U.S. patent application number 12/939601 was filed with the patent office on 2011-03-03 for allosteric modulators of the a1 adenosine receptor.
Invention is credited to Pier Giovanni Baraldi, Allan R. Moorman, Romeo Romagnoli.
Application Number | 20110053917 12/939601 |
Document ID | / |
Family ID | 39464454 |
Filed Date | 2011-03-03 |
United States Patent
Application |
20110053917 |
Kind Code |
A1 |
Baraldi; Pier Giovanni ; et
al. |
March 3, 2011 |
Allosteric Modulators of the A1 Adenosine Receptor
Abstract
The present invention provides compounds of formula (I)
##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Q have
a meaning as defined herein in the specification. The compounds of
formula (I) are allosteric modulators of the A.sub.1 adenosine
receptor and, thus, may be employed for the treatment of conditions
mediated by the A.sub.l adenosine receptor. Accordingly, the
compounds of formula (I) may be employed for treatment of pain, in
particular, chronic pain such as neuropathic pain; cardiac disease
or disorder such as cardiac disarrhythmias, e.g., peroxysmal
supraventricular tachycardia, angina, myocardial infarction and
stroke; neurological disease or injury; sleep disorder; epilepsy;
and depression.
Inventors: |
Baraldi; Pier Giovanni;
(Ferrara, IT) ; Moorman; Allan R.; (Durham,
NC) ; Romagnoli; Romeo; (Ferrara, IT) |
Family ID: |
39464454 |
Appl. No.: |
12/939601 |
Filed: |
November 4, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11938465 |
Nov 12, 2007 |
7855209 |
|
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12939601 |
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60858505 |
Nov 13, 2006 |
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Current U.S.
Class: |
514/218 ;
514/249; 514/252.13; 514/253.11; 514/278; 514/326; 514/409;
514/414 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 487/08 20130101; C07D 333/36 20130101; C07D 409/04 20130101;
A61P 9/00 20180101; C07D 409/06 20130101; C07D 491/10 20130101;
A61P 25/00 20180101; C07D 409/12 20130101; C07D 487/10
20130101 |
Class at
Publication: |
514/218 ;
514/252.13; 514/326; 514/249; 514/414; 514/409; 514/278;
514/253.11 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/496 20060101 A61K031/496; A61K 31/4535
20060101 A61K031/4535; A61K 31/4995 20060101 A61K031/4995; A61K
31/407 20060101 A61K031/407; A61K 31/438 20060101 A61K031/438; A61P
25/00 20060101 A61P025/00; A61P 29/00 20060101 A61P029/00; A61P
9/00 20060101 A61P009/00 |
Claims
1. A method for the treatment of pain, cardiac disease or disorder,
neurological disease or injury, sleep disorder, epilepsy and
depression in mammals which method comprises administering to a
mammal, in need thereof, a therapeutically effective amount of a
compound of formula (I) ##STR00106## wherein R.sub.1 is hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl or
substituted cycloalkyl; R.sub.2, R.sub.3, and R.sub.4 are,
independently from each other, hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy; Q is
selected from the group consisting of ##STR00107## in which R.sub.5
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or
substituted acyl; R.sub.6 and R.sub.7 are, independently from each
other, hydrogen, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3
substituted alkyl; or R.sub.6 and R.sub.7, provided they are
attached to the same carbon atom, combined are alkylene which
together with the carbon atom to which they are attached form a 3-
to 7-membered spirocyclic ring; R.sub.8, R.sub.9, R.sub.10,
R.sub.11, R.sub.12 and R.sub.13 are, independently from each other,
hydrogen, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 substituted
alkyl; X is N; or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1, wherein R.sub.1 is hydrogen,
alkyl, substituted alkyl, aryl or substituted aryl; or a
pharmaceutically acceptable salt thereof.
3. A method according to claim 2, wherein Q is ##STR00108## in
which R.sub.5 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,
acyl or substituted acyl; R.sub.6 and R.sub.7 are, independently
from each other, hydrogen, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3
substituted alkyl; or R.sub.6 and R.sub.7, provided they are
attached to the same carbon atom, combined are alkylene which
together with the carbon atom to which they are attached form a 3-
to 7-membered spirocyclic ring; R.sub.8 and R.sub.9 are,
independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 substituted alkyl; or a pharmaceutically acceptable
salt thereof.
4. A method according to claim 3, wherein a compound of formula (I)
is of formula (IA) ##STR00109## wherein R.sub.1 is hydrogen, alkyl,
substituted alkyl, aryl or substituted aryl; R.sub.2, R.sub.3, and
R.sub.4 are, independently from each other, hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted
cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy or substituted
alkoxy; R.sub.5 is alkyl, substituted alkyl, aryl, substituted
aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or
substituted acyl; R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are,
independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 substituted alkyl; or a pharmaceutically acceptable
salt thereof.
5. A method according claim 4, wherein R.sub.1 is hydrogen or
C.sub.1-C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
6. A method according to claim 4, wherein R.sub.5 is monocyclic
aryl optionally substituted by one to three substituents selected
from the group consisting of halogen, cyano or trifluoromethyl; or
a pharmaceutically acceptable salt thereof.
7. A method according to claim 4, wherein R.sub.2 and R.sub.4 are
hydrogen; or a pharmaceutically acceptable salt thereof.
8. A method according to claim 7, wherein R.sub.3 is halogen, cyano
or trifluoromethyl; or a pharmaceutically acceptable salt
thereof.
9. A method according to claim 4, wherein R.sub.2 and R.sub.3 are
hydrogen; or a pharmaceutically acceptable salt thereof.
10. A method according to claim 9, wherein R.sub.4 is halogen,
cyano or trifluoromethyl; or a pharmaceutically acceptable salt
thereof.
11. A method according to claim 4, wherein R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are, independently from each other, hydrogen or
C.sub.1-C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
12. A method according to claim 11, wherein R.sub.5 is monocyclic
aryl optionally substituted by one to three substituents selected
from the group consisting of halogen, cyano or trifluoromethyl; or
a pharmaceutically acceptable salt thereof.
13. A method according to claim 12, wherein R.sub.2 and R.sub.4 are
hydrogen; or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 13, wherein R.sub.3 is halogen,
cyano or trifluoromethyl; or a pharmaceutically acceptable salt
thereof.
15. A compound according claim 14, wherein R.sub.1 is hydrogen or
C.sub.1-C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
16. A compound according to claim 12, wherein R.sub.2 and R.sub.3
are hydrogen; or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 16, wherein R.sub.4 is halogen,
cyano or trifluoromethyl; or a pharmaceutically acceptable salt
thereof.
18. A compound according claim 17, wherein R.sub.1 is hydrogen or
C.sub.1-C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
19. A method for the treatment of pain, cardiac disease or
disorder, neurological disease or injury, sleep disorder, epilepsy
and depression in mammals which method comprises administering to a
mammal, in need thereof, a therapeutically effective amount of a
compound selected from the group consisting of:
{2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone;
{2-Amino-4-[(4-methylpiperazin-1-Amethyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone;
{2-Amino-4-[4-((4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[4-((4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[4-((4-methoxyphenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone;
{2-Amino-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl-
)methanone;
{2-Amino-4-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone;
{2-Amino-4-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-(3,4-dichlorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(-
4-chlorophenyl)methanone;
4-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}ben-
zonitrile;
{2-Amino-4-[(4-(3-chlorophenyl)-piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-(2-fluorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone;
{2-Amino-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone;
1-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-2--
(4-chlorophenyl)ethanone;
{2-Amino-4-[(4-(4-chlorobenzoyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone;
{2-Amino-4-[(4-(pyridin-4-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone;
{2-Amino-4-[(4-(benzo[d][1,3]dioxol-5-yl)piperazin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-(3,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone;
2-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-1--
(4-chlorophenyl)ethanone;
{2-Amino-4-[(4-(2,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(3-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-cyclohexylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone;
{2-Amino-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone;
{2-Amino-4-[(4-isopropyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone;
{2-Amino-4-[(4-naphthalen-1-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-(3,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-cyclopentylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloroph-
enyl)methanone;
{2-Amino-4-[(4-cycloheptylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloroph-
enyl)methanone;
{2-Amino-4-[(4-(4-chlorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone;
(2-Amino-4-{[4-(2-(4-chlorophenypethyl)piperazin-1-yl]methyl}th-
iophen-3-yl)(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-fluorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-cyclooctylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone;
(2-Amino-4-{[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]methyl}thiophen-3-
-yl)(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,4-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl-
}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(2-fluoro-4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(3,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,6-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)methyl]thiophen-
-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(pyridin-3-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone;
{2-Amino-4-[(4-(2,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(2,3-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}[3-(trifluoromethyl)phenyl]methanone;
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(tr-
ifluoromethyl)phenyl]methanone;
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-
-(trifluoromethyl)phenyl]methanone;
{2-Amino-4-[(4-(4-chlorophenyl)41,4]diazepan-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone;
{2-Amino-4-[(7-(4-chlorophenyl)-2,7-diaza-spiro[4.4]non-2-yl)methyl]thiop-
hen-3-yl }(4-chlorophenyl)methanone;
{2-Amino-4-[(5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-5-methyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone;
{2-Amino-5-methyl-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-bromophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-iodophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl-
}(4-chlorophenyl)methanone;
{2-Amino-5-methyl-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone;
4-{4-[(5-Amino-4-(4-chlorobenzoyl)-2-methylthiophen-3-yl)methyl]piperazin-
-1-yl}benzonitrile
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl)-5-methylthiophen-3-yl](4-chlo-
rophenyl)methanone;
{2-Amino-4-[(4-(4-methoxyphenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-
-yl}(4- chlorophenyl)methanone;
{2-Amino-5-methyl-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone;
{2-Amino-4-[(4-(3,4-dichlorophenyl)piperazin-1-yl)methyl]-5-methylthiophe-
n-3-yl}(4-chlorophenyl)methanone;
{2-Amino-5-methyl-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(3-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone;
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;
{2-Amino-4-[4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl-
}(4-chlorophenyl)methanone;
[2-Amino-5-ethyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl](4-chlor-
ophenyl)methanone;
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-y-
l}(4-chlorophenyl)methanone; and
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone; or a pharmaceutically acceptable salt
thereof.
20. A method according to claim 1, wherein the pain is neuropathic
pain.
Description
[0001] This application is a division of U.S. application Ser. No.
11/938,465 filed Nov. 12, 2007 which claims the benefit of U.S.
Provisional Application No. 60/858,505 filed Nov. 13, 2006, the
entire contents of both are incorporated herein by reference.
[0002] The present invention relates to 2-aminothiophene
derivatives, pharmaceutical compositions containing them, and to
methods of treating conditions mediated by the A.sub.1 adenosine
receptor including pain, in particular, chronic pain such as
neuropathic pain, cardiac disease or disorder such as cardiac
disarrhythmias, e.g., peroxysmal supraventricular tachycardia,
angina, myocardial infarction and stroke, neurological disease or
injury, sleep disorders, epilepsy and depression, by employing such
compounds.
[0003] Accordingly, the present invention provides compounds of
formula (I)
##STR00002##
wherein [0004] R.sub.1 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl or substituted cycloalkyl; [0005]
R.sub.2, R.sub.3, and R.sub.4 are, independently from each other,
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro,
cyano, alkoxy or substituted alkoxy; [0006] Q is selected from the
group consisting of
##STR00003##
[0006] in which [0007] R.sub.5 is hydrogen, alkyl, substituted
alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heteroaralkyl, substituted
heteroaralkyl, acyl or substituted acyl; [0008] R.sub.6 and R.sub.7
are, independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl
or C.sub.1-C.sub.3 substituted alkyl; or [0009] R.sub.6 and
R.sub.7, provided they are attached to the same carbon atom,
combined are alkylene which together with the carbon atom to which
they are attached form a 3- to 7-membered spirocyclic ring; [0010]
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 are,
independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 substituted alkyl; [0011] X is N; or [0012] X is
C--H; or [0013] X is C--NR.sub.14R.sub.15 wherein R.sub.14 and
R.sub.15 are, independently from each other, hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 substituted alkyl, aryl or
substituted aryl; or [0014] X is C--R.sub.16 wherein R.sub.16 and
R.sub.5 combined are a carbonyl oxygen; or [0015] X is C--R.sub.16
wherein R.sub.16 and R.sub.5 combined are a divalent radical of the
formula
[0015]
.rarw.Y--CHR.sub.17--(CH.sub.2).sub.n--CHR.sub.18--Y.fwdarw.
which together with the carbon atom to which R.sub.16 and R.sub.5
are attached form a 5- to 7-membered spirocyclic ring, and in which
[0016] Y is oxygen or sulfur; [0017] R.sub.17 and R.sub.18 are,
independently from each other, hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl or substituted aryl; n is zero, or an integer of 1
or 2; or [0018] X is C--R.sub.16 wherein R.sub.16 and R.sub.5
combined are a divalent radical of the formula
##STR00004##
[0018] which together with the carbon atom to which R.sub.16 and
R.sub.5 are attached form a 5-membered spirocyclic ring, and in
which [0019] Y is oxygen or sulfur; [0020] R.sub.19 and R.sub.20
are, independently from each other, hydrogen, halogen, cyano,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl or C.sub.1-C.sub.6 alkoxy; or a pharmaceutically acceptable
salt thereof.
[0021] The compounds of the present invention provide
pharmacological agents which are allosteric modulators of the
A.sub.1 adenosine receptor and, thus, may be employed for the
treatment of conditions mediated by the A.sub.1 adenosine receptor.
Accordingly, the compounds of formula (I) may be employed for the
treatment of pain, in particular, chronic pain such as neuropathic
pain, cardiac disease or disorder such as cardiac disarrhythmias,
e.g., peroxysmal supraventricular tachycardia, angina, myocardial
infarction and stroke, neurological disease or injury, sleep
disorders, epilepsy and depression.
[0022] Listed below are definitions of various terms used to
describe the compounds of the present invention. These definitions
apply to the terms as they are used throughout the specification
unless they are otherwise limited in specific instances either
individually or as part of a larger group, e.g., wherein an
attachment point of a certain group is limited to a specific atom
within that group, the point of attachment is defined by an arrow
at the specific atom.
[0023] The term "alkyl" refers to a hydrocarbon chain having 1-20
carbon atoms, preferably 1-10 carbon atoms, and more preferably 1-7
carbon atoms. The hydrocarbon chain may be straight, as for a hexyl
or n-butyl chain, or branched, as for example t-butyl,
2-methyl-pentyl, 3-propyl-heptyl. Exemplary alkyl groups include
methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,
pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, and the
like.
[0024] The term "substituted alkyl" refers to those alkyl groups as
described above substituted by one or more, preferably 1-3, of the
following groups: halo, hydroxy, alkanoyl, alkoxy, cycloalkyl,
cycloalkoxy, alkanoyloxy, thiol, alkylthio, alkylthiono, sulfonyl,
sulfamoyl, carbamoyl, cyano, carboxy, acyl, aryl, aryloxy, alkenyl,
alkynyl, aralkoxy, guanidino, optionally substituted amino,
heterocyclyl including imidazolyl, furyl, thienyl, thiazolyl,
pyrrolidyl, pyridyl, pyrimidyl and the like.
[0025] The term "lower alkyl" refers to those alkyl groups as
described above having 1-6, preferably 1-4 carbon atoms.
[0026] The term "alkenyl" refers to any of the above alkyl groups
having at least two carbon atoms and further containing a
carbon-to-carbon double bond at the point of attachment. Groups
having 2-6 carbon atoms are preferred.
[0027] The term "alkynyl" refers to any of the above alkyl groups
having at least two carbon atoms and further containing a
carbon-to-carbon triple bond at the point of attachment. Groups
having 2-6 carbon atoms are preferred.
[0028] The term "alkylene" refers to a straight-chain bridge of 1-6
carbon atoms connected by single bonds, e.g., --(CH.sub.2).sub.x--,
wherein x is 1-6, in those cases where x is greater than 1, the
chain may be interrupted with one or more groups selected from O,
S, S(O), S(O).sub.2, CH.dbd.CH, C.ident.C or NR, wherein R may be
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl,
aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl,
aryloxycarbonyl or aralkoxycarbonyl and the like; and the alkylene
may further be substituted with one or more substituents selected
from optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl,
oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the
like.
[0029] The term "cycloalkyl" refers to monocyclic, bicyclic or
tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which
may contain one or more carbon-to-carbon double bonds.
[0030] The term "substituted cycloalkyl" refers to those cycloalkyl
groups as described above substituted by one or more substituents,
preferably 1-3, such as alkyl, halo, oxo, hydroxy, alkoxy,
alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol,
alkylthio, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido,
sulfamoyl, heterocyclyl and the like.
[0031] Exemplary monocyclic hydrocarbon groups include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, 4,4-dimethylcyclohex-1-yl, cyclooctenyl
and the like.
[0032] Exemplary bicyclic hydrocarbon groups include bornyl, indyl,
hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,
6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the
like.
[0033] Exemplary tricyclic hydrocarbon groups include adamantyl and
the like.
[0034] In the definitions listed herein, when a reference to an
alkyl, cycloalkyl, alkenyl or alkynyl group is made as part of the
term, a substituted alkyl, cycloalkyl, alkenyl or alkynyl group is
also intended.
[0035] The term "alkoxy" refers to alkyl-O'.
[0036] The term "cycloalkoxy" refers to cycloalkyl-O--.
[0037] The term "alkanoyl" refers to alkyl-C(O)--.
[0038] The term "cycloalkanoyl" refers to cycloalkyl-C(O)--.
[0039] The term "alkenoyl" refers to alkenyl-C(O)--.
[0040] The term "alkynoyl" refers to alkynyl-C(O)--.
[0041] The term "alkanoyloxy" refers to alkyl-C(O)--O--.
[0042] The terms "alkylamino" and "dialkylamino" refer to
alkyl-NH-- and (alkyl).sub.2N--, respectively.
[0043] The term "alkanoylamino" refers to alkyl-C(O)--NH--.
[0044] The term "alkylthio" refers to alkyl-S--.
[0045] The term "trialkylsilyl" refers to (alkyl).sub.3Si--.
[0046] The term "trialkylsilyloxy" refers to
(alkyl).sub.3SiO--.
[0047] The term "alkylthiono" refers to alkyl-S(O)--.
[0048] The term "alkylsulfonyl" refers to alkyl-S(O).sub.2--.
[0049] The term "alkoxycarbonyl" refers to alkyl-O--C(O)--.
[0050] The term "alkoxycarbonyloxy" refers to alkyl-O--C(O)O--.
[0051] The term "carbamoyl" refers to H.sub.2NC(O)--,
alkyl-NHC(O)--, (alkyl).sub.2NC(O)--, aryl-NHC(O)--,
alkyl(aryl)-NC(O)--, heteroaryl-NHC(O)--,
alkyl(heteroaryl)--NC(O)--, aralkyl-NHC(O)--,
alkyl(aralkyl)-NC(O)-- and the like.
[0052] The term "sulfamoyl" refers to H.sub.2NS(O).sub.2--,
alkyl-NHS(O).sub.2--, (alkyl).sub.2NS(O).sub.2--,
aryl-NHS(O).sub.2--, alkyl(aryl)-NS(O).sub.2--,
(aryl).sub.2NS(O).sub.2--, heteroaryl-NHS(O).sub.2--,
aralkyl-NHS(O).sub.2--, heteroaralkyl-NHS(O).sub.2-- and the
like.
[0053] The term "sulfonamido" refers to alkyl-S(O).sub.2--NH--,
aryl-S(O).sub.2--NH--, aralkyl-S(O).sub.2--NH--,
heteroaryl-S(O).sub.2--NH--, heteroaralkyl-S(O).sub.2--NH--,
alkyl-S(O).sub.2--N(alkyl)-, aryl-S(O).sub.2--N(alkyl)-,
aralkyl-S(O).sub.2--N(alkyl)-, heteroaryl-S(O).sub.2--N(alkyl)-,
heteroaralkyl-S(O).sub.2--N(alkyl)- and the like.
[0054] The term "sulfonyl" refers to alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the
like.
