U.S. patent application number 13/323183 was filed with the patent office on 2012-07-12 for dibenzo [b,f] [1,4]oxazapine compounds.
This patent application is currently assigned to ARYX THERAPEUTICS, INC.. Invention is credited to Jason Adams, Cyrus Becker, Pascal Druzgala, Monica Palme, Courtney Rubens.
Application Number | 20120178738 13/323183 |
Document ID | / |
Family ID | 39472572 |
Filed Date | 2012-07-12 |
United States Patent
Application |
20120178738 |
Kind Code |
A1 |
Becker; Cyrus ; et
al. |
July 12, 2012 |
DIBENZO [B,F] [1,4]OXAZAPINE COMPOUNDS
Abstract
The present invention relates to
11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazapine compounds of the
formula: ##STR00001## where the variables are as defined herein,
their salts and pharmaceutically acceptable compositions thereof.
Methods of preparing these compounds are also described. These
compounds may be used in the treatment of disorders such as
schizophrenia, treatment resistant schizophrenia, bipolar disorder,
psychotic depression, treatment resistant depression,
schizophrenia-associated depression, treatment resistant OCD,
autism, senile psychosis, psychotic dementia, L-DOPA induced
psychosis, psychogenic polydipsia, psychotic symptoms of
neurological disorders, sleep disorders.
Inventors: |
Becker; Cyrus; (Fremont,
CA) ; Rubens; Courtney; (San Jose, CA) ;
Adams; Jason; (Fremont, CA) ; Palme; Monica;
(Fremont, CA) ; Druzgala; Pascal; (Santa Rosa,
CA) |
Assignee: |
ARYX THERAPEUTICS, INC.
Fremont
CA
|
Family ID: |
39472572 |
Appl. No.: |
13/323183 |
Filed: |
December 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12047858 |
Mar 13, 2008 |
8093237 |
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13323183 |
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60895046 |
Mar 15, 2007 |
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Current U.S.
Class: |
514/211.13 ;
540/551 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/18 20180101; A61P 25/20 20180101; A61P 25/22 20180101; A61P
25/00 20180101; C07D 453/02 20130101; A61P 25/24 20180101; C07D
413/04 20130101; C07D 405/14 20130101 |
Class at
Publication: |
514/211.13 ;
540/551 |
International
Class: |
A61K 31/553 20060101
A61K031/553; A61P 25/18 20060101 A61P025/18; A61P 25/22 20060101
A61P025/22; A61P 25/00 20060101 A61P025/00; A61P 25/28 20060101
A61P025/28; C07D 413/04 20060101 C07D413/04; A61P 25/24 20060101
A61P025/24 |
Claims
1. A compound having the structure ##STR00117## or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 and
R.sup.2 are independently --Cl, --F, --Br, --I or --H; R.sup.3 is
--R (nonoptionally substituted in this single instance at R.sup.3),
--(C.sub.0-C.sub.6 alk)C(O)OR.sup.e, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)-OR,
--(C.sub.0-C.sub.6 alk)C(O)R.sup.k, or --(C.sub.0-C.sub.6 alk)-N
R.sup.aR.sup.19; R.sup.4 is --H or --R; each R.sup.5, R.sup.6 and
R.sup.7 is independently --R, --(C.sub.0-C.sub.6 alk)-OR,
--(C.sub.0-C.sub.6 alk)-NR.sup.aR.sup.19, --NO.sub.2, -halogen,
--CN, --OH, --OOCR, --(C.sub.0-C.sub.6 alk)COOR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)Ar, --(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6 alk)C(O)Hca,
--(C.sub.0-C.sub.6 alk)C(O)Ar, --(C.sub.0-C.sub.6 alk)C(O)Het, or
--(C.sub.0-C.sub.6 alk)C(O)Cak; w is 0, 1, 2 or 3; x is 0, 1, 2 or
3; and y is 0, 1, 2 or 3; in which each R.sup.e is independently
--H, --R, --(C.sub.1-C.sub.6 alk)C(O)Hca, --(C.sub.1-C.sub.6 alk)
C(O)Cak, --(C.sub.1-C.sub.6 alk)C(O)Het, --(C.sub.1-C.sub.6
alk)C(O)Ar, --(C.sub.1-C.sub.6 alk)C(O)O-Hca, --(C.sub.1-C.sub.6
alk)C(O)O-Cak, --(C.sub.1-C.sub.6 alk)C(O)O-Het, --(C.sub.1-C.sub.6
alk)C(O)O--Ar, --(C.sub.0-C.sub.6 alk)Hca, --(C.sub.0-C.sub.6
alk)Het, --(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Cak,
--(C.sub.1-C.sub.6 alk)C(O)OR, --(C.sub.1-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)-OR, or
--(C.sub.0-C.sub.6 alk)-OH; each R.sup.a is independently --H, --R,
--(C.sub.1-C.sub.6 alk)-OR, --(C.sub.1-C.sub.6 alk)-OH,
--(C.sub.0-C.sub.6 alk)C(O)OR, --(C.sub.1-C.sub.6
alk)-NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Het, or
--(C.sub.0-C.sub.6 alk)Cak; each R.sup.k is independently --H, --R,
--(C.sub.1-C.sub.6 alk)C(O)Hca, --(C.sub.1-C.sub.6 alk)C(O)Cak,
--(C.sub.1-C.sub.6 alk)C(O)Het, --(C.sub.1-C.sub.6 alk)C(O)Ar,
--(C.sub.1-C.sub.6 alk)Hca, --(C.sub.0-C.sub.6 alk)Het,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Cak,
--(C.sub.1-C.sub.6 alk)C(O)OR, or --(C.sub.1-C.sub.6
alk)C(O)NR.sup.19.sub.2; each Cak is a cycloalkyl or cycloalkenyl
group, optionally substituted with 1, 2 or 3 substituents
independently selected from --R, --(C.sub.0-C.sub.6 alk)C(O)OR,
.dbd.O, --OH, --CN, --(C.sub.0-C.sub.6 alk)OR,
--OCH.sub.2CH.sub.2--O--, --OCH.sub.2--O--, --SO.sub.2--R,
--SO.sub.2--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)Het,
--SO.sub.2(C.sub.0-C.sub.6 alk)-Hca, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)C(O)R, --SO.sub.2(C.sub.0-C.sub.6 alk)Ar,
--SO.sub.2(C.sub.0-C.sub.6 alk)Het, and --SO.sub.2(C.sub.0-C.sub.6
alk)cycloalk, each Ar is an aryl group, optionally substituted with
1, 2 or 3 substituents independently selected from --R, --OR,
--(C.sub.0-C.sub.6 alk)NR.sup.19.sub.2, --NO.sub.2, --Cl, --F,
--Br, --I, --CN, --(C.sub.0-C.sub.6 alk)OH, --(C.sub.0-C.sub.6
alk)C(O)OR, --(C.sub.0-C.sub.6 alk)C(O)OH, --(C.sub.1-C.sub.6
haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)heterocycloalk, --SO.sub.2R, --(C.sub.0-C.sub.6
alk)-C)(O)-heterocycloalk, --(C.sub.0-C.sub.6 alk)-C(O)-cycloalk,
--(C.sub.0-C.sub.6 alkyl)-C(O)-heteroaryl, --(C.sub.0-C.sub.6
alk)-C(O)-aryl, --(C.sub.0-C.sub.6 alkyl)-C(O)O-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)O-cycloalk, --(C.sub.0-C.sub.6
alkyl)-C(O)O-heteroaryl, --(C.sub.0-C.sub.6 alk)-C(O)O-aryl,
--(C.sub.0-C.sub.6 alk)-heterocycloalkyl, --(C.sub.0-C.sub.6
alk)-heteroaryl, --(C.sub.0-C.sub.6 alk)-aryl, and
--(C.sub.0-C.sub.6 alk)-cycloalk; each Het is a heteroaryl group,
optionally substituted with 1, 2 or 3 groups independently selected
from --R, --OR, --(C.sub.0-C.sub.6 alk)NR.sup.19.sub.2, --NO.sub.2,
--Cl, --F, --Br, --I, --CN, --(C.sub.0-C.sub.6 alk)OH,
--(C.sub.0-C.sub.6 alk)CO.sub.2R, --(C.sub.0-C.sub.6 alk)C(O)OH,
--(C.sub.1-C.sub.6 haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)heterocycloalk, --SO.sub.2R,
--(C.sub.0-C.sub.6 alk)-C(O)-heterocycloalk, --(C.sub.0-C.sub.6
alk)-C(O)-cycloalk, --(C.sub.0-C.sub.6 alk)-C(O)-heteroaryl,
--(C.sub.0-C.sub.6 alk)-C(O)-aryl, --(C.sub.0-C.sub.6
alk)-C(O)O-heterocycloalk, --(C.sub.0-C.sub.6 alk)-C(O)O-cycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)O-heteroaryl, --(C.sub.0-C.sub.6
alk)-C(O)O-aryl, --(C.sub.0-C.sub.6 alk)-heterocycloalkyl,
--(C.sub.0-C.sub.6 alk)-heteroaryl, --(C.sub.0-C.sub.6 alk)-aryl,
and --(C.sub.0-C.sub.6 alk)-cycloalk; each Hca is a heterocycloalk
group, optionally substituted with 1, 2 or 3 substituents
independently selected from --R, --(C.sub.1-C.sub.6 haloalkyl),
--O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alk)-C(O)OR,
--(C.sub.0-C.sub.6 alk)-C(O)R, .dbd.O, --OH, --CN,
--(C.sub.0-C.sub.6 alk)OR, --OCH.sub.2CH.sub.2--O--,
--OCH.sub.2O--, --SO.sub.2R, --SO.sub.2--(C.sub.1-C.sub.6
haloalkyl), --(C.sub.0-C.sub.6 alk)C(O)NR.sup.19.sub.2,
--(C.sub.0-C.sub.6 alk)-heterocycloalk, --(C.sub.0-C.sub.6
alk)-aryl, --(C.sub.0-C.sub.6 alk)-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-cycloalk, --SO.sub.2(C.sub.0-C.sub.6
alk)-heterocycloalk, --SO.sub.2(C.sub.0-C.sub.6 alk)-aryl,
--SO.sub.2(C.sub.0-C.sub.6 alk)-heteroaryl
--SO.sub.2(C.sub.0-C.sub.6 alkyl)heteroaryl,
--SO.sub.2(C.sub.0-C.sub.6 alk)-cycloalk; each R.sup.10 and
R.sup.11 is independently --H or --R; each R.sup.19 is
independently selected from --H, --OH and --R in which any
(C.sub.1-C.sub.8 alk) or --(C.sub.1-C.sub.8 haloalkyl) groups are
optionally substituted with 1, 2 or 3 substituents independently
selected from .dbd.O, --(C.sub.1-C.sub.6 alkoxy), --OH, or
-halogen; --(C.sub.1-C.sub.6 haloalkyl), wherein the
--(C.sub.1-C.sub.6 haloalkyl)may be substituted with from 1 to 6
halogens, --SO.sub.2--(C.sub.1-C.sub.6 alk), and
--C(O)--(C.sub.1-C.sub.6 alk); each R.sup.20 is a Hca or Het ring
wherein that N from the --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20, is a
heteroatom in the Hca or Het ring, the ring optionally substituted
with 1 or 2 substituents independently selected from .dbd.O,
--(C.sub.1-C.sub.6 alkoxy), --OH, or -halogen; --(C.sub.1-C.sub.6
haloalkyl), --SO.sub.2--(C.sub.1-C.sub.6 alk), and
--C(O)--(C.sub.1-C.sub.6 alk), each R is independently
--(C.sub.1-C.sub.8 alk), --(C.sub.3-C.sub.8 cycloalk),
--(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8 haloalkyl),
or --(C.sub.3-C.sub.8 halocycloalk), optionally substituted with 1,
2 or 3 substituents independently selected from --(C.sub.1-C.sub.6
alkoxy), --(C.sub.1-C.sub.6 hydroxyalkyoxy), --(C.sub.1-C.sub.6
hydroxyalkyl), acetoxyalkyl, --C(O)O(C.sub.1-C.sub.6 alkyl), --OH,
.dbd.O, --N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6alk),
--NH.sub.2, --OC(O)(C.sub.0-C.sub.6 alk),
--SO.sub.2--(C.sub.1-C.sub.6 alk), and --CO--(C.sub.0-C.sub.6 alk);
and each (C.sub.0-C.sub.6 alk), (C.sub.1-C.sub.6 alk), and
--(C.sub.1-C.sub.8 alk) is independently optionally substituted
with 1, 2, 3 or 4 substitutents selected independently from
--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH,
.dbd.O, -halogen, --C(O)O(C.sub.1-C.sub.3 alkyl) and
--C(O)(C.sub.1-C.sub.3 alkyl); and is optionally halogenated.
2.-32. (canceled)
33. A method of treating schizophrenia, treatment-resistant
schizophrenia, bipolar disorder, psychotic depression,
treatment-resistant depression, obsessive-compulsive disorder
(OCD), autism, senile psychosis, psychotic dementia, L-DOPA induced
psychosis, psychogenic polydipsia, psychotic symptoms associated
with neurological disorders, sleep disorders, depressed states
associated with schizophrenia, the method comprising administering
a compound or salt according to claim 1 to a patient in need of
such treatment.
34.-35. (canceled)
36. The method of claim 33 wherein the compound or salt according
to claim 1 is administered to a patient in need of such treatment
is administered in combination with one or more antipsychotics,
antidepressants, anti-anxiety agents, or nicotine.
37.-39. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates generally to
dibenzo[b,f][1,4]oxazapine compounds, and more particularly to
11-(piperazin-1-yl)benzo[b,f][1,4]oxazapine compounds.
[0003] 2. Technical Background
[0004] Serotonin or 5-hydroxytryptamine (5-HT) plays a significant
role in the functioning of the mammalian body. In the central
nervous system, 5-HT is an important neurotransmitter and
neuromodulator that is implicated in such diverse behaviors and
responses as sleeping, eating, locomotion, perceiving pain,
learning and memory, sexual behavior, controlling body temperature
and blood pressure. In the spinal column, serotonin plays an
important role in the control systems of the afferent peripheral
nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). Peripheral
functions in the cardiovascular, hematological and gastrointestinal
systems have also been ascribed to 5-HT. 5-HT has been found to
mediate a variety of contractile, secretory, and electrophysiologic
effects including vascular and nonvascular smooth muscle
contraction, and platelet aggregation. (Fuller, Biology of
Serotonergic Transmission, 1982; Boullin, Serotonin In Mental
Abnormalities 1:316 (1978); Barchas, et al., Serotonin and
Behavior, (1973)). The 5-HT.sub.2A receptor subtype (also referred
to as subclass) is widely yet discretely expressed in the human
brain, including many cortical, limbic, and forebrain regions
postulated to be involved in the modulation of higher cognitive and
affective functions.
[0005] Serotonin receptors are members of a large human gene family
of membrane-spanning proteins that function as transducers of
intercellular communication. They exist on the surface of various
cell types, including neurons and platelets, where, upon their
activation by either their endogenous ligand serotonin or
exogenously administered drugs, they change their conformational
structure and subsequently interact with downstream mediators of
cellular signaling. Many of these receptors, including the
5-HT.sub.2A subclass, are G-protein coupled receptors (GPCRs) that
signal by activating guanine nucleotide binding proteins
(G-proteins), resulting in the generation, or inhibition of, second
messenger molecules such as cyclic AMP, inositol phosphates, and
diacylglycerol. These second messengers then modulate the function
of a variety of intracellular enzymes, including kinases and ion
channels, which ultimately affect cellular excitability and
function.
[0006] Traditionally, these receptors have been assumed to exist in
a quiescent state unless activated by the binding of an agonist (a
drug that activates a receptor). It is now appreciated that many,
if not most, of the GPCR monoamine receptors, including serotonin
receptors, can exist in a partially activated state in the absence
of their endogenous agonists. This increased basal activity
(constitutive activity) can be inhibited by compounds called
inverse agonists. Both agonists and inverse agonists possess
intrinsic activity at a receptor, in that they can activate or
inactivate these molecules, respectively. In contrast, classic or
neutral antagonists compete against agonists and inverse agonists
for access to the receptor, but do not possess the intrinsic
ability to inhibit elevated basal or constitutive receptor
responses.
[0007] At least 15 genetically distinct 5-HT receptor subtypes have
been identified and assigned to one of seven families
(5-HT.sub.1-7). Each subtype displays a unique distribution,
preference for various ligands, and functional correlate(s).
[0008] Serotonin may be an important component in various types of
pathological conditions such as psychiatric disorders (depression,
aggressiveness, panic attacks, obsessive compulsive disorders,
psychosis, schizophrenia, suicidal tendency), neurodegenerative
disorders (Alzheimer-type dementia, Parkinsonism, Huntington's
chorea), anorexia, bulimia, disorders associated with alcoholism,
cerebral vascular accidents, and migraine (Meltzer,
Neuropsychopharmacology, 21:106 S-115S (1999); Barnes & Sharp,
Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci.
Biobehavioral Rev., 14:35 (1990)). Recent evidence strongly
implicates the 5-HT.sub.2 receptor subtype in the etiology of such
medical conditions as, among others, hypertension, thrombosis,
migraine, vasospasm, ischemia, depression, anxiety, psychosis,
schizophrenia, sleep disorders, and appetite disorders.
[0009] Schizophrenia is a particularly devastating neuropsychiatric
disorder that affects approximately 1% of the human population. It
has been estimated that the total financial cost for the diagnosis,
treatment, and lost societal productivity of individuals affected
by this disease exceeds 2% of the gross national product (GNP) of
the United States. Current treatment primarily involves
pharmacotherapy with a class of drugs known as antipsychotics.
Antipsychotics are effective in ameliorating positive symptoms
(e.g., hallucinations and delusions), yet they frequently do not
improve negative symptoms (e.g., social and emotional withdrawal,
apathy, and poverty of speech).
[0010] Currently, nine major classes of antipsychotics are
prescribed to treat psychotic symptoms. Use of these compounds is
limited, however, by their side effect profiles. Nearly all of the
"typical" or older generation compounds have significant adverse
effects on human motor function. These "extrapyramidal" side
effects, so termed due to their effects on modulatory human motor
systems, can be both acute (e.g., dystonic reactions, a potentially
life threatening but rare neuroleptic malignant syndrome) and
chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug
development efforts have, therefore, focused on newer "atypical"
agents free of these adverse effects.
[0011] Antipsychotic drugs have been shown to interact with a large
number of central monoaminergic neurotransmitter receptors,
including dopaminergic, serotonergic, adrenergic, muscarinic, and
histaminergic receptors. It is likely that the therapeutic and
adverse effects of these drugs are mediated by distinct receptor
subtypes and the degree to which an antipsychotic drug agonizes or
antagonizes the various receptor subtypes. The high degree of
genetic and pharmacological homology between these receptor
subtypes has hampered the development of drug compounds
(antipsychotic and other indications mentioned above and elsewhere
herein) that possess a desired pharmacological profile in the
absence of, or with acceptably reduced, undesired side effects.
