U.S. patent application number 10/101980 was filed with the patent office on 2002-10-10 for piperidine derivatives and anti-platelet agents containing the same.
This patent application is currently assigned to AJINOMOTO CO., INC.. Invention is credited to Arisaka, Harumi, Makino, Shingo, Shoji, Masataka, Yamamoto, Hiroshi, Yoshimoto, Ryota.
Application Number | 20020147195 10/101980 |
Document ID | / |
Family ID | 13748073 |
Filed Date | 2002-10-10 |
United States Patent
Application |
20020147195 |
Kind Code |
A1 |
Makino, Shingo ; et
al. |
October 10, 2002 |
Piperidine derivatives and anti-platelet agents containing the
same
Abstract
The present invention relates to a novel serotonin antagonist
and an anti-platelet agent, more particularly, a serotonin
antagonist and an anti-platelet agent which potently and
specifically inhibit the serotonin 2 receptor with low adverse side
effect.
Inventors: |
Makino, Shingo;
(Kawasaki-shi, JP) ; Arisaka, Harumi;
(Kawasaki-shi, JP) ; Yamamoto, Hiroshi;
(Kawasaki-shi, JP) ; Shoji, Masataka;
(Kawasaki-shi, JP) ; Yoshimoto, Ryota;
(Kawasaki-shi, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
AJINOMOTO CO., INC.
Tokyo
JP
|
Family ID: |
13748073 |
Appl. No.: |
10/101980 |
Filed: |
March 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10101980 |
Mar 21, 2002 |
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09245846 |
Feb 8, 1999 |
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09245846 |
Feb 8, 1999 |
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08917180 |
Aug 25, 1997 |
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5932593 |
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08917180 |
Aug 25, 1997 |
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08425645 |
Apr 20, 1995 |
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Current U.S.
Class: |
514/227.8 ;
514/228.2; 514/232.8; 514/235.5; 514/252.13; 514/253.01; 514/316;
514/325 |
Current CPC
Class: |
A61P 9/06 20180101; C07D
409/14 20130101; A61K 31/4535 20130101; C07D 211/70 20130101; A61P
3/10 20180101; C07D 401/12 20130101; A61K 31/5377 20130101; A61P
17/00 20180101; A61P 7/00 20180101; A61P 9/08 20180101; A61P 43/00
20180101; A61P 9/00 20180101; A61K 31/4545 20130101; A61P 9/12
20180101; A61P 9/10 20180101; A61P 13/12 20180101; A61K 31/444
20130101; A61K 31/496 20130101; A61K 31/451 20130101; A61K 31/541
20130101; C07D 409/04 20130101; A61P 7/02 20180101; A61P 17/02
20180101 |
Class at
Publication: |
514/227.8 ;
514/228.2; 514/235.5; 514/232.8; 514/252.13; 514/253.01; 514/316;
514/325 |
International
Class: |
A61K 031/541; A61K
031/5377; A61K 031/496; A61K 031/4545; A61K 031/4535 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 20, 1994 |
JP |
081499/1994 |
Claims
What is claimed as new and is desired to be secured by Letters
Patent of the United States is:
1. A method of treating or preventing a disease caused by seretonin
comprising administering effective amount of a piperidine
derivative of general formula (I) or pharmaceutically acceptable
salt thereof: 39wherein A.sup.1 represents an unsubstituted or
substituted pyridyl, piperidyl, piperidino, morpholinyl,
morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a
substituted alkyl group having from 1 to 8 carbon atoms, a
substituted cycloalkyl group having from 4 to 8 carbon atoms, or an
unsubstituted or substituted alkoxyl group having 1 to 8 carbon
atoms, X.sup.1 is a hydrogen atom or a halogen atom, Y.sup.1 is
--CONH--, --NHCO--, --CONHCH.sup.2--, --(CH.sub.2) n or --COO--,
wherein n is an integer of from 0 to 4, and Z.sup.1 is
--CH.dbd.CH--, --S--CH.sub.2--, --S-- or
--CH.sub.2--CH.sub.2--.
2. The composition of claim 1, wherein A.sup.1 has a substituent
and said substituent is R.sup.1--CO-- or 40wherein R.sup.1 is a
hydrogen atom, an alkyl or alkoxyl group having from 1 to 6 carbon
atoms, an amino group which may be substituted by an alkyl group
having from 1 to 6 carbon atoms, or an acylaminoalkyl group having
from 1 to 6 carbon atoms, and R.sup.2 and R.sup.3, which may be the
same or different, each represents a hydrogen atom, an alkyl, acyl
or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an
aminocarbonyl group which may be substituted by an alkyl group
having from 1 to 6 carbon atoms.
