U.S. patent application number 10/096269 was filed with the patent office on 2002-09-12 for benzylpiperazinyl-indolinylethanones.
This patent application is currently assigned to Neurogen Corporation.. Invention is credited to Thurkauf, Andrew, Zhao, He.
Application Number | 20020128274 10/096269 |
Document ID | / |
Family ID | 26836742 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128274 |
Kind Code |
A1 |
Zhao, He ; et al. |
September 12, 2002 |
Benzylpiperazinyl-indolinylethanones
Abstract
Disclosed are benzylpiperazinyl-indolinylethanone compounds
which are useful for the treatment and/or prevention of
neuropsychological disorders including, but not limited to,
schizophrenia, mania, dementia, depression, anxiety, compulsive
behavior, substance abuse, Parkinson-like motor disorders and
motion disorders related to the use of neuroleptic agents.
Pharmaceutical compositions, including packaged pharmaceutical
compositions, are further provided. Compounds of the invention are
also useful as probes for the localization of GABA.sub.A receptors
in tissue samples.
Inventors: |
Zhao, He; (Branford, CT)
; Thurkauf, Andrew; (Danbury, CT) |
Correspondence
Address: |
Steven J. Sarussi
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Assignee: |
Neurogen Corporation.
Branford
CT
|
Family ID: |
26836742 |
Appl. No.: |
10/096269 |
Filed: |
March 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10096269 |
Mar 12, 2002 |
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09594040 |
Jun 14, 2000 |
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6355644 |
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60138974 |
Jun 14, 1999 |
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Current U.S.
Class: |
514/254.09 ;
544/373 |
Current CPC
Class: |
C07D 209/12 20130101;
C07D 209/14 20130101; C07D 209/42 20130101; C07D 209/08 20130101;
C07D 209/86 20130101; C07D 209/10 20130101 |
Class at
Publication: |
514/254.09 ;
544/373 |
International
Class: |
A61K 031/496; C07D
43/02 |
Claims
What is claimed is:
1. A compound of the formula: 46or a pharmaceutically acceptable
salt thereof, wherein A represents a phenyl group optionally
substituted with up to four groups independently selected from
halogen, hydroxy, amino, mono- or
di(C.sub.1-C.sub.6)hydrocarbylamino, aminosulfonyl, C.sub.1-C.sub.6
hydrocarbylaminosulfonyl, di(C.sub.1-C.sub.6)hydrocarbyla-
minosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl,
trifluoromethyl, C.sub.1-C.sub.6 hydrocarbyl, trifluoromethoxy,
C.sub.3-C.sub.6 cyclohydrocarbyl, and C.sub.1-C.sub.6 alkoxy;
R.sub.1 represents hydrogen, halogen, hydroxy, amino,
aminosulfonyl, C.sub.1-C.sub.6 hydrocarbylaminosulfonyl,
di(C.sub.1-C.sub.6)hydrocarbylaminosulfonyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, C.sub.1-C.sub.6 hydrocarbyl,
cyclohydrocarbylhydrocarbyl, C.sub.3-C.sub.7 cyclohydrocarbyl, and
C.sub.1-C.sub.6 alkoxy; and R.sub.2 is C.sub.1-C.sub.6 hydrocarbyl
and R.sub.3 is hydrogen or C.sub.1-C.sub.6 hydrocarbyl; or R.sub.2
is hydrogen and R.sub.3 is mono, di, or trifluoromethyl,
hydroxy(C.sub.1-C.sub.3)hydrocarbyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.3)hydrocarbyl, mono or
di(C.sub.1-C.sub.6)hydrocarby- lamino(C.sub.1-C.sub.3)hydrocarbyl,
carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl,
carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)hydrocarbylcarbamoy- l,
aryl(C.sub.1-C.sub.6)hydrocarbylcarbamoyl, or
N,N-(aryl(C.sub.1-C.sub.6- )
hydrocarbyl)((C.sub.1-C.sub.6)hydrocarbyl)carbamoyl; or R.sub.2 and
R.sub.3 taken together with the atoms to which they are attached
form a saturated ring having from 5 to 7 carbon atoms; or R.sub.3
is hydrogen and R.sub.2 is mono, di, or trifluoromethyl,
hydroxy(C.sub.1-C.sub.3)hydr- ocarbyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.3)hydrocarbyl, mono or
di(C.sub.1-C.sub.6)hydrocarbylamino(C.sub.1-C.sub.3)hydrocarbyl,
carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl,
carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)hydrocarbylcarbamoyl,
aryl(C.sub.1-C.sub.6)hydrocarbyl- carbamoyl,
N,N-(aryl(C.sub.1-C.sub.6)hydrocarbyl)((C.sub.1-C.sub.6)hydroca-
rbyl)carbamoyl, or alkenyl.
2. A compound of the formula: 47or a pharmaceutically acceptable
salt thereof, wherein A represents a phenyl group optionally
substituted with up to four groups independently selected from
halogen, hydroxy, amino, mono- or di(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl, C.sub.1-C.sub.6 alkylaminosulfonyl,
di(C.sub.1-C.sub.6)alkylaminosulfonyl, cyano, nitro,
cycloalkylalkyl, trifluoromethyl, (C.sub.1-C.sub.6)alkyl,
trifluoromethoxy, C.sub.3-C.sub.6 cycloalkyl, and C.sub.1-C.sub.6
alkoxy; R.sub.1 represents hydrogen, halogen, hydroxy, amino,
aminosulfonyl, C.sub.1-C.sub.6 alkylaminosulfonyl,
di(C.sub.1-C.sub.6)alkylaminosulfonyl- , cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)alkyl,
cycloalkylalkyl, C.sub.3-C.sub.6 cycloalkyl, and C.sub.1-C.sub.6
alkoxy; and R.sub.2 is (C.sub.1-C.sub.6)alkyl and R.sub.3 is
hydrogen or (C.sub.1-C.sub.6)alkyl; or R.sub.2 is hydrogen and
R.sub.3 is mono, di, or trifluoromethyl,
hydroxy(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.3)alkyl, mono or
di(C.sub.1-C.sub.6)alkylamino(C.sub- .1-C.sub.3)alkyl, carboxamido,
mono or dialkylaminocarbonyl, aminoalkyl, carboxy, C.sub.1-C.sub.6
alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)alkylcarbamoyl,
aryl(C.sub.1-C.sub.6)alkylcarbamoyl,
N,N-(aryl(C.sub.1-C.sub.6)alkyl)((C.sub.1-C.sub.6)alkyl) carbamoyl,
or alkenyl; or R.sub.2 and R.sub.3 taken together with the atoms to
which they are attached form a saturated ring having from 5 to 7
carbon atoms.
3. A compound according to claim 1, wherein A is a group of the
formula: 48where R.sub.4 and R.sub.5 independently represent
hydrogen, halogen, hydroxy, amino, mono- or
di(C.sub.1-C.sub.6)alkylamino, aminosulfonyl, C.sub.1-C.sub.6
alkylaminosulfonyl, di(C.sub.1-C.sub.6)alkylaminosulfonyl- , cyano,
nitro, trifluoromethoxy, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
alkoxy.
4. A compound according to claim 3, wherein R.sub.3 is hydrogen and
R.sub.2 is C.sub.1-C.sub.6 alkyl.
5. A compound according to claim 4, wherein R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl.
6. A compound according to claim 3, wherein both R.sub.2 and
R.sub.3 are C.sub.1-C.sub.6 alkyl.
7. A compound according to claim 6, wherein R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl.
8. A compound according to claim 3, wherein R.sub.2 and R.sub.3
together form a C.sub.3-C.sub.5-alkylene group.
9. A compound according to claim 3, wherein R.sub.2 and R.sub.3
together form a C.sub.4-alkylene group.
10. A compound according to claim 9, wherein R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl.
11. A compound according to claim 3, wherein R.sub.2 is hydrogen
and R.sub.3 is mono, di, or trifluoromethyl,
hydroxy(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.3)alkyl, mono or
di(C.sub.l-C.sub.6)alkylamino(C.sub.1-C.sub.3)alkyl, aminoalkyl,
carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)alkylcarbamoyl,
aryl(C.sub.1-C.sub.6)alkylcarbamoyl,
N,N-(aryl(C.sub.1-C.sub.6)alkyl) ((C.sub.1-C.sub.6)alkyl)
carbamoyl, or alkenyl.
12. A compound according to claim 11, wherein R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl.
13. A compound according to claim 1, which is
2-{4-[(4-chlorophenyl)methyl-
]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
14. A compound according to claim 1, which is
2-{4-[(4-methylphenyl)methyl-
]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
15. A compound according to claim 1, which is
2-{4-[(4-ethylphenyl)methyl]-
piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
16. A compound according to claim 1, which is
2-{4-[(4-isopropylphenyl)met-
hyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one.
17. A compound according to claim 1, which is
1-((2R,3R)-2,3-dimethylindol-
inyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl}ethan-1-one.
18. A compound according to claim 1, which is
1-((2S,3S)-2,3-dimethylindol-
inyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl}ethan-1-one.
19. A compound according to claim 1, which is
1-(2,3-cis-dimethylindolinyl-
)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
20. A compound according to claim 1, which is
1-(2,3-cis-dimethylindolinyl-
)-2-{4-[(4-methoxyphenyl)methyl]piperazinyl}ethan-1-one.
21. A compound according to claim 1, which is
1-(2,3-cis-dimethylindolinyl-
)-2-{4-[(3-chloro-6-methoxyphenyl)methyl]piperazinyl}ethan-1-one.
22. A compound according to claim 1, which is
1-(2,3-cis-dimethylindolinyl-
)-2-{4-[(4-ethylphenyl)methyl]piperazinyl}ethan-1-one.
23. A compound according to claim 1, which is
1-(2,3-trans-dimethylindolin-
yl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
24. A compound according to claim 1, which is
1-(2,3-trans-dimethylindolin-
yl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
25. A compound according to claim 1, which is
1-[(4b,8a-cis-5,6,7,8,9,4b,8-
a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-chlorophenyl)methyl]piperaz-
inyl}ethan-1-one.
26. A compound according to claim 1, which is
1-[(4b,8a-cis-5,6,7,8,9,4b,8-
a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-methylphenyl)methyl]piperaz-
inyl}ethan-1-one (FIG. 1, 1o).