SUMMARY OF THE INVENTION
[0012] One aspect of the invention provides compounds having the
structure depicted by Formula I:
##STR00002##
and pharmaceutically acceptable salts thereof, in which: [0013]
R.sup.1 and R.sup.2 are independently --Cl, --F, --Br, --I or --H;
[0014] R.sup.3 is --R (nonoptionally substituted in this single
instance at R.sup.3), --(C.sub.0-C.sub.6 alk)C(O)OR.sup.k,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)-OR,
--(C.sub.0-C.sub.6 alk)C(O)R.sup.k, or --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19; [0015] R.sup.4 is --H or --R; [0016] each
R.sup.5, R.sup.6 and R.sup.7 is independently --R,
--(C.sub.0-C.sub.6 alk)-OR, --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19, --NO.sub.2, -halogen, --CN, --OH, --OOCR,
--(C.sub.0-C.sub.6 alk)COOR.sup.e, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6 alk)C(O)Hca,
--(C.sub.0-C.sub.6 alk)C(O)Ar, --(C.sub.0-C.sub.6 alk)C(O)Het, or
--(C.sub.0-C.sub.6 alk)C(O)Cak; [0017] w is 0, 1, 2 or 3; [0018] x
is 0, 1, 2 or 3; and [0019] y is 0, 1, 2 or 3, in which [0020] each
R.sup.e is independently --H, --R, --(C.sub.1-C.sub.6 alk)C(O)Hca,
--(C.sub.1-C.sub.6 alk)C(O)Cak, --(C.sub.1-C.sub.6 alk)C(O)Het,
--(C.sub.1-C.sub.6 alk)C(O)Ar, --(C.sub.1-C.sub.6 alk)C(O)O-Hca,
--(C.sub.1-C.sub.6 alk)C(O)O-Cak, --(C.sub.1-C.sub.6 alk)C(O)O-Het,
--(C.sub.1-C.sub.6 alk)C(O)O--Ar, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.1-C.sub.6 alk)C(O)OR,
--(C.sub.1-C.sub.6 alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6
alk)-OR, or --(C.sub.0-C.sub.6 alk)-OH; [0021] each R.sup.a is
independently --H, --R, --(C.sub.1-C.sub.6 alk)-OR,
--(C.sub.1-C.sub.6 alk)-OH, --(C.sub.0-C.sub.6 alk)C(O)OR,
--(C.sub.1-C.sub.6 alk)-NR.sup.19.sub.2, --(C.sub.0-C.sub.6
alk)Hca, --(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Het, or
--(C.sub.0-C.sub.6 alk)Cak; [0022] each R.sup.k is independently
--H, --R, --(C.sub.1-C.sub.6 alk)C(O)Hca, --(C.sub.1-C.sub.6
alk)C(O)Cak, --(C.sub.1-C.sub.6 alk)C(O)Het, --(C.sub.1-C.sub.6
alk)C(O)Ar, --(C.sub.1-C.sub.6 alk)Hca, --(C.sub.0-C.sub.6 alk)Het,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Cak,
--(C.sub.1-C.sub.6 alk)C(O)OR, or --(C.sub.1-C.sub.6
alk)C(O)NR.sup.19.sub.2; [0023] each Cak is a cycloalkyl or
cycloalkenyl group, optionally substituted with 1, 2 or 3
substituents independently selected from --R, --(C.sub.0-C.sub.6
alk)C(O)OR, .dbd.O, --OH, --CN, --(C.sub.0-C.sub.6 alk)OR,
--OCH.sub.2CH.sub.2--O--, --OCH.sub.2--O--, --SO.sub.2--R,
--SO.sub.2--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)Het,
--SO.sub.2(C.sub.0-C.sub.6 alk)-Hca, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)C(O)R, --SO.sub.2(C.sub.0-C.sub.6 alk)Ar,
--SO.sub.2(C.sub.0-C.sub.6 alk)Het, and --SO.sub.2(C.sub.0-C.sub.6
alk)cycloalk, [0024] each Ar is an aryl group, optionally
substituted with 1, 2 or 3 substituents independently selected from
--R, --OR, --(C.sub.0-C.sub.6 alk)NR.sup.19.sub.2, --NO.sub.2,
--Cl, --F, --Br, --I, --CN, --(C.sub.0-C.sub.6 alk)OH,
--(C.sub.0-C.sub.6 alk)C(O)OR, --(C.sub.0-C.sub.6 alk)C(O)OH,
--(C.sub.1-C.sub.6 haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)heterocycloalk, --SO.sub.2R,
--(C.sub.0-C.sub.6 alk)-C)(O)-heterocycloalk, --(C.sub.0-C.sub.6
alk)-C(O)-cycloalk, --(C.sub.0-C.sub.6 alkyl)-C(O)-heteroaryl,
--(C.sub.0-C.sub.6 alk)-C(O)-aryl, --(C.sub.0-C.sub.6
alkyl)-C(O)O-heterocycloalk, --(C.sub.0-C.sub.6
alk)-C(O)O-cycloalk, --(C.sub.0-C.sub.6 alkyl)-C(O)O-heteroaryl,
--(C.sub.0-C.sub.6 alk)-C(O)O-aryl, --(C.sub.0-C.sub.6
alk)-heterocycloalkyl, --(C.sub.0-C.sub.6 alk)-heteroaryl,
--(C.sub.0-C.sub.6 alk)-aryl, and --(C.sub.0-C.sub.6 alk)-cycloalk;
[0025] each Het is a heteroaryl group, optionally substituted with
1, 2 or 3 groups independently selected from --R, --OR,
--(C.sub.0-C.sub.6 alk)NR.sup.19.sub.2, --NO.sub.2, --Cl, --F,
--Br, --I, --CN, --(C.sub.0-C.sub.6 alk)OH, --(C.sub.0-C.sub.6
alk)CO.sub.2R, --(C.sub.0-C.sub.6 alk)C(O)OH, --(C.sub.1-C.sub.6
haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)heterocycloalk, --SO.sub.2R, --(C.sub.0-C.sub.6
alk)-C(O)-heterocycloalk, --(C.sub.0-C.sub.6 alk)-C(O)-cycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)-heteroaryl, --(C.sub.0-C.sub.6
alk)-C(O)-aryl, --(C.sub.0-C.sub.6 alk)-C(O)O-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)O-cycloalk, --(C.sub.0-C.sub.6
alk)-C(O)O-heteroaryl, --(C.sub.0-C.sub.6 alk)-C(O)O-aryl,
--(C.sub.0-C.sub.6 alk)-heterocycloalkyl, --(C.sub.0-C.sub.6
alk)-heteroaryl, --(C.sub.0-C.sub.6 alk)-aryl, and
--(C.sub.0-C.sub.6 alk)-cycloalk; [0026] each Hca is a
heterocycloalk group, optionally substituted with 1, 2 or 3
substituents independently selected from --R, --(C.sub.1-C.sub.6
haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alk)-C(O)OR, --(C.sub.0-C.sub.6 alk)-C(O)R, .dbd.O, --OH, --CN,
--(C.sub.0-C.sub.6 alk)OR, --OCH.sub.2CH.sub.2--O--,
--OCH.sub.2O--, --SO.sub.2R, --SO.sub.2--(C.sub.1-C.sub.6
haloalkyl), --(C.sub.0-C.sub.6 alk)C(O)NR.sup.19.sub.2,
--(C.sub.0-C.sub.6 alk)-heterocycloalk, --(C.sub.0-C.sub.6
alk)-aryl, --(C.sub.0-C.sub.6 alk)-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-cycloalk, --SO.sub.2(C.sub.0-C.sub.6
alk)-heterocycloalk, --SO.sub.2(C.sub.0-C.sub.6 alk)-aryl,
--SO.sub.2(C.sub.0-C.sub.6 alk)-heteroaryl
--SO.sub.2(C.sub.0-C.sub.6 alkyl)heteroaryl,
--SO.sub.2(C.sub.0-C.sub.6 alk)-cycloalk; [0027] each R.sup.10 and
R.sup.11 is independently --H or --R; [0028] each R.sup.19 is
independently selected from --H, --OH and --R in which any
(C.sub.1-C.sub.8 alk) or --(C.sub.1-C.sub.8 haloalkyl) groups are
optionally substituted with 1, 2 or 3 substituents independently
selected from .dbd.O, --(C.sub.1-C.sub.6 alkoxy), --OH, or
-halogen; --(C.sub.1-C.sub.6 haloalkyl), wherein the
--(C.sub.1-C.sub.6 haloalkyl) may be substituted with from 1 to 6
halogens, --SO.sub.2--(C.sub.1-C.sub.6 alk), and
--C(O)--(C.sub.1-C.sub.6 alk); [0029] each R.sup.20 is a Hca or Het
ring wherein that N from the --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20
is a heteroatom in the Hca or Het ring, e.g., piperidine,
piperizine and the like, the ring optionally substituted with 1 or
2 substituents independently selected from .dbd.O,
--(C.sub.1-C.sub.6 alkoxy), --OH, or -halogen; --(C.sub.1-C.sub.6
haloalkyl), --SO.sub.2--(C.sub.1-C.sub.6 alk), and
--C(O)--(C.sub.1-C.sub.6 alk); [0030] each R is independently
--(C.sub.1-C.sub.8 alk), --(C.sub.3-C.sub.8 cycloalk),
--(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8 haloalkyl),
or --(C.sub.3-C.sub.8 halocycloalk), optionally substituted with 1,
2 or 3 substituents independently selected from --(C.sub.1-C.sub.6
alkoxy), --(C.sub.1-C.sub.6 hydroxyalkyoxy), --(C.sub.1-C.sub.6
hydroxyalkyl), acetoxyalkyl, --C(O)O(C.sub.1-C.sub.6 alkyl), --OH,
.dbd.O, --N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6
alk), --NH.sub.2, --OC(O)(C.sub.0-C.sub.6 alk),
--SO.sub.2--(C.sub.1-C.sub.6 alk), and --CO--(C.sub.0-C.sub.6 alk);
and [0031] each (C.sub.0-C.sub.6 alk), (C.sub.1-C.sub.6 alk), and
--(C.sub.1-C.sub.8 alk) is independently optionally substituted
with 1, 2, 3 or 4 substitutents selected independently from
--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH,
.dbd.O, -halogen, --C(O)O(C.sub.1-C.sub.3 alkyl) and
--C(O)(C.sub.1-C.sub.3 alkyl); and is optionally halogenated.
[0032] Another aspect of the invention relates to compounds and
salts having the structure of Formula I, wherein [0033] R.sup.1 and
R.sup.2 are independently --Cl, --F, --Br, --I or --H, with the
proviso that at least one of R.sup.1 and R.sup.2 is --Cl, --F, --Br
or --I; [0034] R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, or --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar; [0035] R.sup.4 is --H, or --R;
[0036] each R.sup.5, R.sup.6 and R.sup.2 is independently --R,
--OR, --NR.sup.aR.sup.19, --NO.sub.2, --Cl, --F, --Br, --I, --CN,
--OH, --OOCR, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19, or
--(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19; and [0037] w, x and
y are independently 0, 1 or 2; [0038] in which each R.sup.e is
independently --H or --R, each R.sup.a is independently --H or --R,
each R.sup.19 is independently --H or --R, each Ar is independently
phenyl optionally substituted with 1, 2 or 3 substituents selected
from --R, --OR, --NR.sub.2, --NO.sub.2, --Cl, --F, --Br, --I, --CN,
--OH, --C(O)OR, --(C.sub.1-C.sub.6 haloalkyl) and
--O(C.sub.1-C.sub.6 haloalkyl), each R is independently
--(C.sub.1-C.sub.8 alkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8
fluoroalkyl), --(C.sub.3-C.sub.8 fluorocycloalk),
--(C.sub.1-C.sub.8 chloroalkyl), or --(C.sub.3-C.sub.8
chlorocycloalk), wherein the --(C.sub.1-C.sub.6 fluoroalkyl),
--(C.sub.3-C.sub.8 fluorocycloalk), --(C.sub.1-C.sub.6
chloroalkyl), or --(C.sub.3-C.sub.8 chlorocycloalk) may be
substituted with from 1 to 6 fluorines or chlorines, respectively,
each R optionally substituted with 1, 2 or 3 substituents selected
from --(C.sub.1-C.sub.6 alkoxy), --(C.sub.1-C.sub.8 hydroxyalkyl),
acetoxyalkyl, and --C(O)O(C.sub.1-C.sub.4 alkyl).
[0039] In further desirable embodiments, R is independently
--(C.sub.1-C.sub.8 alkyl), --(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8
fluoroalkyl), --(C.sub.3-C.sub.8 fluorocycloalk),
--(C.sub.1-C.sub.8 chloroalkyl), or --(C.sub.3-C.sub.8
chlorocycloalk), wherein the --(C.sub.1-C.sub.6 fluoroalkyl),
--(C.sub.3-C.sub.8 fluorocycloalk), --(C.sub.1-C.sub.6
chloroalkyl), --(C.sub.3-C.sub.8 chlorocycloalk) may be substituted
with from 1 to 6 fluorines or chlorines, respectively, each R
optionally substituted with 1, 2 or 3 substituents selected from
--(C.sub.1-C.sub.6 alkoxy), --(C.sub.1-C.sub.8 hydroxyalkyl),
acetoxyalkyl, and --C(O)O(C.sub.1-C.sub.4 alkyl), with the proviso
that at least one R is a --(C.sub.3-C.sub.12 heterocycloalk).
[0040] Another aspect of the invention relates to compounds and
salts having the structure of Formula I, wherein [0041] R.sup.1 and
R.sup.2 are independently --Cl, --F, --Br, --I or --H, with the
proviso that at least one of R.sup.1 and R.sup.2 is --Cl, --F, --Br
or --I; [0042] R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20;
[0043] R.sup.4 is --H, or --R; [0044] each R.sup.5, R.sup.6 and
R.sup.2 is independently --R, --OR, --NR.sup.aR.sup.19, --NO.sub.2,
--Cl, --F, --Br, --I, --CN, --OH, --OOCR, --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.e, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19,
or --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19; and [0045] w, x
and y are independently 0, 1 or 2; 0 or 1; or 0.
[0046] Another aspect of the invention relates to compounds and
salts having the structure of Formula I, wherein [0047] R.sup.1 and
R.sup.2 are independently --Cl, --F, --Br, --I or --H, with the
proviso that at least one of R.sup.1 and R.sup.2 is --Cl, --F, --Br
or --I; [0048] R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e;
[0049] R.sup.4 is --H, or --R; [0050] each R.sup.5, R.sup.6 and
R.sup.2 is independently --R, --OR, --NR.sup.aR.sup.19, --NO.sub.2,
--Cl, --F, --Br, --I, --CN, --OH, --OOCR, --(C.sub.0-C.sub.6
alkyl)C(O)OR.sup.e, --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19,
or --(C.sub.0-C.sub.6 alkyl)C(O)NR.sup.aR.sup.19; and [0051] w, x
and y are independently 0, 1 or 2; 0 or 1; or most preferably
0.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIG. 1. Schild plot of 5-HT.sub.2A receptor antagonism of
Compound K and Compound Q versus clozapine.
[0053] FIG. 2. Antagonism of apomorphine-induced disruption of
swimming in mice for Compound K and clozapine (minus
apomorphine).
[0054] FIG. 3. Antagonism of apomorphine-induced disruption of
swimming in mice for Compound K and clozapine (plus
apomorphine).
[0055] FIG. 4. Antagonism of apomorphine-induced disruption of
swimming in mice for Compound Q (plus and minus apomorphine).
[0056] FIG. 5. Catalepsy assessment in mouse catalepsy model for
Compound K and Compound Q.
[0057] FIG. 6. Catalepsy assessment in mouse catalepsy model for
clozapine.
[0058] FIG. 7. Compound K and Compound Q restore NMDA
antagonist-induced deficits in prepulse inhibition.
[0059] FIG. 8. Compound K does not reduce spontaneous locomotor
activity in rats (open field).
DEFINITIONS
[0060] As used herein, the term "alk" includes alkyl, alkenyl, and
alkynyl groups, both with all carbon chains or rings or including
one or more heteroatoms, e.g., N, O, or S. The term
"C.sub.m-C.sub.n alk" means an alkyl, alkenyl or alkynyl group
having between m and n carbon atoms, with the proviso that an
alkenyl group or an alkynyl group must have at least two carbon
atoms. For example, "C.sub.0-C.sub.6 alk" is an alkyl group having
between zero and six carbon atoms, and alkenyl group having between
two and six carbon atoms, or an alkynyl group having between two
and six carbon atoms. Preferred alk groups are alkyl.
[0061] As used herein, the term "alkyl" includes alkyl groups of a
designed number of carbon atoms, desirably between 1 and about 12
carbons. The term "C.sub.m-C.sub.n alkyl" means an alkyl group
having between m and n carbon atoms. For example, "C.sub.0-C.sub.6
alkyl" is an alkyl group having between zero and six carbon atoms.
In the case of an alkyl group having zero carbon atoms (i.e.,
C.sub.0), the group is simply a single covalent bond. Alkyl groups
may be straight, or branched, and depending on context, may be a
monovalent radical or a divalent radical (i.e., an alkylene group).
For example, the moiety "--(C.sub.0-C.sub.6 alkyl)-Ar" signifies
connection of an aryl through a single bond or an alkylene bridge
having between 1 and 6 carbons. Examples of "alkyl" include methyl,
ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl,
hexyl, heptyl, 3-ethylbutyl, and the like. If the number of carbon
atoms is not specified, the subject "alkyl" moiety has from 1 to 12
carbons.
[0062] As used herein, the term "alkenyl" includes alkenyl groups
having at least 2 carbon atoms, desirably between 2 and about 12.
Like alkyl groups, alkenyl groups may be straight, or branched, and
depending on context, may be a monovalent radical or a divalent
radical. There may be one or more double bonds, and they may be
internal to the alkenyl (e.g., --CH.sub.2CH.dbd.CHCH.sub.2--), at a
connecting end of the alkenyl (e.g.,
--CH.dbd.CHCH(CH.sub.3).sub.2), or at a terminal end of the alkenyl
(e.g., --CH.sub.2CH.sub.2CH.sub.2C.dbd.CH). As used herein,
"alkenyl" also refers to carbon chains that include one or more
heteroatoms in place of one or more carbons, heteroatom being, for
example, O, N, or S.
[0063] As used herein, the term "alkynyl" includes alkynyl groups
having at least 2 carbon atoms, desirably between 2 and about 12.
Like alkyl groups, alkynyl groups may be straight, or branched, and
depending on context, may be a monovalent radical or a divalent
radical. There may be one or more double bonds, and they may be
internal to the alkynyl (e.g., --CH.sub.2CH.dbd.CHCH.sub.2--), at a
connecting end of the alkynyl (e.g.,
--CH.dbd.CH--CH(CH.sub.3).sub.2), or at a terminal end of the
alkynyl (e.g., --CH.sub.2CH.sub.2CH.sub.2CCH). As used herein,
"alkynyl" also refers to carbon chains that include one or more
heteroatoms in place of one or more carbons, heteroatom being, for
example, O, N, or S.
[0064] The term "alkoxy" represents an alkyl group of indicated
number of carbon atoms attached to the parent molecular moiety
through an oxygen bridge. Examples of alkoxy groups include, for
example, methoxy, ethoxy, n-propoxy and isopropoxy.
