U.S. patent application number 14/266076 was filed with the patent office on 2014-10-02 for 4-phenylpiperazine derivatives with functionalized linkers as dopamine d3 receptor selective ligands and methods of use.
This patent application is currently assigned to The United States of America, as Represented by the Secretary, Department of Health and Human Serv. The applicant listed for this patent is The United States of America, as Represented by the Secretary, Department of Health and Human Serv, THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE AT FORT WORTH. Invention is credited to Jianjing Cao, George C. Cyriac, Peter Grundt, Robert Luedtke, Amy Hauck Newman.
Application Number | 20140296249 14/266076 |
Document ID | / |
Family ID | 40129996 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140296249 |
Kind Code |
A1 |
Newman; Amy Hauck ; et
al. |
October 2, 2014 |
4-PHENYLPIPERAZINE DERIVATIVES WITH FUNCTIONALIZED LINKERS AS
DOPAMINE D3 RECEPTOR SELECTIVE LIGANDS AND METHODS OF USE
Abstract
Dopamine D.sub.3 receptor antagonists and partial agonists are
known to modulate the reinforcing and drug-seeking effects induced
by cocaine and other abused substances. By introducing
functionality into the butylamide linking chain of the
4-phenylpiperazine class of ligands, improved D.sub.3 receptor
affinity and selectivity, as well as water solubility, is achieved.
A series of linking-chain derivatives are disclosed wherein
functionality such as OH, OAc, and cis or trans-cyclopropyl groups
have been introduced into the linking chain. In general, these
modifications are well tolerated at D.sub.3 receptors and achieve
high selectivity over D.sub.2 and D.sub.4 receptors.
Inventors: |
Newman; Amy Hauck; (Pheonix,
MD) ; Grundt; Peter; (Duluth, MN) ; Cyriac;
George C.; (Severna Park, MD) ; Luedtke; Robert;
(Fort Worth, TX) ; Cao; Jianjing; (Ellicott City,
MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The United States of America, as Represented by the Secretary,
Department of Health and Human Serv
THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE AT FORT WORTH |
Bethesda
Fort Worth |
MD
TX |
US
US |
|
|
Assignee: |
The United States of America, as
Represented by the Secretary, Department of Health and Human
Serv
Bethesda
MD
THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE AT FORT
WORTH
Fort Worth
TX
|
Family ID: |
40129996 |
Appl. No.: |
14/266076 |
Filed: |
April 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12664668 |
Jun 25, 2010 |
8748608 |
|
|
PCT/US07/71412 |
Jun 15, 2007 |
|
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14266076 |
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Current U.S.
Class: |
514/253.01 ;
435/7.1; 514/252.12; 514/254.09; 514/254.11 |
Current CPC
Class: |
A61P 25/30 20180101;
C07D 295/13 20130101; C07D 295/092 20130101; A61P 25/16 20180101;
C07D 295/096 20130101; C07D 213/56 20130101; C07D 209/42 20130101;
C07D 213/64 20130101; C07D 213/81 20130101; C07D 333/70 20130101;
C07D 209/48 20130101; C07D 295/145 20130101; C07D 307/85 20130101;
G01N 33/566 20130101; A61P 25/18 20180101; A61P 25/00 20180101;
C07D 213/89 20130101 |
Class at
Publication: |
514/253.01 ;
514/252.12; 514/254.09; 514/254.11; 435/7.1 |
International
Class: |
C07D 307/85 20060101
C07D307/85; G01N 33/566 20060101 G01N033/566; C07D 209/42 20060101
C07D209/42; C07D 213/56 20060101 C07D213/56; C07D 295/13 20060101
C07D295/13 |
Claims
1. A method of treating an addiction comprising: administering a
pharmaceutically effective amount of a compound of the following
chemical formula: ##STR00056## wherein: A=CHR.sub.4 or trans
CH.dbd.CH; n=0 or 1; R.sub.1 and R.sub.2=independently represent
hydrogen, halogen, or alkoxy; R.sub.3 and R.sub.4=H, OH, OAc,
alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or
pyridyl; R.sub.5=phenyl, indole, thiophene, benzofuran, fluorenyl,
or 2-pyridylphenyl; and R.sub.5 is optionally substituted with one
or more of hydrogen, halogen, amino, nitro, hydroxyl, alkoxy,
alkyl, and pyridyl, substitution may occur at any of the ortho,
meta, or para positions; including all enantiomers and
pharmaceutical salts thereof, wherein alkyl is a branched or
unbranched, saturated or unsaturated, monovalent hydrocarbon
radical having from 1-8 carbons, optionally substituted with one or
more C.sub.1 to C.sub.3 alkyl, halogen, hydroxyl, amino, alkoxyl,
or mercapto groups, and wherein alkoxy is --OR group, wherein R is
a C.sub.1 to C.sub.3 alkyl optionally substituted with one or more
C.sub.1 to C.sub.3 alkyl, halogen, hydroxyl, amino, alkoxyl, or
mercapto groups; wherein when A=trans CH.dbd.CH, then R.sub.3=OH,
OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and wherein
when A=CHR.sub.4, then one of R.sub.3 or R.sub.4=OH, OAc, alkoxy,
halogen, amino, nitro, alkyl, or pyridyl, to a patient in need
thereof.
2. The method of claim 1, in which A is CHR.sub.4.
3. The method of claim 1, wherein the compound is:
N-(3-hydroxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-
-benzamide;
N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-c-
arboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-c-
arboxamide;
N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carb-
oxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-iod-
o-benzofuran-2 carboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-fluorobenzo
furan-2 carboxamide;
5-fluoro-N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indo-
le-2-carboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-methoxy-1H--
indole-2-carboxamide;
(R)--N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indol-
e-2-carboxamide; or
(S)--N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indol-
e-2-carboxamide.
4. The method of claim 1, wherein R.sub.3=OH, OAc, alkoxy, halogen,
amino, nitro, alkyl having from 2-8 carbons, or pyridyl.
5. The method of claim 1, wherein R.sub.4=OH, OAc, alkoxy, halogen,
amino, nitro, alkyl having from 2-8 carbons, or pyridyl.
6. The method of claim 1, wherein A=CHR.sub.4; n=1; R.sub.1 and
R.sub.2=independently represent hydrogen, halogen, or alkoxy;
R.sub.3=OH or halogen; R.sub.4=H; and R.sub.5=indole or fluorenyl,
and R.sub.5 is optionally substituted with alkoxy.
7. The method of claim 1, wherein A=CHR.sub.4; n=1; R.sub.1 and
R.sub.2=Cl; R.sub.3=F; R.sub.4=H; and R.sub.5=indole or fluorenyl,
and R.sub.5 is optionally substituted with methoxy.
8. The method of claim 1, wherein A=CHR.sub.4; n=1; R.sub.1=H;
R.sub.2=methoxy; R.sub.3=OH; R.sub.4=H; and R.sub.5=indole
substituted with methoxy.
9. A method of treating schizophrenia or Parkinson's disease or
dyskinesias associated with these diseases comprising:
administering a pharmaceutically effective amount of a compound of
the following chemical formula: ##STR00057## wherein: A=CHR.sub.4
or trans CH.dbd.CH; n=0 or 1; R.sub.1 and R.sub.2=independently
represent hydrogen, halogen, or alkoxy; R.sub.3 and R.sub.4=H, OH,
OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons,
or pyridyl; R.sub.5=phenyl, indole, thiophene, benzofuran,
fluorenyl, or 2-pyridylphenyl; and R.sub.5 is optionally
substituted with one or more of hydrogen, halogen, amino, nitro,
hydroxyl, alkoxy, alkyl, and pyridyl, substitution may occur at any
of the ortho, meta, or para positions; including all enantiomers
and pharmaceutical salts thereof, wherein alkyl is a branched or
unbranched, saturated or unsaturated, monovalent hydrocarbon
radical having from 1-8 carbons, optionally substituted with one or
more C.sub.1 to C.sub.3 alkyl, halogen, hydroxyl, amino, alkoxyl,
or mercapto groups, and wherein alkoxy is --OR group, wherein R is
a C.sub.1 to C.sub.3 alkyl optionally substituted with one or more
C.sub.1 to C.sub.3 alkyl, halogen, hydroxyl, amino, alkoxyl, or
mercapto groups; wherein when A=trans CH.dbd.CH, then R.sub.3=OH,
OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and wherein
when A=CHR.sub.4, then one of R.sub.3 or R.sub.4=OH, OAc, alkoxy,
halogen, amino, nitro, alkyl, or pyridyl, to a patient in need
thereof.
10. The method of claim 9, in which A is CHR.sub.4.
11. The method of claim 9, wherein the compound is:
N-(3-hydroxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-
-benzamide;
N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-c-
arboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-c-
arboxamide;
N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carb-
oxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-iod-
o-benzofuran-2 carboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-fluorobenzo-
furan-2 carboxamide;
5-fluoro-N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indo-
le-2-carboxamide;
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-methoxy-1H--
indole-2-carboxamide;
(R)--N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indol-
e-2-carboxamide; or
(S)--N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indol-
e-2-carboxamide.
12. The method of claim 9, wherein R.sub.3=OH, OAc, alkoxy,
halogen, amino, nitro, alkyl having from 2-8 carbons, or
pyridyl.
13. The method of claim 9, wherein R.sub.4=OH, OAc, alkoxy,
halogen, amino, nitro, alkyl having from 2-8 carbons, or
pyridyl.
14. The method of claim 9, wherein A=CHR.sub.4; n=1; R.sub.1 and
R.sub.2=independently represent hydrogen, halogen, or alkoxy;
R.sub.3=OH or halogen; R.sub.4=H; and R.sub.5=indole or fluorenyl,
and R.sub.5 is optionally substituted with alkoxy.
15. The method of claim 9, wherein A=CHR.sub.4; n=1; R.sub.1 and
R.sub.2=Cl; R.sub.3=F; R.sub.4=H; and R.sub.5=indole or fluorenyl,
and R.sub.5 is optionally substituted with methoxy.
16. The method of claim 9, wherein A=CHR.sub.4; n=1; R.sub.1=H;
R.sub.2=methoxy; R.sub.3=OH; R.sub.4=H; and R.sub.5=indole
substituted with methoxy.