3. The method of claim 1, wherein said substituent on A.sup.1 is
formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,
isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl,
N-formyl-.beta.-alanyl, N-acetyl-.beta.-alanyl, N-methyl-N-formyl,
N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl or
N-ethyl-N-acetyl.
4. The method of claim 1, wherein Y.sup.1 is a --CONH--.
5. The method of claim 1, wherein Z.sup.1 is a --CH.dbd.CH--.
6. The method of claim 1, wherein the piperidine derivative is
1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))eth-
ylisonipecotamide.
7. A method of treating or preventing platelet aggregation
comprising administering an effective amount of a piperidine
derivative of the formula (I) or a salt thereof or an active
ingredient of a pharmaceutical composition: 41wherein A.sup.1
represents an unsubstituted or substituted pyridyl, piperidyl,
piperidino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino or piperazinyl group, a substituted alkyl group
having from 1 to 8 carbon atoms, a substituted cycloalkyl group
having from 4 to 8 carbon atoms, or an unsubstituted or substituted
alkoxyl group having 1 to 8 carbon atoms, X.sup.1 is a hydrogen
atom or a halogen atom, Y.sup.1 is --CONH--, --NHCO--,
--CONHCH.sup.2--, --(CH.sub.2) or --COO--, wherein n is an integer
of from 0 to 4, and Z.sup.1 is --CH.dbd.CH--, --S--CH.sub.2--,
--S-- or --CH.sub.2--CH.sub.2--.
8. The method of claim 7, wherein the piperidine derivative is
1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))eth-
ylisonipecotamide.
9. A piperidine derivative represented by the general formula (II)
or a salt thereof: 42wherein A.sup.2 represents an unsubstituted or
substituted piperidino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino or piperazinyl group, a substituted alkyl group
having from 1 to 8 carbon atoms, a substituted cycloalkyl group
having from 4 to 8 carbon atoms, or an unsubstituted or substituted
alkoxyl group having 1 to 8 carbon atoms, wherein suitable
substituents include: R.sup.4--CO-- or 43wherein R.sup.4 represents
an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino
group which may be substituted by an alkyl group having from 1 to 6
carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon
atoms. R.sup.1 and R.sup.6, which may be the same or different,
each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl
group having from 1 to 6 carbon atoms, or an aminocarbonyl group
which may be substituted by an alkyl group having from 1 to 6
carbon atoms, and X.sup.2 is a hydrogen atom or a halogen atom,
Y.sup.2 is --CONH--, --NHCO--, --CONHCH.sup.2--,
--(CH.sub.2).sub.n-- or --COO--, wherein n is an integer of from 0
to 4, and Z.sup.2 is --CH.dbd.CH--, --S--CH.sub.2--, --S-- or
--CH.sub.2--CH.sub.2--.
10. The piperidine derivative of claim 9, wherein A.sup.2 is
substituted with a substituent selected from the group consisting
of acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,
pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,
N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-formylglycyl, N-acetylglycyl, N-formyl-.beta.-alanyl,
N-acetyl-.beta.-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl,
N-methyl-N-propionyl, N-ethyl-N-formyl, and N-ethyl-N-acetyl.
11. The piperidine derivative of claim 9, wherein Y.sup.2 is a
group --CONH--.
12. The piperidine derivative of claim 9, wherein Z.sup.2 is a
group --CH.dbd.CH--.