[0065] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl and
alkoxy groups substituted with at least one halogen atom and
optionally further substituted with at least one additional halogen
atom, where each halogen is independently F, Cl, Br or I. Preferred
halogens are F or Cl, while F is especially preferred. Preferred
haloalkyl and haloalkoxy groups contain, for example 1-6 carbons,
1-4 carbons, or 1-2 carbons. Haloalkyl and haloalkoxy groups may be
perhalogenated, such as in the case of --OCF.sub.3 and
--OCF.sub.2CF.sub.3. As used herein, "haloalkyl" also refers to
carbon chains that include one or more heteroatoms in place of one
or more carbons, heteroatom being, for example, O, N, or S.
[0066] The term "aryl" represents an aromatic carbocyclic group
having a single ring (e.g., phenyl) that is optionally fused or
otherwise attached to other aromatic hydrocarbon rings or
non-aromatic hydrocarbon rings. "Aryl" includes multiple condensed
rings in which at least one is aromatic, (e.g.,
1,2,3,4-tetrahydronaphthyl, naphthyl), wherein each ring is
optionally mono-, di-, or trisubstituted with the groups identified
below, as well as multiple rings that are not fused, such as, for
example, biphenyl or binaphthyl. Preferred aryl groups of the
present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl,
indenyl, dihydronaphthyl, fluorenyl, tetralinyl,
2,3-dihydrobenzofuranyl, or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferably, the
aryl group is a phenyl or naphthyl. Still more preferably, the aryl
group is a phenyl.
[0067] The term "heteroaryl" refers to an aromatic ring system
containing at least one heteroatom selected from nitrogen, oxygen,
and sulfur. The heteroaryl ring may be fused or otherwise attached
to one or more heteroaryl, aryl, cycloalk or heterocycloalk rings.
Examples of heteroaryl groups include, for example, pyridyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl,
tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydro furanyl,
is obenzotetrahydrothienyl, is obenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl,
imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl,
benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl,
benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl
N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl
N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,
thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred
heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl,
pyrrolyl, furanyl, thienyl, and imidazolyl, pyrazolyl, indazolyl,
thiazolyl and benzothiazolyl.
[0068] The term "cycloalk" refers to an non-aromatic carbocyclic
ring or ring system, which may be saturated (i.e., a "cycloalkyl"),
or unsaturated (i.e., a "cycloalkenyl"). The cycloalk ring
optionally fused to or otherwise attached to other cycloalk rings,
heterocycloalk rings, aryl rings or heteroaryl rings. Preferred
cycloalk groups have from 3 to 7 members. More preferred cycloalk
groups have 5 or 6 members. Examples of cycloalk groups include,
for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and
tetrahydronaphthyl.
[0069] The term "heterocycloalk" refers to a non-aromatic ring or
ring system containing at least one heteroatom that is preferably
selected from nitrogen, oxygen, and sulfur, wherein said heteroatom
is in a non-aromatic ring. The heterocycloalk may be saturated
(i.e., a "heterocycloalkyl"), or unsaturated (i.e., a
"heterocycloalkenyl"). The heterocycloalk ring is optionally fused
to or otherwise attached to other heterocycloalk rings and/or
non-aromatic hydrocarbon rings and/or phenyl rings. Preferred
heterocycloalk groups have from 3 to 12 members. More preferred
single heterocycloalk groups have 5 or 6 members; whereas most
preferred heterocycloalk ring systems have from 10 to 12 members.
Examples of heterocycloalk groups include, for example,
azabicyclo[2.2.2]octyl (in each case also "quinuclidinyl" or a
quinuclidine derivative), azabicyclo[3.2.1]octyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl,
piperazinonyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, is
oindolindionyl, homopiperidinyl, homomorpholinyl,
homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,
oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl
S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl
S-oxide. Especially desirable heterocycloalk groups include
morpholinyl, tetrahydropyranyl, piperidinyl,
aza-bicyclo[2.2.2]octyl, .alpha.-butryolactonyl (i.e., an
oxo-substituted tetrahydrofuranyl), pyrrolidinyl, piperazinyl,
thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl,
imidazolidonyl, isoindolindionyl, piperazinonyl, and mono- and
di-saccharide sugars, e.g., glucose, fructose, sucrose, mannose,
arabinose, and galactose.
[0070] The term "pharmaceutically acceptable salts" or "a
pharmaceutically acceptable salt thereof" refer to salts prepared
from pharmaceutically acceptable non-toxic acids or bases including
inorganic acids and bases and organic acids and bases. Since the
compound of the present invention is basic, salts may be prepared
from pharmaceutically acceptable non-toxic acids. Suitable
pharmaceutically acceptable acid addition salts for the compound of
the present invention include acetic, benzenesulfonic (besylate),
benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic, and the like. Preferred acid addition salts are
the chloride and sulfate salts and the salts of di- and
tri-carboxylic acids, for example, tartrate, citrate, maleate,
succinate, and the like.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0071] One aspect of the invention relates to compounds having a
structure according to
##STR00003##
and pharmaceutically acceptable salts thereof.
[0072] The structure of Formula (I) is based on a
dibenzo[b,f][1,4]oxazapine core having the numbering system shown
below in Formula (II).
##STR00004##
R.sup.1 is attached at any one of the 6-9 positions of the
dibenzo[b,f][1,4]oxazapine, while R.sup.2 is attached at any of the
1-4 positions. R.sup.1 and R.sup.2 are independently --Cl, --F,
--Br, --I or --H. Desirably, R.sub.1 is attached at the 7 or 8
position of the dibenzo[b,f][1,4]oxazapine. Simiarly, R.sub.2 is
desirably attached at the 2 or 3 position of the
dibenzo[b,f][1,4]oxazapine. According to a desirable embodiment of
the invention, at least one of R.sup.1 and R.sup.2 is --F, --Cl,
--Br or --I. More desirably, only one of R.sup.1 and R.sup.2 is
--F, --Cl, --Br or --I, and the other is --H.
[0073] The piperazine is substituted with R.sup.3 at a carbon
distal from the dibenzo[b,f][1,4]oxazapine, as shown in Formula
(I). R.sup.3 may be --R (nonoptionally substituted in this instance
at R.sup.3), --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)-OR,
--(C.sub.0-C.sub.6 alk)C(O)R.sup.k, or --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19, in which in which R, Re, Ra, R19, Ar, Het,
Hca, Cak are as described below. Each alk group may be, for
example, an alkyl group. In desirable embodiments of the invention,
R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, or --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar. In other desirable embodiments of
the invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
In further desirable embodiments of the invention, R.sup.3 is
--(C.sub.0-C.sub.6 alk)C(O)OR.sup.e. In yet further desirable
embodiments of the invention, R.sup.3 is --(C.sub.0-C.sub.6
alk)C(O)OR.sup.e in which the --(C.sub.0-C.sub.6 alk) is
--(C.sub.1-C.sub.6 alk), --(C.sub.1-C.sub.4 alk) or
--(C.sub.1-C.sub.2 alk).
[0074] Other desirable R.sup.3 substituents have gem-, mono-, or
dialkyl substitution alpha to a functional group, e.g., a carbonyl
carbon. Accordingly, in certain desirable embodiments of the
invention, each (C.sub.0-C.sub.6 alkyl) connected directly to the
piperazine ring as part of R.sup.3 is a --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2-, in which (C.sub.0-C.sub.5
alkyl) is independently optionally substituted with 1 or 2
substitutents selected independently from --(C.sub.1-C.sub.4
alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH, .dbd.O, -halogen,
--C(O)O(O--C.sub.3 alkyl) and --C(O)(C.sub.1-C.sub.3 alkyl); and is
optionally halogenated.
[0075] In certain especially desirable embodiments of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
In yet other desirable embodiments of the invention, R.sup.3 is
--(C.sub.0-C.sub.6 alk)C(O)OR.sup.e. In these embodiments, each
C.sub.0-C.sub.6 alkyl connected directly to the piperazine ring as
part of R.sup.3 may be, for example, C.sub.2-C.sub.6 alkyl, or
alternatively C.sub.1-C.sub.2 alkyl. In certain embodiments of the
invention R.sup.3 is --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)OR.sup.e, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.a.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.19.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.20, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2Ar, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2Ar,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2CR,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)R.sup.k,
or --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2NR.sup.aR.sup.19. Finally, in these embodiments of the
invention, each R.sup.5, R.sup.6 and R.sup.7 is desirably
independently --R, --OR, --NR.sup.19.sub.2, --NO.sub.2, --Cl, --F,
--Br, --I, --CN, --OH, --OOCR, --(C.sub.0-C.sub.2 alkyl)C(O)OR, or
--(C.sub.0-C.sub.2 alkyl)C(O)NR.sup.19.sub.2.
[0076] The R.sup.3 group will form a stereogenic center on the
piperazine ring. The R.sup.3 group may be attached to the
piperazine ring in an S configuration, or an R configuration. The
compound or salt may exist as a racemic mixture, a scalemic
mixture, or an enantomerically- or diastereomerically-enriched
mixture having at least about 80% enantiomeric or diastereomeric
excess at the carbon of attachment of the R.sup.3 group to the
piperazine.
[0077] The piperazine is substituted with R.sup.4 at the nitrogen
distal from the dibenzo[b,f][1,4]oxazapine, as shown in Formula
(I). R.sup.4 may be, for example, --H or --R. In certain especially
desirable embodiments of the invention, R.sup.4 is H.
[0078] The benzo moieties of the dibenzo[b,f][1,4]oxazapine core
may be substituted with substituents other than R.sup.1 and
R.sup.2. For example, as shown in Formula (I), the 6-9 positions of
the dibenzo[b,f][1,4]oxazapine may be substituted with 0, 1, 2 or 3
R.sup.5 substituents (i.e., x is 0, 1, 2 or 3). Similarly, the 1-4
positions may be substituted with 0, 1, 2 or 3 R.sup.6 substituents
(i.e., y is 0, 1, 2 or 3). The R.sup.5 and R.sup.6 substituents are
independently --R, --(C.sub.0-C.sub.6 alk)-OR, --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19, --NO.sub.2, -halogen, --CN, --OH, --OOCR,
--(C.sub.0-C.sub.6 alk)COOR.sup.e, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6 alk)C(O)Hca,
--(C.sub.0-C.sub.6 alk)C(O)Ar, --(C.sub.0-C.sub.6 alk)C(O)Het, or
--(C.sub.0-C.sub.6 alk)C(O)Cak, in which R, R.sup.a, R.sup.19, Ar,
Het, Hca, Cak are as described below. Each alk group may be, for
example, an alkyl group. Especially desirable R.sup.5 and R.sup.6
substituents include --R, --OR, --NR.sup.19.sub.2, --NO.sub.2,
--Cl, --F, --Br, --I, --CN, --OH, --OOCR, --(C.sub.0-C.sub.2
alkyl)C(O)OR, and --(C.sub.0-C.sub.2 alkyl)C(O)NR.sup.19.sub.2.
Desirably, the dibenzo[b,f][1,4]oxazapine is substituted with 0 or
1 R.sup.5 substituents (i.e., x is 0 or 1). Similarly, the
dibenzo[b,f][1,4]oxazapine is desirably substituted with 0 or 1
R.sup.6 substituents (i.e., y is 0 or 1). In certain desirable
embodiments of the invention, the dibenzo[b,f][1,4]oxazapine is
substituted with no R.sup.5 or R.sup.6 groups (i.e., both x and y
are O).
[0079] Similarly, the piperazine ring of the structure of Formula
(I) may be substituted with substituents other than R.sup.3 and
R.sup.4. For example, as shown in Formula (I), the piperazine ring
may be substituted with 0, 1, 2 or 3 R.sup.7 substituents (i.e., w
is 0, 1, 2 or 3). The R.sup.7 substituents are independently --R,
--(C.sub.0-C.sub.6 alk)-OR, --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19, --NO.sub.2, -halogen, --CN, --OH, --OOCR,
--(C.sub.0-C.sub.6 alk)COOR.sup.e, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.0-C.sub.6 alk)C(O)Hca,
--(C.sub.0-C.sub.6 alk)C(O)Ar, --(C.sub.0-C.sub.6 alk)C(O)Het, or
--(C.sub.0-C.sub.6 alk)C(O)Cak, in which R, R.sup.a, R.sup.19, Ar,
Het, Hca, Cak are as described below. Each alk group may be, for
example, an alkyl group. Especially desirable R.sup.7 substituents
include --R, --OR, --NR.sup.19.sub.2, --NO.sub.2, --Cl, --F, --Br,
--I, --CN, --OH, --OOCR, --(C.sub.0-C.sub.2 alkyl)C(O)OR, and
--(C.sub.0-C.sub.2 alkyl)C(O)NR.sup.19.sub.2. Desirably, the
piperazine is substituted with 0 or 1 R.sup.7 substituents (i.e., w
is 0 or 1). In certain desirable embodiments of the invention, the
piperazine is substituted with no R.sup.7 groups. In certain
especially desirable embodiments of the invention, the
11-piperazin-1-yl dibenzo[b,f][1,4]oxazapine core is substituted
with no R.sup.5, R.sup.6 or R.sup.7 groups (i.e., w, x and y are
each zero). In other desirable embodiments, w, x, and y are each
zero and R.sup.4 is --H.
[0080] In the compounds according to this aspect of the invention,
each R.sup.e may independently be --H, --R, --(C.sub.1-C.sub.6
alk)C(O)Hca, --(C.sub.1-C.sub.6 alk)C(O)Cak, --(C.sub.1-C.sub.6
alk)C(O)Het, --(C.sub.1-C.sub.6 alk)C(O)Ar, --(C.sub.1-C.sub.6
alk)C(O)O-Hca, --(C.sub.1-C.sub.6 alk)C(O)O-Cak, --(C.sub.1-C.sub.6
alk)C(O)O-Het, --(C.sub.1-C.sub.6 alk)C(O)O--Ar, --(C.sub.0-C.sub.6
alk)Hca, --(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.1-C.sub.6 alk)C(O)OR,
--(C.sub.1-C.sub.6 alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6
alk)-OR, or --(C.sub.0-C.sub.6 alk)-OH, in which R, R.sup.19, Ar,
Het, Hca, Cak are as described below. Each alk group may be, for
example, an alkyl group. Desirably, each R.sup.e is independently
--H or --R.
[0081] In the compounds according to this aspect of the invention,
each R.sup.a may independently be --H, --R, --(C.sub.1-C.sub.6
alk)-OR, --(C.sub.1-C.sub.6 alk)-OH, --(C.sub.0-C.sub.6 alk)C(O)OR,
--(C.sub.1-C.sub.6 alk)-NR.sup.19.sub.2, --(C.sub.0-C.sub.6
alk)Hca, --(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Het, or
--(C.sub.0-C.sub.6 alk)Cak, in which R, R.sup.19, Hca, Ar, Het and
Cak are as described below. Each alk group may be, for example, an
alkyl group. Desirably, each R.sup.a is independently --H or
--R.
[0082] In the compounds according to this aspect of the invention,
each R.sup.k may independently be --H, --R, --(C.sub.1-C.sub.6
alk)C(O)Hca, --(C.sub.1-C.sub.6 alk)C(O)Cak, --(C.sub.1-C.sub.6
alk)C(O)Het, --(C.sub.1-C.sub.6 alk)C(O)Ar, --(C.sub.1-C.sub.6
alk)Hca, --(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Cak, --(C.sub.1-C.sub.6 alk)C(O)OR, or
--(C.sub.1-C.sub.6 alk)C(O)NR.sup.19.sub.2, in which R, Hca, Cak,
Het, Ar and R.sup.19 are as described below. Each alk group may be,
for example, an alkyl group.
[0083] In the compounds according to this aspect of the invention,
each Cak is a cycloalk group, optionally substituted with 1, 2 or 3
substituents independently selected from --R, --(C.sub.0-C.sub.6
alk)C(O)OR, .dbd.O, --OH, --CN, --(C.sub.0-C.sub.6 alk)OR,
--OCH.sub.2CH.sub.2--O--, --OCH.sub.2--O--, --SO.sub.2--R,
--SO.sub.2--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)Het,
--SO.sub.2(C.sub.0-C.sub.6 alk)-Hca, --(C.sub.0-C.sub.6 alk)Ar,
--(C.sub.0-C.sub.6 alk)Het, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)C(O)R, --SO.sub.2(C.sub.0-C.sub.6 alk)Ar,
--SO.sub.2(C.sub.0-C.sub.6 alk)Het, and --SO.sub.2(C.sub.0-C.sub.6
alk)cycloalk, in which R, R.sup.19, Het, Hca and Ar are as
described below. Each alk group may be, for example, an alkyl
group. Each cycloalk group may be, for example, a cycloalkyl group.
Desirably, Cak is a cycloalkyl group. In certain desirable
embodiments of the invention, each Cak is optionally substituted
cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.
[0084] In the compounds according to this aspect of the invention,
each Ar is an aryl group, optionally substituted with 1, 2 or 3
substituents independently selected from --R, --OR,
--(C.sub.0-C.sub.6 alk)NR.sup.19.sub.2, --NO.sub.2, --Cl, --F,
--Br, --I, --CN, --(C.sub.0-C.sub.6 alk)OH, --(C.sub.0-C.sub.6
alk)C(O)OR, --(C.sub.0-C.sub.6 alk)C(O)OH, --(C.sub.1-C.sub.6
haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)heterocycloalk, --SO.sub.2R, --(C.sub.0-C.sub.6
alk)-C)(O)-heterocycloalk, --(C.sub.0-C.sub.6 alk)-C(O)-cycloalk,
--(C.sub.0-C.sub.6 alkyl)-C(O)-heteroaryl, --(C.sub.0-C.sub.6
alk)-C(O)-aryl, --(C.sub.0-C.sub.6 alkyl)-C(O)O-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)O-cycloalk, --(C.sub.0-C.sub.6
alkyl)-C(O)O-heteroaryl, --(C.sub.0-C.sub.6 alk)-C(O)O-aryl,
--(C.sub.0-C.sub.6 alk)-heterocycloalkyl, --(C.sub.0-C.sub.6
alk)-heteroaryl, --(C.sub.0-C.sub.6 alk)-aryl, and
--(C.sub.0-C.sub.6 alk)-cycloalk, in which R and R.sup.19 are as
described below. Each alk group may be, for example, an alkyl
group. Each cycloalk group may be, for example, a cycloalkyl group.
Each heterocycloalk group may be, for example, a heterocycloalkyl
group. In certain desirable embodiments of the invention, each Ar
is phenyl optionally independently substituted with 1, 2 or 3
substituents selected from --R, --OR, --NR.sub.2, --NO.sub.2, --Cl,
--F, --Br, --I, --CN, --OH and --C(O)OR.
[0085] In the compounds according to this aspect of the invention,
each Het is a heteroaryl group, optionally substituted with 1, 2 or
3 groups independently selected from --R, --OR, --(C.sub.0-C.sub.6
alk)NR.sup.19.sub.2, --NO.sub.2, --Cl, --F, --Br, --I, --CN,
--(C.sub.0-C.sub.6 alk)OH, --(C.sub.0-C.sub.6 alk)CO.sub.2R,
--(C.sub.0-C.sub.6 alk)C(O)OH, --(C.sub.1-C.sub.6 haloalkyl),
--O(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)heterocycloalk, --SO.sub.2R, --(C.sub.0-C.sub.6
alk)-C(O)-heterocycloalk, --(C.sub.0-C.sub.6 alk)-C(O)-cycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)-heteroaryl, --(C.sub.0-C.sub.6
alk)-C(O)-aryl, --(C.sub.0-C.sub.6 alk)-C(O)O-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-C(O)O-cycloalk, --(C.sub.0-C.sub.6
alk)-C(O)O-heteroaryl, --(C.sub.0-C.sub.6 alk)-C(O)O-aryl,
--(C.sub.0-C.sub.6 alk)-heterocycloalkyl, --(C.sub.0-C.sub.6
alk)-heteroaryl, --(C.sub.0-C.sub.6 alk)-aryl, and
--(C.sub.0-C.sub.6 alk)-cycloalk, in which R and R.sup.19 are
described below. Each alk group may be, for example, an alkyl
group. Each cycloalk group may be, for example, a cycloalkyl group.