17. A method of selectively imaging dopamine D.sub.2 family binding
sites of the central nervous system to detect or monitor a disease
resulting from abnormal distribution and/or density of dopamine
D.sub.3 receptor in the central nervous system of a patient
comprising: contacting central nervous system tissue with a
compound of the following chemical formula: ##STR00058## wherein:
A=CHR.sub.4 or trans CH.dbd.CH; n=0 or 1; R.sub.1 and
R.sub.2=independently represent hydrogen, halogen, or alkoxy;
R.sub.3 and R.sub.4=H, OH, OAc, alkoxy, halogen, amino, nitro,
alkyl having from 2-8 carbons, or pyridyl; R.sub.5=phenyl, indole,
thiophene, benzofuran, fluorenyl, or 2-pyridylphenyl; and R.sub.5
is optionally substituted with one or more of hydrogen, halogen,
amino, nitro, hydroxyl, alkoxy, alkyl, and pyridyl, substitution
may occur at any of the ortho, meta, or para positions; including
all enantiomers and pharmaceutical salts thereof, wherein alkyl is
a branched or unbranched, saturated or unsaturated, monovalent
hydrocarbon radical having from 1-8 carbons, optionally substituted
with one or more C.sub.1 to C.sub.3 alkyl, halogen, hydroxyl,
amino, alkoxyl, or mercapto groups, and wherein alkoxy is --OR
group, wherein R is a C.sub.1 to C.sub.3 alkyl optionally
substituted with one or more C.sub.1 to C.sub.3 alkyl, halogen,
hydroxyl, amino, alkoxyl, or mercapto groups; wherein when A=trans
CH.dbd.CH, then R.sub.3=OH, OAc, alkoxy, halogen, amino, nitro,
alkyl, or pyridyl; and wherein when A=CHR.sub.4, then one of
R.sub.3 or R.sub.4=OH, OAc, alkoxy, halogen, amino, nitro, alkyl,
or pyridyl; and detecting the binding of the compound to the
central nervous system tissue.
18. The method of claim 17, further comprising: determining the
distribution and/or density of the dopamine D.sub.3 receptor in the
central nervous system tissue; comparing the distribution and/or
density obtained with the distribution and/or density of dopamine
D3 receptor in a corresponding normal tissue; and diagnosing a
disease state by a difference in the distribution and/or density
between the normal tissue and the subject tissue.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Nonprovisional
patent application Ser. No. 12/664,668, having a 371(c) date of
Jun. 25, 2010, which is a 371 national stage application of
international application number PCT/US07/071412 filed Jun. 15,
2007, both of which are fully incorporated herein by reference.
BACKGROUND
[0002] The dopamine receptor system plays a key role in numerous
neuropsychiatric and neurological disorders and investigation into
mechanistic underpinnings and neuroadaptations within this family
of receptors has been the focus of intensive research over the past
decade. The dopamine D.sub.3 receptor subtype has been hypothesized
to play a fundamental role, for example, in the abuse-related
effects of cocaine and other drugs of abuse. Hence, there is a
well-recognized need to develop novel, selective and bioavailable
dopamine D.sub.3 receptor ligands.
[0003] Further reasons for pursuing dopamine D.sub.3 receptor
selective ligands as medications for various conditions comes from
the brain localization of D.sub.3 receptors, which are primarily
expressed in limbic regions of the brain, including the nucleus
accumbens. D.sub.3 receptor blockade may attenuate drug reward
and/or reinforcement while avoiding the risk of extrapyramidal side
effects associated with the blockade of the more ubiquitous D.sub.2
receptors.
[0004] The high degree of amino acid homology within the binding
sites of the dopamine D.sub.2-like receptors, and especially
between the D.sub.2 and D.sub.3 dopamine receptor subtypes, has
provided a formidable challenge in the pursuit to discover dopamine
D.sub.3-selective compounds. Thus far, high dopamine
D.sub.2/D.sub.3 selectivity has generally been achieved with
relatively large molecules, characterized, for example, by a
heterocyclic moiety bridged by an unsubstituted 4-carbon chain or
carbocycle to an extended or substituted arylamide or a
corresponding bioisotere.
[0005] In addition to optimizing pharmacological selectivity, it is
also important that dopamine D.sub.3-selective compounds be able to
penetrate the blood brain barrier (BBB) and have appropriate
pharmacokinetics to facilitate interpretation of in vivo results.
However, generally relatively high doses of D.sub.3-selective
agents have been required for behavioral activity. It is not known
whether these required high doses are due to a low permeability
surface area product of these agents for crossing the BBB, high
peripheral metabolism, large uptake in some other organ or
compartment, or is due to some other reason.
[0006] Therefore, there is a well-recognized need in the art for
highly D.sub.3-selective compounds that are able to penetrate the
blood brain barrier, and that show activity at relatively low
dosages.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1: Synthesis of the 3-hydroxyl amines 27.
[0008] FIG. 2: Synthesis of the 2-hydroxyl amines 30.
[0009] FIG. 3: Synthesis of Compounds 2-23.
DESCRIPTION OF THE INVENTION
[0010] The present invention relates to chemical compounds of the
following chemical formula:
##STR00001##
[0011] wherein:
[0012] A=CHR.sub.4 or trans CH.dbd.CH;
[0013] n=0 or 1;
[0014] R.sub.1 and R.sub.2=independently represent hydrogen,
halogen, or alkoxy;
[0015] R.sub.3 and R.sub.4=H, OH, OAc, alkoxy, halogen, amino,
nitro, alkyl, acyl or pyridyl;
[0016] R.sub.5=phenyl, indole, thiophene, benzofuran, fluorenyl, or
2-pyridylphenyl; and R.sub.5 is optionally substituted with one or
more of hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl,
acyl and pyridyl, substitution may occur at any of the ortho, meta,
or para positions;
[0017] including all enantiomers and pharmaceutical salts.
[0018] In particular, when R.sub.3 and R.sub.4 are not H, chiral
centers are present on the butyl amide linking chain and are
included within the scope of the invention.
[0019] In one embodiment of the invention A in Formula (I) is
C.
[0020] In one embodiment, the present invention is directed to
compounds of the following chemical formula:
##STR00002##
[0021] wherein
[0022] R.sub.1 and R.sub.2=2-methoxy or 2,3-dichloro;
[0023] R.sub.3 and R.sub.4=OH, OAc, H; and
[0024] R.sub.5=indole, thiophene, benzofuran, fluorenyl, or
2-pyridylphenyl, and R.sub.5 is substituted with one or more of
methoxy, fluoro, or iodo;
[0025] including all enantiomers and pharmaceutical salts.
[0026] Dopamine D.sub.3 receptor antagonists and partial agonists
are known to modulate the reinforcing and drug-seeking effects
induced by cocaine and other abused substances. The introduction of
functionality into the butylamide linking chain of the
4-phenylpiperazine class of ligands, improves D.sub.3 receptor
affinity and selectivity, as well as water solubility. See J. Med.
Chem. 2005, 48, 839-848. Along these lines, a series of
linking-chain derivatives wherein functionality such as OH, OAc,
etc., are introduced into the linking chain is disclosed.
[0027] In general, these modifications are well tolerated at
D.sub.3 receptors (K.sub.i=<1-5 nM) and several analogues
demonstrated >100-fold selectivity over D.sub.2 and D.sub.4
receptors using competition binding assays in HEK 293 cells
transfected with either hD.sub.2L, hD.sub.3 or hD.sub.4 dopamine
receptors. Furthermore, addition of these groups affected efficacy
of the compounds as measured by quinpirole stimulation of
mitogenesis at human dopamine D.sub.3 receptors transfected into
Chinese hamster ovary (CHO) cells. These compounds also provide
additional tools with which to elucidate the role of D.sub.3
receptors in drug reinforcement in vivo.
[0028] The dopamine D.sub.3 receptor subtype is a member of the
dopamine D.sub.2 family of receptors. These receptors are involved
in a number of CNS disorders including but not limited to
psychostimulant abuse, psychosis, and Parkinson's disease. (Newman,
A. H.; Grundt, P.; Nader, M. A., Dopamine D3 receptor partial
agonists and antagonists as potential drug abuse therapeutic
agents. J. Med. Chem. 2005, 48, 3663-3679.; Heidbreder, C. A.;
Andreoli, M.; Marcon, C; Thanos, P. K.; Ashby, C. R.; Gardner, E.
L., Role of dopamine D-3 receptors in the addictive properties of
ethanol. Drugs Today 2004, 40, 355-365.; Joyce, J. N.; Millan, M.
J., Dopamine D-3 receptor antagonists as therapeutic agents. Drug
Discov. Today 2005, 10, 917-925; See also, Le Foil, B.; Goldberg,
S. R.; Sokoloff, P., The dopamine D-3 receptor and drug dependence:
Effects on reward or beyond? Neuropharmacology 2005, 49, 525-541;
Luedtke, R. R.; Mach, R. H., Progress in developing D3 dopamine
receptor ligands as potential therapeutic agents for neurological
and neuropsychiatric disorders Curr. Pharm. Design 2003, 9,
643-671; Boeckler, F.; Gmeiner, P., The structural evolution of
dopamine D-3 receptor ligands: Structure-activity relationships and
selected neuropharmacological aspects Pharmacol. Ther. 2006, 112,
281-333.)
[0029] Compounds that bind with high affinity and selectivity to
D.sub.3 receptors not only provide important tools with which to
study the structure and function of this receptor subtype, but also
have a therapeutic effect in the treatment of numerous psychiatric
and neurologic disorders.
[0030] It is known in the art that the D.sub.2 family of receptors
(which includes D.sub.3) are increased in cocaine addicts and
monkeys trained to self-administer cocaine. See Volkow, N. D.;
Wang, G. J.; Fowler, J. S.; Logan, J.; Gatley, S. J.; Wong, C;
Hitzemann, R.; Pappas, N. R., Reinforcing effects of
psychostimulants in humans are associated with increases in brain
dopamine and occupancy of D-2 receptors, J. Pharmacol. Exp. Ther.
1999, 291, 409-415; Volkow, N. D.; Fowler, J. S.; Wang, G. J.;
Swanson, J. M., Dopamine in drug abuse and addiction: results from
imaging studies and treatment implications, MoI. Psychiatry 2004,
9, 557-569; Nader, M. A.; Morgan, D.; Gage, H. D.; Nader, S. H.;
Calhoun, T. L.; Buchheimer, N.; Ehrenkaufer, R.; Mach, R. H., PET
imaging of dopamine D2 receptors during chronic cocaine
self-administration in monkeys, Nat. Neurosci. 2006, 9,
1050-1056.
[0031] The 4-phenylpiperazine derivatives are an important class of
dopamine D.sub.3 selective ligands. However, due to their highly
lipophilic nature, these compounds often suffer from solubility
problems in aqueous media and reduced bioavailability. To address
these problems, functionality (e.g. OH, OCH3, OAc, etc.,) is
introduced into the carbon chain linker of these compounds.
