydrogen atom, halogen atom, hydroxy group, C.sub.1-C.sub.6 alkoxy
group, cyano group, and trifluoromethyl group.
17. The method according to claim 16 wherein said heterocyclic
compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan].
18. The method according to claim 16 or 17 wherein said
administration is oral.
Description
FIELD OF THE INVENTION
[0001] The present invention is in the filed of medicinal chemistry
and relates to an antidepressant, neuroprotectant, amyloid .beta.
deposition inhibitor, or age retardant composition comprising
containing a heterocyclic compound having a specific structure.
BACKGROUND OF THE INVENTION
[0002] Among drugs currently used in drug therapy for depression
and panic disorder, fluvoxamine maleate (1991) and paroxetine
hydrochloride (2000) were developed as selective serotonin reuptake
inhibitors (SSRI). SSRI is a first-line drug for both acute
treatment and long-term treatment of depression and panic disorder.
However, SSRI has some issues such as drug effects appearing only
through chronic administration, drug withdrawal because of adverse
effects, and side effects including withdrawal signs and influence
on cognitive functions. Therefore, there is a strong demand for
development of effective drugs having an immediate activity and
fewer side effects.
[0003] One of factors involved with ageing is oxidative stress.
Antioxidative substances reportedly have antiaging activity. For
example, oolong tea containing antioxidants is considered to have
antiaging activity (Biol Pharm Bull Vol 26 No 5 739-742 2003). On
the other hand, while deprenyl reportedly increases the survival
rate and is used as a monoamine oxidase B inhibitor in treatment
for Parkinson's disease, this has been confirmed to be due to its
antioxidant activity (Mech Ageing Dev Vol 46 No 1-3 237-262 1988).
However, these substances do not offer antiaging activity and
increase in the survival rate of animals at satisfactory
levels.
[0004] Edaravone is a free radical scavenger having antioxidative
activity and used as a neuroprotectant. However, it is not highly
effective and various side effects including kidney failure have
been reported (The Japan Stroke Society: Clinical Guideline for
Stroke (2004), 42-43.).
[0005] Curcumin is a component of Curcuma longa contained in curry
in a large amount and has antiinflammatory and antioxidative
activity equivalent to prescribed nonsteroidal antiinflammatory
drugs (NSAIDs). Studies have shown that curcumin inhibits
amyloid-related pathologies (Pharmacia, Japanese Pharmacology
Association, Vol. 38, No. 9, 891-892, 2002.). However, curcumin
does not inhibit p amyloid deposition at satisfactory levels.
[0006] Booklet of International Publication No. 01/009131 and
Booklet of International Publication No. 2002/060907 disclose brain
function improvers containing heterocyclic compounds having
specific structures. The heterocyclic compounds are disclosed as
brain function improvers leading to treatment for memory loss and
memory acquisition/retention disorder in senile dementia,
Alzheimer's disease and related disorders. Other effects useful as
antidepressant, neuroprotectant, amyloid .beta. inhibitor, and age
retardant are not disclosed.
SUMMARY OF THE INVENTION
[0007] The present invention provides an antidepressant,
neuroprotectant, amyloid p deposition inhibitor, or age retardant
containing a heterocyclic compound having the general Formula (I):
##STR2## or a pharmaceutically acceptable salt or hydrate
thereof.
[0008] In the general Formula (I), the structural unit having the
general formula (II) is one or more structural units selected from
multiple types of structural units having the general Formula
(III). ##STR3##
[0009] In the general Formula (I), R.sub.1 and R.sub.2 each are one
or more functional groups independently selected from the group
consisting of a hydrogen atom, halogen atom, hydroxy group, amino
group, acetylamino group, benzylamino group, trifluoromethyl group,
C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6 alkoxy group, and
--O--(CH.sub.2)n-R.sub.5, wherein R.sub.5 is a vinyl group,
C.sub.3-C.sub.6 cycloalkyl group, or phenyl group, and n is 0 or
1.
[0010] Furthermore, in the general Formula (I), R.sub.3 and R.sub.4
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, C.sub.1-C.sub.6 alkyl
group, C.sub.3-C.sub.8 cycloalkyl group, and
--CH(R.sub.7)--R.sub.6; alternatively, R.sub.3 and R.sub.4 together
form a spiro ring having the general Formula (IV): ##STR4##
[0011] R.sub.6 is one or more functional groups selected from the
group consisting of a vinyl group; ethinyl group; phenyl optionally
substituted by a C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, hydroxy group, 1 or 2 halogen atoms, di
C.sub.1-C.sub.6 alkylamino group, cyano group, nitro group, carboxy
group, or phenyl group; phenethyl group; pyridyl group; thienyl
group; and furyl group. The above R.sub.7 is a hydrogen atom or
C.sub.1-C.sub.6 alkyl group.
[0012] Furthermore, in the general Formula (IV), the structural
unit B is one or more structural units selected from multiple types
of structural units having the general Formula (V). The structural
unit B binds at a position marked by * in the general Formula (V)
to form a spiro ring. ##STR5##
[0013] R.sub.8 is one or more functional groups selected from the
group consisting of a hydrogen atom, halogen atom, hydroxy group,
C.sub.1-C.sub.6 alkoxy group, cyano group, and trifluoromethyl
group.
[0014] The compounds of Formula (I) may be used as an
antidepressant, neuroprotectant, amyloid .beta. deposition
inhibitor, delayer of senescence, as an age retardant and extender
of life spans of animals.
[0015] The invention relates in particular to a method of treating
or preventing depression, manic depressive psychoses,
obsessive-compulsive disorder, panic disorder, or anxiety disorder
in a mammal in need thereof, comprising administering to the mammal
an effective amount of a heterocyclic compound having the general
Formula (I), or a pharmaceutically acceptable salt or hydrate
thereof.
[0016] The invention also relates to a method of reducing or
preventing neurodegeneration in a mammal in need thereof,
comprising administering to the mammal an effective amount of a
compound having the general Formula (I), or a pharmaceutically
acceptable salt thereof. In one embodiment, the neurodegeneration
is the result of one or more cerebrovascular disorders selected
from the group consisting of transient ischemic attack, cerebral
hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage,
cerebral infarct, and/or hypertensive encephalopathy.
[0017] The invention also relates to a method of inhibiting amyloid
deposition in an mammal in need thereof, comprising administering
to the mammal an effective amount of a compound having the general
Formula (I). In one embodiment, the amyloid deposition is the
result of or associated with one or more amyloid-related
pathologies selected from amyloidosis, cerebral amyloid angiopathy,
cataract, glaucoma, the progression of glaucoma, age-related
macular degeneration, rheumatism, osteoporosis, metabolic syndrome,
wrinkles, and hair loss.
[0018] The invention also relates to a method of delaying
senescence is an animal in need thereof, comprising administering
to the animal an effective amount of a heterocyclic compound having
the general Formula (I). In one embodiment, the invention provides
an improvement and/or delay in worstening symptoms of one or more
conditions associated with senescence, including reactivity,
passivity, glossiness and/or coarseness of hair, hair loss, ulcers,
periophthalmic lesions, cataracts, corneal opacity and/or
lordokyphosis.
[0019] The invention also relates to a method of extending the life
span of a mammal in need thereof, comprising administering to the
mammal an effective amount of a compound having the general Formula
(I).
BRIEF EXPLANATION OF THE DRAWINGS
[0020] FIG. 1 is a graphical representation for explaining the
hippocampus CA1 region protective activity of Compound 24 in the
gerbil transient forebrain ischemia model.
[0021] FIG. 2 contains photographs for explaining the
neuroprotective activity in delayed neuronal death in the
hippocampus CA1 region in the gerbil transient forebrain ischemia
model.
[0022] FIG. 3 contains photographs for explaining the effect of
Compound 24 on the number of amyloid .beta.-immunoreactive cells in
senescene accelerated mice (SAMP8).
[0023] FIG. 4 depicts a graphical representation for explaining the
effect of Compound 24 on the number of amyloid
.beta.-immunoreactive cells in senescene accelerated mice
(SAMP8).
[0024] FIG. 5 depicts a graphical representation for explaining the
effect of Compound 24 on the grading scores in senescene
accelerated mice (SAMP8).
[0025] FIG. 6 depicts a graphical representation for explaining the
effect of Compound 24 on the survival rate of senescene accelerated
mice (SAMP8).
BEST MODES FOR CARRYING OUT THE INVENTION
[0026] Embodiments of the present invention are described
hereafter. Embodiments below relate to an antidepressant,
neuroprotectant, amyloid .beta. deposition inhibitor, or age
retardant composition containing a heterocyclic compound having the
above described specific structure (azaindolizinone derivatives)
and pharmaceutically acceptable carriers or diluents.
[0027] The compounds useful in the present invention all contain a
heterocyclic compound having the general Formula (I): ##STR6## or a
pharmaceutically acceptable salt or hydrate thereof.
[0028] In the general Formula (I), the structural unit having the
general Formula (II) is one or more structural units selected from
multiple types of structural units having the general Formula
(III). ##STR7##
[0029] Furthermore, in the general formula (I), R.sub.1 and R.sub.2
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, amino group, acetylamino group, benzylamino group,
trifluoromethyl group, C.sub.1-C.sub.6 alkyl group, C.sub.1-C.sub.6
alkoxy group, and --O--(CH.sub.2)n-R.sub.5, wherein R.sub.5 is a
vinyl group, C.sub.3-C.sub.6 cycloalkyl group, or phenyl group, and
n is 0 or 1.
[0030] Furthermore, in the general Formula (I), R.sub.3 and R.sub.4
each are one or more functional groups independently selected from
the group consisting of a hydrogen atom, C.sub.1-C.sub.6 alkyl
group, C.sub.3-C.sub.8 cycloalkyl group, and --C
H(R.sub.7)--R.sub.8; alternatively, R.sub.3 and R.sub.4 together
form a spiro ring having the general formula (IV): ##STR8##
[0031] The above R.sub.6 is one or more functional groups selected
from the group consisting of a vinyl group; ethinyl group; phenyl
optionally substituted by a C.sub.1-C.sub.6 alkyl group,
C.sub.1-C.sub.6 alkoxy group, hydroxy group, 1 or 2 halogen atoms,
di C.sub.1-C.sub.6 alkylamino group, cyano group, nitro group,
carboxy group, or phenyl group), phenethyl group, pyridyl group,
thienyl group, and furyl group. The above R.sub.7 is a hydrogen
atom or C.sub.1-C.sub.6 alkyl group.
[0032] In the general Formula (IV), the structural unit B is one or
more structural units selected from multiple types of structural
units having the general Formula (V). The structural unit B binds
at a position marked by * in the general Formula (V) to form a
spiro ring. ##STR9##
[0033] Here, R.sub.8 is one or more functional groups selected from
the group consisting of a hydrogen atom, halogen atom, hydroxy
group, C.sub.1-C.sub.6 alkoxy group, cyano group, and
trifluoromethyl group.
[0034] When the heterocyclic compound having the general Formula
(I) has asymmetric carbon atoms in the structure, its isomer from
asymmetric carbon atoms and their mixture (racemic modification) is
present. In such cases, all of them are included in the
heterocyclic compound used in the embodiments described later.
[0035] The heterocyclic compound has the general Formula (I). In
the general Formula (I), the following terms have the meanings
specified below along with their examples.
[0036] The term "C.sub.1-C.sub.6" refers to 1 to 6 carbon atoms
unless otherwise defined. The term "C.sub.3-C.sub.8" refers to 3 to
8 carbon atoms unless otherwise defined. The term "C.sub.1-C.sub.6
alkyl" includes linear or branched alkyl groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl,
n-pentyl, and n-hexyl. The term "C.sub.1-C.sub.6 alkoxy" includes
linear or branched alkoxy groups such as methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentyloxy, and n-hexyloxy. The term "C.sub.3-C.sub.8 cycloalkyl"
includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. The term "halogen atom" includes
fluorine, chlorine, bromine, and iodine.