Each heterocycloalk group may be, for example, a heterocycloalkyl
group. In certain desirable embodiments of the invention, each Het
is optionally substituted pyridyl, pyrimidyl, quinolinyl, indolyl,
pyrrolyl, furanyl, thienyl, and imidazolyl, pyrazolyl, indazolyl,
thiazolyl or benzothiazolyl.
[0086] In the compounds according to this aspect of the invention,
each Hca is a heterocycloalk group, optionally substituted with 1,
2 or 3 substituents independently selected from --R,
--(C.sub.1-C.sub.6 haloalkyl), --O(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alk)-C(O)OR, --(C.sub.0-C.sub.6 alk)-C(O)R,
.dbd.O, --OH, --CN, --(C.sub.0-C.sub.6 alk)OR,
--OCH.sub.2CH.sub.2--O--, --OCH.sub.2O--, --SO.sub.2R,
--SO.sub.2--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)-heterocycloalk,
--(C.sub.0-C.sub.6 alk)-aryl, --(C.sub.0-C.sub.6
alk)-heterocycloalk, --(C.sub.0-C.sub.6 alk)-cycloalk,
--SO.sub.2(C.sub.0-C.sub.6 alk)-heterocycloalk,
--SO.sub.2(C.sub.0-C.sub.6 alk)-aryl, --SO.sub.2(C.sub.0-C.sub.6
alk)-heteroaryl --SO.sub.2(C.sub.0-C.sub.6 alkyl)heteroaryl,
--SO.sub.2(C.sub.0-C.sub.6 alk)-cycloalk, in which R and R.sup.19
are as described below. Each alk group may be, for example, an
alkyl group. Each cycloalk group may be, for example, a cycloalkyl
group. Each heterocycloalk group may be, for example, a
heterocycloalkyl group. In certain desirable embodiments of the
invention, Hca is optionally substituted morpholinyl,
tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl,
.alpha.-butryolactonyl, pyrrolidinyl, piperazinyl, thiomorpholinyl,
thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl,
isoindolindionyl, piperazinonyl.
[0087] In the compounds according to this aspect of the invention,
each R.sup.10 and R.sup.11 is independently --H or --R, in which
--R is as described below.
[0088] In the compounds according to this aspect of the invention,
each R.sup.19 is independently selected from --H, --OH and --R, in
which R is as described below. Each alk group may be, for example,
an alkyl group.
[0089] In the compounds according to this aspect of the invention,
each R.sup.20 is a Hca or Het ring wherein that N from the
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.20, is a heteroatom in the Hca or
Het ring, the ring optionally substituted with 1 or 2 substituents
independently selected from .dbd.O, --(C.sub.1-C.sub.6 alkoxy),
--OH, or -halogen; --(C.sub.1-C.sub.6 haloalkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alk), and --C(O)--(C.sub.1-C.sub.6
alk).
[0090] In the compounds according to this aspect of the invention,
each R is independently --(C.sub.1-C.sub.8 alk), --(C.sub.3-C.sub.8
cycloalk), --(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8
haloalkyl), or --(C.sub.3-C.sub.8 halocycloalk), optionally
substituted with 1, 2 or 3 substituents independently selected from
--(C.sub.1-C.sub.6 alkoxy), --(C.sub.1-C.sub.6 hydroxyalkyoxy),
--(C.sub.1-C.sub.6 hydroxyalkyl), acetoxyalkyl,
--C(O)O(C.sub.1-C.sub.6 alkyl), --OH, .dbd.O, --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.1-C.sub.6 alk), --NH.sub.2,
--OC(O)(C.sub.0-C.sub.6 alk), --SO.sub.2--(C.sub.1-C.sub.6 alk),
and --CO--(C.sub.0-C.sub.6 alk). Each --(C.sub.1-C.sub.8 haloalkyl)
or --(C.sub.3-C.sub.8 halocycloalk), may be further optionally
substituted with from 1 to 6 additional halogens. Each alk group
may be, for example, an alkyl group.
[0091] In the compounds according to this aspect of the invention,
each (C.sub.0-C.sub.6 alk), (C.sub.1-C.sub.6 alk), and
--(C.sub.1-C.sub.8 alk) is independently optionally substituted
with 1, 2, 3 or 4 substitutents selected independently from
--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH,
.dbd.O, -halogen, --C(O)O(O--C.sub.3 alkyl) and --C(O)(O--C.sub.3
alkyl); and is optionally halogenated. Each alk group may be, for
example, an alkyl group.
[0092] In this aspect of the invention, one or more of the alk
groups may be alkenyl groups or alkynyl groups. In certain
embodiments of the invention, at least one of the alk groups is an
alkenyl group or an alkynyl group. Alternatively, in certain
desirable embodiments of the invention, all of the alk groups are
alkyl groups.
[0093] Another aspect of the invention relates to compounds of
Formula (I) and pharmaceutically acceptable salts thereof, in which
R.sup.1 and R.sup.2 are independently --Cl, --F, --Br, --I or --H,
with the proviso that at least one of R.sup.1 and R.sup.2 is --Cl,
--F, --Br or --I; R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, or --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar; R.sup.4 is --H or --R; each
R.sup.5, R.sup.6 and R.sup.7 is independently --R, --OR,
--NR.sup.aR.sup.19, --NO.sub.2, --Cl, --F, --Br, --I, --CN, --OH,
--OOCR, --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.e, --(C.sub.0-C.sub.6
alkyl)C(O)NR.sup.aR.sup.19, or --(C.sub.0-C.sub.6
alkyl)C(O)NR.sup.aR.sup.19; and w, x and y are independently 0, 1
or 2, in which each R.sup.e is independently --H or --R, each
R.sup.a is independently --H or --R, each R.sup.19 is independently
--H or --R, each Ar is phenyl independently optionally substituted
with 1, 2 or 3 substituents selected from --R, --OR, --NR.sub.2,
--NO.sub.2, --Cl, --F, --Br, --I, --CN, --OH, --C(O)OR,
--(C.sub.1-C.sub.6 haloalkyl) and --O(O--C.sub.6 haloalkyl), and
each R is independently --(C.sub.1-C.sub.8 alkyl),
--(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.12
heterocycloalk), --(C.sub.1-C.sub.8 fluoroalkyl),
--(C.sub.3-C.sub.8 fluorocycloalk), --(C.sub.1-C.sub.8
chloroalkyl), or --(C.sub.3-C.sub.8 chlorocycloalk), wherein the
--(C.sub.1-C.sub.6 fluoroalkyl), --(C.sub.3-C.sub.8
fluorocycloalk), --(C.sub.1-C.sub.6 chloroalkyl), or
--(C.sub.3-C.sub.8 chlorocycloalk) may be substituted with from 1
to 6 fluorines or chlorines, respectively, each R optionally
substituted with 1, 2 or 3 substituents selected from
--(C.sub.1-C.sub.6 alkoxy), --(C.sub.1-C.sub.8 hydroxyalkyl),
acetoxyalkyl, and --C(O)O(O--C.sub.4 alkyl).
[0094] In desirable compounds according to this aspect of the
invention, only one of R.sup.1 and R.sup.2 is --Cl, --F, --Br or
--I, and the other is H. For example, one of R.sup.1 or R.sup.2 may
be Cl, and the other may be --H. R.sup.1 is desirably attached at
the 7 or 8 position of the dibenzo[b,f][1,4]oxazapine, and R.sup.2
is desirably attached at its 2 or 3 position.
[0095] In desirable compounds according to this aspect of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
More desirably, R.sup.3 is --(CH.sub.2).sub.pCO.sub.2R.sup.e,
--(CH.sub.2).sub.pCONR.sup.a.sub.2,
--(CH.sub.2).sub.pC(O)NR.sup.aR.sup.19,
--(CH.sub.2).sub.pC(O)NR.sup.20, or
--(CH.sub.2).sub.pCONR.sup.19.sub.2 in which p is 0, 1, 2, 3, 4, 5
or 6. For example, p may be 1 or 2. In yet other desirable
embodiments of the invention, R.sup.3 is
--(CH.sub.2).sub.pCO.sub.2R.sup.e,
--(CH.sub.2).sub.pCONR.sup.a.sub.2,
--(CH.sub.2).sub.pC(O)NR.sup.aR.sup.19. In certain desirable
embodiments of the invention, the R.sup.3 group has gem-mono- or
dialkyl substitution alpha to its functional group. As such, each
(C.sub.0-C.sub.6 alkyl) connected directly to the piperazine ring
as part of R.sup.3 is desirably a --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2- group. For example, R.sup.3
may be --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)OR.sup.e, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.a.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.19.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.20,
--(CH.sub.2).sub.qCR.sup.d.sub.2CO.sub.2R.sup.e,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.a.sub.2,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.19.sub.2,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.aR.sup.19, or
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.20, wherein q is 0, 1, 2,
3, 4 or 5, and each R.sup.d is individually -Me, -Et or --Pr. q is
desirably 0, 1 or 2. In especially desirable embodiments of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.e.
R.sup.e may be, for example, --H, -Me, -Et, --Pr or --Bu. In
further especially desirable embodiments of the invention, R.sup.3
is --(C.sub.0-C.sub.3 alkyl)C(O)OR.sup.e, wherein R.sup.e may be,
for example, --H, -Me, -Et, --Pr or --Bu. In yet further especially
desirable embodiments of the invention, R.sup.3 is
--(C.sub.1-C.sub.2 alkyl)C(O)OR.sup.e, wherein R.sup.e may be, for
example, --H, -Me, -Et, --Pr or --Bu. In other desirable
embodiments of the invention, R.sup.3 is --(C.sub.0-C.sub.6
alkyl)C(O)NHR.sup.a, --(C.sub.0-C.sub.3 alkyl)C(O)NHR.sup.a, or
--(C.sub.1-C.sub.2 alkyl)C(O)NHR.sup.a, wherein R.sup.a may be, for
example, --H, -Me, -Et, --Pr or --Bu.
[0096] In this aspect of the invention, The R.sup.3 group may be
attached to the piperazine ring in an S configuration, or an R
configuration. The compound or salt may exist as a racemic mixture,
a scalemic mixture, or an enantiomerically- or
diastereomerically-enriched mixture having at least about 80%
enantiomeric or diastereomeric excess at the carbon of attachment
of the R.sup.3 group to the piperazine.
[0097] In certain embodiments according to this aspect of the
invention, R.sup.4 is --H. In other desirable embodiments, w, x and
y are each zero.
[0098] In other preferred embodiments, the alk groups are
alkyl.
[0099] Another aspect of the invention relates to a compound having
the structure of Formula
##STR00005##
and pharmaceutically acceptable salts thereof.
[0100] The structure of Formula (III) is also based on a
dibenzo[b,f][1,4]oxazapine core having the numbering system shown
above in Formula (II).
[0101] In embodiments of this aspect of the invention, R.sup.1 is
attached at the 8 position of the dibenzo[b,f][1,4]oxazapine, while
R.sup.2 is attached at the 2 position. R.sup.1 and R.sup.2 are
independently --Cl, --F, --Br, --I or --H. According to a desirable
embodiment of the invention, at least one of R.sup.1 and R.sup.2 is
--F, --Cl, --Br or --I. More desirably, only one of R.sup.1 and
R.sup.2 is --F, --Cl, --Br or --I, and the other is --H.
[0102] The piperazine is substituted with R.sup.3 at a carbon
distal from the dibenzo[b,f][1,4]oxazapine, as shown in Formula
(III), or the 3' position. R.sup.3 may be --R (nonoptionally
substituted in this instance at R.sup.3), --(C.sub.0-C.sub.6
alk)C(O)OR.sup.e, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)-OR,
--(C.sub.0-C.sub.6 alk)C(O)R.sup.k, or --(C.sub.0-C.sub.6
alk)-NR.sup.aR.sup.19, in which in which R, R.sup.e, R.sup.a,
R.sup.19, Ar, Het, Hca, Cak are as described below. Each alk group
may be, for example, an alkyl group. In desirable embodiments of
the invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)N R.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)C(O)NR.sup.20,
--(C.sub.0-C.sub.6 alk)Ar, or --(C.sub.0-C.sub.6
alk)-O--(C.sub.0-C.sub.6 alk)Ar. In other desirable embodiments of
the invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
In further desirable embodiments of the invention, R.sup.3 is
--(C.sub.0-C.sub.6 alk)C(O)OR.sup.e. In yet further desirable
embodiments of the invention, R.sup.3 is --(C.sub.0-C.sub.6
alk)C(O)OR.sup.e in which the --(C.sub.0-C.sub.6 alk) is
--(C.sub.1-C.sub.6 alk), --(C.sub.1-C.sub.4 alk) or
--(C.sub.1-C.sub.2 alk).
[0103] Other desirable R.sup.3 substituents have gem-dialkyl or a
monoalkyl substitution alpha to a functional group, e.g., a
carbonyl carbon. Accordingly, in certain desirable embodiments of
the invention, each (C.sub.0-C.sub.6 alkyl) connected directly to
the piperazine ring as part of R.sup.3 is a --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2-, in which (C.sub.0-C.sub.5
alkyl) is independently optionally substituted with 1 or 2
substitutents selected independently from --(C.sub.1-C.sub.4
alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH, .dbd.O, -halogen,
--C(O)O(C.sub.1-C.sub.3 alkyl) and --C(O)(C.sub.1-C.sub.3 alkyl);
and is optionally halogenated.
[0104] In certain especially desirable embodiments of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
In these embodiments, each C.sub.0-C.sub.6 alkyl connected directly
to the piperazine ring as part of R.sup.3 may be, for example,
C.sub.2-C.sub.6 alkyl, or alternatively C.sub.1-C.sub.2 alkyl. In
certain embodiments of the invention R.sup.3 is --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)OR.sup.e,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.aR.sup.19,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.19.sub.2, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.20,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2Ar,
--(C.sub.0-C.sub.6 alk)-O--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2Ar, --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2CR, --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)R.sup.k, or --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2NR.sup.aR.sup.19.
[0105] The R.sup.3 group will form a stereogenic center on the
piperazine ring. The R.sup.3 group may be attached to the
piperazine ring in an S configuration, or an R configuration. The
compound or salt may exist as a racemic mixture, a scalemic
mixture, or an enantomerically- or diastereomerically-enriched
mixture having at least about 80% enantiomeric or diastereomeric
excess at the carbon of attachment of the R.sup.3 group to the
piperazine.
[0106] The piperazine is substituted with R.sup.4 at the nitrogen
distal from the dibenzo[b,f][1,4]oxazapine, as shown in Formula
(I). R.sup.4 may be, for example, --H or --R. In certain especially
desirable embodiments of the invention, R.sup.4 is H.
[0107] In the compounds according to this aspect of the invention,
each R.sup.e, R.sup.a, R.sup.k, Cak, Ar, Het, Hca are defined as in
the section under Formulae (I) and (II) above.
[0108] In the compounds according to this aspect of the invention,
each R.sup.10 and R.sup.11 is independently --H or --R, in which
--R is as described below.
[0109] In the compounds according to this aspect of the invention,
each R.sup.19 is independently selected from --H, --OH and --R, in
which R is as described below. Each alk group may be, for example,
an alkyl group.
[0110] In the compounds according to this aspect of the invention,
each R.sup.20 is a Hca or Het ring wherein that N from the
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.20, is a heteroatom in the Hca or
Het ring, the ring optionally substituted with 1 or 2 substituents
independently selected from .dbd.O, --(C.sub.1-C.sub.6 alkoxy),
--OH, or -halogen; --(C.sub.1-C.sub.6 haloalkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alk), and --C(O)--(C.sub.1-C.sub.6
alk).
[0111] In the compounds according to this aspect of the invention,
each R is independently --(C.sub.1-C.sub.8 alk), --(C.sub.3-C.sub.8
cycloalk), --(C.sub.3-C.sub.12 heterocycloalk), --(C.sub.1-C.sub.8
haloalkyl), or --(C.sub.3-C.sub.8 halocycloalk), optionally
substituted with 1, 2 or 3 substituents independently selected from
--(C.sub.1-C.sub.6 alkoxy), --(C.sub.1-C.sub.6 hydroxyalkyoxy),
--(C.sub.1-C.sub.6 hydroxyalkyl), acetoxyalkyl,
--C(O)O(C.sub.1-C.sub.6 alkyl), --OH, .dbd.O, --N(C.sub.1-C.sub.6
alkyl).sub.2, --NH(C.sub.1-C.sub.6 alk), --NH.sub.2,
--OC(O)(C.sub.0-C.sub.6 alk), --SO.sub.2--(C.sub.1-C.sub.6 alk),
and --CO--(C.sub.0-C.sub.6 alk). Each --(C.sub.1-C.sub.8 haloalkyl)
or --(C.sub.3-C.sub.8 halocycloalk), may be further optionally
substituted with from 1 to 6 additional halogens. Each alk group
may be, for example, an alkyl group.
[0112] In the compounds according to this aspect of the invention,
each (C.sub.0-C.sub.6 alk), (C.sub.1-C.sub.6 alk), and
--(C.sub.1-C.sub.8 alk) is independently optionally substituted
with 1, 2, 3 or 4 substitutents selected independently from
--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4 alkoxy), --OH,
.dbd.O, -halogen, --C(O)O(C.sub.1-C.sub.3 alkyl) and
--C(O)(C.sub.1-C.sub.3 alkyl); and is optionally halogenated. Each
alk group may be, for example, an alkyl group.
[0113] In this aspect of the invention, one or more of the alk
groups may be alkenyl groups or alkynyl groups. In certain
embodiments of the invention, at least one of the alk groups is an
alkenyl group or an alkynyl group. Alternatively, in certain
desirable embodiments of the invention, all of the alk groups are
alkyl groups.
[0114] In desirable compounds according to this aspect of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alk)C(O)OR.sup.e,
--(C.sub.0-C.sub.6 alk)C(O)NR.sup.a.sub.2, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.6
alk)C(O)NR.sup.19.sub.2, or --(C.sub.0-C.sub.6 alk)-C(O)NR.sup.20.