27. A compound according to claim 1, which is
1-[(4b,8a-cis-5,6,7,8,9,4b,8-
a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-ethylphenyl)methyl]piperazi-
nyl}ethan-1-one.
28. A compound according to claim 1, which is
1-[(4b,8a-cis-5,6,7,8,9,4b,8-
a-heptahydro-4aH-carbazol-9-yl)ethyl]-2-{4-[(4-isopropylphenyl)methyl]pipe-
razinyl}ethan-1-one.
29. A compound according to claim 1, which is methyl
(2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2-carboxylate.
30. A compound according to claim 1, which is methyl
(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
31. A compound according to claim 1, which is methyl
(2S)-1-(2-{4-[(4-ethylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
32. A compound according to claim 1, which is methyl
(2S)-1-(2-{4-[(4-isopropylphenyl)methyl]piperazinyl}indoline-2-carboxylat-
e.
33. A compound according to claim 1, which is methyl
(2R)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2-carboxylate.
34. A compound according to claim 1, which is methyl
(2R)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indoline-2-carboxylate.
35. A compound according to claim 1, which is
(2S)-1-(2-{4-[(4-methylpheny-
l)methyl]piperazinyl}acetyl)indoline-2-carboxylic acid.
36. A compound according to claim 1, which is
(2R)-1-(2-{4-[(4-chloropheny-
l)methyl]piperazinyl}acetyl)indoline-2-carboxylic acid.
37. A compound according to claim 1, which is
[(2S)-1-(2-{4-[(4-chlorophen-
yl)methyl]piperazinyl}acetyl)indoline-2-yl]-N-carboxamide.
38. A compound according to claim 1, which is
[(2S)-1-(2-{4-[(4-methylphen-
yl)methyl]piperazinyl}acetyl)indoline-2-yl]-N,N-dimethylcarboxamide.
39. A compound according to claim 1, which is
1-[(2S)-2-(hydroxymethyl)ind-
olinyl]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
40. A compound according to claim 1, which is
1-[(2S)-2-(hydroxymethyl)ind-
olinyl]-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
41. A compound according to claim 1, which is
1-[(2S)-2-(hydroxymethyl)ind-
olinyl]-2-{4-[(4-ethylphenyl)methyl]piperazinyl}ethan-1-one.
42. A compound according to claim 1, which is
1-[(2S)-2-(hydroxymethyl)ind-
olinyl]-2-{4-[(4-isopropylphenyl)methyl]piperazinyl}ethan-1-one.
43. A compound according to claim 1, which is
1-[(2S)-2-(methoxymethyl)ind-
olinyl]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
44. A compound according to claim 1, which is
1-[(2S)-2-(methoxymethyl) indolinyl]-2-{4- [(4-methylphenyl)
methyl]piperazinyl}ethan-1-one.
45. A compound according to claim 1, which is
1-((2S)-2-vinylindolinyl)-2--
{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
46. A compound according to claim 1, which is
1-((2S)-2-vinylindolinyl)-2--
{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
47. A compound according to claim 1, which is
1-((2S)-2-(fluoromethylindol-
inyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
48. A compound according to claim 1, which is
1-((2S)-2-(fluoromethylindol-
inyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
49. A compound according to claim 1, which is
1-((2S)-2-(difluoromethylind-
olinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
50. A compound according to claim 1, which is
1-((2S)-2-(difluoromethylind-
olinyl)-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
51. A compound according to claim 1, which is
1-{(2S)-2-[(dimethylamino)me-
thyl]indolinyl}-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one.
52. A compound according to claim 1, which is
1-{(2S)-2-[(dimethylamino)me-
thyl]indolinyl}-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one.
53. A pharmaceutical composition comprising a compound according to
claim 1, together with at least one pharmaceutically acceptable
carrier or excipient.
54. A method for the treatment or prevention of a disease or
disorder associated with pathogenic dopamine receptor activation,
said method comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1.
55. A method according to claim 54 wherein the disease or disorder
is schizophrenia, psychotic depression, obsessive compulsive
disorder, mania, Parkinson's disease, or tardive dyskinesia.
56. A method according to claim 54 wherein the disease or disorder
is attention deficit disorder or Alzheimer's disease.
57. A method according to claim 54 wherein the disease or disorder
is extrapyramidal side effects associated with the use of a
neuroleptic agent.
58. The use of a compound according to claim 1 for the manufacture
of a medicament for the treatment or prevention of a disease or
disorder associated with pathogenic dopamine receptor
activation.
59. A method for localizing dopamine receptors in a tissue sample
comprising: contacting with the sample a detectably-labeled
compound of claim 1 under conditions that permit binding of the
compound to dopamine receptors, washing the sample to remove
unbound compound, and detecting the bound compound.
60. The method of claim 59 wherein the dopamine receptor is a D4
receptor.
61. A method of inhibiting the binding of a dopamine to a dopamine
receptor, said method comprising contacting a compound of claim 1
with cells expressing such a receptor in the presence of a
dopamine, wherein the compound is present at a concentration
sufficient to inhibit dopamine binding to cells expressing a cloned
human dopamine receptor in vitro.
62. The method of claim 61 wherein the dopamine receptor is a
dopamine D4 receptor.
63. A packaged pharmaceutical composition comprising the
pharmaceutical composition of claim 53 in a container and
instructions for using the composition to treat a patient suffering
from a disorder responsive to dopamine receptor antagonism.
64. The packaged pharmaceutical composition of claim 63, wherein
said patient is suffering from schizophrenia, psychotic depression,
mania, Parkinson's disease, or tardive dyskinesia, attention
deficit disorder, Alzheimer's disease, or the extrapyramidyl side
effects associated with the use of a neuroleptic agent.
65. A compound according to claim 1 wherein in an assay of dopamine
receptor binding the compound exhibits a K.sub.i of 1 micromolar or
less.
66. A compound according to claim 1 wherein the compound exhibits a
K.sub.i of 100 nanomolar or less.
66-1. A compound according to claim 1 wherein the compound exhibits
a K.sub.i of 10 nanomolar or less.
68. A compound according to claim 1 wherein the compound exhibits a
20-fold greater affinity for the dopamine D4 receptor than or the
dopamine D2 receptor in an assay of dopamine receptor binding.
69. A compound according to claim 1 wherein the compound exhibits a
100-fold greater affinity for the dopamine D4 receptor than for the
dopamine D2 receptor in an assay of dopamine receptor binding.
Description
BACKGROUND OF THE INVENTION
[0001] This application claims priority to provisional application
No. 60/138,974 filed Jun. 14, 1999, which is hereby incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to
benzylpiperazinyl-indolinylethanones, and to compounds that bind to
dopamine receptors. This invention also relates to pharmaceutical
compositions comprising such compounds and to the treatment of
central nervous system (CNS) diseases, particularly the treatment
or prevention of psychotic disorders such as schizophrenia.
Additionally this invention relates to the use of compounds as
probes for the localization of dopamine receptors in tissue
sections.
DESCRIPTION OF THE RELATED ART
[0003] The therapeutic effect of conventional antipsychotics, known
as neuroleptics, is generally believed to be exerted through
blockade of dopamine receptors. However, neuroleptics are
frequently responsible for undesirable extrapyramidal side effects
(EPS) and tardive dyskinesias, which are attributed to blockade of
D.sub.2 receptors in the striatal region of the brain. The dopamine
D.sub.4 receptor subtype has been identified and cloned. Its unique
localization in limbic brain areas and its differential recognition
of various antipsychotics suggest that the D.sub.4 receptor may
play a major role in the etiology of schizophrenia. The dopamine
D.sub.4 receptor shares sequence homology with dopamine D.sub.2 and
D.sub.3 receptors, however the D.sub.4 receptor possesses a unique
pharmacological profile. Selective D.sub.4 antagonists, including
the marketed antipsychotic chlozapine, are considered effective
antipsychotics free from the neurological side effects displayed by
conventional neuroleptics. Compounds that possess a 10-fold or more
higher affinity for dopamine D.sub.4 receptors than D.sub.2
receptors are considered particularly desirable as
antipsychotics.
[0004] Since dopamine D.sub.4 receptors are concentrated in the
limbic system which controls cognition and emotion, compounds which
interact with these receptors have utility in the treatment of
cognitive disorders. Such disorders include the cognitive deficits
which are a significant component of the negative symptoms (social
withdrawal and unresponsiveness) of schizophrenia. Other disorders
involving memory impairment or attention deficit disorder can also
be treated with compound that interact specifically with the
dopamine D.sub.4 receptor subtype.
SUMMARY OF THE INVENTION
[0005] This invention provides benzylpiperazinyl-indolinylethanone
compounds that bind, preferably with high affinity and selectivity,
to the D.sub.4 receptor subtype, including human D.sub.4 receptors.
These compounds are therefore useful in treatment of a variety of
neurospychological disorders, such as, for example, schizophrenia,
psychotic depression and mania. Other dopamine-mediated diseases
such as Parkinsonism and tardive dyskinesias can also be treated
directly or indirectly by modulation of D.sub.4 receptors.
[0006] In another aspect, the invention provides intermediates
useful in the preparation of compounds of Formula I. The invention
also provides methods for preparing the compounds of the
invention.
[0007] Thus, the invention provides compounds of Formula I (shown
below), and pharmaceutical compositions comprising compounds of
Formula I.
[0008] The invention further comprises methods of treating patients
suffering from CNS disorder with an effective amount of a compound
of the invention. The patient may be a human or other mammal.
Treatment of humans, domesticated companion animals (pets) or
livestock animals suffering from CNS disorder with an effective
amount of a compound of the invention is encompassed by the
invention. Particularly methods for the treatment and/or prevention
of neuropsychochological or affective disorders, for example,
schizophrenia, mania, dementia, depression, anxiety, compulsive
behavior, substance abuse, memory impairment, cognitive deficits,
Parkinson-like motor disorders, e.g., Parkinsonism and dystonia,
and motion disorders related to the use of neuroleptic agents are
included. In addition, the compounds of the invention are useful in
treatment of depression, memory-impairment or Alzheimer's disease
by modulation of D.sub.4 receptors which selectively exist in
limbic areas known to control emotion and cognitive functions.
Further, the compounds of the present invention are useful for the
treatment of other disorders that respond to dopaminergic blockade,
e.g., substance abuse and obsessive compulsive disorder. These
compounds are also useful in treating the extrapyramidal side
effects associated with the use of conventional neuroleptic
agents.