[0055] The term "optionally substituted amino" refers to a primary
or secondary amino group which may optionally be substituted by a
substituent such as acyl, sulfonyl, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the
like.
[0056] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-12 carbon atoms in the ring portion,
such as phenyl, biphenyl, naphthyl, 2,3-dihydro-1H-indenyl and
tetrahydronaphthyl.
[0057] The term "substituted aryl" refers to those aryl groups as
described above substituted by 1-4 substituents in each ring
portion, such as alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy,
alkoxy, methylenedioxy, acyl, alkanoyloxy, aryloxy, optionally
substituted amino, thiol, alkylthio, arylthio, nitro, cyano,
carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl,
sulfonamido, heterocyclyl and the like.
[0058] The term "monocyclic aryl" refers to optionally substituted
phenyl as described above under aryl. Preferably, the monocyclic
aryl is substituted by 1-3 substituents selected from the group
consisting of halogen, cyano or trifluoromethyl.
[0059] In the definitions listed herein, when a reference to an
aryl group is made as part of the term, a substituted aryl group is
also intended.
[0060] The term "aralkyl" refers to an aryl group bonded directly
through an alkyl group, such as benzyl.
[0061] The term "aralkanoyl" refers to aralkyl-C(O)--.
[0062] The term "aralkylthio" refers to aralkyl-S--.
[0063] The term "aralkoxy" refers to an aryl group bonded directly
through an alkoxy group.
[0064] The term "arylsulfonyl" refers to aryl-S(O).sub.2--.
[0065] The term "arylthio" refers to aryl-S--.
[0066] The term "aroyl" refers to aryl-C(O)--.
[0067] The term "aroyloxy" refers to aryl-C(O)--O--.
[0068] The term "aroylamino" refers to aryl-C(O)--NH--.
[0069] The term "aryloxycarbonyl" refers to aryl-O--C(O)--.
[0070] The term "heterocyclyl" or "heterocyclo" refers to fully
saturated or unsaturated, aromatic or nonaromatic cyclic group,
e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered
bicyclic or 10- to 15-membered tricyclic ring system, which has at
least one heteroatom in at least one carbon atom-containing ring.
Each ring of the heterocyclic group containing a heteroatom may
have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen
atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms
may also optionally be oxidized. The heterocyclic group may be
attached at a heteroatom or a carbon atom.
[0071] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl,
oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl,
thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl,
tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl (pyridyl),
pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl
and the like.
[0072] Exemplary bicyclic heterocyclic groups include indolyl,
dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl,
benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl,
tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl,
tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl
or furo[2,3-b]pyridinyl), dihydroisoindolyl,
1,3-dioxo-1,3dihydroisoindol-2-yl, dihydroquinazolinyl (such as
3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.
[0073] Exemplary tricyclic heterocyclic groups include carbazolyl,
dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,
acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl,
xanthenyl, carbolinyl and the like.
[0074] The term "substituted heterocyclyl" refers to those
heterocyclic groups described above substituted with 1, 2 or 3
substituents selected from the group consisting of the following:
[0075] (a) alkyl; [0076] (b) hydroxyl (or protected hydroxyl);
[0077] (c) halo; [0078] (d) oxo, i.e., .dbd.O; [0079] (e)
optionally substituted amino; [0080] (f) alkoxy; [0081] (g)
cycloalkyl; [0082] (h) carboxy; [0083] (i) heterocyclooxy; [0084]
(j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;
[0085] (k) thiol; [0086] (l) nitro; [0087] (m) cyano; [0088] (n)
sulfamoyl; [0089] (o) alkanoyloxy; [0090] (p) aroyloxy; [0091] (q)
arylthio; [0092] (r) aryloxy; [0093] (s) alkylthio; [0094] (t)
formyl; [0095] (u) carbamoyl; [0096] (v) aralkyl; and [0097] (w)
aryl optionally substituted with alkyl, cycloalkyl, alkoxy,
hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.
[0098] The term "heterocyclooxy" denotes a heterocyclic group
bonded through an oxygen bridge.
[0099] The term "heterocycloalkyl" refers to nonaromatic
heterocyclic groups as described above.
[0100] The term "heteroaryl" refers to an aromatic heterocycle,
e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like,
optionally substituted by, e.g., halogen, cyano, nitro,
trifluoromethyl, lower alkyl or lower alkoxy.
[0101] The term "heterocycloalkanoyl" refers to
heterocycloalkyl-C(O)--.
[0102] The term "heteroarylsulfonyl" refers to
heteroaryl-S(O).sub.2--.
[0103] The term "heteroaroyl" refers to heteroaryl-C(O)--.
[0104] The term "heteroaroylamino" refers to
heteroaryl-C(O)NH--.
[0105] The term "heteroaralkyl" refers to a heteroaryl group bonded
through an alkyl group.
[0106] The term "heteroaralkanoyl" refers to
heteroaralkyl-C(O)--.
[0107] The term "heteroaralkanoylamino" refers to
heteroaralkyl-C(O)NH--.
[0108] The term "acyl" refers to alkanoyl, cycloalkanoyl, alkenoyl,
alkynoyl, aroyl, heterocycloalkanoyl, heteroaroyl, aralkanoyl,
heteroaralkanoyl and the like.
[0109] The term "substituted acyl" refers to those acyl groups
described above wherein the alkyl, cycloalkyl, alkenyl, alkynyl,
aryl, heterocycloalkyl, heteroaryl, aralkyl or heteroaralkyl group
is substituted as described herein above respectively.
[0110] The term "acylamino" refers to alkanoylamino, aroylamino,
heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the
like.
[0111] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0112] Pharmaceutically acceptable salts of the compounds of the
present invention refer to salts formed with acids, namely acid
addition salts, such as of mineral acids, organic carboxylic acids
and organic sulfonic acids, e.g., hydrochloric acid, maleic acid
and methanesulfonic acid, respectively.
[0113] Similarly, pharmaceutically acceptable salts of the
compounds of the invention refer to salts formed with bases, namely
cationic salts, such as alkali and alkaline earth metal salts,
e.g., sodium, lithium, potassium, calcium and magnesium, as well as
ammonium salts, e.g., ammonium, trimethylammonium, diethylammonium
and tris(hydroxymethyl)-methyl-ammonium salts and salts with amino
acids provided an acidic group constitutes part of the
structure.
[0114] As described herein above, the present invention provides
2-aminothiophene derivatives of formula (I), pharmaceutical
compositions containing them, methods for preparing said compounds,
and methods of treating conditions mediated by the A.sub.1
adenosine receptor including, but not limited to, pain, in
particular, chronic pain such as neuropathic pain; cardiac disease
or disorder such as congestive heart failure, cardiac
disarrhythmias, e.g., peroxysmal supraventricular, tachycardia,
angina, myocardial infarction and stroke, neurological disease or
injury, sleep disorders, epilepsy, depression, and various
inflammatory conditions, by administration of a therapeutically
effective amount of a compound of the present invention, or a
pharmaceutical composition thereof.
[0115] In one aspect, the present invention provides compounds of
formula (I), designated as the A group, wherein [0116] X is N; or a
pharmaceutical composition thereof.
[0117] Preferred are the compounds in the A group, wherein [0118]
R.sub.1 is hydrogen, alkyl, substituted alkyl, aryl or substituted
aryl; or a pharmaceutical composition thereof.
[0119] Further preferred are the compounds in the A group,
designated as the B group, wherein Q is
##STR00005##
in which [0120] R.sub.5 is hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heteroaralkyl, substituted
heteroaralkyl, acyl or substituted acyl; [0121] R.sub.6 and R.sub.7
are, independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl
or C.sub.1-C.sub.3 substituted alkyl; or [0122] R.sub.6 and
R.sub.7, provided they are attached to the same carbon atom,
combined are alkylene which together with the carbon atom to which
they are attached form a 3- to 7-membered spirocyclic ring; [0123]
R.sub.8 and R.sub.9 are, independently from each other, hydrogen,
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 substituted alkyl; or a
pharmaceutically acceptable salt thereof.
[0124] Preferred are the compounds in the B group having formula
(IA)
##STR00006##
wherein [0125] R.sub.1 is hydrogen, alkyl, substituted alkyl, aryl
or substituted aryl; [0126] R.sub.2, R.sub.3, and R.sub.4 are,
independently from each other, hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy;
[0127] R.sub.5 is alkyl, substituted alkyl, aryl, substituted aryl,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or
substituted acyl; [0128] R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are,
independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 substituted alkyl; or a pharmaceutically acceptable
salt thereof.
[0129] Preferred are the compounds of formula (IA), wherein [0130]
R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a pharmaceutically
acceptable salt thereof.
[0131] Preferred are also the compounds of formula (IA), wherein
[0132] R.sub.5 is monocyclic aryl optionally substituted by one to
three substituents selected from the group consisting of halogen,
cyano or trifluoromethyl; or a pharmaceutically acceptable salt
thereof.
[0133] Preferred are also the compounds of formula (IA), designated
as the C group, wherein [0134] R.sub.2 and R.sub.4 are hydrogen; or
a pharmaceutically acceptable salt thereof.
[0135] Preferred are the compounds in the C group, wherein [0136]
R.sub.3 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0137] Preferred are also the compounds of formula (IA), designated
as the D group, wherein [0138] R.sub.2 and R.sub.3 are hydrogen; or
a pharmaceutically acceptable salt thereof.
[0139] Preferred are the compounds in the D group, wherein [0140]
R.sub.4 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0141] Preferred are also the compounds of formula (IA), designated
as the E group, wherein [0142] R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are, independently from each other, hydrogen or
C.sub.1-C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
[0143] Preferred are the compounds in the E group, designated as
the F group, wherein [0144] R.sub.5 is monocyclic aryl optionally
substituted by one to three substituents selected from the group
consisting of halogen, cyano or trifluoromethyl; or a
pharmaceutically acceptable salt thereof.
[0145] Preferred are the compounds in the F group, designated as
the G group, wherein [0146] R.sub.2 and R.sub.4 are hydrogen; or a
pharmaceutically acceptable salt thereof.
[0147] Preferred are the compounds in the G group, wherein [0148]
R.sub.3 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0149] Further preferred are the compounds in the G group, wherein
[0150] R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0151] Preferred are also the compounds in the F group, designated
as the H group, wherein [0152] R.sub.2 and R.sub.3 are hydrogen; or
a pharmaceutically acceptable salt thereof.
[0153] Preferred are the compounds in the H group, wherein [0154]
R.sub.4 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0155] Further preferred are the compounds in the H group, wherein
[0156] R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0157] In another aspect, the present invention provides compounds
of formula (I), designated as the I group, wherein [0158] X is
C--H; or [0159] X is C--NR.sub.14R.sub.15 wherein R.sub.14 and
R.sub.15 are, independently from each other, hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 substituted alkyl, aryl or
substituted aryl; or [0160] X is C--R.sub.16 wherein R.sub.16 and
R.sub.5 combined are a carbonyl oxygen; or [0161] X is C--R.sub.16
wherein R.sub.16 and R.sub.5 combined are a divalent radical of the
formula
[0161]
.rarw.Y--CHR.sub.17--(CH.sub.2).sub.n--CHR.sub.18--Y.fwdarw.
which together with the carbon atom to which R.sub.16 and R.sub.5
are attached form a 5- to 7-membered spirocyclic ring, and in which
[0162] Y is oxygen or sulfur; [0163] R.sub.17 and R.sub.18 are,
independently from each other, hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl or substituted aryl; [0164] n is zero, or an
integer of 1 or 2; or [0165] X is C--R.sub.16 wherein R.sub.16 and
R.sub.5 combined are a divalent radical of the formula
##STR00007##
[0165] which together with the carbon atom to which R.sub.16 and
R.sub.5 are attached form a 5-membered spirocyclic ring, and in
which [0166] Y is oxygen or sulfur; [0167] R.sub.19 and R.sub.20
are, independently from each other, hydrogen, halogen, cyano,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl or C.sub.1-C.sub.6 alkoxy; or a pharmaceutically acceptable
salt thereof.
[0168] Preferred are the compounds in the I group, wherein [0169]
R.sub.1 is hydrogen, alkyl, substituted alkyl, aryl or substituted
aryl; or a pharmaceutical composition thereof.
[0170] Further preferred are the compounds in the I group,
designated as the J group, wherein Q is
##STR00008##
in which [0171] R.sub.5 is hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heteroaralkyl, substituted
heteroaralkyl, acyl or substituted acyl; [0172] R.sub.6 and R.sub.7
are, independently from each other, hydrogen, C.sub.1-C.sub.3 alkyl
or C.sub.1-C.sub.3 substituted alkyl; or [0173] R.sub.6 and
R.sub.7, provided they are attached to the same carbon atom,
combined are alkylene which together with the carbon atom to which
they are attached form a 3- to 7-membered spirocyclic ring; [0174]
X is C--H; or [0175] X is C--NR.sub.14R.sub.15 wherein R.sub.14 and
R.sub.15 are, independently from each other, hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 substituted alkyl, aryl or
substituted aryl; or [0176] X is C--R.sub.16 wherein R.sub.16 and
R.sub.5 combined are a divalent radical of the formula
##STR00009##
[0176] which together with the carbon atom to which R.sub.16 and
R.sub.5 are attached form a 5-membered spirocyclic ring, and in
which [0177] Y is oxygen or sulfur; [0178] R.sub.19 and R.sub.20
are, independently from each other, hydrogen, halogen, cyano,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl or C.sub.1-C.sub.6 alkoxy; or a pharmaceutically acceptable
salt thereof.
[0179] Preferred are the compounds in the J group wherein [0180] X
is C--R.sub.16 wherein R.sub.16 and R.sub.5 combined are a divalent
radical of the formula
##STR00010##
[0180] which together with the carbon atom to which R.sub.16 and
R.sub.5 are attached form a 5-membered spirocyclic ring, and in
which [0181] Y is oxygen; [0182] R.sub.19 and R.sub.20 are,
independently from each other, hydrogen, halogen, cyano,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl or C.sub.1-C.sub.6 alkoxy; or a pharmaceutically acceptable
salt thereof.
[0183] Further preferred are the compounds in the J group having
formula (IB)
##STR00011##
wherein [0184] R.sub.1 is hydrogen, alkyl, substituted alkyl, aryl
or substituted aryl; [0185] R.sub.2, R.sub.3, and R.sub.4 are,
independently from each other, hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy;
[0186] R.sub.8, R.sub.7, R.sub.8 and R.sub.9 are, independently
from each other, hydrogen, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3
substituted alkyl; or [0187] R.sub.19 and R.sub.20 are,
independently from each other, hydrogen, halogen, cyano,
trifluoromethyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl or C.sub.1-C.sub.6 alkoxy; or a pharmaceutically acceptable
salt thereof.
[0188] Preferred are the compounds of formula (IB), wherein [0189]
R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a pharmaceutically
acceptable salt thereof.
[0190] Preferred are also the compounds of formula (IB), wherein
[0191] R.sub.19 and R.sub.20 are, independently from each other,
hydrogen, halogen, cyano, trifluoromethyl or C.sub.1-C.sub.4 alkyl;
or a pharmaceutically acceptable salt thereof.
[0192] Preferred are also the compounds of formula (IB), designated
as the K group, wherein [0193] R.sub.2 and R.sub.4 are hydrogen; or
a pharmaceutically acceptable salt thereof.
[0194] Preferred are the compounds in the K group, wherein [0195]
R.sub.3 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0196] Preferred are also the compounds of formula (IB), designated
as the L group, wherein [0197] R.sub.2 and R.sub.3 are hydrogen; or
a pharmaceutically acceptable salt thereof.
[0198] Preferred are the compounds in the L group, wherein [0199]
R.sub.4 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0200] Preferred are also the compounds of formula (IB), designated
as the M group, wherein [0201] R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are hydrogen; or a pharmaceutically acceptable salt
thereof.
[0202] Preferred are the compounds in the M group, designated as
the N group, wherein [0203] R.sub.19 and R.sub.20 are,
independently from each other, hydrogen, halogen, cyano,
trifluoromethyl or C.sub.1-C.sub.4 alkyl; or a pharmaceutically
acceptable salt thereof.
[0204] Preferred are the compounds in the N group, designated as
the O group, wherein [0205] R.sub.2 and R.sub.4 are hydrogen; or a
pharmaceutically acceptable salt thereof.
[0206] Preferred are the compounds in the O group, wherein [0207]
R.sub.3 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0208] Further preferred are the compounds in the O group, wherein
[0209] R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0210] Preferred are also the compounds in the N group, designated
as the P group, wherein
[0211] R.sub.2 and R.sub.3 are hydrogen;
or a pharmaceutically acceptable salt thereof.
[0212] Preferred are the compounds in the P group, wherein [0213]
R.sub.4 is halogen, cyano or trifluoromethyl; or a pharmaceutically
acceptable salt thereof.
[0214] Further preferred are the compounds in the P group, wherein
[0215] R.sub.1 is hydrogen or C.sub.1-C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0216] The compounds of the invention depending on the nature of
the substituents may possess one or more asymmetric centers. The
resulting diastereoisomers, optical isomers, i.e., enantiomers, and
geometric isomers, and mixtures thereof, are encompassed by the
instant invention.
