U.S. patent application number 10/618743 was filed with the patent office on 2004-01-22 for amide compounds.
This patent application is currently assigned to Fujisawa Pharmaceutical Co. Ltd.. Invention is credited to Aoki, Satoshi, Yamada, Akira.
Application Number | 20040014745 10/618743 |
Document ID | / |
Family ID | 3812385 |
Filed Date | 2004-01-22 |
United States Patent
Application |
20040014745 |
Kind Code |
A1 |
Yamada, Akira ; et
al. |
January 22, 2004 |
Amide compounds
Abstract
This invention relates to new amide compounds having the
potentiation of the cholinergic activity, etc., and represented by
general formula [I]. 1 wherein R.sup.1 is acyl, R.sup.2 is lower
alkyl, etc., A is a single bond, 2 or --SO.sub.2--, E is lower
alkylene, etc, X is CH or N, Y is a single bond, etc., Q is
--CH.sub.2--, etc., and R.sup.3 and R.sup.4 are taken together to
form lower alkylene, etc., and pharmaceutically acceptable salts
thereof, to processes for preparation thereof and a pharmaceutical
composition comprising the same.
Inventors: |
Yamada, Akira; (Osaka,
JP) ; Aoki, Satoshi; (Osaka, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Fujisawa Pharmaceutical Co.
Ltd.
Osaka
JP
|
Family ID: |
3812385 |
Appl. No.: |
10/618743 |
Filed: |
July 15, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10618743 |
Jul 15, 2003 |
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09869962 |
Jul 10, 2001 |
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09869962 |
Jul 10, 2001 |
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PCT/JP00/00017 |
Jan 6, 2000 |
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Current U.S.
Class: |
514/218 ;
514/212.01; 514/255.01; 514/255.02; 514/396; 540/575; 544/383;
544/386; 548/331.1 |
Current CPC
Class: |
A61P 21/04 20180101;
C07D 213/75 20130101; C07D 401/12 20130101; A61P 7/12 20180101;
C07D 295/26 20130101; A61P 25/18 20180101; A61P 25/22 20180101;
A61P 25/34 20180101; A61P 25/16 20180101; A61P 43/00 20180101; A61P
25/36 20180101; A61P 25/14 20180101; C07D 211/58 20130101; A61P
25/24 20180101; A61P 25/28 20180101; A61P 13/00 20180101 |
Class at
Publication: |
514/218 ;
514/212.01; 514/255.02; 514/255.01; 514/396; 540/575; 544/383;
544/386; 548/331.1 |
International
Class: |
A61K 031/551; A61K
031/495; A61K 031/4164 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 14, 1999 |
AU |
PP8180 |
Claims
1. A compound of the formula: 24wherein R.sup.1 is acyl, R.sup.2 is
lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower
alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy,
lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy,
cyclo(lower)alkylamino, aryl, aryloxy, arylamino, a heterocyclic
group or amino substituted with a heterocyclic group, each of which
may be substituted with suitable substituent(s); or acyl; A is a
single bond, 25 or --SO.sub.2--, E is lower alkylene optionally
substituted with suitable substituent(s), X is CH or N, Y is a
single bond, lower alkylene or 26 (wherein R.sup.5 is hydrogen,
lower alkyl, substituted-lower alkyl, an N-protective group, aryl,
acyl or a heterocyclic group), Q is --CH.sub.2--, 27 --SO.sub.2--
or --N.dbd.CH--, and R.sup.3 and R.sup.4 are each hydrogen or lower
alkyl, or are taken together to form lower alkylene optionally
condensed with a cyclic hydrocarbon or a heterocyclic ring,
provided that when X is N, then 1) Y is a single bond, and Q is
--CH.sub.2--, 28 or --SO.sub.2--, or 2) Y is lower alkylene, and
pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R.sup.2 is aryl,
aryloxy or arylamino, each aryl of which may be substituted with
halogen; pyridyl; or pyridylamino; A is a single bond, E is
ethylene, X is CH or N, R.sup.5 Y is a single bond, lower alkylene
or 29 (wherein R.sup.5 is hydrogen, lower alkyl or an N-protective
group), Q is --CH.sub.2--, 30 or --SO.sub.2--, and R.sup.3 and
R.sup.4 are taken together to form ethylene.
3. A compound according to claim 2, wherein R.sup.1 is lower
alkanoyl, esterified carboxy, substituted or unsubstituted aroyl,
lower alkylsulfonyl, substituted or unsubstituted arylsulfonyl, or
cyclo(lower)alkylcarbonyl, and R.sup.2 is aryl or arylamino, each
aryl of which may be substituted with halogen.
4. A compound according to claim 3, wherein R.sup.1 is lower
alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with
halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl
substituted with halogen, or cyclo(lower)alkylcarbonyl, X is CH, H
Y is a single bond or 31and Q is 32 or --SO.sub.2--.
5. A compound according to claim 3, wherein R.sup.1 is lower
alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with
halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl
substituted with halogen, or cyclo(lower)alkylcarbonyl, X is N, Y
is a single bond or lower alkylene, and Q is 33 or
--SO.sub.2--.
6. A compound according to claim 4, wherein Y is 34and Q is 35
7. A compound according to claim 5, wherein Y is a single bond, and
Q is 36
8. A process for preparing a compound of the formula: 37wherein
R.sup.1 is acyl, R.sup.2 is lower alkyl, lower alkoxy, lower
alkylamino, lower alkenyl, lower alkenyloxy, lower alkenylamino,
lower alkynyl, lower alkynyloxy, lower alkynylamino,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, cyclo(lower)alkylamino,
aryl, aryloxy, arylamino, a heterocyclic group or amino substituted
with a heterocyclic group, each of which may be substituted with
suitable substituent(s); or acyl; A is a single bond, 38 or
--SO.sub.2--, E is lower alkylene optionally substituted with
suitable substituent(s), X is CH or N Y is a single bond, lower
alkylene or 39 (wherein R.sup.5 is hydrogen, lower alkyl,
substituted-lower alkyl, an N-protective group, aryl, acyl or a
heterocyclic group), Q is --CH.sub.2--, 40 --SO.sub.2-- or
--N.dbd.CH--, and R.sup.3 and R.sup.4 are each hydrogen or lower
alkyl, or are taken together to form lower alkylene optionally
condensed with a cyclic hydrocarbon or a heterocyclic ring,
provided that when X is N, then 1) Y is a single bond, and Q is
--CH.sub.2--, 41 or --SO.sub.2--, or 2) Y is lower alkylene, or
pharmaceutically acceptable salt thereof, which comprises, 1)
reacting a compound of the formula: 42or its salt with a compound
of the formula: HO-Q.sub.a-R.sup.2 [III]or its reactive derivative
at the carboxy or sulfo group, or a salt thereof to provide a
compound of the formula: 43or its salt, in the above formulas,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, A and E are each as defined
above, and Q.sub.a is 44 or --SO.sub.2--, or 2) reacting a compound
of the formula: 45or its salt with a compound of the formula:
R.sup.6--NCO [IV]to provide a compound of the formula: 46or its
salt, in the above formulas, R.sup.1, R.sup.3, R.sup.4, A and E are
each as defined above, and R.sup.6 is aryl which may be substituted
with suitable substituent(s); or pyridyl, or 3) reacting a compound
of the formula: 47or its salt with a compound of the formula:
HO-Q.sub.a-R.sup.2 [III]or its reactive derivative at the carboxy
or sulfo group, or a salt thereof to provide a compound of the
formula: 48or its salt, in the above formulas, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, A, E and Q.sub.a are each as defined above, or 4)
reacting a compound of the formula: 49or its salt with a compound
of the formula: R.sup.6--NCO [IV]to provide a compound of the
formula: 50or its salt, in the above formulas, R.sup.1, R.sup.3,
R.sup.4, R.sup.6, A and E are each as defined above, or 5) reacting
a compound of the formula: 51or its salt with a compound of the
formula: R.sup.1-A-OH [VII]or its reactive derivative at the
carboxy or sulfo group, or a salt thereof to provide a compound of
the formula: 52or its salt, in the above formulas, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, A, E, X, Y and Q are each as defined
above, or 6) reacting a compound of the formula: 53or its reactive
derivative at the carboxy or sulfo group, or a salt thereof with a
compound of the formula: H.sub.2N--R.sup.7 [IX]or its salt to
provide a compound of the formula: 54or its salt, in the above
formulas, R.sup.1, R.sup.3, R.sup.4, A, E, X and Q.sub.a are each
as defined above, and R.sup.7 is lower alkyl, lower alkenyl, lower
alkynyl, cyclo(lower)alkyl, aryl or a heterocyclic group, each of
which may be substituted with suitable substituent(s), or 7)
reacting a compound of the formula: 55or its salt with a compound
of the formula: R.sub.a.sup.2-Q.sub.b-Z.sub.a [XI]to provide a
compound of the formula: 56or its salt, in the above formulas,
R.sup.1, R.sup.3, R.sup.4, A and E are each as defined above,
R.sub.a.sup.5 is an N-protective group, R.sub.a.sup.2 is lower
alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, aryl or a
heterocyclic group, each of which may be substituted with suitable
substituent(s), Q.sub.b is --CH.sub.2--, 57 --SO.sub.2--, and
Z.sub.a is an acid residue, or 8) subjecting a compound of the
formula: 58or its salt to elimination reaction of the N-protective
group to provide a compound of the formula: 59or its salt, in the
above formulas, R.sup.1, R.sub.a.sup.2, R.sup.3, R.sup.4, A, E and
Q.sub.b, are each as defined above, or 9) reacting a compound of
the formula: 60or its salt with a compound of the formula:
R.sub.b.sup.5-Z.sub.b [XII]to provide a compound of the formula:
61or its salt, in the above formulas, R.sup.1, R.sub.a.sup.2,
R.sup.3, R.sup.4, A and E are each as defined above, Z.sub.b is an
acid residue, Q.sub.c is 62 and R.sub.b.sup.5 is lower alkyl, or
10) reacting a compound of the formula: 63or its salt with a
compound of the formula: Z.sub.c-Y.sub.a--Q.sub.a-R.sup.2 [XIII]to
provide a compound of the formula: 64or its salt, in the above
formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, E and Q.sub.a are
each as defined above, Z.sub.c is an acid residue, and Y.sub.a is
lower alkylene.
9. A pharmaceutical composition comprising a compound of claim 1,
as an active ingredient, in association with a pharmaceutically
acceptable, substantially non-toxic carrier or excipient.
10. A compound of claim 1 for use as a medicament.
11. A method for therapeutic treatment and/or prevention of amnesia
or dementia which comprises administering an effective amount of a
compound of claim 1 to mammals.
12. Use of a compound of claim 1 for manufacture of a medicament
for treating and/or preventing amnesia or dementia in mammals.
Description
TECHNICAL FIELD
[0001] This invention relates to new amide compounds and
pharmaceutically acceptable salts thereof which are useful as a
medicament.