[0009] Accordingly, a broad embodiment of the invention is directed
to a compound of Formula I: 1
[0010] wherein
[0011] A represents a phenyl group optionally substituted with up
to four groups independently selected from halogen, hydroxy, amino,
mono- or di(C.sub.1-C.sub.6)hydrocarbylamino, aminosulfonyl,
C.sub.1-C.sub.6 hydrocarbylaminosulfonyl, di(C.sub.1-C.sub.6)
hydrocarbylaminosulfonyl, cyano, nitro,
cyclohydrocarbylhydrocarbyl, trifluoromethyl, C.sub.1-C.sub.6
hydrocarbyl, trifluoromethoxy, C.sub.3-C.sub.6 cyclohydrocarbyl,
and C.sub.1-C.sub.6 alkoxy;
[0012] R.sub.1 represents hydrogen, halogen, hydroxy, amino,
aminosulfonyl, C.sub.1-C.sub.6 hydrocarbylaminosulfonyl,
di(C.sub.1-C.sub.6)hydrocarbylaminosulfonyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, C.sub.1-C.sub.6 hydrocarbyl,
cyclohydrocarbylhydrocarbyl, C.sub.3-C.sub.6 cyclohydrocarbyl, and
C.sub.1-C.sub.6 alkoxy; and
[0013] R.sub.2 is C.sub.1-C.sub.6 hydrocarbyl and R.sub.3 is
hydrogen or C.sub.1-C.sub.6 hydrocarbyl; or
[0014] R.sub.2 is hydrogen and R.sub.3 is mono, di, or
trifluoromethyl, hydroxy(C.sub.1-C.sub.3)hydrocarbyl,
C.sub.1-C.sub.6 alkoxy(C.sub.1-C.sub.3)hydrocarbyl, mono or
di(C.sub.1-C.sub.6)hydrocarby- lamino(C.sub.1-C.sub.3)hydrocarbyl,
carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl,
carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)hydrocarbylcarbamoy- l, aryl(C.sub.1-C.sub.6)
hydrocarbylcarbamoyl, N,N-(aryl(C.sub.1-C.sub.6)h- ydrocarbyl)
((C.sub.1-C.sub.6)hydrocarbyl)carbamoyl, or alkenyl; or
[0015] R.sub.2 and R.sub.3 taken together with the atoms to which
they are attached form a saturated ring having from 5 to 7 carbon
atoms; or
[0016] R.sub.3 is hydrogen and R.sub.2 is mono, di, or
trifluoromethyl, hydroxy(C.sub.1-C.sub.3)hydrocarbyl,
C.sub.1-C.sub.6 alkoxy(C.sub.1-C.sub.3)hydrocarbyl, mono or
di(C.sub.1-C.sub.6)hydrocarby- lamino(C.sub.1-C.sub.3)hydrocarbyl,
carboxamido, mono or dihydrocarbylaminocarbonyl, aminohydrocarbyl,
carboxy, C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)hydrocarbylcarbamoy- l,
aryl(C.sub.1-C.sub.6)hydrocarbylcarbamoyl,
N,N-(aryl(C.sub.1-C.sub.6)hy- drocarbyl)
((C.sub.1-C.sub.6)hydrocarbyl)carbamoyl, or alkenyl.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The invention encompasses the compounds of Formula I
described above.
[0018] Preferred compounds of Formula I are those where A is a
group of the formula IA: 2
[0019] where R.sub.4 and R.sub.5 independently represent hydrogen,
halogen, hydroxy, amino, mono- or di(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl, C.sub.1-C.sub.6 alkylaminosulfonyl,
di(C.sub.1-C.sub.6)alkylaminosulfonyl, cyano, nitro,
trifluoromethoxy, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
alkoxy.
[0020] Preferably R.sub.4 and R.sub.5 independently represent
hydrogen, halogen, C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6
alkyl.
[0021] The most preferred compounds of Formula I are those where
only one of R.sub.4 and R.sub.5 is a non-hydrogen substituent, most
preferably fluoro, chloro, bromo, methyl, ethyl, or amino. Highly
preferred of these latter compounds are those where the fluoro,
chloro, or methyl group is in the para position of the phenyl
ring.
[0022] Particularly preferred compounds of Formula I are those
where R.sub.1 is hydrogen.
[0023] A first set of preferred compounds of the invention are
those where R.sub.3 and R.sub.2 in Formula I are hydrogen and
C.sub.1-C.sub.6 alkyl, respectively. Such compounds are represented
by Formula II. 3
[0024] wherein
[0025] R.sub.1 and A are as defined above for Formula I and R.sub.2
is C.sub.1-C.sub.6 alkyl.
[0026] Preferred compounds of II are those where A is a group of
the formula IA and R.sub.4 and R.sub.5 are as defined above for
Formula IA. More preferred compounds of Formula II are those where
A represents a group of Formula IA and R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl. Particularly preferred compounds of
Formula II are those where R.sub.2 is C.sub.1-C.sub.3 alkyl; even
more preferred compounds of II are those where R.sub.2 is
methyl.
[0027] The most preferred compounds of Formula II are those where
both of R.sub.2 and R.sub.3 are methyl and only one of R.sub.4 and
R.sub.5 is a non-hydrogen substituent, most preferably fluoro,
chloro, or methyl. Highly preferred of these latter compounds are
those where the fluoro, chloro, or methyl group is in the para
position of the phenyl ring.
[0028] The most preferred compounds of Formula II have the
following stereochemistry at R.sub.2: 4
[0029] where R.sub.2 is a non-hydrogen substituent.
[0030] Another set of preferred compounds of Formula I are those
where both R.sub.2 and R.sub.3 are C.sub.1-C.sub.6 alkyl. Such
compounds are identified hereinafter as compounds of Formula
III.
[0031] Preferred compounds of III are those where A is a group of
the formula IA and R.sub.4 and R.sub.5 are as defined above for
Formula IA. More preferred compounds of Formula III are those where
A represents a group of Formula IA and R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl. Particularly preferred compounds of
Formula III are those where R.sub.2 and R.sub.3 independently
represent C.sub.1-C.sub.3 alkyl; even more preferred compounds of
III are those where both R.sub.2 and R.sub.3 are methyl.
[0032] Another preferred set of compounds of Formula I are those
where R.sub.2 and R.sub.3 together form a straight C.sub.3-C.sub.5
alkylene group, i.e., where R.sub.2 and R.sub.3 together with the
atoms to which they are attached form a saturated ring having from
5 to 7 carbon atoms. Such compounds are represented herein by
Formula IV: 5
[0033] wherein
[0034] R.sub.1 and A are as defined above for Formula I and n is an
integer of from 3-5.
[0035] Preferred compounds of IV are those where A is a group of
the formula IA and R.sub.4 and R.sub.5 are as defined above for
Formula IA. More preferred compounds of Formula IV are those where
A represents a group of Formula IA and R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.3-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl. Particularly preferred compounds of
Formula IV are those where R.sub.2 and R.sub.3 represent a butylene
group. The resulting ring system may be identified as a 5, 6, 7, 8,
9, 4b, 8a-heptahydro-4aH-carbazole, shown below as Formula IV-A.
6
[0036] The most preferred compounds of Formula IV are those where
only one of R.sub.4 and R.sub.5 is a non-hydrogen substituent, most
preferably fluoro, chloro, or methyl. Highly preferred of these
latter compounds are those where the fluoro, chloro, or methyl
group is in the para position of the phenyl ring.
[0037] The most preferred compounds of Formulas III and IV have the
following stereochemistry at R.sub.2 and R.sub.3: 7
[0038] In this formula, neither of R.sub.2 and R.sub.3 is
hydrogen.
[0039] Another preferred set of compounds of the invention are
those where R.sub.2 is hydrogen and R.sub.3 is mono, di, or
trifluoromethyl, hydroxymethyl, C.sub.1-C.sub.6 alkoxymethyl,
di(C.sub.1-C.sub.6)alkylamin- omethyl, carboxy, C.sub.1-C.sub.6
alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)alkylcarbamoyl,
aryl(C.sub.1-C.sub.6)alkylcarbamoyl,
N-(aryl(C.sub.1-C.sub.6)alkyl)-N-((C.sub.1-C.sub.6)alkyl)carbamoyl,
or vinyl. Such compounds are generally represented by Formula V:
8
[0040] wherein
[0041] R.sub.1 and A are as defined above for Formula I and R.sub.3
is mono, di, or trifluoromethyl, hydroxymethyl, C.sub.1-C.sub.6
alkoxymethyl, di(C.sub.1-C.sub.6)alkylaminomethyl, carboxy,
C.sub.1-C.sub.6 alkoxycarbonyl, carbamoyl, mono or
di(C.sub.1-C.sub.6)alkylcarbamoyl,
aryl(C.sub.1-C.sub.6)alkylcarbamoyl,
N-(aryl(C.sub.1-C.sub.6)alkyl)-N-((C.sub.1-C.sub.6)alkyl)carbamoyl,
or vinyl.
[0042] Preferred compounds of V are those where A is a group of the
formula IA and R.sub.4 and R.sub.5 are as defined above for Formula
IA. More preferred compounds of Formula V are those where A
represents a group of Formula IA and R.sub.4 and R.sub.5
independently represent hydrogen, halogen, C.sub.1-C.sub.6 alkoxy,
or C.sub.1-C.sub.6 alkyl.
[0043] The most preferred compounds of Formula V are those where
R.sub.3 is C.sub.1-C.sub.3 alkoxycarbonyl or vinyl and only one of
R.sub.4 and R.sub.5 is a non-hydrogen substituent, most preferably
fluoro, chloro, or methyl. Highly preferred of these latter
compounds are those where the fluoro, chloro, or methyl group is in
the para position of the phenyl ring. A particularly preferred
alkoxycarbonyl group is methoxycarbonyl.
[0044] The most preferred compounds of Formula V have the following
stereochemistry at R.sub.3: 9
[0045] The invention also provides intermediates useful in
preparing compounds of Formula I. These intermediates have Formula
VI. 10
[0046] In Formula VI, R.sub.1, R.sub.2, and R.sub.3 are as defined
above for Formula I. L is hydrogen, a nitrogen protecting group, or
--CH.sub.2--A. R.sub.3 is carboxy, alkoxycarbonyl, aminocarbonyl,
mono or dialkylaminocarbonyl, and carboxaldehyde.