[0217] Particular embodiments of the invention are: [0218]
{2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone; [0219]
{2-Amino-4-[(4-methylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone; [0220]
{2-Amino-4-[4-((4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0221]
{2-Amino-4-[4-((4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0222]
{2-Amino-4-[4-((4-methoxyphenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone; [0223]
{2-Amino-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl-
)methanone; [0224]
{2-Amino-4-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone; [0225]
{2-Amino-4-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0226]
{2-Amino-4-[(4-(3,4-dichlorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(-
4-chlorophenyl)methanone; [0227]
4-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}ben-
zonitrile; [0228]
{2-Amino-4-[(4-(3-chlorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone; [0229]
{2-Amino-4-[(4-(2-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0230]
{2-Amino-4-[(4-(2-fluorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone; [0231]
{2-Amino-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone; [0232]
1-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-2--
(4-chlorophenyl)ethanone; [0233]
{2-Amino-4-[(4-(4-chlorobenzoyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-ch-
lorophenyl)methanone; [0234]
{2-Amino-4-[(4-(pyridin-4-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone; [0235]
{2-Amino-4-[(4-(benzo[d][1,3]dioxol-5-yl)piperazin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone; [0236]
{2-Amino-4-[(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0237]
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0238]
{2-Amino-4-[(4-(3,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0239]
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone; [0240]
2-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-1--
(4-chlorophenyl)ethanone; [0241]
{2-Amino-4-[(4-(2,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0242]
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0243]
{2-Amino-4-[(4-(3-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone; [0244]
{2-Amino-4-[(4-cyclohexylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone; [0245]
{2-Amino-4-[(4-(4-chlorophenyl)piperidin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0246]
{2-Amino-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone; [0247]
{2-Amino-4-[(4-isopropyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone; [0248]
{2-Amino-4-[(4-naphthalen-1-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0249]
{2-Amino-4-[(4-(3,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0250]
{2-Amino-4-[(4-cyclopentylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloroph-
enyl)methanone; [0251]
{2-Amino-4-[(4-cycloheptylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloroph-
enyl)methanone; [0252]
{2-Amino-4-[(4-(4-chlorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0253]
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone; [0254]
(2-Amino-4-{[4-(2-(4-chlorophenypethyl)piperazin-1-yl]methyl}thiophen-3-y-
l)(4-chlorophenyl)methanone; [0255]
{2-Amino-4-[(4-(4-fluorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0256]
{2-Amino-4-[(4-cyclooctylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone; [0257]
(2-Amino-4-{[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]methyl}thiophen-3-
-yl)(4-chlorophenyl)methanone; [0258]
{2-Amino-4-[(4-(2,4-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl)(4-
-chlorophenyl)methanone; [0259]
{2-Amino-4-[(4-(2,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0260]
{2-Amino-4-[(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone; [0261]
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone; [0262]
{2-Amino-4-[(4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl-
}(4-chlorophenyl)methanone; [0263]
{2-Amino-4-[(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone; [0264]
{2-Amino-4-[(4-(2-fluoro-4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone; [0265]
{2-Amino-4-[(4-(3,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0266]
{2-Amino-4-[(4-(2,6-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0267]
{2-Amino-4-[(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)methyl]thiophen-
-3-yl}(4-chlorophenyl)methanone; [0268]
{2-Amino-4-[(4-(pyridin-3-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone; [0269]
{2-Amino-4-[(4-(2,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0270]
{2-Amino-4-[(4-(2,3-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone; [0271]
{2-Amino-4-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone; [0272]
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}[3-(trifluoromethyl)phenyl]methanone; [0273]
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(tr-
ifluoromethyl)phenyl]methanone; [0274]
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-
-(trifluoromethyl)phenyl]methanone; [0275]
{2-Amino-4-(spiro[benzo[d][1,3]-dioxole-2,4'piperidine]-1'-ylmethyl)thiop-
hen-3-yl}(4-chlorophenyl)methanone; [0276]
{2-Amino-4-(5-tert-butylspiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-y-
lmethyl)thiophen-3-yl}(4-chlorophenyl)methanone; [0277]
{2-Amino-4-(4-fluorospiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-ylmet-
hyl)thiophen-3-yl}(4-chlorophenyl)methanone; [0278]
{2-Amino-4-(4-methylspiro[benzo[d][1,3]-dioxole-2,4'piperidine]-1'-ylmeth-
yl)thiophen-3-yl}(4-chlorophenyl)methanone; [0279]
{2-Amino-4-(5-methylspiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-ylmet-
hyl)thiophen-3-yl}(4-chlorophenyl)methanone; [0280]
{2-Amino-4-[4-((4-chlorophenylamino)piperidin-1-yl)methyl]thiophen-3-yl}(-
4-chlorophenyl)methanone; [0281]
{2-Amino-4-[(4-(4-chlorophenyl)methylamino]piperidin-1-yl)methyl]thiophen-
-3-yl}(4-chlorophenyl)methanone; [0282]
{2-Amino-4-[(4-(4-chlorophenyl)-[1,4]diazepan-1-yl)methyl]thiophen-3-yl}(-
4-chlorophenyl)methanone; [0283]
{2-Amino-4-[(7-(4-chlorophenyl)-2,7-diaza-spiro[4.4]non-2-yl)methyl]thiop-
hen-3-yl}(4-chlorophenyl)methanone; [0284]
{2-Amino-4-[(5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone; [0285]
{2-Amino-4-[(5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone; [0286]
{2-Amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone; [0287]
{2-Amino-5-methyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone; [0288]
{2-Amino-5-methyl-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone; [0289]
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone; [0290]
{2-Amino-4-[(4-(4-bromophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone; [0291]
{2-Amino-4-[(4-(4-iodophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl-
}(4-chlorophenyl)methanone; [0292]
{2-Amino-5-methyl-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone; [0293]
4-{4-[(5-Amino-4-(4-chlorobenzoyl)-2-methylthiophen-3-yl)methyl]piperazin-
-1-yl}benzonitrile [0294]
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl)-5-methylthiophen-3-yl](4-chlo-
rophenyl)methanone; [0295]
{2-Amino-4-[(4-(4-methoxyphenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-
-yl}(4-chlorophenyl)methanone; [0296]
{2-Amino-5-methyl-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; [0297]
{2-Amino-4-[(4-(3,4-dichlorophenyl)piperazin-1-yl)methyl]-5-methylthiophe-
n-3-yl)(4-chlorophenyl)methanone; [0298]
{2-Amino-5-methyl-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
thiophen-3-yl}(4-chlorophenyl)methanone; [0299]
{2-Amino-4-[(4-(3-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone; [0300]
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-
-5-methylthiophen-3-yl}(4-chlorophenyl)methanone; [0301]
{2-Amino-5-phenyl-4-[(piperidin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl-
)methanone; [0302]
{2-Amino-4-[4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl-
}(4-chlorophenyl)methanone; [0303]
{2-Amino-5-ethyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone; [0304]
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-y-
l}(4-chlorophenyl)methanone; and [0305]
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone; or a pharmaceutically acceptable salt
thereof.
[0306] Preferred embodiments of the present invention include, but
are not limited to: [0307]
{2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone; [0308]
{2-Amino-4-[4-((4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone; and [0309]
{2-Amino-4-[4-((4-trifluoromethylphenyl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone; or a pharmaceutically acceptable salt
thereof.
[0310] Compounds of formula (I) may be prepared using methods well
known in the art, or using modifications thereof, e.g., as outlined
below in Scheme 1 for compounds of formula (I), wherein R.sub.1 is
hydrogen.
##STR00012## ##STR00013##
[0311] As exemplified in Scheme 1, compounds of formula (I),
wherein R.sub.1 is hydrogen, and R.sub.2, R.sub.3, R.sub.4 and Q
have a meaning as defined herein above, i.e., compounds of formula
(I'), may be prepared by condensing a compound of formula (II),
wherein R.sub.2, R.sub.3 and R.sub.4 have a meaning as defined
herein above, with 2,5-dimethyl-[1,4]dithiane-2,5-diol of formula
(II') in the presence of a base such as triethylamine (TEA),
diisopropylethylamine (DIEA), morpholine or N-methylmorpholine
(NMM) in an organic solvent such as a lower alcohol, preferably,
ethanol (EtOH), to afford a compound of formula (III), wherein
R.sub.2, R.sub.3 and R.sub.4 have a meaning as defined herein
above.
[0312] Compounds of formula (II) are known, or if they are novel
they may be prepared using methods well known in the art, or
modifications thereof, e.g., as described in U.S. Pat. No.
6,323,214.
[0313] A resulting compound of formula (III) may then be converted
to a compound (IV), wherein R.sub.2, R.sub.3 and R.sub.4 have a
meaning as defined herein above, and the amino group has been
protected as a phthalimido group, under reaction conditions well
known in the art, e.g., by treating a compound of formula (III)
with phthalic anhydride in the presence of an acid, such as acetic
acid, at an elevated temperature.
[0314] A resulting compound of formula (IV) may then be halogenated
at the 5-position of the thiophene ring to afford a compound of
formula (V), wherein R.sub.2, R.sub.3 and R.sub.4 have a meaning as
defined herein above, and Hal.sub.1 represents chloride, bromide or
iodide, using methods well known in the art, e.g., a compound of
formula of formula (IV) may be treated with a halogenating agent
such as N-halosuccinimide, e.g., N-bromosuccinimide, in the
presence of a catalyst such as benzoyl peroxide, and an inert
organic solvent, such as an aromatic hydrocarbon, e.g., benzene, to
afford a compound of formula (V), wherein Hal.sub.1 is, e.g.,
bromide.
[0315] Subsequent reaction of a resulting compound of formula (V)
with a halogenating agent such as N-halosuccinimide, e.g.,
N-bromosuccinimide, in the presence of a catalyst such as benzoyl
peroxide and an organic solvent such as a halogenated hydrocarbon,
e.g., carbontetrachloride or dichloroethane, affords a compound of
formula (VI), wherein R.sub.2, R.sub.3 and R.sub.4 have a meaning
as defined herein above, and Hal.sub.1 and Hal.sub.2 represent,
independently from each other, chloride, bromide or iodide.
[0316] A resulting compound of formula (VI) may then be coupled
with an amine of formula (VI'), wherein Q has a meaning as defined
herein above, in the presence of a base such as TEA, DIEA, NMM, or
potassium or cesium carbonate, and an appropriate organic solvent,
such as dichloromethane (DCM), chloroform (CHCl.sub.3) and
N,N-dimethylformamide (DMF), to afford a compound of formula (VII),
wherein R.sub.2, R.sub.3, R.sub.4, Q and Hal.sub.1 have a meaning
as defined herein above.
[0317] Amines of formula (VI') are known, or if they are novel they
may be prepared using methods well known in the art, or
modifications thereof.
[0318] A resulting compound of formula (VII) may then be
dehalogenated in the presence of a reducing agent, e.g., molecular
hydrogen in the presence of a catalyst such as palladium on carbon,
and an organic solvent, such as ethyl acetate (EtOAc), a lower
alcohol, e.g., EtOH and methanol (MeOH), tetrahydrofuran (THF) or
DMF, to afford a compound of formula (VIII), wherein R.sub.2,
R.sub.3, R.sub.4 and Q have a meaning as defined herein above.
Preferably, the dehalogenation is conducted in the presence of an
extrinsic base, e.g., TEA.
[0319] Finally, a compound of formula (VIII) may be converted to a
compound of formula (I'), wherein R.sub.2, R.sub.3, R.sub.4 and Q
have a meaning as defined herein above, by removal of the
phthalimido protecting group, e.g., by treatment with hydrazine in
an organic solvent such as lower alcohol, e.g., EtOH.
[0320] As exemplified in Scheme 2, compounds of formula (I),
wherein R.sub.1 is alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, aryl or substituted aryl, and R.sub.2,
R.sub.3, R.sub.4, and Q have a meaning as defined herein above may
be prepared by the reaction of a compound of formula (II), wherein
R.sub.2, R.sub.3, and R.sub.4 have a meaning as defined herein
above, with a ketone of formula (IX), wherein R.sub.1 is alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or
substituted aryl, in the presence of elemental sulfur and an
appropriate base, such as TEA, DIEA, morpholine or NMM, preferably
morpholine, in an organic solvent such as a lower alcohol,
preferably EtOH, to afford a compound of formula (III'), wherein
R.sub.1 is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, aryl or substituted aryl, and R.sub.2, R.sub.3, and
R.sub.4 have a meaning as defined herein above.
##STR00014## ##STR00015##
[0321] Alternatively, compounds of formula (II), wherein R.sub.2,
R.sub.3, and R.sub.4 have a meaning as defined herein above, may be
first condensed (Knoevenagel condensation) with a ketone of formula
(IX), wherein R.sub.1 is alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, aryl or substituted aryl, in the presence
of a weak base, such as piperidine, pyrrolidine, morpholine or
.beta.-alanine, and an organic solvent, such as benzene or toluene,
to afford a compound of the formula
##STR00016##
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have a meaning as
defined herein above, as a mixture of the E and Z isomers.
Preferably, the condensation is conducted in the presence of an
organic acid, such as acetic acid, at a temperature near the
boiling point of the solvent. A subsequent treatment of a compound
of formula (IX') with an elemental sulfur and an appropriate base,
such as TEA, DIEA, morpholine or NMM, preferably TEA, in an organic
solvent such as a lower alcohol, preferably EtOH, then affords a
compound of formula (III'), wherein R.sub.1 is alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted
aryl, and R.sub.2, R.sub.3, and R.sub.4 have a meaning as defined
herein above.
[0322] Compounds of formula (IX) are known, or if they are novel
they may be prepared using methods well known in the art, or
modifications thereof.
[0323] A resulting compound of formula (III') may then be converted
to a compound (IV'), wherein R.sub.1 is alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, aryl or substituted aryl, and
R.sub.2, R.sub.3, and R.sub.4 have a meaning as defined herein
above, by treating a compound (III') with phthalic anhydride in the
presence of an acid, such as acetic acid, at an elevated
temperature.
[0324] Alternatively, compounds of formula (IV'), wherein R.sub.1
is aryl or substituted aryl, and R.sub.2, R.sub.3, and R.sub.4 have
a meaning as defined herein above, may be obtained by coupling a
compound of formula (V), wherein Hal.sub.1, R.sub.2, R.sub.3, and
R.sub.4 have a meaning as defined herein above, in the presence of
a catalyst, preferably a palladium catalyst, e.g.,
palladium(II)acetate or tetrakis(triphenylphosphine)palladium(0),
and a base such as sodium hydroxide (NaOH) or sodium, potassium or
cesium carbonate, in an appropriate solvent, e.g., acetonitrile,
DMF, dimethoxyethane (DME) or toluene, or a mixture of solvents
thereof, with a compound of the formula
##STR00017##
wherein R.sub.1 is aryl or substituted aryl, and R' and R'' are
hydrogen or lower alkyl, or R' and R'' combined are alkylene which
together with the boron and the oxygen atoms form a 5- or
6-membered ring, to afford a compound of formula (IV'), wherein
R.sub.1 is aryl or substituted aryl. Preferably, R' and R'' are
hydrogen, and the above coupling reaction, i.e., Suzuki reaction,
is conducted in toluene in the presence of
tetrakis(triphenylphosphine)palladium(0), and potassium carbonate
(K.sub.2CO.sub.3) at a temperature close to the boiling point of
the solvent.
[0325] Compounds of formula (V') are known, or if they are novel
they may be prepared using methods well known in the art, or
modifications thereof.
[0326] A resulting compound of formula (IV') may then be
halogenated on the methyl group at the 4-position of the thiophene
ring to afford a compound of formula (X), wherein R.sub.1 is alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or
substituted aryl, R.sub.2, R.sub.3, and R.sub.4 have a meaning as
defined herein above, and Hal.sub.e represents chloride, bromide or
iodide, using methods well known in the art, e.g., by the reaction
of a compound of formula (IV') with a halogenating agent, such as
an N-halosuccinimide, e.g. N-bromosuccinimide, in the presence of a
catalyst such as benzoyl peroxide, and an organic solvent, such as
acetonitrile (ACN) or a halogenated hydrocarbon, e.g., carbon
tetrachloride or dichloroethane. It should be noted that the
halogenation of the methyl group at the 4-position of the thiophene
ring of compounds of formula (VI') may be conducted in the absence
of a catalyst when ACN is employed as the solvent.
[0327] A resulting compound of formula (X) may then be coupled with
an amine of formula (VI'), wherein Q has a meaning as defined
herein above, in the presence of a base such as TEA, DIEA, NMM, or
potassium or cesium carbonate, and an appropriate organic solvent
such as DCM, CHCl.sub.3 and DMF, to afford a compound of formula
(XI), wherein R.sub.1 is alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, aryl or substituted aryl, and R.sub.2,
R.sub.3, R.sub.4, Q have a meaning as defined herein above.
[0328] Finally, a compound of formula (XI) may be converted to a
compound of formula (I), wherein R.sub.1 is alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted
aryl, and R.sub.2, R.sub.3, R.sub.4 and Q have a meaning as defined
herein above, by removal of the phthalimido protecting group as
described herein above.
[0329] The processes described herein above may be conducted under
inert atmosphere, preferably under nitrogen or argon
atmosphere.
[0330] In starting compounds and intermediates which are converted
to the compounds of the present invention in a manner described
herein, functional groups present, such as amino, thiol, carboxyl
and hydroxyl groups, are optionally protected by conventional
protecting groups that are common in preparative organic chemistry.
Protected amino, thiol, carboxyl and hydroxyl groups are those that
can be converted under mild conditions into free amino thiol,
carboxyl and hydroxyl groups without the molecular framework being
destroyed or other undesired side reactions taking place.
[0331] The purpose of introducing protecting groups is to protect
the functional groups from undesired reactions with reaction
components under the conditions used for carrying out a desired
chemical transformation. The need and choice of protecting groups
for a particular reaction is known to those skilled in the art and
depends on the nature of the functional group to be protected
(hydroxyl group, amino group, etc.), the structure and stability of
the molecule of which the substituent is a part and the reaction
conditions.
[0332] Well-known protecting groups that meet these conditions and
their introduction and removal are described, e.g., in McOmie,
"Protective Groups in Organic Chemistry", Plenum Press, London,
N.Y. (1973); and Greene and Wuts, "Protective Groups in Organic
Synthesis", John Wiley and Sons, Inc., NY (1999).
[0333] The above-mentioned reactions are carried out according to
standard methods, in the presence or absence of diluent,
preferably, such as are inert to the reagents and are solvents
thereof, of catalysts, condensing or said other agents,
respectively and/or inert atmospheres, at low temperatures, room
temperature (RT) or elevated temperatures, preferably at or near
the boiling point of the solvents used, and at atmospheric or
super-atmospheric pressure. The preferred solvents, catalysts and
reaction conditions are set forth in the appended illustrative
Examples.
[0334] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the reaction components are used in the
form of their salts.
[0335] Compounds of the invention and intermediates can also be
converted into each other according to methods generally known per
se.
[0336] The present invention also relates to any novel starting
materials, intermediates and processes for their manufacture.
[0337] Depending on the choice of starting materials and methods,
the new compounds may be in the form of one of the possible isomers
or mixtures thereof, for example, as substantially pure geometric
(cis or trans) isomers, diastereomers, optical isomers, racemates
or mixtures thereof. The aforesaid possible isomers or mixtures
thereof are within the purview of the present invention.
[0338] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure geometric or optical isomers, diastereomers, for example,
by fractional crystallization and/or chromatography, e.g., by high
pressure liquid chromatography (HPLC) using a chiral adsorbent.
[0339] Finally, compounds of the invention are either obtained in
the free form, or in a salt form thereof, preferably, in a
pharmaceutically acceptable salt form thereof.
[0340] In particular, compounds of the invention which contain
basic groups may be converted into acid addition salts, especially
pharmaceutically acceptable acid addition salts. These are formed,
e.g., with inorganic acids, such as mineral acids, e.g., sulfuric
acid, phosphoric or hydrohalic acid, or with organic carboxylic
acids, such as (C.sub.1-C.sub.4)-alkanecarboxylic acids which,
e.g., are unsubstituted or substituted by halogen, e.g., acetic
acid, such as saturated or unsaturated dicarboxylic acids, e.g.,
oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic
acids, e.g., glycolic, lactic, malic, tartaric or citric acid, such
as amino acids, e.g., aspartic or glutamic acid, or with organic
sulfonic acids, such as (C.sub.1-C.sub.4)-alkylsulfonic acids,
e.g., methanesulfonic acid; or arylsulfonic acids which are
unsubstituted or substituted (for example by halogen). Preferred
are salts formed with hydrochloric acid, maleic acid and
methanesulfonic acid. Salts may be formed using conventional
methods, advantageously in the presence of an ethereal or alcoholic
solvent, such as a lower alkohol. From the solutions of the latter,
the salts may be precipitated with ethers, e.g., with diethyl ether
or petroleum ether. Resulting salts may be converted into the free
compounds by treatment with a suitable base, e.g., sodium
hydroxide. These or other salts can also be used for the
purification of the compounds obtained.
[0341] In view of the close relationship between the free compounds
and the compounds in the form of their salts, whenever a compound
is referred to a corresponding salt is also intended, provided such
is possible or appropriate under the circumstances.
[0342] The compounds, including their salts, can also be obtained
in the form of their hydrates, or include other solvents used for
their crystallization.
[0343] As described herein above, the compounds of the present
invention are allosteric modulators of the A.sub.1 adenosine
receptor. Thus, the present invention provides a method for the
modulation of the A.sub.1 adenosine receptor in mammals which
method comprises administering to a mammal in need thereof a
therapeutically effective amount of a compound of formula (I).
[0344] Furthermore, compounds of formula (I) may be employed for
the treatment of conditions mediated by the A.sub.l adenosine
receptor. Such compounds may, thus, be employed therapeutically for
the treatment of pain, in particular, chronic pain such as
neuropathic pain, cardiac disease or disorder such as cardiac
disarrhythmias, e.g., peroxysmal supraventricular tachycardia,
angina, myocardial infarction and stroke, neurological disease or
injury, sleep disorders, epilepsy and depression.
[0345] In other words, the present invention provides a method for
the treatment of conditions mediated by the A.sub.1 adenosine
receptor, which comprises administering to a mammal in need thereof
a therapeutically effective amount of a compound of the present
invention.
[0346] As used throughout the specification and in the claims, the
term "treatment" embraces all the different forms or modes of
treatment as known to those of the pertinent art and, in
particular, includes preventive, curative, delay of progression and
palliative treatment.
[0347] The term "therapeutically effective amount" as used herein
refers to an amount of a drug or a therapeutic agent that will
elicit the desired biological or medical response of a tissue,
system or an animal (including man) that is being sought by a
researcher or clinician.
[0348] The term "mammal" or "patient" are used interchangeably
herein and include, but are not limited to, humans, dogs, cats,
horses, pigs, cows, monkeys, rabbits, mice and laboratory animals.
The preferred mammals are humans.