[0037] The heterocyclic compound useful in the practice of the
present invention is not particularly restricted as long as it has
the above described specific structure. For example, the following
compounds can be used. [0038] 3,3-dimethylimidazo[1,2-a]pyridin-2
(3H)-one, 3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one, [0039]
3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one,
3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one, [0040]
3,3-diallyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one, [0041]
3,3-di(2-propinyl)imidazo[1,2-a]pyridin-2(3H)-one, [0042]
3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one, [0043]
3,3-dibenzyl-8-methylimidazo[1,2-a]pyridin-2(3H)-one, [0044]
3,3-dibenzyl-5,7-dimethylimidazo[1,2-a]pyridin-2(3H)-one, [0045]
3,3-dibenzyl-8-hydroxyimidazo[1,2-a]pyridin-2(3H)-one, [0046]
3,3-dibenzyl-8-methoxyimidazo[1,2-a]pyridin-2(3H)-one, [0047]
3,3-dibenzyl-8-ethoxyimidazo[1,2-a]pyridin-2(3H)-one, [0048]
8-allyloxy-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one, [0049]
3,3-dibenzyl-8-isopropoxyimidazo[1,2-a]pyridin-2(3H)-one, [0050]
3,3-dibenzyl-8-cyclopropylmethyloxyimidazo[1,2-a]pyridin-2(3H)-one,
[0051]
3,3-dibenzyl-8-cycloheptyloxyimidazo[1,2-a]pyridin-2(3H)-one,
[0052] 3,3-dibenzyl-6-chloroimidazo[1,2-a]pyridin-2(3H)-one, [0053]
3,3-dibenzyl-6,8-dichloroimidazo[1,2-a]pyridin-2(3H)-one, [0054]
3,3-dibenzyl-8-chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2(3H)-one,
[0055] 3,3-dibenzyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one,
[0056] 8-amino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one, [0057]
8-acetylamino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one, [0058]
3,3-dibenzyl-8-benzylaminoimidazo[1,2-a]pyridin-2(3H)-one, [0059]
3,3-bis(3-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one, [0060]
3,3-bis(3-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one, [0061]
3,3-bis(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one, [0062]
3,3-bis(2,4-dichlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one, [0063]
3,3-bis(4-dimethylaminobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0064] 3,3-bis(4-methoxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0065] 3,3-bis(4-biphenylmethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0066] 3,3-bis(4-cyanobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0067] 3,3-bis(4-hydroxy-benzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0068] 3,3-bis(3-phenyl-1-propyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0069] 3,3-bis(2,4-difluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0070] 3,3-bis(4-nitrobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0071] 3,3-bis(4-carboxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0072]
8-benzyloxy-3,3-bis(1-phenylethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0073]
8-benzyloxy-3,3-bis(3-methylbenzyl)imidazo[1,2-a]pyridin-2(3H)-on-
e, [0074]
8-benzyloxy-3,3-bis(4-methylbenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0075] 3-benzyl-3-(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0076] 3-ethyl-3(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0077]
8-methyl-3,3-bis(3-pyridylmethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0078]
8-methyl-3,3-bis(4-pyridylmethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0079] 3,3-bis(2-thienylmethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0080] 3,3-bis(2-furilmethyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0081] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan], [0082]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-[2,3]dihydrophenarene],
[0083] spiro[imidazo[2,1-b]thiazol-6(5H)-one-5,2'-benzo[f]indan],
[0084] spiro[imidazo[1,2-b]thiazol-6(5H)-one-5,2'-indan], [0085]
spiro[2-methylimidazo[1,2-b]thiazol-6(5H)-one-5,2'-benzo[f]indan],
[0086] 5,5-bis(4-fluorobenzyl)imidazo[2,1-b]thiazol-6(5H)-one,
[0087] 5,5-dibenzylimidazo[2,1-b]thiazol-6(5H)-one, [0088]
5,5-bis(4-methylbenzyl)imidazo[2,1-b]thiazol-6(5H)-one, [0089]
5,5-bis(4-cyanobenzyl)imidazo[2,1-b]thiazol-6(5H)-one, [0090]
5,5-dibenzyl-2-methylimidazo[2,1-b]thiazol-6(5H)-one, [0091]
5,5-bis(4-fluorobenzyl)-2-methylimidazo[2,1-b]thiazol-6(5H)-one,
[0092] 5,5-dicyclohexyl-2-methylimidazo[2,1-b]thiazol-6(5H)-one,
[0093]
5,5-bis(4-cyanobenzyl)-2-methylimidazo[2,1-b]thiazol-6(5H)-one,
[0094] 5,5-di(2-butenyl)imidazo[2,1-b]thiazol-6(5H)-one,
5,5-dibutylimidazo[2,1-b]thiazol-6(5H)-one, [0095]
5,5-dicyclohexylimidazo[2,1-b]thiazol-6(5H)-one, [0096]
5,5-bis(2-thienylmethyl)imidazo[2,1-b]thiazol-6(5H)-one, [0097]
spiro[2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one-5,2'-benzo[f]indan],
[0098] 5,5-dibutyl-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one,
[0099]
5,5-di(2-butenyl)-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one,
[0100]
5,5-bis(4-methylbenzyl)-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one,
[0101]
5,5-bis(2-thienylmethyl)-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-o-
ne, [0102]
5,5-bis(4-fluorobenzyl)-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one,
[0103] 5,5-dibenzyl-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one,
[0104] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[f]indan],
[0105] 2-hydroxy-3-(2-naphthylmethyl)-imidazo[1,2-a]pyridine,
[0106] 3-benzylimidazo[1,2-a]pyridin-2(3H)-one,
spiro[5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[f]inda-
n], [0107]
3,3-dicyclohexyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one,
[0108]
3,3-bis(2-thienylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin--
2(3H)-one, [0109]
3,3-dibutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one,
[0110]
3,3-dipropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one,
[0111] spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-benzo[f]indan],
[0112] 3,3-di(2-butenyl)imidazo[1,2-a]pyrimidin-2(3H)-one, [0113]
3,3-bis(2-thienylmethyl)imidazo[1,2-a]pyrimidin-2(3H)-one, [0114]
3,3-bis(4-fluorobenzyl)imidazo[1,2-a]pyrimidin-2(3H)-one, [0115]
3,3-dicyclohexylimidazo[1,2-a]pyrimidin-2(3H)-one, [0116]
3,3-bis(4-cyanobenzyl)imidazo[1,2-a]pyrimidin-2(3H)-one, [0117]
3,3-bis(4-methylbenzyl)imidazo[1,2-a]pyrimidin-2(3H)-one, [0118]
4,4-dibenzyl-1-methyl-5-oxo-4,5-dihydroimidazole, [0119]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-fluoroindan)],
[0120]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-methoxyindan)],
[0121] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-iodoindan)],
[0122] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-cyanoindan)],
[0123] spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-indan],
[0124]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-((1,2,5-thiadiazo)[4,5-c]indan-
)], [0125]
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-((1,2,5-thiadiazo)[4,5-c]i-
ndan)], [0126]
spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,4'-(1'-cyclopentene)],
[0127] spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-indan], [0128]
spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-((1,2,5-thiadiazo)
[4,5-c] indan)], [0129]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-trifluoromethylindan)],
[0130] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[e]indan],
[0131]
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,1'-(3'-cyclopentene)]-
, [0132]
spiro[8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,1'-(3'-cyclo-
pentene)], [0133]
spiro[7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-one-3,1'-cyclope-
ntane], [0134]
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,1'-cyclopentane], and
[0135]
spiro[5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan]
[0136] The heterocyclic compound of Formula (I) can be in the form
of hydrate or acid addition salts as a pharmaceutically acceptable
salt. Possible acid addition salts include inorganic acid salts
such as the hydrochloride, sulfate, hydrobromide, nitrate, and
phosphate salts and organic acid salts such as acetate, oxalate,
propionate, glycolate, lactate, pyruvate, malonate, succinate,
maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate,
methanesulfonate, benzenesulfonate, p-toluenesulfonate, and
salicylate salts.
[0137] The administration method, formulation, and dosage of the
heterocyclic compound in mammals, particularly in human, are
described hereafter. The heterocyclic compound can be administrated
orally or parenterally. Formulations for oral administration
include tablets, coated tablets, powder, granules, capsules,
microcapsules, and syrups. Formulations for parenteral
administration include injectable solutions (including those
freeze-dried and dissolved for use), adhesive skin patches, and
suppositories.
[0138] These formulations can be prepared using pharmaceutically
acceptable fillers, binders, lubricants, disintegrators, suspending
agents, emulsifiers, antiseptic agents, stabilizing agents, and
dispersing agents such as lactoses, saccharoses, starches,
dextrines, crystalline celluloses, kaolins, calcium carbonate,
talc, magnesium stearate, and distilled water or saline. Particular
pharmaceutically acceptable components include mannitol,
microcrystalline cellulose, hydroxypropyl cellulose, and magnesium
stearate. The dosage varies according to the symptom, age, and body
weight of patients. An adult can take 0.1 to 100 mg per day in one
to three doses.
[0139] In one embodiment, the invention provides an antidepressant
composition comprising a compound of the general Formula (I).
[0140] The inventors found that heterocyclic compounds having
Formula I exhibit antidepressant activity in forced swimming test
and tail suspension test as described later in examples. Screening
of the compounds for antidepressant activity showed
thatazaindolizinone derivatives in which a dibenzyl group or an
indan ring forms a spiro ring have potent antidepressant activity.
These compounds exhibit antidepressant activity based on a novel
mechanism that does not involve the inhibition of serotonin
reuptake. The compound
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] has also been
shown to be highly safe in a preclinical study.
[0141] The antidepressant of this embodiment exhibits excellent
antidepressant effect. More specifically, the antidepressant of
this embodiment inhibits one or more mood disorders selected from
the group consisting of depression, manic depressive psychoses,
obsessive-compulsive disorder, panic disorder, and anxiety disorder
in mammals.
[0142] The heterocyclic compound contained in the antidepressant
composition of this embodiment is preferably among the compounds
below because these compounds have been shown to have excellent
antidepressive activity in the mouse tail suspension test, which is
a typical test for antidepressive activity of a compound in a mouse
model. [0143] 3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one, [0144]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan], [0145]
3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one,
3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one, [0146]
5,5-dibenzylimidazo[2,1-b]thiazol-6(5H)-one,
3,3-dibenzylimidazo[1,2-a]pyrimidin-2(3H)-one, [0147]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-fluoroindan)],
[0148] spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-cyanoindan)],
[0149] spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-indan],
[0150]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-((1,2,5-thiadiazo)
[4,5-c]indan)], [0151]
spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-indan], [0152]
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,4'-(1'-cyclopentene)],
[0153] 3,3-bis(4-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,
[0154]
8-cyclopropylmethyloxy-3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one,
[0155]
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-hydroxy-indan)],
[0156] spiro[8-hydroxy-imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
[0157]
spiro[8-methoxy-imidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cyclopen-
tene)], and [0158]
spiro[8-cyclopropylmethyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cycl-
opentene)].
[0159] The antidepressant compound may be administered by a means
which acheives reduction or alleviation of depression in a mammal.
In one embodiment, the antidepressant compound is orally
administered. In another embodiment, the antidepressant is
administered as part of an adhesive skin patch. Alternatively, the
antidepressant compound is formulated into tablets, coated tablets,
powder, granules, capsules, microcapsules, and syrups. The
antidepressant in the form of oral formulations is easily
administered to mammals, including human beings.
[0160] The antidepressant compound may be administered at an
effective oral dosage of 0.0005 mg per kilogram of body weight or
higher, more preferably 0.005 mg per kilogram of body weight or
higher, and particularly preferably 0.05 mg per kilogram of body
weight or higher. In one embodiment, the compound is administered
as part of a unitary pharmaceutical dosage form containing 5, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
or 100 mg. When the antidepressant compound is administered at an
effective oral dosage of these lower limits or higher, the
antidepressive activity in mammals including human beings is
improved compared to when lower doses are administered.
[0161] In another embodiment, the invention provides a
neuroprotectant composition comprising a compound of Formula
(I)
[0162] The inventors found
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] within Formula
(I) exhibits neuroprotective activity in a study on reduction in
delayed neuronal death in the hippocampus CA1 field in the gerbil
transient forebrain ischemia model as described later in examples.
Screening of derivatives of the above compound for neuroprotective
activity showed that azaindolizinone derivatives in which an indan
ring forms a spiro ring have potent neuroprotective activity. The
above compound exhibits neuroprotective activity based on a novel
mechanism different from antioxidization.
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] has also been
shown to be highly safe in the preclinical study.