[0047] The compounds of this invention may contain one or more
asymmetric carbon atoms, so that the compounds can exist in
different stereoisomeric forms. These compounds can be, for
example, mixtures of diastereomers, or racemates or resolved
enantiomers. Single enantiomers can be obtained as pure compounds
or in enantiomeric excess by asymmetric synthesis or by resolution
of the racemate. Resolution of the racemate can be accomplished,
for example, by conventional methods such as crystallization in the
presence of a resolving agent, or chromatography, using, for
example a chiral HPLC column.
[0048] Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table I and their pharmaceutically acceptable acid
addition salts. In addition, if the compound of the invention is
obtained as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the product
is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free
base in a suitable organic solvent and treating the solution with
an acid, in accordance with conventional procedures for preparing
acid addition salts from base compounds.
[0049] Non-toxic pharmaceutically acceptable salts include, but are
not limited to salts inorganic acids such as hydrochloric,
sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or
salts of organic acids such as formic, citric, malic, maleic,
fumaric, tartaric, succinic, acetic, lactic, methanesulfonic,
p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic.
Similarly, pharmaceutically acceptable cations include, but are not
limited to sodium, potassium, calcium, aluminum, lithium and
ammonium. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable addition salts.
[0050] The present invention also encompasses prodrugs of the
compounds of Formula I, e.g., acylated compounds and esters of
Formula I. Those skilled in the art will recognize various
synthetic methodologies which may be employed to prepare non-toxic
pharmaceutically acceptable addition salts and prodrugs of the
compounds encompassed by Formula I.
[0051] Where a compound exists in various tautomeric forms, the
invention is not limited to any one of the specific tautormers. The
invention includes all tautomeric forms of a compound.
[0052] Representative compounds of the invention are shown below in
Table 1. 11
[0053] Compounds 1c, 1g, 1l and 1o are particularly preferred
embodiments of the present invention because of their potency in
binding to dopamine receptor subtypes.
[0054] This invention provides benzylpiperazinyl-indolinylethanone
compounds that bind with high affinity to dopamine receptors,
particularly dopamine D.sub.4 receptors, including human dopamine
D.sub.4 receptors. This invention also includes compounds that bind
with high selectivity to dopamine receptors, particularly dopamine
D.sub.4 receptors, including human dopamine D.sub.4 receptors.
Without wishing to be bound to any particular theory, it is
believed that the interaction of the compounds of the invention
with the dopamine D.sub.4 receptor results in the pharmaceutical
utility of these compounds.
[0055] The invention further comprises methods of treating patients
suffering from a CNS disorder with an amount of a compound of the
invention sufficient to alter the symptoms of the CNS disorder.
[0056] The diseases, conditions and disorders that can be treated
using compounds and compositions according to the invention
include, but are not limited to, schizophrenia, psychotic
depression, mania, and the extrapyramidyl side effects associated
with the use of a neuroleptic agent. Other dopamine-mediated
disease such as Parkinsonism and tardive dyskinesias can also be
treat directly or indirectly by modulation of dopamine receptors.
Compounds of the invention are also useful in the treatment of
depression, memory-impairment or Alzheimer's disease by modulation
of D.sub.4 receptors since these receptors are localized in areas
known to control emotion and cognitive functions.
[0057] The invention also provides pharmaceutical compositions
comprising compounds of the invention, including packaged
pharmaceutical compositions, for treating disorders responsive to
dopamine receptor modulation, especially dopamine D.sub.4 receptor
modulation, e.g., treatment of schizophrenia, depression, tardive
diskinesia or cognitive impairment by dopamine D.sub.4 receptor
modulation. The packaged pharmaceutical compositions include a
container holding a defined quantity or unit dose, e.g., a
therapeutically effective amount, of at least one compound of the
invention and instructions (e.g., labeling) indicating how the
compound is to be used in the patient, e.g., for treating a
disorder responsive to dopamine receptor modulation.
[0058] The present invention also pertains to methods of inhibiting
the binding of dopamine to dopamine D.sub.4 receptors which methods
involve contacting a compound of the invention with cells
expressing dopamine D.sub.4 receptors, wherein the compound is
present at a concentration sufficient to inhibit dopamine binding
to dopamine D.sub.4 receptors in vitro. This method includes
inhibiting the binding of dopamine to dopamine D.sub.4 receptors in
vivo, e.g., in a patient given an amount of a compound of Formula I
that would be sufficient to inhibit the binding of dopamine to
dopamine D.sub.4 receptors in vitro. The amount of a compound that
would be sufficient to inhibit the binding of dopamine to the
dopamine D.sub.4 receptor may be readily determined via a dopamine
receptor binding assay, such as the assay described in Example 11.
The dopamine receptors used to determine in vitro binding may be
obtained from a variety of sources, for example from preparations
of rat striatal homogenates or from cells expressing cloned human
or monkey dopamine D.sub.4 receptors, especially CHO (Chinese
hamster ovary) cells expressing such receptors.
[0059] The compounds of this invention and labeled derivatives
thereof are also useful as standards and reagents in determining
the ability of a potential pharmaceutical to bind to the dopamine
D.sub.4 receptor.
[0060] Radiolabeled derivatives of the compounds of the invention
are also useful as radiotracers for positron emission tomography
(PET) imaging or for single photon emission computerized tomography
(SPECT).
[0061] Definitions
[0062] Where the compounds of the present invention have asymmetric
centers, the invention includes all of the optical isomers and
mixtures thereof.
[0063] Compounds with carbon-carbon double bonds may occur in Z-
and E-forms, and all the isomers of the compounds are included in
the invention.
[0064] When any variable (e.g. C.sub.1-6 alkyl, C.sub.1-8 alkyl, A,
R.sub.1, R.sub.2, or R.sub.3) occurs more than one time in any
formula herein, its definition at each occurrence is independent of
its definition at every other occurrence.
[0065] By "C.sub.1-C.sub.6 alkyl" in the present invention is meant
straight or branched chain alkyl groups having 1-6 carbon atoms.
Examples of alkyl groups include, for example, methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,
2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and
3-methylpentyl.
[0066] By "C.sub.1-C.sub.6 hydrocarbyl" in the present invention is
meant straight or branched chain alkyl groups having 1-6 carbon
atoms, optionally containing one or more carbon-carbon double or
triple bonds. Examples of hydrocarbyl groups include, for example,
methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl,
3-methylpentyl, vinyl, 2-pentenyl, 2-butenyl, 3-pentynyl, and
propargyl. When reference is made herein to C.sub.1-C.sub.6
hydrocarbyl containing one or two double or triple bonds it is
understood that at least two carbons are present in the alkyl for
one double or triple bond, and at least four carbons for two double
or triple bonds.
[0067] By "C.sub.1-C.sub.6 alkoxy" or "lower alkoxy" in the present
invention is meant an alkyl group of indicated number of carbon
atoms attached to the parent molecular moiety through an oxygen
bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy,
n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,
neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
Preferred alkoxy groups herein are C.sub.1-C.sub.4 alkoxy
groups.
[0068] The term "cycloalkylalkyl," as used herein, refers to a
C.sub.3-C.sub.7 cycloalkyl group attached to the parent molecular
moiety through an alkyl group, as defined above. Examples of
cycloalkylalkyl groups include cyclopropylmethyl and
cyclopentylethyl.
[0069] The term "halogen" indicates fluorine, chlorine, bromine, or
iodine.
[0070] The term "nitrogen protecting group," as used herein, refers
to groups known in the art that are readily introduced on to and
removed from a nitrogen. Examples of nitrogen protecting groups
include Boc, Cbz, benzoyl, and benzyl. See also "Protective Groups
in Organic Synthesis", 2nd Ed., Greene, T. W. and related
publications.
[0071] Pharmaceutical Preparations
[0072] Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable prodrugs of the compounds encompassed
by Formula I. Those skilled in the art will recognize a wide
variety of non-toxic pharmaceutically acceptable solvents that may
be used to prepare solvates of the compounds of the invention, such
as water, ethanol, mineral oil, vegetable oil, and
dimethylsulfoxide.
[0073] The compounds of general Formula I may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. Oral
administration in the form of a pill, capsule, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The term
parenteral as used herein includes subcutaneous injections,
intradermal, intravascular (e.g., intravenous), intramuscular,
spinal, intrathecal injection or like injection or infusion
techniques. In addition, there is provided a pharmaceutical
formulation comprising a compound of general Formula I and a
pharmaceutically acceptable carrier. One or more compounds of
general Formula I may be present in association with one or more
non-toxic pharmaceutically acceptable carriers and/or diluents
and/or adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general Formula
I may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or
elixirs.
[0074] Compositions intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monosterate or glyceryl distearate may be
employed.
[0075] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0076] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0077] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0078] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0079] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0080] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0081] The compounds of general Formula I may also be administered
in the form of suppositories, e.g., for rectal administration of
the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0082] Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0083] For administration to non-human animals, the compounds of
the invention may also be added to the animal's feed or drinking
water. It will be convenient to formulate these animal feed and
drinking water compositions so that the animal consumes an
appropriate quantity, e.g., a therapeutically effective amount, of
the compound in its diet. It will also be convenient to present the
compound in a composition as a premix for addition to the feed or
drinking water.
[0084] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0085] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most disorders, a dosage regimen of 4 times daily or less is
preferred. For the treatment of schizophrenia, depression, or
cognitive impairment a dosage regimen of 1 or 2 times daily is
particularly preferred.
[0086] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
[0087] Preferred compounds of the invention will have desirable
pharmacological properties that include, but are not limited to
oral bioavailability, low toxicity, low serum protein binding and
desirable in vitro and in vivo half-lifes. Penetration of the blood
brain barrier for compounds used to treat CNS disorders is
necessary, while low brain levels of compounds used to treat
peripheral disorders are often preferred.
[0088] Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Toxicity to cultured hepatocytes
may be used to predict compound toxicity. Penetration of the blood
brain barrier of a compound in humans may be predicted from the
brain levels of the compound in laboratory animals given the
compound intravenously.
[0089] Serum protein binding may be predicted from albumin binding
assays. Such assays are described in a review by Oravcov, et al.
(Journal of Chromatography B (1996) volume 677, pages 1-27).