[0349] Preferably, the methods of the present invention are
directed to the treatment of pain, including pain management
generally, and particularly treatment and management of chronic
pain, especially neuropathic pain. Neuropathic pain has been
recognized as pain resulting from some type of pathological damage
to or condition relating to the nervous system. Various types of
neuropathic pain may be treated in accordance with the present
invention, e.g., diabetic neuropathy and post herpetic neuralgia.
Additional pathological conditions that can give rise to
neuropathic pain that may be treated in accordance with the present
invention include trigeminal neuralgia, AIDS associated
neuropathies due to HIV infection and/or treatment, pain associated
with cancer treatment, whip-lash pain, phantom limb pain, traumatic
injury pain, complex regional pain syndrome, and pain due to
peripheral vascular disease. Furthermore, methods of the present
invention will be useful for the management and treatment of post
surgical pain.
[0350] Preferred methods of the invention also include treatment of
cardiac disease or disorder, and ischemia induced injuries, e.g.,
cardiac disarrhythmias, angina, myocardial infarction, stroke, and
the like. Typical subjects for such treatments include, e.g.,
myocardial infarction, stroke, brain or spinal injury patients,
patients undergoing major surgery such as heart surgery where brain
ischemia is a potential complication, and the like.
[0351] Likewise, the present invention provides a method as defined
above comprising co-administration, e.g., concomitantly or in
sequence, of a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, and a
second drug substance, said second drug substance being a
hypolipidemic agent, an anti-inflammatory agent, an
anti-hypertensive agent or an opioid analgesic agent, e.g., as
indicated herein below.
[0352] The present invention further provides pharmaceutical
compositions comprising a therapeutically effective amount of a
compound of the present invention, alone or in combination with one
or more pharmaceutically acceptable carriers.
[0353] In carrying out the methods of the present invention, the
allosteric adenosine A.sub.1 receptor enhancers of the present
invention may be formulated into pharmaceutical compositions
suitable for administration via a variety of routes, e.g., enteral
such as oral or rectal, transdermal, intrathecal and parenteral
administration to mammals, including man, for the treatment of
conditions mediated by the A.sub.1 adenosine receptor. Such
conditions include, but are not limited to, pain, in particular,
chronic pain such as neuropathic pain, cardiac disease or disorder
such as cardiac disarrhythmias, e.g., peroxysmal supraventricular
tachycardia, angina, myocardial infarction and stroke, neurological
disease or injury, sleep disorders, epilepsy and depression.
[0354] For oral administration the pharmaceutical composition
comprising an allosteric adenosine A.sub.1 receptor enhancer, or a
pharmaceutically acceptable salt thereof, can take the form of
solutions, suspensions, tablets, pills, capsules, powders,
microemulsions, unit dose packets and the like.
[0355] Thus, the compounds of the present invention may be employed
in the manufacture of pharmaceutical compositions comprising an
effective amount thereof in conjunction or admixture with
excipients or carriers suitable for administration via a variety of
routes, in particular, for enteral or parenteral application.
Preferred are tablets and hard or soft shell gelatin capsules
comprising the active ingredient together with: [0356] a) diluents,
e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,
glycine and/or vegetable oils; [0357] b) lubricants, e.g., silica,
talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; for tablets also [0358] c) binders, e.g.,
magnesium aluminum silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; and if desired [0359] d) disintegrants, e.g.,
starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and/or [0360] e) absorbants, colorants, flavors and
sweeteners.
[0361] Injectable compositions are preferably aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions.
[0362] Said compositions may be sterilized and/or contain
adjuvants, such as preserving, stabilizing, wetting or emulsifying
agents, solution promoters, salts for regulating the osmotic
pressure and/or buffers. In addition, they may also contain other
therapeutically valuable substances. Said compositions are prepared
according to conventional mixing, granulating or coating methods,
respectively, and contain about 0.1-75%, preferably about 1-50%, of
the active ingredient.
[0363] Suitable formulations for transdermal application include a
therapeutically effective amount of a compound of the invention
with carrier. Advantageous carriers include absorbable
pharmacologically acceptable solvents to assist passage through the
skin of the host. Characteristically, transdermal devices are in
the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0364] A unit dosage for a mammal of about 50-70 kg may contain
between about 0.005 mg and 2000 mg, advantageously between about
1-1000 mg of the active ingredient. The therapeutically effective
dosage of active compound is dependent on the species of
warm-blooded animal (mammal), the body weight, age and individual
condition, on the form of administration, and on the compound
involved.
[0365] Accordingly, the present invention provides pharmaceutical
compositions as described above for the treatment of conditions
mediated by the A.sub.1 adenosine receptor including pain, in
particular, chronic pain such as neuropathic pain, cardiac disease
or disorder such as cardiac disarrhythmias, e.g., peroxysmal
supraventricular tachycardia, angina, myocardial infarction and
stroke, neurological disease or injury, sleep disorders, epilepsy
and depression.
[0366] The pharmaceutical compositions may contain a
therapeutically effective amount of a compound of the invention as
defined above, either alone or in a combination with another
therapeutic agent, e.g., each at an effective therapeutic dose as
reported in the art. Such therapeutic agents include: [0367] a)
hypolipidemic agents such as HMG-CoA (3-hydroxy-3-methyl-glutaryl
coenzyme A) reductase inhibitors, squalene synthase inhibitors, FXR
(farnesoid X receptor) and LXR (liver X receptor) ligands,
cholestyramine, fibrates, nicotinic acid and aspirin; [0368] b)
anti-inflammatory agents; [0369] c) anti-hypertensive agents, e.g.,
loop diuretics, ACE (angiotensin converting enzyme) inhibitors,
inhibitors of the Na-K-ATPase membrane pump, NEP (neutral
endopeptidase) inhibitors, ACE/NEP inhibitors, angiotensin II
antagonists, renin inhibitors, .beta.-adrenergic receptor blockers,
inotropic agents, calcium channel blockers, aldosterone receptor
antagonists, and aldosterone synthase inhibitors; and [0370] d)
opioid analgesic agents.
[0371] As described above, a compound of the present invention may
be administered either simultaneously, before or after the other
active ingredient, either separately by the same or different route
of administration or together in the same pharmaceutical
formulation.
[0372] The structure of the therapeutic agents known by their
generic or trade names may be taken, e.g., from the actual edition
of the standard compendium "The Merck Index" or from databases,
e.g., Patents International (e.g. IMS World Publications). Any
person skilled in the art is fully enabled to identify the active
agents and, based on these references, likewise enabled to
manufacture and test the pharmaceutical indications and properties
in standard test models, both in vitro and in vivo.
[0373] Accordingly, the present invention provides pharmaceutical
compositions comprising a therapeutically effective amount of a
compound of the invention in combination with another therapeutic
agent, preferably selected from hypolipidemic agents,
anti-inflammatory agents, anti-hypertensive agents and opioid
analgesic agents.
[0374] Since the present invention has an aspect that relates to
treatment with a combination of compounds which may be
co-administered separately, the invention also relates to combining
separate pharmaceutical compositions in kit form. The kit comprises
two separate pharmaceutical compositions: (1) a composition
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, plus a pharmaceutically acceptable carrier
or diluent; and (2) a composition comprising a hypolipidemic agent,
an anti-inflammatory agent, an anti-hypertensive agent, or an
opioid analgesic agent, or a pharmaceutically acceptable salt
thereof, plus a pharmaceutically acceptable carrier or diluent. The
amounts of (1) and (2) are such that, when co-administered
separately, a beneficial therapeutic effect(s) is achieved. The kit
comprises a container for containing the separate compositions such
as a divided bottle or a divided foil packet, wherein each
compartment contains a plurality of dosage forms (e.g., tablets)
comprising (1) or (2). Alternatively, rather than separating the
active ingredient-containing dosage forms, the kit may contain
separate compartments each of which contains a whole dosage which
in turn comprises separate dosage forms. An example of this type of
kit is a blister pack wherein each individual blister contains two
(or more) tablets, one (or more) tablet(s) comprising a
pharmaceutical composition (1), and the second (or more) tablet(s)
comprising a pharmaceutical composition (2). Typically the kit
comprises directions for the administration of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing physician. In the
case of the present invention a kit therefore comprises: [0375] (1)
a therapeutically effective amount of a composition comprising a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier or diluent, in a
first dosage form; [0376] (2) a composition comprising a
hypolipidemic agent, an anti-inflammatory agent, an
anti-hypertensive agent, or an opioid analgesic agent, or a
pharmaceutically acceptable salt thereof, in an amount such that,
following administration, a beneficial therapeutic effect(s) is
achieved, and a pharmaceutically acceptable carrier or diluent, in
a second dosage form; and [0377] (3) a container for containing
said first and second dosage forms.
[0378] The present invention further relates to pharmaceutical
compositions as described above for use as a medicament.
[0379] The present invention further relates to use of
pharmaceutical compositions or combinations as described above for
the preparation of a medicament for the treatment of conditions
mediated by the A.sub.1 adenosine receptor including pain, in
particular, chronic pain such as neuropathic pain, cardiac disease
or disorder such as cardiac disarrhythmias, e.g., peroxysmal
supraventricular tachycardia, angina, myocardial infarction and
stroke, neurological disease or injury, sleep disorders, epilepsy
and depression.
[0380] Thus, the present invention also relates to a compound of
formula (I) for use as a medicament, to the use of a compound of
formula (I) for the preparation of a pharmaceutical composition for
the treatment of conditions mediated by the A.sub.1 adenosine
receptor, and to a pharmaceutical composition for use in conditions
mediated by the A.sub.1 adenosine receptor comprising a compound of
formula (I), or a pharmaceutically acceptable salt thereof, in
association with a pharmaceutically acceptable diluent or carrier
therefore.
[0381] Finally, the present invention provides a method or use
which comprises administering a compound of formula (I) in
combination with a therapeutically effective amount of a
hypolipidemic agent, an anti-inflammatory agent, an
anti-hypertensive agent or an opioid analgesic agent.
[0382] Ultimately, the present invention provides a method or use
which comprises administering a compound of formula (I) in the form
of a pharmaceutical composition as described herein.
[0383] The above-cited properties are demonstrable in vitro and in
vivo tests using advantageously mammals, e.g., mice, rats, dogs,
monkeys or isolated organs, tissues and preparations thereof. Said
compounds can be applied in vitro in the form of solutions, e.g.,
preferably aqueous solutions, and in vivo either enterally,
parenterally, advantageously intrathecal or intravenously, e.g., as
a suspension or in aqueous solution. The dosage in vitro may range
between about 10.sup.-2 molar and 10.sup.-10 molar concentrations.
A therapeutically effective amount in vivo may range depending on
the route of administration, between about 0.000001 mg/kg and 1000
mg/kg, preferably between about 0.00001 mg/kg and 100 mg/kg, more
preferably between about 0.001 mg/kg and 10 mg/kg.
[0384] The activity of compounds according to the invention may be
assessed using methods well-described in the art, e.g., as
described herein below:
Membrane Preparation from CHO Cells Transfected with the Human
Recombinant A.sub.1, A.sub.2A and A.sub.3 Adenosine Receptors:
[0385] The hCHO-A.sub.1, hCHO-A.sub.2A and hCHO-A.sub.3 cell clones
are grown adherently and maintained in Dulbecco's modified Eagle's
medium with nutrient mixture F12, containing 10% fetal calf serum,
penicillin (100 U/mL), streptomycin (100 .mu.g/mL), L-glutamine (2
mM), geneticine (G418, 0.2 mg/mL) at 37.degree. C. in 5%
CO.sub.2/95% air for 30 min (Klotz et al. Naunyn-Schmied. Arch
Pharm. 1998, 357, 1-9). Cells are split two or three times weekly
at a ratio of between 1:5 and 1:10. For membrane preparation the
culture medium is removed. The cells are washed with PBS and
scraped off T75 flasks in ice-cold hypotonic buffer (5 mM Tris HCl,
2 mM EDTA, pH 7.4). The cell suspension is homogenized with
Polytron and the homogenate is spun for 10 min at 1,000.times.g.
The supernatant is then centrifuged for 30 min at 100,000.times.g.
The membrane pellet is resuspended in 50 mM Tris HCl buffer pH 7.4
for A.sub.1 adenosine receptors, 50 mM Tris HCl buffer pH 7.4, 10
mM MgCl.sub.2 for A.sub.2A adenosine receptors, 50 mM Tris HCl
buffer pH 7.4, 10 mM MgCl.sub.2, 1 mM EDTA for A.sub.3 adenosine
receptors and incubated with 3 UI/mL of adenosine deaminase for 30
min at 37.degree. C. The protein concentration is determined
according to a Bio-Rad method (Bradford, 1976) with bovine albumin
as a standard reference.
Adenosine Receptor Binding Experiments:
[0386] To determine the effect of the compounds of the present
invention on the binding to A.sub.1, A.sub.2A and A.sub.3
receptors, membranes from hCHO-A.sub.1, hCHO-A.sub.2A, hCHO-A.sub.3
are incubated in a buffer solution in the absence and in the
presence of the examined compounds. Test agents are dissolved in
DMSO and added to the assay from a 100-fold concentrated solution
in DMSO. Control incubations also contain 1% DMSO. Bound and free
radioactivity are separated by filtering the assay mixture through
Whatman GF/B glass fibre filters using a Micro-mate 196 cell
harvester (Packard Instrument Company). The filter bound
radioactivity was counted on Top Count Microplate Scintillation
Counter (efficacy 57%) with Micro-Scint 20.
Saturation Binding of [.sup.3H]CCPA to hCHO-A.sub.1:
[0387] Saturation binding experiments of [.sup.3H]CCPA (0.05 to 20
nM) to human A.sub.1 receptors expressed in CHO membranes are
performed in triplicate at 25.degree. C. for 1 h in 50 mM Tris-HCl,
pH 7.4, in the absence and presence of the tested compounds (10
.mu.M). Non specific binding is defined as binding in the presence
of 1 .mu.M R-PIA.
Competition Binding of [.sup.3H]CCPA to hCHO-A.sub.1:
[0388] Competition experiments are carried out in triplicate in a
final volume of 250 .mu.L in test tubes containing 1 nM
[.sup.3H]CCPA, 50 mM Tris-HCl, pH 7.4 and 100 .mu.L of diluted
membranes and at least six to eight different concentrations of the
tested compounds in the range from 1 nM to 50 .mu.M for 90 min at
25.degree. C. (Baraldi et al. J. Med. Chem. 2003, 46, 794-809). Non
specific binding is defined as binding in the presence of 1 .mu.M
R-PIA. Allosteric enhancement is measured as the action of
different concentrations of the tested compounds to increase the
specific binding of 1 nM [.sup.3H]CCPA to hCHO-A.sub.1
membranes.
Competition Binding Experiments:
[0389] Competition experiments of 1 nM [.sup.3H]DPCPX (Borea et al.
Life Sciences 1996, 59, 1373-1388), 2 nM [.sup.3H]ZM 241385 (Borea
et al. Biochem. Pharmacol. 1995, 49, 461-469) and 2 nM [.sup.3H]MRE
3008F20 (Varani et al. Mol. Pharmacol. 2000, 57, 968-975) to
hCHO-A.sub.1, hCHO-A.sub.2A and hCHO-A.sub.3 are performed
incubating membranes (100 .mu.g of protein/assay) at 25.degree. C.
for 90 min, at 4.degree. C. for 60 min and at 4.degree. C. for 150
min, respectively. Competition experiments are performed in
duplicate in a final volume of 100 .mu.L in test tubes containing
50 mM Tris HCl buffer (10 mM MgCl.sub.2, 1 mM EDTA for A.sub.3), pH
7.4 and 100 .mu.L of membranes and at least six to eight different
concentrations of the test compound. Non-specific binding is
defined as the binding in the presence of 1 .mu.M DPCPX, ZM 241385
and MRE 3008F20 for A.sub.1, A.sub.2A and A.sub.3, respectively,
and is about 30% of total binding.
[0390] [.sup.3H]DPCPX (specific activity, 120 Ci/mmol) and
[.sup.3H]CCPA (specific activity, 55 Ci/mmol) may be obtained from
NEN Research Products (Boston, Mass.); [.sup.3H]ZM 241385 (specific
activity, 17 Ci/mmol) may be obtained from Tocris Cookson (Bristol,
UK); [.sup.3H]MRE 3008F20 (specific activity, 67 Ci/mmol) may be
obtained from Amersham International (Buckinghamshire, UK).
Measurement of cAMP Enhancement in CHO Cells (Functional
Assay):
[0391] Allosteric enhancement is measured as the action of a test
compound at different concentrations (0.01, 0.1, 1 and 10 .mu.M) to
reduce the cAMP content of hCHO-A.sub.1 cells. To initiate an
experiment, growth medium is removed from the 12-well plates and
cells are washed once with warm Hanks' buffered saline. The wash
solution is then removed and replaced with fresh Hanks' solution
containing forskolin (1 .mu.M), rolipram (20 .mu.M),
N.sup.6-cyclopentyladenosine (CPA, 0.01 nM), adenosine deaminase (2
U/mL), and the test compound. Forskolin is used to stimulate the
activity of adenylyl cyclase, rolipram to inhibit cAMP
phosphodiesterase, adenosine deaminase to degrade endogenous
adenosine, and CPA to cause a small increase of the number of
activated adenosine receptors. After 6 min of incubation at
36.degree. C. in the presence of a test compound, the incubation
solution is removed and hydrochloric acid (final concentration 50
mM) is added to terminate drug action. The content of cAMP in
acidified extracts of cells is determined by radioimmunoassay as
previously described (Kollias-Baker et al. J. Pharmacol. Exp. Ther.
1997, 281, 761-768). Because the magnitude of the effects of
allosteric modulators on hCHO-A.sub.1 cells change subtly with
passage number and differ slightly among different aliquots of
cells, the actions of the test compounds and the action of a
reference compound (PD 81,723) are assessed in each experiment. The
effect of each test compound on cAMP content is presented as a
percentage of the value of cAMP content in the absence of drug
(control, 100%).
Chronic Inflammatory Pain Model:
[0392] The intraplantar injection of zymosan-induced mechanical
hyperalgesia may be used as a model of chronic inflammatory pain
(Meller et al., Neuropharmacology, 33:1471-1478, 1994). In this
model, typically male Sprague-Dawley or Wistar rats (200-250 g)
receives an intraplantar injection of 3 mg/100 .mu.L zymosan into
one hind paw. A marked inflammation occurs in this hind paw. Drugs
are generally administered for evaluation of efficacy, 24 h after
the inflammatory insult, when mechanical hyperalgesia is considered
fully established.
Chronic Neuropathic Pain Models:
[0393] Two animal models of chronic neuropathic pain may be used
that involve some form of peripheral nerve damage. In the Seltzer
model (Seltzer et al., Pain, 43: 205-218, 1990) Sprague-Dawley or
Wistar rats (200-250 g) are anaesthetized and a small incision made
mid-way up one thigh (usually the left) to expose the sciatic
nerve. The nerve is carefully cleared of surrounding connective
tissues at a site near the trochanter just distal to the point at
which the posterior biceps semitendinosus nerve branches off the
common sciatic nerve. A 7-0 silk suture is inserted into the nerve
with a 3/8 curved, reversed-cutting mini-needle, and tightly
ligated so that the dorsal 1/3 to 1/2 of the nerve thickness is
held within the ligature. The muscle and skin are closed with
sutures and clips and the wound dusted with antibiotic powder. In
sham animals the sciatic nerve is exposed but not ligated and the
wound closed as in nonsham animals.
[0394] In the Chronic Constriction Injury (CCI) model (Bennett, G.
J. and Xie, Y. K. Pain, 33: 87-107, 1988) rats are anaesthetized
and a small incision is made mid-way up one thigh (usually the
left) to expose the sciatic nerve. The nerve is cleared of
surrounding connective tissue and four ligatures of 4/0 chromic gut
are tied loosely around the nerve with approximately 1 mm between
each, so that the ligatures just barely constrict the surface of
the nerve. The wound is closed with sutures and clips as described
above. In sham animals the sciatic nerve is exposed but not ligated
and the wound closed as in nonsham animals.
[0395] In contrast to the Seltzer and CCI models, the Chung model
involves ligation of the spinal nerve (Kim, S. O. and Chung, J. M.