[0163] The neuroprotectant composition containing the compound of
Formula (I), in particular,
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan], is effective at
lower dosages based on a mechanism different from that of
Edaravone, which is a neuroprotectant having antioxidative
activity. Therefore, the neuroprotectant composition is expected to
avoid various side effects such as kidney failure as reported for
Edaravone.
[0164] The neuroprotectant composition of this embodiment exhibits
excellent neuroprotective activity. In one embodiment, the
composition inhibit one or more cerebrovascular disorders selected
from the group consisting of transient ischemic attack, cerebral
hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage,
cerebral infarct, and hypertensive encephalopathy in mammals.
[0165] The neuroprotectant compound of this embodiment is
preferably spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan]. This
compound was shown to have an excellent neuroprotective activity in
a study on reduction in delayed neuronal death in the hippocampus
CA1 region in the gerbil transient forebrain ischemia model, which
is a typical animal model for neuroprotection, as described later
in the examples.
[0166] The neuroprotectant compound may be administered by a means
which provides neuroprotection in a mammal. Preferably, the
neuroprotectant compound of this embodiment is orally administered.
In another embodiment, the neuroprotectant compound can be
administered as part of an adhesive skin patch. The neuroprotectant
compound may be formulated into tablets, coated tablets, powder,
granules, capsules, microcapsules, and syrups. The neuroprotectant
in the form of oral formulations is easily administered in mammals,
including human beings.
[0167] The neuroprotectant compound may be administered at an
effective oral dosage of 0.005 mg per kilogram body weight or
higher, more preferably 0.05 mg per kilogram of body weight or
higher, and particularly preferably 0.5 mg per kilogram of body
weight or higher. When the neuroprotectant compound is administered
at an effective oral dosage of these lower limits or higher, the
neuroprotective activity in mammals including human beings is
improved compared to when lower doses are administered.
[0168] In another embodiment, the invention provides an amyloid
.beta. deposition inhibitor composition comprising a compound
having Formula (I).
[0169] The inventors found that a compound of Formula (I), in
particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
exhibits inhibitory activity of amyloid .beta. deposition in the
hippocampus by amyloid .beta. immunohistochemistry as described
later in the examples. Screening of derivatives of the compound for
amyloid .beta. deposition inhibitory activity showed that
azaindolizinone derivatives in which an indan ring forms a spiro
ring have potent amyloid .beta. deposition inhibitory activity. The
above compound exhibits amyloid .beta. deposition inhibitory
activity based on a novel mechanism different from antioxidative
activity. The compound has also been shown to be highly safe in the
preclinical study.
[0170] The amyloid .beta. deposition inhibitor of Formula (I), in
particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan], is
effective at lower dosages based on a mechanism which is different
from curcumin, a component of Curcuma longa contained in curry in a
large amount and which has antioxidative activity. Therefore, it is
a new amyloid .beta. deposition inhibitor having a mechanism of
action different from curcumin.
[0171] The amyloid .beta. deposition inhibitor of Formula (I), in
particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
exhibits excellent inhibitory activity of amyloid .beta.
deposition. More specifically, the amyloid .beta. deposition
inhibitor of Formula (I) inhibits one or more amyloid-related
pathologies selected from the group consisting of amyloidosis,
cerebral amyloid angiopathy, cataract, glaucoma, the progression of
glaucoma, age-related macular degeneration, rheumatism,
osteoporosis, metabolic syndrome, wrinkles, and hair loss in
mammals.
[0172] The amyloid .beta. deposition inhibitor of this embodiment
is preferably spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] as
this compound was shown to have excellent inhibitory activity of
amyloid .beta. deposition in the hippocampus amyloid .beta.
immunohistochemistry, which is a typical animal model test for
inhibitory activity of amyloid .beta. deposition, as described
later in the examples.
[0173] The amyloid .beta. deposition inhibitor compound may be
administered by any means which acheives reduction in amyloid
.beta. deposition in a mammal. Preferably, the amyloid .beta.
deposition inhibitor compound of this embodiment is orally
administered. In another embodiment, the amyloid .beta. deposition
inhibitor compound may be administered as part of an adhesive skin
patch. Alternatively, the amyloid .beta. deposition inhibitor
compound may be formulated into tablets, coated tablets, powder,
granules, capsules, microcapsules, and syrups, as the amyloid
.beta. deposition inhibitor in the form of oral formulations is
easily administered in mammals, including human beings.
[0174] The amyloid .beta. deposition inhibitor compound of this
embodiment is preferably administered at an effective oral dosage
of 0.0005 mg per kilogram of body weight or higher. In one
embodiment, the compound is administered as part of a unitary
pharmaceutical dosage form containing 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg. When the
amyloid .beta. deposition inhibitor is administered at an effective
oral dosage of this lower limit or higher, the amyloid .beta.
deposition inhibitory activity in mammals including human beings is
improved compared to when lower doses are administered.
[0175] In another embodiment, the invention provides an age
retardant composition comprising a compound of general Formula (I).
The invention also provides a composition comprising a compound of
general Formula (I) for delaying senescence in an animal in need
thereof, comprising administering to the animal an effective amount
of a heterocyclic compound having the general Formula (I). In one
embodiment, the composition comprising a compound of general
Formula (I) improves and/or delays in worstening symptoms of one or
more conditions associated with senescence, including reactivity,
passivity, glossiness and/or coarseness of hair, hair loss, ulcers,
periophthalmic lesions, cataracts, corneal opacity and
lordokyphosis. In another embodiment, the invention provides the
composition comprising a compound of general Formula (I) for
extending the life span of a mammal in need thereof, comprising
administering to the mammal an effective amount of a compound
having the general Formula (I).
[0176] The inventors found that the compound of Formula (I), in
particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan],
exhibits age retardant activity in measurement of grading scores in
senescene accelerated mice as described later in the examples.
Screening of compounds for age retardant activity showed that
azaindolizinone derivatives in which an indan ring forms a spiro
ring have potent age retardant activity. The above compound
exhibits age retardant activity based on a novel mechanism which is
different from an antioxidative activity.
Spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] has also been
shown to be highly safe in a preclinical study.
[0177] The age retardant compound of this embodiment is effective
at lower dosages based on a mechanism which is different from
oolong tea and deprenyl, both having antioxidative activity.
Therefore, it is a new age retardant having a mechanism different
from oolong tea and deprenyl. In other words, the compound of
Formula (I) can be used as an antiaging drug having a novel
mechanism which is different from those drugs having antioxidative
activity. It is expected that the compound of Formula (I) will have
an age retardant activity with improved efficacy at lower dosages
compared to oolong tea and deprenyl.
[0178] The age retardant compound of this embodiment exhibits
excellent age retardant activity. The age retardant compound of
this embodiment slows down the aging process in mice and is
expected to slow the aging process in other mammals including human
beings. The age retardant compound also extends the average life
span in mice and is expected to extend the average life span in
other mammals including human beings.
[0179] The age retardant compound of this embodiment is preferably
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] as this compound
was shown to have excellent age retardant activity in measurement
of grading scores in senescene accelerated mice, which is an animal
model for age retardant activity, as described later in examples.
Furthermore, this compound was shown to extend the average life
span in senescene accelerated mice as described later in
examples.
[0180] The age retardant compound may be administered by any means
which acheives delaying of scenescence in a mammal. Preferably, the
age retardant compound of this embodiment is orally administered.
In another embodiment, the age retardant compound can be
administered as part of an adhesive skin patch. The age retardant
compound may be formulated into tablets, coated tablets, powder,
granules, capsules, microcapsules, and syrups, as the age retardant
compound in the form of oral formulations is easily administered to
mammals, including human beings.
[0181] The age retardant compound of this embodiment is preferably
administered at an effective oral dosage of 0.0005 mg per kilogram
of body weight or higher, more preferably 0.005 mg per kilogram of
body weight or higher, and particularly preferably 0.05 mg per
kilogram of body weight or higher. In one embodiment, the compound
is administered as part of a unitary pharmaceutical dosage form
containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, 80, 85, 90, 95, or 100 mg. When the age retardant is
administered at an effective oral dosage of these lower limits or
higher, the age retardant activity in mammals including human
beings is improved compared to when lower doses are
administered.
[0182] The age retardant compound is preferably administered at an
effective oral dosage of 0.005 mg per kilogram of body weight or
higher for extended average life span. When the age retardant
compound is administered at an effective oral dosage of this lower
limit or higher, the average life span is extended in mammals
including human beings.
[0183] Embodiments of the present invention are described above.
These embodiments are given by way of example. The present
invention can be realized in many other ways as the invention is
not so limited.
[0184] For example, some preferable ranges of effective oral
dosages are defined in the above embodiments. However, other ranges
of effective dosages can be determined for other administration
forms. For example, a preferable range of effective dosages for
administration by injection can be determined as appropriate.
Furthermore, preferable ranges of administration intervals can be
determined for particular administration forms in addition to the
effective dosages with no more than routine experimentation.
EXAMPLES
[0185] The present invention is further described using examples.
However, the present invention is not restricted thereto.
Example 1
Antidepressant Activity
[0186] In order to prove the antidepressant activity of the
heterocyclic compound having the specific structure described in
Embodiment 1, a tail suspension test was conducted on ICR mice
(male). First, one hour after oral dosing of 0.001, 0.01, and 0.1
mg/kg of a subject compound, the mice were clipped by the tail
approximately 1 cm from the tip, suspended, and observed for 6
minutes. Motionless time was measured in the last 4 minutes. The
antidepressant activity was considered to be positive when 90
seconds or less motionless time was observed. TABLE-US-00001 TABLE
1 compound dosage (mg/kg, p.o) time (sec) Compound 10 0.001 72.8
Compound 24 0.001 72.8 Compound 29 0.01 61.3 Compound 34 0.001 83.3
Compound 44 0.1 88 Compound 45 0.001 89.5 Compound 56 0.001 88.3
Compound 59 0.01 86.3 Compound 60 0.1 79.5 Compound 61 0.01 82
Compound 63 0.001 73 Compound 69 0.001 58.5 Compound 78 0.01 68.5
Compound 79 0.001 66.5 Compound 80 0.1 64.3 Compound 81 0.001 86.3
Compound 82 0.01 81.8 Compound 83 0.001 78 Solvent Control
113.2
[0187] As shown above, all compounds were considered to have
antidepressant activity because of 90 seconds or less motionless
time in the mice tail suspension test was observed. In other words,
compounds having Formula I were shown to have antidepressant
activity. The structures and names of the above compounds are given
in Exemplary Preparations described later.
Example 2
Neuroprotective Activity
[0188] In order to prove neuroprotection activity of compounds
having Formula I, the activity of Compound 24 on reduction in
delayed neuronal death in the hippocampus CA1 region in the gerbil
transient forbrain ischemia model was examined.
[0189] Gerbils (male, weighing approximately 55 to 80 g) were
pinched with an exposured bilateral common carotid artery by
microclip to cause the cerebral ischemia under 2% halothane
inhalation anesthesia. After four minutes of ischemia, the
microclip was removed to reperfuse the cerebral ischemia and the
anesthesia was stopped. Four days after the reperfusion, the brain
was removed and formalin-fixed. Sections of 4 .mu.m in thickness
were prepared and stained with hematoxylin-eosin. Surviving cells
in the entire hippocampus CA1 field on both sides of each specimen
were counted using a micrometer under the microscope. The number of
surviving cells per 0.5 mm was obtained.
[0190] Compound 24 was suspended in 1% HPC and orally given one
hour before the cerebral ischemia and 5 hours after the
reperfusion. Then, two doses per day were given from the following
day to the third day since the perfusion. The surviving cell count
in the hippocampus CA1 field was expressed by the average
.+-.standard error. The Mann-Whitney's U test was used to obtain
significant differences. The effective oral dosage of Compound 24
was plotted as abscissa and the surviving cell count/0.5 mm was
plotted as ordinate.
[0191] The surviving cell count in the hippocampus CA1 field of a
sham surgery group (n=7) was 117.3.+-.2.3/0.5 mm. On the other
hand, the surviving cell count of the solvent control group (n=7)
was 18.1.+-.1.0/0.5 mm; significant reduction in number of
surviving cells, namely onset of delayed neuronal death, in the
hippocampus CA1 field through the cerebral ischemia--reperfusion
was observed.