13. A compound selected from the group consisting of
1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperid-
inyl))ethylisonipecotamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-
-1-piperidinyl))ethylisonipecotamide,
1-acetyl-N-(2-(4-(5H-dibenzo[a,d]cyc-
lohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[[a,d]cyclohepten-5-ylidene)-1piper-
idinyl))ethylisonipecotamide,
1-carbamoyl-N-(2-(4-(5H-dibenzo[a,d]cyclohep-
ten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-(N,N-dimethylcarbamoyl)-N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-
piperidinyl))ethylisonipecotamide,
1-(N-acetylglycyl)-N-(2-(4(5H-dibenzo[a-
,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidinyl))
ethylpipecolamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piper- idinyl))
ethyl-(N-acetyl)pipecolamide, 1-formyl-4-((2-(4-(5H-dibenzo[a,d]c-
yclohepten-5-ylidene)-1-piperidinyl))ethylcarbamoyl)piperazine,
N-(2-1(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))
ethyl-4-aminocyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-- 5-ylidene)-1-piperidinyl))
ethyl-4-acetylaminocyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))
ethyl-4-(1-t-butoxycarbonylamino)cyclohexanecarboxamide,
4-5H-dibenzo[a,d]cyclohepten-5-ylidene))1-2-ethoxycarbonylamino)ethyl)pip-
eridine,
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxycarbonylamin-
o)ethyl)piperidine,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piper-
idinyl))ethyl-1-(1-amino)cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]c- yclohepten-5-ylidene)-1-piperidinyl))
ethyl-1-(1-acetylamino)cyclohexaneca- rboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))e-
thyl-1-(1-t-butoxycarbonylamino) cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(fo-
rmylamino)cyclohexanecarboxamide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-yl-
idene)-1-piperidinyl))ethyl-1-(1-N,N-dimethylcarbamoylamino)
cyclohexanecarboxamide,
N-(2-(4-(5Hdibenzo[a,d]cyclohepten-5-ylidene)-1-p-
iperidinyl))ethyl-4-aminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5- -ylidene)-piperidinyl))
ethyl-4-formylaminobutyramide, N-(2-(4-(5H-dibenzo[a,d]
cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-ac-
etylaminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-pipe-
ridinyl))ethyl-4-t-butoxycarbonylaminobutyramide,
N-(2-(4-(5H-dibenzo[a,d]-
cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N,N-dimethylcarbamoylamino)
butyramide,
N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))-
ethyl-4-(N-methylamino)butyramide,
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-y-
lidene)-1-piperidinyl))ethyl-4-(N-methyl-t-butoxycarbonylamino)
butyramide,
1-formyl-N-(3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-pip-
eridinyl))propylisonipecotamide,
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-- 1(3-t-butoxycarbonyl
aminopropyl)piperidine, 1-(3-aminopropyl)-4-(5H-diben-
zo[a,d]cyclohepten-5-ylidene)piperidine, 1-formyl-isonipecotic acid
2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl
ester,
1-(2-aminoethyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)pi-
peridine,
4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-bu-
toxycarbonylamino)ethyl)piperidine,
1-formyl-N-(2-(4-(10,11-dihydro-5H-dib-
enzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,
1-(2-aminoethyl)-4-(9-thioxanthinidene)piperidine,
4-(9-thioxanthinidene)-1-((2-t-butoxycarbonylamino)ethyl)
piperidine, 1-formyl-N-(2-(4-(9-thioxanthinidene)piperidinyl))
ethylisonipecotamide,
1-formyl-N-(2(4-(11-H-dibenzo[b,e]thiepin-2-fluoro-11-ylidene)-1-piperidi-
nyl))ethylisonipecotamide,
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)--
1-piperidinyl)butyl)morpholine,
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5ylide-
ne)-1-piperidinyl)butyl)thiomorpholine,
1-(4-(4-(5H-dibenzo[a,d]cyclohepte-
n-5-ylidene)-1-piperidinyl)pentyl)morpholine,
1-(4-(4-(10,11-dihydro-5H-di-
benzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)piperidine and
1-(4-(4-(9-thioxanthilidene)piperidinyl)butyl)morpholine.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a novel serotonin
antagonist and an anti-platelet agent, more particularly, a
serotonin antagonist and an anti-platelet agent which potently and
specifically inhibit the serotonin 2 receptor with low adverse side
effect.
[0003] 2. Discussion of the Background
[0004] It is believed that the thrombus greatly participates in
ischemic disorders such as cardiac infarction and cerebral
infarction and, in particular, the platelet plays an important role
in the formation of the arterial thrombus. Known anti-platelet
agents include arachidonic acid metabolism-inhibiting agents,
platelet cyclic nucleoside-related agents, thromboxane receptor
antagonists. Aspirin and ticlopidine have also been clinically
used. However, the effect of these agents is not sufficient and
thus development of more effective agents has been in demand.
[0005] It is known that serotonin (5HT), which is stored in a
granules of the platelet, is released by activation of the platelet
caused by various stimulations, and the released serotonin
increases the calcium ion level in the cell via the serotonin 2
(5HT.sub.2) receptor on the platelet membrane, resulting in
aggregation of the platelet. It is believed that the 5HT.sub.2
receptor existing in the vascular smooth muscle participates in the
blood vessel contraction. Accordingly, the 5HT.sub.2 receptor
antagonist is expected to have vasoconstriction inhibiting activity
in addition to the platelet aggregation inhibiting activity and,
therefore, may also have potent anti-thrombus function.