Pain, 50: 355-363, 1992). In this model, Sprague-Dawley or Wistar
rats (200-250 g) are anesthetized and placed into a prone position
and an incision is made to the left of the spine at the L4-S2
level. A deep dissection through the paraspinal muscles and
separation of the muscles from the spinal processes at the L4-S2
level will reveal part of the sciatic nerve as it branches to form
the L4, L5 and L6 spinal nerves. The L6 transverse process is
carefully removed with a small rongeur enabling visualization of
these spinal nerves. The L5 spinal nerve is isolated and tightly
ligated with 7-0 silk suture. The wound is closed with a single
muscle suture (6-D silk) and one or two skin closure clips and
dusted with antibiotic powder. In sham animals the L5 nerve is
exposed as before but not ligated and the wound closed as
before.
Behavioral Index:
[0396] In all chronic pain models (inflammatory and neuropathic)
mechanical hyperalgesia is assessed by measuring paw withdrawal
thresholds of both hind paws to an increasing pressure stimulus
using an Analgesymeter. Mechanical allodynia is assessed by
measuring withdrawal thresholds to non-noxious mechanical stimuli
applied with von Frey hairs to the planter surface of both hind
paws. Thermal hyperalgesia is assessed by measuring withdrawal
latencies to a noxious thermal stimulus applied to the underside of
each hind paw. With all models, mechanical hyperalgesia and
allodynia and thermal hyperalgesia develop within 1-3 days
following surgery and persist for at least 50 days. For the assays
described herein, drugs may be applied before and after surgery to
assess their effect on the development of hyperalgesia,
approximately 14 days following surgery, to determine their ability
to reverse established hyperalgesia.
[0397] The percentage reversal of hyperalgesia is calculated as
follows:
% reversal = postdose threshold - predose threshold naive threshold
- predose threshold .times. 100 ##EQU00001##
[0398] In the above described pain models, all surgery may be
performed under enflurane/O.sub.2 inhalation anesthesia. In all
cases the wound is closed after the procedure and the animals are
allowed to recover. In all pain models employed, after a few days,
in all but the sham operated animals, a marked mechanical and
thermal hyperalgesia and allodynia develops in which there is a
lowering of pain threshold and an enhanced reflex withdrawal
response of the hind paw to touch, pressure or thermal stimuli.
After surgery, the animals may also exhibit characteristic changes
to the affected paw. In the majority of animals the toes of the
affected hind paw are held together and the foot is turned slightly
to one side, and in some rats the toes are also curled under. The
gait of the ligated rats varies, but limping is uncommon. Some rats
are seen to raise the affected hind paw from the cage floor and
demonstrate an unusual rigid extension of the hind limb when held.
The rats tend to be very sensitive to touch and may vocalize.
Otherwise the general health and condition of the rats is good.
[0399] Illustrative of the invention, the compound of Example 4
demonstrates an IC.sub.50 value of about 100 nM in a functional
assay measuring the cAMP level in CHO cells expressing the human
A.sub.1-adenosine receptor. Furthermore, the compound of Example 4
increases the B.sub.MAX value of the agonist [.sup.3H]CCPA to human
A.sub.1 adenosine receptors up to 600% at 10 .mu.M concentration.
Likewise, the compound of Example 60 exhibits about 6-fold increase
in the B.sub.MAX value of the agonist [.sup.3H]CCPA.
[0400] The following Examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
If not mentioned otherwise, all evaporations are performed under
reduced pressure, preferably between about 10 mmHg and 100 mmHg.
The structure of final products, intermediates and starting
materials is confirmed by standard analytical methods, e.g.,
microanalysis, melting point (m.p.) and spectroscopic
characteristics, e.g., MS, IR and NMR. Abbreviations used are those
conventional in the art.
EXAMPLE 1
(2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)m-
ethanone
##STR00018##
[0401] A.
(2-Amino-4-methylthiophen-3-yl)(4-chlorophenyl)methanone
[0402] To a suspension of 3-(4-chlorophenyl)-3-oxo-propionitrile
(900 mg, 5 mmol) and 2,5-dimethyl-[1,4]dithiane-2,5-diol (450 mg,
2.5 mmol) in absolute EtOH (10 mL), cooled in a bath of water/ice
(4.degree. C.), is added TEA (5 mmol, 0.7 mL). After stirring for
10 min at RT, the mixture is refluxed for 2 h. The resulting
red-brown solution is cooled and concentrated, and the residue
dissolved in EtOAc (10 mL). The organic phase is subsequently
washed with 1% w/v aqueous HCl (5 mL), a saturated solution of
NaHCO.sub.3 (5 mL), water (5 mL) and brine (5 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give a brown residue. The
residue is suspended in ethyl ether (15 mL), the suspension stirred
for 30 min and filtered. The filtrate is concentrated, suspended
with petroleum ether and the resulting suspension is stirred for 30
min and filtered. The filtrate is concentrated, and the residue is
purified by column chromatography using a mixture of
EtOAc-petroleum ether 2-8 as eluent to give
(2-amino-4-methylthiophen-3-yl)(4-chlorophenyl)methanone as an
orange solid: m.p. 148-150.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.66 (s, 3H), 5.85 (s, 1H), 6.61 (br s, 2H), 7.38 (d,
J=6.4 Hz, 2H), 7.45 (d, J=6.4 Hz, 2H); IR (KBr) cm.sup.-1: 3345,
1589, 1435, 1267.
B.
2-(3-(4-Chlorobenzoyl)-4-methylthiophen-2-yl]isoindoline-1,3-dione
[0403] The title A compound (755 mg, 3 mmol) is dissolved in acetic
acid (20 mL), then to the solution is added phthalic anhydride (3.6
mmol, 533 mg) and the mixture is heated under reflux for 15 h. The
solvent is evaporated and the residual material is dissolved in
ethyl acetate (20 mL). The organic solution is washed with a
saturated solution of NaHCO.sub.3 (5 mL), water (5 mL) and brine (5
mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue is
stirred for 1 h with petroleum ether (20 mL), and the solids are
collected by filtration to afford
2-[3-(4-chlorobenzoyl)-4-methylthiophen-2-yl]isoindoline-1,3-dione
as a brown powder: .sup.1H NMR (CDCl.sub.3) .delta.: 2.24 (s, 3H),
7.02 (s, 1H), 7.22 (d, J=7.2 Hz, 2H), 7.62-8.00 (m, 6H).
C.
2-[5-Bromo-3-(4-chlorobenzoyl)-4-methylthiophen-2-yl]isoindole-1,3-dion-
e
[0404] To a solution of the title B compound (20 mmol, 7.6 g) in
benzene (150 mL) is added benzoyl peroxide (484 mg, 2 mmol) and the
mixture is heated under reflux. At refluxing conditions, a mixture
of N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl peroxide (484
mg, 2 mmol) is added and the mixture is refluxed for 6 h further.
The solvent is removed under reduced pressure, and the residue is
dissolved in EtOAc (330 mL). The organic solution is subsequently
washed a saturated solution of NaHCO.sub.3 (200 mL), water (50 mL)
and brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated to
give a brown powder. The powder is suspended with petroleum ether
(200 mL), the mixture is stirred for 30 min and the solids are
collected by filtration to afford
2-[5-bromo-3-(4-chlorobenzoyl)-4-methylthiophen-2-yl]isoindoline-1,3-dion-
e which is used as such in the next step without further
purification: m.p. 194-195.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta.: 2.09 (s, 3H), 7.19 (d, J=7.4 Hz, 2H), 7.62-7.71 (m, 6H);
IR (KBr) cm.sup.-1: 1728, 1664, 1587, 1368, 717.
[0405] D.
2-[5-Bromo-4-bromomethyl-3-(4-chlorobenzoyl)thiophen-2-yl]isoind-
ole-1,3-dione
[0406] To a suspension of the title C compound (20 mmol, 9.2 g) in
CCl.sub.4 (150 mL) is added benzoyl peroxide (242 mg, 1 mmol) and
the mixture is heated under reflux. At refluxing conditions, a
mixture of N-bromosuccinimide (20 mmol, 3.56 g) and benzoyl
peroxide (242 mg, 1 mmol) is added and the mixture is refluxed for
1 h further. After this time, if the reaction is not finished, a
mixture of N-bromosuccinimide (2 mmol, 356 mg) and benzoyl peroxide
(242 mg, 1 mmol) is added and the mixture is refluxed for another
h. The resulting yellow solution is cooled to RT and the
precipitated succinimide is removed by filtration and washed with
CCl.sub.4 (25 mL). The filtrate is washed with 5% NaHCO.sub.3
solution (50 mL), water (50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give a yellow powder. The
powder is suspended with petroleum ether (100 mL), the mixture is
stirred for 30 min and the solids are collected by filtration to
give
2-[5-bromo-4-bromomethyl-3-(4-chlorobenzoyl)thiophen-2-yl]isoindoline-1,3-
-dione as a yellow solid: m.p. 173-175.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta.: 4.65 (s, 2H), 7.20 (d, J=6.6 Hz, 2H), 7.66
(d, J=6.6 Hz, 2H), 7.62-7.71 (m, 4H). IR (KBr) cm.sup.-1: 1727,
1658, 1348, 1330, 1084.
E.
2-[5-Bromo-3-(4-chlorobenzoyl)-4-((4-phenylpiperazin-1-yl)methyl)thioph-
en-2-yl]isoindoline-1,3-dione
[0407] To a stirred solution of the title D compound (900 mg, 1.6
mmol) in dry DCM (5 mL) is added TEA (1.1 equiv., 1.76 mmol, 243
mg). The mixture is cooled with a bath of ice/water, and
4-phenylpiperazine (3 equiv., 5 mmol, 810 mg) is added. The mixture
is stirred at RT for 2 h, diluted with DCM (5 mL), washed with
water (5 mL) and brine (5 mL). The organic layer is dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give a brown
residue which is purified by column chromatography (EtOAc-petroleum
ether 4-6 as eluent) to afford
2-[5-bromo-3-(4-chlorobenzoyl)-4-((4-phenyl-piperazin-1-yl)methyl)thiophe-
n-2-yl]isoindoline-1,3-dione as a yellow solid: m.p.
186-193.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.: 2.85 (t, J=5.0
Hz, 2H), 3.14 (s, 2H), 3.34 (t, J=5.0 Hz, 2H), 3.42 (t, J=5.2 Hz,
2H), 3.94 (t, J=5.2 Hz, 2H), 6.80-6.93 (m, 4H), 6.93-7.28 (m, 4H),
7.39 (d, J=8.4 Hz, 2H), 7.58-7.62 (m, 2H), 7.82 (d, J=6.8 Hz,
1H).
F.
2-[3-(4-Chlorobenzoyl)-4-((4-phenylpiperazin-1-yl)methyl)thiophen-2-yl]-
isoindoline-1,3-dione
[0408] A solution of the title E compound (2 mmol) in DMF (20 mL),
containing Et.sub.3N (0.3 mL, 2 mmol, 1 equiv) is hydrogenated over
120 mg of 10% Pd/C at 60 psi for 3 h. The catalyst is removed by
filtration, the filtrate is concentrated. The residue is dissolved
in DCM (20 mL), washed with water (5 mL) and brine (5 mL), and
dried (Na.sub.2SO.sub.4). The solvent is removed under reduced
pressure and the residue is purified by column chromatography
(EtOAc-DCM 2-8 as eluent) to afford
2-[3-(4-chloro-benzoyl)-4-((4-phenylpiperazin-1-yl)methyl)thiophen-2-yl]i-
soindoline-1,3-dione as a white solid: m.p. 220-222.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.92 (t, J=5.0 Hz, 2H), 3.14 (s,
2H), 3.34 (t, J=5.0 Hz, 2H), 3.44 (t, J=5.2 Hz, 2H), 3.94 (t, J=5.2
Hz, 2H), 6.69 (s, 1H), 6.87 (d, J=6.8 Hz, 2H), 7.21 (d, J=6.8 Hz,
2H), 7.37-7.52 (m, 4H), 7.52 (t, J=6.8 Hz, 1H), 7.58-7.60 (m. 3H),
7.83 (d, J=6.8 Hz, 1H).
G.
{2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloropheny-
l)methanone
[0409] A stirred suspension of the title F compound (0.5 mmol) and
100% hydrazine monohydrate (1.2 eq, 0.6 mmol, 29 .mu.L) in absolute
ethanol (10 mL) is heated at reflux for 3 h. After this time, the
resulting solution is left at RT for 1 h. The reaction is finished
after the complete solubilization of the starting material. The
solvent is evaporated and the residue is partitioned between EtOAc
(10 mL) and water (5 mL). The organic phase is separated, washed
with brine (2 mL), dried and concentrated in vacuo. The residue is
purified by column chromatography (EtOAc-DCM/2-8 as eluent) to give
{2-amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone as a yellow solid: m.p. 112.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta.: 2.04 (m, 4H), 2.94 (m. 4H), 3.00 (s, 2H),
6.07 (br s, 2H), 6.14 (s, 1H), 6.83 (m, 3H), 7.23 (m, 2H), 7.35 (d,
J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H).
[0410] The following compounds are prepared analogously as
described in Example 1.
EXAMPLE 2
{2-Amino-4-[(4-methylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)m-
ethanone
##STR00019##
[0412] The title compound is purified by column chromatography
(MeOH as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3) .delta.:
2.24 (s, 3H), 2.32 2.44 (m, 6H), 3.37 (t, J=5.4 Hz, 2H), 3.58 (t,
J=5.4 Hz, 2H), 6.10 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4
Hz, 2H).
EXAMPLE 3
{2-Amino-4-[4-((4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00020##
[0414] The title compound is purified by column chromatography
(EtOAc:DCM/2:8 as eluent). Yellow solid, m.p. 70-72.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=5.2 Hz, 4H), 2.85 (t,
J=5.2 Hz, 4H), 3.00 (s, 2H), 6.06 (s, 2H), 6.13 (s, 1H), 6.82 (m,
2H), 6.92 (t, J=9.0 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2
Hz, 2H). IR (KBr) cm.sup.-1: 3421, 1587, 1509, 1262, 1087.
EXAMPLE 4
{2-Amino-4-[4-((4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00021##
[0416] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 148-150.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.6 Hz, 4H), 2.88 (t,
J=4.6 Hz, 4H), 3.00 (s, 2H), 6.07 (br s, 2H), 6.13 (s, 1H), 6.74
(d, J=9.2 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),
7.55 (d, J=8.4 Hz, 2H). IR (KBr) cm.sup.-1: 3366, 1591, 1498, 1426,
1234, 1085, 815.
EXAMPLE 5
{2-Amino-4-[4-((4-methoxyphenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone
##STR00022##
[0418] The title compound is purified by column chromatography
(EtOAc:DCM/2:8 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 2.04 (t, J=5.4 Hz, 4H), 2.83 (t, J=5.4 Hz, 4H), 3.10 (s,
2H)m 3.75 (s, 3H), 6.08 (br s, 2H), 6.14 (s, 1H), 6.82 (d, J=10.2
Hz, 2H), 6.86 (d, J=10.2 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.55 (d,
J=8.4 Hz, 2H). IR (KBr) cm.sup.-1: 3366, 1591, 1498, 1426, 1234,
1085, 815.
EXAMPLE 6
{2-Amino-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone
##STR00023##
[0420] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 73-75.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.26 (s, 3H), 2.32 (t, J=5.6 Hz,
4H), 2.86 (t, J=5.6 Hz, 4H), 3.12 (s, 2H), 6.10 (br s, 2H), 6.13
(s, 1H), 6.83 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.32 (d,
J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H). IR (KBr) cm.sup.-1: 1722,
1614, 1514, 1261, 1089, 1021.
EXAMPLE 7
{2-Amino-4-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chloro-
phenyl)methanone
##STR00024##
[0422] The title compound is purified by column chromatography
(EtOAc:DCM/4:6 as eluent). Yellow solid, m.p. 130-131.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=5.0 Hz, 4H), 3.00 (s,
2H), 3.27 (t, J=5.0 Hz, 4H), 6.09 (br s, 2H), 6.13 (s, 1H),
6.53-6.61 (m, 3H), 7.40 (d, J=6.6 Hz, 2H), 7.57 (d, J=6.6 Hz, 2H),
8.15 (m, 1H). IR (KBr) cm.sup.-1: 2963, 1595, 1434, 1261, 1096,
1022.
EXAMPLE 8
{2-Amino-4-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00025##
[0424] The title compound is purified by column chromatography
(EtOAc:DCM/1:1 as eluent). Yellow solid, m.p. 141-143.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.95 (t, J=4.8 Hz, 4H), 2.99 (s,
2H), 3.55 (t, J=4.8 Hz, 4H), 6.13 (br s, 3H), 6.44 (t, J=4.8 Hz,
1H), 7.40 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 8.26 (d, J=4.8
Hz, 2H). IR (KBr) cm.sup.-1: 3386, 1712, 1586, 1423, 1260, 1084,
798.
EXAMPLE 9
{2-Amino-4-[(4-(3,4-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00026##
[0426] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 102-104.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.6 Hz, 4H), 2.90 (t,
J=4.6 Hz, 4H), 3.00 (s, 2H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.66
(dd, J=9.0 and 2.8 Hz, 1H), 6.87 (d, J=2.8 Hz, 1H), 7.21 (s, 1H),
7.40 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H). IR (KBr) cm.sup.-1:
2964, 1591, 1435, 1262, 1096, 1020, 800.
EXAMPLE 10
4-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}benz-
onitrile
##STR00027##
[0428] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 173-175.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=4.8 Hz, 4H), 3.03 (s,
2H), 3.08 (t, J=4.8 Hz, 4H), 6.08 (br s, 2H), 6.14 (s, 1H), 6.78
(d, J=9.0 Hz, 2H), 7.36 (d, J=7.8 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H),
7.56 (d, J=7.8 Hz, 2H). IR (KBr) cm.sup.-1: 2963, 1606, 1261, 1097,
1016, 808.
EXAMPLE 11
{2-Amino-4-[(4-(3-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00028##
[0430] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 197-199.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=5.2 Hz, 4H), 2.93 (t,
J=5.2 Hz, 4H), 3.00 (s, 2H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.68
(d, J=7.6 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.81 (s, 1H), 7.12 (t,
J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H). IR
(KBr) cm.sup.-1: 3356, 1587, 1512, 1430 and 1076.
EXAMPLE 12
{2-Amino-4-[(4-(2-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00029##
[0432] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 115-117.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=5.2 Hz, 4H), 2.78 (t,
J=5.2 Hz, 4H), 3.10 (s, 2H), 6.06 (br s, 2H), 6.11 (s, 1H), 6.60
(d, J=7.4 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.80 (t, J=7.4 Hz, 1H),
7.02 (t, J=7.4 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz,
2H). IR (KBr) cm.sup.-1: 3342, 1578, 1534, 1432 and 1084.
EXAMPLE 13
{2-Amino-4-[(4-(2-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00030##
[0434] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 102-104.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=5.2 Hz, 4H), 2.86 (t,
J=5.2 Hz, 4H), 3.02 (s, 2H), 6.04 (s, 2H), 6.12 (s, 1H), 6.74 (d,
J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.92
(t, J=7.6 Hz, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H).
IR (KBr) cm.sup.-1: 3417, 1578, 1512, 1264, 1092.
EXAMPLE 14
{2-Amino-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone
##STR00031##
[0436] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 167-169.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=5.2 Hz, 4H), 2.97
(t, J=5.2 Hz, 4H), 3.00 (s, 2H), 6.07 (br s, 2H), 6.14 (s, 1H),
7.01 (m, 3H), 7.26 (t, J=9.6 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.54
(d, J=8.4 Hz, 2H). IR (KBr) cm.sup.-1: 3346, 1578, 1522, 1424 and
1082.