[0192] FIG. 1 is a graphical representation for explaining the
hippocampus CA1 field protection activity of Compound 24 in the
gerbil transient forebrain ischemia model. In FIG. 1, ** indicates
p<0.01 vs the control.
[0193] FIG. 2 is photographs for explaining the neuroprotective
activity in delayed neuronal death in the hippocampus CA1 region in
the gerbil transient forbrain ischemia model. The left photograph
shows the case no Compound 24 was given and the right photograph
shows the case Compound 24 was given.
[0194] When Compound 24 was given at an oral dosage of 0.001 to 20
mg/kg, the number of surviving cells in the hippocampus CA1 field
was dosage-dependently and significantly increased (**) in the
dosage groups of 0.01 mg/kg (n=7), 0.1 mg/kg (n=8), and 1 mg/kg
(n=9) as shown in FIGS. 1 and 2 (the surviving cell counts: 0.01
mg/kg; 27.8.+-.1.9/0.5 mm, 0.1 mg/kg; 32.5.+-.9.4/0.5 mm, 1 mg/kg:
44.3.+-.9.4/0.5 mm).
[0195] From the above results, Compound 24 was shown to reduce
neuronal death and be an effective neuroprotectant. Hence, Compound
24 is expected to be effective as a neuroprotectant for
cerebrovascular disorders such as transient ischemic attack,
cerebral hemorrhage, subarachnoid hemorrhage, intracranial
hemorrhage with cerebral arteriovenous malformation, cerebral
infarct, and hypertensive encephalopathy.
[0196] As described above, a compound having Formula (I) was shown
to have neuroprotective activity in a study on reduction in delayed
neuronal death in the hippocampus CA1 field in the gerbil transient
forebrain ischemia model.
Example 3
Amyloid .beta. Deposition Inhibitory Activity
[0197] In order to show that compounds having Formula (I) have
amyloid .beta. deposition inhibitory activity, the activity of
Compound 24 on amyloid .beta. deposition was examined.
[0198] Senescene accelerated mice (SAMP8) (male, 8 months old at
the beginning of the study) were used for experiment. Approximately
0.1 mg/kg/day of Compound 24 was given in drinking water. Eight
weeks after the dosing, the mouse brain was removed,
Methacarn-fixed (methanol:chloroform:acetic acid=6:3:1), and
paraffin-embedded. Then, sections of 8 .mu.m in thickness were
prepared using a microtome.
[0199] The sections were immunostained with streptavidin-biotin
using a VECTASTATIN ABC kit. After one hour of incubation in 10%
normal goat serum, the anti-amyloid .beta. (A.beta.) antibody was
diluted with PBS to ten fold and incubated at 4.degree. C.
overnight. The following day, PBS rinsing, 1.5 hours of incubation
with biotinylated anti-rabbit secondary antibody, PBS rinsing, and
1.5 hours of incubation with peroxidase-labeled streptavidin were
conducted. The immunoreaction was visualized with DAB and specimens
were prepared.
[0200] Immunoreactive A.beta.-like granules in the hippocampus were
counted under the microscope. The A.beta.-like immunoreactive
granule was observed as brown deposits in the hippocampus. The
count was made for one section per individual.
[0201] FIG. 3 contains photographs showing the influence of
Compound 24 on the number of amyloid .beta.-immunoreactive cells in
senescene accelerated mice (SAMP8). The photographs at the top show
stained images of amyloid .beta.-like granules in the hippocampus
of senescene accelerated mice (SAMP8) given tap water as drinking
water for 2 months from age of 8 months. The photographs at the
bottom show stained images of amyloid .beta.-like immunoreactivity
in the hippocampus of senescene accelerated mice (SAMP8) given
Compound 24 in drinking water at an effective oral dosage of 0.1 mg
per kilogram of body weight for 2 months.
[0202] FIG. 4 is a graphical representation showing the influence
of Compound 24 on the number of amyloid .beta.-immunoreactive cells
in senescene accelerated mice (SAMP8). The effective oral dosage of
Compound 24 is plotted as abscissa and the number of amyloid
.beta.-immunoreactive granules is plotted as ordinate. Nine
senescene accelerated mice (SAMP8) were given no Compound 24. Five,
eight and seven senescene accelerated mice (SAMP8) were given
Compound 24 at oral dosage of 0.002 mg, 0.01 mg and 0.1 mg per
kilogram of body weight respectively.
[0203] As shown in FIGS. 3 and 4, an amyloid .beta.-like
immunoreactivity in the hippocampus was observed in senescene
accelerated mice (SAMP8) given tap water as drinking water for 2
months from age of 8 months. On the other hand, the amyloid
.beta.-like immunoreactivity was reduced in senescene accelerated
mice (SAMP8) given Compound 24 in drinking water at oral dosage of
0.002 mg/kg/day, 0.01 mg/kg/day and 0.1 mg/kg/day for 2 months. The
number of amyloid .beta.-immunoreactive granules was significantly
(*) decreased as a result of dosing of Compound 24.
[0204] As described above, Compound 24 inhibits amyloid .beta.
deposition. Amyloid-related pathologies for which Compound 24 may
be used include cataract, glaucoma, the progression of glaucoma,
age-related macular degeneration, rheumatism, osteoporosis,
metabolic profiling syndrome, wrinkles, and hair loss, in which
amyloid .beta. is considered to be a factor of the disorder.
Compound 24 inhibits amyloid .beta. deposition and, therefore, may
also be used for to treat amyloidosis or cerebral amyloid
angiopathy, which are characterized by amyloid fibrillates and
deposits.
[0205] As described above, a compound having Formula (I) was shown
to have inhibitory activity of amyloid .beta. deposition in an
amyloid .beta. immunohistochemistry.
Example 4
Age Retardant Activity
[0206] In order to show that compounds having Formula (I) have age
retardant activity, a study was conducted on the effect of Compound
24 on prevention of fur deterioration and extension of the average
life span in senescene accelerated mice (SAM).
[0207] Senescene accelerated mice (SAMP8) (male, 8 months old at
the beginning of the study) were used in the study.
[0208] Compound 24 dissolved in tap water was given to the
senescene accelerated mice at a dosage of 0.001, 0.01, or 0.1
mg/kg/day as drinking water. Tap water was given to the control
mice as drinking water.
[0209] As an aging indicator of senescene accelerated mice, grading
scores (Takeda et al., 1981) were measured after 0, 4, 8, 12, and
16 weeks of drinking water dosing in a short term study and after
12, 16, 20, 24, 28, and 32 weeks of drinking water dosing in a long
term study.
[0210] FIG. 5 is a graphical representation showing the influence
of Compound 24 on the grading scores in senescene accelerated mice
(SAMP8). FIG. 5 (A) shows the results of the short term study and
FIG. 5 (B) shows the results of the long term study. In both
figures, the number of weeks of dosing is plotted as abscissa and
the grading score is plotted as ordinate.
[0211] As seen from the results, as shown in FIG. 5 (A), the
grading score as an aging indicator started increasing after Week
12 of the drinking water dosing in senescene accelerated mice
(SAMP8) given water while the grading score did not increase in
senescene accelerated mice (SAMP8) given Compound 24 in drinking
water. Significant differences (*) in this activity were observed
in Week 16 in the groups given Compound 24 in drinking water at
effective oral dosages of 0.001, 0.01, and 0.1 mg/kg/day. The
difference was notable in the group given Compound 24 in drinking
water at effective oral dosage of 0.1 mg/kg/day.
[0212] As shown in FIG. 5 (B), the group given Compound 24 in
drinking water at an effective oral dosage of 0.01 mg/kg/day
exhibited significant differences (*, **) in Weeks 20 to 32. The
group given Compound 24 in drinking water at an effective oral
dosage of 0.1 mg/kg/day exhibited significant differences (*, **)
in Weeks 16 to 32. The results show that Compound 24 significantly
prevented the aging in senescene accelerated mice (SAMP8).
[0213] FIG. 6 is a graphical representation showing the influence
of Compound 24 on the survival rate of senescene accelerated mice
(SAMP8). The age in months of mice is plotted as abscissa and the
survival rate (%) is plotted as ordinate.
[0214] The results in FIG. 6 show that the average life span was
extended in the group given Compound 24 in drinking water at an
effective oral dosage of 0.01 mg/kg/day at any age in month
compared to the control group of senescene accelerated mice (SAMP8)
given tap water. Hence, Compound 24 was shown to extend the average
life span in senescene accelerated mice (SAMP8).
[0215] As described above, a compound of Formula (I) was shown to
have age retardant activity and extend the average life expectancy
in a study of Compound 24 on prevention of fur deterioration and
extension of the average life span in senescene accelerated mice
(SAM).
Preparation of Compounds Referred to in the Embodiments
[0216] Some of the heterocyclic compound having the general Formula
(I) and prepared by the method in examples of Booklet of
International Publication No. 01/09131 are described hereafter by
way of example. More specifically, they were synthesized with
reference to Booklet of International Publication No. 01/09131 and
Booklet of International Publication No. 2002/060907 Brochure.
Exemplary Preparation 1
[0217] An exemplary preparation of
3,3-dibenzyl-8-isopropoxyimidazo[1,2-a]pyridin-2(3H)-one (Compound
1) having the general formula below is described hereafter.
##STR10##
[0218] An amount of 81 mg of metallic sodium was added to 3.0 ml of
absolute ethanol and stirred at room temperature for one hour. An
amount of 586 mg (1.77 mmol) of
2-amino-3-isopropoxy-1-(ethoxycarbonylmethyl)pyridinium bromide was
added and further stirred at room temperature for one hour. Then,
605 mg (3.54 mmol) of benzyl bromide was added to the reaction
mixture at 0.degree. C. and stirred at room temperature for four
hours. The precipitated crystals were filtered off and dried. The
obtained crystals were recrystallized from ethanol to yield 588 mg
of the title compound (yield: 92%).
[0219] Results of analysis of the obtained compound are given
below. The results show that the obtained compound was the targeted
compound.
[0220] Melting Point: 247-248.degree. C.;
[0221] NMR (CDCl.sub.3) .delta.: 1.03 (6H, d, J=6 Hz), 3.15 (2H, d,
J=14 Hz), 3.56 (2H, d, J=14 Hz), 4.60 (1H, sept., J=6 Hz), 6.48
(1H, t, J=7 Hz), 6.79 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
[0222] MS m/z: 372 (M.sup.+)
Exemplary Preparation 2
[0223] Compounds 2 to 40 of Formulae (I) were each prepared from
the respective starting materials in the same manner as in
Exemplary Preparation 1. Results of analysis of the obtained
compounds are given for each compound. The results show that the
obtained compounds were the targeted Compounds 2 to 40.
3,3-dibenzyl-8-methoxyimidazo[1,2-a]pyridin-2(3H)-one (Compound
2)
[0224] ##STR11##
[0225] Melting Point: 274-275.degree. C.;
[0226] NMR (CDCl.sub.3) .delta.: 3.17 (2H, d, J=14 Hz), 3.56 (2H,
d, J=14 Hz), 3.69 (3H, s), 6.49 (1H, t, J=7 Hz), 6.67 (1H, d, J=8
Hz), 6.9-7.2 (11H, m);
[0227] MS m/z: 344 (M.sup.+).
3,3-dibenzyl-8-cyclopropylmethyloxy-imidazo[1,2-a]pyridin-2(3H)-one
(Compound 3)
[0228] ##STR12##
[0229] Melting Point: 236-237.degree. C.;
[0230] NMR (CDCl.sub.3) .delta.: 0.12 (2H, q, J=5 Hz), 0.45 (2H, q,
J=6 Hz), 0.99 (1H, m), 3.16 (2H, d, J=14 Hz), 3.55 (2H, d, J=14
Hz), 3.73 (2H, d, J=7 Hz), 6.47 (1H, t, J=7 Hz), 6.76 (1H, d, J=8
Hz), 7.0-7.2 (11H, m);
[0231] MS m/z: 384 (M.sup.+).
3,3-dibenzyl-6-chloroimidazo[1,2-a]pyridin-2(3H)-one (Compound
4)
[0232] ##STR13##
[0233] Melting Point: 246-248.degree. C.;
[0234] NMR (CDCl.sub.3) .delta.: 3.16 (2H, d, J=14 Hz), 3.55 (2H,
d, J=14 Hz), 6.70 (1H, d, J=10 Hz), 7.0-7.2 (12H, m);
[0235] MS m/z: 348 (M.sup.+).