Compared to currently available dopamine D.sub.3 receptor ligands,
the resulting compounds show improved pharmacological properties
and D.sub.3 selectivities, but due to their more hydrophilic nature
these derivatives also have improved water solubility and
bioavailability.
[0032] The more hydrophilic nature of these derivatives is shown by
the cLogP (calculated measure of lipophilicity) and polar surface
areas (PSA). See Table 1. As expected, the introduction of a
hydroxyl group into the butyl linking chain resulted in lower clogP
values, showing decreased lipophilicity, compared to the
corresponding parent olefinic or aliphatic compounds. The
calculated polar surface area (PSA) was significantly increased (by
20 .ANG..sup.2). Values less than 75 .ANG..sup.2 are considered as
being favorable for brain penetration. See Grundt, P.; Prevatt, K.
M.; Cao, J.; Taylor, J.; Floresca, C. Z.; Choi, J.-K.; Jenkins, B.
G.; Luedtke, R. R.; Newman A. H. Heterocyclic Analogues of
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-butyl)-aryl-carboxamides
with Functionalized Linking Chains as Novel Dopamine D3 Receptor
Ligands: Potential Substance Abuse Therapeutic Agents. J. Med.
Chem. 2007, in press.
[0033] According to Lipinski's "rule of 5" cLogP values in the 2-5
range are expected to have drug like properties. See Lipinski, C.
A., Drug-like properties and the causes of poor solubility and poor
permeability, J. Pharmacol. Toxicol. Methods 2000, 44, 235-249.
Comparisons of the hydroxylated analogues with their saturated
butyl or olefinic counterparts demonstrate that both PSA and
particularly cLogP values are predictive of improved "drug-like",
soluble, bioavailable and CNS penetrant profiles. The PSA values
were calculated according to Ertl, P.; Rohde, B.; Selzer, P., Fast,
Calculation of molecular polar surface area as a sum of
fragment-based contributions and its application to the prediction
of drug transport properties, 2000, 43, 3714-3717. CLogP values
were calculated using Cambridgesoft ChemDraw Ultra 9.0, 2004.
[0034] Based on their neurochemical and behavioral properties, the
dopamine D.sub.3 receptor selective ligands of the present
invention are useful in methods for the treatment of all
addictions, especially including nicotine and alcohol, and
psychostimulant abuse, such as of cocaine, amphetamine, and
derivatives thereof. The dopamine D.sub.3 receptor selective
ligands of the present invention are also useful in the treatment
of schizophrenia and Parkinson's disease and dyskinesias associated
with these disorders and treatment thereof. Generally the methods
involve administering a pharmaceutically effective amount of a
compound of the present invention to a patient in need thereof.
[0035] D.sub.3 selectivity is expressed as D.sub.2/D.sub.3; a ratio
that is derived from the Ki value at D.sub.2 over the Kj value at
D.sub.3 receptors. Hence, a compound that exhibits higher affinity
at D.sub.3 than at D.sub.2 receptors, has a D.sub.2/D.sub.3
ratio>1." See Newman, A. H.; Grundt, P.; Nader, M. A., Dopamine
D3 receptor partial agonists and antagonists as potential drug
abuse therapeutic agents. J. Med. Chem. 2005, 48, 3663-3679.
[0036] The term "pharmaceutically effective amount" as used herein
means an amount of the compound that produces any therapeutic
effect or imaging effect in a patient. Therapeutic effect in a
patient preferably relates to one of the above-mentioned
conditions.
[0037] The term "alkyl" is used herein to refer to a branched or
unbranched, saturated or unsaturated, monovalent hydrocarbon
radical having from 1-8 carbons, including arylalkyls. Suitable
alkyl radicals include, for example, methyl, ethyl, n-propyl,
i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i-butyl (or
2-methylpropyl), i-amyl, n-amyl, hexyl, etc. As used herein, the
term alkyl encompasses "substituted alkyls." The term "substituted
alkyl" refers to alkyl as just described including one or more
functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen
(i.e., alkylhalos, e.g., CF.sub.3), hydroxyl, amino, acylamino,
acyloxy, alkoxyl, mercapto and the like. These groups may be
attached to any carbon atom of the lower alkyl moiety.
[0038] The term "alkoxy" is used herein to refer to the --OR group,
where R is a lower alkyl, substituted lower alkyl, aryl,
substituted aryl, aralkyl or substituted aralkyl. Suitable alkoxy
radicals include, for example, methoxy, ethoxy, phenoxy, t-butoxy,
etc.
[0039] The term "lower alkyl" means C.sub.1 to C.sub.3. The term
"halogen" is used herein to refer to fluorine, bromine, chlorine,
and iodine atoms. The term "hydroxyl" is used herein to refer to
the group --OH.
[0040] As used herein, "psychostimulant abuse" has its conventional
meaning, i.e., misuse or addiction of a psychostimulant, such as
cocaine, amphetamine, and derivatives thereof. Typically, cocaine
is taken by a person due to a craving for cocaine generated by its
prior use. Cocaine is abused when it is used for gratification,
producing effects not required or recommended for therapy. The
resultant high use of cocaine produces many serious and adverse
side effects. As such, it is highly desirable to reduce the number
and/or intensity of episodes in which a person experiences a
craving for the substance or, more preferably, to eliminate the
craving episodes entirely. Dopamine D.sub.3 antagonists or partial
agonists have demonstrated utility in reducing craving in animal
models (Villa, M. et al. Nature 400:371-375 (1999), Vorel, S. R. et
al. J. Neurosci. 22:9595-9603 (2002), DiCiano, P. et al.
Neuropsychopharmacology 28:329-338 (2003)).
[0041] "Treatment" or "treating," as used herein, refers to any
administration of a compound of the present invention and includes:
(i) inhibiting the symptoms of the disease, e.g., cocaine
addiction; and/or (ii) lessening or inhibiting the long term
effects of the disease, e.g., cocaine addiction. In therapeutic
applications, compositions are administered to a patient already
suffering from the disease, e.g., cocaine addiction or Parkinson's
disease, in a pharmaceutically effective amount.
[0042] In conjunction with the foregoing method, the present
invention provides pharmaceutical compositions comprising a
compound disclosed herein and a pharmaceutically acceptable
diluent, carrier or excipient. While it is possible to administer
the active ingredient of this invention alone, it is preferable to
present it as part of a pharmaceutical formulation. The
formulations of the present invention comprise at least one
compound described herein in a therapeutically or pharmaceutically
effective dose together with a pharmacologically or therapeutically
acceptable carrier. The phrase "pharmaceutically or therapeutically
acceptable carrier," as used herein, refers to a carrier medium
which does not interfere with the effectiveness of the biological
activity of the active ingredients, especially D.sub.3 receptor
binding of a compound of the present invention, and which is not
toxic to the host or patient.
[0043] The pharmaceutical compositions of the present invention can
be in a variety of forms. These include, for example, solid,
semi-solid, and liquid dosage forms, such as tablets, pills,
powders, liquid solutions or suspensions, liposomes, injectable and
infusible solutions, inhalable preparations, such as aerosols, are
also included. Preferred formulations are those directed to oral,
intranasal and parenteral applications, but it will be appreciated
that the preferred form will depend on the particular therapeutic
application at hand. The methods for the formulation and
preparation of therapeutic compositions comprising the compounds of
the invention are well known in the art and are described in, for
example, REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing
Company, Philadelphia, Pa., 17th ed. (1985)), THE MERCK INDEX 11th
Ed., (Merck & Co. 1989), and Langer, Science 249: 1527-1533
(1990), the teachings of which are incorporated herein by
reference.
[0044] For parenteral administration, for example, the
pharmaceutical compositions comprise a solution of a compound of
the present invention, as described above, dissolved or suspended
in an acceptable carrier, preferably an aqueous carrier. A variety
of aqueous carriers can be used including, for example, water,
buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the
like. These compositions may be sterilized by conventional,
well-known sterilization techniques, or they may be sterile
filtered. The resulting aqueous solutions may be packaged for use
as is or lyophilized, the lyophilized preparation being combined
with a sterile solution prior to administration. The compositions
may contain pharmaceutically acceptable auxiliary substances as
required to approximate physiological conditions including pH
adjusting and buffering agents, wetting agents and the like, such
as, for example, sodium acetate, sodium lactate, sodium chloride,
potassium chloride, calcium chloride, sorbitan monolaurate,
thethanolamine oleate, etc.
[0045] For solid compositions, conventional nontoxic solid carriers
may be used which include, for example, pharmaceutical grades of
mannitol, lactose, starch, magnesium stearate, sodium saccharin,
talcum, cellulose, glucose, sucrose, magnesium carbonate, and the
like. For oral administration, a pharmaceutically acceptable
nontoxic composition is formed by incorporating any of the normally
employed excipients, such as those carriers previously listed, and
generally about 1% to 95%, preferably 10% to about 95% of the
active ingredient and, more preferably, about 25% to about 75% of
the active ingredient.
[0046] For aerosol administration, the compounds of the present
invention are preferably supplied in a finely divided form along
with a surfactant and propellant. The surfactant must, of course,
be nontoxic, and preferably soluble in the propellant.
Representative of such agents are the esters or partial esters of
fatty acids containing from 6 to 22 carbon atoms, such as caproic,
octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric
and oleic acids with an aliphatic polyhydric alcohol or its cyclic
anhydride. Mixed esters, such as mixed or natural glycerides may be
employed. A carrier can also be included as desired, as with, e.g.,
lecithin, for intranasal delivery.
[0047] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
condition is retained. When the symptoms have been alleviated to
the desired level, treatment can cease. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of the disease symptoms.
[0048] In general, a suitable effective dose of the compounds of
the present invention will be in the range of 0.05 to 1000
milligram (mg) per recipient per day, preferably in the range of
0.1 to 100 mg per day. The desired dosage is preferably presented
in one, two, three, four or more subdoses administered at
appropriate intervals throughout the day. These subdoses can be
administered as unit dosage forms, for example, containing 0.01 to
1000 mg, preferably 0.01 to 100 mg of active ingredient per unit
dosage form. Again, the desired dosage will depend on, for example,
the particular compound employed, the disease to be treated, the
manner of administration, the weight and general state of health of
the patient, and the judgment of the prescribing physician.
[0049] Based on their neurochemical and behavioral properties, the
D.sub.3 receptor selective ligands of the present invention are
also useful as imaging probes. The present compounds may be useful
for functional MRI imaging of D3 receptors. In addition, the
dopamine D.sub.3 receptor selective ligands of the present
invention are useful as imaging agents for dopamine D.sub.3
receptors and as imaging probes for neurodegenerative disorders
(e.g., Parkinson's disease). As such, in another aspect, the
present invention provides a method of selectively imaging dopamine
binding sites of the central nervous system of a subject, such as
the brain of a human patient, the method comprising:
[0050] (a) administering to a human in need thereof an inventive
compound of the present invention; and
[0051] (b) detecting the binding of the compound to the central
nervous system tissue, such as the dopamine D.sub.3 receptors in
the brain.
[0052] Moreover, in yet another aspect, the present invention
provides a method for detecting or monitoring a disease resulting
from abnormal distribution and/or density of dopamine D.sub.3
receptor in the central nervous system of a subject,
comprising:
[0053] (a) administering to the subject a detectably labeled
compound of the invention;
[0054] (b) detecting the binding of that compound to dopamine
D.sub.3 receptor in the central nervous system;
[0055] (c) determining the distribution and/or density of the
dopamine D.sub.3 receptor in the central nervous system tissue;
[0056] (d) comparing the distribution and/or density obtained in
(c) with the distribution and/or density of dopamine D.sub.3
receptor in a corresponding normal tissue; and
[0057] (e) diagnosing a disease state by a difference in the
distribution and/or density between the normal tissue and the
subject tissue.
[0058] In a presently preferred embodiment, the dopamine selective
ligands of the present invention are labeled with a radioactive
label using standard labeling techniques known to and used by those
of skill in the art. Suitable labels include, but are not limited
to: .sup.123I, .sup.11C, .sup.18F, or .sup.99Tc. In addition,
binding of the dopamine D.sub.3 receptor selective ligands to the
brain, such as limbic brain regions, including the Nucleus
Accumbens and islands of Calleja, is detected using methods known
in the art, such as positron emission tomography (PET),
single-photon emission computed tomography (SPECT), or magnetic
resonance imaging (MRI). (See, e.g., Yokoi F. et al.,
Neuropsychopharmacology 27(2):248-59(2002); Pilowsky L. S., Nucl
Med Commun 22(7):829-33(2001); Soares J C and Innis R B, Biol
Psychiatry 46(5):600-15(1999); and Videbaek C, J Cereb Blood Flow
Metab 21(1):92-7(2001), the teachings of which are incorporated
herein by reference.
[0059] Preferably SPECT imaging employs gamma-emitting derivatives
of the ligands described herein (e.g., dopamine D.sub.3 receptor
selective ligands labeled with .sup.123I or .sup.99Tc). Yokoi et
al. (supra) have mapped the normal distribution of dopamine D.sub.2
and D.sub.3 receptors in humans. Using this method, one can
diagnose and/or monitor neurodegenerative disorders, such as
Parkinson's disease, characterized by the progressive degeneration
of dopamergic nerve terminals.
EXAMPLES
[0060] All melting points were determined on a Thomas-Hoover
melting point apparatus and are uncorrected. The .sup.1H and
.sup.13C NMR spectra were recorded on a Varian Mercury Plus 400
instrument. Proton chemical shifts are reported as parts per
million (.delta. ppm) relative to tetramethylsilane (0.00 ppm) as
an internal standard. Coupling constants are measured in hertz
(Hz). Chemical shifts for .sup.13C NMR spectra are reported as
.delta. relative to the deuterium signal of the solvent
(CDCI.sub.3, 77.5 ppm, CD.sub.3OD 49.3). Microanalyses were
performed by Atlantic Microlab, Inc. (Norcross, Ga.) and agree
within 0.4% of calculated values. If not stated otherwise all final
compounds were purified by column chromatography (silica gel,
Merck, 230-400 mesh, 60 .ANG.) or thin layer chromatography (silica
gel, Analtech, 1000 micron) using EtOAc/CHCl.sub.3/MeOH 5:5:1, 1%
triethylamine or CHCI.sub.3/MeOH 10:1, 1% triethylamine as an
eluent. Microwave reactions were performed in a CEM Discover
Labmate system equipped with a 80 mL pressure vessel. Yields and
reaction conditions are not optimized. Generally, yields and
spectroscopic data refer to the free base.
[0061] Methods for performing in vitro dopamine receptor binding
studies are described in Huang et al. J. Med. Chem. 44:1815-1826
(2001) and Luedtke et al. Synapse 38:438-439 (2000), the contents
of which are hereby incorporated by reference. These papers
describe radioactively labeled dopamine receptor selective ligands
binding with picomolar affinity and nonselectivity to D.sub.2 and
D.sub.3 dopamine receptors expressed in Sf9 and HEK 293 cells.
.sup.125I-IABN binds with 7- to 10-fold lower affinity to human
D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation
constants (Kd) calculated from kinetic experiments were found to be
in agreement with equilibrium Kd values obtained from saturation
binding studies. Saturation plots of the binding of .sup.125I-IABN
with rat caudate membrane preparations were monophasic and
exhibited low nonspecific binding. The pharmacologic profile of the
binding of .sup.125I-IABN to rat caudate was found to be consistent
with a D.sub.2-like receptor, suggesting that in the caudate the
ligand binds primarily to D.sub.2 dopamine receptors. IABN was
found to bind with low affinity to .sigma.1 and .sigma.2 binding
sites, as well as to D.sub.1a dopamine receptors. Quantitative
autoradiographic studies using rat brain indicated that
.sup.125I-IABN selectively labels the striatum and the olfactory
tubercle area, which is consistent with the labeling receptors
expressed in HEK cells. Therefore, .sup.125I-IABN appears to be a
high affinity, selective antagonist at D.sub.2-like dopamine
receptors.
[0062] Human dopamine D.sub.2-long (D.sub.2) and D.sub.3 (D.sub.3)
receptors were expressed in HEK cells. In brief, stably transfected
HEK cells expressing the human D.sub.2-long and the D.sub.3
dopamine receptor were developed using the plRES bicistronic
expression vector (CLONTECH; Palo Alto, Calif.). The level of
expression of D.sub.2 or D.sub.3 receptors was determined to be
greater than 2,000 fmoles/mg protein. For comparison, human
dopamine D.sub.4 (D.sub.4) receptors were obtained from HEK 293
cells stably transfected with a PCR product of a human cDNA coding
for the D4.4 form of the human D.sub.4 dopamine receptor. The
density of binding sites is approximately 1000 fmol/mg protein.
[0063] To measure D.sub.2 and D.sub.3 stimulation of mitogenesis
(agonist assay) or D.sub.2 and D.sub.3 inhibition of quinpirole
stimulation of mitogenesis (antagonist assay), CHOp-cells (human
receptor) were seeded in a 96-well plate at a concentration of
5,000 cells/well. The cells were incubated at 37.degree. C. in
.alpha.-MEM with 10% FBS, 0.05% penicillin-streptomycin, and 200
.mu.g/mL of G418. After 48 hours, the cells were rinsed twice with
serum-free .alpha.-MEM and incubated for 24 hours at 37.degree. C.
In the functional assay for agonism, the medium was removed and
replaced with 90 .mu.l of serum-free .alpha.-MEM and 10 .mu.l of
test compound in sterile water; in the antagonist assay, the test
compound was diluted in sterile water plus 30 nM quinpirole. After
another 24-hour incubation at 37.degree. C., 0.25 .mu.Ci of
[.sup.3H]thymidine was added to each well and the plates were
further incubated for 2 hours at 37.degree. C. The cells were then
trypsinized, and the plates were filtered and counted as usual in
the art. Quinpirole was run on every plate as an internal
standard.
[0064] The procedures to determine the binding affinities at the
human dopamine D.sub.2-like receptors, the binding affinities at
the serotonin 5HT.sub.1A, 5HT.sub.2A and 5HT.sub.2c receptors and
functional mitogenesis assay are known in the art. See J. Med.
Chem. 2005, 48, 839-848. See also, NIDA Research Monograph #178,
Proceedings of the College of Drug Dependence, p. 440-466, 1998.
Both of these references are incorporated by reference.
[0065] The racemic hydroxybutyl amine intermediates needed to
prepare the 3-hydroxy derivatives 16-19 and 2-hydroxy analogues
21-23 were synthesized as depicted in FIGS. 1 and 2. In both cases,
the synthetic routes used bifunctional 2-(2-bromoethyl)oxirane as
starting material. See Cruickshank, P. A.; Fishman, M., "Studies In
Alkylation.2. Reactions Of Epoxyalkyl Bromides", J. Org. Chem.
1969, 34, 4060-4065, incorporated by reference. All key steps were
found to be regioselective and only the products depicted were
isolated. The amines (FIG. 1) were synthesized via a modified
Gabriel synthesis. No side products were observed in the alkylation
reaction to form the phthalimide.
[0066] The opening of the oxirane moiety occurred selectively at
the least substituted side to yield the 3-hydroxy phthalimides,
which were then deprotected with hydrazine to afford the
hydroxylamines. In the case of the 2-hydroxy amines (30, FIG. 2)
the butylpiperazine bond was formed first, followed by a
regioselective opening of the epoxide with sodium azide and a
Schlesinger-type reduction. The general reaction sequence used to
prepare the dopamine D.sub.3 receptor preferring analogues 2-23
incorporating a butyl, butenyl or hydroxybutyl linking chain as
depicted in FIG. 3. The required carboxylic acids were prepared
according to procedures known in the art. See J. Med. Chem. 2001,
44, 3175-3186. See also, Synlett 2000, 829-831. Both of these
references are incorporated by reference.
[0067] The general synthesis of the butyl amines and the butenyl
amines is also known in the art. See J. Med. Chem. 2005, 48,
839-848; J. Med. Chem. 2001, J. Med. Chem. 2003, 46, 3883-3899; and
Bioorg. Med. Chem. Lett. 2003, 13, 2179-2183. All of these
references are incorporated by reference.
[0068] General procedure for the synthesis of carboxylic acid
amides. The 1-imidazole adduct appropriate carboxylic acid was
reacted with the suitable secondary amine derivative as known in
the art. See J. Med. Chem. 2005, 48, 839-848, incorporated by
reference. The crude product was purified by chromatography,
structurally characterized, and then converted into its oxalate or
hydrochloride for biological evaluation.
EXAMPLES
Example 1
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide
(7)
[0069] Prepared from 9H-fluorene-2-carboxylic acid and
4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butylamine according to the
general procedure. Yield: 74%. Mp. (hydrochloride): 208-210.degree.
C. .sup.1H NMR (CDCI.sub.3): .delta. 1.67-1.73 (m, 4H), 2.47 (t, J
6.7, 2H), 2.65 (s, 4H), 3.04 (s, 4H), 3.51 (q, J 6.1, 2H), 3.84 (s,
3H), 3.91 (s, 2H), 6.82-6.88 (m, 4H), 6.98 (dt, J 7.8, 4.6, 1H),
7.35 (td, J 7.4, 1.2, 1H), 7.40 (t, J 7.0, 1H), 7.55 (d, J 7.0,
1H), 7.75-7.77 (m, 2H), 7.81 (d, J 8.0, 1H), 7.96 (s, 1H). .sup.13C
NMR (CDCI.sub.3): .delta. 25.0, 27.9, 37.3, 40.5, 50.93, 53.9,
55.8, 58.5, 111.5, 118.6, 120.1, 121.0, 121.4, 123.4, 124.4, 125.6,
126.3, 127.4, 128.0, 133.8, 141.2, 141.6, 143.8, 144.4, 145.1,
152.7, 168.6. Anal. (C.sub.29H.sub.33N.sub.3O.sub.2
HCIO--SH.sub.2O) C, H, N.
Example 2
N-(4-(4-(2-Methoxy-phenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-benzamide
(8)
[0070] Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and
4-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butylamine according to the
general procedure. Yield: 53%. Mp. (oxalate): foam. .sup.1H NMR
(CDCI.sub.3): .delta. 1.67-1.74 (m, 4H), 2.49 (t, J 6.84, 2H), 2.67
(s, 2H), 3.07 (s, 2H), 3.51 (q, J 6.0, 2H), 3.84 (s, 3H), 6.83 (m,
5H), 7.26 (m, 1H), 7.73-7.79 (m, 2H), 7.89 (d, J 8.2, 2H), 8.06 (d,
J 8.6, 2H), 8.71 (dt, J 4.7, 1.3, 1H). .sup.13C NMR (CDCl.sub.3):
.delta. 24.8, 27.9, 40.4, 50.8, 53.9, 55.8, 58.5, 111.6, 118.7,
121.3, 121.4, 123.1, 123.4, 127.4, 127.9, 135.6, 137.3, 142.5,
150.3, 152.7, 156.7, 167.8. Anal. (C.sub.27H.sub.32N.sub.4O.sub.2
(COOH).sub.20.75H.sub.2O) C, H, N.
Example 3
N-(4-(4-(2,3-Dichloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl)-4-(6-oxo-1-
,6-dihydro-pyridin-2-yl)-benzamide (9)
[0071] A suspension of 0.12 g (0.53 mmol)
4-(6-oxo-1,6-dihydro-pyridin-2-yl)-benzoic acid, 0.13 g (0.64 mmol)
dicyclohexylcarbodiimide, 0.1 g (0.7 mmol) 1-hydroxbenzotriazole
hydrate in 15 mL DMF was treated at 0.degree. C. with 0.16 g (0.53
mmol) 4-(4-(2,3-chloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl
amine and 0.17 mL (1.2 mmol) triethylamine. The reaction mixture
was stirred at room temperature for 3 days and filtered. The
solvent was removed in vacuo and the residue was taken up in
saturated sodium bicarbonate and CHCI.sub.3. The combined organics
were dried with sodium sulphate, concentrated and the crude product
was purified by thin layer chromatography. Yield: 0.10 g (38%). Mp.
(oxalate): 153-154.degree. C. .sup.1H NMR (CDCI.sub.3): .delta.
2.67 (s, 4H), 3.06 (s, 6H), 4.11 (m, 2H), 5.74-5.83 (m, 2H),
6.51-6.54 (m, 2H), 6.70 (t, J 5.3, 1 H), 6.95 (dd, J 6.7, 2.9, 1H),
7.11-7.17 (m, 2H), 7.50 (dd, J 9.1, 7.0, 1H), 7.72 (d, J 8.3, 2 H),
7.85 (d, J 8.4, 2 H). .sup.13C NMR (CDCI.sub.3): .delta. 40.6,
50.2, 52.3, 59.4, 105.9, 17.9, 118.1, 124.1, 126.3, 126.6, 126.7,
127.0, 127.3, 130.2, 133.2, 135.0, 135.7, 141.6, 145.6, 150.4,
164.5, 167.0. Anal. (C.sub.26H.sub.26CI.sub.2N.sub.4O.sub.2 1.5
(COOH).sub.2) C, H, N.
Example 4
N-(4-(4-(2,3-Dichloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl)-4-(6-methy-
l-pyridin-2-yl)-benzamide (10)
[0072] Prepared from 4-(6-methylpyridin-2-yl)benzoic acid
hydrochloride and
4-(4-(2,3-chloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl amine
according to the general procedure. Yield: 18%. Mp. (oxalate):
125-126.degree. C. .sup.1H NMR (CDCI.sub.3): .delta. 2.63 (s, 7H),
3.08 (s, 6H), 4.12 (m, 2H), 5.78-5.80 (m, 2H), 6.42 (s, br, 1H),
6.95 (d, J 6.7, 2.7, 1H), 7.11-7.16 (m, 3H), 7.55 (d, J 7.7, 1 H),
7.65 (t, J 7.6, 1H), 7.87 (d, J 8.7, 2H), 8.05 (d, J 8.3, 2H).
.sup.13CNMR (CDCI.sub.3): .delta. 25.2, 42.0, 51.7, 53.7, 60.7,
118.3, 119.1, 122.8, 125.0, 127.5, 127.8, 127.9, 129.4, 130.2,
134.4, 134.7, 137.5, 143.1, 151.7, 156.0, 159.0, 167.4. Anal.
(C.sub.27H.sub.28CI.sub.2N.sub.4O) 2(COOH).sub.2):
C.sub.1H.sub.1N.
Example 5
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-(3-methyl--
pyridin-2-yl)-benzamide (11)
[0073] Prepared from 4-(3-methylpyridin-2-yl)benzoic acid
hydrochloride and
4-(4-(2,3-chloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl amine
according to the general procedure. Yield: 55%. Mp. (oxalate):
foam. .sup.1H NMR (CDCI.sub.3): .delta. 2.34 (s, 3H), 2.65 (s, 4H),
3.07-3.10 (m, 6H), 6.12 (m, 2H), 5.78-5.82 (m, 2H), 6.49 (t, J 5.5,
1H), 6.95 (dd, J 6.5, 2.9, 1H), 7.12-7.16 (m, 2H), 7.21 (dd, J 7.6,
4.8, 1H), 7.57-7.62 (m, 3H), 7.86 (dt, J 8.6, 2.0, 2H), 8.53 (dt, J
4.2, 0.8, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 20.4, 42.0, 51.7,
53.7, 60.7, 119.1, 123.0, 125.0, 127.3, 127.9, 129.4, 129.7, 130.3,
131.4, 134.2, 134.4, 139.2, 144.1, 147.5, 151.6, 158.0, 167.5.
Anal. (C.sub.27H.sub.28CI.sub.2N.sub.4O
IS(COOH).sub.2O--SC.sub.3H.sub.7OHO H.sub.2O) C, H, N.
Example 6
N-(4-(4-(2,3-Dichloro-phenyl)-piperazin-1-yl)-trans-but-2-enyl)-4-(pyridin-
-N-oxide-2-yl)-benzamide (12)
[0074] Prepared from 4-(pyridin-N-oxide-2-yl)-benzoic acid and
4-(4-(2,3-dichloro-phenyl)-piperazin-1-yl)-trans-but-2-enylamine
according to the general procedure. Yield: 27%. Mp. (oxalate):
153-154.degree. C. .sup.1HNMR (CDCI.sub.3): .delta. 2.91 (s, br,
4H), 3.06 (m, 6H), 4.07 (m, 2H), 5.71-5.82 (m, 2H), 6.93-6.96 (m,
2H), 7.12-7.15 (m, 2H), 7.27-7.31 (m, 1H), 7.36 (t, J 7.54, 1H),
7.45 (d, J 7.83, 1.74, 1H), 7.86 (m, 4H), 8.33 (d, J 6.65, 0.78,
1H). .sup.13C NMR (CDCI.sub.3): .delta. 41.8, 51.4, 53.4, 60.4,
118.9, 124.8, 125.4, 126.5, 127.3, 127.7, 127.7, 128.9, 129.7,
130.3, 134.2, 135.5, 135.6, 140.7, 148.7, 151.39, 166.9. Anal.
(C.sub.26H.sub.26CI.sub.2N.sub.4O.sub.2 1.5 (COOH).sub.2):
C.sub.1H.sub.1N.
Example 7
4-(2,3-Dichlorophenyl)-1-(4-(4-(pyridin-2-yl)benzamido)-trans-but-2-enyl)--
piperazine 1-oxide (13)
[0075] A solution of PG01037, see U.S. 2006/0106030 (288 mg, 0.60
mmol) in 10 mL dichloromethane was treated at 0.degree. C. with
meta-chloroperbenzoic acid (0.16 g, 77%, 0.72 mmol). After stirring
for 16 h at room temperature, the reaction mixture was successively
washed with saturated sodium bicarbonate solution, H.sub.2O and
brine and dried with sodium sulphate. The volatiles were removed in
vacuo and the residue was purified by preparative thin layer
chromatography. Yield: 93 mg (32%). Mp. (hydrochloride): foam.
.sup.1H NMR (CD.sub.3OD): .delta. 3.23-3.29 (m, 4H), 3.50-3.61 (m,
4H), 3.99 (d, J 6.5, 1H), 4.13 (d, J 4.6, 1H), 6.04-6.18 (m, 2H),
7.18 (dd, J 7.8, 3.9, 1H), 7.24-7.28 (m, 2H), 7.40 (m, 1H),
7.91-7.93 (m, 2H), 7.99 (d, J 8.4, 2H), 8.06 (d, J 8.7, 2H), 8.64
(dt, J 4.8, 1.2, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 41.0,
45.5, 63.5, 72.0, 119.3, 120.0, 121.6, 123.1, 125.4, 127.0, 127.3,
127.7, 128.0, 133.8, 134.6, 137.8, 137.9, 142.2, 149.3, 150.1,
156.4, 168.3. Anal.
(C.sub.26H.sub.26CI.sub.2N.sub.4O.sub.2:2HCr0.5H.sub.2O) C, H,
N.
Example 8
N-(4-(4-(2-Methoxy-phenyl)-piperazin-1-yl)-trans-but-2-enyl)-4-pyridin-2-y-
l-benzamide (14)
[0076] Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and
4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine
according to the general procedure. Yield: 65%. Mp.
(hydrochloride): 168-170.degree. C. .sup.1H NMR (400 MHz,
CDCI.sub.3): .delta. 2.70 (s, 4H), 3.12 (s, 6H), 3.86 (s, 3H), 4.13
(m, 2H), 5.78-5.85 (m, 2H), 6.43 (m, 1H), 6.85-7.02 (m, 4H), 7.27
(s, 2H), 7.77 (s, 2H), 7.90 (d, J 7.5, 2H), 8.06 (d, J 8.1, 2H),
8.72 (d, J 3.1, 1H). .sup.13C NMR (101 MHz, CDCI.sub.3): .delta.
41.0, 50.9, 53.7, 55.8, 60.7, 111.6, 118.7, 121.3, 121.4, 123.2,
123.5, 127.5, 127.9, 129.1, 130.5, 135.0, 137.4, 141.6, 142.7,
150.3, 152.7, 156.7, 167.4. Anal.
(C.sub.27H.sub.3oN.sub.4O2-3HC|-4H.sub.2O) C, H, N.
Example 9
N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)-trans-but-2-enyl)-9H-fluorene-2-c-
arboxamide (15)
[0077] Prepared from 9H-fluorene-2-carboxylic acid and
4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine
according to the general procedure. Yield: 61%. Mp.
(hydrochloride): 224-226.degree. C. .sup.1H NMR (400 MHz,
CDCI.sub.3): d 2.68 (s, 4H), 3.09-3.10 (m, 6H), 3.86 (s, 3H), 3.94
(s, 2H), 4.13 (m, 2H), 5.81-5.83 (m, 2H), 6.32 (t, J 5.4, 1H), 6.85
(dd, J 8.2, 1.2, 1H), 6.89-6.96 (m, 2H), 7.00 (m, 1H), 7.35 (td, J
7.3, 1.3, 1H), 7.40 (td, J 7.4, 1.6, 1H), 7.57 (d, J 7.4, 1H),
7.78-7.83 (m, 3H), 7.99 (s, 1H). .sup.13C NMR (101 MHz,
CDCI.sub.3): d 37.4, 42.0, 51.0, 53.8, 55.8, 60.8, 111.6, 118.7,
120.2, 121.0, 121.4, 123.4, 124.3, 125.7, 126.2, 127.5, 128.1,
129.3, 130.4, 133.1, 141.1, 141.7, 143.9, 144.5, 145.4, 152.7,
168.0. Anal. (C.sub.29H.sub.31N.sub.3O.sub.2--SHCI) C, H.sub.1
N.
Example 10
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-4-pyridin-2-yl-
-benzamide (16)
[0078] Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and
27a according to the general procedure. Yield: 52%. Mp.
(hydrochloride): foam. .sup.1H NMR (CDCI.sub.3): .delta. 1.62 (m,
1H), 1.83 (m, 1H), 2.39-2.46 (m, 2H), 2.58 (m, 2H), 2.82 (m, 2H),
3.05 (s, 4H), 3.45 (m, 1H), 3.89 (m, 2H), 4.00 (s, 1H), 6.91 (dd, J
7.1, 2.5, 1H), 7.08-7.15 (m, 2H), 7.23 (ddd, J 5.89, 4.83, 2.58,
1H), 7.50 (dd, J 5.9, 3.7, 1H), 7.70-7.76 (m, 2H), 7.88 (d, J 8.3,
2H), 8.02 (d, J 8.3, 2H), 8.67 (dt, J 4.8, 1.2, 1H). .sup.13C NMR
(CDCI.sub.3): .delta. 33.7, 38.8, 51.6, 53.5, 63.9, 66.6, 118.3,
120.5, 122.3, 124.3, 126.6, 127.1, 127.1, 133.6, 134.4, 136.4,
141.5, 149.3, 150.5, 155.7, 166.3. Anal.
(C.sub.26H.sub.28CI.sub.2N.sub.4O.sub.2-2HCI O.52-PrOH I
0.5H.sub.2O) C.sub.1 H, N.
Example 11
N-(3-(4-(2,3-Dichlorophenyl)-piperazin-1-yl)-3-hydroxybutyl)-9H-fluorene-2-
-carboxamide (17)
[0079] Prepared from 9H-fluorene-2-carboxylic acid and 27a
according to the general procedure. Yield: 58%. Mp. (oxalate):
188-190.degree. C. .sup.1H NMR (oxalate, CDCI.sub.3, 5% D.sub.2O)
.delta. 1.60-1.69 (1H, m), 1.83-1.87 (1H, m), 2.42-2.50 (2H, m),
2.61 (2H, m), 2.86-2.87 (2H, m), 3.07 (4H, s), 3.45-3.52 (1H, m),
3.87-3.94 (4H, m), 6.94-8.00 (10H.sub.i m). .sup.13C NMR (oxalate,
CDCI.sub.3, 5% D.sub.2O) .delta. 33.6, 37.2, 38.6, 51.6, 53.5,
63.9, 66.7, 118.8, 119.9, 120.8, 124.1, 125.0, 125.4, 126.0, 127.2,
127.7, 127.8, 127.8, 133.1, 134.3, 141.0, 143.6, 144.3, 145.0,
151.3, 167.4, 167.8. Anal. (C.sub.28H.sub.29CI.sub.2N.sub.3O.sub.2
(COOH).sub.2), C.sub.1H, N.
Example 12
N-(3-Hydroxy-4-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-
-benzamide (18)
[0080] Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and
27b according to the general procedure. Yield: 47%. Mp. (oxalate):
foam. .sup.1H NMR (CDCI.sub.3): .delta. 1.63 (m, 1H), 1.84 (m, 1H),
2.43 (m, 2H), 2.64 (m, 2H), 2.88 (m, 2H), 3.11 (s, 4H), 3.46 (m,
1H), 3.86 (s, 3H), 4.94 (m, 2H), 6.86 (dd, J 7.4, 1.2, 1H),
6.92-6.94 (m, 2H), 7.01 (m, 1H), 7.23 (m), 7.52 (dd, J 5.9, 3.7,
1H), 7.74-7.79 (m, 2H), 7.91 (d, J 8.3, 2H), 8.05 (d, J 8.3, 2H),
8.71 (dt, J 4.8, 1.2, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 33.0,
38.3, 50.5, 53.2, 55, 63.5, 66.3, 110.9, 117.9, 120.6, 120.7,
122.4, 122.8, 126.7, 127.2, 134.6, 136.6, 140.8, 141.7, 149.6,
152.0, 156.1, 166.7. Anal.
(C.sub.27H.sub.32N.sub.4O.sub.22(COOH).sub.20.5H.sub.2O) C, H,
N.
Example 13
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-ca-
rboxamide (19)
[0081] Prepared from 9/-/-fluorene-2-carboxylic acid and 27b
according to the general procedure. Yield: 45%. Mp. (oxalate):
foam. (.sup.1H NMR (CDCI.sub.3): .delta. 1.64 (m, 1H), 1.83 (m,
1H), 2.43 (m, 2H), 2.87 (m, 2H), 3.10 (s, 4H), 3.47 (m, 1H), 3.86
(s, 3H), 3-89-3.99 (m, 6H), 6.86 (d, J 7.4, 1H), 6.91-6.94 (m, 2H),
7.01 (m, 1H), 7.32-7.41 (m, 2H), 7.45 (dd, J 5.9, 3.5, 1H), 7.55
(d, J 7.4, 1H), 7.77-7.83 (m, 3H), 8.00 (s, 1H). .sup.13C NMR
(CDCI.sub.3): .delta. 33.3, 36.9, 38.5, 50.7, 55.3, 63.8, 66.6,
111.1, 118.1, 119.6, 120.5, 120.9, 123.1, 123.8, 125.2, 125.8,
126.9, 127.5, 133.0, 140.7, 141.0, 143.3, 144.0, 144.6, 152.2,
167.5. Anal. (C.sub.29H.sub.33N.sub.3O.sub.3 (COOH).sub.2 H.sub.2O)
C, H, N.
Example 14
1-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-4-(4-(pyridin-2-yl)-benzamido)-bu-
tan-2-yl acetate (20)
[0082] A solution of 16 (0.25 g, 0.5 mmol) in 10 ml of
CH.sub.2CI.sub.2 was treated with 70 .mu.l (0.75 mmol) acetic
anhydride followed by 140 .mu.L (1.0 mmol) triethylamine. After
stirring for 16 h, the mixture was washed with sodium bicarbonate
solution, dried with sodium sulphate, and purified by flash
chromatography. Yield: 0.22 g (82%). Mp. (oxalate): foam. .sup.1H
NMR (CDCI.sub.3): .delta. 1.84 (m, 1H), 2.05 (m, 1H), 2.12 (s, 3H),
2.52 (dd, J 13.2, 5.2, 1H), 2.65 (m, 5H), 2.99 (s, 4H), 3.25 (dq, J
9.7, 5.00, 1H), 3.81 (dt, J 12.3, 5.7, 1H), 5.19 (m, 1H), 6.89 (dd,
J 7.7, 1.8, 1 H), 7.06-7.17 (m, 3H), 7.26 (ddd, J 6.1, 4.8, 2.44,
1H), 7.73-7.76 (m, 2H), 7.93 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H),
8.70 (td, J 4.83, 1.50, 1.50, 1H). .sup.13C NMR (CDCI.sub.3):
.delta. 21.0, 32.4, 36.1, 51.3, 53.7, 61.5, 69.6, 118.6, 120.8,
122.7, 124.5, 127.0, 127.4, 127.5, 133.9, 134.7, 136.9, 142.1,
149.8, 151.1, 156.2, 167.1, 171.5, Anal.
(C.sub.28H.sub.3OCI.sub.2N.sub.4O.sub.3 IS(COOH).sub.2--H.sub.2O)
C, H, N.
Example 15
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-2-hydroxybutyl)-4-(pyridin-2-y-
l)-benzamide (21)
[0083] Prepared from 4-pyridin-2-yl-benzoic acid and 30a according
to the general procedure. Yield: 52%. Mp. (oxalate): foam. .sup.1H
NMR (CDCI.sub.3): .delta. 1.63 (ddd, J 14.6, 6.0, 3.4, 1 H), 1.81
(dtd, J 14.5, 10.9, 10.8, 3.9, 1H), 2.72 (m, 6H), 3.07 (s, 4H),
3.34 (ddd, J 13.4, 7.6, 4.6, 1H), 3.77 (ddd, J 13.4, 6.7, 3.4, 1H),
4.07 (m, 1H), 6.77 (t, J 5.3, 1H), 6.93 (dd, J 7.4, 2.2, 1H),
7.13-7.19 (m, 2H), 7.28 (m, 1H), 7.76-7.81 (m, 2H), 7.91 (d, J 8.6,
2H), 8.07 (d, J 8.6, 2H), 8.72 (td, J 4.8, 1.4, 1.4, 1H). .sup.13C
NMR (CDCI.sub.3): .delta. 28.8, 45.8, 51.4, 53.3, 57.5, 72.7,
118.7, 120.9, 122.8, 125.0, 127.1, 127.5, 127.6, 127.7, 134.2,
134.8, 137.0, 142.2, 149.9, 150.9, 156.3, 167.3. Anal.
(C.sub.26H.sub.28CI.sub.2N.sub.4O.sub.2 (COOH).sub.2 H.sub.2O), C,
H, N.
Example 16
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-2-hydroxybutyl)-9H-fluorene-2--
carboxamide (22)
[0084] Prepared from 9H-fluorene-2-carboxylic acid and 30a
according to the general procedure. Yield: 68%. Mp. (oxalate):
foam. .sup.1H NMR (CDCI.sub.3): .delta. 1.63 (m, 1H), 1.78 (m, 1H),
2.63 (s, 2H), 2.72-2.84 (m, 2H), 2.87 (s, 2H), 3.07 (s, 4H), 3.34
(m, 1H), 3.77 (ddd, 13.7, 7.0, 3.5, 1H), 3.94 (s, 2H), 4.07 (m,
1H), 6.90 (dd, J 5.4, 2.0, 1H), 7.12-7.18 (m, 2H), 7.36 (t, J 5.3,
1H), 7.37 (t, J 5.4, 1H), 7.41 (d, J 7.0, 1H), 7.81-7.82 (m, 3H),
8.00 (s, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 28.9, 37.0, 45.9,
51.4, 53.4, 57.5, 72.8, 118.7, 119.8, 120.7, 124.0, 125.0, 125.3,
126.0, 127.1, 127.6, 127.7, 127.8, 133.0, 134.2, 140.8, 143.6,
144.2, 145.0, 150.9, 168.0. Anal.
(C.sub.28H.sub.29CI.sub.2N.sub.3O.sub.2-2.5HCIO.5EtOA.sigma.1.75H.sub.2O)
C, H, N.
Example 17
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-2-hydroxybutyl)-9H-fluorene-2-car-
boxamide (23)
[0085] Prepared from 9H-fluorene-2-carboxylic acid and 30b
according to the general procedure. Yield: 42%. Mp. (oxalate):
foam. .sup.1H NMR (CDCI.sub.3): .delta. 1.62 (ddd, J 9.9, 6.1, 3.4,
1H), 1.80 (m, 1H), 2.63 (s, 2H), 2.76 (m, 2H), 2.88 (s, 2H), 3.10
(s, 4H), 3.33 (ddd, J 13.4, 7.7, 4.5, 1 H), 3.78 (ddd, J 13.4, 6.8,
3.4, 1H), 3.80 (s, 3H), 3.91 (s, 2H), 4.06 (m, 1H), 6.83-6.87 (m,
2H), 6.89-6.92 (m, 2H), 7.01 (ddd, J 8.0, 5.8, 3.3, 1H), 7.34 (td,
J 7.4, 1.3, 1H), 7.39 (td, J 7.5, 1.3, 1 H), 7.55 (d, J 7.5, 1H),
7.79 (dd, J 7.9, 0.5, 1H), 7.82 (dd, J 8.1, 1.5, 1H), 8.00 (d, J
0.7, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 28.8, 36.9, 45.8,
50.6, 53.5, 55.4, 57.4, 72.6, 111.2, 118.2, 119.7, 120.6, 121.0,
123.2, 123.9, 125.2, 125.9, 127.0, 127.6, 132.9, 140.7, 140.8,
143.4, 144.0, 144.8, 152.2, 167.9. Anal.
(C.sub.29H.sub.33N.sub.3O.sub.3--(COOH).sub.2--I H.sub.2O) C, H,
N.
Example 18
2-(Oxiran-2-yl)-ethyl-isoindoline-1,3-dione (25)
[0086] A suspension of 1.84 g (10.0 mmol) phthalimide potassium
salt in 20 ml DMF was treated with 2.27 g (15.0 mmol) 24 in the
microwave (pressure vessel, P.sub.max 150 W, cooling, 100.degree.
C., 20 min). See J. Org. Chem. 1969, 34, 4060-4065. The cooled
reaction mixture was filtered, diluted with EtOAc (20 mL) and was
washed with H.sub.2O (2.times.10 mL). The organic phase was dried
with sodium sulphate and the volatiles were removed in vacuo to
give 25 (1.68 g, 78%) as a foam, which was used without further
purification. .sup.1H NMR (CDCI.sub.3): .delta. 1.86 (m, 1H), 2.00
(m, 1H), 2.46 (m, 1H), 2.73 (t, J 3.9, 1H), 3.00 (m, 1H), 3.89 (m,
2H), 7.70-7.74 (m, 2H), 7.83-7.87 (m, 2H). .sup.13C NMR
(CDCI.sub.3): .delta. 31.7, 35.2, 46.5, 50.4, 123.4, 132.2, 134.1,
168.4.
Example 19
2-(4-(4-(2,3-Dichlorophenyl)-piperazin-1-yl)-3-hydroxybutyl)-isoindoline-1-
,3-dione (26a)
[0087] A sample of 2.1 g (9.0 mmol)
1-(2,3-dichlorophenyl)-piperazine in 40 mL 2-PrOH was reacted in
the microwave (pressure vessel, P.sub.max 150 W, cooling,
90.degree. C., 20 min) with 2.0 g (9.0 mmol) 25. The solvent was
removed in vacuo and the foamy residue was washed with 10 mL
2-PrOH. Yield: 2.96 g (73%). .sup.1H NMR (CDCI.sub.3): .delta. 1.79
(m, 2H), 2.42 (m, 2H), 2.56 (s, 2H), 2.79 (m, 2H), 3.02 (s, 4H),
3.60 (s, 1H), 3.74-3.83 (m, 3H), 6.90 (m, 1H), 7.06-7.11 (m, 2H),
7.67 (m, 2H), 7.81 (m, 2H). .sup.13C NMR (CDCI.sub.3): .delta.
33.9, 35.3, 51.4, 53.4, 63.8, 64.5, 118.2, 122.7, 124.1, 127.0,
131.6, 133.4, 133.4, 150.4, 167.7.
Example 20
2-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-di-
one (26b)
[0088] Prepared from 1-(2-methoxyphenyl)piperazine and 25 in a
similar fashion as described above for 26a. Yield: 28%. Mp.:
192-194.degree. C. .sup.1H NMR (CDCI.sub.3): .delta. 1.79 (q, J
6.8, 2H), 2.41 (m, 2H), 2.61 (s, 2H), 2.85 (s, 2H), 3.07 (s, 4H),
3.77 (m, 1H), 3.85 (s, 3H), 3.91 (m, 2H), 6.86 (d, J 7.0, 1H),
6.91-6.95 (m, 2H), 7.00 (m, 1H), 7.85 (dd, J 5.5, 3.0, 2H), 7.71
(dd, J 5.4, 3.1, 2H). .sup.13C NMR (CDCI.sub.3): .delta. 33.8,
35.4, 50.9, 53.6, 55.6, 64.1, 64.7, 111.3, 118.4, 121.2, 123.2,
123.4, 132.4, 134.1, 141.4, 152.4.
Example 21
4-Amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-butan-2-ol
(27a)
[0089] A sample of 4.48 g (10.0 mmol) 26a was fully dissolved in 25
ml EtOH and treated with 0.48 g (15.0 mmol) hydrazine in the
microwave (pressure vessel, P.sub.max 150 W, cooling, 90.degree.
C., 20 min). The cooled reaction mixture was filtered and the
filtrate was evaporated in vacuo. Both the residue from the
evaporation and the initial precipitate were partitioned between
CHCI.sub.3 and 20% potassium carbonate solution. The layers were
separated and the aqueous layer was dried with sodium sulphate to
give the title compound as an oil, which was used without further
purification. Yield: 2.25 g (71%). .sup.1H NMR (CDCI.sub.3):
.delta. 1.56 (m, 2H), 2.40 (m, 2H), 2.61 (s, 2H), 2.80 (s, 2H),
2.97-3.05 (m, 9H), 3.89 (m, 1H), 6.92 (dd, J 6.3, 3.1, 1H),
7.09-7.14 (m, 2H). .sup.13C NMR (CDCI.sub.3): .delta. 37.4, 39.7,
51.5, 53.6, 64.5, 66.3, 118.3, 124.2, 127.1, 133.5, 150.6.
Example 22
4-Amino-1-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butan-2-ol
(27b)
[0090] Prepared from 26b in a similar fashion as described above
for 27a. Yield: 69%. Wax. .sup.1H NMR (CDCI.sub.3): .delta. 1.59
(m, 2H), 2.41 (m, 2H), 2.57 (m, 2H), 2.79-2.81 (m, 9H), 3.86 (s,
3H), 3.91 (m, 1H), 6.86 (d, J 7.5, 1H), 6.91-6.96 (m, 2H),
6.98-7.03 (m, 1H). .sup.13C NMR (CDCI.sub.3): .delta. 37.3, 39.7,
50.9, 53.6, 55.5, 64.5, 66.2, 111.2, 118.3, 121.1, 123.1, 141.3,
152.3.
Example 23
1-(2,3-Dichlorophenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine (28a)
[0091] 2.31 g (10.0 mmol) 1-(2,3-dichlorophenyl)piperazine was
added to a suspension of 2.27 g (15.0 mmol) 24, 4.15 g (30.0 mmol)
potassium carbonate in 150 ml acetone and the reaction mixture was
refluxed for 24 h. The reaction mixture was filtered and the
volatiles were removed in vacuo to give an oil (2.86 g, 95%), which
was used without further purification. .sup.1H NMR (CDCI.sub.3):
.delta. 1.72 (m, 1H), 1.83 (m, 1H), 2.53 (dd, J 5.0, 2.7, 1H), 2.61
(ddd, J 8.3, 6.5, 3.0, 2H), 2.66 (s, 4H), 2.79 (dd, J 4.9, 4.0,
1H), 3.01 (m, 1H), 3.07 (s, 4H), 6.96 (dd, J 6.5, 3.1, 1H),
7.11-7.19 (m, 2H). .sup.13C NMR (CDCI.sub.3): .delta. 30.2, 47.1,
51.0, 51.4, 53.3, 55.0, 118.6, 124.6, 127.5, 134.0, 151.3.
Example 24
1-(2-Methoxyphenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine (28b)
[0092] Prepared from 24 and 1-(2-methoxyphenyl)piperazine in a
similar fashion as described above for 28a. Yield: 87%. .sup.1H NMR
(CDCI.sub.3): .delta. 2.60 (m, 2H), 2.67 (s, 4H), 2.78 (dd, J 4.9,
4.0), 3.00 (m, 1H), 3.10 (s, 4H), 3.86 (s, 3H), 6.86 (dd, J 7.8,
1.3, 1H), 6.88-7.03 (m, 3H). .sup.13C NMR (CDCI.sub.3): .delta.
30.2, 47.2, 50.7, 51.0, 53.5, 55.2, 55.4, 111.2, 118.3, 121.1,
123.0, 141.4, 152.3.
Example 25
1-Azido-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
(29a)
[0093] A suspension of 0.75 g (2.5 mmol), 0.24 g (3.8 mmol) sodium
azide and 0.27 g (5.0 mmol) ammonium chloride in 5 imL DMF was
heated at 100.degree. C. for 5 h. The reaction mixture was
partitioned between 10 ml CHCI.sub.3 and 10 ml H.sub.2O. The
aqueous organic layer was extracted twice with 10 ml CHCI.sub.3,
dried over sodium sulphate and the volatiles were removed in vacuo.
The residue was purified by flash chromatography to give the 29a as
an oil. Yield: 0.44 g (51%). .sup.1H NMR (CDCI.sub.3): .delta. 1.56
(ddd, J 14.7, 6.5, 3.4, 1H), 1.81 (m, 1H), 2.62 (s, 2H), 2.75 (m,
2H), 2.87 (s, 2H), 3.07 (s, 4H), 3.27 (dd, J 5.1, 1.4, 2H), 4.04
(dtd, J 7.9, 5.3, 2.6, 1H), 6.52 (s, 1H), 6.93 (dd, J 7.2, 2.4,
1H), 7.12-7.19 (m, 2H). .sup.13C NMR (CDCI.sub.3): .delta. 28.4,
51.3, 53.3, 56.5, 57.3, 73.0, 118.7, 124.9, 127.6, 134.1,
150.9.
Example 26
1-Azido-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-ol
[0094] Prepared from 28b in a similar fashion as described above
for 29a. Yield: 15%. .sup.1H NMR (CDCI.sub.3): .delta. 1.55 (ddd, J
14.6, 6.7, 3.6, 1H), 1.80 (m, 1H), 2.62 (s, 2H), 2.74 (m, 2H), 2.89
(s, 2H), 3.09 (s, 4H), 3.24 (dd, J 11.6, 4.1, 1H), 3.29 (dd, J
11.6, 4.9, 1H), 3.86 (s, 3H), 4.03 (dtd, J 9.8, 5.5, 2.5, 1H), 6.86
(d, J 8.0, 1H), 6.89-6.95 (m, 2H), 7.01 (ddd, J 8.0, 5.1, 4.1, 1H).
.sup.13C NMR (CDCI.sub.3): .delta. 28.4, 50.7, 53.5, 53.5, 55.4,
56.6, 57.4, 73.0, 111.2, 118.3, 121.1, 123.2, 140.9, 152.3.
Example 27
1-Amino-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
(30a)
[0095] A solution of 29a (0.41 g, 1.2 mmol) and 1.87 g (7.2 mmol)
triphenylphosphine in 20 ml of a THF/H.sub.2O mixture (10:1 v/v)
was stirred at room temperature for 16 h. The volatiles were
removed in vacuo and the residue was taken up in 2-PrOH (5 ml) and
treated with ethereal hydrochloric acid to give desired amine as a
hydrochloride (0.33 g, 77%). .sup.1H NMR (CDCI.sub.3): .delta. 1.53
(ddd, J 14.5, 6.8, 4.0, 1H), 1.71 (m, 1H), 2.61 (s, 2H), 2.65-2.77
(m, 4H), 2.84 (s, 2H), 3.07 (m, 4H), 3.77 (m, 1H), 6.93 (dd, J 7.0,
2.5, 1H), 7.12-7.17 (m, 2H). .sup.13C NMR (CDCI.sub.3): .delta.
29.0, 48.3, 51.3, 53.3, 74.9, 118.6, 124.8, 127.5, 134.0,
150.9.
Example 28
1-Amino-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-oI (30b)
[0096] Prepared from 29b in a similar fashion as described above
for 30a. Yield: 13%. .sup.1H NMR (CDCI.sub.3): .delta. 1.52 (ddd, J
14.5, 6.5, 3.9, 1H), 1.71 (m, 1H), 2.54-2.77 (m, 4H), 2.86 (s, 2H),
3.09 (S.sub.1 4H), 3.77 (m, 1H), 3.87 (s, 3H), 6.86 (d, J 7.9, 1H),
6.90-6.95 (m, 2H), 7.00 (m, 1H). .sup.13C NMR (CDCI.sub.3): .delta.
29.0, 48.4, 50.7, 53.6, 55.4, 57.6, 75.2, 111.2, 118.3, 121.1,
123.2, 141.0, 152.3.
TABLE-US-00001 TABLE 1 Human D.sub.2-like Family Receptor Subtype
Binding Data in HEK Cells D3 Compd. structure D2 SEM K.sub.i [nM]
SEM D4 SEM D2/D3 D4/D2 9 ##STR00003## 23.6 5.7 0.6 0.1 39 10
##STR00004## 105 24 1.4 0.3 75 11 ##STR00005## 92.0 9.4 1.6 0.4 58
12 ##STR00006## 25.8 3.1 1.1 0.3 23 13 ##STR00007## 1160 230 49.2
9.3 24 14 ##STR00008## 69.0 13 2.9 1.1 24 15 ##STR00009## 48.4 7.3
1.2 0.1 40 16 ##STR00010## 267 20 3.0 0.2 4620 200 89 1540 17
##STR00011## 319 54 1.8 0.0 16400 2600 177 9110 18 ##STR00012## 284
48 2.8 0.8 1490 150 101 532 19 ##STR00013## 249 14 1.8 0.3 1230 330
138 683 20 ##STR00014## 134 28 11.7 1.0 11 21 ##STR00015## 28.4 6.4
0.5 0.1 57 22 ##STR00016## 84.0 5.3 2.5 0.3 34 23 ##STR00017## 68.4
6.4 1.3 0.4 53 34 ##STR00018## 200 52 0.9 0.3 225 34 Enantiomer A
##STR00019## 441 52 1.1 0.3 400 34 Enantiomer B ##STR00020## 1083
379 16.5 3.2 65 35 ##STR00021## 248.6 62.7 1.37 0.2 1919 373 181
1401 36 ##STR00022## 28.4 6.5 0.26 0.06 109 37 ##STR00023## 52.5
4.5 0.5 0.03 105 38 ##STR00024## 47.1 7.4 62.1 3.1 1 39
##STR00025## 337 21.7 4.6 0.6 73 42 ##STR00026## 185 0.98 188 43
##STR00027## 233 5.4 43 44 ##STR00028## 158 2.2 71 45 ##STR00029##
697 3.5 200 46 ##STR00030## 245 1.6 149 47 ##STR00031## 180 0.65
276 48 ##STR00032## 244 1.3 185 49 ##STR00033## 174 1.0 172
TABLE-US-00002 TABLE 2 In Vitro Functional Data at D.sub.2-like
Family Receptor for selected ligands.sup.a IC.sub.50 (nM) .+-.
S.E.M. Compd. Structure D2 D3 9 ##STR00034## 41 .+-. 8 1.0 .+-. 0.2
10 ##STR00035## 1300 .+-. 320 6.7 .+-. 2.6 11 ##STR00036## 368 .+-.
113 25.6 .+-. 8.5 12 ##STR00037## 22.9 .+-. 2.0 231 .+-. 1
(31).sup.b 1.2 .+-. 0.0 14 ##STR00038## 175 .+-. 17 42.6 .+-. 7.9
15 ##STR00039## 179 .+-. 48 18.9 .+-. 4.2 16 ##STR00040## 15.8 .+-.
2.7 (26).sup.b 1.0 .+-. 0.1 (48).sup.b 17 ##STR00041## ND 42.0 .+-.
1.3 (26).sup.b 18 ##STR00042## ND 12.8 .+-. 1.3 20 ##STR00043## ND
3.9 .+-. 1.4 (47).sup.b 21 ##STR00044## 88.3 .+-. 15.7 5.4 .+-. 1.8
3.4 .+-. 0.5 (20).sup.b .sup.aData were obtained through the NIDA
Addiction Treatment Discovery Program contract with SRI
(N01DA-1-8816). .sup.bpartial agonist activity: EC.sub.50 (%
stimulation)
TABLE-US-00003 TABLE 3 Binding affinities for a serotonin receptor
subtypes for selected ligands..sup.a Ki(nM) .+-. S.E.M. Compd.
Structure 5HT.sub.1A 5HT.sub.2A 5HT.sub.2C D.sub.3 5HT.sub.1A/D3
5HT.sub.2A/D3 5HT.sub.2C/D 9 ##STR00045## 29.7 .+-. 0.2 15.5 .+-.
3.8 10.6 .+-. 0.0 0.6 .+-. 0.1 50 26 18 10 ##STR00046## 309 .+-. 39
92.7 .+-. 16 96.4 .+-. 1.1 1.4 .+-. 0.3 221 66 69 11 ##STR00047##
92 .+-. 8.3 46.9 .+-. 5.4 31 .+-. 2.3 1.6 .+-. 0.4 58 29 19 12
##STR00048## 60.6 .+-. 4.3 57.9 .+-. 0.6 74.3 .+-. 3 1.1 .+-. 0.3
55 53 68 14 ##STR00049## 21.7 .+-. 3.5 75.3 .+-. 1.1 256 .+-. 33
2.9 .+-. 1.1 7 26 88 15 ##STR00050## 71.8 .+-. 2.1 65.7 .+-. 12 176
.+-. 14 1.2 .+-. 0.1 60 55 147 16 ##STR00051## 34.3 .+-. 0.3 42.3
.+-. 9.1 115 .+-. 20 3.0 .+-. 0.2 11 14 38 17 ##STR00052## 1810
.+-. 350 545 .+-. 150 2830 .+-. 360 1.8 .+-. 0.0 1006 303 1572 18
##STR00053## 36.2 .+-. 7 695 .+-. 20 3940 .+-. 130 2.8 .+-. 0.8 13
248 1407 20 ##STR00054## 117 .+-. 12 88.7 .+-. 7.5 84.3 .+-. 5.3
11.7 .+-. 1.0 10 7 7 21 ##STR00055## 15.1 .+-. 2.4 15.4 .+-. 2.8
25.2 .+-. 3.2 0.5 .+-. 0.1 30 31 50 .sup.aData were obtained
through NIDA Addiction Treatment Discovery Program contract with
SRI (N01DA-1-8816).
* * * * *