[0090] Compound half-life is inversely proportional to the
frequency of dosage of a compound. In vitro half-lifes of compounds
may be predicted from assays of microsomal half-life as described
by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998)
volume 26, pages 1120-1127).
[0091] Preparation of Compounds
[0092] A representative synthesis of the compounds of the invention
is presented in Schemes 1, 2, 3, 4, 5, and 6. Those having skill in
the art will recognize that the starting materials and reaction
conditions may be varied, the order of the steps may be altered and
additional steps may be employed to produce compounds encompassed
by the present invention. 12 13 14 15 16
[0093] In the above shemes, R.sub.1, R.sub.2, R.sub.3, and A are as
defined for Formula I.
[0094] The starting materials used herein are either commercially
available, known, or capable of being prepared by methods known in
the art. Unless otherwise stated, all standard commercial grade
starting materials are used without further purification. In some
cases, protection of reactive functionalities may be necessary to
achieve some of the above transformations. In general, the need for
such protecting groups as well as the conditions necessary to
attach and remove such groups will be apparent to those skilled in
the art of organic synthesis. See also "Protective Groups in
Organic Synthesis", 2nd Ed., Greene, T. W. and related
publications.
EXAMPLE 1
2-{4-[(4-Chlorophenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one
Part A: 3-Methylindoline
[0095] 17
[0096] Hydrochloric acid (10.5 N, 6 mL) is added dropwise to a
stirred mixture of 3-methylindole (3.93 g, 30 mmol) and
trimethylamine-borane (8.75 g, 120 mmol) in room temperature
dioxane (30 mL). The mixture is then heated at reflux for about 30
min. After cooling to room temperature, 6 N hydrochloric acid (24
mL) is carefully added and the mixture is refluxed for 15 min. Most
of the dioxane is then removed under reduced pressure, and the
residue is diluted with water (200 mL). Some insoluble material is
extracted with ether, and the aqueous solution is basified with 30%
aqueous sodium hydroxide to pH.about.10. The oily product is
extracted with ether, the extracts are washed with water and brine,
dried over anhydrous MgSO.sub.4, filtered and evaporated under
reduced pressure to provide the product as a light yellow oil (3.75
g, 94% yield).
[0097] .sup.1HNMR (CDCl.sub.3) .delta.7.08-6.69 (m, 4H), 3.75-3.70
(m, 1H), 3.39-3.37 (m, 1H), 3.14-3.10 (m, 1H), 1.33 (d, J=7.2 Hz,
4H; LC-MS (APCI, m/z) 134 (M+1).sup.+.
Part B: 2-Chloro-1-(3-methylindolinyl)ethan-1-one
[0098] 18
[0099] Chloroacetyl chloride (3 mL, 37.5 mmol) is added dropwise to
triethylamine (5 mL, 36 mmol) and 3-methylindoline (4 g, 30 mmol)
in 0.degree. C. chloroform (60 mL). The cooling bath is then
removed, and after about two hours, the reaction mixture is poured
into cold water, and extracted several times with dichloromethane.
The combined dichloromethane extracts are washed with brine, dried
over anhydrous magnesium sulfate, and filtered. The solvent is
removed under reduced pressure, and the residue is crystallized
from ether-hexanes to provide the product as a colorless solid (5.5
g, 87% yield). mp 78-79.degree. C.;
[0100] .sup.1HNMR (CDCl.sub.3) .delta.8.19 (d, J=7.8 Hz, 1H),
7.26-7.07 (m, 3H), 4.32 (t, J=6.8 Hz, 1H), 4.16 (s, 2H), 3.72-3.66
(m, 1H), 3.59-3.51 (m, 1H), 1.38 (d, J=6.9 Hz, 3H); LC-MS (APCI,
m/z) 210 (M+1).sup.+.
Part C:
2-{4-[(4-Chlorophenyl)methyl]piperazinyl}-1-(3-methylindolinyl)eth-
an-1-one
[0101] 19
[0102] Potassium carbonate (206 mg, 1.5 mmol) and
[(4-chlorophenyl)methyl]- piperazine (210 mg, 1 mmol) are added to
a solution of 2-chloro-1-(3-methylindolinyl)ethan-1-one (210 mg, 1
mmol) in acetonitrile (12 mL). After refluxing for about 3 h, the
reaction mixture is filtered through silica gel, and concentrated.
The residue is crystallized from ethyl acetate and hexanes to
provide the product as a colorless solid. mp 101-103.degree. C.;
.sup.1HNMR (CDCl.sub.3) .delta.8.20 (d, J=7.8 Hz, 1H), 7.29-7.15
(m, 6H), 7.06-7.01 (m, 1H), 4.31 (t, J=6.9 Hz, 1H), 3.70-3.65 (m,
1H), 3.49 (m, 1H), 3.46 (s, 2H), 3.24 (s, 2H), 2.61 (m, 4H), 2.49
(m, 4H), 1.34 (d, J=7.5 Hz, 3H); LC-MS (APCI, m/z) 384 (M+1).sup.+.
Anal. Calcd for C.sub.22H.sub.26N.sub.3ClO: C, 68.83; H, 6.83; N,
10.95. Found: C, 69.18; H, 6.66; N, 10.86.
EXAMPLE 2
1-((2R,3R)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl-
}ethan-1-one, and
1-((2S,3S)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl-
}ethan-1-one
Part A: cis- and trans-2,3-Dimethylindolines
[0103] 20
[0104] These two indolines are prepared starting from
2,3-dimethylindole according to a literature procedure. (Synthesis,
508, (Berger, 1974)).
Part B: 2-Chloro-1-(cis-2,3-Dimethylindolinyl)ethan-1-one
[0105] 21
[0106] The title compound is prepared by the procedure as described
in Example 1 (part B) to provide a colorless solid in 75% yield. mp
83-84.degree. C.; .sup.1HNMR (CDCl.sub.3) .delta.8.17 (m, 1H),
7.28-7.08 (m, 7H), 4.24 (m, 1H), 4.18 (s, 2H), 2.90 (m, 1H), 1.32
(d, J=6.3 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H); LC-MS (APCI, m/z) 224
(M+1).sup.+.
Part C:
1-((2R,3R)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]pip-
erazinyl}ethan-1-one and
1-((2S,3S)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl-
}ethan-1-one
[0107] 22
[0108] These two compounds are prepared from
2-chloro-1-(cis-2,3-dimethyli- ndolinyl)ethan-1-one and
[(4-chlorophenyl)methyl]piperazine using the procedure described in
Example 1 (Part C). The enantiomers are separated by chiral
preparative chromatography to provide each enantiomer as a
colorless syrup in 92% overall yield. These two isomers have the
same physical data except for the direction of their optical
rotation as measured on a polarimeter. (2R,3R)-Isomer:
[.alpha.].sub.D +7.0.degree. (C=0.4, CHCl.sub.3); .sup.1HNMR
(CDCl.sub.3) .delta.8.17 (m, 1H), 7.30-7.18 (m, 6H), 7.08-7.02 (m,
1H), 4.42 (m, 1H), 3.47 (s, 2H), 3.43 (m, 1H), 2.85 (m, 1H), 2.65
(m, 4H), 2.51 (m, 4H), 1.26 (d, J=6.3 Hz, 3H), 1.21 (d, J=7.2 Hz,
3H); LC-MS (APCI, m/z) 398 (M+1).sup.+. A portion of the product is
converted to the dihydrochloride salt, mp 247-248.degree. C. Anal.
Calcd for C.sub.23H.sub.28N.sub.3ClO.2HCl: C, 58.67; H, 6.42; N,
8.92. Found: C, 58.36; H, 6.26; N, 8.69.
EXAMPLE 3
Methyl
(2S)-1-(2-{4-[(4-chlorophenyl)methyl]-piperazinyl}indoline-2-carbox-
ylate
Part A: Methyl (2S)-1-(2-chloroacetyl)indoline-2-carboxylate
[0109] 23
[0110] The title compound is prepared starting from methyl
(2S)-1-(2-chloroacetyl)indoline-2-carboxylate monohydrate (J. Org.
Chem. 62, Bertini Gross, 7679 (1997)) and chloroacetyl chloride by
the procedure described in Example 1 (step B, 3 eq. triethylamine
is used) to provide the product as a colorless oil in 89% yield.
.sup.1HNMR (CDCl.sub.3) .delta.7.29-7.06 (m, 4H), 5.16 (m, 1H),
4.12 (s, 2H), 3.77 (s, 3H), 3.64 (m, 1H), 3.41-3.35 (m, 1H); LC-MS
(APCI, m/z) 254 (M+1).sup.+.
Part B: Methyl
(2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2-
-carboxylate
[0111] 24
[0112] The title compound is prepared starting from methyl
(2S)-1-(2-chloroacetyl)indoline-2-carboxylate and
[(4-chlorophenyl)methyl- ]piperazine by the procedure described in
Example 1 (Part C), and purified by crystallization from ethyl
acetate and hexanes to provide the product as a colorless solid in
82% yield. mp 125-126.degree. C.; .sup.1HNMR (CDCl.sub.3)
.delta.8.20-8.18 (m, 1H), 7.29-7.16 (m, 6H), 7.06-7.01 (m, 1H),
5.35-5.31 (m, 1H), 3.71 (s, 3H), 3.59-3.54 (m, 1H), 3.46 (s, 2H),
3.22 (s, 2H), 3.17 (m, 1H), 2.53 (m, 4H), 2.43 (m, 4H); LC-MS
(APCI, m/z) 428 (M+1).sup.+. Anal. Calcd for
C.sub.23H.sub.26N.sub.3ClO.sub.3: C, 64.55; H, 6.12; N, 9.82.
Found: C, 64.62; H, 6.36; N, 9.60.