8-allyloxy-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one (Compound
5)
[0236] ##STR14##
[0237] Melting Point: 214-215.degree. C.;
[0238] NMR (CDCl.sub.3) .delta.: 3.16 (2H, d, J=14 Hz), 3.56 (2H,
d, J=14 Hz), 4.4-4.5 (2H, m), 5.0-5.2 (2H, m), 5.7-5.9 (1H, m),
6.47 (1H, t, J=7 Hz), 6.74 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
[0239] MS m/z: 370 (M.sup.+).
3,3-dibenzyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one (Compound
6)
[0240] ##STR15##
[0241] Melting Point: 240-241.degree. C.;
[0242] NMR (CDCl.sub.3) .delta.: 3.17 (2H, d, J=14 Hz), 3.57 (2H,
d, J=14 Hz), 5.03 (2H, s), 6.39 (1H, t, J=8 Hz), 6.65 (1H, d, J=8
Hz), 7.0-7.2 (16H, m);
[0243] MS m/z: 420 (M.sup.+).
8-benzyloxy-3,3-bis(1-phenylethyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 7)
[0244] ##STR16##
[0245] Melting Point: 234-235.degree. C.;
[0246] NMR (CDCl.sub.3) .delta.: 1.52 (6H, d, J=7 Hz), 3.51 (2H, q,
J=7 Hz), 5.11 (2H, s), 6.14 (1H, t, J=7 Hz), 6.41 (1H, d, J=7 Hz),
6.63 (1H, d, J=8 Hz), 7.0-7.2 (15H, m);
[0247] MS m/z: 448 (M.sup.+).
3,3-dibenzyl-8-methylimidazo[1,2-a]pyridin-2(3H)-one (Compound
8)
[0248] ##STR17##
[0249] Melting Point: 262-263.degree. C.;
[0250] NMR (CDCl.sub.3) .delta.: 2.05 (3H, s), 3.31 (2H, d, J=14
Hz), 3.56 (2H, d, J=14 Hz), 6.60 (1H, t, J=7 Hz), 6.9-7.2 (12H,
m);
[0251] MS m/z: 328 (M.sup.+).
3,3-dibenzyl-5,7-dimethylimidazo[1,2-a]pyridin-2(3H)-one (Compound
9)
[0252] ##STR18##
[0253] Melting Point: 237-238.degree. C.;
[0254] NMR (CDCl.sub.3) .delta.: 2.07 (3H, s), 2.80 (3H, s), 3.40
(2H, d, J=15 Hz), 3.71 (2H, d, J=15 Hz), 6.11 (1H, s), 6.34 (1H,
s), 7.0-7.2 (10H, m);
[0255] MS m/z: 342 (M.sup.+).
3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one (Compound 10)
[0256] Melting Point: >300.degree. C.; ##STR19##
[0257] NMR (DMSO-D6) .delta.: 3.39 (4H, s), 6.60 (1H, d, J=9 Hz),
6.8-7.2 (11H, m), 7.56 (1H, t, J=7 Hz), 8.75 (1H, d, J=7 Hz);
[0258] MS m/z: 314 (M.sup.+).
3,3-dibenzyl-8-cyclopentyloxyimidazo[1,2-a]pyridin-2(3H)-one
(Compound 11)
[0259] ##STR20##
[0260] Melting Point: 268-269.degree. C.;
[0261] NMR (CDCl.sub.3) .delta.: 1.4-1.7 (8H, m), 3.15 (2H, d, J=14
Hz), 3.55 (1H, d, J=14 Hz), 4.7-4.9 (1H, m), 6.47 (1H, t, J=7 Hz),
6.72 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
[0262] MS m/z: 398 (M.sup.+).
3,3-dibenzyl-6,8-dichloroimidazo[1,2-a]pyridin-2(3H)-one (Compound
12)
[0263] ##STR21##
[0264] Melting Point: 260-261.degree. C.;
[0265] NMR (CDCl.sub.3) .delta.: 3.17 (2H, d, J=14 Hz), 3.55 (2H,
d, J=14 Hz), 6.9-7.3 (11H, m), 7.41 (1H, d, J=2 Hz);
[0266] MS m/z: 382 (M.sup.+).
3,3-dibenzyl-8-chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2(3H)-one
(Compound 13)
[0267] ##STR22##
[0268] Melting Point: 234-236.degree. C.;
[0269] NMR (CDCl.sub.3) .delta.: 3.22 (2H, d, J=14 Hz), 3.55 (2H,
d, J=14 Hz), 6.9-7.0 (4H, m), 7.1-7.4 (7H, m), 7.51 (1H, d, J=2
Hz);
[0270] MS m/z: 416 (M.sup.+).
8-benzyloxy-3,3-bis(3-methylbenzyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 14)
[0271] ##STR23##
[0272] Melting Point: 233-235.degree. C.;
[0273] NMR (CDCl.sub.3) .delta.: 2.20 (6H, s), 3.14 (2H, d, J=14
Hz), 3.48 (2H, d, J=14 Hz), 5.05 (2H, s), 6.38 (1H, t, J=7 Hz),
6.68 (1H, d, J=8 Hz), 6.7-7.3 (14H, m);
[0274] MS m/z: 448 (M.sup.+).
8-methyl-3,3-bis(4-pyridylmethyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 15)
[0275] ##STR24##
[0276] Melting Point: 228-230.degree. C.;
[0277] NMR (CDCl.sub.3) .delta.: 2.01 (3H, s), 3.13 (2H, d, J=14
Hz), 3.60 (2H, d, J=14 Hz), 6.60 (1H, t, J=7 Hz), 6.95 (4H, d, J=6
Hz), 7.22 (1H, d, J=7 Hz), 7.46 (1H, d, J=7 Hz), 8.40 (4H, d, J=6
Hz);
[0278] MS m/z: 330 (M.sup.+).
3,3-bis(4-fluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
16)
[0279] ##STR25##
[0280] Melting Point: 290-292.degree. C.;
[0281] NMR (CDCl.sub.3) .delta.: 3.13 (2H, d, J=14 Hz), 3.56 (2H,
d, J=14 Hz), 6.62 (1H, t, J=7 Hz), 6.7-6.9 (5H, m), 6.9-7.1 (4H,
m), 7.39 (1H, t, J=7 Hz), 7.52 (1H, brd, J=7 Hz);
[0282] MS m/z: 350 (M.sup.+).
3,3-bis(4-dimethylaminobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 17)
[0283] ##STR26##
[0284] Melting Point: >300.degree. C.;
[0285] NMR (CDCl.sub.3) .delta.: 2.86 (12H, s), 3.09 (2H, d, J=14
Hz), 3.37 (2H, d, J=14 Hz), 6.4-6.6 (5H, m), 6.7-6.9 (5H, m),
7.2-7.3 (1H, m), 7.37 (1H, t, J=7 Hz);
[0286] MS m/z: 400 (M.sup.+).
3,3-bis(3-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
18)
[0287] ##STR27##
[0288] Melting Point: 271-272.degree. C.;
[0289] NMR (CDCl.sub.3) .delta.: 3.14 (2H, d, J=14 Hz), 3.53 (2H,
d, J=14 Hz), 6.66 (1H, t, J=7 Hz), 6.80 (1H, d, J=7 Hz), 6.9-7.2
(8H, m), 7.43 (1H, t, J=7 Hz), 7.51 (1H, brd, J=7 Hz);
[0290] MS m/z: 382 (M.sup.+).
3,3-bis(4-methoxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
19)
[0291] ##STR28##
[0292] Melting Point: 248-251.degree. C.;
[0293] NMR (CDCl.sub.3) .delta.: 3.66 (6H, s), 3.67 (2H, d, J=15
Hz), 4.00 (2H, d, J=15 Hz), 6.59 (4H, d, J=9 Hz), 6.93 (4H, d, J=9
Hz), 7.50 (1H, t, J=7 Hz), 6.71 (1H, d, J=7 Hz), 7.91 (1H, t, J=7
Hz), 9.78 (1H, d, J=7 Hz);
[0294] MS m/z: 374 (M.sup.+).
3,3-bis(4-biphenylmethyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
20)
[0295] ##STR29##
[0296] Melting Point: >300.degree. C.;
[0297] NMR (CDCl.sub.3) .delta.: 3.25 (2H, d, J=14 Hz), 3.62 (2H,
d, J=14 Hz), 6.58 (1H, t, J=7 Hz), 6.77 (1H, d, J=7 Hz), 7.11 (4H,
d, J=7 Hz), 7.3-7.6 (16H, m);
[0298] MS m/z: 466 (M.sup.+).
3,3-bis(4-cyanobenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
21)
[0299] ##STR30##
[0300] Melting Point: 294.degree. C. (decomposition);
[0301] NMR (CDCl.sub.3) .delta.: 3.19 (2H, d, J=14 Hz), 3.70 (2H,
d, J=14 Hz), 6.6-6.8 (2H, m), 7.13 (4H, d, J=7 Hz), 7.43 (1H, t,
J=7 Hz), 7.45 (4H, d, J=7 Hz), 7.62 (1H, brd, J=7 Hz);
[0302] MS m/z: 364 (M.sup.+).
3,3-bis(4-hydroxybenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
22)
[0303] ##STR31##
[0304] Melting Point: 276.5-277.5.degree. C.;
[0305] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.62 (2H, d, J=14
Hz), 3.66 (2H, d, J=14 Hz), 6.58 (4H, d, J=9 Hz), 6.78 (4H, d, J=9
Hz), 7.17 (1H, d, J=7 Hz), 7.63 (1H, t, J=7 Hz), 8.12 (1H, t, J=7
Hz), 9.25 (1H, d, J=7 Hz);
[0306] MS m/z: 346 (M.sup.+).
3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one (Compound 23)
[0307] ##STR32##
[0308] Melting Point: 64-66.degree. C.;
[0309] NMR (CDCl.sub.3) .delta.: 2.56 (2H, dd, J=9 Hz, J=14 Hz),
2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.99 (2H, dd, J=1 Hz, J=7 Hz), 5.04
(2H, d, J=1 Hz), 5.4-5.6 (2H, m), 6.67 (1H, t, J=7 Hz), 7.17 (1H,
d, J=7 Hz), 7.52 (1H, d, J=7 Hz), 7.59 (1H, d, J=7 Hz);
[0310] MS m/z: 214 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan] (Compound 24)
[0311] ##STR33##
[0312] Melting Point: 206.degree. C. (decomposition);
[0313] NMR (CDCl.sub.3) .delta.: 3.16 (2H, d, J=16 Hz), 3.89 (2H,
d, J=16 Hz), 6.49 (1H, t, J=7 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (4H,
m), 7.61 (1H, t, J=7 Hz);
[0314] MS m/z: 236 (M.sup.+).
3,3-diallyl-8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one (Compound
25)
[0315] ##STR34##
[0316] Melting Point: 160-162.degree. C.;
[0317] NMR (CDCl.sub.3) .delta.: 2.54 (2H, dd, J=8 Hz, J=14 Hz),
2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.96 (2H, dd, J=1 Hz, J=5 Hz), 5.01
(2H, d, J=1 Hz), 5.29 (2H, s), 5.4-5.6 (2H, m), 6.53 (1H, dd, J=7
Hz, J=8 Hz), 6.94 (1H, d, J=7 Hz), 7.16 (1H, d, J=8 Hz), 7.3-7.5
(5H, m);
[0318] MS m/z: 320 (M.sup.+).
3,3-bis(3-phenyl-1-propyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
26)
[0319] ##STR35##
[0320] Melting Point: 227-228.degree. C.;
[0321] NMR (CDCl.sub.3) .delta.: 0.9-1.1 (2H, m), 1.4-1.6 (2H, m),
1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 2.3-2.5 (2H, m), 2.5-2.7 (2H, m),
6.61 (1H, t, J=7 Hz), 7.0-7.1 (4H, m), 7.1-7.3 (8H, m), 7.58 (1H,
t, J=7 Hz);
[0322] MS m/z: 370 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-[2,3]dihydrophenarene]
(Compound 27)
[0323] ##STR36##
[0324] Melting Point: 262.degree. C. (decomposition);
[0325] NMR (CDCl.sub.3): 3.12 (2H, d, J=17 Hz), 3.98 (2H, d, J=17
Hz), 6.18 (1H, t, J=7 Hz), 6.48 (1H, d, J=7 Hz), 7.24 (1H, d, J=7
Hz), 7.34 (2H, d, J=7 Hz), 7.4-7.6 (3H, m), 7.86 (2H, d, J=7
Hz);
[0326] MS m/z: 286 (M.sup.+).