More desirably, R.sup.3 is --(CH.sub.2).sub.pCO.sub.2R.sup.e,
--(CH.sub.2).sub.pCONR.sup.a.sub.2,
--(CH.sub.2).sub.pC(O)NR.sup.aR.sup.19,
--(CH.sub.2).sub.pC(O)NR.sup.20, or
--(CH.sub.2).sub.pCONR.sup.19.sub.2 in which p is 0, 1, 2, 3, 4, 5
or 6. For example, p may be 1 or 2. In certain desirable
embodiments of the invention, the R.sup.3 group has gem-dialkyl
substitution alpha to its functional group. As such, each
(C.sub.0-C.sub.6 alkyl) connected directly to the piperazine ring
as part of R.sup.3 is desirably a --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2- group. For example, R.sup.3
may be --(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)OR.sup.e, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.a.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.aR.sup.19, --(C.sub.0-C.sub.5
alkyl)C(C.sub.1-C.sub.3 alkyl).sub.2C(O)NR.sup.19.sub.2,
--(C.sub.0-C.sub.5 alkyl)C(C.sub.1-C.sub.3
alkyl).sub.2C(O)NR.sup.20,
--(CH.sub.2).sub.qCR.sup.d.sub.2CO.sub.2R.sup.e,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.a.sub.2,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.19.sub.2,
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.aR.sup.19, or
--(CH.sub.2).sub.qCR.sup.d.sub.2CONR.sup.20, wherein q is 0, 1, 2,
3, 4 or 5, and each R.sup.d is individually -Me, -Et or --Pr. q is
desirably 0, 1 or 2. In especially desirable embodiments of the
invention, R.sup.3 is --(C.sub.0-C.sub.6 alkyl)C(O)OR.sup.e.
R.sup.e may be, for example, --H, -Me, -Et, --Pr or -Bu. In further
especially desirable embodiments of the invention, R.sup.3 is
--(C.sub.0-C.sub.3 alkyl)C(O)OR.sup.e, wherein R.sup.e may be, for
example, --H, -Me, -Et, --Pr or -Bu. In yet further especially
desirable embodiments of the invention, R.sup.3 is
--(C.sub.1-C.sub.2 alkyl)C(O)OR.sup.e, wherein R.sup.e may be, for
example, --H, -Me, -Et, --Pr or --Bu. In other desirable
embodiments of the invention, R.sup.3 is --(C.sub.0-C.sub.6
alkyl)C(O)NHR.sup.a, --(C.sub.0-C.sub.3 alkyl)C(O)NHR.sup.a, or
--(C.sub.1-C.sub.2 alkyl)C(O)NHR.sup.a, wherein R.sup.a may be, for
example, --H, -Me, -Et, --Pr or -Bu.
[0115] In this aspect of the invention, The R.sup.3 group may be
attached to the piperazine ring in an S configuration, or an R
configuration. The compound or salt may exist as a racemic mixture,
a scalemic mixture, or an enantomerically- or
diastereomerically-enriched mixture having at least about 80%
enantiomeric or diastereomeric excess at the carbon of attachment
of the R.sup.3 group to the piperazine.
[0116] In certain embodiments according to this aspect of the
invention, R.sup.4 is --H.
[0117] Another aspect of the invention relates to a compound having
the structure of Formula
##STR00006##
or a pharmaceutically acceptable salt thereof, in which R.sup.1 and
R.sup.2 are independently --Cl, --F, --Br, --I or --H, with the
proviso that at least one of R.sup.1 and R.sup.2 is --Cl, --F, --Br
or --I; R.sub.4 is --H or --R; R.sup.8 is --H, -Me, -Et or --Pr;
R.sup.9 is --H, -Me, -Et or --Pr; B is O or NH, and R.sup.12 is
--H, -Me, -Et or --Pr. In certain desirable embodiments of the
invention, B is O. In certain desirable embodiments of the
invention, R.sup.8 and R.sup.9 are both -Me. In certain other
desirable embodiments of the invention, R.sup.8 and R.sup.9 are
both -Et. In certain other desirable embodiments of the invention,
one of R.sup.8 and R.sup.9 is --H and the other is -Me, -Et or
--Pr. The --Cl may be attached at the 7 position of the
dibenzo[b,f][1,4]oxazepine or at the 8 position of the
dibenzo[b,f][1,4]oxazepine. In other desirable embodiments of the
invention, R.sub.4 is --H.
[0118] Another aspect of the invention relates to compounds having
one of the following structures, or pharmaceutically acceptable
salts thereof:
TABLE-US-00001 Compound Cmpnd (E)-ethyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)ace-
tate; A (E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-N- isobutylacetamide ##STR00007## B (E)-ethyl
2-(4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)ace-
tate C * (S) or (R) at stereocenter; (R,E)-methyl 4-((4-(2-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)methoxy)benzoate ##STR00008## D
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic
acid; E (E)-ethyl 4-(2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)ethyl)benzoate ##STR00009## F (E)-methyl
4-((4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)methoxy)benzoate ##STR00010## G (E)-ethyl
2-(4-(7- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)acetate ##STR00011## H (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)ac-
etate; I (E)-ethyl 2-(4-(7- fluorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)acetate ##STR00012## J (S,E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00013## K (E)-isopropyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00014## L (E)-isopropyl 2-(4-(7-
fluorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00015## M (S,E)-methyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00016## N (R,E)-ethyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetate;
O (R,E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetate;
P (S,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)acetic acid ##STR00017## Q (R)-2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoic
acid ##STR00018## R (S)-2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoic
acid ##STR00019## S
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)b-
utanoic acid; T
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)b-
utanoic acid; U (S,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoic acid ##STR00020## X
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethy-
lbutanoic acid; Y (R,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetic acid
##STR00021## AB (R)-2-((R)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoic
acid ##STR00022## AC (S)-2-((R)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoic
acid ##STR00023## AD (R)-2-((R)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoic acid
##STR00024## AE (S)-2-((R)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoic acid
##STR00025## AF (R,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoic acid ##STR00026## AI
(R,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-ethylbutanoic acid ##STR00027## AJ
(2R)-2-(4-((E)-2- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)propanoic acid * (S) or (R) at stereocenter
##STR00028## AM (2S)-2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoic
acid * (S) or (R) at stereocenter ##STR00029## AN (2R)-2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoic acid
* (S) or (R) at stereocenter ##STR00030## AO (2S)-2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoic acid
* (S) or (R) at stereocenter ##STR00031## AP (E)-2-(4-(2-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoic acid * (S) or (R) at
stereocenter ##STR00032## AS (E)-2-(4-(2-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-ethylbutanoic acid * (S) or (R) at
stereocenter ##STR00033## AT (E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate
##STR00034## AW (E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoate
##STR00035## AX (E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)pentanoate
##STR00036## AY (E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoate ##STR00037## AZ (E)-ethyl
2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-ethylbutanoate ##STR00038## BA (E)-ethyl
2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylbutanoate ##STR00039## BB (2R)-ethyl
2-(4-((E)-2- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)propanoate * (S) or (R) at stereocenter
##STR00040## BC (2S)-ethyl 2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate *
(S) or (R) at stereocenter ##STR00041## BD (2R)-ethyl 2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoate *
(S) or (R) at stereocenter ##STR00042## BE (2S)-ethyl 2-(4-((E)-2-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)butanoate *
(S) or (R) at stereocenter ##STR00043## BF (E)-ethyl 2-(4-(2-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoate * (S) or (R) at stereocenter
##STR00044## BI (E)-ethyl 2-(4-(2-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-ethylbutanoate * (S) or (R) at stereocenter
##STR00045## BJ (R)-ethyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)propanoate; BM (S)-ethyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)propanoate; BN (R)-ethyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)butanoate; BO (S)-ethyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)butanoate; BP (R,E)-ethyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-methylpro-
panoate; BS (R,E)-ethyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethylbuta-
noate; BT (S)-ethyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate;
##STR00046## BW (R)-ethyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate
##STR00047## BX (S)-ethyl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)butanoate; BY (R)-ethyl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin--
2-yl)butanoate; BZ (S,E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoate ##STR00048## CC (S,E)-ethyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethylbuta-
noate; CD (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)pr-
opanoate; CG (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)bu-
tanoate; CH (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)pe-
ntanoate; CI (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-
-methylpropanoate; CJ (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-
-ethylbutanoate; CK (E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-
-methylbutanoate; CL
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)propanoic
acid; CM
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)butanoic
acid; CN
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)pentanoic
acid; CO
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-methyl-
propanoic acid; CP
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethylb-
utanoic acid; CQ
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-methyl-
butanoic acid; CR (R)-methyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)propanoate; CS (S)-methyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)propanoate; CT (R)-methyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)butanoate; CU (S)-methyl
2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)butanoate; CV (R,E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-methylpro-
panoate; CY (R,E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethylbuta-
noate; CZ (S)-methyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate
##STR00049## DC (R)-methyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)propanoate
##STR00050## DD (R)-methyl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)butanoate; DE (S)-methyl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-
-2-yl)butanoate; DF (S,E)-methyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-2-methylpropanoate ##STR00051## DI (S,E)-methyl
2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethylbuta-
noate; DJ (E)-methyl 2-((4-(2- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2- yl)methoxy)acetate ##STR00052## DM
(E)-ethyl 2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)acetate ##STR00053## DN (E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)acetic acid ##STR00054## DO (E)-methyl
2-(4-(8- (trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)acetate ##STR00055## DQ (S,E)-cyclopentyl
2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)acetate ##STR00056## DR (S)-quinuclidin-3-yl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazin--
2-yl)acetate; DS (R)-quinuclidin-3-yl 2-((S)-4-((E)- 8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00057## DT (S)-quinuclidin-3-yl 2-((S)-4-((E)- 8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00058## DU (S,E)-tetrahydro-2H-pyran-4-yl 2- (4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00059## DV (S,E)-methyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)-1-methylpiperazin-2-
yl)acetate ##STR00060## DW (S,E)-cyclopentyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)-1-methylpiperazin-2-
yl)acetate ##STR00061## DX sec-butyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)-1-methylpiperazin-2-
yl)acetate ##STR00062## DY (S,E)-tetrahydro-2H-pyran-4-yl 2- (4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)-1-methylpiperazin-2-
yl)acetate ##STR00063## DZ (S,E)-neopentyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00064## EA (S,E)-3-methoxy-3-methylbutyl 2- (4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00065## EB (S,E)-3-hydroxy-3-methylbutyl 2- (4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
##STR00066## EC (R)-4-hydroxy-4-methylpentan-2-yl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acet-
ate; ED (S)-((R)-4-hydroxy-4-methylpentan-2-yl)
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)prop-
anoate; EE (R)-((R)-4-hydroxy-4-methylpentan-2-yl)
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)prop-
anoate; EF (S)-((R)-4-hydroxy-4-methylpentan-2-yl)
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)buta-
noate; EG (R)-((R)-4-hydroxy-4-methylpentan-2-yl)
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)buta-
noate; EH (R)-4-hydroxy-4-methylpentan-2-yl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-m-
ethylpropanoate; EK (R)-4-hydroxy-4-methylpentan-2-yl
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-e-
thylbutanoate; EL (2S,4S)-4-hydroxypentan-2-yl 2-((S)- 4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00067## EO sec-butyl 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00068## EP (S)-tetrahydrofuran-3-yl 2-((S)-4-((E)-
8-chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)acetate
##STR00069## EQ (S,E)-ethyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-isopentylpiperazin-2-yl)acetate ##STR00070## ER
(R)-1-methylpyrrolidin-3-yl 2-((S)-4- ((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)acetate ##STR00071## ES (S,E)-methyl
2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-(cyclopropylmethyl)piperazin-2- yl)acetate ##STR00072## ET
(S,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)-N- (2,2,3,3,3-
pentafluoropropyl)acetamide ##STR00073## EU (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)-N-(1,3- difluoropropan-2-yl)acetamide
##STR00074## EV (S,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)-N,N- bis(2,2,2-trifluoroethyl)acetamide
##STR00075## EW (S,E)-3-fluoropropyl 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-methylpiperazin-2-yl)acetate ##STR00076## EX
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(1-h-
ydroxy-2-methylpropan-2-yl)acetamide; EY (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-N-(2-
hydroxyethyl)-N-propylacetamide ##STR00077## EZ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(2-h-
ydroxyethyl)acetamide; FA
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-((-
R)-2-hydroxypropyl)acetamide; FB
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(2-m-
ethoxyethyl)acetamide; FC
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(2-methoxyethyl)propanamide; FD
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(2-methoxyethyl)propanamide; FE
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(2-methoxyethyl)butanamide; FF
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(2-methoxyethyl)butanamide; FG
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(2-m-
ethoxyethyl)-2-methylpropanamide; FJ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethy-
l-N-(2-methoxyethyl)butanamide; FK
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(2-(-
2-hydroxyethoxy)ethyl)acetamide; FN (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-N-(2-
hydroxyethyl)-N-methylacetamide ##STR00078## FO (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-N-(6-
methoxypyridin-3-yl)acetamide ##STR00079## FP (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-N-(2,2-
difluoroethyl)acetamide ##STR00080## FQ
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-((-
(S)-tetrahydrofuran-2-yl)methyl)acetamide; FR
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(3-h-
ydroxypropyl)acetamide; FS
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(3-hydroxypropyl)propanamide; FT
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(3-hydroxypropyl)propanamide; FU
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(3-hydroxypropyl)butanamide; FV
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)--
N-(3-hydroxypropyl)butanamide; FW
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-N-(3-h-
ydroxypropyl)-2-methylpropanamide; FZ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-2-ethy-
l-N-(3-hydroxypropyl)butanamide; GA (S,E)-2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-N-(3-
methoxypropyl)acetamide ##STR00081## GD 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-1-((R)-3-
hydroxypyrrolidin-1-yl)ethanone ##STR00082## GE 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11-
yl)piperazin-2-yl)-N-(3,3,3-trifluoro- 2-hydroxypropyl)acetamide
##STR00083## GF
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)-1-morp-
holinoethanone; GG 2-((S)-4-((E)-8-
chlorodibenzo[b,f][1,4]oxazepin-11- yl)piperazin-2-yl)-1-((S)-2-
(trifluoromethyl)pyrrolidin-1- yl)ethanone ##STR00084## GH
(S,E)-2-(4-(8- chlorodibenzo[b,f][1,4]oxazepin-11-
yl)-1-(2-hydroxyethyl)piperazin-2-yl)- N-(2-methoxyethyl)acetamide
##STR00085## GI
[0119] All names and structures were generated using ChemDraw Ultra
v. 9.01, which is available from Cambridgesoft
(www.cambridgesoft.com).
[0120] Another aspect of the invention relates to the compounds
recited herein that are hydroxylated one or more times at positions
1-4 or 6-9 according to the numbering illustrated in Formula
(V)
##STR00086## [0121] wherein the hydroxyl group replaces a H.
[0122] Another aspect of the invention relates to methods for
preparing a compound of Formula F
##STR00087## [0123] comprising converting a compound of formula
(A)
[0123] ##STR00088## [0124] or its salt to a compound of formula
(B)
[0124] ##STR00089## [0125] or it's salt, respectively, wherein
Z.sub.1 and Z.sub.2 are nitrogen protecting groups (wherein
commonly known and used N protecting groups can be used, e.g.,
N-benzyl; N-nitrobenzyl; N-BoC; N-oxide; N-paramethoxybenzyl;
N-benzylsulfonyl; N-carbobenzyloxy (N--CBZ)); converting compound
of formula (B)
[0125] ##STR00090## [0126] to an acid chloride followed by
converting to the corresponding diazide, formula (C)
[0126] ##STR00091## [0127] wherein Z.sub.1 and Z.sub.2 are again
nitrogen protecting groups; treating a compound of formula (C)
[0127] ##STR00092## [0128] with a silver catalyst and an alcohol to
make formula (D)
[0128] ##STR00093## [0129] wherein Z.sub.1 and Z.sub.2 are nitrogen
protecting groups, R.sup.e is as defined for Formula I herein, here
in the form of an ester. In additional embodiments of the
invention, R.sup.e can be --(C.sub.1-C.sub.6 alk),
--(C.sub.1-C.sub.6 alk)-OR, --(C.sub.1-C.sub.6 alk)-OH,
--(C.sub.0-C.sub.6 alk)C(O)OR, --(C.sub.1-C.sub.6
alk)-NR.sup.19.sub.2, --(C.sub.0-C.sub.6 alk)Hca,
--(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Het, or
--(C.sub.0-C.sub.6 alk)Cak. In further embodiments of the
invention, R.sup.e can be --(C.sub.1-C.sub.6 alk),
--(C.sub.1-C.sub.4 alk), --(C.sub.1-C.sub.2 alk), or --(C.sub.2
alk); deprotecting a compound of formula (D)
[0129] ##STR00094## [0130] or its salt to a compound of formula
(E)
[0130] ##STR00095## [0131] or it's salt, respectively; alkylating a
compound of formula (E)
[0131] ##STR00096## [0132] or its salt with a compound of formula
(G)
[0132] ##STR00097## [0133] or it's salt to a compound of formula
(F)
[0133] ##STR00098## [0134] or it's salt, respectively, wherein
R.sub.2 and R.sub.1 are independently H, I, Br, Cl, or I, and
wherein in each instance the bond between the piperizine and
carbonyl moiety is racemic, R or S. R.sup.e is as defined for
Formula I herein. In additional embodiments of the invention,
R.sup.e can be --(C.sub.1-C.sub.6 alk), --(C.sub.1-C.sub.6 alk)-OR,
--(C.sub.1-C.sub.6 alk)-OH, --(C.sub.0-C.sub.6 alk)C(O)OR,
--(C.sub.1-C.sub.6 alk)-NR.sup.19.sub.2, --(C.sub.0-C.sub.6
alk)Hca, --(C.sub.0-C.sub.6 alk)Ar, --(C.sub.0-C.sub.6 alk)Het, or
--(C.sub.0-C.sub.6 alk)Cak. In further embodiments of the
invention, R.sup.e can be --(C.sub.1-C.sub.6 alk),
--(C.sub.1-C.sub.4 alk), --(C.sub.1-C.sub.2 alk), or --(C.sub.2
alk). See Example 1 for an example synthesis.
[0135] Another aspect of the invention relates to methods of
treating various disorders related to affector binding at the
receptors recited elsewhere herein. Exemplary indications for each
of the compounds, salts and compositions recited herein include one
or more of the following: acute treatment and maintenance of
treatment for: schizophrenia, treatment-resistant schizophrenia,
pediatric schizophrenia, cognitive symptoms or impairment (e.g.,
problems in speed of processing, attention/vigilance, working
memory, verbal learning, visual learning, reasoning and problem
solving, and social cognition), negative symptoms (e.g., flattened
or masked affect, alogia, avolition, anhedonia, and attentional
impairment), bipolar disorder, pediatric bipolar disorder,
depression, psychotic depression, treatment-resistant depression,
treatment of obsessive-compulsive disorder (OCD), autism, senile
psychosis, psychotic dementia, L-DOPA induced psychosis,
psychogenic polydipsia, other delusional states (e.g., erotomania,
secondary alcoholism, etc), psychotic symptoms associated with
neurological disoreders (e.g. Huntington's Chorea, Wilson's
Disease), sleep disorders, depressed states associated with
schizophrenia (e.g., in suicidal patients; suicidiality),
agitation, attention deficit disorder (ADD) and attention deficit
hyperactivity disorder (ADHD), atypical psychosis, mania,
schizophreniform disorder, drug- or substance-induced psychotic
disorder, schizoaffective disorder, cluster A personality
disorders, delusional disorder, and brief psychotic disorder.
Compounds, salts and compositions of the invention can be used
alone, in combination therapy, i.e., with each other or in
combination with other agents, e.g., antidepressants,
antipsychotics, etc. The invention also relates to combination
therapy utilizing compounds, salts and composition of the invention
with nicotine.