SUMMARY OF THE INVENTION
[0006] Accordingly, one object of this invention is to provide a
novel serotonin antagonist and an anti-platelet agent which
potently and specifically inhibit the serotonin 2 receptor with low
adverse side effect.
[0007] This and objects which will become apparent hereinafter have
been achieved with the following novel serotonin agents.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0008] The present invention relates to a serotonin antagonist or
an anti-platelet agent which comprises as an active ingredient a
piperidine derivative represented by the following general formula
(I): 1
[0009] wherein
[0010] A.sup.1 represents an unsubstituted or substituted pyridyl,
piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino or piperazinyl group, a substituted alkyl group
having from 1 to 8 carbon atoms, a substituted cycloalkyl group
having from 4 to 8 carbon atoms, or an unsubstituted or substituted
alkoxyl group having 1 to 8 carbon atoms,
[0011] X.sup.1 represents a hydrogen atom or a halogen atom
selected from the group consisting of bromine, chlorine, flourine
and iodine,
[0012] Y.sup.1 represents one of the following organic groups:
[0013] --CONH--, --NHCO--, --CONHCH.sub.2--, --(CH.sub.2).sub.n--
or --COO--,
[0014] wherein n is an integer of from 0 to 4, and
[0015] Z.sup.1 represents one of the following organic groups:
[0016] --CH.dbd.CH--, --S--CH.sub.2--, --S-- or
--CH.sub.2--CH.sub.2--,
[0017] or a salt thereof.
[0018] Preferred substituents for A.sup.1 in the above general
formula (I) include:
[0019] R.sup.1--CO-- and 2
[0020] wherein
[0021] R.sup.1 is a hydrogen atom, an alkyl or alkoxyl group having
from 1 to 6 carbon atoms, an amino group which may be substituted
by an alkyl group having from 1 to 6 carbon atoms, or an
acylaminoalkyl group having from 1 to 6 carbon atoms, and R.sup.2
and R.sup.3, which may be the same or different, each represents a
hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1
to 6 carbon atoms, or an aminocarbonyl group which may be
substituted by an alkyl group having from 1 to 6 carbon atoms.
[0022] Illustrative examples of such preferred substituents of
A.sup.1 include formyl, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl,
N-formyl-.beta.-alanyl, N-acetyl-N-alanyl, N-methyl-N-formyl,
N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl and
N-ethyl-N-acetyl.
[0023] Preferred examples of Y.sup.1 in the general formula (I)
include a group --CONH--.
[0024] Preferred examples of Z.sup.1 include --CH.dbd.CH--.
[0025] Among the compounds represented by the general formula (I),
the compounds represented by the following general formula (II) are
novel compounds. 3
[0026] wherein
[0027] A.sup.2 represents an unsubstituted or substituted
piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino or piperazinyl group, a substituted alkyl group
having from 1 to 8 carbon atoms, a substituted cycloalkyl group
having from 4 to 8 carbon atoms, or an unsubstituted or substituted
alkoxyl group having 1 to 8 carbon atoms.
[0028] When A.sup.2 has a substituent, the substituent is one of
the following groups.
[0029] R.sup.4--CO-- and 4
[0030] wherein
[0031] R.sup.4 represents an alkyl or alkoxyl group having from 1
to 6 carbon atoms, an amino group which may be substituted by an
alkyl group, or an acylaminoalkyl group, and
[0032] R.sup.5 and R.sup.6, which may be the same or different,
each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl
group having from 1 to 6 carbon atoms, or an aminocarbonyl group
which may be substituted by an alkyl group, and
[0033] X.sup.2, Y.sup.2, and Z.sup.2, respectively, have the same
meanings as X.sup.1, Y.sup.1, and Z.sup.1.
[0034] Preferred substituents for A.sup.2 include acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl,
N-acetylglycyl, N-formyl-.beta.-alanyl, N-acetyl-.beta.-alanyl,
N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl,
N-ethyl-N-formyl, N-ethyl-N-acetyl, and the like.
[0035] Preferably, Y.sup.2 is a group --CONH--.
[0036] Preferably, Z.sup.2 is a group --CH.dbd.CH--.
[0037] The piperidine derivative represented by the above general
formula (I) may be prepared by the conventional method, for
example, by the method described in an unexamined published
Japanese patent application 3-47168, incorporated herein by
reference.