EXAMPLE 4
(2S)-1-(2-{4-[(4-Chlorophenyl)methyl]piperazinyl}-acetyl)indoline-2-carbox-
ylic acid
[0113] 25
[0114] Lithium hydroxide monohydrate (160 mg, 4 mmol) is added to a
solution of methyl
(2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indol-
ine-2-carboxylate (1 g, 2.34 mmol) in methanol (12 mL) and water (4
mL). After stirring overnight at room temperature, the pH is
adjusted to .about.6 with 1 N hydrochloric acid. After removal of
the methanol under reduced pressure, the residue is extracted
several times with ethyl acetate. The combined ethyl acetate
extracts are washed with brine, dried over anhydrous magnesium
sulfate, and filtered. The solvent is removed under reduced
pressure, and the residue is crystallized from chloroform-ether to
provide the product as a colorless solid in 75% yield. mp
219-22.degree. C.;
[0115] .sup.1HNMR (DMSO-d.sub.6) .delta.7.98 (d, J=8.0 Hz, 1H),
7.49-7.42 (m, 4H), 7.23 (d, J=6.8 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H),
7.01 (t, J=7.6 Hz, 1H), 5.15 (d, J=8.0 Hz, 1H), 3.90 (s, 2H),
3.55-3.49 (m, 2H), 3.22-3.10 (m, 2H), 2.77 (m, 4H), 2.64 (m, 4H);
LC-MS (APCI, m/z) 414 (M+1).sup.+, 412 (M-1).sup.-. Anal. Calcd for
C.sub.22H.sub.24N.sub.3ClO.- sub.3.1.5HCl.0.25H.sub.2O: C, 55.85;
H, 5.54; N, 8.88. Found: C, 55.88; H, 5.58; N, 8.91.
EXAMPLE 5
[(2S)-1-(2-{4-[(4-Chlorophenyl)methyl]piperazinyl}acetyl)-indoline-2-yl]-N-
-benzylcarboxamide
[0116] 26
[0117] Benzylamine (32 mg, 0.3 mmol) and triethylamine (0.042 mL,
0.3 mmol) are added to a room temperature solution of
(2S)-1-(2-{4-[(4-chloro-
phenyl)methyl]piperazinyl}acetyl)indoline-2-carboxylic acid (124
mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (3 mL). After
stirring for 5 min, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (58 mg, 0.3 mmol) is added and the reaction mixture
is stirred overnight. The reaction mixture is then poured into
saturated sodium bicarbonate, and extracted several times with
ethyl acetate. The combined ethyl acetate extracts are washed with
brine, dried over anhydrous magnesium sulfate, and filtered. The
solvent is removed under reduced pressure, and the residue is
purified by silica gel chromatography with chloroform and methanol
as eluents to provide the product as a colorless solid in 70%
yield. mp 154-155.degree. C.; .sup.1HNMR (CDCl.sub.3) .delta.8.13
(m, 1H), 7.29-7.21 (m, 10H), 7.09 (t, J=7.6 Hz, 2H), 6.36 (br s,
1H), 5.30 (d, J=6.0 Hz, 1H), 4.42-4.36 (m, 2H), 3.62 (m, 1H), 3.45
(s, 2H), 3.28 (m, 3H), 2.55 (m, 4H), 2.44 (m, 4H); LC-MS (APCI,
m/z) 503 (M+1).sup.+, 501 (M-1).sup.-. Anal. Calcd for
C.sub.29H.sub.31N.sub.4ClO.sub.2.1 H.sub.2O: C, 66.85; H, 6.38; N,
10.75. Found: C, 66.72; H, 6.09; N, 11.05.
EXAMPLE 6
1-[(2S)-2-(Hydroxymethyl)indolinyl]-2-{4-[(4-chlorophenyl)methyl]piperazin-
yl}ethan-1-one
Part A: Ethyl 2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetate
[0118] 27
[0119] Potassium carbonate (3.12 g, 22.5 mmol),
1-[(4-chlorophenyl)methyl]- piperazine (3.15 g, 15 mmol) and ethyl
chloroacetate (1.84 g, 15 mmol) are refluxed in acetonitrile (100
mL) for about 3 h. The room temperature reaction mixture is
filtered through silica gel, concentrated under reduced pressure,
and then dried in vacuo to provide the product as a light yellow
syrup (4.3 g, 97% yield). .sup.1HNMR (CDCl.sub.3) .delta.7.29-7.23
(m, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.47 (s, 2H), 3.20 (s, 2H), 2.60
(br s, 4H), 2.52 (br s, 4H), 1.26 (td, J=7.2, 0.6 Hz, 3H); LC-MS
(APCI, m/z) 297 (M+1).sup.+.
Part B: 2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetic acid
[0120] 28
[0121] The title compound is prepared starting from ethyl
2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetate by the procedure
described in Example 4 to provide the product as a white solid in
80% yield. mp 190-192.degree. C.; .sup.1HNMR (CD.sub.3OD)
.delta.7.50-7.46 ( m, 4H), 4.15 (s, 2H), 3.56 (s, 2H), 3.15 (br s,
4H), 3.09 (br s, 4H); LC-MS (APCI, m/z) 269 (M+1).sup.+, 267
(M-1).
Part C:
1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-chlorophenyl)methyl]p-
iperazinyl}ethan-1-one
[0122] 29
[0123] The title compound is prepared from
((2S)-indolin-2-yl)methan-1-ol (J. Org. Chem. 62, Bertini Gross,
7679 (1997)) and chloroacetyl chloride by the procedure described
in Example 5. The sample is purified by silica gel chromatography
to provide the product as a colorless oil. .sup.1HNMR (CDCl.sub.3)
.delta.8.07 (m, 1H), 7.29-7.18 (m, 6H), 7.08-7.02 (m, 1H), 4.03 (br
s, 1H), 3.66 (m, 2H), 3.58 (s, 2H), 3.47 (s, 2H), 3.38-3.31 (m,
2H), 3.18-3.07 (m, 1H); LC-MS (APCI, m/z) 400 (M+1).sup.+. A
portion of the product is converted to the dihydrochloride salt.
Anal. Calcd for C.sub.22H.sub.26N.sub.3ClO.sub.2.2HCl.1.25
H.sub.2O: C, 53.34; H, 6.21; N, 8.48. Found: C, 53.36; H, 6.04; N,
8.77.
EXAMPLE 7
1-((2S)-2-Vinylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-
-one
Part A: tert-Butyl (2S)-2-formylindolinecarboxylate
[0124] 30
[0125] A solution of dimethyl sulfoxide (2.83 mL, 40 mmol) in
anhydrous dichloromethane (5 mL) is added to a -60.degree. C.
solution of oxalyl chloride (10 mL, 2.0 M in dichloromethane, 20
mmol) in anhydrous dichloromethane (20 mL). After 5 min, tert-butyl
(2S)-2-(hydroxymethyl)in- dolinecarboxylate (J. Org. Chem. 62,
Bertini Gross, 7679 (1997)) (2.49 g, 10 mmol) in anhydrous
dichloromethane (10 mL) is added dropwise maintaining the
temperature at -50.about.-6020 C. After another 3 h, triethylamine
(8.2 mL) is added dropwise to the reaction mixture while keeping
the temperature at or below -50.degree. C. After stirring at room
temperature for 30 min, water is added, and the reaction mixture is
stirred for an additional 30 min. The reaction mixture is extracted
several times with ethyl acetate, and the combined ethyl acetate
extracts are washed with brine, dried over anhydrous magnesium
sulfate, and filtered. The solvent is removed under reduced
pressure, and the residue is purified by silica gel chromatography
with ethyl acetate and hexanes as eluents to provide the product as
a colorless oil (2.1 g, 84% yield). .sup.1HNMR (CDCl.sub.3)
.delta.9.66 (s, 1H), 7.27-7.22 (m, 2H), 7.16-7.14 (m 1H), 7.01-6.96
(m, 1H), 4.77 (m, 1H), 3.40 (m, 1H), 3.17-3.13 (m, 1H), 1.53 (s,
9H).
Part B: tert-Butyl (2S)-2-vinylindolinecarboxylate
[0126] 31
[0127] n-Butyl lithium (2.2 mL, 2.5 M in hexane, 5.5 mmol) is added
dropwise to a suspension of methyltriphenylphosphonium bromide
(2.14 g, 6 mmol) in 0.degree. C. anhydrous tetrahydrofuran (16 mL).
The cooling bath is then removed and the yellow solution is stirred
at room temperature for 30 min. The solution is cooled to 0.degree.
C. again and tert-butyl (2S)-2-formylindolinecarboxylate (1.24 g, 5
mmol) is added dropwise over 10 min. After continued stirring for
additional 30 min, the mixture is poured into ice-water, and
extracted several times with ether. The extracts are washed with
brine, dried over anhydrous magnesium sulfate, and filtered. The
solvent is removed under reduced pressure, and the residue is
purified by silica gel chromatography with ethyl acetate and
hexanes as eluents to provide the product as a colorless oil (1.9
g, 89% yield). .sup.1HNMR (CDCl.sub.3) .delta.1.72 (m, 1H),
7.20-7.11 (m, 2H), 6.96-6.91 (m 1H), 5.90-5.78 (m, 1H), 5.15 (d,
J=17.1 Hz, 1H), 5.07 (d, J=10.2 Hz, 1H), 4.87 (m, 1H), 3.45-3.37
(m, 1H), 2.79 (dd, J=16.2, 2.7 Hz, 1H), 1.54 (s, 9H).
Part C: (2S)-2-Vinylindoline
[0128] 32
[0129] Trifluoroacetic acid (2 mL) is added dropwise to a solution
of tert-butyl (2S)-2-vinylindolinecarboxylate (536 mg, 2.2 mmol) in
anhydrous, 0.degree. C. dichloromethane (4 mL). After stirring at
room temperature overnight, the solvent and excess TFA are removed
under reduced pressure to provide a syrup which is used in the next
step without further purification. LC-MS (APCI, m/z) 146
(M+1).sup.+.
Part D: 1-((2S)-2-Vinylindolinyl)-2-chloroethan-1-one
[0130] 33
[0131] The title compound is prepared from (2S)-2-vinylindoline and
chloroacetyl chloride by the procedure described in Example 1 (step
B, 5 eq. triethylamine is used) to provide the product as a
colorless oil in 82% yield (two steps). .sup.1HNMR (CDCl.sub.3)
.delta.8.21 (m, 1H), 7.27-7.18 (m, 2H), 7.11-7.06 (m, 1H),
5.96-5.85 (m, 1H), 5.126-5.17 (m, 2H), 5.01 (m, 1H), 4.28 (d,
J=12.9 Hz, 1H), 4.17-4.09 (m, 1H), 3.62-3.54 (m, 1H), 2.89 (d,
J=15.6 Hz, 1H); LC-MS (APCI, m/z) 222 (M+1).sup.+.