3,3-bis(2,4-difluorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 28)
[0327] ##STR37##
[0328] Melting Point: 269-271.degree. C.;
[0329] NMR (CDCl.sub.3) .delta.: 3.38 (2H, d, J=14 Hz), 3.47 (2H,
d, J=14 Hz), 6.5-6.7 (3H, m), 6.7-6.8 (3H, m), 7.2-7.5 (3H, m),
7.6-7.7 (1H, m);
[0330] MS m/z: 368 (M.sup.+).
3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one (Compound 29)
[0331] ##STR38##
[0332] Melting Point: 73-75.degree. C.;
[0333] NMR (CDCl.sub.3) .delta.: 0.7-0.9 (8H, m), 1.1-1.3 (2H, m),
1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 6.73 (1H, t, J=7 Hz), 7.19 (1H,
d, J=7 Hz), 7.50 (1H, d, J=7 Hz), 7.63 (1H, t, J=7 Hz);
[0334] MS m/z: 218 (M.sup.+).
3,3-bis(2-thienylmethyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
30)
[0335] ##STR39##
[0336] Melting Point: 289.5.degree. C. (decomposition);
[0337] NMR (CDCl.sub.3) .delta.: 3.41 (2H, d, J=15 Hz), 3.70 (2H,
d, J=15 Hz), 6.64 (1H, t, J=7 Hz), 6.7-7.0 (5H, m), 7.07 (2H, dd,
J=1 Hz, J=5 Hz), 7.38 (1H, d, J=7 Hz), 7.48 (1H, t, J=7 Hz);
[0338] MS m/z: 326 (M.sup.+).
8-acetylamino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one (Compound
31)
[0339] ##STR40##
[0340] Melting Point: 235-237.degree. C.;
[0341] NMR (CDCl.sub.3) .delta.: 2.05 (3H, s), 3.20 (2H, d, J=14
Hz), 3.55 (2H, d, J=14 Hz), 6.61 (1H, t, J=7 Hz), 6.9-7.1 (4H, m),
7.1-7.2 (7H, m), 7.78 (1H, brs), 8.39 (1H, d, J=7 Hz);
[0342] MS m/z: 371 (M.sup.+).
3,3-bis(2-furylmethyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
32)
[0343] ##STR41##
[0344] Melting Point: 205.degree. C. (decomposition);
[0345] NMR (CDCl.sub.3) .delta.: 3.37 (4H, s), 6.11 (2H, d, J=3
Hz), 6.23 (2H, dd, J=2 Hz, J=3 Hz), 6.56 (1H, t, J=7 Hz), 6.97 (1H,
d, J=7 Hz), 7.20 (2H, d, J=2 Hz), 7.22 (1H, d, J=7 Hz), 7.51 (1H,
t, J=7 Hz);
[0346] MS m/z: 294 (M.sup.+).
3,3-dimethylimidazo[1,2-a]pyridin-2(3H)-one (Compound 33)
[0347] ##STR42##
[0348] Melting Point: 200-202.degree. C.;
[0349] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 1.93 (6H, s),
7.72 (1H, t, J=7 Hz), 7.78 (1H, d, J=7 Hz), 8.50 (1H, t, J=7 Hz),
9.01 (1H, d, J=7 Hz);
[0350] MS m/z: 162 (M.sup.+).
3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one (Compound 34)
[0351] ##STR43##
[0352] Melting Point: 100.5-102.degree. C.;
[0353] NMR (CDCl.sub.3) .delta.: 0.6-0.9 (8H, m), 1.0-1.3 (6H, m),
1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 6.71 (1H, t, J=7 Hz), 7.19 (1H,
d, J=7 Hz), 7.50 (1H, d, J=7 Hz), 7.62 (1H, t, J=7 Hz);
[0354] MS m/z: 246 (M.sup.+).
3,3-di(2-propinyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound 35)
[0355] ##STR44##
[0356] Melting Point: 172-175.degree. C.;
[0357] NMR (CDCl.sub.3) .delta.: 2.07 (2H, t, J=3 Hz), 2.80 (2H,
dd, J=3 Hz, J=17 Hz), 3.08 (2H, dd, J=2.6 Hz, J=17 Hz), 6.75 (1H,
t, J=7 Hz), 7.24 (1H, d, J=7 Hz), 7.69 (1H, t, J=7 Hz), 8.02 (1H,
d, J=7 Hz);
[0358] MS m/z: 210 (M.sup.+).
3,3-dibenzyl-8-hydroxyimidazo[1,2-a]pyridin-2(3H)-one (Compound
36)
[0359] ##STR45##
[0360] Melting Point: 283-285.degree. C.;
[0361] NMR (CDCl.sub.3) .delta.: 3.20 (2H, d, J=14 Hz), 3.55 (2H,
d, J=14 Hz), 6.58 (1H, t, J=7 Hz), 6.87 (1H, d, J=7 Hz), 6.9-7.0
(4H, m), 7.07 (1H, d, J=7 Hz), 7.1-7.2 (6H, m);
[0362] MS m/z: 330 (M.sup.+).
3,3-dibenzyl-8-benzylaminoimidazo[1,2-a]pyridin-2(3H)-one (Compound
37)
[0363] ##STR46##
[0364] Melting Point: 250.degree. C.;
[0365] NMR (CDCl.sub.3) .delta.: 3.42 (2H, d, J=14 Hz), 3.70 (2H,
d, J=14 Hz), 4.35 (2H, d, J=6 Hz), 6.93 (1H, d, J=7 Hz), 7.0-7.3
(16H, m), 7.48 (1H, d, J=7 Hz), 8.66 (1H, brs);
[0366] MS m/z: 419 (M.sup.+).
3,3-bis(4-nitrobenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
38)
[0367] ##STR47##
[0368] Melting Point: >300.degree. C.;
[0369] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.21 (2H, d, J=14
Hz), 3.67 (2H, d, J=14 Hz), 6.66 (1H, t, J=7 Hz), 6.75 (1H, d, J=7
Hz), 7.15 (4H, d, J=9 Hz), 7.39 (1H, t, J=7 Hz), 7.42 (4H, d, J=9
Hz), 7.56 (1H, d, J=7 Hz);
[0370] MS m/z: 404 (M.sup.+).
8-amino-3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one (Compound
39)
[0371] ##STR48##
[0372] Melting Point: 283-285.degree. C.;
[0373] NMR (CDCl.sub.3) .delta.: 3.17 (2H, d, J=14 Hz), 3.53 (2H,
d, J=14 Hz), 4.06 (2H, brs), 6.4-6.5 (2H, m), 6.94 (1H, t, J=7 Hz),
7.0-7.1 (4H, m), 7.1-7.2 (6H, m);
[0374] MS m/z: 330 (M.sup.+).
3,3-bis(4-methoxycarbonylbenzyl)imidazo[1,2-a]pyridin-2(3H)-one
(Compound 40)
[0375] ##STR49##
[0376] Melting Point: 289-290.degree. C.;
[0377] NMR (CDCl.sub.3) .delta.: 3.22 (2H, d, J=14 Hz), 3.66 (2H,
d, J=14 Hz), 3.86 (6H, s), 6.60 (1H, t, J=7 Hz), 6.70 (1H, d, J=7
Hz), 7.0-7.1 (4H, m), 7.35 (1H, t, J=7 Hz), 7.50 (1H, d, J=7 Hz),
7.8-7.9 (4H, m);
[0378] MS m/z: 430 (M.sup.+).
Exemplary Preparation 3
[0379] An exemplary preparation of
5,5-bis(4-fluorobenzyl)imidazo[2,1-b]thiazol-6(5H)-one (Compound
43) having the general formula below is described hereafter.
##STR50##
[0380] First, 300 mg (1.4 mmol) of
2-amino-3-ethoxycarbonylmethylthiazolium bromide and then 1.15 ml
(9.0 mmol) of p-fluorobenzyl bromide were added to an ethanol
solution (10 ml) of sodium ethoxide prepared from 210 mg (9.0 mmol)
of metallic sodium while cooling over ice and stirred at room
temperature overnight. The solvent was removed by distillation
under reduced pressure and water was added to the residue. The
resultant mixture was extracted several times using ethyl acetate,
rinsed with saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under reduced
pressure and the residue was chromatographed over silica gel column
(ethyl acetate:methanol=10:1). An amount of 852 mg (80.0%) of the
title compound was obtained in the form of crystals.
Recrystallization from ethanol yielded white crystals having a
melting point of higher than 300.degree. C.
[0381] Results of analysis of the obtained compound are given
below. The results show that the obtained compound was the targeted
compound.
[0382] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.23 (2H, d, J=14
Hz), 3.43 (2H, d, J=14 Hz), 6.66 (1H, d, J=4 Hz), 6.8-6.9 (4H, m),
6.9-7.1 (4H, m), 7.28 (1H, d, J=4 Hz);
[0383] MS m/z: 356 (M.sup.+).
Exemplary Preparation 4
[0384] Compounds 44 to 68 having the general formulae corresponding
to starting materials were each prepared in the same manner as in
Exemplary Preparation 3. Results of analysis of the obtained
compounds are given below. The results show the obtained compounds
were the targeted compounds.
5,5-dibenzylimidazo[2,1-b]thiazol-6(5H)-one (Compound 44)
[0385] ##STR51##
[0386] Melting Point: >300.degree. C.;
[0387] NMR (DMSO-d.sub.6) .delta.: 3.69 (2H, d, J=15 Hz), 3.74 (2H,
d, J=15 Hz), 7.27 (1H, d, J=4 Hz), 7.3-7.4 (4H, m), 7.5-7.6 (6H,
m), 8.44 (1H, d, J=4 Hz);
[0388] MS m/z: 320 (M.sup.+).
3,3-dibenzylimidazo[1,2-a]pyrimidin-2(3H)-one (Compound 45)
[0389] ##STR52##
[0390] Melting Point: >300.degree. C.;
[0391] NMR (DMSO-d.sub.6) .delta.: 3.42 (4H, dd, J=14 Hz, J=16 Hz),
6.9-7.0 (5H, m), 7.1-7.2 (6H, m), 8.46 (1H, dd, J=3 Hz, J=5 Hz),
9.07 (1H, dd, J=2 Hz, J=6 Hz);
[0392] MS m/z: 315 (M.sup.+).
5,5-bis(4-methylbenzyl)imidazo[2,1-b]thiazol-6(5H)-one (Compound
46)
[0393] ##STR53##
[0394] Melting Point: >300.degree. C.;
[0395] NMR (DMSO-d.sub.6) .delta.: 2.20 (6H, s), 3.24 (2H, d, J=14
Hz), 3.36 (2H, d, J=14 Hz), 6.84 (4H, d, J=8 Hz), 6.89 (1H, d, J=4
Hz), 6.97 (4H, d, J=8 Hz), 8.03 (4H, d, J=4 Hz);
[0396] MS m/z: 348 (M.sup.+).
5,5-bis(4-cyanobenzyl)imidazo[2,1-b]thiazol-6(5H)-one (Compound
47)
[0397] ##STR54##
[0398] Melting Point: 264-267.degree. C.;
[0399] NMR (CDCl.sub.3) .delta.: 3.23 (2H, d, J=14 Hz), 3.56 (2H,
d, J=14 Hz), 6.54 (1H, d, J=6 Hz), 7.02 (1H, d, J=6 Hz), 7.15 (4H,
d, J=9 Hz), 7.51 (4H, d, J=9 Hz);
[0400] MS m/z: 370 (M.sup.+).
5,5-dibenzyl-2-methylimidazo[2,1-b]thiazol-6(5H)-one (Compound
48)
[0401] ##STR55##
[0402] Melting Point: >300.degree. C.;
[0403] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 2.34 (3H, d, J=1
Hz), 3.28 (2H, d, J=13 Hz), 3.43 (2H, d, J=13 Hz), 7.0-7.1 (4H, m),
7.1-7.3 (7H, m);
[0404] MS m/z: 334 (M.sup.+).
5,5-bis(2-thienylmethyl)imidazo[2,1-b]thiazol-6(5H)-one (Compound
49)
[0405] ##STR56##
[0406] Melting Point: 286.degree. C. (decomposition);
[0407] NMR (CDCl.sub.3) .delta.: 3.43 (2H, d, J=15 Hz), 3.60 (2H,
d, J=15 Hz), 6.49 (1H, d, J=5 Hz), 6.7-7.0 (5H, m), 7.12 (2H, dd,
J=1 Hz, J=6 Hz);
[0408] MS m/z: 332 (M.sup.+). ##STR57##
3,3-bis(2-thienylmethyl)imidazo[1,2-a]pyrimidin-2(3H)-one (Compound
50)
[0409] Melting Point: 192.degree. C. (decomposition);
[0410] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.54 (2H, d, J=15
Hz), 3.76 (2H, d, J=15 Hz), 6.7-6.9 (5H, m), 7.11 (2H, dd, J=1 Hz,
J=5 Hz), 8.23 (1H, dd, J=2 Hz, J=6 Hz), 8.62 (1H, dd, J=2 Hz, J=4
Hz);
[0411] MS m/z: 327 (M.sup.+).
5,5-dibenzyl-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one (Compound
51)
[0412] ##STR58##
[0413] Melting Point: 233-236.degree. C.;
[0414] NMR (CDCl.sub.3) .delta.: 3.03 (2H, d, J=14 Hz), 3.23 (2H,
t, J=7 Hz), 3.41 (2H, d, J=14 Hz), 3.63 (2H, t, J=7 Hz), 7.1-7.2
(4H, m), 7.2-7.3 (6H, m);
[0415] MS m/z: 322 (M.sup.+).
2-hydroxy-3-(2-naphthylmethyl)imidazo[1,2-a]pyridine (Compound
52)
[0416] ##STR59##
[0417] Melting Point: 205.degree. C. (decomposition);
[0418] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.41 (1H, d, J=15
Hz), 3.76 (1H, d, J=15 Hz), 6.72 (1H, t, J=7 Hz), 7.02 (1H, d, J=9
Hz), 7.29 (1H, d, J=9 Hz), 7.4-7.5 (2H, m), 7.58 (2H, brs), 7.6-7.9
(4H, m);
[0419] MS m/z: 274 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[f]indan] (Compound
53)
[0420] ##STR60##
[0421] Melting Point: 214.degree. C. (decomposition);
[0422] NMR (CD.sub.3OD-CDCl.sub.3 (1:1)) .delta.: 3.33 (2H, d, J=16
Hz), 4.02 (2H, d, J=16 Hz), 6.58 (1H, t, J=7 Hz), 7.16 (1H, d, J=7
Hz), 7.24 (1H, d, J=9 Hz), 7.5-7.6 (2H, m), 7.74 (1H, t, J=8 Hz),
7.8-7.9 (4H, m);
[0423] MS m/z: 286 (M.sup.+).
3-benzylimidazo[1,2-a]pyridin-2(3H)-one (Compound 54)
[0424] ##STR61##
[0425] Melting Point: 182.degree. C. (decomposition);
[0426] NMR (CDCl.sub.3) .delta.: 3.09 (1H, dd, J=8 Hz, J=15 Hz),
3.64 (1H, dd, J=4 Hz, J=15 Hz), 4.58 (1H, dd, J=4 Hz, J=8 Hz), 6.47
(1H, t, J=7 Hz), 7.0-7.1 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (3H, m),
7.54 (1H, t, J=7 Hz);
[0427] MS m/z: 224 (M.sup.+).
3,3-di(2-butenyl)imidazo[1,2-a]pyrimidin-2(3H)-one (Compound
55)
[0428] ##STR62##
[0429] Melting Point: 149.5.degree. C. (decomposition);
[0430] NMR (CDCl.sub.3) .delta.: 1.55 (6H, d, J=6 Hz), 2.51 (2H,
dd, J=8 Hz, J=15 Hz), 2.76 (2H, dd, J=8 Hz, J=15 Hz), 5.1-5.3 (2H,
m), 5.4-5.7 (2H, m), 6.69 (1H, dd, J=5 Hz, J=6 Hz), 7.75 (1H, dd,
J=2 Hz, J=6 Hz), 8.7 (1H, dd, J=2 Hz, J=5 Hz);
[0431] MS m/z: 243 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-fluoroindan)]
(Compound 56)
[0432] ##STR63##
[0433] Melting Point: 148.0.degree. C. (decomposition);
[0434] NMR (CDCl.sub.3) .delta.: 3.24 (2H, dd, J=18 Hz, J=22 Hz),
3.88 (2H, t, J=18 Hz), 6.55 (1H, t, J=7 Hz), 7.01 (1H, t, J=9 Hz),
7.10 (1H, d, J=7 Hz), 7.2-7.3 (3H, m), 7.63 (1H, t, J=8 Hz);
[0435] MS m/z: 254 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-methoxyindan)]
(Compound 57)
[0436] ##STR64##
[0437] Melting Point: 150.0-152.0.degree. C.;
[0438] NMR (CDCl.sub.3) .delta.: 3.08 (2H, dd, J=6 Hz, J=17 Hz),
3.8-4.0 (5H, m), 6.49 (1H, t, J=7 Hz), 6.8-6.9 (2H, m), 7.1-7.3
(3H, m), 7.60 (1H, t, J=7 Hz);
[0439] MS m/z: 266 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-iodoindan)]
(Compound 58)
[0440] ##STR65##
[0441] Melting Point: 167-171.degree. C.;
[0442] NMR (CDCl.sub.3) .delta.: 3.14 (2H, dd, J=6 Hz, J=17 Hz),
3.82 (2H, dd, J=17 Hz, J=18 Hz), 6.57 (1H, t, J=7 Hz), 7.08 (1H, d,
J=8 Hz), 7.1-7.3 (2H, m), 7.6-7.7 (3H, m);
[0443] MS m/z: 362 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-cyanoindan)]
(Compound 59)
[0444] ##STR66##
[0445] Melting Point: 247.7.degree. C. (decomposition);
[0446] NMR (CDCl.sub.3) .delta.: 3.26 (2H, dd, J=3 Hz, J=18 Hz),
3.93 (2H, dd, J=6 Hz, J=18 Hz), 6.56 (1H, t, J=7 Hz), 7.15 (1H, d,
J=7 Hz), 7.23 (1H, d, J=9 Hz), 7.44 (1H, d, J=8 Hz), 7.6-7.7 (3H,
m);
[0447] MS m/z: 261 (M.sup.+).
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-indan] (Compound
60)
[0448] ##STR67##
[0449] Melting Point: 201-203.degree. C.;
[0450] NMR (CDCl.sub.3) .delta.: 3.22 (2H, d, J=17 Hz), 3.91 (2H,
d, J=17 Hz), 6.74 (1H, d, J=7 Hz), 6.89 (1H, d, J=7 Hz), 7.32 (4H,
s), 7.6-7.7 (2H, m), 7.79 (1H, t, J=7 Hz), 8.63 (1H, d, J=8
Hz);
[0451] MS m/z: 286 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-((1,2,5-thiadiazo)[4,5-c]indan)-
] (Compound 61)
[0452] ##STR68##
[0453] Melting Point: 86-88.degree. C.;
[0454] NMR (CDCl.sub.3--CD.sub.3OD (1:1)) .delta.: 3.44 (2H, d,
J=18 Hz), 4.00 (2H, d, J=18 Hz), 6.71 (1H, t, J=7 Hz), 7.2-7.4 (2H,
m), 7.81 (1H, t, J=7 Hz), 7.97 (2H, s);
[0455] MS m/z: 294 (M.sup.+).
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2'-((1,2,5-thiadiazo)[4,5-c]in-
dan)] (Compound 62)
[0456] ##STR69##
[0457] Melting Point: 271.5.degree. C. (decomposition);
[0458] NMR (CDCl.sub.3) .delta.: 3.39 (2H, d, J=16 Hz), 4.04 (2H,
brd, J=16 Hz), 6.77 (1H, d, J=7 Hz), 6.81 (1H, d, J=7 Hz), 7.6-7.8
(2H, m), 7.82 (1H, brs, J=8 Hz), 7.95 (2H, brs), 8.65 (1H, d, J=8
Hz);
[0459] MS m/z: 344 (M.sup.+).
spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2'-indan] (Compound
63)
[0460] ##STR70##
[0461] Melting Point: 195.5.degree. C. (decomposition);
[0462] NMR (CDCl.sub.3) .delta.: 3.17 (2H, d, J=17 Hz), 3.92 (2H,
d, J=17 Hz), 6.53 (1H, dd, J=5 Hz, J=6 Hz), 7.44 (1H, dd, J=2 Hz,
J=6 Hz), 7.32 (4H, s), 8.72 (1H, dd, J=2 Hz, J=5 Hz);
[0463] MS m/z: 237 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(5'-trifluoromethylindan)]
(Compound 64)
[0464] ##STR71##
[0465] Melting Point: 176.5-179.5.degree. C.;
[0466] NMR (CDCl.sub.3) .delta.: 3.25 (2H, d, J=17 Hz), 3.92 (2H,
d, J=17 Hz), 6.57 (1H, t, J=7 Hz), 7.1-7.2 (2H, m), 7.44 (1H, d,
J=8 Hz), 8.5-8.7 (3H, m);
[0467] MS m/z: 304 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[e]indan] (Compound
65)
[0468] ##STR72##
[0469] Melting Point: 256.0.degree. C. (decomposition);
[0470] NMR (CDCl.sub.3) .delta.: 3.33 (1H, d, J=17 Hz), 3.56 (1H,
d, J=17 Hz), 4.09 (2H, t, J=17 Hz), 6.50 (1H, t, J=7 Hz), 7.22 (1H,
d, J=9 Hz), 7.29 (1H, d, J=7 Hz), 7.42 (1H, d, J=8 Hz), 7.5-7.7
(4H, m), 7.83 (1H, d, J=8 Hz), 7.92 (1H, d, J=6 Hz);
[0471] MS m/z: 286 (M.sup.+).
3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one (Compound 66)
[0472] ##STR73##
[0473] Melting Point: 64-66.degree. C.;
[0474] NMR (CDCl.sub.3) .delta.: 2.56 (2H, dd, J=9 Hz, J=14 Hz),
2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.99 (2H, dd, J=1 Hz, J=7 Hz), 5.40
(2H, d, J=1 Hz), 5.4-5.6 (2H, m), 6.67 (1H, t, J=7 Hz), 7.17 (1H,
d, J=7 Hz), 7.52 (1H, d, J=7 Hz), 7.59 (1H, d, J=7 Hz);
[0475] MS m/z: 214 (M.sup.+).
3,3-bis(2-cyclohexenyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
67)
[0476] ##STR74##
[0477] Melting Point: 245-247.degree. C.;
[0478] NMR (CDCl.sub.3) .delta.: 1.4-2.0 (12H, m), 2.9-3.1 (2H, m),
5.29 (1H, brd, J=10 Hz), 5.8-6.0 (3H, m), 6.62 (1H, t, J=7 Hz),
7.17 (1H, d, J=9 Hz), 7.5-7.7 (2H, m);
[0479] MS m/z: 294 (M.sup.+).
3,3-diallylimidazo[2,1-a]isoquinolin-2(3H)-one (Compound 68)
[0480] ##STR75##
[0481] Melting Point: 108-110.degree. C.;
[0482] NMR (CDCl.sub.3) .delta.: 2.62 (2H, dd, J=8 Hz, J=14 Hz),
2.89 (2H, dd, J=6 Hz, J=14 Hz), 4.9-5.1 (4H, m), 5.4-5.6 (2H, m),
6.91 (1H, d, J=7 Hz), 7.25 (1H, d, J=7 Hz), 7.6-7.7 (2H, m), 7.80
(1H, t, J=8 Hz), 8.57 (1H, d, J=8 Hz);
[0483] MS m/z: 264 (M.sup.+).
Exemplary Preparation 5
[0484] An exemplary preparation of
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,4'-(1'-cyclopentene)]
(Compound 69) having the general formula below is described
hereafter. ##STR76##
[0485] An amount of 80 mg of Grubbs reagent (0.24 mmol) was added
to a chloroform solution (80 ml) of 1.0 g (3.8 mmol) of
3,3-diallylimidazo[2,1-a]isoquinolin-2(3H)-one obtained in the same
manner as in Exemplary Preparation 1 under an argon atmosphere and
heated under flux for 14 hours. The reaction mixture was allowed to
stand for cooling and the solvent was removed by distillation under
reduced pressure. Water was added to the residue and the mixture
was extracted with dichloromethane several times. The extracted
layers were rinsed together with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure and the residue was
chromatographed over silica gel column for purification (ethyl
acetate:methanol=10:1) to obtain 748 mg (83.5%) of the title
compound in the form of light brown crystals.
[0486] Results of analysis of the obtained compound are given
below. The results show that the obtained compound was the targeted
compound.
[0487] Melting Point: 173.5.degree. C. (decomposition);
[0488] NMR (CDCl.sub.3) .delta.: 2.70 (2H, d, J=17 Hz), 3.30 (2H,
d, J=17 Hz), 5.92 (2H, s), 6.89 (1H, d, J=7 Hz), 7.33 (1H, d, J=7
Hz), 7.6-7.8 (2H, m), 7.79 (1H, t, J=7 Hz), 8.60 (1H, d, J=7
Hz);
[0489] MS m/z: 236 (M.sup.+).
Exemplary Preparation 6
[0490] Compound 70 having the general formula below corresponding
to starting materials was prepared in the same manner as in
Exemplary Preparation 5. Results of analysis of the obtained
compound are given below for each compound. The results show that
the obtained compound was the targeted Compound 70.
spiro[8-benzyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cyclopentene)]
(Compound 70)
[0491] ##STR77##
[0492] Melting Point: 178.5-180.5.degree. C.;
[0493] NMR (CDCl.sub.3) .delta.: 2.64 (2H, d, J=16 Hz), 3.29 (2H,
d, J=16 Hz), 5.30 (2H, s), 5.88 (2H, s), 6.49 (1H, dd, J=6 Hz, J=8
Hz), 6.94 (1H, dd, J=6 Hz, J=8 Hz), 6.94 (1H, d, J=8 Hz), 7.2-7.5
(5H, m);
[0494] MS m/z: 292 (M.sup.+).
Exemplary Preparation 7
[0495] An exemplary preparation of
3,3-dipropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one
(Compound 71) having the general formula below is described
hereafter. ##STR78##
[0496] An amount of 100 mg of 10% palladium on carbon was added to
an ethanol solution (30 ml) of 300 mg (1.4 mmol) of
3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one obtained in the same
manner as in Exemplary Preparation 5 and the mixture was subject to
catalytic reduction at room temperature under a hydrogen atmosphere
overnight. The insoluble substances were filtered off and the
solvent was removed from the filtrate by distillation under reduced
pressure. The residue was chromatographed over silica gel column
(hexane:ethyl acetate=10:1) to obtain 281 mg (90.3%) of the title
compound in the form of crystals. Recrystallization from
hexane-ethyl acetate (10:1) yielded white crystals having a melting
point of 98.5-101.degree. C.
[0497] Results of analysis of the obtained compound are given
below. The results show that the obtained compound was the targeted
compound.
[0498] NMR (CDCl.sub.3) .delta.: 0.86 (6H, t, J=7 Hz), 0.9-1.1 (2H,
m), 1.1-1.2 (2H, m), 1.4-1.6 (2H, m), 1.7-2.0 (6H, m), 2.79 (2H, t,
J=6 Hz), 3.19 (2H, t, J=6 Hz);
[0499] MS m/z: 222 (M.sup.+).
Exemplary Preparation 8
[0500] Compounds 72 to 77 having the general formulae corresponding
to starting materials were prepared in the same manner as in
Exemplary Preparation 7.
[0501] Results of analysis of the obtained compounds are given
below for each compound. The results show that the obtained
compounds were the targeted Compounds 72 to 77.
3,3-dicyclohexyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one
(Compound 72)
[0502] ##STR79##
[0503] Melting Point: 218-220.degree. C.;
[0504] NMR (CDCl.sub.3) .delta.: 0.9-1.4 (8H, m), 1.5-2.0 (18H, m),
2.79 (2H, t, J=6 Hz), 3.30 (2H, t, J=6 Hz);
[0505] MS m/z: 302 (M.sup.+).
3,3-dibutyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one
(Compound 73)
[0506] ##STR80##
[0507] Melting Point: 35-40.degree. C.;
[0508] NMR (CDCl.sub.3) .delta.: 0.88 (6H, t, J=7 Hz), 0.9-1.4 (8H,
m), 1.6-2.2 (8H, m), 3.2-3.4 (4H, m);
[0509] MS m/z: 250 (M.sup.+).
spiro[7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-one-3,1'-cyclopen-
tane] (Compound 74)
[0510] ##STR81##
[0511] Melting Point: 270.5.degree. C. (decomposition);
[0512] NMR (CDCl.sub.3) .delta.: 1.8-2.2 (10H, m), 2.3-2.5 (2H, m),
2.6-2.8 (4H, m), 6.44 (1H, d, J=7 Hz), 7.35 (1H, d, J=7 Hz);
[0513] MS m/z: 242 (M.sup.+).
spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,1'-cyclopentane]
(Compound 75)
[0514] ##STR82##
[0515] Melting Point: 164.5-167.5.degree. C.;
[0516] NMR (CDCl.sub.3) .delta.: 1.8-2.3 (6H, m), 2.4-2.6 (2H, m),
6.94 (1H, d, J=7 Hz), 7.33 (1H, d, J=7 Hz), 7.6-7.7 (2H, m), 7.79
(1H, t, J=6 Hz), 8.60 (1H, d, J=8 Hz);
[0517] MS m/z: 238 (M.sup.+).
spiro[5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one-3,2'-benzo[f]indan-
] (Compound 76)
[0518] ##STR83##
[0519] Melting Point: 252.5.degree. C. (decomposition);
[0520] NMR (CDCl.sub.3--CD.sub.3OD(1:1)) .delta.: 1.9-2.1 (4H, m),
3.0-3.2 (4H, m), 3.50 (2H, d, J=18 Hz), 3.79 (2H, d, J=18 Hz),
7.4-7.5 (2H, m), 7.75 (2H, s), 7.8-7.9 (2H, m);
[0521] MS m/z: 290 (M.sup.+).
spiro[5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan]
(Compound 77)
[0522] ##STR84##
[0523] Melting Point: 276.5.degree. C. (decomposition);
[0524] NMR (CDCl.sub.3-CD.sub.3OD (1:1)) .delta.: 1.9-2.1 (4H, m),
3.0-3.3 (4H, m), 3.45 (2H, d, J=17 Hz), 3.66 (2H, d, J=17 Hz), 7.30
(4H, s);
[0525] MS m/z: 240 (M.sup.+).
Exemplary Preparation 9
[0526] Compounds 78 to 81 having the general formulae corresponding
to starting materials were each prepared in the same manner as in
Exemplary Preparation 1. Results of analysis of the obtained
compounds are given below for each compound. The results show that
the obtained compounds were the targeted Compounds 78 to 81.
3,3-bis(4-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one (Compound
78)
[0527] ##STR85##
[0528] Melting Point: 293.0-296.0 (.degree. C.).
[0529] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.11 (2H, d, J=14 Hz),
3.55 (2H, d, J=14 Hz), 6.62 (1H, t, J=7 Hz), 6.78 (1H, d, J=8 Hz),
6.94 (4H, d, J=8 Hz), 7.12 (4H, d, J=8 Hz), 7.40 (1H, t, J=7 Hz),
7.47 (1H, d, J=7 Hz);
[0530] MS m/z: 382 (M.sup.+)
8-cyclopropylmethyloxy-3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one
(Compound 79)
[0531] ##STR86##
[0532] Melting Point: 139.0-142.0 (.degree. C.);
[0533] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.35-0.40 (2H, m),
0.60-0.65 (2H, m), 1.30-1.40 (1H, m), 2.50-2.60 (2H, m), 2.80-2.90
(2H, m), 3.94 (2H, d, J=7 Hz), 4.96 (2H, brs), 5.02 (2H, brs),
5.40-5.65 (2H, m), 6.57 (1H, t, J=7 Hz, J=8 Hz), 6.91 (1H, d, J=8
Hz), 7.16 (1H, d, J=7 Hz);
[0534] MS m/z: 284 (M.sup.+).
spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2'-(4'-hydroxy-indan)]
(Compound 80)
[0535] ##STR87##
[0536] Melting Point: 240.0.degree. C. (dec.);
[0537] .sup.1H-NMR (CD.sub.3OD) .delta.: 3.17 (1H, d, J=17 Hz),
3.19 (1H, d, J=17 Hz), 3.50 (1H, d, J=17 Hz), 3.61 (1H, d, J=17
Hz), 6.63 (1H, d, J=8 Hz), 6.70-6.80 (2H, m), 7.07 (1H, d, J=8 Hz),
7.12 (1H, d, J=9 Hz), 7.51 (1H, d, J=7 Hz), 7.81 (1H, d, J=8
Hz);
[0538] MS m/z: 352 (M.sup.+).
spiro[8-hydroxy-imidazo[1,2-a]pyridin-2(3H)-one-3,2'-indan]
(Compound 81)
[0539] ##STR88##
[0540] Melting Point: 285.0-290.0.degree. C.;
[0541] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.22 (2H, d, J=17 Hz),
3.91 (2H, d, J=17 Hz), 6.57 (1H, dd, J=6 Hz, J=7 Hz), 6.82 (1H, d,
J=6 Hz), 7.27 (1H, d, J=7 Hz), 7.31 (4H, s);
[0542] MS m/z: 352 (M.sup.+).
Exemplary Preparation 10
[0543] Compounds 82 to 83 having the general formulae corresponding
to starting materials were each prepared in the same manner as in
Exemplary Preparation 5. Results of analysis of the obtained
compounds are given below for each compound. The results show that
the obtained compounds were the targeted Compounds 82 to 83.
spiro[8-methoxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cyclopentene)]
(Compound 82)
[0544] ##STR89##
[0545] Melting Point: 200.0-202.0.degree. C.;
[0546] .sup.1H-NMR (CDCl.sub.3): 2.64 (2H, d, J=17 Hz), 3.29 (2H,
d, J=17 Hz), 3.96 (3H, s), 5.88 (2H, s), 6.57 (1H, dd, J=7 Hz, J=8
Hz), 6.91 (1H, d, J=8 Hz), 7.29 (1H, d, J=7 Hz);
[0547] MS m/z: 216 (M.sup.+).
spiro[8-cyclopropylmethyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,4'-(1'-cyclo-
pentene)] (Compound 83)
[0548] ##STR90##
[0549] Melting Point: 134.0-137.0.degree. C.;
[0550] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.35-0.40 (2H, m),
0.60-0.70 (2H, m), 1.30-1.40 (1H, m), 2.64 (2H, d, J=16 Hz), 3.28
(2H, d, J=16 Hz), 3.98 (2H, d, J=7 Hz), 5.88 (2H, s), 6.54 (1H, dd,
J=7 Hz, J=8 Hz), 6.92 (1H, d, J=8 Hz), 7.28 (1H, d, J=7 Hz);
[0551] MS m/z: 256 (M.sup.+).
Exemplary Pharmaceutical Formulation
[0552] The following table shows a typical pharmaceutical
composition that may be administered according to the invention.
TABLE-US-00002 Quantity per Quantity per Component 10 mg tablet 60
mg tablet Compound 24 10 mg 60 mg Mannitol 95.9 mg 45.9 mg
Microcrystalline cellulose 19.3 mg 19.3 mg Low-substituted 7.0 mg
7.0 mg hydroxypropyl cellulose Hydroxypropyl cellulose 5.0 mg 5.0
mg Magnesium stearate 2.8 mg 2.8 mg Total 140.0 mg 140.0 mg
[0553] The present invention is described above using examples. The
examples are given by way of example. It is understood by a person
in the art that various modifications are available and those
modifications are included in the scope of the present
invention.
[0554] For example, the above examples used mice as a mammal.
However, other mammals including human can be used. Even in such
cases, the above Compounds 1 to 83 exhibit antidepressant,
neuroprotection, amyloid .beta. deposition inhibitory, or age
retardant activity in other mammals including human.
* * * * *