[0038] For example,
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxyc-
arbonylamino)ethyl)piperidine (compound (3)) included in the
general formula (I) can be easily obtained by subjecting
N-t-butoxycarbonyl-2-bro- moethylamine (compound (1)) and
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)pi- peridine (compound (2))
to the condensation reaction in the presence of a base such as
triethylamine, as shown in the Reaction Scheme I. 5
[0039] Similarly,
1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)--
1-piperidinyl))ethylisonipecotamide (compound (6)) included in the
general formula (I) can be easily obtained by subjecting the
compound 4, which is obtained by removing a t-butoxycarbonyl group
from the compound 3 using 4 M hydrochloric acid/dioxane, etc., and
1-formylisonipecotic-acid (compound (5)) to the condensation
reaction using a condensation agent such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, as shown in the
Reaction Scheme II. 6
[0040] The reaction product obtained by these production methods is
isolated and purified as a free compound or a salt thereof.
Isolation and purification may be carried out by extraction,
concentration, evaporation, crystallization, and various types of
chromatography.
[0041] Examples of the salt of the piperidine derivative include
acid addition salts with inorganic acid such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
and with organic acids such as formic acid, acetic acid, lactic
acid, salicylic acid, mandelic acid, citric acid, oxalic acid,
maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid,
p-toluenesulfonic acid, methanesulfonic acid, and benzenesulfonic
acid.
[0042] The piperidine derivative represented by the general formula
(I) exhibits a serotonin antagonizing activity and is useful as an
agent for the treatment of ischemic disorders, thrombosis,
obstruction, mental diseases (depression, anxiety), diabetic
complication, arteriosclerosis, hypertension, arrhythmia, migraine,
microcirculation failure, and the like. In particular, as an
anti-platelet agent, the piperidine derivative represented by the
general formula (I) is useful as an agent for the treatment of
various ischemic disorders, thrombosis, obstruction, angiitis,
diabetic complication, arteriosclerosis, nephropathy, and ulcer,
pain, rhigosis, etc. due to chronic arterial obstruction, and also
can be used as a treating agent for improving various ischemia
accompanying circulation failure, for preventing restenosis after
surgical treatment of ischemic heart diseases, and for improving
blood circulation.
[0043] When the piperidine derivative of the general formula (I) is
used as a serotonin antagonist or an anti-platelet agent, the
administration route may be either oral or parenteral. Though the
clinical dose may differ depending on the age, body weight, and
condition of the patient and on the administration method, but the
dose per an adult per day is generally from 0.01 mg to 500
preferably from 0.1 mg to 50 mg in the case of oral administration
and 1 .mu.g to 100 mg preferably from 0.01 mg to 10 mg in the case
of parenteral administration.
[0044] As the dosage form, usual dosage forms such as tablets,
powders, sugar-coated preparations, capsules and solutions may be
employed and such dosage forms can be prepared by the conventional
method making use of usual pharmaceutical adjuvants.
[0045] This application is based on Japanese Patent Application No.
081499/1944, the text of which is incorporated herein by
reference.
EXAMPLES
[0046] Having generally described this invention, a further
understanding can be obtained by reference to certain specific
examples which are provided herein for purposes of illustration
only and are not intended to be limiting unless otherwise
specified.
Preparation Procedure A
Synthesis of
1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylide-
ne)-1-piperidinyl)) ethylisonipecotamide hydrochloride
[0047] Step 1
Synthesis of 2-t-Butoxycarbonylaminoethylbromide
[0048] 2-Aminoethylbromide hydrobromide (35.77 g, 174.6 mmol) and
di-t-butyl dicarbonate (22.80 g, 104.5 mmol) were added to a mixed
solvent of 300 ml of diethyl ether and 300 ml of water. Then,
sodium hydrogencarbonate (44.00 g, 523.7 mmol) was gradually added
and the mixture was stirred at room temperature overnight. The
diethyl ether layer was washed with 80 ml of 1N hydrochloric acid
and then with 80 ml of a saturated aqueous sodium chloride
solution, and dried over magnesium sulfate powder. The solvent was
evaporated to obtain the titled compound. Amount obtained: 21.57 g
(96.25 mmol); Yield: 92%
[0049] Step 2
Synthesis of
4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbony-
lamino)ethyl)piperidine
[0050] 2-t-Butoxycarbonylaminoethylbromide (4.5 g, 20.1 mmol),
4(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (2.7 g, 10.0
mmol), and triethylamine (4.2 ml, 30 mmol) were added to
acetonitrile (300 ml), and the mixture was stirred on an oil bath
at 50.degree. C. for 16 hours. The temperature was lowered to room
temperature, the solvent was evaporated, and the residue was
dissolved in 300 ml of ethyl acetate. After removing insoluble
matters by filtration, the filtrate was washed with 100 ml of 1N
hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxide
solution, and 100 ml of a saturated sodium chloride aqueous
solution, and dried over magnesium sulfate powder. The solvent was
evaporated and the residue was purified by silica gel column
chromatography to obtain the titled compound. Amount obtained: 3.6
g (8.6 mmol); Yield: 86%
[0051] Step 3
Synthesis of
1-(2-aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)pipe-
ridine dihydrochloride
[0052]
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino-
)ethyl)piperidine (8.47 g, 20.4 mmol) was dissolved in 100 ml of
dichloromethane, and 100 ml of a 4N hydrochloric acid-dioxane
solution was added thereto, followed by stirring at room
temperature for 1 hour. The solvent was evaporated to obtain the
titled compound (8.56 g).
[0053] Step 4
Synthesis of 1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a,
d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide
[0054]
1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine
dihydrochloride (2.3 g, 6.0 mmol), 1-t-butoxycarbonylisonipecotic
acid (1.6 g, 7.2 mmol), triethylamine (3.0 ml, 21.6 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g,
7.2 mmol) were mixed, and the mixture was stirred at room
temperature overnight. After evaporating the solvent, the residue
was dissolved in 100 ml of dichloromethane, washed with 100 ml of
1N hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxide
solution, and 50 ml of a saturated aqueous sodium chloride
solution. The solvent was evaporated and the residue was purified
by silica gel chromatography to obtain the titled compound. Amount
obtained: 2.0 g (3.8 mmol); Yield: 63%
[0055] Step 5
Synthesis of
N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))-
ethylisonipecotamide dihydrochloride
[0056] 10 ml of 4N hydrochloric acid-dioxane solution was added to
1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piper-
idinyl))ethylisonipecotamide (0.10 g, 0.185 mmol), and the mixture
was stirred at room temperature for 1 hour. The solvent was
evaporated to obtain the titled compound. Amount obtained: 0.093 g
(0.186 mmol); Yield: 100%
[0057] Step 6
Synthesis of
1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylide-
ne-1-piperidinyl))ethylisonipecotamide hydrochloride
[0058]
N-(2-(4-(5H-Dibenzo[a,dlcyclohepten-5-ylidene)-1-piperidinyl))ethyl-
isonipecotamide dihydrochloride (0.59 g, 1.18 mmol) and
triethylamine (0.8 ml, 5.70 mmol) were dissolved in 50 ml of
dichloromethane, and methyl chloroformate (0.1 ml, 1.40 mmol) was
added. The mixture was stirred for 1 hour and 100 ml of
dichloromethane was added. The mixture was washed with 70 ml of
water, 70 ml of a 1N aqueous sodium hydroxide solution, and 70 ml
of a saturated aqueous sodium chloride solution, and purified by
silica gel chromatography. The product obtained was converted into
the hydrochloride form to give the titled compound. Amount
obtained: 0.39 g (0.75 mmol); Yield: 63%
[0059] The compounds shown in Table 1 were produced by the similar
manner as described in Preparation procedure A.
1 7 A Y X Z pKi pIC.sub.50 1 8 --CONH-- H --CH.dbd.CH-- 8.2 7.5 2 9
8.6 7.3 3 10 8.4 7.2 4 11 8.5 7.2 5 12 8.0 6.5 6 13 -- 6.9 7 14 8.5
6.7 8 15 7.9 6.6 9 16 7.8 7.1 10 17 8.8 -- 11 18 8.8 7.0 12 19 8.6
6.6 13 20 9.3 -- 14 21 --CONH-- H --CH.dbd.CH-- -- -- 15 22 -- --
16 CH.sub.3CH.sub.2O-- -- 7.6 17 (CH.sub.3).sub.3CO-- -- 7.0 18 23
8.9 7.3 19 24 8.3 6.4 20 25 8.0 6.3 21 26 7.8 6.5 22 27 8.2 5.8 23
H.sub.2N(CH.sub.2).sub.3-- -- 7.6 24 HCONH(CH2).sub.3-- 9.8 7.2 25
CH.sub.3CONH(CH.sub.2).sub.3-- 9.2 6.6 26
(CH.sub.3).sub.3COCONH(CH.sub.2).sub.3-- -- 7.2 27
(CH.sub.3).sub.2NCONH(CH.sub.2).sub.3-- --CONH-- H --CH.dbd.CH--
9.2 6.9 28 CH.sub.3NH(CH.sub.2).sub.3-- -- 6.6 29
(CH.sub.3).sub.3COCON(CH.sub.2).sub.3--CH.sub.3 -- 7.1 30 28
--CONHCH.sub.2-- 8.3 6.4 31 (CH.sub.3).sub.3CO-- 8.8 -- 32
H.sub.2N-- --CH.sub.2-- -- -- 33 29 --COO-- 8.3 7.4 34 H.sub.2N--
-- --CH.sub.2--CH.sub.2-- -- -- 35 (CH.sub.3).sub.3CO-- --CONH--
8.3 -- 36 30 8.9 5.8 37 H.sub.2N-- -- --S-- 8.4 5.0 38
(CH.sub.3).sub.3CO-- --CONH-- 9.1 7.3 39 31 9.2 7.1 40 32 F
--S--CH.sub.2-- 7.1 5.6
Preparation Procedure B
Synthesis of
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-
butyl)morpholine
[0060] Step 1
Synthesis of
1-(4-oxo-4-morpholinobutyryl)-4-(5H-dibenzo[a,d]cyclohepten-5-
-ylidene)piperidine
[0061] In 50 ml of dichloromethane,
4-(5H-dibenzo[a,d]cyclohepten-5-yliden- e)piperidine (0.27 g, 1.0
mmol), succinic anhydride (0.12 g, 1.2 mmol), and triethylamine
(0.17 ml, 1.2 mmol) were stirred at room temperature overnight.
Morpholine (0.14 ml, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminop-
ropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) were added and
the mixture was further stirred at room temperature for 8 hours.
The reaction mixture was washed with 30 ml of 1N hydrochloric acid,
30 ml of a 1N aqueous sodium hydroxide solution, and 30 ml of a
saturated aqueous sodium chloride solution, dried over magnesium
sulfate powder, and purified by silica gel chromatography to obtain
the titled compound. Amount obtained: 0.44 g (1.0 mol); Yield:
100%
[0062] Step 2
Synthesis of
1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl)b-
utyl)morpholine dihydrochloride
[0063] In tetrahydrofuran (60 ml),
1-(4-oxo-4-morpholinobutyryl)-4-(5H-dib-
enzo[a,d]cyclohepten-5-ylidene)piperidine (0.44 g, of 1.00 mmol)
was reacted with lithium aluminum hydride (0.38 g, 10.0 mol) at
0.degree. C., and further treated in accordance with the
conventional method to obtain the titled compound. Amount obtained:
0.32 g (0.66 mmol); Yield: 66%
[0064] The compounds shown in Table 2 were produced by the similar
manner as described in Preparation procedure B.
2 33 A Y X Z pKi pIC.sub.50 41 34 --(CH.sub.2).sub.2-- H
--CH.dbd.CH-- 8.2 6.9 42 35 8.7 6.6 43 36 --(CH.sub.2).sub.3-- 7.3
-- 44 37 --(CH.sub.2).sub.2-- --CH.sub.2--CH.sub.2-- 7.9 -- 45 38
--S-- 8.1 --
Test Example 1
[0065] The binding affinity to the serotonin 2 receptor was
evaluated using a bovine cerebral cortex membrane sample. To 200
.mu.l of a bovine membrane sample adjusted to 50 mg (wet weight)
membrane/ml were added 200 .mu.l of 3 nM [.sup.3H]-ketanserin and
200 .mu.l of a test compound solution prepared by dissolving a test
compound in 1.7% ethanol, followed by mixing. The mixture was
incubated at 25.degree. C. for 30 minutes and filtered-with a glass
filter. The radioactivity trapped on the filter was measured with a
liquid scintillation counter. The non-specific binding was defined
by 10.sup.-6 M LY53857. The concentration of the test compound
which inhibits 50% of the specific binding of [.sup.3H]-ketanserin
(i.e., IC.sub.50 value) was obtained, and the Ki value was
calculated in accordance with the following equation. The results
are shown as the negative logarithm of the Ki value (i.e., pKi
value). 1 K i = IC 50 1 + [ L ] K d
[0066] In the equation, Ki indicates the dissociation constant and
[L] indicates the concentration of [.sup.3H]-ketanserin.
[0067] From the results in Tables 1 and 2, it is apparent that the
piperidine derivative of the present invention exhibits strong
binding affinity to the serotonin 2 receptor.
Test Example 2
[0068] The anti-platelet effect due to the serotonin antagonistic
activity was measured in vitro using the platelet of SD rats (body
weight: about 300 to 400 g, male). Platelet rich plasma (PRP) and
platelet poor plasma (PPP) were prepared from blood with 0.38%
sodium citrate which was obtained from aorta abdominalis of a rat
under diethyl ether anesthesia. The platelet concentration of PRP
was adjusted to 5.times.10.sup.8 platelets/ml by adding PPP. Then,
the test compound dissolved in 0.4% aqueous ethanol was added, and
the mixture was incubated at 37.degree. C. for 3 minutes. The
platelet aggregation induced by addition of 0.5 .mu.M or 0.8 .mu.M
adenosine diphosphate (ADP)+serotonin was measured as an increase
in optical transmittance of PRP. The concentration of the test
compound which inhibits 50% of the increase in platelet aggregation
which is obtained with serotonin without a test compound was
measured, and its negative logarithm (pIC.sub.50) was calculated.
The results are shown in the Table 1 and 2. From these results, it
is apparent that the piperidine compound of the present invention
potently inhibits the platelet aggregation by serotonin.
Test Example 3
[0069] The anti-platelet effect due to the serotonin antagonistic
activity was measured in vivo using SD rats (body weight: about 210
to 330 g, male). The test compound was dissolved or suspended in
arabic gum and orally administered to the rat in a dose shown in
Table 3. Two hours after the administration of the test compound,
the rat was anesthetized with diethyl ether and platelet rich
plasma (PRP) and platelet poor plasma (PPP) were prepared from
blood with 0.38% sodium citrate which was obtained from aorta
abdominalis of the rat. The platelet concentration of PRP was
adjusted to 5.times.10.sup.8 platelets/ml by adding PPP. Then, the
PRP was incubated at 37.degree. C. for 3 minutes, and platelet
aggregation induced by addition of 0.7 .mu.M adenosine diphosphate
(ADP)+serotonin was measured as an increase in optical
transmittance of PRP. The aggregation occurred by addition of ADP
alone and the maximum aggregation ratio by the simultaneous
addition of ADP and serotonin were measured with respect to each
group, and increase in aggregation caused by serotonin was
calculated. The increase in aggregation caused by serotonin in the
arabic gum administered group was taken as 100%, and the effect of
the test compound was judged using as an index the increase in
aggregation caused by the serotonin in the test
compound-administered group (n=3). The results are shown in the
Table 3.
3 Amount of Increase in aggregation administration by serotonin
Test Compound (mg/kg) (%) arabic gum -- 100 compound of No. 3 0.1
75.7 0.3 57.3 1 24.3 3 27 10 -2.7 compound of No. 9 0.3 57.3
compound of No. 17 0.3 50.7 compound of No. 18 0.3 94.9 compound of
No. 38 0.3 82.4 compound of No. 39 0.3 54.5 compound of No. 41 0.3
91.5
[0070] From the results in the Table 3, it is apparent that the
piperidine compound of the present invention potently inhibits the
platelet aggregation by serotonin even in the case of oral
administration.
Test Example 4
[0071] The serotonin antagonistic activity in the central nerve
system was evaluated by measuring the inhibiting effect on head
twitch of mouse induced by 5-hydroxytryptophan (5HTP) A test
compound in an amount of 1, 3, 10, or 30 mg was respectively
dissolved in 100 ml of water and, 90 minutes before 5HTP
administration, the solution (10 ml/kg body weight) was orally
administered to a ICR mouse (body wight: 27 to 32 g, male) fasted
from the previous day. As a control, 5% arabic gum was used.
Carbidopa (6 mg/kg) was subcutaneously administered and, after 15
minutes, 5HTP (180 mg/kg) was intraperitoneally administered. From
the 15 minutes after 5HTP administration, the number of head
twitches occurred within 2 minutes were counted. The concentration
of the test compound which inhibits 50% of the number of head
twitches in the 5% arabic gum administered group was obtained. The
results are shown in the Table 4.
4 TABLE 4 Test compound ID.sub.50 (mg/kg) compound of No. 3 0.39
cycloheptadine 0.12
[0072] From the results in the Table 4, it is apparent that the
piperidine compound of the present invention has low effect on the
central nerve system and is a highly safe compound.
[0073] Having now fully described the invention, it will be
apparent to one of ordinary skill in the art that many changes and
modifications can be made thereto without departing from the spirit
or scope of the invention as set forth herein.
* * * * *