BACKGROUND ART
[0002] Some aminopiperazine derivatives have been known as useful
anti-amnesia or anti-dementia agents, for example, in PCT
International Publication Nos. WO 91/01979 and WO 98/35951.
DISCLOSURE OF INVENTION
[0003] This invention relates to new amide compounds and
pharmaceutically acceptable salts thereof.
[0004] More particularly, it relates to new amide compounds and
pharmaceutically acceptable salts thereof which have the
potentiation of the cholinergic activity, to processes for the
preparation thereof, to a pharmaceutical composition comprising the
same, and to a method for the treatment and/or prevention of
disorders in the central nervous system for mammals, and more
particularly to method for the treatment and/or prevention of
amnesia, dementia (e.g., senile dementia, Alzheimer's dementia,
dementia associated with various diseases such as cerebral vascular
dementia, cerebral posttraumatic dementia, dementia due to brain
tumor, dementia due to chronic subdural hematoma, dementia due to
normal pressure hydrocephalus, post-meningitis dementia,
Parkinson's disease type dementia, etc.), and the like.
Additionally, the object compound is expected to be useful as
therapeutical and/or preventive agents for schizophrenia,
depression, stroke, head injury, nicotine withdrawal, spinal cord
injury, anxiety, pollakiuria, incontinence of urine, myotonic
dystrophy, attention deficit hyperactivity disorder, excessive
daytime sleepiness (narcolepsy), Parkinson's disease or autism.
[0005] One object of this invention is to provide new and useful
amide compounds and pharmaceutically acceptable salts thereof which
possess the potentiation of the cholinergic activity.
[0006] Another object of this invention is to provide processes for
preparation of said amide compounds and salts thereof.
[0007] A further object of this invention is to provide a
pharmaceutical composition comprising, as an active ingredient,
said amide compounds and pharmaceutically acceptable salt
thereof.
[0008] Still further object of this invention is to provide a
therapeutic method for the treatment and/or prevention of aforesaid
diseases in mammals, using said amide compounds and
pharmaceutically acceptable salts thereof.
[0009] The amide compounds of this invention are new and can be
represented by the following general formula [I]: 3
[0010] wherein
[0011] R.sup.1 is acyl,
[0012] R.sup.2 is lower alkyl, lower alkoxy, lower alkylamino,
lower alkenyl, lower alkenyloxy, lower alkenylamino, lower alkynyl,
lower alkynyloxy, lower alkynylamino, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, cyclo(lower)alkylamino, aryl, aryloxy,
arylamino, a heterocyclic group or amino substituted with a
heterocyclic group, each of which may be substituted with suitable
substituent(s); or acyl;
[0013] A is a single bond, 4
[0014] or --SO.sub.2--,
[0015] E is lower alkylene optionally substituted with suitable
substituent(s),
[0016] X is CH or N,
[0017] Y is a single bond, lower alkylene or 5
[0018] (wherein R.sup.5 is hydrogen, lower alkyl, substituted-lower
alkyl, an N-protective group, aryl, acyl or a heterocyclic
group),
[0019] Q is --CH.sub.2--, 6
[0020] --SO.sub.2-- or --N.dbd.CH--, and
[0021] R.sup.3 and R.sup.4 are each hydrogen or lower alkyl, or are
taken together to form lower alkylene optionally condensed with a
cyclic hydrocarbon or a heterocyclic ring,
[0022] provided that when X is N,
[0023] then 1) Y is a single bond, and Q is --CH.sub.2--, 7
[0024] or --SO.sub.2--, or
[0025] 2) Y is lower alkylene,
[0026] and pharmaceutically acceptable salts thereof.
[0027] The object compound [I] or its salt can be prepared by
processes as illustrated in the following reaction schemes. 8 9 10
11 12 13 14 15 16 17
[0028] wherein
[0029] R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, E, Q, X and Y are
each as defined above,
[0030] Q.sub.a is 18
[0031] or --SO.sub.2--,
[0032] R.sup.6 is aryl which may be substituted with suitable
substituent(s), or pyridyl,
[0033] R.sup.7 is lower alkyl, lower alkenyl, lower alkynyl,
cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may
be substituted with suitable substituent(s),
[0034] R.sub.a.sup.5 is an N-protective group,
[0035] R.sub.a.sup.2 is lower alkyl, lower alkenyl, lower alkynyl,
cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may
be substituted with suitable substituent(s),
[0036] Q.sub.b is --CH.sub.2--, 19
[0037] or --SO.sub.2--,
[0038] Z.sub.a is an acid residue,
[0039] Q.sub.c is 20
[0040] R.sub.b.sup.5 is lower alkyl,
[0041] Z.sub.b is an acid residue,
[0042] Z.sub.c is an acid residue, and
[0043] Y.sub.a is lower alkylene.
[0044] In the above and subsequent description of the present
specification, suitable examples of the various definitions to be
included within the scope of the invention are explained in detail
in the following.
[0045] The term "lower" is intended to mean a group having 1 to 6
carbon atom(s), unless otherwise provided.
[0046] The lower moiety in the term "lower alkenyl", "lower
alkenyloxy", "lower alkenylamino", "lower alkynyl", "lower
alkynyloxy" and "lower alkynylamino" is intended to mean a group
having 2 to 6 carbon atoms.
[0047] The lower moiety in the terms "cyclo(lower)alkyl",
"cyclo(lower)alkyloxy" and "cyclo(lower)alkylamino" is intended to
mean a group having 3 to 6 carbon atoms.
[0048] Suitable "lower alkyl" and lower alkyl moiety in the terms
"substituted-lower alkyl", "ar(lower)alkyl", "halo(lower)alkyl",
"lower alkylamino", "lower alkylsilyl", "lower alkylthio" and
"lower alkylsulfonyl" may be a straight or branched C.sub.1-C.sub.6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which
preferable one is methyl.
[0049] Suitable "lower alkenyl" and lower alkenyl moiety in the
terms "lower alkenyloxy" and "lower alkenylamino" may be a straight
or branched C.sub.2-C.sub.6 alkenyl such as ethenyl, propenyl,
butenyl, pentenyl, hexenyl, isopropenyl, butadienyl, pentadienyl,
hexadienyl or the like, in which preferable one is ethenyl,
propentyl or butadienyl.
[0050] Suitable "lower alkynyl" and lower alkynyl moiety in the
terms "lower alkynyloxy" and "lower alkynylamino" may be a straight
or branched C.sub.2-C.sub.6 alkynyl such as ethynyl, propargyl,
butynyl or the like, in which preferable one is ethynyl.
[0051] Suitable "cyclo(lower)alkyl" and cyclo(lower)alkyl moiety in
the terms "cyclo(lower)alkyloxy" and "cyclo(lower)alkylamino" may
be cyclo(C.sub.3-C.sub.6)alkyl such as cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, in which preferable one is
cyclopropyl.
[0052] Suitable "aryl" and aryl or ar moiety in the terms
"ar(lower)alkoxy", "aryloxy", "arylamino", "arylsulfonyl", "aroyl"
and "ar(lower)alkyl" may be phenyl, naphthyl, phenyl substituted
with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl,
di(tert-butyl)phenyl, etc.] and the like, in which preferable one
is phenyl or tolyl.
[0053] Suitable "ar(lower)alkyl" may be benzyl, phenethyl,
phenylpropyl, benzhydryl, trityl and the like, in which preferable
one is benzyl.
[0054] Suitable "lower alkylene" and lower alkylene moiety in the
term "lower alkylenedioxy" may be a straight or branched
C.sub.1-C.sub.6 alkylene such as methylene, ethylene, trimethylene,
propylene, tetramethylene, pentamethylene, hexamethylene,
ethylethylene or the like, in which preferable one is methylene,
ethylene or trimethylene.
[0055] Suitable "lower alkoxy" and lower alkoxy moiety in the terms
"ar(lower)alkoxy" and "halo(lower)alkoxy" may be a straight or
branched C.sub.1-C.sub.6 alkoxy such as methoxy, ethoxy, propoxy,
isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy,
pentyloxy, hexyloxy or the like, in which preferable one is methoxy
or tert-butoxy.
[0056] Suitable "ar(lower)alkoxy" may be benzyloxy, phenethyloxy,
phenylpropoxy, benzhydryloxy, trityloxy and the like.
[0057] Suitable "halogen" and halo moiety in the term
"halo(lower)alkyl" may be fluorine, chlorine, bromine and iodine,
in which preferable one is fluorine, chlorine or iodine.
[0058] Suitable "halo(lower)alkyl" may be lower alkyl substituted
with one or more halogens such as chloromethyl, dichloromethyl,
fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or
the like, in which preferable one is trifluoromethyl.
[0059] Suitable "halo(lower)alkoxy" may be lower alkoxy substituted
with one or more halogens such as chloromethoxy, dichloromethoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy,
pentachloromethoxy or the like, in which preferable one is
trifluoromethoxy.
[0060] Suitable "lower alkylamino" may be mono or di(lower
alkylamino) such as methylamino, ethylamino, porpylamino,
isopropylamino, butylamino, tert-butylamino, isobutylamino,
pentylamino, hexylamino, dimethylamino, diethylamino,
dipropylamino, dibutylamino, diisopropylamino, dipentylamino,
dihexylamino, N-methylethylamino or the like, in which preferable
one is dimethylamino.
[0061] Suitable "lower alkylsilyl" may be mono, di, or
tri(lower)alkylsilyl such as trimethylsilyl, dimethylsilyl,
triethylsilyl or the like, in which preferable one is
trimethylsilyl.
[0062] Suitable "lower alkylenedioxy" may be methylenedioxy,
ethylenedioxy and the like, in which preferable one is
methylenedioxy.
[0063] Suitable "heterocyclic group" may be one containing at least
one hetero atom selected from nitrogen, sulfur and oxygen atom, and
may include saturated or unsaturated, monocyclic or polycyclic
heterocyclic group, and preferable heterocyclic group may be
N-containing heterocyclic group such as unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.],
tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
saturated 3 to 7-membered heteromonocyclic group containing 1 to 4
nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidyl,
piperazinyl, homopiperazinyl, etc.]; unsaturated condensed
heterocyclic group containing 1 to 5 nitrogen atoms, for example,
indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl, etc.],
quioxalinyl, etc.;
[0064] unsaturated 3 to 6-membered heteromonocyclic group
containing an oxygen atom, for example, pyranyl, furyl, etc.;
[0065] saturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, 1H-tetrahydropyranyl,
tetrahydrofuranyl, etc.;
[0066] unsaturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms, for example, thienyl, etc.;
[0067] unsaturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for
example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g.
2-oxazolinyl, etc.], etc.;
[0068] saturated 3 to 6-membered heteromonocyclic group containing
1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl,
etc.];
[0069] unsaturated condensed heterocyclic group containing 1 to 2
oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl,
benzoxazolyl, benzoxadiazolyl, etc.];
[0070] unsaturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for
example, thiazolyl, thiadiazolyl [e.g. 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;
[0071] saturated 3 to 6-membered heteromonocyclic group containing
1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl,
etc.];
[0072] unsaturated condensed heterocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl,
benzothiadiazolyl, etc.];
[0073] unsaturated condensed heterocyclic group containing 1 to 2
oxygen atoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.]
and the like.