Part E:
1-((2S)-2-Vinylindolinyl)-2-{4-[(4-chlorolhenyl)methyl]piperazinyl-
}ethan-1-one
[0132] 34
[0133] The title compound is prepared from
1-((2S)-2-Vinylindolinyl)-2-chl- oroethan-1-one and
[(4-chlorophenyl)methyl]piperazine by the procedure described in
Example 1 (Part C), and purified by silica gel chromatography with
chloroform and methanol as eluents to provide the product as a
colorless syrup in 90% yield. .sup.1HNMR (CDCl.sub.3) .delta.8.23
(m, 2H), 7.26-7.15 (m, 6H), 7.05-7.0 (m, 1H), 5.90-5.79 (m, 1H),
5.23 (m, 1H), 5.15-5.09 (m, 2H), 3.48-3.40 (m, 4H), 3.24-3.12 (m,
1H), 2.81 (d, J=15.9 Hz, 1H), 2.61 (m, 4H), 2.50 (m, 4H); LC-MS
(APCI, m/z) 396 (M+1).sup.+. A portion of the product can be
converted to the dihydrochloride salt, mp 229-230.degree. C.; Anal.
Calcd for C.sub.23H.sub.26N.sub.3ClO.2 HCl.1 H.sub.2O: C, 56.74; H,
6.21; N, 8.63. Found: C, 56.79; H, 5.97; N, 8.44.
EXAMPLE 8
1-((2S)-2-(Fluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazinyl-
}ethan-1-one
Part A: Methyl (2S)-1-benzylindoline-2-carboxylate
[0134] 35
[0135] Potassium carbonate (1.4 g, 10 mmol), benzyl bromide (0.62
mL, 5.1 mmol) and methyl
(2S)-1-(2-chloroacetyl)indoline-2-carboxylate monohydrate (1.07 g,
5 mmol) are refluxed in acetonitrile (30 mL) for about 8 h. The
room temperature reaction mixture is filtered through silica gel
and the filtrate is concentrated under reduced pressure. The
residue is then dried in vacua to provide the product as a light
yellow syrup (2.64 g, 99% yield). [.alpha.].sub.D +25.3.degree.
(c=1.8, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3) .delta.7.36-7.26 ( m,
5H), 7.07-7.02 (m, 2H), 6.71-6.67 (m, 1H), 6.46 (d, J=7.8 Hz, 1H),
4.52 (d, J=15.3 Hz, 1H), 4.32 (d, J=15.3 Hz, 1H), 4.25 (m, 1H),
3.67 (s, 3H), 3.39 (dd, J=15.9, 9.9 Hz, 1H), 3.19 (dd, J=15.9, 9.9
Hz, 1H); LC-MS (APCI, m/z) 268 (M+1).sup.+.
Part B: [(2S)-1-benzylindolin-2-yl]methan-1-ol
[0136] 36
[0137] Lithium aluminum hydride (20 mL, 1 M in anhydrous
tetrahydrofuran, 4 mmol) is added dropwise to a 0.degree. C. the
solution of methyl (2S)-1-benzylindoline-2-carboxylate (5.35 g, 20
mmol) in anhydrous tetrahydrofuran (60 mL). The cooling bath is
then removed and the reaction mixture is stirred at room
temperature for about 5 h. Freshly prepared saturated sodium
sulfate solution is added to quench the reaction. The reaction
mixture is filtered through silica gel, dried over anhydrous sodium
sulfate, and filtered. The solvent is removed under reduced
pressure, and dried in vacua to provide the product as a light
yellow oil (4.56 g, 95% yield). [.alpha.].sub.d -22.degree. (c=1.9,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3) .delta.7.38-7.25 (m, 5H),
7.11-7.02 (m, 2H), 6.74-6.69 (m, 1H), 6.50 (d, J=7.8 Hz, 1H), 4.36
(s, 2H), 3.86-3.77 (m, 2H), 3.14-3.09 (m, 2H), 1.71-1.59 (m, 2H);
LC-MS (APCI, m/z) 240 (M+1).sup.+.
Part C: [(2S)-2-(Fluoromethyl)]-1-benzylindoline
[0138] 37
[0139] Diethylaminosulfur trifluoride (DAST, 2.02 mL, 15 mmol) is
added dropwise to a -70.degree. C. solution of
[(2S)-1-benzylindolin-2-yl]metha- n-1-ol (3.59 g, 15 mmol) in
anhydrous dichloromethane (60 mL). The reaction mixture is stirred
at -70.degree. C. for 2 h, and then at room temperature for about 2
h. The reaction is quenched by addition of sodium carbonate
solution, and the reaction mixture is extracted several times with
dichloromethane. The combined dichloromethane extracts were washed
with brine, dried over anhydrous magnesium sulfate, and filtered.
The solvent is removed under reduced pressure, and the residue is
purified by silica gel chromatography with ethyl acetate and
hexanes as eluents to provide the product as a colorless oil (3.36
g, 94% yield). [.alpha.].sub.D +6.0.degree. (c=1.1,
CHCl.sub.3);
[0140] .sup.1HNMR (CDCl.sub.3) .delta.7.36-7.25 (m, 5H), 7.06-7.01
(m, 2H), 6.69-6.64 (m, 1H), 6.57 (d, J=6.9 Hz, 1H), 5.27-5.24,
5.11-5.06 (m, 1H), 4.53 (s, 2H), 3.59-3.49 (m, 2H), 3.19-3.08 (m,
2H); LC-MS (APCI, m/z) 241.9 (M+1).sup.+.
Part D: (2S)-2-Fluoromethylindoline
[0141] 38
[0142] A mixture of [(2S)-2-(Fluoromethyl)]-1-benzylindoline (2.34
g, 9.7 mmol) and 10% Pd/C (Degussa type E101 NE/W, 2 g) in
anhydrous methanol (80 mL) is hydrogenated at room temperature
under 45 psi pressure until the uptake of hydrogen ceases
(approximately 24 h). The reaction mixture is filtered through
celite and concentrated under reduced pressure at temperatures
below 30.degree. C. The residue is purified by silica gel
chromatography to provide the product as a syrup (1.12 g, 76%
yield). [.alpha.].sub.D +19.5.degree. (c=1.2, CHCl.sub.3);
.sup.1HNMR (CDCl.sub.3) .delta.7.04-6.98 (m, 2H), 7.71-6.66 (m,
1H), 6.55 (d, J=6.9 Hz, 1H), 5.21-5.18, 5.06-5.0 (m, 1H), 3.78 (br
s, 1H), 3.50-3.42 (m, 2H), 3.14-3.03 (m, 2H); LC-MS (APCI, m/z)
151.9 (M+1).sup.+.
Part E: 1-((2S)-2-Fluoromethylindolinyl)-2-chloroethan-1-one
[0143] 39
[0144] The title compound is prepared from
(2S)-2-fluoromethylindoline and chloroacetyl chloride by the
procedure described in Example 1 (step B, 1.2 eq. triethylamine is
used), and purified by silica gel chromatography to provide the
product as a colorless solid in 88% yield. mp 60-61.degree. C.;
[.alpha.].sub.D -32.degree. (c=0.5, CHCl.sub.3); .sup.1HNMR
(CDCl.sub.3) .delta.7.31-7.25 (m, 4H), 5.39-5.33, 5.22-5.16 (m,
1H), 4.24 (s, 2H), 4.12-4.05 (m, 2H), 3.12-3.0 (m, 2H); LC-MS
(APCI, m/z) 228 (M+1).sup.+.
Part F:
1-((2S)-2-(Fluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]pip-
erazinyl}ethan-1-one
[0145] 40
[0146] The title compound is prepared from
1-((2S)-2-fluoromethylindolinyl- )-2-chloroethan-1-one and
[(4-chlorophenyl)methyl]piperazine by the procedure described in
Example 1 (Part C), and purified by silica gel chromatography with
chloroform and methanol as eluents to provide the product as a
colorless syrup in 92% yield. [.alpha.].sub.D -7.8.degree. (c=1.2,
CHCl.sub.3);
[0147] .sup.1HNMR (CDCl.sub.3) .delta.7.42 (m, 1H), 7.29-7.13 (m,
7H), 5.31-5.27, 5.15-5.10 (m, 1H), 4.22-3.92 (m, 2H), 3.43 (s, 2H),
3.33-3.24 (m, 2H), 3.06 (m, 1H), 2.99 (m, 1H), 2.52 (m, 4H), 2.42
(m, 4H); LC-MS (APCI, m/z) 402 (M+1).sup.+. A portion of the
product is converted to the dihydrochloride salt, mp
219-220.degree. C.
EXAMPLE 9
1-((2S)-2-(Difluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]piperazin-
yl}ethan-1-one
Part A: (2S)-Indoline-2-carbaldehyde
[0148] 41
[0149] The title compound is prepared from
[(2S)-1-benzylindolin-2-yl]meth- an-1-ol by the procedure described
in Example 7 (Part A), and purified by silica gel chromatography
with ethyl acetate and hexanes as eluents to provide the product as
a colorless syrup in 82% yield. [.alpha.].sub.D +36.degree. (c=2.2,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3) .delta.9.49 (d, J=7.2 Hz, 1H),
7.35-7.31 (m, 5H), 7.14-7.09 (m, 2H), 6.78-6.73 (m, 1H), 6.59 (d,
J=7.8 Hz, 1H), 4.46 (d, J=15.0 Hz, 1H), 4.28 (d, J=15.3 Hz, 1H),
4.12-4.04 (m, 1H), 3.33-3.24 (m, 1H), 3.13-3.05 (m, 1H); LC-MS
(APCI, m/z) 238 (M+1).sup.+.
Part B: [(2S)-2-(Difluoromethyl)]-1-benzylindoline
[0150] 42
[0151] The title compound is prepared from
(2S)-indoline-2-carbaldehyde by the procedure described in Example
8 (Part C), and purified by silica gel chromatography with ethyl
ether and hexanes as eluents to provide the product as a colorless
syrup in 77% yield. .sup.1HNMR (CDCl.sub.3) .delta.7.32-7.26 (m,
5H), 7.10-7.03 (m, 2H), 6.72 (t, J=7.5 Hz, 2H), 6.46 (d, J=7.8 Hz,
1H), 5.94, 5.76, 5.57 (d, J=5.4 Hz, 1H), 4.56 (d, J=16.2 Hz, 1H),
4.36 (d, J=15.9 Hz, 1H), 3.34-3.25 (m, 1H), 3.10-3.02 (m, 1H);
[0152] .sup.19FNMR (CDCl.sub.3) .delta.44.3-37.0 (m, 2F); LC-MS
(APCI, m/z) 260 (M+1).sup.+.