[0136] "Combination therapy" (or "co-therapy") includes the
administration of a compound, salt or composition of the invention
and at least a second agent as part of a specific treatment regimen
intended to provide the beneficial effect from the co-action of
these therapeutic agents. The beneficial effect of the combination
includes, but is not limited to, pharmacokinetic or pharmacodynamic
co-action resulting from the combination of therapeutic agents.
Combinations of the compounds of the present invention and the
other active agents may be administered together in a single
combination or separately. Where separate administration is
employed, the administration of one element may be prior to,
concurrent with, or subsequent to the administration of other
agents. Administration of these therapeutic agents in combination
typically is carried out over a defined time period (usually
minutes, hours, days or weeks depending upon the combination
selected). In one embodiment, "combination therapy" encompasses the
administration of two or more of these therapeutic agents as part
of separate monotherapy regimens that incidentally and arbitrarily
result in the combinations of the present invention. In another
embodiment, "combination therapy" is intended to embrace
administration of these therapeutic agents in a sequential manner,
that is, wherein each therapeutic agent is administered at a
different time, as well as administration of these therapeutic
agents, or at least two of the therapeutic agents, in a
substantially simultaneous manner. Substantially simultaneous
administration can be accomplished, for example, by administering
to the subject a single capsule having a fixed ratio of each
therapeutic agent or in multiple, single capsules for each of the
therapeutic agents. Sequential or substantially simultaneous
administration of each therapeutic agent can be effected by any
appropriate route including, but not limited to, oral routes,
intravenous routes, intramuscular routes, and direct absorption
through mucous membrane tissues.
[0137] The therapeutic agents can be administered by the same route
or by different routes. For example, a first therapeutic agent of
the combination selected may be administered by intravenous
injection while the other therapeutic agents of the combination may
be administered orally. Alternatively, for example, all therapeutic
agents may be administered orally or all therapeutic agents may be
administered by intravenous injection. The sequence in which the
therapeutic agents are administered is not narrowly critical.
"Combination therapy" also embraces the administration of the
therapeutic agents as described above in further combination with
other biologically active ingredients and non-drug therapies (e.g.,
surgery, radiation treatment, or a medical device). Where the
combination therapy further comprises a non-drug treatment, the
non-drug treatment may be conducted at any suitable time so long as
a beneficial effect from the co-action of the combination of the
therapeutic agents and non-drug treatment is achieved. For example,
in appropriate cases, the beneficial effect is still achieved when
the non-drug treatment is temporally removed from the
administration of the therapeutic agents, perhaps by days or even
weeks.
[0138] "Treating" includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder, etc. "Treating" or "treatment" of a
disease state includes: (1) preventing the disease state, i.e.,
causing the clinical symptoms of the disease state not to develop
in a subject that may be exposed to or predisposed to the disease
state, but does not yet experience or display symptoms of the
disease state; (2) inhibiting the disease state, i.e., arresting
the development of the disease state or its clinical symptoms; or
(3) relieving the disease state, i.e., causing temporary or
permanent regression of the disease state or its clinical symptoms.
"Disease state" means any disease, condition, symptom, or
indication.
[0139] As used herein, the term "sleep disorder" includes
conditions recognized by one skilled in the art as sleep disorders,
for example, conditions known in the art or conditions that are
proposed to be sleep disorders or discovered to be sleep disorders.
A sleep disorder also arises in a subject that has other medical
disorders, diseases, or injuries, or in a subject being treated
with other medications or medical treatments, where the subject, as
a result, has difficulty falling asleep and/or remaining asleep, or
experiences unrefreshing sleep or non-restorative sleep, e.g., the
subject experiences sleep deprivation. Treating a sleep disorder
with one or more compounds, salts or compositions herein, alone or
in combination, also includes treating a sleep disorder component
of other disorders, such as CNS disorders (e.g., mental or
neurological disorders such as anxiety).
[0140] Dosage rates and routes of administration of the disclosed
compounds are similar to those already used in the art and known to
the skilled artisan (see, for example, Physicians' Desk Reference,
54th Ed., Medical Economics Company, Montvale, N.J., 2000).
[0141] The compounds of general Formulae I, III, IV and -V of the
invention 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. The term parenteral as used
herein includes percutaneous, subcutaneous, intravascular (e.g.,
intravenous), intramuscular, or intrathecal injection or infusion
techniques and the like. In addition, there is provided a
pharmaceutical formulation comprising a compound of general
Formulae I, III, IV and -V and a pharmaceutically acceptable
carrier. One or more compounds of general Formulae I, III, IV and
-V 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, e.g., other
antidepressant or antipsychotic drugs. The pharmaceutical
compositions containing compounds of general Formulae I, III, IV
and -V 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 and as such, may be combined with at least one
pharmaceutically acceptable glidant, solvent, adjuvant, diluent,
lubricant, excipient, or combination thereof.
[0142] 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 preservative 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. In some cases such coatings may be
prepared 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. Further, delayed release formulations without one or more
coatings may be prepared.
[0143] 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.
[0144] Formulations for oral use may also be presented as
lozenges.
[0145] 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,
hydropropyl-methylcellulose, 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.
[0146] 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
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.
[0147] 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 or suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0148] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil or a mineral oil 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.
[0149] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol, glucose 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 that have been mentioned above. The sterile
injectable preparation may also be a 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.
[0150] The compounds of general Formulae I, III, IV and -V 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 include cocoa butter and polyethylene glycols.
[0151] Compounds of general Formulae I, III, IV and -V 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.
[0152] The formulations may also be applied as a topical gel,
spray, ointment or cream, or as a suppository, containing the
active ingredients in a total amount of, for example, 0.075 to 30%
w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment
base.
[0153] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane. The
transdermal patch may include the compound in a suitable solvent
system with an adhesive system, such as an acrylic emulsion, and a
polyester patch. The oily phase of the emulsions of this invention
may be constituted from known ingredients in a known manner. While
the phase may comprise merely an emulsifier, it may comprise a
mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make-up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others. The choice of suitable oils or fats for the
formulation is based on achieving the desired cosmetic properties,
since the solubility of the active compound in most oils likely to
be used in pharmaceutical emulsion formulations is very low. Thus,
the cream should preferably be a non-greasy, non-staining and
washable product with suitable consistency to avoid leakage from
tubes or other containers. Straight or branched chain, mono- or
dibasic alkyl esters such as di-isoadipate, isocetyl stearate,
propylene glycol diester of coconut fatty acids, isopropyl
myristate, decyl oleate, isopropyl palmitate, butyl stearate,
2-ethylhexyl palmitate or a blend of branched chain esters may be
used. These may be used alone or in combination depending on the
properties required. Alternatively, high melting point lipids such
as white soft paraffin and/or liquid paraffin or other mineral oils
can be used.
[0154] 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 conditions indicated below (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. The daily
dose can be administered in one to four doses per day.
[0155] 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.
[0156] For administration to non-human animals, the composition may
also be added to the animal feed or drinking water. It may be
convenient to formulate the animal feed and drinking water
compositions so that the animal takes in a therapeutically
appropriate quantity of the composition along with its diet. It may
also be convenient to present the composition as a premix for
addition to the feed or drinking water.
Example 1
Preparation of Compound K and Additional Esters
##STR00099##
[0158] In a 2 liter 3-neck flask, dissolve 20 g (98.5 mmol) of
R-piperazinecarboxylic acid dihydrochloride (1) in 500 mL water and
500 mL stabilized dioxane. Cool with an ice bath and add
phenolphthalein indicator. Using an addition funnel, add conc. NaOH
to pH 10 (solution just turns pink). Using a second addition
funnel, add 30.6 mL (216.7 mmol) benzyl chloroformate in portions
while maintaining the pink color (pH 10) with conc. NaOH. Add more
phenolphthalein halfway through the addition which takes about 0.5
hr. Stir overnight at room temperature (RT). Extract with 1 liter
of ether. Acidify the ice cooled aqueous layer with 6 N HCl and
extract with ethyl acetate. Wash with brine and dry over magnesium
sulfate. Concentrate to about 40 g oil. No loss of optical purity
was confirmed by chiral HPLC.
##STR00100##
[0159] Dissolve 19.5 g (49.0 mmol) 2 in 200 mL anhydrous toluene
(SM can be azeotropically dried with toluene if necessary). Chill
over ice, under nitrogen. Add 1 mL DMF and 8.55 mL (98.0 mmol)
oxalyl chloride over 1 min. Stir cold about 1 hour then at RT for
about 1.5 hr. Gently sparge with nitrogen to remove HCl. Check for
remaining SM by quenching a sample with pyrrolidine, shaking with a
dilute HCl solution. and ethyl acetate (EA). TLC the EA layer using
50:10:1 DCM/MeOH/NH.sub.4OH. Additional oxalyl chloride is added as
necessary to consume all SM. Decant or filter if necessary (toluene
wash) discarding insoluble material. Concentrate at about 30 C to
an orange syrup. Dissolve in 200 mL anhydrous acetonitrile and
chill over ice, under nitrogen. A 2M solution of
TMS-diazomethane/ether is added rapidly. After a brief induction
period, nitrogen is evolved. Stir cold for about 1 hour and
concentrate at 40 C to an oil. Dissolve in EA and wash with sodium
bicarbonate solution, brine, and dry over sodium sulfate. The
sample was concentrated to about 21 g amber syrup. Use
directly.
##STR00101##
[0160] Dissolve 21 g (.about.49 mmol) 4 in 200 mL ethanol. Add a
solution of 2.2 g (9.8 mmol) silver benzoate in 27 mL (196 mmol)
TEA while reaction mixture is sonicated in a standard water bath
sonicator. Addition is completed in about 5 minutes, pausing
several times to swirl the mixture. Nitrogen is evolved and a brown
ppt forms. Sonicate for about 15 minutes then concentrate to an
oil. Dissolve in EA and filter through a plug of silica. The
described sample was chromatographed on 250 g silica eluting with
1:1 EA/hexane to give 18.4 g lt. brown oil.
##STR00102##
[0161] Dissolve 18 g (39 mmol) of 6 in 400 mL EtOH and add 1.8 g
10% Pd/C as a slurry in EtOH. Hydrogenating on a Parr apparatus for
about 12 hours, then filtering through celite and concentrating
yielded about 5.2 g oil, which forms a waxy crystalline solid on
standing. Use as is.
##STR00103##
[0162] Combine 5 g (29 mmol) of ethyl piperazine-2-acetate, 4.7 g
(29 mmol) chloroimidate and 12 ml, 3 eq. TEA in 100 mL EA/20 ml
EtOH and heat at about 80 C for about 36 hours. The reaction
mixture is then concentrated on rotovap, partitioned between EA and
dil. sodium carbonate solution, and washed with brine. Dry over
sodium sulfate. Chromatographing on silica gel, eluting with 1%
(10% TEA/EtOH)/EA to remove remaining starting material and
increasing to 3% (10% TEA/EtOH) then 5% (10% TEA/EtOH), yielded 4.2
g product as a yellow foam.
Example 2
Preparation of Additional 3'-(S) Substituted Esters
##STR00104##
[0164] Dissolve 1.2 g (3 mmol) Compound K in 30 ml THF. Add 720 mg
(3.3 mmol) BOC-anhydride and heat at RT for about 5 hrs, then at 80
C for about 12 hr. Cool over ice and add 30 ml MeOH and 10 ml of 4
N KOH solution and stir RT overnight. Adjust to pH 3 with 1 M
citric acid solution and extract into MTBE. Wash with brine and dry
over sodium sulfate. Concentrate to about 1.4 g tan solid and use
as is for the synthesis of different esters according to the
invention. Use standard Boc deprotection conditions for Boc
removal, e.g., TFA/DCM or 1M HCl/EtOH or, e.g., 1M HCL/dioxane-EA
for higher ester.
Example 3
Preparation of Compound ED
##STR00105##
[0166]
(S)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-
-11-yl)piperazin-2-yl)acetic acid (288 mg, 0.61 mmol) can be
dissolved in DMF (5 ml).
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222
mg, 1.16 mmol), and 4-Dimethylaminopyridine (48 mg, 0.39 mmol) can
be added respectively at room temperature under nitrogen. After
about fifteen minutes R-(-)-2-Methyl-2,4-pentanediol (92 mg, 0.78
mmol) can be added and the mixture should be heated to about 50 C
under nitrogen. The product can be purified by flash chromatography
using 10% Acetone/Dichloromethane as the eluent to give
(S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate.
(S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate can be
dissolved in dichloromethane (1.1 ml) and cooled in an ice bath.
Trifluoroacetic acid (0.5 ml) should be added drop wise under
nitrogen and slowly allowed to reach room temperature while running
overnight. The mixture should be concentrated under vacuum and
purified by flash chromatography using 10% Acetone/Dichloromethane
as the eluent to give Compound ED.
Example 4
Preparation of Compound EK
##STR00106##
[0168]
(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazep-
in-11-yl)piperazin-2-yl)acetic acid (300 mg, 0.60 mmol) can be
dissolved in DMF (0.25M).
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9
mmol), and 4-Dimethylaminopyridine (0.3 mmol) may be added
respectively at room temperature under nitrogen. After about
fifteen minutes R-(-)-2-Methyl-2,4-pentanediol (0.60 mmol) may be
added and the mixture heated to about 50.degree. C. under nitrogen.
The product can be worked up as usual and purified by flash
chromatography using 10% Acetone/Dichloromethane as the eluent to
give (S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate as a white
foam. The (S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate may be
dissolved in anhydrous THF and cooled in a dry ice acetone bath
under nitrogen. A 2.0M solution of Butyl lithium in cyclohexane
(about 1 mole equivalent) may be added dropwise under nitrogen.
After about 15 minutes, iodomethane (about 1 mole equivalent) may
be added dropwise under nitrogen. After about one hour, a 2.0M
solution of Butyl lithium in cyclohexane (about 1 equivalent) may
be added dropwise under nitrogen. After about 15 minutes,
iodomethane (about 1 equivalent) may be added dropwise under
nitrogen. After about one hour the solution may be concentrated
under vacuum to give (S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate
as a white foam. The (S)-tert-butyl
4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-met-
hylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate
may be dissolved in dichloromethane (about 1.1 ml) and cooled in an
ice bath. Trifluoroacetic acid (about 0.5 ml) may be added dropwise
under nitrogen and slowly allowed to reach room temperature while
running overnight. The mixture may be concentrated under vacuum and
purified by flash chromatography using 10% Acetone/Dichloromethane
as the eluent to give Compound EK.
Example 5
Preparation of gemdimethylated 3' esters:
[0169]
(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazep-
in-11-yl)piperazin-2-yl)acetic acid can be dissolved in DMF
(0.25M). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.9 mmol), and 4-dimethylaminopyridine (about 0.5
mole equivalents) can be added respectively at room temperature
under nitrogen. After about fifteen minutes, the alcohol (to make
the relevant ester, e.g., propanol for a propyl ester (about 1
equivalent)) should be added and the mixture should be heated to
about 50.degree. C. under nitrogen. The product can be worked up as
usual and purified by flash chromatography using standard
acetone/dichloromethane as the eluent to give the BOC protected
ester. The BOC protected ester may be dissolved in anhydrous THF
and cooled in a dry ice acetone bath under nitrogen. A 2.0M
solution of Butyl lithium in cyclohexane (about 1 mole equivalent)
may be added dropwise under nitrogen. After about 15 minutes,
iodomethane (about 1 mole equivalent) may be added dropwise under
nitrogen. After about one hour, a 2.0M solution of Butyl lithium in
cyclohexane (about 1 equivalent) may be added dropwise under
nitrogen. After about 15 minutes, iodomethane (about 1 equivalent)
may be added dropwise under nitrogen. After about one hour the
solution may be concentrated under vacuum to give the gemdimethyl
product. The BOC protected gemdimethyl product can be dissolved in
dichloromethane (1.1 ml) and cooled in an ice bath. Trifluoroacetic
acid (0.5 ml) should be added drop wise under nitrogen and slowly
allowed to reach room temperature while running overnight. The
mixture should be concentrated under vacuum and purified by flash
chromatography using standard acetone/dichloromethane as the eluent
to give free base gemdimethyl product.
Example 6
Preparation of compound BW, BX racemate:
[0170] Mono(S,E)-tert-butyl
4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-ethoxy-2-oxoethyl)pipera-
zine-1-carboxylate should be dissolved in anhydrous THF and cooled
to -78 C under nitrogen. Butyllithium should be added dropwise in
hexane. After about 30 mins methyl iodide (0.95 eq) should be added
and allowed to slowly reach room temperature. The mixture should be
concentrated under vacuum and purified by flash chromatography
using standard acetone/dichloromethane as the eluent to give free
base monomethyl BOC protected product. The BOC protected monomethyl
product should be dissolved in dichloromethane and cooled in an ice
bath. Trifluoroacetic acid should be added drop wise under nitrogen
and slowly allowed to reach room temperature while running
overnight. The mixture should be concentrated under vacuum and
purified by flash chromatography using standard
acetone/dichloromethane as the eluent to give free base monomethyl
product. See scheme for Example 7 below.
Example 7
Preparation of Compound CC
##STR00107##
[0172] Mono(S,E)-tert-butyl
4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-ethoxy-2-oxoethyl)pipera-
zine-1-carboxylate should be dissolved in anhydrous THF and cooled
to -78 C under nitrogen. Butyllithium should be added dropwise in
hexane. After about 30 mins methyl iodide (about 2.2 eq) should be
added and allowed to slowly reach room temperature. The mixture
should be concentrated under vacuum and purified by flash
chromatography using standard acetone/dichloromethane as the eluent
to give free base gemdimethyl BOC protected product. The BOC
protected gemdimethyl product should be dissolved in
dichloromethane and cooled in an ice bath. Trifluoroacetic acid
should be added drop wise under nitrogen and slowly allowed to
reach room temperature while running overnight. The mixture should
be concentrated under vacuum and purified by flash chromatography
using standard acetone/dichloromethane as the eluent to give free
base gemdimethyl product.
Example 8
Preparation of Compound N and Compound P Racemate
Preparation of (E)-8,11-dichlorodibenzo[b,f][1,4]oxazepine
##STR00108##
[0174] Phosphorus oxychloride (40 mL) and dimethylaniline (7.6 mL,
60 mmol) were added to a solution of amide (7.35 g, 30 mmol) in
toluene (120 mL) under nitrogen. Fit with condenser and heat at
reflux under nitrogen overnight. The reaction was heated at
100.degree. C. for about 48 h. The reaction was then cooled and
diluted with toluene (100 mL), then distilled rapidly at
150.degree. C. to approximately half of the initial volume. The
reaction was diluted again with toluene (120 mL) and distilled
again to remove excess phosphorus oxychloride. The reaction was
cooled and toluene (150 mL) was added, then the mix was poured into
ethyl acetate (200 mL). The reaction was washed with 1M HCl
solution, and dried over MgSO.sub.4, then used immediately as a
solution in toluene/ethyl acetate.
Preparation of Substituted Piperizine
1. Preparation of Ethyl 1,4-dibenzylpiperazine-2-carboxylate
##STR00109##
[0176] To a hot (about 80.degree. C.) solution of
N,N'-dibenzylethylenediamine (216 g, 0.9 mol) and triethylamine
(300 .mu.L, 2.16 mol) in toluene (650 mL) was added rapidly
dropwise ethyl 2,3-dibromopropionate (240 g, 0.93 mol) in toluene
(650 mL). After the addition, the reaction mixture was stirred at
80.degree. C. for about three hours. A temperature below about
95.degree. C. was maintained. The heavy precipitate was filtered
off and then solvent and excess TEA removed. t-butyl methyl ether
(about 300 mL) was added. The reaction was stirred well, and any
precipitate that was formed was filtered. The reaction was
concentrated to a pale yellow oil (about 287 g, about 94%)
[0177] 2. Preparation of
1,4-Dibenzyl-2-(hydroxymethyl)piperazine
##STR00110##
[0178] To a stirred ice cold (0.degree. C.) solution of LAH (2.0 M
in THF, 2 mL, 4.0 mmol) in THF (20 mL), was added a solution of
ester (1.8 g, 5.3 mmol) dropwise over 15 minutes. The mixture was
stirred for about 20 hours at room temperature, then cooled and
treated carefully with wet ether and aqueous NaOH (0.5 M, 200 mL)
until no more reaction occurred upon addition. The aqueous layer
was extracted with ether, and the extracts were dried over
NaSO.sub.4. The reaction was concentrated to a clear oil (1.55 g,
99%).
[0179] 3. Preparation of
1,4-Dibenzyl-2-(chloromethyl)piperazine
##STR00111##
[0180] The alcohol (1.6 g, 5.3 mmol) was dissolved in chloroform
(50 mL) and cooled to 0.degree. C. (ice bath). A solution of
thionyl chloride (3.0 mL, 40.3 mmol) in chloroform (about 20 mL)
was added dropwise over about 5 minutes. The reaction was allowed
to warm to room temperature and monitored by TLC. A reaction flask
was fitted with a condenser, and the reaction was heated at reflux
for about 15 hours. The reaction mixture was cooled and diluted
with dichloromethane, then washed with saturated sodium bicarbonate
solution and dried over NaSO.sub.4. The product was filtered and
concentrated to a yellow oil.
4. Preparation of 1,4-Dibenzyl-2-(cyanomethyl)piperazine
##STR00112##
[0182] To a refluxing solution of KCN (4.0 g, 61.5 mmol) in water
(75 mL) and ethanol (80 mL) was added dropwise a solution of the
previous step's halide (12.7 g, 40.3 mmol) in ethanol (20 mL). The
mixture was stirred and refluxed for about 7 hours, then
concentrated to remove ethanol. The crude residue was taken up in
dichloromethane, washed with water, and dried over MgSO.sub.4. The
product was filtered and concentrated to 12 g orange oil, which was
then purified on silica using flash chromatography with 4:1
Hex/EtOAc.
[0183] 5. Preparation of Methyl
1,4-Dibenzylpiperazin-2-ylacetate
##STR00113##
[0184] The nitrile from the previous step (0.3 g, 0.98 mmol) was
dissolved in methanol (about 30 mL), to which concentrated sulfuric
acid (5 mL) was added. The reaction was fitted with a condenser and
heated at reflux overnight and monitor the reaction by TLC.
Additional sulfuric acid (8 mL) was added and the mixture heated at
reflux about 20 hours. The reaction was cooled and poured into
dichloromethane and water. The pH was carefully neutralized by
adding saturated sodium bicarbonate solution to pH 9. The resulting
product was extracted into dichloromethane and dried over
MgSO.sub.4 then filtered and concentrated to obtain a clear oil
(0.3 g, 91%).
6. Preparation of methyl piperazin-2-ylacetate
##STR00114##
[0186] The dibenzyl piperizine ester (0.87 g, 2.5 mmol) was
dissolved in ethanol (10 mL) and added to Parr shaker flask.
Palladium hydroxide (20 wt % Pd on carbon, 0.54 g) was added. The
flask was evacuated with H.sub.2 (3.times.) and shaken under
H.sub.2 (50 psi) for about 15 hours. The product was filtered
through a filter disc (Whatman 0.7 um) to remove palladium on
carbon, and then concentrated to a yellow oil.
7. Coupling of Core to Substituted Piperizine
##STR00115##
[0188] Triethylamine (14 mL, 100 mmol) was added to a solution of
piperizine ester (6.3 g, 40.1 mmol) in methanol (25 mL) under
nitrogen. The reaction mixture heated to 50.degree. C., and a
solution of chloroimidate in toluene/ethyl acetate (650 mL, 0.46M)
was added over about 30 seconds with stirring. The reaction was
fitted with a condenser and heated at about 90.degree. C. (reflux)
with stirring overnight. The reaction mixture was cooled then
methanol (30 mL) and triethylamine (15 mL) were added. The reaction
was sonicated for about 2 minutes and heated at reflux for
additional 7 hours. The reaction mixture was cooled and diluted
with ethyl acetate (250 mL), washed with saturated bicarbonate
solution, and dried over Na.sub.2SO.sub.4. The reaction was
filtered and concentrated to about 100 mL of crude product in
toluene, which was filtered to remove white solid precipitate, and
purified by silica gel chromatography (230-400 mesh) using 1:1
hexanes/ethyl acetate and 100:10:1 dichloromethane/MeOH/NH.sub.4OH
gradient elution. The main fraction was isolated and concentrated
to obtain 3.84 g (10 mmol, 33% yield) light yellow foam of high
purity (99% by HPLC).
Example 9
[0189] Preparation of Compound FS: The ethyl ester (400 mg, 1.0
mmol) was dissolved in amine (1.5 mL, 20 mmol) in a 20 mL vial and
heated at 90.degree. C. with stirring for about 48 hours. The
reaction mixture was cooled and purified directly by HPLC using
acetonitrile/water. The collected fractions were frozen and
lyophilized to yield Compound FS as a white solid (95 mg, 22%).
##STR00116##
Example 10
Methods
[0190] Neuronal Cultures. Cerebral cortices were dissected from
newborn rats and treated with 0.25% trypsin to dissociate the
cells. Dissociated cells were resuspended in Dulbecco's Modified
Eagle's Medium (DMEM) containing 10% plasma derived horse serum
(PDHS) and were plated in poly-L-lysine-coated, 35 mm Nunc plastic
tissue culture dishes (3.0.times.106 cells/dish/2 ml media).
Cultures were maintained in an atmosphere of 5% CO2/95% air.
Acute Effects of Compounds of the Invention on NMDA Receptor
Function
[0191] Electrophysiological recordings: Voltage-clamp recordings of
membrane ionic currents were conducted by using Axopatch 200B and
Axoclamp 1D amplifiers (Axon Instruments, Foster City, Calif.).
Neurons were used for electrophysiological recordings between 12
and 20 days in vitro. If a neuron showed either a marked change in
holding current or a noticeable alteration in amplitude or shape of
capacitance transients during the experiment, the data from that
neuron were discarded. Patch microelectrodes were pulled from 1.5
mm borosilicate glass tubing using a two-stage vertical pipette
puller (Narishige, East Meadow, N.Y.). When filled with recording
solution, patch microelectrodes will have a resistance of 3-5
M.OMEGA.. For rapid application of agonist-containing solutions to
neurons, the SF-77B system (Warner Instrument Corp., Hamden, Conn.)
were used. Otherwise a slower exchange of extracellular solution
were done by a home-made bath-application system.
[0192] NMDA receptor activity was measured as the standard
deviation (SD) of membrane current. To study acute effects of drugs
the SD of membrane current were measured in vehicle control
solution and in the presence of different concentrations of drugs
(1-100 .mu.M). For screening purposes, 1 and 10 .mu.M were used for
most compounds. For lead compounds and classic comparators (e.g.,
clozapine), complete concentration-response curves were created.
Drugs were applied at least for 10 min. The vehicle control was
monitored at the same period of time. To measure functional changes
in the NMDA receptor function during chronic exposure of drugs the
currents evoked by saturating concentration of NMDA (1 mM) were
recorded in drug treated and control culture. After plating neurons
for 5-7 days, half of culture dishes were treated with a fixed
concentration of drug and other half with vehicle only. The
recordings were preformed after 7-14 days of drug application. The
Amplitude of NMDA-induced currents in vehicle control and treated
cultures were compared. The SD of membrane current and NMDA-induced
currents were recorded in TTX-containing (0.3-1 .mu.M)
extracellular solution. In case of NMDA receptor-mediated mEPSC
recordings, Mg.sup.2+ was omitted from the extracellular solution.
In order to isolate the NMDA component of glutamate
receptor-mediated currents, the non-NMDA (AMPA/kainate) receptor
antagonist NBQX (10-20 .mu.M) were added to extracellular
solutions, Vh=-60 mV. The NMDA-induced currents were recorded at
-30 mV in the presence of physiological concentration of Mg2+ (1
mM). Strychnine (1 .mu.M) and picrotoxin (100 .mu.M) were added in
all cases to the extracellular solution to block glycine and GABA
receptors, respectively. The basic extracellular solution contained
(in mM): NaCl (140), KCl (4), CaCl.sub.2 (2), MgCl.sub.2 (1),
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (10),
and glucose (11). The pH of the extracellular solution were
adjusted to 7.4 using NaOH. The main solution for filling the patch
electrodes contain (in mM): Cs gluconate (135), NaCl (5), KCl (10),
MgCl.sub.2 (1), CaCl.sub.2 (1), EGTA (11), HEPES (10), Na.sub.2ATP
(2), Na.sub.2GTP (0.2) mM. The pH of the intracellular solution
were adjusted to 7.4 using CsOH. Various concentrations of
clozapine and ATI-compounds were added to the extracellular
solution according to the protocols described.
[0193] The digitized data were analyzed off-line using the
Mini-Analysis Program (Synaptosoft, Leonia, N.J.) or pCLAMP9 (Axon
Instruments, Union City, Calif.).
Example 11
Acute Effects of ATI-9000 Compounds on GABAA Receptor Function
Electrophysiological Recordings
[0194] To study the effect of ATI-9000 compounds on GABA
receptor-mediated mIPSCs, bicuculline (20 .mu.M) in the
extracellular solution and Cs gluconate (135 mM) in the
intrapipette solution, which were used for the NMDA receptor
experiments, were replaced with
1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide
(NB QX; 5-10 .mu.M) and with KCl (135 mM), respectively. All IPSCs
were recorded at a holding potential of -60 mV. The digitized data
were analyzed off-line using the Mini-Analysis Program
(Synaptosoft, Leonia, N.J.) with a detection threshold for a mEPSC
amplitude set at .gtoreq.8 pA.
Example 12
Compound K, but not Compound Q, Binds to D.sub.2S and D.sub.2L
Dopamine Receptors
[0195] The D.sub.2 receptors are known to be a receptor subtype
involved in the activity of clozapine. Compound K has low
micromolar IC.sub.50 binding affinity for D.sub.zs and D.sub.2L
receptors. The affinity of Compound K for the D.sub.2S and D.sub.2L
receptors was comparable to the affinity of clozapine for these
receptors.
[0196] Compound K and its metabolite Compound Q also bind to
H.sub.1, 5-HT.sub.1A and 5-HT.sub.2c, but with very low affinity to
M.sub.3 and M.sub.1 receptors. The affinity of Compound K for the
H.sub.1 and 5-HT.sub.2c receptors was 69- and 1.2-fold lower than
clozapine and 4-fold higher for the 5-HT.sub.1A receptors.
Radioligand Binding Assay Methodology
[0197] Consistent with standard competition radioligand binding
assays, the methodology was based on displacement of radioligand
from tissues (or cell lines) bearing the receptor of interest
(Cheng, Y. and Prusoff, W. H. (1973). Biochem. Pharmacol. 22,
3099-3108). The measurements were based on the binding of a single
concentration of radiolabeled ligand in the presence of various
concentrations of unlabeled ligand.
[0198] Tissues (or cellular plasma membrane fractions) were
incubated in the presence of radioligand at equilibrium and in the
presence of a range of concentrations of the test compounds (which
were non-radiolabeled), and the displaced radioligand was separated
from the membranes by filtration. Nonspecific binding was assessed
by measuring displacement of the radioligand in the presence of a
compound known to block binding of the radioligand to the receptor.
Finally, the concentration-response relationship for radioligand
displacement (corrected for non-specific binding) was used to
assess binding of the test compound to the receptor.
[0199] Protocol conditions are summarized in Table 1 (FIG. 9).
Example 13
Compound K is a Partial Agonist at Human D.sub.2S Receptor
[0200] In vitro assays were performed based on adenylyl cyclase
stimulation in cells engineered to stably express human D.sub.2S
receptor. Compound K appeared to be a partial D.sub.2 receptor
agonist and a D.sub.2 receptor antagonist, like clozapine. The
estimated IC.sub.50 of Compound K is 13 .mu.M.
Adenylyl Cyclase Methodology
[0201] HitHunter.TM. cAMP XS (DiscoveRx, CA) is a chemiluminescent
assay ideally suited for monitoring Gi-coupled GPCRs with robust
signal to background ratios for both agonist and antagonist
responses. It is an in-vitro based competitive immunoassay. Free
cAMP from cell lysates compete for antibody binding against labeled
ED-cAMP conjugate, a small peptide fragment of .beta.-galactosidase
(.beta.-gal). In the absence of free cAMP, ED-cAMP conjugates are
captured by the antibody and are unavailable for complementation,
resulting in low signal. In the presence of free cAMP, antibody
sites are occupied, leaving ED-cAMP conjugate free to complement
with EA, forming active .beta.-gal EFC enzyme for substrate
hydrolysis to produce a chemiluminescent signal. A positive signal
is generated in direct proportion to the amount of free cAMP bound
by the antibody.
[0202] HEK 293 cells expressing functional human D.sub.2S receptors
(Scottish Biomedical) were harvested and resuspended with PBS
buffer (serum-free medium). The cells were plated in a 96-well
plate at 20,000 cells/well. Serial dilutions of forskolin and
dopamine were tested (positive controls for the agonist assay).
Serial dilutions of proprietary compounds were tested at a 10 .mu.l
volume in the presence of 27 .mu.M forskolin (agonist assay) or in
presence of both 27 .mu.M forskolin and 30 nM dopamine (antagonist
assay). The plates were incubated at 37.degree. C. for 30 minutes.
After cell induction, the assay reagents were added and incubated
for 60 minutes at room temperature. The luminescence was read using
a TopCount NXT detector (PerkinElmer).
Example 14
Compound K is a Potent 5-HT.sub.2A Receptor Antagonist
[0203] The ability of antipsychotic drugs to affect 5-HT.sub.2A
receptor function has been widely suggested to contribute to their
therapeutic properties. Compound K is a potent antagonist for
5-HT.sub.2A receptors (pA.sub.2=8.5), comparable to clozapine
(pA.sub.2=8.4). The affinity of Compound Q for the 5-HT.sub.2A
receptors was 8-fold lower than Compound K. See FIG. 1.
Organ Bath Methodology
[0204] The rat aorta (approximately 7 cm) was isolated and removed
from the animal (male Sprague Dawley rat, Charles River
Laboratories, Hollister, Calif.). The endothelium was removed
mechanically. Eight strips of tissue (0.5 cm long) were cut. and
were mounted in 10 ml organ baths kept at 37.degree. C. with Krebs
solution (composition in mM: NaCl (118.2), KCl (4.6), CaCl.sub.2
(2.5), MgSO.sub.4 (1.2), KH.sub.2PO.sub.4 (1.2), NaHCO.sub.3 (24.8)
and dextrose (10.0)) that was constantly aerated with carbogen gas
(95% O.sub.2/5% CO.sub.2) to obtain a pH of 7.4. The tissues were
subjected to a resting tension of 2 g (3 times, 15 minutes apart,
equilibrated in Krebs solution). The tissues were then washed 15
minutes later. Ten minutes later, the tissues were then exposed to
0.1 .mu.M phenylephrine. At the maximal effect, 1 .mu.M
acetylcholine was added to confirm the absence of endothelium and
then washed twice, 2 minutes apart. Fifteen minutes later, vehicle
(DMSO), a reference compound (clozapine) or the test compound
(Compound K or Compound Q, 10 nM-0.3 .mu.M or 0.1-1 .mu.M) was
added to the baths and the tissues were washed every 10 minutes for
60 minutes with vehicle, clozapine, Compound K or Compound Q. A
non-cumulative concentration effect curve to 5-HT (serotonin, 0.01
.mu.M-0.1 mM or until maximal response is obtained) was then
constructed.
[0205] Contractions were recorded as changes in tension from
baseline and expressed as a percentage of the maximum response of
the agonist (5-HT) concentration-effect curve. Agonist
concentration-response curves were fitted using a nonlinear
iterative fitting program (GraphPad Prism) using the relationship
of Parker and Waud (Parker, R. B. and Waud, D. R. (1971).
Pharmacological estimation of drug-receptor dissociation constants.
Statistical evaluation. I. Agonists. J. Pharmacol. Exp. Ther., 177,
1-12). Agonist potency was expressed as EC.sub.50 (molar
concentration of agonist producing 50% of the maximum response).
Concentration-ratios (CRs) were determined from EC.sub.50 values in
the presence and absence of antagonist and antagonist affinity
estimates (pK.sub.B and pA.sub.2 values) were determined. All data
are expressed as mean.+-.s.e. mean.
Example 15
Compound K is a Potent Antagonist of Apomorphine-Induced Disruption
of Swimming
[0206] The antagonism of apomorphine-induced disruption of swimming
in mice (Warawa, E. J. et al. (2001). Behavioral approach to
nondyskinetic dopamine antagonists: identification of seroquel. J.
Med. Chem., 44, 372-389) was used to assess test compounds.
Apomorphine-treated mice fail to swim and remain in place, pawing
the walls of the swimming chamber, or making abortive swims.
Certain atypical antipsychotic compounds "normalize" the swimming
behavior of such mice.
[0207] Compound K was more potent than clozapine in antagonizing
the apomorphine-induced disruption of swimming in mice (see FIGS.
2, 3). Compound Q also reversed the apomorphine-induced disruption
of swimming (3 and 10 mg/kg; FIG. 4).
Swim Test Methodology
[0208] The animals (Swiss Webster, female, about 20 g; Charles
River) were administered compounds of the invention (0.1
.mu.g/kg-30 mg/kg ip) thirty minutes before they were dosed with
apomorphine HCl at 1.25 mg/kg sc. Twenty seven minutes after test
compound injection, and fifteen minutes after apomorphine
injection, each mouse was placed into a circular swimming tank for
2 minutes and the number of "swims" were counted. The height of the
tank is 15 cm and the diameter is 28 cm. A circular obstacle, 10.5
cm in diameter and 17 cm high was placed in the center of the tank
creating a circular swimming channel 8.75 cm wide. The water level
is 5.5 cm and the water was kept at room temperature (about
20.degree. C.). Marks are placed on the floor and side of the tank
180 degrees apart. A "swim" was scored each time a mouse swims from
one mark to the other and the median number of swims for all the
mice was used as the score for that treatment.
Example 16
Compound K and Catalepsy
[0209] A catalepsy mouse model was used to investigate a potential
side effect of antipsychotic agents. Compound K did not cause
catalepsy at concentrations up to 30 mg/kg, IP, whereas the highest
dose of clozapine (30 mg/kg) induced catalepsy. See FIGS. 5 and 6,
respectively.