[0074] Said "heterocyclic group" may be substituted with lower
alkyl as exemplified above, in which preferable one is thienyl,
pyridyl, methylpyridyl, quinolyl, indolyl, quinoxalinyl,
benzofuranyl or tetramethylchromanyl, and more preferable one is
pyridyl.
[0075] Suitable "acyl" may be carboxy; esterified carboxy;
carbamoyl substituted with lower alkyl, aryl, ar(lower)alkyl,
arylsulfonyl, lower alkylsulfonyl or a heterocyclic group;
substituted or unsubstituted arylsulfonyl;
[0076] lower alkylsulfonyl; cyclo(lower)alkylcarbonyl;
[0077] lower alkanoyl; substituted or unsubstituted aroyl;
[0078] a heterocycliccarbonyl and the like.
[0079] The esterified carboxy may be substituted or unsubstituted
lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
hexyloxycarbonyl, 2-iodoethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted
aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl,
2-naphthyloxycarbonyl, etc.], substituted or unsubstituted
ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl,
phenethyloxycarbonyl, benzhydryloxycarbonyl,
4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable
one is unsubstituted lower alkoxycarbonyl and more preferable one
is methoxycarbonyl or tert-butoxycarbonyl.
[0080] The carbamoyl substituted with lower alkyl may be
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and
the like.
[0081] The carbamoyl substituted with aryl may be phenylcarbamoyl,
naphthylcarbamoyl, lower alkyl-substituted phenylcarbamoyl [e.g.
tolylcarbamoyl, xylylcarbamoyl, etc.] and the like.
[0082] The carbamoyl substituted with ar(lower)alkyl may be
benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl and the
like, in which preferable one is benzylcarbamoyl.
[0083] The carbamoyl substituted with arylsulfonyl may be
phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.
[0084] The carbamoyl substituted with lower alkylsulfonyl may be
methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.
[0085] The carbamoyl substituted with a heterocyclic group may be
one substituted with a heterocyclic group as mentioned above.
[0086] The lower alkanoyl may be formyl, acetyl, propionyl,
butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and
the like, in which preferable one is acetyl or pivaloyl.
[0087] The substituted or unsubstituted aroyl may be benzoyl,
naphthoyl, toluoyl, di(tert-butyl)benzoyl, halo(lower)alkoxybenzoyl
[e.g. trifluoromethoxybenzoyl, etc.] and the like, in which
preferable one is benzoyl or trifluoromethoxybenzoyl.
[0088] The substituted or unsubstituted arylsulfonyl may be
phenylsulfonyl, tolylsulfonyl, halophenylsulfonyl [e.g.
fluorophenylsulfonyl, etc.] and the like, in which preferable one
is fluorophenylsulfonyl.
[0089] The lower alkylsulfonyl may be methylsulfonyl, ethylsulfonyl
and the like, in which preferable one is methylsulfonyl.
[0090] The cyclo(lower)alkylcarbonyl may be
cyclo(C.sub.3-C.sub.6)-alkylca- rbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl, in
which preferable one is cyclopropylcarbonyl.
[0091] The heterocyclic moiety in the term "a heterocycliccarbonyl"
may be one mentioned above as a heterocyclic group.
[0092] Suitable "acid residue" may be halogen [e.g. fluoro, chloro,
bromo, iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy,
etc.], alkanesulfonyloxy [e.g. mesyloxy, ethanesulfonyloxy, etc.],
and the like, in which preferable one is halogen.
[0093] Suitable "N-protective group" may be common N-protective
group such as substituted or unsubstituted lower alkanoyl [e.g.
formyl, acetyl, propionyl, trifluoroacetyl, etc.], lower
alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl,
etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g.
benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.],
9-fluorenylmethoxycarbonyl, substituted or unsubstituted
arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.],
nitrophenylsulfenyl, aralkyl [e.g. trityl, benzyl, etc.] or the
like, in which preferable one is lower alkoxycarbonyl and more
preferable one is tert-butoxycarbonyl.
[0094] Suitable "cyclic hydrocarbon" may be a saturated or
unsaturated cyclic hydrocarbon such as cyclopentane, cyclohexane,
benzene, naphthalene, indan, indene or the like.
[0095] Suitable "substituted-lower alkyl" may be lower alkyl
substituted with halogen, aryl, acyl, lower alkoxy, aryloxy and the
like, in which preferable one is benzyl.
[0096] Suitable "heterocyclic ring" may be one which is a
heterocyclic group, as mentioned above, added by hydrogen.
[0097] Preferred "acyl" for R.sup.1 may be lower alkanoyl; lower
alkoxycarbonyl; aroyl optionally substituted with
halo(lower)alkoxy; arylsulfonyl optionally substituted with
halogen; lower alkylsulfonyl; or cyclo(lower)alkylcarbonyl, in
which more preferable one is acetyl, pivaloyl, methoxycarbonyl,
tert-butoxycarbonyl, benzoyl, trifluoromethoxybenzoyl,
fluorophenylsulfonyl, methylsulfonyl or cyclopropylcarbonyl.
[0098] Preferred "suitable substituent" as the substituent of lower
alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower
alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy,
lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy,
cyclo(lower)alkylamine, aryl, aryloxy, arylamino, a heterocyclic
group or amino substituted a heterocyclic group for R.sup.2 may be
halo(lower)alkyl, halo(lower)alkoxy, lower alkenyl, lower alkynyl,
lower alkylamino, acylamino, acyl, lower alkylsilyl, lower alkoxy,
aryl, lower alkylenedioxy, acyloxy, hydroxy, nitro, amino, cyano,
halogen, aryloxy, lower alkylthio and the like.
[0099] Preferred "aryl which may be substituted with suitable
substituent(s)" for R.sup.2 may be aryl optionally substituted with
halogen, in which more preferable one is fluorophenyl.
[0100] Preferred "arylamino which may be substituted with suitable
substituent(s)" for R.sup.2 may be arylamino optionally substituted
with halogen, in which preferable one is phenylamino or
fluorophenylamino.
[0101] Preferred "aryloxy which may be substituted with suitable
substituent(s)" for R.sup.2 may be aryloxy optionally substituted
with halogen, in which preferable one is fluorophenoxy.
[0102] Preferred "lower alkylene" for Y may be methylene.
[0103] Preferred "lower alkyl" for R.sup.5 in Y may be methyl.
[0104] Preferred "N-protective group" for R.sup.5 in Y may be
tert-butoxycarbonyl.
[0105] Preferred "suitable substituent" as the substituent of lower
alkylene for E may be oxo, lower alkyl, hydroxy(lower)alkyl or
acyl, in which more preferable one is oxo, dioxo, methyl, dimethyl,
hydroxymethyl, or benzylcarbamoyl.
[0106] Preferred "lower alkylne" for E may be methylene, ethylene
or trimethylene, and more preferable one is ethylene.
[0107] Preferred "lower alkyl" for R.sup.3 and R.sup.4 may be
methyl.
[0108] Preferred "lower alkylene which R.sup.3 and R.sup.4 are
taken together to form" may be ethylene or trimethylene.
[0109] Preferred "a cyclic hydrocarbon with which lower alkylene is
condensed" may be benzene.
[0110] Preferred compound [I] is one having lower alkanoyl, lower
alkoxcarbonyl, aroyl, aroyl substituted with halo(lower)alkoxy,
lower alkylsulfonyl, arylsulfonyl, arylsulfonyl substituted with
halogen or cyclo(lower)alkylcarbonyl for R.sup.1, aryl, aryloxy or
arylamino, each aryl of which may be substituted with halogen;
pyridyl; or pyridylamino for R.sup.2, a single bond for A, ethylene
for E, CH for X, 21
[0111] for Y, 22
[0112] for Q, and ethylene for R.sup.3 and R.sup.4 to be taken
together to form, or lower alkanoyl, lower alkoxycarbonyl, aroyl,
aroyl substituted with halo(lower)alkoxy, lower alkylsulfonyl,
arylsulfonyl, arylsulfonyl substituted with halogen; pyridyl; or
pyridylamino for R.sup.2, a single bond for A, ethylene for E, N
for X, a single bond for Y, 23
[0113] for W, and ethylene for R.sup.3 and R.sup.4 to be taken
together to form.
[0114] Suitable pharmaceutically acceptable salts of the object
compound [I] are conventional non-toxic salts and include acid
addition salt such as an organic acid addition salt [e.g.
hydrocyhloride, hydrobomide, sulfate, phosphate, etc.,], an organic
acid addition salt [e.g. formate, acetate, trifluoroacetate,
maleate, tartrate, methanesulfonate, benzenesulfonate,
toluenesulfonate, etc.], a salt with an amino acid [e.g. aspartic
acid salt, glutamic acid salt, etc.], a metal salt such as an
alkali metal salt [e.g. calcium salt, magnesium salt, etc.] and the
like.
[0115] The processes for preparing the object compound [I] are
explained in detail in the following.
[0116] Process 1
[0117] The compound [Ia] or its salt can be prepared by reacting a
compound [II] or its salt with a compound [III] or its reactive
derivative at the carboxy or sulfo group, or a salt thereof.
[0118] Suitable salts of the compounds [Ia] and [II] may be the
same as those exemplified for the compound [I].
[0119] Suitable salts of the compound [III] and its reactive
derivative at the carboxy or sulfo group may be metal salt or
alkaline earth metal salt as exemplified for the compound [I].
[0120] Suitable reactive derivative at the carboxy or sulfo group
or the compound [III] may include an ester, an acid halide, an acid
anhydride and the like. The suitable examples of the reactive
derivatives may be an acid halide [e.g. acid chloride, acid
bromide, etc.];
[0121] a symmetrical acid anhydride; a mixed acid anhydride with an
acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic
acid, etc.], substituted phosphoric acid [e.g. dialkylphosphoric
acid, diphenylphosphoric acid, etc.]; an ester such as substituted
or unsubstituted lower alkyl ester [e.g. methyl ester, ethyl ester,
propyl ester, hexyl ester, trichloromethyl ester, etc.],
substituted or unsubstituted ar(lower)alkyl ester [e.g. benzyl
ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted
or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester,
4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl
ester, naphthyl ester, etc.], or an ester with
N,N-dimethylhydroxylamine, N-hydroxysuccinimide,
N-hydroxyphthalimide or 1-hydroxybenzotriazole,
1-hydroxy-6-chloro-1H-benzotriazole, or the like. These reactive
derivatives can be optionally selected according to the kind of the
compound [III] to be used.
[0122] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, chloroform, methylene
chloride, ethylene dichloride, tetrahydrofuran, acetonitrile, ethyl
acetate, N,N-dimethylformamide, pyridine or any other organic
solvent which does not adversely influence the reaction. Among
these solvents, hydrophilic solvent may be used in a mixture with
water.
[0123] The reaction is also preferably carried out in the presence
of a conventional base such as triethylamine,
diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, etc.,
or a mixture thereof.
[0124] When the compound [III] is used in a free acid form or its
salt form in the reaction, the reaction is preferably carried out
in the presence of a conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-morpholinoethylcarbodiimid- e,
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, thionyl chloride,
oxalyl chloride, lower alkoxycarbonyl halide [e.g. ethyl
chloroformate, isobutyl chloroformate, etc.],
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H- -benzotriazole, or the
like.
[0125] The reaction temperature is not critical, and the reaction
can be carried out under cooling to heating.
[0126] Process 2
[0127] The compound [Ib] or its salt can be prepared by reacting a
compound [II] or its salt with a compound [IV].
[0128] Suitable salts of the compounds [Ib] and [II] may be the
same as those exemplified for the compound [I].
[0129] This reaction is usually carried out in a solvent such as
dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene
chloride or any other organic solvent which does not adversely
influence the reaction.
[0130] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to warming.
[0131] Process 3
[0132] The compound [Ic] or its salt can be prepared by reacting a
compound [V] or its salt with a compound [III] or its reactive
derivative at the carboxy or sulfo group, or a salt thereof.
[0133] Suitable salts of the compounds [Ic] and [V] may be the same
as those exemplified for the compound [I].
[0134] Suitable salts of the compound [III] and its reactive
derivative at the carboxy or sulfo group may be metal salt or
alkaline earth metal salt as exemplified for the compound [I].
[0135] This reaction can be carried out in substantially the same
manner as Process 1, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those as explained in Process 1.
[0136] Process 4
[0137] The compound [Id] or its salt can be prepared by reacting a
compound [V] or its salt with a compound [IV].
[0138] Suitable salts of the compounds [Id] and [V] may be the same
as those exemplified for the compound [I].
[0139] This reaction can be carried out in substantially the same
manner as Process 2, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those explained in Process 2.
[0140] Process 5
[0141] The compound [I] or its salt can be prepared by reacting a
compound [VI] or its salt with a compound [VII] or its reactive
derivative at the carboxy or sulfo group, or a salt thereof.
[0142] Suitable salt of the compound [VI] may be acid addition salt
as exemplified for the compound [I].
[0143] Suitable salts of the compound [VII] and its reactive
derivative at the carboxy or sulfo group may be metal salt or
alkaline earth metal salt as exemplified for the compound [I].
[0144] This reaction can be carried out in substantially the same
manner as Process 1, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those as explained in Process 1.
[0145] Process 6
[0146] The compound [Ie] or its salt can be prepared by reacting a
compound [VIII] or its reactive derivative at the carboxy group or
sulfo group, or a salt thereof with a compound [IX] or its
salt.
[0147] Suitable salts of the compounds [Ie], [VIII] and its
reactive derivative at the carboxy or sulfo group may be the same
as those exemplified for the compound [I].
[0148] Suitable salt of the compound [IX] may be acid addition salt
as exemplified for the compound [I].
[0149] This reaction can be carried out in substantially the same
manner as Process 1, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those as explained in Process 1.
[0150] Process 7
[0151] The compound [If] can be prepared by reacting a compound
[.alpha.]or its salt with a compound [XI].
[0152] Suitable salts of the compounds [If] and [.alpha.]may be the
same as those exemplified for the compound [I].
[0153] The present reaction is preferably carried out in the
presence of base such as an alkali metal [e.g. lithium, sodium,
potassium, etc.], alkaline earth metal [e.g. calcium, etc.], alkali
metal hydride [e.g. sodium hydride, etc.], alkaline earth metal
hydride [e.g. calcium hydride, etc.], the hydroxide or carbonate or
bicarbonate of an alkali metal or an alkaline earth metal [e.g.
potassium bicarbonate, etc.] and the like.
[0154] This reaction is usually carried out in a solvent such as
N,N-dimethylformamide, diethyl ether, tetrahydrofuran, dioxane,
benzene, toluene, acetonitrile or any other solvent which does not
adversely influence the reaction.
[0155] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to heating.
[0156] Process 8
[0157] The object compound [Ig] of its salt can be prepared by
subjecting a compound [If] or its salt to elimination reaction of
the N-protective group.
[0158] Suitable salts of the compounds [If] and [Ig] may be acid
addition salts as exemplified for the compound [I].
[0159] This reaction is carried out in accordance with a
conventional method such as hydrolysis, reduction or the like.
[0160] The hydrolysis is preferably carried out in the presence of
a base or an acid including Lewis acid.
[0161] Suitable base may include an inorganic base and an organic
base such as an alkali metal [e.g. sodium, potassium, etc.], an
alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide
or carbonate or bicarbonate thereof, hydrazine, alkylamine [e.g.
methylamine, trimethylamine, triethylamine, etc.], picoline,
1,5-diazabicyclo[4.3.0]no- n-5-ene, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo-[5.4.0]undec-7-en- e, or the like.
[0162] Suitable acid may include an organic acid [e.g. formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic
acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen
fluoride, etc.] and an acid addition salt compound [e.g. pyridine
hydrochloride, etc.].
[0163] The elimination using trihaloacetic acid [e.g.
trichloroacetic acid, trifluoroacetic acid, etc.] or the like is
preferably carried out in the presence of cation trapping agents
[e.g. anisole, phenol, etc.].
[0164] The reaction is usually carried out in a solvent such as
water, an alcohol [e.g. methanol, ethanol, etc.], methylene
chloride, chloroform, tetrachloromethane, dioxane, tetrahydrofuran,
a mixture thereof or any other solvent which does not adversely
influence the reaction. A liquid base or acid can be also used as
the solvent. The reaction temperature is not critical and the
reaction is usually carried out under cooling to heating.
[0165] The reduction method applicable for the elimination reaction
may include chemical reduction and catalytic reduction.
[0166] Suitable reducing agents to be used in chemical reduction
are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic
compound [e.g. chromium chloride, chromium acetate, etc.] and an
organic or inorganic acid [e.g. formic acid, acetic acid, propionic
acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric
acid, hydrobromic acid, etc.].
[0167] Suitable catalysts to be used in catalytic reduction are
conventional ones such as platinum catalysts [e.g. platinum plate,
spongy platinum, platinum black, colloidal platinum, platinum
oxide, platinum wire, etc.], palladium catalysts [e.g. spongy
palladium, palladium black, palladium oxide, palladium on carbon,
colloidal palladium, palladium on barium sulfate, palladium on
barium carbonate, etc.], nickel catalysts [e.g. reduced nickel,
nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced
cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron,
Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney
copper, Ullman copper, etc.] and the like.
[0168] In case that the N-protective group is benzyl, the reduction
is preferably carried out in the presence of a combination of
palladium catalysts [e.g. palladium black, palladium on carbon,
etc.] and formic acid or its salt [e.g. ammonium formate,
etc.].
[0169] The reduction is usually carried out in a conventional
solvent which does not adversely influence the reaction such as
water, methanol, ethanol, propanol, N,N-dimethylformamide, or a
mixture thereof. Additionally, in case that the above-mentioned
acids to be used in chemical reduction are in liquid, they can also
be used as a solvent. Further, a suitable solvent to be used in
catalytic reduction may be the above-mentioned solvent, and other
conventional solvent such as diethyl ether, dioxane,
tetrahydrofuran, etc. or a mixture thereof.
[0170] The reaction temperature of this reduction is not critical
and the reaction is usually carried out under cooling to
heating.
[0171] Process 9
[0172] The compound [Ii] or its salt can be prepared by reacting a
compound [Ih] or its salt with a compound [XII].
[0173] Suitable salts of the compounds [Ih] and [Ii] may be the
same as those exemplified for the compound [I].
[0174] This reaction can be carried out in substantially the same
manner as Process 7, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those explained in Process 7.
[0175] Process 10
[0176] The compound [Ij] or its salt can be prepared by reacting a
compound [II] or its salt with a compound [XIII].
[0177] Suitable salts of the compounds [Ij] and [II] may be the
same as those exemplified for the compound [I].
[0178] This reaction can be carried out in substantially the same
manner as Process 7, and therefore the reaction mode and reaction
condition [e.g. solvent, reaction temperature, etc.] of this
reaction are to be referred to those explained in Process 7.
[0179] The compounds obtained by the above processes can be
isolated and purified by a conventional method such as
pulverization, recrystallization, column chromatography,
reprecipitation, or the like.
[0180] It is to be noted that the compound [I] and the other
compounds may include one or more stereoisomer(s) such as optical
isomer(s) or geometrical isomer(s) due to asymmetric carbon atom(s)
and double bond(s), and all of such isomers and mixture thereof are
included within the scope of this invention.
[0181] Additionally, it is to be noted that any solvate [e.g.
enclosure compound (e.g. hydrate, etc.)] of the compound [I] or a
pharmaceutically acceptable salt thereof is also included within
the scope of this invention.
[0182] The object compound [I] and pharmaceutically acceptable
salts thereof possess strong potentiation of the cholinergic
activity, and are useful for the treatment and/or prevention of
disorders in the central nervous system for mammals, and more
particularly of amnesia, dementia (e.g., senile dementia,
Alzheimer's dementia, dementia associated with various diseases
such as cerebral vascular dementia, cerebral posttraumatic
dementia, dementia due to brain tumor, dementia due to chronic
subdural hematoma, dementia due to normal pressure hydrocephalus,
post-meningitis dementia, Parkinson's disease type dementia, etc.)
and the like. Additionally, the object compound is expected to be
useful as therapeutical and/or preventive agents for schizophrenia,
depression, stroke, head injury, nicotine withdrawal, spinal cord
injury, anxiety, pollakiuria, incontinence of urine, myotonic
dystrophy, attention deficit hyperactivity disorder, excessive
daytime sleepiness (narcolepsy), Parkinson's disease or autism.
[0183] In order to illustrate the usefulness of the object
compound. [I], the pharmacological data of the compound [I] is
shown in the following.
[0184] Test
[0185] Penile Erection in Rat
[0186] (This test was carried out according to a similar manner to
that described in Jpn. J. Pharmacol., Vol. 64, 147-153 (1994))
[0187] (i) Method
[0188] Male Fischer 344 rats at the age of 8 weeks (n=7) were used.
All rats were handled 3 minutes a day for three successive days
before the tests. The rats were tested in groups of seven and
various doses of the test compound were given in semi-randomized
order. The test compounds were suspended in 0.5% methyl-cellulose
immediately before use, and given intraperitoneally in a volume of
1 ml/kg just before the start of test. Immediately after injection,
each rat was placed in a perspex box (25.times.25.times.35 cm) and
its behavior was observed for 60 minutes, during which time the
number of penile erections was counted. A mirror was situated
behind each box to facilate of the rat. Data was expressed as a
mean number.
[0189] (ii) Test Result
1 Test Compound Dose Penile Erection (Example No.) (mg/kg)
(number/hr) 2 1 1.14 19 0.32 0.75
[0190] It is clear that the compound having the above-mentioned
activity ameliorates the memory deficits (i.e. amnesia, dementia,
etc.) from the description in the Journal of Pharmacology and
Experimental Therapeutics, Vo. 279, No. 3, 1157-1173 (1996).
Further, it is expected that the compound having the
above-mentioned activity is useful as therapeutical and/or
preventive agent for aforesaid diseases from some patent
applications (e.g. PCT International Publication No. WO 98/27930,
etc.).
[0191] For therapeutic purpose, the compound [I] and a
pharmaceutically acceptable salt thereof of the present invention
can be used in a form of pharmaceutical preparation containing one
of said compounds, as an active ingredient, in admixture with a
pharmaceutically acceptable carrier such as an organic or inorganic
solid, semi-solid or liquid excipient suitable for oral or
parenteral administration. The pharmaceutical preparations may be
capsules, tablets, dragees, granules, suppositories, solution,
suspension, emulsion, or the like. If desired, there may be
included in these preparations, auxiliary substances, stabilizing
agents, wetting or emulsifying agents, buffers and other commonly
used additives.
[0192] While the dosage of the compound [I] will vary depending
upon the age and condition of the patient, an average single dose
of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and
1000 mg of the compound [I] may be effective for treating the
above-mentioned diseases. In general, amounts between 0.1 mg/body
and about 1,000 mg/body may be administered per day.
[0193] The following Preparations and Examples are given for the
purpose of illustrating this invention.
[0194] Preparation 1
[0195] To a solution of 1-benzyl-4-aminopiperidine (50 g) in water
(360 ml) was added a solution of di-tert-butyl dicarbonate (61 g)
in acetone (360 ml) dropwise under cooling on an ice-water bath.
After stirring for 2.5 hours, a precipitate was collected on a
filter, washed with water, and dried. The crude product was poured
into a mixture of diisopropyl ether (200 ml) and n-hexane (200 ml)
and the mixture was stirred. After filtration, O-tert-butyl
N-(1-benzylpiperidin-4-yl)carbamate (66.9 g) was obtained.
[0196] NMR (DMSO-d.sub.6, .delta.): 1.2-1.5 (2H, m), 1.37 (9H, s),
1.66 (2H, br d, J=9.9 Hz), 1.91 (2H, br t, J=10.7 Hz), 2.73 (2H,
distorted d, J=11.8 Hz), 3.2 (1H, m), 3.41 (2H, s), 6.75 (1H, d,
J=7.8 Hz), 7.1-7.4 (5H, m)
[0197] MASS (APCI) (m/z): 291
[0198] Preparation 2
[0199] To a mixture of O-tert-butyl
N-(1-benzylpiperidin-4-yl)carbamate (45 g) and 10% palladium on
carbon (50% wet, 9 g) in methanol (1 l) was bubbled hydrogen gas
under stirring at ambient temperature. The catalyst was removed by
glass filter and the solvent was removed under reduced pressure.
After rinse with diisopropyl ether, O-tert-butyl
N-(piperidin-4-yl)carbamate (28.35 g) was obtained. The washed
solvent was removed under reduced pressure, and the residue was
rinsed with diisopropyl ether. The second fraction of O-tert-butyl
N-(piperidin-4-yl)carbamate (344 mg) was obtained.
[0200] NMR (DMSO-d.sub.6, .delta.): 1.18 (2H, ddd, J=3.8, 11.8,
11.8 Hz), 1.37 (9H, s), 1.62 (2H, distorted d, J=10.8 Hz), 1.85
(1H, m), 2.38 (2H, dt, J=2.2, 12.0 Hz), 2.86 (2H, distorted d,
J=12.3 Hz), 3.2 (1H, m), 6.72 (1H, br d)
[0201] MASS (APCI)(m/z): 201
[0202] Preparation 3
[0203] To a suspension of O-tert-butyl N-(piperidin-4-yl)carbamate
(4.0 g) in dichloromethane (40 ml) were added pyridine (1.94 ml),
dichloromethane (40 ml), acetic anhydride (20.8 ml) and then
N,N-dimethylaminopyridine (0.1 g) at ambient temperature. After
stirring for 3 hours, the mixture was washed with 0.1N hydrochloric
acid, water, and brine. After drying with magnesium sulfate, the
solvents were removed under reduced pressure. After rinse with
diisopropyl ether, O-tert-butyl N-(1-acetylpiperidin-4-y-
l)carbamate (4.01 g) was obtained.
[0204] NMR (DMSO-d.sub.6, .delta.): 1.23 (2H, m), 1.38 (9H, s),
1.70 (2H, distorted t, J=11.4 Hz), 1.97 (3H, s), 2.64 (1H, br t,
J=11.1 Hz), 3.04 (1H, dt, J=2.8, 11.5 Hz), 3.42 (1H, m), 3.72 (1H,
br d, J=15.0 Hz), 4.19 (1H, br d, J=13.1 Hz), 6.86 (1H, d, J=7.5
Hz)
[0205] MASS (APCI)(m/z): 243
[0206] Preparation 4
[0207] To a solution of O-tert-butyl
N-(1-acetylpiperidin-4-yl)carbamate (2.42 g) in dichloromethane (24
ml) was added 4N hydrogen chloride in dioxane (24 ml). The solvents
were removed under reduced pressure. After rinse with diisopropyl
ether, 1-acetyl-4-aminopiperidine hydrochloride (2.02 g) was
obtained.
[0208] NMR (DMSO-d.sub.6, .delta.): 1.41 (2H, m), 1.93 (2H,
distorted t), 2.00 (3H, s), 2.60 (1H, br t, J=10.4 Hz), 3.06 (1H,
br t, J=11.3 Hz), 3.12 (1H, m), 3.84 (1H, br d, J=14.0 Hz), 4.34
(1H, br d, J=13.0 Hz), 8.32 (3H, br s)
[0209] MASS (APCI)(m/z): 143
[0210] Preparation 5
[0211] To a solution of phenyl chloroformate (5.64 g) in
dichloromethane (70 ml) was added a solution of 4-aminopyridine
(2.84 g) and triethylamine (5.02 ml) in dichloromethane (100 ml)
dropwise under cooling on an ice-water bath. After stirring for 1
hour, the solvents were removed under reduced pressure. A residue
was diluted with dichloromethane (200 ml) and water (200 ml). An
organic phase was separated and washed with water and brine. After
drying with magnesium sulfate, the solvents were removed under
reduced pressure. The reaction mixture was diluted with diisopropyl
ether and the precipitates were filtered. After rinse with diethyl
ether, O-phenyl N-(4-pyridyl)carbamate (5.07 g) was obtained.
[0212] NMR (CDCl.sub.3, .delta.): 7.17 (2H, m), 7.27 (1H, m),
7.3-7.5 (4H, m), 8.50 (2H, dd, J=1.4, 5.0 Hz), 8.06 (1H, s)
[0213] MASS (APCI)(m/z): 215
[0214] Preparation 6
[0215] A solution of sulfuryl chloride (3.55 ml) in chloroform (45
ml) was added a solution of 1-acetylpiperazine (5.66 mg) and
triethylamine (6.16 ml) in chloroform (15 ml) dropwise under
cooling on an ice-water bath. After stirring for 6 hours, a
precipitate was collected by filtration. After drying over sodium
hydroxide, 1-acetylpiperazine-4-sulfonyl chloride (2.43 g) was
obtained.
[0216] NMR (CDCl.sub.3, .delta.): 2.15 (3H, s), 3.35 (4H, m), 3.69
(2H, t, J=5.1 Hz), 3.83 (2H, br s)
[0217] MASS (APCI)(m/z): 227
[0218] Preparation 7
[0219] To a solution of 1-benzyl-4-aminopiperidine (1.13 g) in
dichloromethane (10 ml) were added a solution of 4-fluorobenzoyl
chloride (0.99 g) in dichloromethane (1 ml) and
diisopropylethylamine (1.09 ml) under cooling on an ice-water bath.
The mixture was warmed to ambient temperature slowly under
stirring. The mixture was diluted with dichloromethane and washed
with water, saturated aqueous sodium hydrogen carbonate, water, and
brine. After drying with magnesium sulfate, the solvents were
removed under reduced pressure. A residue was purified by column
chromatography (silica gel 100 ml, dichloromethane:methanol=15:1).
After rinse with diisopropyl ether-n-hexane (1:1),
N-(1-benzylpiperidin-4-yl)-4-fluorobenzamide (1.31 g) was
obtained.
[0220] NMR (DMSO-d.sub.6, .delta.): 1.4-1.7 (2H, m), 1.7-1.9 (2H,
m), 2.01 (2H, br t, J=10.7 Hz), 2.81 (2H, br d, J=11.6 Hz), 3.46
(2H, s), 3.73 (1H, m), 7.2-7.4 (7H, m), 7.90 (2H, dd, J=5.6, 8.9
Hz), 8.26 (1H, br d, J=7.7 Hz)
[0221] MASS (APCI)(m/z): 313
[0222] Preparation 8
[0223] The following compound was obtained by using
4-amino-1-benzylpiperidine as a starting compound according to a
similar manner to that of Example 2.
[0224] N-(1-Benzylpiperidin-4-yl)-N'-(4-fluorophenyl)urea NMR
(DMSO-d.sub.6, .delta.): 1.25-1.5 (2H, m), 1.7-1.9 (2H, m), 2.0-2.2
(2H, m), 2.65-2.8 (2H, m), 3.4-3.6 (3H, m), 6.07 (1H, d, J=7.6 Hz),
7.05 (2H, t, J=9 Hz), 7.2-7.45 (2H, m), 8.35 (1H, s)
[0225] MASS (APCI) (m/z): 328
[0226] Preparation 9
[0227] To a solution of
N-(1-benzylpiperidin-4-yl)-N'-(4-fluorophenyl)urea (3.0 g) in a
mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added
palladium on carbon (10% w/w, 50% wet, 0.6 g), and the mixture was
hydrogenated under atmospheric pressure of hydrogen for 8 hours.
The catalyst was filtered off, and the solvents were evaporated
under reduced pressure to give a residue, which was triturated with
diisopropyl ether to give
N-(piperidin-4-yl)-N'-(4-fluorophenyl)urea (1.97 g).
[0228] NMR (DMSO-d.sub.6, .delta.): 1.1-1.4 (2H, m), 1.65-1.85 (2H,
m), 2.3-2.65 (2H, m), 2.8-3.0 (2H, m), 3.3-3.7 (1H, m), 6.08 (1H,
d, J=8 Hz), 7.04 (2H, t, J=9 Hz), 7.25-7.5
[0229] NMR (DMSO-d.sub.6, .delta.): 1.1-1.4 (2H, m), 1.65-1.85 (2H,
m), 2.3-2.65 (2H, m), 2.8-3.0 (2H, m), 3.3-3.7 (1H, m), 6.08 (1H,
d, J=8 Hz), 7.04 (2H, t, J=9 Hz), 7.25-7.5 (2H, m), 8.33 (1H,
s)
[0230] MASS (APCI) (m/z): 238
[0231] Preparation 10
[0232] A mixture of N-(1-benzylpiperidin-4-yl)-4-fluorobenzamide
(937 mg) and 10% palladium on carbon (50% wet, 0.2 g) in methanol
(20 ml) was stirred under hydrogen atmosphere for 7.5 hours at
ambient temperature. The catalyst was removed by glass filter and
the solvent was removed under reduced pressure. After rinse with
diisopropyl ether, N-(piperidin-4-yl)-4-fluorobenzamide (653 mg)
was obtained.
[0233] NMR (DMSO-d.sub.6, .delta.): 1.40 (2H, ddd, J=4.0, 11.9,
23.8 Hz), 1.72 (2H, br d, J=9.5 Hz), 2.3-2.7 (2H, m), 2.8-3.2 (2H,
m), 3.80 (1H, m), 7.27 (2H, t, J=8.9 Hz), 7.92 (2H, dd, J=5.6, 8.9
Hz), 8.26 (1H, d, J=7.7 Hz)
[0234] MASS (APCI) (m/z): 223
EXAMPLE 1
[0235] To a solution of O-phenyl N-(4-pyridyl)carbamate (446 mg) in
1,2-dichloroethane (5 ml) was added a suspension of
1-acetylpiperazine (1.12 g) in 1,2-dichloroethane (20 ml) at
ambient temperature. The mixture was heated at 60.degree. C. with
stirring for 9 hours. The mixture was cooled to ambient
temperature, and diluted with dichloromethane and water. The
aqueous phase was separated and adjusted to pH 11.5 with sodium
hydroxide solution. Excess sodium chloride was added to the aqueous
solution. The mixture was extracted with a mixture of
dichloromethane and methanol (about 10:1) and the organic phase was
washed with brine. After drying with magnesium sulfate, the
solvents were removed under reduced pressure. A residue was
purified by column chromatography (silica gel 100 ml,
dichloromethane:methanol:aqueous ammonia=10:1:0.1). After rinse
with diisopropyl ether,
1-acetyl-4-(4-pyridylaminocarbonyl)piperazine (398 mg) was
obtained.
[0236] NMR (DMSO-d.sub.6, .delta.): 2.03 (3H, s), 3.3-3.6 (8H, m),
7.47 (2H, dd, J=1.5, 4.8 Hz), 8.31 (2H, dd, J=1.5, 4.8 Hz), 9.01
(1H, s)
[0237] MASS (APCI)(m/z): 271
EXAMPLE 2
[0238] To a stirred solution of 1-acetylpiperazine (0.648 g) in
tetrahydrofuran (10 ml) was added 4-fluorophenyl isocyanate (0.574
g) at ambient temperature. After stirring at ambient temperature
for 1 hour, the solvent was removed by evaporation under reduced
pressure, and the residue was triturated with diisopropyl ether to
give 1-acetyl-4-(4-fluorophenylcarbamoyl)piperazine (1.25 g).
[0239] NMR (DMSO-d.sub.6, .delta.): 2.03 (3H, s), 3.3-3.6 (8H, m),
7.07 (2H, t, J=9 Hz), 7.46 (2H, dd, J=5, 9 Hz), 8.61 (1H, s)
[0240] MASS (APCI) (m/z): 266
EXAMPLE 3
[0241] The following compound was obtained by using
1-tert-butoxycarbonylpiperazine as a starting compound according to
a similar manner to that of Example 2.
[0242]
1-tert-Butoxycarbonyl-4-(4-fluorophenylcarbamoyl)-piperazine
[0243] NMR (DMSO-d.sub.6, .delta.): 1.42 (9H, s), 3.25-3.5 (8H, m),
7.07 (2H, t, J=9 Hz), 7.45 (2H, dd, J=5, 9 Hz), 8.60 (1H, s)
[0244] MASS (LD) (m/z): 346.2
EXAMPLE 4
[0245] To a solution of pyridine-4-carboxylic acid (1.0 g) and
triethylamine (1.2 ml) in toluene (20 ml) was added
diphenylphosphoryl azide (1.75 ml) at ambient temperature. The
resulting mixture was heated to reflux for 30 minutes and cooled to
0.degree. C. To the mixture was added
1-tert-butoxycarbonylpiperazine (1.51 g), and the mixture was
allowed to heat to 90.degree. C. for 1 hour. After cooling to
ambient temperature, the reaction mixture was taken up into ethyl
acetate, washed in turn with water and brine, dried over magnesium
sulfate, and evaporated under reduced pressure. The residue was
chromatographed on silica gel (150 ml) eluting with 0-7% methanol
in dichloromethane. Trituration with a mixture of diisopropyl ether
and ethanol gave
1-tert-butoxycarbonyl-4-(pyridin-4-ylcarbamoyl)piperazine (0.66
g).
[0246] NMR (DMSO-d.sub.6, .delta.): 1.42 (9H, s), 3.25-3.5 (8H, m),
7.46 (2H, d, J=1.5, 5 Hz), 8.30 (2H, d, J=1.5, 5 Hz), 9.00 (1H,
s)
[0247] MASS (LD)(m/z): 307.2
EXAMPLE 5
[0248] To a suspension of 1-acetyl-4-aminopiperidine hydrochloride
(0.4 g) in dichloromethane (5 ml) were added in turn pyridine (0.54
ml) and 4-fluorophenyl chloroformate (0.29 ml) at 0.degree. C. The
mixture was allowed to warm to ambient temperature and stirred for
1 hour, which was taken up into a mixture of water and ethyl
acetate. The separated organic layer was washed in turn with
hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and
brine, and dried over magnesium sulfate. Evaporation under reduced
pressure gave a residue, which was triturated with diisopropyl
ether to give 1-acetyl-4-(4-fluorophenoxycarbonylamino)p- iperidine
(347 mg).
[0249] NMR (DMSO-d.sub.6, .delta.): 1.15-1.55 (2H, m), 1.7-1.95
(2H, m), 2.00 (3H, s), 2.65-2.85 (1H, m), 3.0-3.25 (1H, m), 3.5-3.7
(1H, m), 3.7-3.9 (1H, m), 4.15-4.3 (1H, m), 7.05-7.3 (4H, m), 7.86
(1H, d, J=8 Hz)
[0250] MASS (APCI) (m/z): 281
EXAMPLE 6
[0251] To a suspension of 1-acetyl-4-aminopiperidine hydrochloride
(715 mg) in dichloromethane (7 ml) were added diisopropylethylamine
(1.83 ml) and a solution of 4-fluorobenzoyl chloride (0.83 mg) in
dichloromethane (2 ml) at ambient temperature. After stirring for
6.5 hours, the reaction mixture was diluted with dichloromethane
and washed with water, saturated aqueous sodium hydrogen carbonate,
and brine. After drying with magnesium sulfate, the solvents were
removed under reduced pressure. A residue was purified by column
chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to
10:1). After rinse with diisopropyl ether,
N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (738 mg) was
obtained.
[0252] NMR (DMSO-d.sub.6, .delta.): 1.40 (2H, m), 1.81 (2H,
distorted t, J=12.4 Hz), 2.01 (3H, s), 2.68 (1H, br t, J=11.4 Hz),
3.13 (1H, br t, J=11.6 Hz), 3.83 (1H, br t, J=13.9 Hz), 4.01 (1H,
m), 4.33 (1H, br d, J=13.7 Hz), 7.29 (2H, t, J=8.9 Hz), 7.92 (2H,
dd, J=5.5, 8.8 Hz), 8.31 (1H, d, J=7.7 Hz)
[0253] MASS (APCI)(m/z): 265
EXAMPLE 7
[0254] To a suspension of 1-acetyl-4-aminopiperidine hydrochloride
(536 mg) in dichloromethane (5 ml) were added isonicotinoyl
chloride hydrochloride (534 mg) and diisopropylethylamine (1.05 ml)
at ambient temperature. After stirring for 8 hours, the reaction
mixture was poured into water and diluted with dichloromethane. The
mixture was adjusted to pH 8.5 with 1N sodium hydroxide solution.
Sodium chloride was added to the mixture and an organic phase was
separated. The aqueous phase was extracted with dichloromethane and
a combined organic phase was dried over magnesium sulfate. The
solvents were removed under reduced pressure. A residue was
purified by column chromatography (silica gel 50 ml,
dichloromethane:methanol=10:1). After crystallization from
diisopropyl ether:n-hexane,
N-(1-acetylpiperidin-4-yl)-N-isonicotinamide (477 mg) was
obtained.
[0255] NMR (DMSO-d.sub.6, .delta.): 1.4 (2H, m), 1.83 (2H,
distorted t, J=11Hz), 2.01 (3H, s), 2.69 (1H, br t, J=11Hz), 3.14
(1H, br t, J=12 Hz), 3.83 (1H, br d, J=14.1 Hz), 4.03 (1H, m), 4.33
(1H, br d, J=13.1 Hz), 7.75 (2H, dd, J=1.7, 4.4 Hz), 8.62 (1H, d,
J=7.5 Hz), 8.72 (2H, dd, J=1.6, 4.4 Hz)
[0256] MASS (APCI)(m/z): 248
EXAMPLE 8
[0257] To a suspension of 1-acetyl-4-aminopiperidine hydrochloride
(715 mg) in dichloromethane (7 ml) were added diisopropylethylamine
(1.83 ml) and a solution of 4-fluorobenzenesulfonyl chloride (0.83
mg) in dichloromethane (2 ml) at ambient temperature. After
stirring for 6.5 hours, the reaction mixture was diluted with
dichloromethane and washed with water, saturated aqueous sodium
hydrogen carbonate, and brine. After drying with magnesium sulfate,
the solvents were removed under reduced pressure. A residue was
purified by column chromatography (silica gel 50 ml,
dichloromethane:methanol=50:1 to 20:1). After rinse with
diisopropyl ether,
N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide (859 mg) was
obtained.
[0258] NMR (DMSO-d.sub.6, .delta.): 1.21 (2H, m), 1.54 (2H, m),
1.94 (3H, s), 2.66 (1H, br t, J=10.8 Hz), 3.02 (1H, dt, J=2.9, 12.0
Hz), 3.22 (1H, m), 3.64 (1H, br d, J=14.0 Hz), 4.05 (1H, br d,
J=13.2 Hz), 7.44 (2H, t, J=8.9 Hz), 7.8-8.0 (3H, m)
[0259] MASS (APCI)(m/z): 301
EXAMPLE 9
[0260] To a solution of O-phenyl N-(4-pyridyl)carbamate (0.81 g) in
chloroform (10 ml) were added 1-acetyl-4-aminopiperidine
hydrochloride (0.68 g) and triethylamine (1.06 ml) at ambient
temperature. After stirring for 1 day, the mixture changed to a
solution. The solvents were removed under reduced pressure. A
residue was purified by column chromatography (silica gel 100 ml,
dichloromethane:methanol=10:1 to 5:1, and silica gel 50 ml,
dichloromethane:methanol:aqueous ammonia=10:1:0.1). The solvents of
desired fractions were removed under reduced pressure. A residue
was dissolved with methanol (5 ml) and dichloromethane (5 ml), and
4N hydrogen chloride in dioxane (1.5 ml) was added to the solution.