EXAMPLE 15
1-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-2-(-
4-chlorophenyl)ethanone
##STR00032##
[0438] The title compound is purified by column chromatography
(EtOAc:DCM/2:8 as eluent). Yellow solid, m.p. 60-61.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.73 (t, J=4.8 Hz, 2H), 1.78 (t,
J=4.8 Hz, 2H), 2.93 (s, 2H), 3.19 (t, J=5.2 Hz, 2H), 3.64 (t, J=5.2
Hz, 2H), 3.59 (s, 2H), 6.06 (s, 1H), 6.09 (s, 2H), 7.10 (d, J=8.4
Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 7.53 (d,
J=8.6 Hz, 2H). IR (KBr) cm.sup.-1: 3342, 1578, 1502, 1442 and
1082.
EXAMPLE 16
{2-Amino-4-[(4-(4-chlorobenzoyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chl-
orophenyl)methanone
##STR00033##
[0440] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 185-186.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.83 (t, J=4.8 Hz, 2H), 1.92 (t,
J=4.8 Hz, 2H), 2.99 (s, 2H), 3.15 (t, J=5.0 Hz, 2H), 3.49 (t, J=5.0
Hz, 2H), 6.08 (s, 1H), 6.10 (s, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.28
(d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H).
IR (KBr) cm.sup.-1: 3352, 1564, 1512, 1434 and 1068.
EXAMPLE 17
{2-Amino-4-[(4-(pyridin-4-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chloro-
phenyl)methanone
##STR00034##
[0442] The title compound is purified by column chromatography
(EtOAc:MeOH/7:3 as eluent). Yellow solid, m.p. 86-88.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=5.2 Hz, 4H), 3.00 (s,
2H), 3.24 (t, J=5.2 Hz, 4H), 6.09 (br s, 2H), 6.12 (s, 1H), 6.72
(d, J=5.6 Hz, 2H), 6.87 (d, J=5.6 Hz, 2H), 8.06 (d, J=7.4 Hz, 2H),
8.19 (d, J=7.4 Hz, 2H). IR (KBr) cm.sup.-1: 2956, 1578, 1445, 1256,
1077, 1012.
EXAMPLE 18
{2-Amino-4-[(4-(benzo[d][1,3]dioxol-5-yl)piperazin-1-yl)methyl]thiophen-3--
yl}(4-chlorophenyl)methanone
##STR00035##
[0444] The title compound is purified by column chromatography
(EtOAc:DCM/1:1 as eluent). Yellow solid, m.p. 85-86.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.38 (t, J=5.2 Hz, 4H), 2.66 (t,
J=5.2 Hz, 4H), 3.34 (s, 2H), 5.72 (s, 2H), 5.84 (s, 2H), 5.86 (dd,
J=8.2 and 2.4 Hz, 1H), 6.05 (d, J=2.2 Hz, 1H), 6.24 (d, J=2.2 Hz,
1H), 6.65 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4
Hz, 2H). IR (KBr) cm.sup.-1: 3376, 1577, 1532, 1423 and 1054.
EXAMPLE 19
{2-Amino-4-[(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00036##
[0446] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 2.05 (t, J=4.4 Hz, 4H), 2.78 (t, J=4.4 Hz, 4H), 3.01 (s,
2H), 6.07 (br s, 2H), 6.14 (s, 1H), 6.89 (d, J=4.8 Hz, 1H), 7.11
(d, J=5.2 Hz, 2H), 7.43 (t, J=7.0 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H).
IR (KBr) cm.sup.-1: 2978, 1578, 1452, 1267, 1078, 1012.
EXAMPLE 20
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00037##
[0448] The title compound is purified by column chromatography
(EtOAc:DCM/2:8 as eluent). Yellow solid, m.p. 150-152.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.02 (t, J=4.8 Hz, 4H), 2.93 (t,
J=4.8 Hz, 4H), 3.00 (s, 2H), 6.08 (s, 2H), 6.13 (s, 1H), 6.45 (t,
J=7.0 Hz, 1H), 6.53 (m, 2H), 7.17 (q, J=7.6 Hz, 1H), 7.40 (d, J=8.2
Hz, 2H), 7.56 (d, J=8.2 Hz, 2H). IR (KBr) cm.sup.-1: 3434, 1577,
1534, 1256, 1077.
EXAMPLE 21
{2-Amino-4-[(4-(3,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00038##
[0450] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 185-187.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=4.8 Hz, 4H), 2.92 (t,
J=4.8 Hz, 4H), 2.99 (s, 2H), 6.09 (br s, 2H), 6.13 (s, 1H), 6.64
(s, 2H), 6.76 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz,
2H). IR (KBr) cm.sup.-1: 2965, 1587, 1444, 1272, 1085 and 1033.
EXAMPLE 22
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone
##STR00039##
[0452] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 198-200.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 2.02 (t, J=4.8 Hz, 4H), 3.00
(t, J=4.8 Hz, 4H), 3.04 (s, 2H), 6.08 (br s, 2H), 6.14 (s, 1H),
6.82 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz,
2H), 7.54 (d, J=8.8 Hz, 2H). IR (KBr) cm.sup.-1: 3352, 1568, 1512,
1423 and 1077.
EXAMPLE 23
2-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-1-(-
4-chlorophenyl)ethanone
##STR00040##
[0454] The title compound is purified by column chromatography
(EtOAc:MeOH/9.5:0.5 as eluent). Yellow solid, m.p. 77-78.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.73 (t, J=4.8 Hz, 4H), 3.42 (t,
J=4.8 Hz, 4H), 3.56 (s, 2H), 3.72 (s, 2H), 6.06 (br s, 2H), 6.08
(s, 1 H), 7.22 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.44 (d,
J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H). IR (KBr) cm.sup.-1: 3333,
1584, 1512, 1434 and 1074.
EXAMPLE 24
{2-Amino-4-[(4-(2,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00041##
[0456] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 170-172.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.8 Hz, 4H), 2.77 (t,
J=4.8 Hz, 4H), 3.00 (s, 2H), 6.06 (br s, 2H), 6.13 (s, 1H), 6.80
(m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H). IR (KBr)
cm.sup.-1: 2955, 1592, 1424, 1278, 1092 and 1034.
EXAMPLE 25
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00042##
[0458] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.99 (t, J=4.8 Hz, 4H), 2.95 (t, J=4.8 Hz, 4H), 2.98 (s,
2H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.82 (m, 3H), 7.36 (d, J=6.6
Hz, 2H), 7.58 (d, J=6.6 Hz, 2H). IR (meat) cm.sup.-1: 2988, 1564,
1433, 1256, 1082 and 1047.
EXAMPLE 26
{2-Amino-4-[(4-(3-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00043##
[0460] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 161-163.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=4.6 Hz, 4H), 2.85 (t,
J=4.6 Hz, 4H), 3.00 (s, 2H), 6.07 (br s, 2H), 6.13 (s, 1H), 6.68
(m, 1H), 6.81 (dd, J=6.4 and 3.0 Hz, 1H), 6.93 (t, J=8.8 Hz, 1H),
7.38 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H). IR (KBr) cm.sup.-1:
2972, 1577, 1432, 1271, 1094 and 1032.
EXAMPLE 27
{2-Amino-4-[(4-cyclohexylpiperazin-1-yl)methyl]thiophen-3-yl)(4-chlorophen-
yl)methanone
##STR00044##
[0462] The title compound is purified by column chromatography
(EtOAc:MeOH/1:1 as eluent). Yellow solid, m.p. 120-122.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.17 (m, 6H), 1.64 (m, 5H), 1.78
(t, J=5.2 Hz, 4H), 2.39 (t, J=5.2 Hz, 4H), 3.13 (s, 2H), 5.69 (br
s, 2H), 6.91 (s, 1H), 7.39 (d, J=7.2 Hz, 2H), 7.48 (d, J=7.2 Hz,
2H).
EXAMPLE 28
{2-Amino-4-[(4-(4-chlorophenyl)piperidin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00045##
[0464] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.67 (m, 4H), 2.27 (m, 1H), 2.54 (t, J=5.4 Hz, 4H), 3.04
(s, 2H), 6.09 (s, 2H), 6.16 (s, 1H), 7.33 (s, 4H), 7.39 (d, J=8.6
Hz, 2H), 7.51 (t, J=8.6 Hz, 2H). IR (KBr) cm.sup.-1: 3378, 1556,
1443, 1412, 1074 and 822.
EXAMPLE 29
{2-Amino-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone
##STR00046##
[0466] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 110-112.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.46 (t, J=5.4 Hz, 4H), 2.84 (t,
J=5.4 Hz, 4H), 3.03 (s, 2H), 6.21 (br s, 2H), 6.24 (s, 1 H), 6.81
(d, J=9.6 Hz, 2H), 7.46 (d, J=9.2 Hz, 2H), 7.65 (d, J=9.6 Hz, 2H),
8.13 (d, J=9.2 Hz, 2H). IR (KBr) cm.sup.-1: 3455, 1733, 1551,
1533.
EXAMPLE 30
{2-Amino-4-[(4-isopropylpiperazin-1-yl]methyl)thiophen-3-yl}(4-chloropheny-
l)methanone
##STR00047##
[0468] The title compound is purified by column chromatography
(EtOAc:MeOH/3:7 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.02 (m, 6H), 1.99 (t, J=5.2 Hz, 4H), 2.35 (t, J=5.2 Hz,
4H), 2.57 (m, 1H), 2.93 (s, 2H), 6.05 (br s, 2H), 6.10 (s, 1H),
7.36 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H).
EXAMPLE 31
{2-Amino-4-[(4-naphthalen-1-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00048##
[0470] The title compound is purified by column chromatography
(EtOAc:DCM/2:8 as eluent). Brown solid, m.p. 178.degree. C. .sup.1H
NMR (CDCl.sub.3) .delta.: 2.42 (t, J=5.4 Hz, 4H), 2.54 (t, J=5.4
Hz, 4H), 3.03 (s, 2H), 6.04 (s, 2H), 6.11 (s, 1H), 6.93 (d, J=7.2
Hz, 2H), 7.06 (d, J=7.2 Hz, 2H), 7.33 (m, 3H), 7.56 (d, J=7.8 Hz,
2H), 7.87 (d, J=7.8 Hz, 2H).
EXAMPLE 32
{2-Amino-4-[(4-(3,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00049##
[0472] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 143-145.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=4.8 Hz, 4H), 2.84 (t,
J=4.8 Hz, 4H), 3.00 (s, 2H), 6.07 (br s, 2H), 6.13 (s, 1H), 6.52
(m, 2H), 7.02 (m, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz,
2H). IR (KBr) cm.sup.-1: 2967, 1587, 1433, 1267, 1085 and 1033.
EXAMPLE 33
{2-Amino-4-[(4-cyclopentylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone
##STR00050##
[0474] The title compound is purified by column chromatography
(EtOAc:MeOH/6:4 as eluent). Yellow solid, m.p. 95-97.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.16 (m, 4H), 1.48 (m, 5H), 1.82
(t, J=5.2 Hz, 4H), 2.79 (s, 2H), 2.85 (t, J=5.2 Hz, 4H), 5.72 (br
s, 2H), 6.90 (s, 1H), 7.32 (d, J=7.0 Hz, 2H), 8.00 (d, J=7.0 Hz,
2H).
EXAMPLE 34
{2-Amino-4-[(4-cycloheptylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophe-
nyl)methanone
##STR00051##
[0476] The title compound is purified by column chromatography
(EtOAc:MeOH/7:3 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.26 (m, 12H), 1.79 (t, J=5.2 Hz, 4H), 2.09 (t, J=5.2 Hz,
4H), 2.81 (m, 1H), 3.03 (s, 2H), 6.03 (br s, 2H), 6.09 (s, 1H),
7.31 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H).
EXAMPLE 35
{2-Amino-4-[(4-(4-chlorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00052##
[0478] The title compound is purified by column chromatography
(EtOAc:DCM/1:1 as eluent). Yellow solid, m.p. 65-67.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.88 (t, J=4.6 Hz, 4H), 2.21 (m,
4H), 2.92 (s, 2H), 3.36 (s, 2H), 6.02 (br s, 2H), 6.09 (s, 1H),
7.24 (m, 4H), 7.34 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H). IR
(KBr) cm.sup.-1: 3372, 1589, 1478, 1433, 1241.
EXAMPLE 36
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)m-
ethanone
##STR00053##
[0480] The title compound is purified by column chromatography
(DCM:MeOH/9.5:0.5 as eluent). Yellow solid, m.p. 153-155.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.88 (t, J=4.6 Hz, 4H), 2.24 (t,
J=4.6 Hz, 4H), 3.41 (s, 2H), 3.48 (s, 2H), 6.01 (br s, 2H), 6.06
(s, 1H), 7.24 (m, 5H), 7.42 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz,
2H). IR (KBr) cm.sup.-1: 3377, 1592, 1468, 1423, 1251.
EXAMPLE 37
(2-Amino-4-{[4-(2-(4-chlorophenyl)ethyl)piperazin-1-yl)methyl}thiophen-3-y-
l)(4-chlorophenyl)methanone
##STR00054##
[0482] The title compound is purified by column chromatography
(DCM:MeOH/9.5:0.5 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.92 (t, J=4.6 Hz, 4H), 2.27 (m, 4H), 2.47 (t, J=7.2 Hz,
2H), 2.67 (t, J=7.2 Hz, 2H), 2.95 (s, 2H), 6.09 (br s, 3H), 7.08
(d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H),
7.52 (d, J=8.6 Hz, 2H). IR (KBr) cm.sup.-1: 3376, 1588, 1456, 1434,
1242.
EXAMPLE 38
{2-Amino-4-[(4-(4-fluorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00055##
[0484] The title compound is purified by column chromatography
(MeOH:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 230-231.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.55 (t, J=4.6 Hz, 4H), 1.88 (t,
J=4.6 Hz, 4H), 2.92 (s, 2H), 2.92 (s, 2H), 6.02 (br s, 2H), 6.09
(s, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.21 (dd, J=8.8 and 5.6 Hz, 2H),
7.35 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H). IR (KBr) cm.sup.-1:
3358, 1577, 1468, 1423, 1267.
EXAMPLE 39
{2-Amino-4-[(4-cyclooctylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophen-
yl)methanone
##STR00056##
[0486] The title compound is purified by column chromatography
(DCM:MeOH/0.5:9.5 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 1.21 (m, 10H), 1.44 (m, 4H), 1.76 (m, 5H), 2.42 (t, J=5.2
Hz, 4H), 3.14 (s, 2H), 5.74 (br s, 2H), 6.88 (s, 1H), 7.41 (d,
J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H).
EXAMPLE 40
(2-Amino-4-{[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]methyl}thiophen-3--
yl)(4-chlorophenyl)methanone
##STR00057##
[0488] The title compound is purified by column chromatography
(DCM:MeOH/9.5:0.5 as eluent). Yellow solid, m.p. 60-61.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.62 (m, 2H), 1.90 (t, J=4.8 Hz,
4H), 2.24 (m, 4H), 2.58 (t, J=4.8 Hz, 4H), 2.95 (s, 2H), 6.02 (br
s, 2H), 6.09 (s, 1H), 7.10 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.6 Hz,
2H), 7.34 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H). IR (KBr)
cm.sup.-1: 3382, 1578, 1455, 1432, 1222.
EXAMPLE 41
{2-Amino-4-[(4-(2,4-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl)(4--
chlorophenyl)methanone
##STR00058##
[0490] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 142-143.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.6 Hz, 4H), 2.76 (t,
J=4.6 Hz, 4H), 3.01 (s, 2H), 6.05 (br s, 2H), 6.14 (s, 1H), 6.88
(d, J=8.6 Hz, 1H), 7.14 (dd, J=11 and 2.6 Hz, 1H), 7.31 (d, J=2.6
Hz, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H). IR (KBr)
cm.sup.-1: 2972, 1578, 1455, 1265.
EXAMPLE 42
{2-Amino-4-[(4-(2,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00059##
[0492] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 62-63.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=4.8 Hz, 4H), 2.95 (t,
J=4.8 Hz, 4H), 2.98 (s, 2H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.82
(m, 3H), 7.36 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H). IR (neat)
cm.sup.-1: 2976, 1555, 1442, 1265, 1077.
EXAMPLE 43
{2-Amino-4-[(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone
##STR00060##
[0494] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta.: 2.01 (t, J=4.8 Hz, 4H), 2.67 (t, J=5.2 Hz, 4H), 3.00 (s,
2H), 6.05 (br s, 2H), 6.13 (s, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.18
(m, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.44 (m, 1H), 7.57 (d, J=8.8 Hz,
2H). IR (KBr) cm.sup.-1: 3353, 1563, 1533, 1438 and 1077.
EXAMPLE 44
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone
##STR00061##
[0496] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 141-143.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.96 (t, J=4.4 Hz, 4H), 2.87 (t,
J=4.4 Hz, 4H), 2.94 (s, 2H), 6.01 (br s, 2H), 6.07 (s, 1H), 6.78
(dd, J=8.2 and 2.8 Hz, 1H), 7.00 (s, 1H), 7.19 (d, J=8.2 Hz, 1H),
7.33 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H). IR (KBr) cm.sup.-1:
2977, 1578, 1443, 1277, 1078.
EXAMPLE 45
{2-Amino-4-[(4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}-
(4-chlorophenyl)methanone
##STR00062##
[0498] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 153-155.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=4.6 Hz, 4H), 2.87 (t,
J=4.8 Hz, 4H), 2.98 (s, 2H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.58
(t, J=9.0 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H).
IR (KBr) cm.sup.-1: 2977, 1583, 1443, 1277, 1083.
EXAMPLE 46
{2-Amino-4-[(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00063##
[0500] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 59-61.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.06 (t, J=4.6 Hz, 4H), 2.75 (t,
J=4.6 Hz, 4H), 3.02 (s, 2H), 6.07 (br s, 2H), 6.15 (s, 1H), 6.92
(d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.93 (t, J=8.8 Hz, 1H),
7.38 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H). IR (KBr) cm.sup.-1:
2984, 1583, 1443, 1283, 1123.
EXAMPLE 47
{2-Amino-4-[(4-(2-fluoro-4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00064##
[0502] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 161-163.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.8 Hz, 4H), 2.80 (t,
J=4.8 Hz, 4H), 3.01 (s, 2H), 6.07 (br s, 2H), 6.14 (s, 1H), 6.78
(t, J=7.6 Hz, 1H), 7.01 (m, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.55 (d,
J=8.6 Hz, 2H). IR (KBr) cm.sup.-1: 2967, 1577, 1452, 1271,
1110.
EXAMPLE 48
{2-Amino-4-[(4-(3,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00065##
[0504] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 162-163.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.00 (t, J=4.8 Hz, 4H), 2.93 (t,
J=4.8 Hz, 4H), 3.00 (s, 2H), 6.10 (br s, 2H), 6.13 (s, 1H), 6.26
(m, 3H), 7.38 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H). IR (neat)
cm.sup.-1: 2982, 1551, 1434, 1255, 1082.
EXAMPLE 49
{2-Amino-4-[(4-(2,6-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00066##
[0506] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 128-130.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.02 (t, J=4.8 Hz, 4H), 2.82 (t,
J=4.6 Hz, 4H), 3.02 (s, 2H), 6.05 (br s, 2H), 6.09 (s, 1H), 7.01
(d, J=8.6 Hz, 1H), 7.17 (t, J=8.6 Hz, 1H), 7.29 (d, J=2.6 Hz, 1H),
7.34 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H). IR (KBr) cm.sup.-1:
2977, 15678, 1466, 1272.
EXAMPLE 50
{2-Amino-4-[(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)methyl]thiophen--
3-yl}(4-chlorophenyl)methanone
##STR00067##
[0508] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 151-153.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.8 Hz, 4H), 2.92 (t,
J=4.8 Hz, 4H), 3.01 (s, 2H), 6.09 (br s, 2H), 6.14 (s, 1H), 6.80
(d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H),
7.56 (d, J=7.8 Hz, 2H). IR (KBr) cm.sup.-1: 2973, 1614, 1264, 1087,
1032.
EXAMPLE 51
{2-Amino-4-[(4-(pyridin-3-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chloro-
phenyl)methanone
##STR00068##
[0510] The title compound is purified by column chromatography
(EtOAc:MeOH/6:4 as eluent). Yellow solid, m.p. 101-103.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.01 (t, J=4.8 Hz, 4H), 2.84 (t,
J=4.8 Hz, 4H), 3.00 (s, 2H), 6.09 (br s, 2H), 6.13 (s, 1H), 6.52
(d, J=7.8 Hz, 1H), 6.78 (m, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.57 (d,
J=8.6 Hz, 2H), 8.07 (s, 1H), 8.24 (d, J=9.0 Hz, 1H). IR (KBr)
cm.sup.-1: 2958, 1586, 1444, 1270, 1096.
EXAMPLE 52
{2-Amino-4-[(4-(2,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00069##
[0512] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 78-80.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.07 (t, J=4.6 Hz, 4H), 2.81 (t,
J=4.6 Hz, 4H), 3.03 (s, 2H), 6.08 (br s, 2H), 6.15 (s, 1H), 6.93
(s, 1H), 7.24 (d, J=9.2 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 7.57 (d,
J=8.6 Hz, 2H). IR (KBr) cm.sup.-1: 2988, 1568, 1462, 1271.
EXAMPLE 53
{2-Amino-4-[(4-(2,3-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4--
chlorophenyl)methanone
##STR00070##
[0514] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 138.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=4.8 Hz, 4H), 2.78 (t,
J=4.8 Hz, 4H), 2.95 (s, 2H), 6.00 (br s, 2H), 6.07 (s, 1H), 6.54
(t, J=7.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.85 (t, J=8.2 Hz, 1H),
7.31 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H). IR (KBr) cm.sup.-1:
2981, 1565, 1453, 1254, 1072.
EXAMPLE 54
{2-Amino-4-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]thiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00071##
[0516] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 105.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.12 (d, J=6.6 Hz, 3H), 2.12 (t,
J=5.4 Hz, 2H), 2.21 (t, J=5.4 Hz, 2H), 2.67 (m, 2H), 3.11 (s, 2H),
3.21 (m, 1H), 6.08 (br s, 2H), 6.13 (s, 1H), 6.72 (d, J=8.8 Hz,
2H), 6.82 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.42 (d, J=9.0
Hz, 2H), IR (KBr) cm.sup.-1: 3372, 1588, 1523, 1233.
EXAMPLE 55
{2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-
-yl}[3-(trifluoromethyl)phenyl]methanone
##STR00072##
[0518] The title compound is purified by column chromatography
(EtOAc:DCM/0.25:9.75 as eluent). Yellow solid, m.p. 143-145.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.95 (t, J=4.8 Hz, 4H), 2.94
(s, 2H), 2.98 (t, J=4.8 Hz, 4H), 6.14 (s, 1H), 6.28 (br s, 2H),
6.82 (t, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.54 (t, J=8.0 Hz,
1H), 7.74 (m, 2H), 7.85 (s, 1H).
EXAMPLE 56
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(tri-
fluoromethyl)phenyl]methanone
##STR00073##
[0520] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 100-102.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.94 (t, J=4.8 Hz, 4H), 2.90 (t,
J=4.8 Hz, 4H), 2.93 (s, 2H), 6.14 (s, 1H), 6.29 (br s, 2H), 6.49
(m, 2H), 6.57 (d, J=9.6 Hz, 1H), 7.15 (q, J=7.2 Hz, 1H), 7.54 (t,
J=8.0 Hz, 1H), 7.74 (m, 2H), 7.84 (s, 1H).
EXAMPLE 57
{2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(3--
(trifluoromethyl)phenyl]methanone
##STR00074##
[0522] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 163-165.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.92 (t, J=4.8 Hz, 4H), 2.89
(t, J=4.8 Hz, 4H), 3.02 (s, 2H), 6.73 (s, 1H), 6.84 (m, 5H), 7.34
(t, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H),
8.01 (s, 1H).
EXAMPLE 58
{2-Amino-4-(spiro[benzo[d][1,3]-dioxole-2,4'piperidine]-1'-ylmethyl)thioph-
en-3-yl}(4-chlorophenyl)methanone
##STR00075##
[0524] The title compound is purified by column chromatography
(DCM:EtOAc/1:9 as eluent). Yellow solid, m.p. 209-211.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.06 (t, J=6.0 Hz, 4H), 3.02 (t,
J=6.0 Hz, 4H), 3.52 (s, 2H), 6.02 (br s, 2H), 6.76 (m, 5H), 7.42
(d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H).
EXAMPLE 59
{2-Amino-4-(5-tert-butylspiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-yl-
methyl)thiophen-3-yl}(4-chlorophenyl)methanone
##STR00076##
[0526] The title compound is purified by column chromatography
(DCM:EtOAc/1:9 as eluent). Yellow solid, m.p. 100-102.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.27 (s, 9H), 1.96 (t, J=5.6 Hz,
2H), 2.06 (t, J=5.6 Hz, 2H), 3.01 (t, J=6.0 Hz, 4H), 3.67 (s, 2H),
6.15 (br s, 2H), 6.62 (d, J=8.2 Hz, 1H), 6.78 (m, 2H), 6.84 (s,
1H), 7.39 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H).
EXAMPLE 60
{2-Amino-4-(4-fluorospiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-ylmeth-
yl)thiophen-3-yl}(4-chlorophenyl)methanone
##STR00077##
[0528] The title compound is purified by column chromatography
(DCM:EtOAc/9.9:0.1 as eluent). Yellow solid, m.p. 80-81.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.81 (t, J=6.0 Hz, 4H), 2.08 (t,
J=6.0 Hz, 4H), 3.03 (s, 2H), 6.10 (s, 1H), 6.13 (br s, 2H), 6.52
(d, J=7.6 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 6.72 (m, 1H), 7.40 (d,
J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H).
EXAMPLE 61
{2-Amino-4-(4-methylspiro[benzo[d][1,3]-dioxole-2,4'piperidine]-1'-ylmethy-
l)thiophen-3-yl}(4-chlorophenyl)methanone
##STR00078##
[0530] The title compound is purified by column chromatography
(DCM:EtOAc/7:3 as eluent). Yellow solid, m.p. 184-186.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.93 (t, J=5.6 Hz, 4H), 2.20 (s,
3H), 3.14 (m, 4H), 3.46 (s, 2H), 5.84 (m, 2H), 6.64 (m, 3H), 6.88
(s, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H).
EXAMPLE 62
{2-Amino-4-(5-methylspiro[benzo[d][1,3]-dioxole-2,4'-piperidine]-1'-ylmeth-
yl)thiophen-3-yl}(4-chlorophenyl)methanone
##STR00079##
[0532] The title compound is purified by column chromatography
(petroleum ether:EtOAc/2:8 as eluent). White solid, m.p.
119-121.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.77 (t, J=5.2
Hz, 4H), 2.06 (t, J=5.2 Hz, 4H), 2.23 (s, 3H), 3.02 (s, 2H), 6.08
(br s, 2H), 6.12 (s, 1H), 6.54 (m, 3H), 7.38 (d, J=8.4 Hz, 2H),
7.54 (d, J=8.4 Hz, 2H).
EXAMPLE 63
{2-Amino-4-[(4-(4-chlorophenylamino)piperidin-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone
##STR00080##
[0534] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 460.48 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 1.18 (m, 1H), 1.81 (m, 5H), 2.24
(m, 3H), 3.06 (s, 2H), 3.09 (m, 1H), 6.04 (br s, 2H), 6.18 (s, 1H),
6.36 (d, 2H, J=8.8 Hz), 7.07 (d, 2H, J=8.8 Hz), 7.38 (d, 2H, J=8.4
Hz), 7.54 (d, 2H, J=8.4 Hz).
EXAMPLE 64
{2-Amino-4-[(4-(4-chlorophenylmethylamino)piperidin-1-yl)methyl]thiophen-3-
-yl}(4-chlorophenyl)methanone
##STR00081##
[0536] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 476.47 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 1.40 (m, 3H), 1.67 (m, 3H), 2.20
(m, 2H), 2.70 (s, 3H), 2.92 (s, 2H), 3.30 (m, 1H), 6.02 (br s, 2H),
6.11 (s, 1H), 6.62 (d, 2H, J=9.2 Hz), 7.12 (d, 2H, J=9.2 Hz), 7.39
(d, 2H, J=8.4 Hz), 7.56 (d, 2H, J=8.4 Hz).
EXAMPLE 65
{2-Amino-4-[(4-(4-chlorophenyl)-[1,4]diazepan-1-yl)methyl]thiophen-3-yl}(4-
-chlorophenyl)methanone
##STR00082##
[0538] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 460.56 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 1.60 (m, 2H), 2.02 (m, 2H), 2.18
(m, 2H), 3.06 (s, 2H), 3.21 (m, 2H), 3.29 (m, 2H), 5.97 (br s, 2H),
6.11 (s, 1H), 6.49 (d, 2H, J=8.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 7.36
(d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4 Hz).
EXAMPLE 66
{2-Amino-4-[(7-(4-chlorophenyl)-2,7-diaza-spiro[4.4]non-2-yl)methyl]thioph-
en-3-yl}(4-chlorophenyl)methanone
##STR00083##
[0540] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 486.48 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 1.61 (m, 2H), 1.84 (m, 2H),
2.01-2.14 (m, 4H), 3.00-3.09 (m, 4H), 3.18 (m, 2H), 6.09 (br s,
2H), 6.11 (s, 1H), 6.39 (d, 2H, J=8.8 Hz), 7.15 (d, 2H, J=8.8 Hz),
7.34 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 Hz).
EXAMPLE 67
{2-Amino-4-[(5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone
##STR00084##
[0542] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 472.42 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 2.03 (m, 2H), 2.10 (m, 2H), 2.73
(m, 2H), 2.85 (m, 2H), 3.06 (s, 2H), 3.34 (m, 2H), 6.06 (br s, 2H),
6.10 (s, 1H), 6.54 (d, 2H, J=8.8 Hz), 7.20 (d, 2H, J=8.8 Hz), 7.24
(d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=8.4 Hz).
EXAMPLE 68
{2-Amino-4-[(5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]th-
iophen-3-yl}(4-chlorophenyl)methanone
##STR00085##
[0544] The title compound is purified by column chromatography
(cyclohexane:EtOAc/8:2 as eluent). Mass (m/z): 458.64 (M+1).
.sup.1H NMR (CDCl.sub.3) .delta.: 1.62 (m, 2H), 2.04 (m, 1H), 2.35
(m, 1H), 2.79 (m, 2H), 2.96-3.12 (m, 4H), 6.01 (br s, 2H), 6.29 (d,
2H, J=8.8 Hz), 6.36 (m, 1H), 7.06 (d, 2H, J=8.8 Hz), 7.23 (d, 2H,
J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz).
EXAMPLE 69
{2-Amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00086##
[0545] A.
2-[3-(4-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-
-dione
[0546] To a solution of
(2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (532
mg, 2 mmol; prepared as described in U.S. Pat. No. 6,323,214) in
acetic acid (15 mL) is added phthalic anhydride (360 mg, 2.4 mmol)
and the mixture is heated to reflux for 15 h. The solvent is
evaporated in vacuo and the residual material is dissolved in ethyl
acetate (20 mL). The organic solution is washed with a saturated
aqueous solution of NaHCO.sub.3 (5 mL), water (5 mL), then brine (5
mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo.
The crude product is stirred for 1 h in petroleum ether (20 mL),
then filtered, affording
(2-[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-dione
as a yellow powder. .sup.1H NMR (CDCl.sub.3) .delta.: 2.10 (s, 3H),
2.43 (s, 3H), 7.24 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.78
(m, 4H).
B.
2-[4-(Bromomethyl)-3-(4-chlorobenzoyl)-5-methylthiophen-2-yl]isoindolin-
e-1,3-dione
[0547] To the title A compound (2 mmol, 798 mg) in acetonitrile (10
mL) is added N-bromosuccinimide (2 mmol, 356 mg.) and the mixture
is heated at reflux for 2 h. After this time, another portion of
N-bromosuccinimide (2 mmol, 356 mg.) is added and the reflux is
continued for another 2 h. The solvent is then removed under
reduced pressure, and the residue dissolved in DCM (15 mL), washed
with water (5 mL), brine (5 mL), dried (Na.sub.2SO.sub.4), and
concentrated to give a dark oil. This residue is then purified by
flash chromathography (EtOAc:petroleum ether/2:8 as eluent) to
furnish the compound as a yellow solid. The powder is suspended in
petroleum ether (10 mL), the mixture is stirred for 30 min, and
then filtered to give
2-[4-bromomethyl-3-(4-chlorobenzoyl)-5-methylthiophen-2-yl]isoindoline-1,-
3-dione: m.p. 173-175.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.:
2.53 (s, 3H), 4.65 (s, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4
Hz, 2H), 7.63 (m, 2H), 7.73 (m, 2H).
C.
2-[3-(4-Chlorobenzoyl)-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-5-m-
ethylthiophen-2-yl]isoindoline-1,3-dione
[0548] To a stirred solution of the title B compound (900 mg, 0.5
mmol) in dry DMF (5 mL) is added K.sub.2CO.sub.3 (0.6 mmol, 83 mg).
The mixture is cooled with a bath of ice/water, and then the
1-(4-fluorophenyl)piperazine (3 equiv., 1.5 mmol) is added. The
mixture is stirred at room temperature for one hour, the solvent is
then removed under reduced pressure, and a mixture of DCM (15 mL)
and water (5 mL) is added to the residue. The organic phase is
washed with brine (5 mL) and dried (Na.sub.2SO.sub.4), filtered,
then concentrated in vacuo to give a brown residue that is purified
by column chromatography (ethyl acetate:DCM/1:9 as eluent) to
afford
2-[3-(4-chlorobenzoyl)-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-5-met-
hylthiophen-2-yl]isoindoline-1,3-dione: m.p. 110-112.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.23 (t, J=4.8 Hz, 4H), 2.42 (s,
2H), 2.72 (t, J=4.8 Hz, 4H), 3.23 (s, 2H), 6.60 (d, J=8.6 Hz, 1H),
6.64 (d, J=8.6 Hz, 1H), 6.85 (t, J=8.6 Hz, 2H), 7.32 (d, J=8.4 Hz,
2H), 7.61 (d, J=8.4 Hz, 2H), 7.68 (m, 2H), 7.72 (m, 2H).
D.
{2-Amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen--
3-yl}(4-chlorophenyl)methanone
[0549] A stirred suspension of the title C compound (0.5 mmol) and
hydrazine monohydrate (0.6 mmol, 29 .mu.L) in absolute EtOH (10 mL)
is heated to reflux for 3 h. The resulting solution is left cooled
RT for 1 h. The reaction is finished after the complete
solubilization of the starting material. The solvent is evaporated
and the residue partitioned between DCM (10 mL) and water (5 mL).
The separated organic phase is washed with brine (2 mL), dried
(Na.sub.2SO.sub.4), filtered, and then concentrated in vacuo to
obtain a residue that is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent) to afford
{2-amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}-(4-chlorophenyl)methanone as a yellow solid: m.p. 70-72.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=4.8 Hz, 4H), 2.23
(s, 3H), 2.83 (t, J=4.8 Hz, 4H), 2.96 (s, 2H), 5.82 (br s, 2H),
6.76 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.94 (t, J=8.6 Hz,
2H), 7.36 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H).
[0550] The following compounds are prepared analogously as
described in Example 69.
EXAMPLE 70
{2-Amino-5-methyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlor-
ophenyl)methanone
##STR00087##
[0552] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 78-80.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=4.8 Hz, 4H), 2.22 (s,
3H), 2.91 (t, J=4.8 Hz, 4H), 2.95 (s, 2H), 5.80 (br s, 2H), 6.83
(d, J=8.4 Hz, 2H), 7.23 (t, J=8.4 Hz, 3H), 7.35 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 71
{2-Amino-5-methyl-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone
##STR00088##
[0554] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 76-78.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 2.04 (t, J=4.8 Hz, 4H), 2.22 (s,
3H), 2.95 (s, 2H), 3.00 (t, J=4.8 Hz, 4H), 5.82 (br s, 2H), 6.82
(d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 72
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00089##
[0556] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 83-85.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=4.8 Hz, 4H), 2.22 (s,
3H), 2.87 (t, J=4.8 Hz, 4H), 2.95 (s, 2H), 5.80 (br s, 2H), 6.73
(d, J=9.2 Hz, 2H), 7.16 (d, J=9.2 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 73
{2-Amino-4-[(4-(4-bromophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl-
}(4-chlorophenyl)methanone
##STR00090##
[0558] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 73-75.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.96 (t, J=5.2 Hz, 4H), 2.22 (s,
3H), 2.87 (t, J=5.2 Hz, 4H), 2.94 (s, 2H), 5.81 (br s, 2H), 6.68
(d, J=9.2 Hz, 2H), 7.29 (d, J=9.2 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 74
{2-Amino-4-[(4-(4-iodophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}-
(4-chlorophenyl)methanone
##STR00091##
[0560] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 72-73.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=5.2 Hz, 4H), 2.04 (s,
3H), 2.89 (t, J=5.2 Hz, 4H), 2.98 (s, 2H), 5.80 (br s, 2H), 6.58
(d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 75
{2-Amino-5-methyl-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl-
}(4-chlorophenyl)methanone
##STR00092##
[0562] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 85-87.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=5.4 Hz, 4H), 2.331 (s,
3H), 3.08 (s, 2H), 3.11 (t, J=5.4 Hz, 4H), 6.26 (br s, 2H), 6.70
(d, J=8.8 Hz, 2H), 6.80 (d, J=9.2 Hz, 2H), 8.05 (d, J=9.2 Hz, 2H),
8.13 (d, J=8.8 Hz, 2H).
EXAMPLE 76
4-{4-[(5-Amino-4-(4-chlorobenzoyl)-2-methylthiophen-3-yl)methyl]piperazin--
1-yl}benzonitrile
##STR00093##
[0564] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 76-77.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.96 (t, J=4.8 Hz, 4H), 2.21 (s,
3H), 2.95 (s, 2H), 3.04 (t, J=4.8 Hz, 4H), 5.84 (br s, 2H), 6.74
(d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H),
7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 77
{2-Amino-4-[(4-benzylpiperazin-1-yl)methyl)-5-methylthiophen-3-yl](4-chlor-
ophenyl)methanone
##STR00094##
[0566] The title compound is purified by column chromatography
(EtOAc as eluent). Yellow solid, m.p. 48-50.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta.: 1.84 (t, J=5.2 Hz, 4H), 2.18 (s, 3H), 2.86
(t, J=5.2 Hz, 4H), 3.40 (s, 2H), 3.49 (s, 2H), 5.79 (br s, 2H),
7.26 (m, 5H), 7.33 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H).
EXAMPLE 78
{2-Amino-4-[(4-(4-methoxyphenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone
##STR00095##
[0568] The title compound is purified by column chromatography
(EtOAc:DCM/1.5:8.5 as eluent). Yellow solid, m.p. 63-65.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=5.4 Hz, 4H), 2.21 (s,
3H), 2.80 (t, J=5.4 Hz, 4H), 2.94 (s, 2H), 3.75 (s, 3H), 5.81 (br
s, 2H), 6.81 (s, 4H), 7.34 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz,
2H).
EXAMPLE 79
{2-Amino-5-methyl-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlo-
rophenyl)methanone
##STR00096##
[0570] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 77-79.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=5.2 Hz, 4H), 2.22 (s,
3H), 2.25 (s, 3H), 2.85 (t, J=5.2 Hz, 4H), 2.94 (s, 2H), 5.81 (br
s, 2H), 6.75 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.34 (d,
J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H).
EXAMPLE 80
{2-Amino-4-[(4-(3,4-dichlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-
-3-yl}(4-chlorophenyl)methanone
##STR00097##
[0572] The title compound is purified by column chromatography
(EtOAc:DCM/1:9 as eluent). Yellow solid, m.p. 63-65.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.96 (t, J=4.8 Hz, 4H), 2.22 (s,
3H), 2.88 (t, J=4.8 Hz, 4H), 2.94 (s, 2H), 5.82 (br s, 2H), 6.63
(dd, J=9.2 and 2.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 7.22 (d, J=9.2
Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H).
EXAMPLE 81
{2-Amino-5-methyl-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]t-
hiophen-3-yl}(4-chlorophenyl)methanone
##STR00098##
[0574] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 60-61.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.99 (t, J=5.2 Hz, 4H), 2.22 (s,
3H), 2.96 (m, 6H), 5.81 (br s, 2H), 6.96 (d, J=7.6 Hz, 1 H), 7.00
(s, 1 H), 7.03 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.37 (d,
J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H).
EXAMPLE 82
{2-Amino-4-[(4-(3-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00099##
[0576] The title compound is purified by column chromatography
(EtOAc:DCM/0.75:9.25 as eluent). Yellow solid, m.p. 58-60.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.96 (t, J=4.8 Hz, 4H), 2.22
(s, 3H), 2.92 (t, J=4.8 Hz, 4H), 3.00 (s, 2H), 5.82 (br s, 2H),
6.68 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.78 (s, 1H), 7.12
(t, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz,
2H).
EXAMPLE 83
{2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]--
5-methylthiophen-3-yl}(4-chlorophenyl)methanone
##STR00100##
[0578] The title compound is purified by column chromatography
(EtOAc:DCM/0.5:9.5 as eluent). Yellow solid, m.p. 133-135.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta.: 1.98 (t, J=4.4 Hz, 4H), 2.22
(s, 3H), 2.93 (t, J=4.4 Hz, 4H), 2.96 (s, 2H), 5.82 (br s, 2H),
6.84 (dd, J=8.8 and 2.8 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 7.29 (d,
J=8.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H).
EXAMPLE 84
{2-Amino-5-ethyl-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl-
}(4-chlorophenyl)methanone
##STR00101##
[0579] A. A mixture of (Z) and (E)
2-(4-chlorobenzoyl)-3-methylhex-2-enenitrile
[0580] A mixture of pentan-2-one (20 mmol),
3-(4-chlorophenyl)-3-oxopropanenitrile (3.6 g, 20 mmol),
.beta.-alanine (180 mg, 2 mmol), acetic acid (2.6 mL) and toluene
(60 mL) is heated to reflux in a Dean-Stark system for 18 h. The
solution is cooled to RT, then diluted with EtOAc (50 mL), washed
with 5% NaHCO.sub.3 (3.times.20 mL), water (20 mL), brine (20 mL),
dried (Na.sub.2SO.sub.4) and finally concentrated in vacuo. A
mixture of the two isomers is obtained as a colorless oil by
chromatographic purification of the crude residue on silica gel
using EtOAc:petroleum ether (0.5:9.5) as eluent.
B.
(2-Amino-5-ethyl-4-methylthiophen-3-yl)(4-chlorophenyl)methanone
[0581] The title A compound(s) (5 mmol), TEA (0.7 mL, 5 mmol) and
sulfur (192 mg, 6 mmol) in EtOH (10 mL) are heated at reflux for 2
h. After cooling to RT, the solvent is removed and the residue is
dissolved in DCM (20 mL). The organic solution is washed with 0.1 N
HCl (5 mL), 5% NaHCO.sub.3 (5 mL), water (5 mL), brine (5 mL),
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude
residue was purified by chromatography on a silica gel column,
eluting with EtOAc:petroleum ether (1:9) to afford
(2-amino-5-ethyl-4-methylthiophen-3-yl)(4-chlorophenyl)methanone as
a yellow oil. .sup.1H-NMR (CDCl.sub.3): .delta. 1.18 (t, J=7.6 Hz,
3H), 2.18 (s, 3H), 2.55 (q, J=7.6 Hz, 2H), 5.77 (bs, 2H), 7.36 (d,
J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H).
C.
2-[3-(4-Chlorobenzoyl)-4-methyl-5-ethyl-thiophen-2-yl]-isoindole-1,3-di-
one
[0582] The title B compound (4 mmol) is dissolved in acetic acid
(25 mL). To the solution is added phthalic anhydride (5 mmol, 740
mg) and the mixture is heated under reflux for 5 h. The solvent is
evaporated in vacuo and the residual material is dissolved in DCM
(30 mL). The organic solution is washed with water (10 mL), brine
(10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
crude product is first triturated for 1 h in petroleum ether (20
mL), then purified by column chromatography (EtOAc:petroleum
ether/2:8 as eluent) to afford
2-[3-(4-chlorobenzoyl)-4-methyl-5-ethyl-thiophen-2-yl]-isoindole-1,3-dion-
e as a white solid: m.p. 115-117.degree. C. .sup.1H-NMR
(CDCl.sub.3): .delta. 1.34 (t, J=7.6 Hz, 3H), 2.17 (s, 3H), 2.82
(q, J=7.6 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H),
7.77 (m, 2H), 7.79 (m, 2H).
D.
2-[5-Ethyl-4-bromomethyl-3-(4-chloro-benzoyl)-thiophen-2-yl]-isoindole--
1,3-dione
[0583] To a solution of title C compound (2 mmol) in CCl.sub.4 (40
mL), a mixture of N-bromosuccinimide (784 mg, 4.4 mmol) and benzoyl
peroxide (32 mg) is added and the mixture refluxed for 2 h. The
resulting yellow solution is then cooled to RT, during which
succinimide separates and is removed by filtration. The filtrate is
concentrating in vacuo, and the residue is diluted with DCM (20
mL). The organic solution is washed with 5% NaHCO.sub.3 (10 mL),
water (10 mL), brine (10 mL), dried (Na.sub.2SO.sub.4) and
concentrated to give a yellow residue which is purified by column
chromatography (EtOAc:petroleum ether/2:8 as eluent) to give
2-[5-ethyl-4-bromomethyl-3-(4-chloro-benzoyl)-thiophen-2-yl]-isoi-
ndole-1,3-dione as an orange oil. .sup.1H-NMR (CDCl.sub.3): .delta.
1.39 (t, J=7.6 Hz, 3H), 2.96 (q, J=7.6 Hz, 2H), 4.66 (s, 2H), 7.17
(d, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.73 (m, 2H), 7.76 (m,
2H).
E.
2-{3-(4-Chlorobenzoyl)-4-(4-(4-fuorophenyl)-piperazin-1-ylmethyl-5-ethy-
l]-thiophen-2-yl}-isoindole-1,3-dione
[0584] To an ice/water cooled, stirred solution of the title D
compound (0.5 mmol) in dry DMF (2.5 mL) is added TEA (0.12 mL, 1
mmol) and then the appropriate 1-(4-fluorophenyl)piperazine (0.6
mmol). The mixture is then stirred at RT for 2 h. The solvent is
removed under reduced pressure, the residue dissolved in DCM (10
mL), and washed with water (5 mL), brine (5 mL), and dried
(Na.sub.2SO.sub.4). After evaporation under vacuum, the residue is
purified by column chromatography on silica gel (EtOAc:petroleum
ether/1.5:8.5 as eluent) to afford
2-{3-(4-chlorobenzoyl)-4-[4-(4-fluorophenyl)-piperazin-1-ylmethyl-5-ethyl-
]-thiophen-2-yl}-isoindole-1,3-dione as a white solid: m.p.
122-124.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 1.20 (t, J=7.6
Hz, 3H), 1.99 (m, 4H), 2.68 (q, J=7.6 Hz, 2H), 3.02 (m, 4H), 3.22
(s, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.38 (d,
J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.72 (m, 2H), 7.84 (m,
2H).
F.
{2-Amino-4-[4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3--
yl}(4-chlorophenyl)methanone
[0585] A stirred suspension of the title E compound (0.25 mmol) and
100% hydrazine monohydrate (0.3 mmol, 14 .mu.L) in absolute EtOH (5
mL) is refluxed for 3 h. The solvent is evaporated and the residue
is partitioned between DCM (10 mL) and water (5 mL). The separated
organic phase is washed with brine (2 mL) and dried, then
concentrated in vacuo to obtain a residue which is purified by
column chromatography (EtOAc:DCM/8:2 as eluent) to give
{2-amino-4-[4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl-
}(4-chlorophenyl)methanone as a yellow solid: m.p. 123-125.degree.
C. .sup.1H-NMR (CDCl.sub.3): .delta. 1.21 (t, J=7.6 Hz, 3H), 1.98
(m. 4H), 2.61 (q, J=7.6 Hz, 2H), 2.84 (m, 4H), 2.96 (s, 2H), 5.77
(bs, 2H), 6.82 (m, 2H), 6.93 (d J=9.0 Hz, 2H), 7.34 (d J=8.6 Hz,
2H), 7.57 (d, J=8.6 Hz, 2H).
[0586] The following compounds are prepared analogously as
described in Example 84.
EXAMPLE 85
{2-Amino-5-ethyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chloro-
phenyl)methanone
##STR00102##
[0588] The title compound is purified by column chromatography
(EtOAc:petroleum ether/1.5:8.5 as eluent). Yellow solid, m.p.
104-106.degree. C. .sup.1H-NMR (CDCl.sub.3): .delta. 1.22 (t, J=7.6
Hz, 3H), 1.98 (m. 4H), 2.64 (q, J=7.6 Hz, 2H), 2.92 (m, 4H), 2.96
(s, 2H), 5.78 (bs, 2H), 6.85 (m 3H), 7.23 (m, 2H), 7.37 (d, J=8.4
Hz, 2H), 7.56 (d, J=8.4 Hz, 2H).
EXAMPLE 86
{2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl-
}(4-chlorophenyl)methanone
##STR00103##
[0590] The title compound is purified by column chromatography
(EtOAc:petroleum ether/1.5:8.5 as eluent). Yellow solid, m.p.
115-117.degree. C. .sup.1H-NMR (CDCl.sub.3): .delta. 1.23 (t, J=7.6
Hz, 3H), 1.97 (m. 4H), 2.61 (q, J=7.6 Hz, 2H), 2.88 (m, 4H), 2.96
(s, 2H), 5.77 (bs, 2H), 6.72 (d J=9.0 Hz, 2H), 7.19 (d J=9.0 Hz,
2H), 7.34 (d J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H).
EXAMPLE 87
{2-Amino-5-phenyl-4-[(piperidin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)-
methanone
##STR00104##
[0591] A.
2-[3-(4-Chlorobenzoyl)-4-methyl-5-phenylthiophen-2-ylisoindole-1-
,3-dione
[0592] The title A compound is prepared from the title C compound
of Example 1 following the procedure described by Romagnoli et al.
in J. Med. Chem. 2006, 49(13), 3906-3915. The product is purified
by column chromatography (eluent EtOAc:petroleum ether/1.5:8.5 as
eluent) to afford
2-[3-(4-chlorobenzoyl)-4-methyl-5-phenylthiophen-2-yl]isoindole-1,3-dione
as a brown solid, m.p. 223-225.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta.: 2.24 (s, 3H), 7.24 (d, J=8.4 Hz, 2H), 7.74 (m, 5H), 7.80
(m, 6H).
B.
2-[4-Bromomethyl-3-(4-chlorobenzoyl)-5-phenylthiophen-2-yl]isoindole-1,-
3-dione
[0593] To a refluxing suspension of the title A compound (458 mg, 1
mmol) in CCl.sub.4 (10 mL), is added NBS (180 mg, 1 mmol) and
benzoyl peroxide (14 mg, 0.06 mmol) and the mixture is refluxed for
1 h. After this time, a mixture of N-bromosuccinimide (180 mg, 1
mmol.) and benzoyl peroxide (14 mg, 0.06 mmo) is added and the
mixture refluxed for another hour. The yellow solution is then
cooled to RT, and succinimide that separates upon cooling is
removed by filtration and the filtercake is washed with CCl.sub.4
(5 mL). The filtrate is washed with 5% NaHCO.sub.3 solution (5 mL),
water (5 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, and
concentrated to give a yellow solid which is suspended with
petroleum ether (10 mL). The mixture is stirred for 30 min, and the
solid is collected by filtration to afford
2-[4-bromomethyl-3-(4-chlorobenzoyl)-5-phenylthiophen-2-yl]isoindole-1,3--
dione which is used as such for the next reaction without further
purification, m.p. 160-161.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta.: 4.73 (s, 2H), 7.21 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz,
2H), 7.52 (m, 1H), 7.68 (m, 8H).
C.
2-[3-(4-Chlorobenzoyl)-5-phenyl-4-((piperidin-1-yl)methyl)thiophen-2-yl-
]isoindole-1,3-dione
[0594] To a stirred solution of the title B compound (265 mg, 0.5
mmol) in dry DMF (5 mL) is added K.sub.2CO.sub.3 (70 mg, 0.5 mmol).
The mixture is cooled with a bath of ice/water, and then piperidine
(4 equiv., 2 mmol) is added. The mixture is stirred at RT for 2 h.
After this time, the solvent is removed under reduced pressure, and
the residue is taken up in a mixture of EtOAc (15 mL) and water (5
mL). The organic phase is washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, and concentrated under vacuo to give a brown
residue which is purified by column chromatography (EtOAc:petroleum
ether/1.5:8.5 as eluent) to afford
2-[3-(4-chlorobenzoyl)-5-phenyl-4-((piperidin-1-yl)methyl)thiophen-2-yl]i-
soindole-1,3-dione as a yellow solid, m.p. 187-189.degree. C.
.sup.1H NMR (CDCl.sub.3) .delta.: 1.25 (m, 6H), 1.65 (m, 4H), 2.98
(s, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.53 (m, 3H), 7.73 (m, 8H).
D.
{2-Amino-5-phenyl-4-[(piperidin-1-yl)methyl]thiophen-3-yl}(4-chlorophen-
yl)methanone
[0595] A stirred suspension of the title C compound (0.5 mmol) and
100% hydrazine monohydrate (1.2 eq, 0.6 mmol, 29 .mu.L) in absolute
ethanol (10 mL) is refluxed for 1 h. After this time, the solvent
is evaporated and the residue is portioned between EtOAc (10 mL)
and water (5 mL). The separated organic phase is washed with brine
(2 mL), dried, and concentrated under vacuo to obtain a residue
which is purified by column chromatography (EtOAc: petroleum
ether/4:6 as eluent) to give
{2-amino-5-phenyl-4-[(piperidin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl-
)methanone as a yellow solid, m.p. 185-187.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta.: 1.24 (m, 6H), 1.66 (m, 4H), 2.99 (s, 2H),
5.69 (br s, 2H), 7.33 (m, 7H), 7.65 (d, J=8.6 Hz, 2H).
EXAMPLE 88
Example of a Scale-Up Synthesis
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-y-
l}(4-chlorophenyl)methanone
##STR00105##
[0596] A.
(2-Amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone
[0597] A 12 L, 3 neck round bottom flask equipped with a mechanical
stirrer and a thermometer is charged with
3-(4-chlorophenyl)-3-oxopropanenitrile (800 g, 4.46 mol), absolute
EtOH (4 L), sulphur (321 g, 4.46 mol) and ethylmethylketone (321 g,
4.46 mol). Morpholine (388 g, 4.46 mol) is added and the reaction
mixture thickens, and the temperature increases from 18.degree. C.
to 30.degree. C. The reaction mixture is stirred for 1 h at ambient
temperature, heated at reflux overnight, then cooled to ambient
temperature and concentrated in vacuo. The residue is combined with
a previous batch of crude material from a 500 g reaction. The
combined residues are taken up in EtOAc (12 L), washed with water
(6 L), 10% NaHSO.sub.4 (3 L) and brine (2 L), dried over anhydrous
NaSO.sub.4 and filtered through Celite. The filtrate is
concentrated in vacuo to give a gummy solid. The solids are
collected by filtration, washed with hexanes and air dried to yield
(2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone as a
tan coloured solid (680 g).
B.
2-[3-(4-Chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-dione
[0598] A 12 L, 3 neck round bottom flask equipped with a mechanical
stirrer and a thermometer is charged with the title A compound (800
g, 3.01 mol), acetic acid (6 L), and phthalic anhydride (535 g,
3.62 mol). The reaction mixture is stirred at reflux overnight,
then allowed to cool to ambient temperature and concentrated in
vacuo. Methyl-t-butylether (MTBE, 2 L) is added to the residue, and
the resulting slurry is filtered. The solids are washed with MTBE
(500 mL) and hexanes (1 L), then air dried to yield
2-[3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl]isoindoline-1,3-dione
as a tan colored solid (1050 g). The .sup.1H NMR spectrum is
consistent with the structure.
C.
2-(4-(Bromomethyl)-3-(4-chlorobenzoyl)-5-methylthiophen-2-yl]isoindolin-
e-1,3-dione
[0599] A three-neck 3 L round bottom flask equipped with a
mechanical stirrer and a thermometer is charged with the title B
compound (150 g, 0.38 mol), N-bromosuccinimide (67 g, 0.38 mol),
and acetonitrile (1.5 L). The reaction mixture is stirred at reflux
for 2 h, then treated with more N-bromosuccinimide (67 g, 0.38
mol). Heating at refluxing is continued for 2 h more, and the
reaction mixture is allowed to cool to ambient temperature, and
concentrated in vacuo. The residue is taken up in DCM (600 mL) and
washed with water (200 mL), saturated NaHCO.sub.3 (200 mL), water
(200 mL), and brine (200 mL), dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The dark brown solid is purified by
chromatography (DCM as eluent) to yield a tan solid which is
slurried in diethyl ether (Et.sub.2O, 300 mL), then filtered and
dried to afford
2-[4-(bromomethyl)-3-(4-chlorobenzoyl)-5-methylthiophen-2-yl]isoindoline--
1,3-dione as an off-white solid (86 g). The .sup.1H NMR spectrum is
consistent with the structure.
D.
2-[3-(4-Chlorobenzoyl)-4-((4-(3-fluorophenyl)piperazin-1-yl)methyl)-5-m-
ethylthiophen-2-yl]isoindoline-1,3-dione
[0600] A 2 L round bottom flask equipped with a mechanical stirrer
is charged with the title C compound (80.7 g, 0.17 mol), CHCl.sub.3
(1.2 L), and triethylamine (3 equiv). The mixture is cooled in an
ice/water bath to .about.5.degree. C., then the appropriate
4-(3-fluorophenyl)piperazine (0.9 equiv) is added. The reaction
mixture is stirred at 0.degree. C. for 5 min, then at ambient
temperature for 1 h. The reaction mixture is washed with water (500
mL), saturated NaHCO.sub.3 (500 mL), and brine (500 mL), then dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo
to half volume. The crude material was purified by chromatography
(2% EtOAc in DCM). The eluent is concentrated in vacuo, then
slurried in Et.sub.2O (300 mL), filtered and dried to give
2-[3-(4-chlorobenzoyl)-4-((4-(3-fluorophenyl)piperazin-1-yl)methyl)-5-met-
hylthiophen-2-yl]isoindoline-1,3-dione (40 g) as an off-white
solid.
E.
{2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen--
3-yl}(4-chlorophenyl)methanone
[0601] A 2 L round bottom flask is charged with the title D
compound (40 g, 0.07 mol), toluene (0.2 M), and EtOH (0.2 M).
Hydrazine hydrate (1.5 equiv, 64% hydrazine) is added in one
portion, and the mixture is heated to reflux. Upon reaching the
reflux temperature, the reaction mixture becomes a clear yellow
solution, and upon continued heating a precipitate is formed. The
reaction is monitored by TLC, and when the reaction is complete
(usually .about.5 h), the reaction mixture is allowed to cool to
ambient temperature and concentrated. The residue is taken up in
Et.sub.2O (600 mL), washed with water (150 mL), saturated
NaHCO.sub.3 (150 mL), and brine (150 mL), then dried
(Na.sub.2SO.sub.4). The solvent is removed in vacuo, and the
resulting yellow solid is stirred in ethanol (80 mL) then filtered
and dried to afford
{2-amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3--
yl}(4-chlorophenyl)methanone as a yellow solid (24 g), m.p.
140-141.degree. C. ESI-MS: 444 (M+H).sup.+. Elemental Analysis:
calc C 62.22%, H 5.22%, N 9.46%; found C 62.21%, H 5.27%, N 9.48%.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 7.54 (d, J=8.4 Hz, 2H),
7.37 (d, J=8.4 Hz), 7.09-7.21 (m, 1H), 6.46-6.59 (m, 3H), 5.82 (s,
2H), 2.89-2.95 (m, 6H), 2.22 (s, 3H), 1.95-1.99 (m, 4H).
* * * * *