Catalepsy Methodology
[0210] The catalepsy methodology used herein has been adapted from
Tada, M. et al. ((2004). Psychopharmacol., 176, 94-100) as well as
Wang et al. ((2000). J. Neurosci., 20, 8305-8314).
[0211] The animals (Swiss Webster, female, about 20 g; Charles
River) were administered compounds of the invention (1 .mu.g/kg-30
mg/kg ip). Twenty seven minutes after test compound injection, the
mice's forepaws were placed on a horizontal steel bar (diameter 0.2
cm), elevated 3-5 cm above the tabletop and the time taken for the
animals to remove both paws was recorded for up to 2 min.
Example 17
Compound K and Compound Q Restore NMDA Antagonist-Induced Deficits
in Prepulse Inhibition
[0212] The purpose of the studies was to evaluate the effect of
proprietary compounds on the disruption of auditory prepulse
inhibition (PPI) in rats. With the PPI procedure, a whole-body
startle reflex that is produced by an intense sound is reduced or
inhibited by the prior presentation of a weaker sound (prepulse).
PPI is a measure of sensorimotor gating, which is disrupted in
schizophrenics (Braff, D. L. et al. (1995). Gating and habituation
deficits in the schizophrenia disorders. Clin. Neurosci., 3,
131-139). Because reduced glutamate function is postulated to
contribute to schizophrenic symptomatology (Carlsson, M. and
Carlsson, A. (1990). Interactions between glutamatergic and
monoaminergic systems within the basal ganglia: Implications for
schizophrenia and Parkinson's disease. Trends Neurosci., 13,
272-276). MK-801-, PCP- and also apomorphine-disrupted PPI are
proposed as animal models for specific neurochemical imbalances.
Animals were administered antipsychotics such as clozapine or test
compounds to antagonize the induced disruption to evaluate their
potential beneficial effects in this model. See FIG. 7.
PPI Methodology
[0213] The PPI methodology used herein was adapted from Bast, T. et
al. ((2000) Effects of MK-801 and neuroleptics on prepulse
inhibition: re-examination in two strains of rats. Pharmacol.
Biochem. Behay., 67, 647-658) as well as Bubenikova et al. ((2005)
The effect of zotepine, risperidone, clozapine and olanzapine on
MK-801-disrupted sensorimotor gating. Pharmacol. Biochem. Behay.,
80, 591-596).
[0214] Rats (Sprague Dawley, 300-450 g; Charles River) were
injected with vehicle (DMSO) or compounds Ip. (0.5 ml/kg) 45 min
before the PPI experiment. PCP (1.5 mg/kg, 0.5 ml/kg) s.c. was
given 15 min before the PPI assay. The animals were then placed in
a startle chamber (SR-LAB, San Diego Instruments, USA) which
consisted of a clear Plexiglas cylinder (8.2 cm diameter,
10.times.20 cm) that rested on a piezoelectric accelerometer inside
a ventilated and illuminated chamber. The piezoelectric
accelerometer detected and transduced motion within the cylinder. A
high frequency loudspeaker inside the chamber (24 cm above the
animal) produced both a background noise of 77 dB and the acoustic
stimuli. The background noise (77 dB) was presented alone for 5 min
(acclimatization period) and then continued throughout the session.
After the acclimatization period, the test began with 5 initial
startle stimuli followed by different trial types presented in a
random order: single pulse 120 dB, 20 ms duration; prepulse (83, 86
or 89 dB), 20 ms duration, 100 ms before the onset of the pulse
alone; prepulse alone (83, 86 or 89 dB), 20 ms duration; no
stimulus. A total of 5 presentations of each trial type were given
with an interstimulus interval of about 30 sec. The PPI was
measured as a difference between the average values of the single
pulse and prepulse-pulse trials and was expressed as a percent of
the PPI [100-(mean response for prepulse-pulse trials/startle
response for single pulse trials).times.100].
Example 18
Compound K Did not Reduce Spontaneous Locomotor Activity (Open
Field) in Rats
[0215] One of the common side effects of many antipsychotic drugs
is sedation. It has been shown that agents that have sedative
actions in man have the same effect in animals. The purpose of
these studies was to evaluate the effect of test compounds on the
locomotor activity in rats, which is used to assess the sedative
properties of antipsychotic compounds.
[0216] Compound K (0.03-10 mg/kg) or Compound Q (10 mg/kg) did not
reduce the locomotor activity in rat (see graph below), while
clozapine demonstrated a trend toward sedation. See FIG. 8.
Open Field Methodology
[0217] The animals (male Sprague Dawley rats, about 300-450 g;
Charles River) were assessed for ambulation for 30 minutes before
and for 30 min after vehicle or test compounds. The animals were
placed in an open field chamber (San Diego Instruments, USA) which
consisted of a clear Plexiglas cylinder (16.times.16) equipped with
crisscross photocellbeams. Locomotor activity is quantified by the
number of photobeams crossed by the animal over several 3.times.10
min intervals.
Example 19
Metabolism Studies Using Human Liver Microsomal Preparations
[0218] Compounds were incubated in pooled human liver microsomes
(HLMs) in the presence or absence of an NADPH-generating system.
NADPH is required for the activity of cytochrome P450 (CYP) and
other oxidative enzymes present in HLMs, but not for esterase
activity. An additional incubation was carried out in the absence
of HLM to assess compound stability. The disappearance of parent
and the appearance of the corresponding acid metabolite were
monitored over the time course of the incubations using
LC-MS/MS.
[0219] A stock solution (20 mM) of each proprietary compound in
DMSO was prepared and stored at -20.degree. C. until needed. A
working stock solution (0.2 mM) was prepared for each proprietary
compound by adding an aliquot of the stock solution (10 .mu.L) to
acetonitrile (990 .mu.L).
[0220] An aliquot of the HLM solution was removed from the
-80.degree. C. freezer and placed on ice. Tris Buffer (50 mM, pH
7.4) containing MgCl2 (hexahydrate, 5 mM) was pre-incubated in a
37.degree. C. water bath. A set of Eppendorf microfuge tubes (1.5
mL) was appropriately labeled. To each tube was added Tris buffer
with or without the NADPH generating system. An aliquot of pooled
HLMs was added to all the incubations except those that were the
buffer control.
[0221] Tubes were preincubated for 5 min in a shaking incubator
bath (37.degree. C., 900 rpm) and the reaction was initiated by
adding an aliquot of the proprietary working solution (5 .mu.L).
The additions were timed carefully in order to coordinate the
sample collections below. A small aliquot (50 .mu.L) was removed at
0, 5, 15, 30, 60 and 90 mM and delivered to the respective tubes
containing dextrorphan (100 .mu.L of 0.5 .mu.g/mL solution)
dissolved in methanol or acetonitrile. The samples were centrifuged
at 14000 g for 15 minutes at 4.degree. C. The supernatant was
transferred to clean labeled HPLC injection vials and stored at
-80.degree. C. until analyzed. An aliquot of the supernatant (25
.mu.L) was added to water (75 .mu.L), mixed and injected onto the
LC-MS/MS system for analysis. Results for some compounds of the
invention can be found below in the table in Example 20.
Example 20
Metabolism Studies Using Pig Liver Esterase
[0222] The esterase-mediated metabolism of these compounds was
studied using commercially available pig liver esterase in the
presence and absence of human plasma proteins. The disappearance of
parent was monitored over the time course of the incubations using
a LC-UV detection system.
[0223] A stock solution and working stock solution was prepared for
each proprietary compound as described for the human liver
microsomal incubations. Working solutions of pig liver esterase in
potassium phosphate buffer (10 mM, pH 7.4) and pig liver esterase
in human plasma protein were prepared by dissolving pig liver
esterase (2.51 mg) in the phosphate buffer or plasma protein
solutions, respectively.
[0224] A set of three Eppendorf microfuge tubes (1.5 mL) was
appropriately labeled. To each tube was added 1.5 mL of phosphate
buffer, pig liver esterase in buffer, or pig liver esterase in
human plasma protein solution. These solutions were pre-incubated
(37.degree. C., 900 rpm) and the reactions were initiated by adding
an aliquot (37.5 .mu.L) of the working solution of proprietary
compound to each tube. An aliquot (100 .mu.L) from each tube was
removed at time 0, 5, 30, 60, and 120 min and added to a tube
containing acetonitrile (200 .mu.L) to stop the reaction.
[0225] The samples were centrifuged at 14000 g for 15 minutes at
4.degree. C. The supernatant was transferred to clean labeled HPLC
injection vials and stored at -80.degree. C. until analyzed. An
aliquot of the supernatant (25 .mu.L) was injected onto the LC-UV
system for analysis. Results for some compounds of the invention
are presented in the table below.
TABLE-US-00002 Pig Liver Esterase HLMs (t.sub.1/2 min.) t.sub.1/2
(+) (-) Compound (min) Enzyme plasma plasma A (E)-ethyl 2-(4-(8- 30
Esterase 15 <5 chlorodibenzo[b,f][1,4]oxazepin-
11-yl)piperazin-2-yl)acetate J (E)-ethyl 2-(4-(7- 10 Esterase 15
<5 fluorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate
L (E)-isopropyl 2-(4-(8- 30 P450 30 <5
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate M
(E)-isopropyl 2-(4-(7- 30 P450 15 <5
fluorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate DR
(S,E)-cyclopentyl 2-(4-(8- 30 Esterase 15 <5
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate DV
(S,E)-tetrahydro-2H-pyran-4-yl 60 Esterase 15 <5 2-(4-(8-
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)piperazin-2-yl)acetate DY
sec-butyl 2-((S)-4-((E)-8- <5 Esterase 30 <5
chlorodibenzo[b,f][1,4]oxazepin- 11-yl)-1-methylpiperazin-2-
yl)acetate EQ (S)-tetrahydrofuran-3-yl 2-((S)- 15 Esterase 30 5
4-((E)-8- chlorodibenzo[b,f][1,4]oxazepin-
11-yl)piperazin-2-yl)acetate ER (S,E)-ethyl 2-(4-(8- 5 Esterase 60
<5 chlorodibenzo[b,f][1,4]oxazepin-
11-yl)-1-isopentylpiperazin-2- yl)acetate EU (S,E)-2-(4-(8- 60 P450
Stable Stable chlorodibenzo[b,f][1,4]oxazepin-
11-yl)-1-methylpiperazin-2-yl)- N-(2,2,3,3,3-
pentafluoropropyl)acetamide
Example 21
[0226] In the following tables, proprietary compound pKi and pKb
values (negative logKi and negative logKb, respectively) for
various receptors are reported on a scale of 1 through 5, wherein
the pKi and pKb scale is defined for each receptor as follows:
TABLE-US-00003 Receptor 1 2 3 4 5 5HT.sub.2A .ltoreq.7.00 7.01-7.50
7.51-8.00 8.01-8.50 .gtoreq.8.51 D2.sub.S .ltoreq.5.00 5.01-5.60
5.61-6.20 6.21-6.80 .gtoreq.6.81 D2.sub.L .ltoreq.5.00 5.01-5.60
5.61-6.20 6.21-6.80 .gtoreq.6.81 5HT.sub.1A .ltoreq.5.00 5.01-6.00
6.01-7.00 7.01-8.00 .gtoreq.8.01 5HT.sub.2C .ltoreq.5.00 5.01-6.00
6.01-7.00 7.01-8.00 .gtoreq.8.01 M.sub.3 .ltoreq.5.00 5.01-5.10
5.11-5.20 5.21-5.30 .gtoreq.5.31 H.sub.1 .ltoreq.5.00 5.01-6.00
6.01-7.00 7.01-8.00 .gtoreq.8.01 5HT.sub.7 .ltoreq.5.00 5.01-5.40
5.41-5.80 5.81-6.20 .gtoreq.6.21 M.sub.1 .ltoreq.5.00 5.01-5.30
5.31-5.60 5.61-5.90 .gtoreq.5.91
TABLE-US-00004 5HT.sub.2A D2.sub.S D2.sub.L 5HT.sub.1A 5HT.sub.2C
M.sub.3 H.sub.1 5HT.sub.7 M.sub.1 Compound (pKb) (pKi) (pKi) (pKi)
(pKi) (pKi) (pKi) (pKi) (pKi) A 3 2 3 3 4 1 3 2 B 2 4 1 C 2 2 1 D 2
3 3 1 E 2 1 1 2 3 1 3 1 F 1 3 2 4 G 3 2 2 2 H 2 3 3 4 1 3 1 I 3 2 2
3 4 1 3 2 J 2 2 2 3 3 1 3 1 K 4 3 3 3 4 1 3 4 1 L 3 2 3 3 4 1 3 1 M
3 1 2 3 3 1 2 1 N 4 3 3 3 4 1 3 4 2 O 2 2 2 3 4 1 3 P 2 2 2 2 3 1 3
Q 3 1 1 3 3 1 3 1 AB 2 1 1 1 3 1 3 DM 3 1 DN 2 2 2 3 1 3 3 DO 1 2 3
4 DQ 1 2 2 3 3 1 2 2 1 DR 3 3 3 4 4 1 2 3 4 DS 1 1 2 2 1 1 DT 1 1 1
3 3 1 2 1 2 DU 1 2 2 4 3 1 3 2 2 DV 4 3 2 4 4 1 2 3 1 DW 2 1 2 2 3
1 3 2 5 DX 3 2 2 2 3 1 3 1 2 DY 3 2 2 3 1 4 1 1 DZ 2 2 3 3 1 1 EA 3
2 4 4 1 3 1 4 EB 3 3 5 4 1 4 3 2 EC 3 3 4 4 1 4 4 1 ED 4 3 3 4 5 1
4 4 2 EO 3 3 5 4 1 4 4 1 EP 3 4 4 3 2 EQ 4 3 4 4 2 ER 2 2 2 3 1 ES
1 2 4 1 ET 1 3 2 3 3 EU 1 2 2 3 1 EV 2 2 2 4 2 EW 1 1 2 2 3 2 EX 2
2 3 4 2 EY 4 3 3 4 4 1 4 4 1 EZ 2 2 2 5 4 1 4 4 1 FA 9313 4 3 3 4 4
1 4 4 1 FB 5 3 3 4 4 1 4 4 1 FC 4 3 3 4 4 1 4 4 1 FN 4 3 3 4 4 1 4
4 1 FO 3 2 2 3 4 1 4 4 3 FP 3 3 3 5 4 1 4 3 2 FQ 3 3 3 4 4 1 4 4 2
FR 4 4 4 4 4 1 4 4 1 FS 4 3 3 4 4 1 5 5 1 GD 3 3 3 4 4 1 4 4 1 GE 3
2 3 3 GF 3 3 2 3 4 1 4 4 1 GG 4 2 2 4 4 2 5 4 4 GH 2 2 3 3 3 2 4 3
5 GI 2 1 2 1
Example 22
Overview of hD.sub.2S Receptor and h5-HT.sub.2S Receptor Assay
Conditions
TABLE-US-00005 [0227] hD.sub.2S Receptor h5-HT.sub.7 Receptor
membranes from Chinese membranes from Chinese hamster ovary cells
hamster ovary cells transfected with human transfected with human
Source D.sub.2s dopamine receptors 5HT.sup.7 receptors Ligand 0.1
nM/0.2 nM 0.3 nM [.sup.3H]5-CT [.sup.3H]spiperone K.sub.D 0.1 nM
0.2 nM B.sub.MAX 2.5 pmole/mg protein 1.6 pmole/mg protein
Nonspecific 5 .mu.M (+)-butaclamol 25 mM Clozapine ligand Specific
78% 66% Binding Vehicle 0.1% DMSO 0.1% DMSO Incubation 180 min 120
min time Incubation 26.degree. C. 27.degree. C. temperature
Incubation 20 mM Hepes, pH 7.4, 1 mM 50 mM Tris-HCl, pH 7.4, buffer
EGTA, 6 mM MgCl.sub.2*6H.sub.2O, 10 mM MgSO4*7H20, 1 mM EDTA 0.5 mM
EDTA
Example 23
Overview of hD.sub.2L Receptor and hH.sub.1 Receptor Assay
Conditions
TABLE-US-00006 [0228] hD.sub.2L Receptor hH.sub.1 Receptor
membranes from membranes from insect sf9 cells Chinese hamster
ovary expressing human D.sub.2L cells transfected with Source
dopamine receptors human H.sub.1 receptors Ligand 0.4 nM
[.sup.3H]spiperone 2.0 nM [.sup.3H]Pyrilamine K.sub.D 0.4 nM 1.1 nM
B.sub.MAX 1.36 pmole/mg protein 1.55 pmole/mg protein Nonspecific 1
.mu.M (+)-butaclamol 1 .mu.M pyrilamine ligand Specific 81% 88%
Binding Vehicle 0.1% DMSO 0.1% DMSO Incubation 60 min 60 min time
Incubation 27.degree. C. 27.degree. C. temperature Incubation 50 mM
Tris HCl, 50 mM Tris-HCl, buffer pH 7.4, 120 mM NaCl, 10 .mu.g/mL 1
mM EDTA, Saponin, pH 7.4 10 mM MgCl.sub.2*6H.sub.2O
Example 24
Overview of hM.sub.1 Receptor r and hM.sub.3 Receptor Assay
Conditions
TABLE-US-00007 [0229] hM.sub.1 Receptor hM.sub.3 Receptor membranes
from membranes from Chinese hamster ovary Chinese hamster ovary
cells transfected with cells transfected with Source human M.sub.1
receptors human M.sub.3 receptors Ligand 1 nM [.sup.3H]NMS 0.1 nM
[.sup.3H]NMS K.sub.D 0.49 nM 0.1 nM B.sub.MAX 1.42 pmole/mg protein
3.57 pmole/mg protein Nonspecific 2 .mu.M NMS 5 .mu.M atropine
ligand Specific 90% 96% Binding Vehicle 0.1% DMSO 0.1% DMSO
Incubation 60 mon 135/75 min time Incubation 25.degree. C.
26.degree. C. temperature Incubation 50 mM Tris-HCl, 10 .mu.g/mL
DPBS w/o calcium or buffer Saponin, pH 7.4 magnesium, pH 7.4
Example 25
Overview of h5-HT.sub.1A Receptor and h5-HT.sub.2c Receptor Assay
Conditions
TABLE-US-00008 [0230] h5-HT.sub.1A Receptor h5-HT.sub.2C Receptor
membranes from membranes from Chinese hamster ovary human embryo
kidney cells transfected with cells expressing human Source human
5HT.sub.1A receptors 5HT.sub.2C receptors Ligand 2.5 nM
[.sup.3H]8OH-DPAT 1.2 nM [.sup.3H]Mesulergine K.sub.D 9 nM 1.2 nM
B.sub.MAX 4.98 pmole/mg protein 1.7 pmole/mg protein Nonspecific 4
.mu.M 5-HT 1 .mu.M mianserine ligand creatinine sulfate Specific
84% 68% Binding Vehicle 0.1% DMSO 0.1% DMSO Incubation 120 min 60
min time Incubation 37.degree. C. 27.degree. C. temperature
Incubation 50 mM Tris HCl, pH 7.4 , 50 mM Tris-HCl, pH 7.4, buffer
5 mM MgSO.sub.4*7H.sub.2O 0.1% BSA, 1 mM EDTA, 10 mM
MgCl.sub.2*6H.sub.2O
[0231] 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 invention and that
modifications may be made therein without departing from the spirit
or scope of the 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.
* * * * *