The solvents were removed under reduced pressure, and the residue
was evaporated azeotropically with methanol. After crystallization
from diisopropyl ether and n-hexane,
N-(1-acetylpiperidin-4-yl)-N'-(4-pyridyl)- urea (343 mg) was
obtained.
[0261] NMR (DMSO-d.sub.6, .delta.): 1.1-1.6 (2H, m), 1.77 (2H, m),
2.01 (3H, s), 2.94 (1H, br t, J=10.4 Hz), 3.22 (1H, br t, J=10.1
Hz), 3.76 (2H, m), 4.05 (1H, d, J=13.6 Hz), 7.60 (1H, d, J=7.8 Hz),
7.83 (2H, d, J=6.8 Hz), 8.52 (2H, d, J=7.1 Hz), 11.21 (1H, s),
14.66 (1H, br s)
[0262] MASS (APCI) (m/z): 263
EXAMPLE 10
[0263] To a suspension of 1-acetyl-4-aminopiperidine hydrochloride
(536 mg) in dichloromethane (5 ml) were added 4-fluorophenyl
isocyanate (375 .mu.l) and diisopropylethylamine (575 .mu.l) at
ambient temperature. After stirring for 3 hours, the reaction
mixture was diluted with dichloromethane. An organic phase was
separated and an aqueous phase was extracted with dichloromethane.
A combined organic phase was dried over magnesium sulfate and the
solvents were removed under reduced pressure. After crystallization
from diisopropyl ether and n-hexane,
N-(1-acetylpiperidin-4-yl)-N'-(4-fluorophenyl)urea (448 mg) was
obtained.
[0264] NMR (DMSO-d.sub.6, .delta.): 1.1-1.5 (2H, m), 1.80 (2H,
distorted t, J=10 Hz), 2.00 (3H, s), 2.77 (1H, br d, J=10.8 Hz),
3.14 (1H, br d, J=11.1 Hz), 3.5-3.9 (2H, m), 4.16 (1H, br d, J=13.2
Hz), 6.15 (1H, d, J=7.6 Hz), 7.05 (2H, t, J=8.9 Hz), 7.40 (2H, dd,
J=5.0, 9.2 Hz), 8.37 (1H, s)
[0265] MASS (APCI)(m/z): 280
EXAMPLE 11
[0266] To a solution of 4-(4-fluorobenzoylamino)piperidine (0.25 g)
in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and
methyl chloroformate (87 .mu.l) at 0.degree. C. The mixture was
allowed to warm to ambient temperature and stirred for 1 hour. To
the mixture was added N,N-dimethylaminopyridine (0.13 g) and
allowed to stir for another 1 hour. The reaction mixture was taken
up into a mixture of water and ethyl acetate. The separated organic
layer was washed in turn with hydrochloric acid (1N), aqueous
sodium hydrogen carbonate, and brine, and dried over magnesium
sulfate. Evaporation under reduced pressure gave a residue, which
was triturated with diisopropyl ether to give
4-(4-fluorobenzoylamino)-1-methoxycarbonylpiperidine (0.265 g).
[0267] NMR (DMSO-d.sub.6, .delta.): 1.3-1.6 (2H, m), 1.75-1.9 (2H,
m), 2.8-3.05 (2H, m), 3.60 (3H, s), 3.85-4.1 (2H, m), 7.29 (2H, t,
J=9 Hz), 7.90 (2H, dd, J=6, 9 Hz), 8.30 (1H, d, J=8 Hz)
[0268] MASS (APCI)(m/z): 281
EXAMPLE 12
[0269] To a solution of 4-(4-fluorobenzoylamino)piperidine (0.25 g)
in pyridine (5 ml) were added in turn 4-trifluorobenzenesulfonyl
chloride (0.219 g) and catalytic amount of
N,N-dimethylaminopyridine at 0.degree. C.
[0270] The mixture was allowed to warm to ambient temperature and
stirred for 1 hour, which was taken up into a mixture of water and
dichloromethane. The separated organic layer was washed in turn
with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and
brine, and dried over magnesium sulfate. Evaporation under reduced
pressure gave a residue, which was triturated with diisopropyl
ether to give
4-(4-fluorobenzoylamino)-1-(4-rifluorophenylsulfonyl)-piperidine
(0.38 g).
[0271] NMR (DMSO-d.sub.6, .delta.): 1.45-1.7 (2H, m), 1.8-1.95 (2H,
m), 2.35-2.55 (2H, m), 3.5-3.85 (3H, m), 7.28 (2H, t, J=9 Hz), 7.50
(2H, t, J=9 Hz), 7.75-7.95 (4H, m), 8.31 (1H, d, J=8 Hz)
[0272] MASS (APCI) (m/z): 381
EXAMPLE 13
[0273] To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g)
in dichloromethane (5 ml) were added in turn pyridine (82 .mu.l)
and 4-trifluoromethoxybenzoyl chloride (106 .mu.l) at 0.degree. C.
The mixture was allowed to warm to ambient temperature and stirred
for 4 hours, which was taken up into a mixture of water and
dichloromethane. The separated organic layer was washed in turn
with hydrochloric acid (IN), aqueous sodium hydrogen carbonate, and
brine, and dried over magnesium sulfate. Evaporation of the solvent
under reduced pressure gave
4-(4-fluorobenzoylamino)-1-(4-trifluoromethoxybenzoyl)piperidine
(205 mg).
[0274] NMR (DMSO-d.sub.6, .delta.): 1.3-1.7 (2H, m), 1.7-2.0 (2H,
m), 2.7-3.4 (2H, m), 3.4-3.8 (1H, m), 3.9-4.2 (1H, m), 4.2-4.6 (1H,
m), 7.30 (2H, t, J=9 Hz), 7.35-7.6 (4H, m), 7.91 (2H, dd, J=6, 9
Hz), 8.35 (1H, d, J=8 Hz)
[0275] MASS (LD)(m/z): 433.2
EXAMPLE 14
[0276] To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g)
in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and
methanesulfonyl chloride (96 .mu.l) at 0.degree. C. The mixture was
allowed to warm to ambient temperature and stirred for 1 hour. To
the mixture was added N,N-dimethylaminopyridine (0.13 g) and
allowed to stir for another 1 hour. The reaction mixture was taken
up into a mixture of water and dichloromethane. The separated
organic layer was washed in turn with hydrochloric acid (1N),
aqueous sodium hydrogen carbonate, and brine, and dried over
magnesium sulfate. Evaporation under reduced pressure gave a
residue, which was triturated with diisopropyl ether to give
4-(4-fluorobenzoylamino)-1-methylsulfonylpiperidine (0.30 g).
[0277] NMR (DMSO-d.sub.6, .delta.): 1.45-1.7 (2H, m), 1.8-2.05 (2H,
m), 2.7-2.95 (2H, m), 2.88 (3H, s), 3.5-3.65 (2H, m), 3.8-4.05 (1H,
m), 7.30 (2H, t, J=9 Hz), 7.91 (2H, dd, J=6, 9 Hz), 8.36 (1H, d,
J=8 Hz)
[0278] MASS (APCI)(m/z): 301
EXAMPLE 15
[0279] To a solution of N-(piperidin-4-yl)-N'-(4-fluorophenyl)urea
(0.3 g) in tetrahydrofuran (4 ml) were added in turn pyridine (0.28
ml), methyl chloroformate (98 .mu.l) and catalytic amount of
N,N-dimethylaminopyridin- e at 0.degree. C. The mixture was allowed
to warm to ambient temperature and stirred for 2 hours. The
reaction mixture was taken up into a mixture of water and ethyl
acetate. The separated organic layer was washed in turn with
hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and
brine, and dried over magnesium sulfate. Evaporation under reduced
pressure gave a residue, which was triturated with diisopropyl
ether to give
N-(1-methoxycarbonylpiperidin-4-yl)-N'-(4-fluorophenyl)urea (0.312
g).
[0280] NMR (DMSO-d.sub.6, .delta.): 1.1-1.4 (2H, m), 1.7-1.9 (2H,
m), 2.8-3.1 (2H, m), 3.5-3.75 (1H, m), 3.59 (3H, s), 3.75-3.95 (2H,
m), 6.15 (1H, d, J=7.6 Hz), 7.05 (2H, t, J=9 Hz), 7.37 (2H, dd,
J=5, 9 Hz), 8.37 (1H, s)
[0281] MASS (APCI)(m/z): 296
EXAMPLE 16
[0282] To a solution of N-(piperidin-4-yl)-N'-(4-fluorophenyl)urea
(0.3 g) in tetrahydrofuran (4 ml) were added in turn
N,N-dimethylaminopyridine (0.23 g) and 4-fluorobenzenesulfonyl
chloride (0.25 g) at 0.degree. C. The mixture was allowed to warm
to ambient temperature and stirred for 1 hour. The reaction mixture
was taken up into a mixture of water and dichloromethane. The
separated organic layer was washed in turn with hydrochloric acid
(1N), aqueous sodium hydrogen carbonate, and brine, and dried over
magnesium sulfate. Evaporation under reduced pressure gave a
residue, which was triturated with diisopropyl ether to give
N-(1-(4-fluorophenylsulfonyl)-piperidin-4-yl)-N'-(4-fluorophenyl)urea
(0.468 g).
[0283] NMR (DMSO-d.sub.6, .delta.): 1.3-1.6 (2H, m), 1.75-1.95 (2H,
m), 2.45-2.7 (2H, m), 3.35-3.6 (3H, m), 6.14 (1H, d, J=7.5 Hz),
7.03 (2H, t, J=9 Hz), 7.34 (2H, dd, J=5, 9 Hz), 7.50 (2H, t, J=9
Hz), 7.75-7.95 (2H, m), 8.31 (1H, s)
[0284] MASS (APCI) (m/z): 396
EXAMPLE 17
[0285] To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (0.5
g) in dichloromethane (5 ml) were added pyridine (218 .mu.l),
dichloromethane (5 ml) and benzoyl chloride (290 .mu.l) at ambient
temperature. After stirring for 3.5 hours, water (5 ml) was poured
into the mixture. An organic layer was separated, and washed with
water and brine. After drying with magnesium sulfate, the solvents
were removed under reduced pressure. A residue was purified by
column chromatography (silica gel, toluene:ethyl acetate=1:1 to
ethyl acetate). After rinse with diisopropyl ether,
N-(1-benzoylpiperidin-4-yl)-4-fluorobenzamide (515 mg) was
obtained.
[0286] NMR (DMSO-d.sub.6, .delta.): 1.50 (2H, br s), 1.85 (2H, br
s), 2.8-3.3 (2H, m), 3.61 (1H, m), 4.1 (1H, m), 4.35 (1H, m), 7.29
(2H, t, J=8.9 Hz), 7.3-7.5 (5H, m), 7.92 (2H, dd, J=5.6, 8.9 Hz),
8.34 (1H, d, J=7.9 Hz)
[0287] MASS (APCI)(m/z): 327
EXAMPLE 18
[0288] To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (556
mg) in dichloromethane (5 ml) were added pivaloyl chloride (0.37
ml), pyridine (0.24 ml) and N,N-dimethylaminopyridine (25 mg) at
ambient temperature. After stirring for 1 day, the mixture was
diluted with dichloromethane, and washed with water and brine.
After drying with magnesium sulfate, the solvents were removed
under reduced pressure. After trituration with diisopropyl ether,
N-(1-pivaloylpiperidin-4-yl)-4-fluorobenzamide (305 mg) was
obtained.
[0289] NMR (DMSO-d.sub.6, .delta.): 1.20 (9H, s), 1.41 (2H, m),
1.7-1.9 (2H, m), 2.91 (2H, br t, J=11.9 Hz), 4.07 (1H, m), 4.27
(2H, br d, J=13.3 Hz), 7.29 (2H, t, J=8.9 Hz), 7.92 (2H, dd, J=5.5,
8.9 Hz), 8.30 (1H, d, J=7.8 Hz) MASS (APCI)(m/z): 329
EXAMPLE 19
[0290] To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (556
mg) in dichloromethane (6 ml) were added cyclopropanecarboxylic
acid (0.20 ml), 1-hydroxybenzotriazole (338 mg) and
1-ethyl-3-(3-dimethylaminopropyl)carb- odiimide hydrochloride (480
mg) at ambient temperature. After stirring for 21 hours, the
mixture was diluted with dichloromethane, and washed with water,
saturated aqueous sodium hydrogen carbonate, and brine. After
drying with magnesium sulfate, the solvents were removed under
reduced pressure. After crystallization from diisopropyl ether,
N-(1-cyclopropylcarbonylpiperidin-4-yl)-4-fluorobenzamide (627 mg)
was obtained.
[0291] NMR (DMSO-d.sub.6, .delta.): 0.6-0.8 (4H, m), 1.2-1.6 (2H,
m), 1.7-2.0 (2H, m), 1.85 (1H, m), 2.72 (1H, m), 3.21 (1H, m), 4.04
(1H, m), 4.30 (2H, m), 7.29 (2H, t, J=8.9 Hz), 7.92 (2H, dd, J=5.6,
8.9 Hz), 8.31 (1H, d, J=7.7 Hz) MASS (APCI) (m/z): 313
EXAMPLE 20
[0292] 1-tert-Butoxycarbonyl-4-(4-fluorophenylcarbamoyl)-piperazine
(0.30 g) was dissolved in a solution of hydrogen chloride in ethyl
acetate (4N, 2 ml), and the solution was stirred at ambient
temperature for 1 hour. The solvent was removed by evaporation
under reduced pressure to give
1-(4-fluorophenylcarbamoyl)piperazine as a white powder, which was
taken up into dichloromethane (3 ml), and to the mixture were added
in turn pyridine (0.25 ml), 4-trifluoromethoxybenzoyl chloride
(0.146 ml), and catalytic amount of N,N-dimethylaminopyridine.
After stirring at ambient temperature for 12 hours, the mixture was
washed in turn with hydrochloric acid (0.5N), aqueous sodium
hydrogen carbonate, and brine, dried over magnesium sulfate, and
evaporated under reduced pressure. The residue was chromatographed
on silica gel (50 ml) eluting with 0%-3% methanol in
dichloromethane to give 1-(4-fluorophenylcarbamoyl)-4-(4-trif-
luoromethoxybenzoyl)-piperazine (0.19 g).
[0293] NMR (DMSO-d.sub.6, .delta.): 3.2-3.8 (8H, m), 7.08 (2H, t,
J=9 Hz), 7.35-7.5 (4H, m), 7.5-7.65 (2H, m) MASS (LD)(m/z):
434.1
EXAMPLE 21
[0294] The following compound was obtained by using methyl
chloroformate as a reactive derivative at the carboxy group
according to a similar manner to that of Example 20.
[0295] 1-Methoxycarbonyl-4-(4-fluorophenylcarbamoyl)piperazine NMR
(DMSO-d.sub.6, .delta.): 3.3-3.5 (8H, m), 3.62 (3H, s), 7.07 (2H,
t, J=9 Hz), 7.44 (2H, dd, J=5, 9 Hz), 8.62 (1H, s)
[0296] MASS (APCI)(m/z): 282
EXAMPLE 22
[0297] A mixture of N-acetylpiperidine-4-carboxylic acid (514 mg),
1-hydroxybenzotriazole (405 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride (575
mg) and 4-fluoroaniline (284.2 ml) in dichloromethane (5 ml) was
stirred for 18 hours at ambient temperature. The mixture was
diluted with dichloromethane and washed with water, saturated
aqueous sodium hydrogen carbonate, water, and brine. After drying
with magnesium sulfate, the solvents were removed under reduced
pressure. A residue was purified by column chromatography (silica
gel 40 ml, dichloromethane:methanol=15:1). After trituration with
diisopropyl ether, 1-acetyl-4-(4-fluorophenyl)-carbamoylpiperidine
(532 mg) was obtained.
[0298] NMR (DMSO-d.sub.6, .delta.): 1.3-1.7 (2H, m), 1.8 (2H, m),
2.01 (3H, s), 2.5 (2H, m), 3.05 (1H, br t, J=10.6 Hz), 3.87 (1H, br
d, J=14.1 Hz), 4.40 (1H, br d, J=13.1 Hz), 7.12 (2H, t, J=8.9 Hz),
7.61 (2H, dd, J=5.1, 9.1 Hz), 9.96 (1H, s)
[0299] MASS (APCI)(m/z): 265
EXAMPLE 23
[0300] A solution of 1-acetylpiperazine-4-sulfonyl chloride (0.91
g) in chloroform (10 ml) were added 4-fluoroaniline (0.38 ml) and
triethylamine (0.56 ml) at ambient temperature. After stirring for
6 days, the solvents were removed under reduced pressure. A residue
was purified by column chromatography (silica gel 100 ml,
dichloromethane:methanol=19:1). After rinse with diisopropyl ether,
1-acetyl-4-(4-fluorophenyl)-sulfamoylpipera- zine (716 mg) was
obtained.
[0301] NMR (CDCl.sub.3, .delta.): 1.97 (3H, s), 3.09 (4H, m), 3.37
(4H, m), 7.20 (4H, m), 10.00 (1H, s)
[0302] MASS (APCI)(m/z): 302
EXAMPLE 24
[0303] To a solution of O-tert-butyl
(1-acetylpiperidin-4-yl)carbamate (0.97 g) in N,N-dimethylformamide
(10 ml) was added 60% sodium hydride (0.18 g) at ambient
temperature. After stirring for 40 minutes, 4-fluorobenzyl bromide
(0.6 ml) was added to the reaction mixture. After additional
stirring for 4 hours, the reaction mixture was poured into a
mixture of ethyl acetate (50 ml) and water (10 ml). An organic
phase was separated and washed with water and brine. After drying
with magnesium sulfate, the solvents were removed under reduced
pressure. A residue was purified by column chromatography (silica
gel 100 ml, toluene:ethyl acetate=1:1 to 1:2). After
crystallization from diisopropyl ether and n-hexane, O-tert-butyl
N-(4-fluorobenzyl)-N-(1-acetylpiperidin-4-yl)carba- mate (922 mg)
was obtained.
[0304] NMR (DMSO-d.sub.6, .delta.): 1.35 (9H, br s), 1.3-1.8 (4H,
m), 1.95 (3H, s), 2.3-2.6 (1H, m), 2.97 (1H, m), 3.80 (1H, br d,
J=15.2 Hz), 4.0 (1H, m), 4.32 (2H, s), 4.2-4.6 (1H, m), 7.0-7.4
(4H, m)
[0305] MASS (APCI) (m/z): 295
EXAMPLE 25
[0306] To a solution of O-tert-butyl
N-(4-fluorobenzyl)-N-(1-acetylpiperid- in-4-yl)carbamate (0.5 g) in
dichloromethane (5 ml) was added 4N hydrogen chloride in dioxane (5
ml). The reaction mixture was diluted with diisopropyl ether and
the precipitates were collected by filtration. After drying under
reduced pressure, 1-acetyl-4-(4-fluorobenzyl)-aminopip- eridine
hydrochloride (409 mg) was obtained.
[0307] NMR (DMSO-d.sub.6+D.sub.2O, .delta.): 1.54 (2H, m), 2.02
(3H, s), 2.0-2.3 (2H, m), 2.4-2.7 (1H, m), 3.04 (1H, br t, J=12.1
Hz), 3.29 (1H, m), 3.9 (1H, m), 4.17 (2H, s), 4.44 (1H, br d,
J=13.6 Hz), 7.27 (2H, t, J=8.9 Hz), 7.66 (2H, br t, J=6.8 Hz)
[0308] MASS (APCI)(m/z): 251
EXAMPLE 26
[0309] To a solution of
N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (529 mg) in
N,N-dimethylformamide (5 ml) was added sodium hydride (0.1 g).
After stirring for 45 minutes, methyl iodide (623 ml) was added to
the solution. After stirring for 45 minutes, the mixture was
diluted with ethyl acetate (100 ml) and water (50 ml). An organic
phase was separated, and washed with water and brine. After drying
with magnesium sulfate, the solvents were removed under reduced
pressure. After trituration with diisopropyl ether,
N-(1-acetylpiperidin-4-yl)-N-methyl-4-fluorobenzamide (248 mg) was
obtained.
[0310] NMR (DMSO-d.sub.6, .delta.): 1.65 (4H, m), 2.00 (3H, s),
2.78 (3H, s), 3.8 (1H, m), 4.4 (1H, m), 2.0-4.6 (3H, br m), 7.26
(2H, t, J=8.9 Hz), 7.46 (2H, dd, J=5.6, 8.7 Hz)
[0311] MASS (APCI)(m/z): 301
EXAMPLE 27
[0312] A suspension of 1-acetylpiperazine (0.627 g),
2-chloro-4'-fluoroacetophenone (0.844 g), and potassium hydrogen
carbonate (0.735 g) in acetonitrile (12 ml) was stirred at ambient
temperature for 3 days. After removal of the solid by filtration,
the filtrate was evaporated under reduced pressure to give a
residue, which was chromatographed on silica gel (100 ml) eluting
with 0%-5% methanol in dichloromethane. The objective compound of
the free form was taken up into ethyl acetate (2 ml) and to the
solution was added a solution of hydrogen chloride in ethyl acetate
(4N, 2 ml). The resulting precipitate was collected by filtration,
washed with diisopropyl ether, and dried in vacuo to give
1-acetyl-4-(4-fluorophenylcarbonylmethyl)-piperazine hydrochloride
(1.47 g).
[0313] NMR (DMSO-d.sub.6, .delta.): 2.06 (3H, s), 2.95-3.8 (6H, m),
3.9-4.15 (1H, m), 4.2-4.45 (1H, m), 5.13 (2H, s), 7.48 (2H, t, J=9
Hz), 8.09 (2H, dd, J=5, 9 Hz)
[0314] MASS (APCI)(m/z): 265
* * * * *