Part C: (2S)-2-Difluoromethylindoline
[0153] 43
[0154] The title compound is prepared from
(2S)-indoline-2-carbaldehyde by the procedure described in Example
8 (Part D), and purified by silica gel chromatography with ethyl
ether and hexanes as eluents to provide the product as a colorless
syrup in 78% yield.
Part D: 1-((2S)-2-Difluoromethylindolinyl)-2-chloroethan-1-one
[0155] 44
[0156] The compound is prepared from (2S)-2-difluoromethylindoline
and chloroacetyl chloride by the procedure described in Example 1
(step B, 1.2 eq. triethylamine is used), and purified by silica gel
chromatography to provide the product as a colorless solid in 88%
yield.
Part E:
1-((2S)-2-(Difluoromethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]p-
iperazinyl}ethan-1-one
[0157] 45
[0158] The title compound is prepared from
1-((2S)-2-Fluoromethylindolinyl- )-2-chloroethan-1-one and
[(4-chlorophenyl)methyl]piperazine by the procedure described in
Example 1 (Part C), and purified by silica gel chromatography with
chloroform and methanol as eluents to provide the product as a
colorless syrup in 92% yield.
EXAMPLE 10
[0159] The following compounds are prepared essentially according
to the procedures set forth above in Schemes 1-6 and the above
examples.
[0160] (a)
2-{4-[(4-methylphenyl)methyl]piperazinyl}-1-(3-methylindolinyl)-
ethan-1-one,
[0161] (b)
2-{4-[(4-fluorophenyl)methyl]piperazinyl}-1-(3-methylindolinyl)-
ethan-1-one,
[0162] (c)
2-{4-[(4-ethylphenyl)methyl]piperazinyl}-1-(3-methylindolinyl)e-
than-1-one,
[0163] (d)
2-{4-[(4-isopropylphenyl)methyl]piperazinyl}-1-(3-methylindolin-
yl)ethan-1-one,
[0164] (e)
2-{4-[(4-trifluoromethylphenyl)methyl]piperazinyl}-1-(3-methyli-
ndolinyl)ethan-1-one,
[0165] (f)
2-{4-[(4-methoxyphenyl)methyl]piperazinyl}-1-(3-methylindolinyl-
)ethan-1-one,
[0166] (g)
1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-methylphenyl)methyl]pipe-
razinyl}ethan-1-one,
[0167] (h)
1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-methoxyphenyl)methyl]pip-
erazinyl}ethan-1-one,
[0168] (i)
1-(2,3-cis-dimethylindolinyl)-2-{4-[(3-chloro-6-methoxyphenyl)m-
ethyl]piperazinyl}ethan-1-one,
[0169] (j)
1-(2,3-cis-dimethylindolinyl)-2-{4-[(4-ethylphenyl)methyl]piper-
azinyl}ethan-1-one,
[0170] (k)
1-(2,3-trans-dimethylindolinyl)-2-{4-[(4-chlorophenyl)methyl]pi-
perazinyl}ethan-1-one,
[0171] (l)
1-(2,3-trans-dimethylindolinyl)-2-{4-[(4-methylphenyl)methyl]pi-
perazinyl}ethan-1-one,
[0172] (m)
1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethy-
l]-2-{4-[(4-chlorophenyl)methyl]piperazinyl}ethan-1-one,
[0173] (n)
1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethy-
l]-2-{4-[(4-methylphenyl)methyl]piperazinyl}ethan-1-one (Table 1,
1o),
[0174] (o)
1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethy-
l]-2-{4-[(4-isopropylphenyl)methyl]piperazinyl}ethan-1-one,
[0175] (p)
1-[(4b,8a-cis-5,6,7,8,9,4b,8a-heptahydro-4aH-carbazol-9-yl)ethy-
l]-2-{4-[(4-fluorophenyl)methyl]piperazinyl}ethan-1-one,
[0176] (q) methyl
(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indolin-
e-2-carboxylate,
[0177] (r) methyl
(2R)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indolin-
e-2-carboxylate,
[0178] (s) methyl
(2R)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}indolin-
e-2-carboxylate,
[0179] (t)
(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}acetyl)indolin-
e-2-carboxylic acid,
[0180] (u)
(2R)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetyl)indolin-
e-2-carboxylic acid,
[0181] (v)
[(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}acetyl)indoli-
ne-2-yl]-N-benzylcarboxamide,
[0182] (w)
[(2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}acetyl)indoli-
ne-2-yl]-N-carboxamide,
[0183] (x)
[(2S)-1-(2-{4-[(4-methylphenyl)methyl]piperazinyl}acetyl)indoli-
ne-2-yl]-N,N-dimethylcarboxamide,
[0184] (y)
1-[(2S)-2-(hydroxymethyl)indolinyl]-2-{4-[(4-methylphenyl)methy-
l]piperazinyl}ethan-1-one,
[0185] (z)
1-[(2S)-2-(methoxymethyl)indolinyl]-2-{4-[(4-chlorophenyl)methy-
l]piperazinyl}ethan-1-one (Table 1, 1k),
[0186] (aa)
1-((2S)-2-vinylindolinyl)-2-{4-[(4-methylphenyl)methyl]piperaz-
inyl}ethan-1-one,
[0187] (bb)
1-((2S)-2-(fluoromethylindolinyl)-2-{4-[(4-methylphenyl)methyl-
]piperazinyl}ethan-1-one,
[0188] (cc)
1-((2S)-2-(difluoromethylindolinyl)-2-{4-[(4-chlorophenyl)meth-
yl]piperazinyl}ethan-1-one.
EXAMPLE 11
[0189] Determination of D.sub.2 and D.sub.4 Receptor Binding
Activity
[0190] The following assay is used for determining the binding
affinity of compounds to dopamine D.sub.4 and D.sub.2
receptors.
[0191] Pellets of Chinese hamster ovary (CHO) cells containing
recombinantly expressing primate D.sub.2, human D.sub.4 or human 1
receptors are used for the assays. The sample is homogenized in 100
volumes (w/vol) of 0.05 M Tris HCl buffer containing 120 mM NaCl, 5
mM MgCl.sub.2 and 1 mM EDTA at 4.degree. C. and pH 7.4. The sample
is then centrifuged at 30,000.times.g, resuspended and
rehomogenized. The sample is then recentrifuged at 30,000.times.g,
the supernatant is removed and the final tissue sample is frozen
until it is needed. The tissue is resuspended 1:20 (wt/vol) in 0.05
M Tris HCl buffer containing 120 mM NaCl.
[0192] Incubations for dopaminergic binding are carried out at
25.degree. C. and contain 0.4 ml of tissue sample, 0.1 nM
.sup.3H-YM 09151-2 (Nemonapride,
cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(pheny-
lmethyl)-3-pyrrolidinyl)benzamide) and the compound of interest in
a total incubation volume of 1.0 ml. Nonspecific binding is defined
as that binding found in the presence of 1 M spiperone; without
further additions, nonspecific binding is less than 20% of total
binding.
[0193] Binding characteristics for various compounds of the
invention for D.sub.2 and D.sub.4 primate or human dopamine
receptor subtypes are shown in Table 2.
1TABLE 2 Compound Number D.sub.2 K.sub.i (nM) D.sub.4 K.sub.i (nM)
1a 4375 96 1b 2638 93 1c 185 2 1d 473 70 1e 128 22 1f 183 206 1g
1178 5 1j 3207 10 1l 271 5 1m 1096 21 1o 200 11
[0194] Preferred compounds of the invention exhibit Ki values of
less than 500 nM at the dopamine D.sub.4 receptor, more preferred
compounds exhibit K.sub.i values of less than 100 nM and most
preferred compounds of the invention exhibit K.sub.i values of less
than 20 nM. Preferred compounds of the invention also exhibit
greater than 20-fold selectivity for the dopamine D.sub.4 receptor
over the dopamine D.sub.2 receptor; more preferred compounds of the
invention exhibit greater than 100-fold selectivity for the
dopamine D.sub.4 receptor over the dopamine D.sub.2 receptor.
EXAMPLE 12
[0195] Preparation of Radiolabeled Probe Compounds of the
Invention
[0196] The compounds of the invention are prepared as radiolabeled
probes by carrying out their synthesis using precursors comprising
at least one atom that is a radioisotope. The radioisotope is
preferably selected from of at least one of carbon (preferably
.sup.14C), hydrogen (preferably .sup.3H), sulfur (preferably
.sup.35S), or iodine (preferably .sup.125I). Such radiolabeled
probes are conveniently synthesized by a radioisotope supplier
specializing in custom synthesis of radiolabeled probe compounds.
Such suppliers include Amersham Corporation, Arlington Heights,
Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI
International, Menlo Park, Calif.; Wizard Laboratories, West
Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American
Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek
Biochemicals Inc., Brea, Calif.
[0197] Tritium labeled probe compounds are also conveniently
prepared catalytically via platinum-catalyzed exchange in tritiated
acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic
acid, or heterogeneous-catalyzed exchange with tritium gas. Tritium
labeled probe compounds can also be prepared, when appropriate, by
sodium borotritide reduction. Such preparations are also
conveniently carried out as a custom radiolabeling by any of the
suppliers listed in the preceding paragraph using the compound of
the invention as substrate.
EXAMPLE 12a
[0198] Radiolabeled compounds of the invention may be synthesized
via the method shown in Scheme I using ARC-802 Indole,
[2-.sup.14C(U)], supplied by American Radiolabeled Chemicals, Inc.,
St. Louis, Mo., as the radioisotope precursor.
EXAMPLE 13
[0199] Use of Compounds of the Invention as Probes for Dopamine
Receptors in Cultured Cells and Tissue Samples
[0200] Receptor autoradiography (receptor mapping) of dopamine
receptors in cultured cells or tissue samples is carried out in
vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current
Protocols in Pharmacology (1998) John Wiley & Sons, New York,
using radiolabeled compounds of the invention prepared as described
in the preceding Example.
[0201] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *