U.S. patent application number 11/863587 was filed with the patent office on 2008-06-26 for cocaine receptor binding ligands.
This patent application is currently assigned to Research Triangle Institute. Invention is credited to Philip ABRAHAM, John W. BOJA, Frank I. CARROLL, Michael J. KUHAR, Anita H. LEWIN.
Application Number | 20080153870 11/863587 |
Document ID | / |
Family ID | 29255373 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080153870 |
Kind Code |
A1 |
KUHAR; Michael J. ; et
al. |
June 26, 2008 |
COCAINE RECEPTOR BINDING LIGANDS
Abstract
A class of binding ligands for cocaine receptors and other
receptors in the brain. Specifically, a novel family of compounds
shows high binding specificity and activity, and, in a radiolabeled
form, can be used to bind to these receptors, for biochemical
assays and imaging techniques. Such imaging is useful for
determining effective doses of new drug candidates in human
populations. In addition, the high specificity, slow onset and long
duration of the action of these compounds at the receptors makes
them particularly well suited for therapeutic uses, for example as
substitute medication for psychostimulant abuse. Some of these
compounds may be useful in treating Parkinson's Disease or
depression, by virtue of their inhibitory properties at monoamine
transporters.
Inventors: |
KUHAR; Michael J.;
(Baltimore, MD) ; CARROLL; Frank I.; (Durham,
NC) ; BOJA; John W.; (Baltimore, MD) ; LEWIN;
Anita H.; (Chapel Hill, NC) ; ABRAHAM; Philip;
(Cary, NC) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Research Triangle Institute
Research Triangle Park
NC
|
Family ID: |
29255373 |
Appl. No.: |
11/863587 |
Filed: |
September 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10986352 |
Nov 12, 2004 |
7291737 |
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11863587 |
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10279851 |
Oct 25, 2002 |
7189737 |
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10986352 |
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08706263 |
Sep 4, 1996 |
6531483 |
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10279851 |
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08506541 |
Jul 24, 1995 |
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08706263 |
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08164576 |
Dec 10, 1993 |
5496953 |
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08506541 |
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07972472 |
Mar 23, 1993 |
5413779 |
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08164576 |
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PCT/US91/05553 |
Aug 7, 1991 |
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07972472 |
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07564755 |
Aug 9, 1990 |
5128118 |
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PCT/US91/05553 |
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07792648 |
Nov 15, 1991 |
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07972472 |
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08436970 |
May 8, 1995 |
5736123 |
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08506541 |
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08164576 |
Dec 10, 1993 |
5496953 |
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08436970 |
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Current U.S.
Class: |
514/304 |
Current CPC
Class: |
A61P 25/24 20180101;
C07D 451/02 20130101; A61P 15/00 20180101; A61P 25/34 20180101;
A61K 31/439 20130101; A61P 25/32 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/304 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 25/00 20060101 A61P025/00; A61P 25/24 20060101
A61P025/24; A61P 25/32 20060101 A61P025/32; A61P 25/34 20060101
A61P025/34; A61P 15/00 20060101 A61P015/00 |
Claims
1-42. (canceled)
43. A method of inhibiting the action of a psychostimulant,
inhibiting neurotransmitter re-uptake, treating neurodegenerative
disorders, treating depression, treating anorexia, treating cocaine
addiction, treating nicotine addiction, treating alcohol addiction,
treating bipolar disorder, treating eating disorders, treating
obesity, treating attention deficit disorder, treating panic
attacks, treating panic disorders, treating obsessive-compulsive
disorder and/or sexual dysfunction, comprising administering to a
patient in need of such treatment an effective amount of a
2.beta.,3.beta.-cis substituted compound having the formula:
##STR00128## or a salt thereof.
44. The method of claim 43, which comprises inhibiting the action
of a psychostimulant.
45. The method of claim 45, wherein the psychostimulant is cocaine,
nicotine, alcohol or amphetamine.
46. The method of claim 43, wherein the compound is in the form an
HCl salt.
47. The method of claim 43, which comprises inhibiting
neurotransmitter re-uptake.
48. The method of claim 47, wherein the neurotransmitter is
dopamine, norepinephrine, serotonin or another monomaine.
49. The method of claim 47, wherein the compound is in the form an
HCl salt.
50. The method of claim 43, which comprises treating
neurodegenerative disorders.
51. The method of claim 50, wherein the neurodegenerative disorder
is Parkinson's disease.
52. The method of claim 50, wherein the compound is in the form an
HCl salt.
53. The method of claim 43, which comprises treating
depression.
54. The method of claim 53, wherein the compound is in the form an
HCl salt.
55. The method of claim 43, which comprises treating anorexia.
56. The method of claim 55, wherein the compound is in the form an
HCl salt.
57. The method of claim 43, which comprises treating cocaine
addiction.
58. The method of claim 57, wherein the compound is in the form an
HCl salt.
59. The method of claim 43, which comprises treating alcohol
addiction.
60. The method of claim 59, wherein the compound is in the form an
HCl salt.
61. The method of claim 43, which comprises treating bipolar
disorder.
62. The method of claim 61, wherein the compound is in the form an
HCl salt.
63. The method of claim 43, which comprises treating eating
disorders.
64. The method of claim 63, wherein the compound is in the form an
HCl salt.
65. The method of claim 43, which comprises treating obesity.
66. The method of claim 65, wherein the compound is in the form an
HCl salt.
67. The method of claim 43, which comprises treating attention
deficit disorder.
68. The method of claim 67, wherein the compound is in the form an
HCl salt.
69. The method of claim 43, which comprises treating panic
attacks.
70. The method of claim 69, wherein the compound is in the form an
HCl salt.
71. The method of claim 43, which comprises treating panic
disorders.
72. The method of claim 71, wherein the compound is in the form an
HCl salt.
73. The method of claim 43, which comprises treating
obsessive-compulsive disorder.
74. The method of claim 73, wherein the compound is in the form an
HCl salt.
75. The method of claim 43, which comprises treating sexual
dysfunction.
76. The method of claim 75, wherein the compound is in the form an
HCl salt.
Description
[0001] This application is a continuation-in-part application of
U.S. patent application Ser. No. 08/506,541, filed Jul. 24, 1995,
which is a continuation-in-part of (1) U.S. patent application Ser.
No. 07/972,472, filed Mar. 23, 1993, which issued May 9, 1995 as
U.S. Pat. No. 5,413,779; (2) U.S. patent application Ser. No.
08/164,576, filed Dec. 10, 1993, which is in turn a
continuation-in-part of U.S. patent application Ser. No.
07/792,648, filed Nov. 15, 1991, now U.S. Pat. No. 5,380,848, which
is in turn a continuation-in-part of U.S. patent application Ser.
No. 07/564,755, filed Aug. 9, 1990, now U.S. Pat. No. 5,128,118 and
U.S. PCT Application PCT/US91/05553, filed Aug. 9, 1991, filed in
the U.S. PCT Receiving Office and designating the United States;
and (3) U.S. patent application Ser. No. 08/436,970, filed May 8,
1995, all of which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] This invention is directed to a class of binding ligands for
cocaine receptors and other receptors in the brain. Specifically, a
novel family of compounds shows high binding specificity and
activity, and, in a radiolabeled form, can be used to bind to these
receptors, for biochemical assays and imaging techniques. Such
imaging is useful for determining effective doses of new drug
candidates in human populations. In addition, the high specificity,
slow onset and long duration of the action of these compounds at
the receptors makes them particularly well suited for therapeutic
uses, for example as substitute medication for psychostimulant
abuse. Some of these compounds may be useful in treating
Parkinson's Disease or depression, by virtue of their inhibitory
properties at monoamine transporters.
DISCLOSURE OF PARENT APPLICATIONS
[0003] This application claims priority, inter alia, from of U.S.
patent application Ser. No. 07/972,472 filed Mar. 23, 1993, now
U.S. Pat. No. 5,413,779, the entirety of which is incorporated by
reference. This application also claims priority from U.S. patent
application Ser. No. 07/564,755, now U.S. Pat. No. 5,128,118, and
U.S. PCT Application PCT/US91/05553 (the U.S. National Phase of
which is U.S. Ser. No. 07/972,472), filed Aug. 9, 1991, both
applications being incorporated herein by reference. In U.S.
application Ser. No. 07/564,755, there is disclosure of a family of
compounds exhibiting particularly high specificity and affinity for
cocaine receptors and other neurotransmitter receptors in the brain
of the formula:
##STR00001##
[0004] Where the broken line represents an optional chemical bond
and the substituents at 2 and 3 may be at any position;
[0005] The iodo substituent may be at o, m, p, or
multisubstituted;
R.sub.1.dbd.CH.sub.3, CH.sub.2CH.dbd.CH.sub.2,
(CH.sub.2).sub.nC.sub.6H.sub.5 n=1-4; R.sub.2.dbd.CH.sub.3,
C.sub.2H.sub.5, CH.sub.3(CH.sub.2).sub.3, (CH.sub.3).sub.2CH,
C.sub.6HS, C.sub.6H.sub.5CH.sub.2, C.sub.6H.sub.5(CH.sub.2).sub.2;
X=pharmacologically acceptable anion Sites of specific interest
included cocaine receptors associated with dopamine (DA)
transporter sites.
[0006] Subsequently, in the U.S. PCT Application from which
priority is claimed, and which is incorporated herein by reference,
the values for R.sub.1 and R.sub.2 were expanded, such that R.sub.1
may be an alkyl of 1-7 carbon atoms,
CH.sub.2CR.sub.3.dbd.CR.sub.4R.sub.5 wherein R.sub.3-R.sub.5 are
each, independently C.sub.1-6 alkyl, or phenyl compounds of the
formula C.sub.6H.sub.5(CH.sub.2).sub.y, wherein y=1-6. The PCT
filing also reveals the affinity of these compounds for cocaine
receptors associated with serotonin (5-hydroxytryptamine, 5-HT)
transporters, and confirms, for the first time, that the in vitro
binding reported in the earlier-filed application, is confirmed in
in vivo testing. Specific disclosure for a variety of applications,
including using the compounds in both PET and SPECT scanning,
wherein either the iodine substituent, or one of the carbon groups
is radioactive (I-123, 125 or 131 and C11) thus providing methods
for scanning for the presence of specific cocaine receptors. Such
scanning processes may be used to determine physiological
conditions associated with dopamine and serotonin reuptabe
inhibitors, which lead to behavioral and neurodegenerative
disorders/diseases. Such disorders include depression, bipolar
disorder, eating disorders, obesity, attention deficit disorder,
panic attacks and disorders, obsessive-compulsive disorder,
Parkinson's Disease, and cocaine, nicotine and alcohol addiction.
These compounds, in addition to being used in treatment of these
disorders, may be used to examine in general the density and
distribution of specific cocaine receptors in various parts of the
brain and/or body, to determine the efficacy of neurological
treatments aimed at halting or reversing the degeneration of
specific nerves in the brain, and for screening drugs, such as
antidepressant drugs.
[0007] The affinity and specificity of these compounds, as reported
in the applications incorporated, is surprisingly high, and
compared with prior art compounds, such as [.sup.3H]WIN 35,428, the
novel compounds of these applications exhibit extremely low
IC.sub.50 values for binding inhibition.
[0008] In U.S. patent application Ser. No. 08/164,576, filed Dec.
10, 1993, also incorporated herein by reference in its entirety, a
family of compounds was disclosed, having the formula:
##STR00002##
[0009] Wherein Y is
##STR00003##
Wherein
[0010] R.sub.1 is hydrogen, C.sub.1-5 alkyl R.sub.a is phenyl,
C.sub.1-6 alkyl, C.sub.1-6 alkyl-substituted phenyl R.sub.b is
C.sub.1-6 alkyl, phenyl, C.sub.1-6 alkyl substituted phenyl and Z
is phenyl or naphtyl bearing 1-3 substituents selected from the
group consisting of F, Cl, I, and C.sub.1-6 alkyl.
[0011] These compounds exhibit unusually high affinity and
specificity for binding to receptors for the dopamine transporter
site, as well as the serotonin transporter site, based on
inhibition of [.sup.3H]paroxetine binding. This high affinity makes
certain of these compounds particularly well suited for use as
therapeutic agents, as well as for imaging agents for dopamine and
serotonin transporters.
SUMMARY OF THE INVENTION
[0012] Accordingly, one object of this invention is to provide
novel compounds which bind to cocaine receptors.
[0013] Another object of the invention is to provide novel
3-(substituted phenyl)-2-(substituted)tropane analogs which bind to
cocaine receptors.
[0014] Still another object of the invention is to provide
3-(substituted phenyl)-2-(substituted)tropane analogs which bind
preferentially to the dopamine transporter.
[0015] Yet another object of the invention is to provide
3-(substituted phenyl)-2-(substituted)tropane analogs which bind
preferentially to the serotonin transporter.
[0016] Another object of the invention is to provide a compound of
the formula
##STR00004##
wherein R is CH.sub.3, C.sub.2H.sub.5, CH.sub.2CH.sub.2CH.sub.3, or
CH(CH.sub.3).sub.2, R.sub.1 is CH.sub.3, CH.sub.2C6H.sub.5,
(CH.sub.2).sub.2C.sub.6H.sub.5, (CH.sub.2).sub.3C.sub.6Hs, or
##STR00005##
wherein X is H, OCH.sub.3, or Cl and Y is H, OCH.sub.3, or Cl, and
n=1-8.
[0017] Another object of the invention is to provide compounds
having the following formulas:
##STR00006##
wherein R.sub.1=hydrogen, C.sub.1-5 alkyl, X.dbd.H, C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-6 alkynyl,
halogen, amino, acylamido, and Z=H, I, Br, Cl, F, CN, CF.sub.3,
NO.sub.2, N.sub.3, OR.sub.1, CONH.sub.2, CO.sub.2R.sub.1, C.sub.1-6
alkyl, NR.sub.4R.sub.5, NHCOR.sub.5, NHCO.sub.2R.sub.6, R.sub.b is
C.sub.1-6 alkyl, phenyl, C.sub.1-6 alkyl substituted phenyl
##STR00007##
[0018] A further object of the invention is to provide a method for
treating psychostimulant abuse, by administering to a patient in
need of such treatment a pharmaceutically effective amount of a
3-(substituted phenyl)-2-(substituted)tropane analog.
[0019] A still further object of the invention is to provide method
for inhibiting the action of a psychostimulant, by administering to
a patient in need of such treatment a psychostimulant-inhibiting
amount of a 3-(substituted phenyl)-2-(substituted)tropane
analog.
[0020] Still another object of the invention is to provide a method
for inhibiting neurotransmitter re-uptake by administering to a
patient in need of such treatment a neurotransmitter
transporter-inhibiting amount of a 3-(substituted
phenyl)-2-(substituted)tropane analog.
[0021] Another object of the invention is to provide a method for
treating neurodegenerative disorders, by administering to a patient
in need of such treatment a pharmaceutically effective amount of a
3-(substituted phenyl)-2-(substituted)tropane analog.
[0022] Still another object of the invention is to provide a method
for treating depression, by administering to a patient in need of
such treatment a pharmaceutically effective amount of a
3-(substituted phenyl)-2-(substituted)tropane analog.
[0023] Briefly, the invention pertains to the discovery that
certain cocaine analogs are particularly well suited for
therapeutic use as neurochemical agents. These particular cocaine
analogs, in modulating neurotransmitter actions, may also be useful
for modulating the actions of pyschostimulant drugs, for modulating
endocrine function, for modulating motor function, and for
modulating complex behaviors.
[0024] With the foregoing and other objects, advantages and
features of the invention that will become here in after apparent,
the nature of the invention may be more clearly understood by
reference to the following detailed description of the preferred
embodiments of the invention and to the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same becomes better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0026] FIG. 1 depicts the scheme for converting 3-(substituted
phenyl)-2-tropane carboxylic acid (tropane acid) to 2-substituted
tetrazoles, oxazoles, oxadiazoles, thiazoles, thiadiazoles and
benzothiazole.
[0027] FIG. 2 depicts the scheme in which the carboxamide obtained
from the tropane acid was treated to obtain nitriles and
tetrazoles.
[0028] FIG. 3 depicts the scheme used to prepare 3-substituted
isoxazoles.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention includes novel compounds having the
following formula:
##STR00008##
[0030] The compounds of this invention can be prepared according to
the synthesis methods described in the parent applications.
Alternative synthesis for related compounds will be apparent to
those of ordinary skill in the art. Particular synthesis schemes
are exemplified in U.S. Pat. No. 5,444,070, which is incorporated
herein in its entirety. Additional schemes follow hereinbelow.
Preparation of 3.beta.-(Substituted
phenyl)tropane-2.beta.-heterocyclic Analogues
Chemistry
[0031] The known 3.beta.-(substituted phenyl)-2.beta.-tropane
carboxylic acid (tropane acid) (Carroll et al., J. Med. Chem.
35:1813-1817 (1992)) served as the starting material for the
synthesis of 2.beta.-substituted tetrazoles, oxazoles, oxadiazoles,
thiazoles, thiadiazoles and benzothiazole as shown in FIG. 1.
[0032] The tropane acid was refluxed with N-acetyl and benzoic
hydrazide in phosphorous oxychloride to obtain the corresponding
5-substituted 1,3,4-oxadiazoles (Afanasiadi et al., Chem.
Heterocyclic Compd. 397-400 (1995)). N-benzoyl hydrazide amide
obtained by the reaction of the acid chloride of tropane acid with
N-benzoic hydrazide was cyclized with Lawesson's reagent
(El-Barbary et al., Acta Chimica Scandinavica 597-601 (1980)) in
refluxing THF to the 5-substituted 1,3,4-thiadiazoles. The
N-phenylacyl carboxamide obtained from tropane acid and
2-aminoacetophenone was cyclized by refluxing the amide in
phosphorous oxychloride to obtain the required 5-substituted
oxazoles (Carroll et al., Med. Chem. Res. 3:468 (1993)).
Cyclization of the same amide with Lawesson's reagent (El-Barbary
et al., 1980) in refluxing THF gave the 5-substituted thiazoles
respectively. The benzothiazole was obtained without the
cyclization step by the reaction of acid chloride obtained from the
appropriate tropane acid with 2-aminothiophenol.
[0033] The previously reported carboxamide (Carroll et al., 1993)
obtained from the tropane acid was dehydrated with trifluoroacetic
acid and pyridine in THF to the nitrites (Campagna et al., Tet.
Letts. 22:1813-1816 (1977)) as shown in FIG. 2. Cycloaddition of
trimethylsilylazide to the nitrile afforded the corresponding
tetrazoles (Saunders et al., Med. Chem. 33:1128-1138 (1990)).
[0034] FIG. 3 outlines the route used to prepare 3-substituted
isoxazole. The known tropane compounds (Carroll et al., J. Med.
Chem. 34:2719-2725 (1991)) were treated with dilithiated methyl or
phenyl acetoneoximes, obtained by the treatment of acetone or
acetophenoneoxime with n-BuLi at 0.degree. C. The corresponding
addition product was cyclized without isolation using sulfuric acid
at reflux temperature to furnish the required isoxazoles (Saunders
et al., 1990).
[0035] The therapeutic effects of the present cocaine analogs can
be analyzed in various ways, many of which are well known to those
of skill in the art. In particular, both in vitro and in vivo assay
systems may be used for the screening of potential drugs which act
as agonists or antagonists at cocaine receptors, or drugs which are
effective to modulate neurotransmitter level or activity, in
particular by binding to a transporter of that
neurotransmitter.
[0036] The compounds of the invention may be prepared and labeled
with any detectable moiety, in particular a radioactive element,
and may then be introduced into a tissue or cellular sample. After
the labeled material or its binding partner(s) has had an
opportunity to react with sites within the sample, the location and
concentration of binding of the compound may be examined by known
techniques, which may vary with the nature of the label
attached.
[0037] Illustrative in vitro assays for binding are described in
Boja et al Ann. NY Acad. Sci. 654:282-291 (1992), which is
incorporated herein by reference in its entirety. A particularly
preferred in vitro assay involves the ability of a compound in
question to displace the binding of a known labelled compound to
binding sites in a tissue sample, isolated membranes or
synaptosomes. Alternatively, the compounds may be analyzed by their
ability to inhibit reuptake of a labelled neurotransmitter in a
sample, in particular, in synaptosomes.
[0038] The compound or its binding partner(s) can also be labeled
with any detectable moiety, but are preferably labelled with a
radioactive element. The radioactive label can be detected by any
of the currently available counting procedures, including the
imaging procedures detailed in the disclosures of the parent
applications. The preferred isotope may be selected from .sup.3H,
.sup.11C, .sup.14C, .sup.11C, .sup.32P, .sup.35S, .sup.36Cl,
.sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.90Y, .sup.125I,
.sup.131I, and .sup.186Re.c,
[0039] As noted in the parent disclosures, the binding of the
labelled compounds may be analyzed by various imaging techniques,
including positron emission tomography (PET), single photon
emission computed tomography (SPECT), autoradiogram, and the like.
Such imaging techniques are useful for determining effective doses
of new drug candidates. By performing in vivo competition studies,
it is possible to use brain imaging studies to determine the oral
doses of new drug candidates, which produce significant receptor
occupancy in the brain. In vivo displacement studies which
determine in vivo IC50's which in turn reflect doses that occupy
receptors in vivo are described in Cline et al ((1992) Synapse
12:37-46). In addition to its uses in determining in vivo
potency/occupancy, these same brain imaging methods can be used to
determine rate of entry of compounds into the brain (Stathis et al
(1995) Psychopharmacology 119:376-384) and duration of action
(Volkow et al (1995) Synapse 19:206-211).
[0040] The binding of the compounds of the invention may be at any
location where a receptor for a particular psychostimulant is
present, and more specifically, any location where a dopamine or
serotonin transporter is present. Such locations are in general any
area comprising a part of the dopamine or serotonin pathway, in
particular at synapses. Examples of locations known to be
associated with dopamine transport include the cerebral cortex,
hypothalamus, substantia nigra, nucleus accumbens, arcuate nucleus,
anterior periventricular nuclei, median eminence and amygdala.
Examples of locations known to be associated with serotonin include
the striatum, cerebral cortex, hypothalamus, Raphe nuclei,
pre-optic area and suprachiasmatic nucleus.
[0041] By "psychostimulant" is meant any compounds whose abuse is
dependent upon mesolimbic and mesocortical dopaminergic pathways.
In particular, psychostimulant relates to cocaine. However, the
compounds of the invention may also be used to treat abuse of
compounds not traditionally classified as "psychostimulants," but
which act at a dopamine or serotonin transporter. Such abused
compounds include ethanol and nicotine.
[0042] For in vivo studies, the compounds of the invention may be
prepared in pharmaceutical compositions, with a suitable carrier
and at a strength effective for administration by various means to
a patient experiencing an adverse medical condition associated with
cocaine receptor binding or neurotransmitter release and reuptake,
for the treatment thereof. The action of the compounds may be
analyzed by the imaging methods noted above, and also by behavioral
studies. In particular, the pharmaceutical effects of the compounds
of the invention may be reflected in locomotor activity, including
the induction of ipsilateral rotation, stereotyped sniffing and the
"swim test", in schedule-controlled operant behavior (i.e.,
response for food or shock termination) or drug
self-administration. In general, maximal behavioral effects are
seen at near complete occupancy of transporter sites. Such
protocols are described in Boja et al (1992), Balster et al Drug
and Alcohol Dependence 29:145-151 (1991), Cline et al Pharm. Exp.
Ther. 260:1174-1179 (1992), and Cline et al Behavioral Pharmacology
3:113-116 (1992), which are hereby incorporated herein by reference
in their entireties.
[0043] A variety of administrative techniques may be utilized,
among them oral or parenteral techniques such as subcutaneous,
intravenous, intraperitoneal, intracerebral and
intracerebroventricular injections, catheterizations and the like.
Average quantities of the compounds may vary in accordance with the
binding properties of the compound (i.e., affinity, onset and
duration of binding) and in particular should be based upon the
recommendations and prescription of a qualified physician or
veterinarian.
[0044] The compounds of the invention preferably have a long
duration of action, which is important to facilitate dosing
schedules. In rats, the present compounds have a 7-10 fold longer
duration of action than cocaine (Fleckenstein et al, "Highly potent
cocaine analogs cause long-lasting increases in locomotor
activity," Eur. J. Pharmacol., in press, which is incorporated
herein by reference in its entirety). In addition, the present
compounds also preferably have a slow rate of entry into the brain,
which is important in decreasing the potential for abuse (Stathis
et al, supra, which is incorporated herein by reference in its
entirety). The present compounds enter the brain more slowly than
cocaine.
[0045] The therapeutic compositions useful in practicing the
therapeutic methods of this invention may include, in admixture, a
pharmaceutically acceptable excipient (carrier) and one or more of
the compounds of the invention, as described herein as an active
ingredient.
[0046] The preparation of therapeutic compositions which contain
such neuroactive compounds as active ingredients is well understood
in the art. Such compositions may be prepared for oral
administration, or as injectables, either as liquid solutions or
suspensions however, solid forms suitable for solution in, or
suspension in, liquid prior to injection can also be prepared. The
preparation can also be emulsified. The active therapeutic
ingredient is often mixed with excipients which are
pharmaceutically acceptable and compatible with the active
ingredient. Suitable excipients are, for example, water, saline,
dextrose, glycerol, ethanol, or the like and combinations thereof.
In addition, if desired, the composition can contain minor amounts
of auxiliary substances such as wetting or emulsifying agents, and
pH buffering agents which enhance the effectiveness of the active
ingredient. The compounds of the invention can be formulated into
the therapeutic composition as neutralized pharmaceutically
acceptable salt forms.
[0047] The therapeutic compositions are conventionally administered
orally, by unit dose, for example. The term "unit dose" when used
in reference to a therapeutic composition of the present invention
refers to physically discrete units suitable as unitary dosage for
humans, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect in
association with the required diluent; i.e., carrier, or
vehicle.
[0048] The compositions are administered in a manner compatible
with the dosage formulation, and in a therapeutically effective
amount. The quantity to be administered depends on the subject to
be treated, the presence of other agonists and antagonists in the
subject's system, and degree of binding or inhibition of binding
desired. Precise amounts of active ingredient required to be
administered depend on the judgment of the practitioner and are
peculiar to each individual. However, suitable dosages may range
from about 0.01 to about 1000, preferably about 0.25 to about 500,
and more preferably 10 to 50 milligrams of active ingredient per
kilogram body weight of individual per day and depend on the route
of administration. However, the exact dosage must be determined by
factoring in rate of degradation in the stomach, absorption from
the stomach, other medications administered, etc. Suitable regimes
for administration and are also variable, but are typified by an
initial administration followed by repeated doses at one or more
hour intervals by a subsequent injection or other administration.
Alternatively, continuous intravenous infusion sufficient to
maintain appropriate concentrations in the blood are
contemplated.
[0049] The compounds of the present invention may be administered
for their activities as surrogate agonist medications for cocaine,
nicotine, alcohol, amphetamine and other psychostimulant abuse.
Because of their favorable binding characteristics to transporters
of neurotransmitters, they may be used for inhibiting the uptake of
dopamine, norepinephrine, serotonin and other monoamines. The
compounds of the present invention may find use as antipsychotics,
antidepressants, local anesthetics, anti-Parkinsonian agents,
anti-obesity drugs, drugs useful in the treatment of bipolar
disorder, eating disorders, obesity, attention deficit disorder,
panic attacks and disorder, obsessive-compulsive disorder, sexual
dysfunction, as anticholinergic agents and as sigma receptor
drugs.
[0050] The compounds of the invention may also be useful in
treating neurodegenerative disorders, in particular for treating
Parkinson's Disease, but also may be useful in the treatment of
cocaine, nicotine and alcohol addiction.
[0051] The preferred compounds of the present invention are derived
from the series of compounds designated RTI-4229. The physical
properties of some of these compounds are given in Table I.
TABLE-US-00001 TABLE I Physical Properties of 2.beta.-substituted
Hetrocyclic Analogs of 3.beta.-(4-Substituted-phenyl) Tropane and
Cocaine Molecular code name Compound Formulae.sup.a mp.degree. C.
[.alpha.].sub.D (c) MeOH Yield % RTI-188
C.sub.22H.sub.23Cl.sub.2N.sub.3O.sup.e 160-162 +84.59 (0.36) 42
RTI-195 C.sub.23H.sub.26ClN.sub.3O.sup.e 175-178 +97.22 (0.25) 40
RTI-194 C.sub.18H.sub.24ClN.sub.3O.sup.d 146 (dec) -43.05 (0.15) 58
RTI-200 C.sub.22H.sub.23Cl.sub.2N.sub.3S.sup.e 165-170 -42.81
(0.16) 58 RTI-199 C.sub.23H.sub.26ClN.sub.3S.sup.d 180-185 -33.50
(0.20) 58 RTI-189 C.sub.27H.sub.29ClN.sub.2O.sub.7.sup.b,e 126
(dec) +101.43 (0.21) 49 RTI-178
C.sub.28H.sub.32N.sub.2O.sub.7.sup.b,f 175-181 -104.04 (0.60) 72
RTI-219 C.sub.23H.sub.24ClN.sub.2S.sup.f 228-230 +27.43 (0.11) 30
RTI-202 C.sub.21H.sub.22Cl.sub.2N.sub.2S.sup.c 140-150 (dec)
-172.49 (0.28) 41 RTI-161 C.sub.15H.sub.18Cl.sub.2N.sub.2.sup.e
>220 (dec) -71.00 (0.50) 77 RTI-158 C.sub.16H.sub.21ClN.sub.2
270 (dec) -76.40 (0.50) 67 RTI-163 C.sub.15H.sub.18ClN.sub.5.sup.e
296-300 -124.94 (0.39) 33 RTI-157
C.sub.16H.sub.23Cl.sub.2N.sub.5.sup.c >212 (dec) -110.97 (0.16)
88 RTI-165 C.sub.18H.sub.22Cl.sub.2N.sub.2O 235 (dec) -102.89
(0.46) 46 RTI-171 C.sub.19H.sub.25ClN.sub.2O 277 -107.28 (0.71) 62
RTI-180 C.sub.18H.sub.22ClN.sub.2O.sup.c >235 (dec) -94.57
(0.39) 49 RTI-177 C.sub.23H.sub.24Cl.sub.2N.sub.2O.sup.c 287 -97.50
(0.28) 50 RTI-176 C.sub.24H.sub.27ClN.sub.2O 270-295 (dec) -102.22
(0.68) 77 RTI-181 C.sub.23H.sub.24ClN.sub.2O.sup.d >2679 (dec)
-91.11 (0.43) 56 RTI-184 C.sub.19H.sub.23ClN.sub.2O.sub.3.sup.d
117-121 -53.60 (0.25) 82 RTI-185
C.sub.2.sub.4H.sub.25ClN.sub.2O.sub.3 205 -56.71 (0.43) 68
.sup.aHCl Salt; .sup.bTartrate Salt; .sup.c0.25 mol water;
.sup.d0.5 mol water; .sup.e0.75 mol water; .sup.f1 mol water.
Many of the preferred compounds of the invention fall within the
broad class of compounds described by the formula:
##STR00009##
R.sub.1=hydrogen, C.sub.1-5 alkyl,
##STR00010##
R.sub.2=hydrogen, C.sub.1-6 alkyl, C.sub.3-8, cycloalkyl, C.sub.1-4
alkoxy, C.sub.1-6alkynyl, halogen, amine, CH.sub.2C.sub.6H.sub.5,
(CH.sub.2).sub.2C.sub.6H.sub.5, (CH.sub.2).sub.3C.sub.6H.sub.5
or
##STR00011##
[0052] R.sub.3.dbd.OH, hydrogen, C.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, C.sub.1-4 alkoxy, Cl, Br, I, CN, NH.sub.2, NHC.sub.1-6
alkyl, NC.sub.1-6 alkyl, OCOC.sub.1-6 alkyl, OCOC.sub.1-3
alkylaryl,
A=S, O or N
[0053] X.dbd.H, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-4
alkoxy, C.sub.1-6 alkynyl, halogen, amino, acylamido,
C.sub.2H.sub.5, CH.sub.2CH.sub.3CH.sub.3, CH(CH.sub.3).sub.2, Z=H,
I, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3, OR.sub.1,
CONH.sub.2, CO.sub.2R.sub.1, C.sub.1-6 alkyl, NR.sub.4R.sub.5,
NHCOR.sub.5, NHCO.sub.2R.sub.6, and Q.sup.1 and Q.sup.2 may be the
same or different and .dbd.H, OCH.sub.3, or Cl, wherein
R.sub.4-R.sub.6 are each C.sub.1-6 alkyl, R and R.sup.1 are
independently H, C.sub.1-6 alkyl, C.sub.1-6 alkene, C.sub.1-6
alkyne, phenyl, phenyl substituted with 1-3 of C.sub.1-6 alkyl,
alkene, alkyl or alkoxy, C.sub.1-6 alkoxy, phenoxy, amine, amine
substituted with 1-2 of C.sub.1-6 alkyl, alkene, alkyne, alkoxy or
phenyl or phenoxy or R and R.sup.1 may combine to form heterocyclic
structure including pyrrolidinyl, piperidinyl and morpholino
moieties, unsubstituted or substituted with 1-2 C.sub.1-6 alkyl,
alkene, alkyne or alkoxy groups.
[0054] The present inventors have surprisingly found that certain
of the RTI-4229 series of compounds are particularly potent
pharmaceutical agents in accordance with the present invention.
[0055] Preferred compounds of the RTI-4229 series include the
following: RTI-4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108,
110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146,
147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203,
204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277,
278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309,
318, and 330. The chemical structures of these compounds, along
with their IC.sub.50 values for inhibition of radioligand binding
are given below. DA is dopamine, 5-HT is 5-hydroxytryptamine
(serotonin) and NE is norepinephrine, DA=[.sup.3H]WIN 35,428;
5-HT=[.sup.3H] paroxetine and NE.sub.N=[.sup.3H] nisofetine:
TABLE-US-00002 RTI-4229-31 DA5-HTNE.sub.N 1.12 .+-. 0.1 44.5 .+-.
1.34 37 .+-. 2.1 ##STR00012## RTI-4229-32 DA5-HTNE.sub.N 1.71 .+-.
0.31240 .+-. 27 60 .+-. 0.53 ##STR00013## RTI-4229-51
DA5-HTNE.sub.N 1.69 .+-. 0.2310.6 .+-. 0.2437.4 .+-. 5.2
##STR00014## RTI-4229-55 DA5-HTNE.sub.N 1.26 .+-. 0.044.21 .+-.
0.3436 .+-. 3 ##STR00015## RTI-4229-83 DA5-HTNE.sub.N 55 .+-. 2
28.4 .+-. 3.834,027.87 .+-. 380.70 ##STR00016## RTI-4229-96
DA5-HTNE.sub.N 2.95 .+-. 0.58 76 .+-. 2.8 520 .+-. 10.4
##STR00017## RTI-4229-97 DA5-HTNE.sub.N 3.91 .+-. 0.59181 .+-. 14
282 .+-. 30 ##STR00018## RTI-4229-98 DA5-HTNE.sub.N 0.69 .+-. 0.2
0.36 .+-. 0.04710.97 .+-. 0.88 ##STR00019## RTI-4229-101
DA5-HTNE.sub.N 2.2 .+-. 0.19 26 .+-. 3.2.+-. ##STR00020##
RTI-4229-105 DA5-HTNE.sub.N 1.60 .+-. 0.05143 .+-. 25 127.2 .+-.
5.9 ##STR00021## RTI-4229-108 DA5-HTNE.sub.N 2.64 .+-. 0.31 98 .+-.
8.7129.3 .+-. 15 ##STR00022## RTI-4229-110 DA5-HTNE.sub.N 0.62 .+-.
0.094.13 .+-. 0.625.45 .+-. 0.21 ##STR00023## RTI-4229-111
DA5-HTNE.sub.N 0.79 .+-. 0.083.13 .+-. 0.3617.96 .+-. 0.85
##STR00024## RTI-4229-112 DA5-HTNE.sub.N 0.82 .+-. 0.0510.5 .+-.
0.4136.2 .+-. 1.02 ##STR00025## RTI-4229-116 DA5-HTNE.sub.N 33 .+-.
3.91,227 .+-. 176 967.55 .+-. 26.25 ##STR00026## RTI-4229-121
DA5-HTNE.sub.N 0.43 .+-. 0.0566.84 .+-. 6.53 285 .+-. 7.6
##STR00027## RTI-4229-122 DA5-HTNE.sub.N 1.50 .+-. 0.35184.38 .+-.
21.91 3,791 .+-. 149 ##STR00028## RTI-4229-127 DA5-HTNE.sub.N 19
.+-. 1 4,499 .+-. 557 3,444 .+-. 44 ##STR00029## RTI-4229-132
DA5-HTNE.sub.N 3.48 .+-. 0.11208 .+-. 18 137.3 .+-. 10.5
##STR00030## RTI-4229-139 DA5-HTNE.sub.N 1.67 .+-. 0.13 85 .+-.
9.356.9 .+-. 2.6 ##STR00031## RTI-4229-140 DA5-HTNE.sub.N 101 .+-.
16 5,701 .+-. 721 2,076 .+-. 285 ##STR00032## RTI-4229-142
DA5-HTNE.sub.N 4.39 .+-. 0.2068.59 .+-. 2.02 18.78 .+-. 0.68
##STR00033## RTI-4229-145 DA5-HTNE.sub.N 9.60 .+-. 0.422,932 .+-.
181 1,478 .+-. 96 ##STR00034## RTI-4229-146 DA5-HTNE.sub.N 2.05
.+-. 0.2398 .+-. 10144 .+-. 3 ##STR00035## RTI-4229-147
DA5-HTNE.sub.N 1.38 .+-. 0.0312,393.99 .+-. 1207.03 3,949 .+-. 72
##STR00036## RTI-4229-150 DA5-HTNE.sub.N 3.74 .+-. 0.522,019 .+-.
133 4,738 .+-. 322 ##STR00037## RTI-4229-153 DA5-HTNE.sub.N 1.06
.+-. 0.123.59 .+-. 0.27132 .+-. 5 ##STR00038## RTI-4229-173
DA5-HTNE.sub.N 49.9 .+-. 7.3 8.13 .+-. 0.30122 .+-. 12 ##STR00039##
RTI-4229-178 DA5-HTNE.sub.N 35.4 .+-. 1.741,698.77 .+-. 166.68 677
.+-. 67.5 ##STR00040## RTI-4229-188 DA5-HTNE.sub.N 12.56 .+-. 1.03
3,303.76 .+-. 195.85 929 .+-. 88.1 ##STR00041## RTI-4229-189
DA5-HTNE.sub.N 19.71 .+-. 1.98 1,116.18 .+-. 107.148 496 .+-. 42.1
##STR00042## RTI-4229-190 DA5-HTNE.sub.N 0.96 .+-. 0.10168 .+-. 1.8
235 .+-. 8.39 ##STR00043## RTI-4229-191 DA5-HTNE.sub.N 0.61 .+-.
0.0815.5 .+-. 0.72101.7 .+-. 10.5 ##STR00044## RTI-4229-193
DA5-HTNE.sub.N 1.68 .+-. 0.141,066.38 .+-. 109.12 644 .+-. 27.7
##STR00045## RTI-4229-195 DA5-HTNE.sub.N 47.48 .+-. 4.76 22,310.9
.+-. 822.83 1,310 .+-. 36.7 ##STR00046## RTI-4229-199
DA5-HTNE.sub.N 35.88 .+-. 3.40 51,459.7 .+-. 4,513.1024,320.8 .+-.
3,822.61 ##STR00047## RTI-4229-200 DA5-HTNE.sub.N 15.29 .+-. 2.43
18,416.5 .+-. 1,508.794,142.08 .+-. 466.07 ##STR00048##
RTI-4229-203 DA5-HTNE.sub.N 9.37 .+-. 0.522,153.39 .+-. 143.18
2,743.73 .+-. 140.92 ##STR00049## RTI-4229-204 DA5-HTNE.sub.N 3.91
.+-. 0.233,772.17 + 383.64 4,782.70 .+-. 487.10 ##STR00050##
RTI-4229-205 DA5-HTNE.sub.N 8.19 .+-. 0.905,237.30 .+-. 453.397
2,136.62 .+-. 208.52 ##STR00051## RTI-4229-206 DA5-HTNE.sub.N 27.38
.+-. 1.47 1,203.39 .+-. 41.79 1,277.60 .+-. 117.68 ##STR00052##
RTI-4229-219 DA5-HTNE.sub.N 5.71 .+-. 0.3610,341.5 .+-. 76.11 8,563
.+-. 824 ##STR00053## RTI-4229-230 DA5-HTNE.sub.N 1.28 .+-.
0.1757.41 .+-. 5.04 141 .+-. 16.1 ##STR00054## RTI-4229-239
DA5-HTNE.sub.N 0.61 .+-. 0.07114.3 .+-. 3.69 35.6 .+-. 2.57
##STR00055## RTI-4229-240 DA5-HTNE.sub.N 1.38 .+-. 0.0338.4 .+-.
2.3184.5 .+-. 3.09 ##STR00056## RTI-4229-241 DA5-HTNE.sub.N 1.02
.+-. 0.06618.5 .+-. 28 124 .+-. 3.56 ##STR00057## RTI-4229-242
DA5-HTNE.sub.N 7.67 .+-. 0.31226.54 .+-. 27.37 510.1 .+-. 51.4
##STR00058## RTI-4229-251 DA5-HTNE.sub.N 1.93 .+-. 0.1410.1 .+-.
1.1 114 .+-. 13.1 ##STR00059## RTI-4229-252 DA5-HTNE.sub.N 2.56
.+-. 0.2235.2 .+-. 2.45124.6 .+-. 8.3 ##STR00060## RTI-4229-274
DA5-HTNE.sub.N 3.96 .+-. 0.2 5.62 .+-. 0.2 14.4 .+-. 1.3
##STR00061## RTI-4229-277 DA5-HTNE.sub.N 5.94 .+-. 0.612,909.71
.+-. 255.41 5,695.38 .+-. 214.72 ##STR00062## RTI-4229-278
DA5-HTNE.sub.N 8.14 .+-. 3.732,146.50 .+-. 138.71 4,095.01 .+-.
413.45 ##STR00063## RTI-4229-279 DA5-HTNE.sub.N 5.98 .+-. 0.481.06
.+-. 0.1074.3 .+-. 3.8 ##STR00064## RTI-4229-280 DA5-HTNE.sub.N
3.12 .+-. 0.396.81 .+-. 0.41484.13 .+-. 51.6 ##STR00065##
RTI-4229-281 BIH-141-7 DA5-HTNE.sub.N 2.37 .+-. 0.2815.69 .+-. 1.5
820.5 .+-. 45.8 ##STR00066## RTI-4229-282 BIH-141-2 DA5-HTNE.sub.N
68.53 .+-. 7.08 70.38 .+-. 4.13 3921.58 .+-. 130 ##STR00067##
RTI-4229-283 BIH-141-12 DA5-HTNE.sub.N 14.35 .+-. 0.3 3.13 .+-.
0.163125 .+-. 333 ##STR00068## RTI-4229-286 DA5-HTNE.sub.N 20.7
.+-. 0.575062 .+-. 485 1231 .+-. 91 ##STR00069## RTI-4229-287
DA5-HTNE.sub.N 325 .+-. 20 1686 .+-. 140 17,819 .+-. 440
##STR00070## RTI-4229-296 BIH-141-1 DA5-HTNE.sub.N 5.29 .+-.
0.5311.39 + 0.28 1592.23 .+-. 93.4 ##STR00071## RTI-4229-304
BIH-141-11 DA5-HTNE.sub.N 15.04 .+-. 1.2 7.09 .+-. 0.712799 .+-.
300 ##STR00072## RTI-4229-305 BIH-141-18 DA5-HTNE.sub.N 1.24 .+-.
0.111.59 .+-. 0.2 21.8 .+-. 1.0 ##STR00073## RTI-4229-307
BIH-141-15 DA5-HTNE.sub.N 6.11 .+-. 0.673.16 .+-. 0.33115.6 .+-.
5.1 ##STR00074## RTI-4229-309 BIH-141-17 DA5-HTNE.sub.N 1.73 .+-.
0.052.25 .+-. 0.1714.9 .+-. 1.18 ##STR00075## RTI-4229-318
DA5-HTNE.sub.N 0.51 .+-. 0.030.80 .+-. 0.0621.1 .+-. 1.0
##STR00076## RTI-4229-330 DA5-HTNE.sub.N 310.2 .+-. 21 15.1 .+-.
0.97.+-.
[0056] Particularly preferred compounds include RTI-4229-77, 87,
113, 114, 117, 119, 120, 124, 125, 126, 130, 141, 143, 144, 151,
152, 154, 165, 171, 173, 176, 177, 180, 181, 194, 202, 295, 298,
319, 334, 335, 336, 337, 338, 345, 346, 347, 348, 352 and 353. The
chemical structures of these compounds are given below:
[0057] Particularly preferred compounds include RTI-4229-77, 87,
113, 114, 117, 119, 120, 124, 125, 126, 130, 141, 143, 144, 151,
152, 154, 165, 171, 173, 176, 177, 180, 181, 194, 202, 295, 298,
319, 334, 335, 336, 337, 338, 345, 346, 347, 348, 352 and 353. The
chemical structures of these compounds are given below:
TABLE-US-00003 RTI-4229-77 DA5-HTNE.sub.N 2.51 .+-.
0.25.+-.2,246.86 .+-. 238.99 ##STR00077## RTI-4229-87
DA5-HTNE.sub.N 204 .+-. 29 29,391 .+-. 2,324 35,782 .+-. 6,245
##STR00078## RTI-4229-113 DA5-HTNE.sub.N 1.98 .+-. 0.052.336 .+-.
178 2.955 .+-. 223 ##STR00079## RTI-4229-114 DA5-HTNE.sub.N 1.40
.+-. 0.131.404 .+-. 7.1 778 .+-. 21 ##STR00080## RTI-4229-117
DA5-HTNE.sub.N 6.45 .+-. 0.856.090 .+-. 488 1.926 .+-. 38
##STR00081## RTI-4229-119 DA5-HTNE.sub.N 167 .+-. 13 40,615 .+-.
9,416 6.985 .+-. 635 ##STR00082## RTI-4229-120 DA5-HTNE.sub.N 3.26
.+-. 0.0624,471 .+-. 1,515 5.833 .+-. 373 ##STR00083## RTI-4229-124
DA5-HTNE.sub.N 1,028 .+-. 6533,085 .+-. 5,434 70,993 .+-. 3,563
##STR00084## RTI-4229-125 DA5-HTNE.sub.N 4.05 .+-. 0.572,584 .+-.
799 363 .+-. 36 ##STR00085## RTI-4229-126 DA5-HTNE.sub.N 100 .+-.
6.3 3.824 .+-. 418 7,878 .+-. 551 ##STR00086## RT-4229-130
DA5-HTNE.sub.N 1.52 .+-. 0.02195 .+-. 4.8 245 .+-. 13 ##STR00087##
RTI-4229-141 DA5-HTNE.sub.N 1.81 .+-. 0.19337 .+-. 43 835 .+-. 7.5
##STR00088## RTI-4229-143 DA5-HTNE.sub.N 4.1 .+-. 0.22404 .+-. 56
4,069 .+-. 177 ##STR00089## RTI-4229-144 DA5-HTNE.sub.N 3.44 .+-.
0.36106 .+-. 10 1,825 .+-. 166 ##STR00090## RTI-4229-151
DA5-HTNE.sub.N 2.33 .+-. 0.261,074 .+-. 125 60 .+-. 2 ##STR00091##
RTI-4229-152 DA5-HTNE.sub.N 494 .+-. 37 1.995 .+-. 109 22,689 .+-.
1,957 ##STR00092## RTI-4229-154 DA5-HTNE.sub.N 6.0 .+-. 0.553,460
.+-. 245 135 .+-. 13 ##STR00093## RTI-4229-165 DA5-HTNE.sub.N 0.59
.+-. 0.04572 .+-. 5816.1 .+-. 12 ##STR00094## RTI-4229-171
DA5-HTNE.sub.N 0.93 .+-. 0.093,818.25 .+-. 348.14 254 .+-. 31
##STR00095## RTI-4229-176 DA5-HTNE.sub.N 1.58 .+-. 0.025,109.72
.+-. 187.101 398 .+-. 17.6 ##STR00096## RTI-4229-177 DA5-HTNE.sub.N
1.28 .+-. 0.182,418.21 .+-. 135.58 504 .+-. 29 ##STR00097##
RTI-4229-180 DA5-HTNE.sub.N 0.73 .+-. 0.0436.35 .+-. 4.99 67.9 .+-.
5.25 ##STR00098## RTI-4229-181 DA5-HTNE.sub.N 2.57 .+-. 0.14100
.+-. 9.0 868 .+-. 95 ##STR00099## RTI-4229-194 DA5-HTNE.sub.N 4.45
.+-. 0.124,884.47 .+-. 155.42 253 .+-. 18.9 ##STR00100##
RTI-4229-202 DA5-HTNE.sub.N 1.37 .+-. 0.141,118.85 .+-. 120.00
402.8 .+-. 29.5 ##STR00101## RTI-4229-279 BIH-141-4 DA5-HTNE.sub.N
21.31 .+-. 0.87 2.96 .+-. 0.041349 .+-. 105 ##STR00102##
RTI-4229-298 BIH-141-4 DA5-HTNE.sub.N 3.7 .+-. 0.1646.8 .+-. 5.8
346.6 .+-. 25 ##STR00103## RTI-4229-319 DA5-HTNE.sub.N 1.1 .+-.
0.0911.4 .+-. 1.3 70.2 .+-. 6.28 ##STR00104## RTI-4229-334
DA5-HTNE.sub.N 0.50 .+-. 0.033086 .+-. 153 120 .+-. 10.4
##STR00105## RTI-4229-335 DA5-HTNE.sub.N 1.19 .+-. 0.122318 .+-.
153 954 .+-. 97.3 ##STR00106## RTI-4229-336 DA5-HTNE.sub.N 4.09
.+-. 0.445741 .+-. 421 1714 .+-. 38.5 ##STR00107## RTI-4229-337
DA5-HTNE.sub.N 7.31 .+-. 0.6136,842 .+-. 3616 6321 .+-. 703
##STR00108## RTI-4229-338 DA5-HTNE.sub.N 1104.2 .+-. 54.6 7.41 .+-.
0.553366 .+-. 584 ##STR00109## RTI-4229-345 DA5-HTNE.sub.N 6.42
.+-. 0.46>76,000 .+-. 5290.4 .+-. 448.99 ##STR00110##
RTI-4229-346 DA5-HTNE.sub.N 1.57 .+-. 0.105880.4 .+-. 179 762.01
.+-. 37.8 ##STR00111## RTI-4229-347 DA5-HTNE.sub.N 1.86 .+-.
0.097256.95 .+-. 210 918.4 .+-. 108.34 ##STR00112## RTI-4229-348
DA5-HTNE.sub.N 28.2 .+-. 1.9 34,674 .+-. 3954 2667.2 .+-. 6267.3
##STR00113## RTI-4229-352 DA5-HTNE.sub.N 2.86 .+-. 0.2164.9 .+-.
1.97 52.4 .+-. 4.9 ##STR00114## RTI-4229-353 DA5-HTNE.sub.N 330.54
.+-. 17.12 0.69 .+-. 0.07148.4 .+-. 9.15 ##STR00115##
[0058] It should be noted that compound RTI-353 is a highly potent
compound at the serotonin site, and is selective relative to the
dopamine and norepinephrine sites. This compound is particularly
useful as an antidepressant, and as an imaging agent for serotonin
transporters.
[0059] Having generally described this invention, a further
understanding can be obtained by reference to certain specific
examples which are provided herein for purposes of illustration
only and are not intended to be limiting unless otherwise
specified.
EXAMPLES
[0060] All certified grade reagents or solvents were purchased from
Aldrich Chemical Co. or Fluka Chemical Co. All reagents were
normally used without further purification. When anhydrous
conditions were required, solvents were distilled and dried by
standard techniques immediately prior to use.
[0061] All air and moisture sensitive reactions were conducted
under a prepurified nitrogen atmosphere in flame-dried glassware,
previously dried at 150.degree. C. Anhydrous solvents were
transferred using conventional syringe or steel canula techniques
under an inert atmosphere. Removal of solvents in vacuo was done on
a Buchi rotavapor rotary evaporator operated at water aspirator
pressure.
[0062] .sup.1H NMR and .sup.13C NMR spectra were recorded at 250
Mhz on a Bruker AM250 spectrometer. Optical rotations were recorded
on at the Sodium D line on a Rudolph Research Autopol III
polarimeter (1 dm cell). Melting point was recorded on a Uni-melt
Thomas Hoover capillary melting point apparatus in open capillary
tubes and were uncorrected. Elemental analysis were performed by
Atlantic Microlab, Inc., Norcross, Ga.
[0063] Reaction products were purified by flash column
chromatography using silica gel (mesh size 230-400) purchased from
VWR Scientific. Thin layer chromatography (TLC) was performed on
Whatman 254 nm fluorescent silica gel 60A (1.times.3 inches, 250
[.mu.L thickness]) precoated TLC plates using the solvent systems
indicated. Developed chromatograms were evaluated under 254 nm UV
light or with iodine.
Example 1
General Procedure for the Preparation of Amides
[0064] To a solution of 1 mmol of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxylic acid or
3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxylic acid in 5 ml of
methylene chloride was added dropwise with stirring under nitrogen
2.0 eq oxalyl chloride (2 M solution in methylene chloride). The
resulting solution was stirred at room temperature for an hour
after evolution of gas has ceased. The solvent was removed in vacuo
at room temperature and then at high vacuum to remove residual
traces of oxalyl chloride. The resulting residue of acid chloride
was suspended in 5 ml methylene chloride under nitrogen at
0.degree. C., and 2.0 eq of the amine hydrochloride containing 4.0
eq of triethylamine, or 2.5 eq of the amine free base was added.
The mixture was stirred at room temperature overnight. Aqueous 3N
NaOH (5 ml) was added to basify the reaction mixture, the organic
layer was separated and the aqueous layer extracted with 3.times.10
ml chloroform. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and the solvent removed in vacuo to
give crude product. The crude was purified by flash column
chromatography or crystallization.
Example 2
3.beta.-(4-Chlorophenyl)-2.beta.-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane
Hydrochloride (RTI-188)
[0065] To a solution of 0.59 g (2 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxylic acid (chloro
acid) in 2 ml Of POCl.sub.3 was added 0.31 g (2-2 mmol) of
N-benzoic hydrazide and refluxed under nitrogen- for 2 hours. The
reaction mixture was cooled, poured into ice and rendered basic to
pH 7-8 using concentrated NH.sub.4OH. To the ice cold aqueous layer
was added 10 ml brine and extracted thrice with 10 ml methylene
chloride. The organic layers were combined dried (NaSO.sub.4),
filtered, and the solvent removed in vacuo to give 0.9 g of crude
residue. Purification of the residue by flash column chromatography
[50% (ether/triethylamine 9:1) in hexane] gave 0.33 g (42%) of pure
oxadiazole (RTI-188) which was recrystallized from ether/petroleum
ether: .sup.1H NMR (CDCl.sub.3) 1.81 (m, 3H), 2.18 (s, 3H), 2.26
(m, 2H), 2.66 (m, 1H), 3.33 (m, 2H), 3.51 (m, 2H), 7.16 (m, 4H)
7.45 (m, 3H), 7.86 (m, 2H); IR (CHCl.sub.3) 2950, 1550, 1490, 1450,
1340, 1090 cm.sup.-1; [.alpha.].sub.D -106.25.degree. (c=0.08,
CHCl.sub.3).
[0066] The oxadiazole was converted into hydrochloride salt:
.sup.1H NMR (MeOD) 2.08 (m, 1H), 2.57 (m, 5H), 3.0 (s, 3H), 4.01
(m, 2H), 4.15 (m, 1H), 4.39 (m, 1H), 7.24 (m, 4H), 7-52 (m, 5H): mp
160-162.degree. C.; Anal calcd for
C.sub.22H.sub.23Cl.sub.2N.sub.3O0.75H.sub.2O; C=61.47; H=5.74,
N=9.78; Cl=16.50; found C=61.47, H=5.73, N=9.76; Cl=16.56;
[.alpha.].sub.D +84.59.degree. (c=0.36, CH.sub.3OH).
[0067] Further elution gave as a second fraction 0.1 g (13%) of
white solid which was characterized to be
3.beta.-(4-Chlorophenyl)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane:
.sup.1H NMR (CDCl.sub.3) 1.76 (m, 3H), 2.06 (s, 3H), 2.45 (s, 3H),
3.36 (m, 2H), 3.51 (m, 1H), 3.65 (m, 1H), 7-21 (m, 4H), 7.47 (m,
3H) 7.91 (m, 2H); mp 170-171.degree. C.; Anal calcd for
C.sub.22H.sub.22ClN.sub.3O; C=69.55; H=5.84, N=11.06; Cl=9.33;
found C=69.49, H=5.85, N=11.01; Cl=9.41; [.alpha.].sub.D
+33.06.degree. (c=0.18, CHCl.sub.3).
Example 3
3.beta.-(4-Methylphenyl)-2%-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane
Hydrochloride (RTI-195)
[0068] Reaction of 0.65 g (2.5 mmol) of
3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxylic acid (Methyl
acid) as described above for RTI-188 gave after work-up and
purification by flash column chromatography [(50%
(ether/triethylamine 9:1) in hexane] 0.36 g (40%) of pure
oxadiazole (RTI-195) which was recrystallized from ether/petroleum
ether: .sup.1H NMR (CDCl.sub.3) 1.83 (m, 3H), 2.18 (s, 3H), 2.21
(s, 3H), 2.3 (m, 2H), 2.67 (m, 1H), 3.33 (m, 1H), 3.41 (m, 1H),
3.53 (m, 1H), 3.61 (m, 1H) 7.0 (m, 2H).7.13 (m, 2H), 7.44 (m, 3H),
7.86 (m, 2H); IR (CHCL.sub.3) 2990, 1545, 1505, 1440, 1350.
cm.sup.-1; [.alpha.].sub.D -163.92.degree. (c=0.2, CHCl.sub.3).
[0069] The oxadiazole was converted into hydrochloride salt:
.sup.1H NMR (MeOD) 2.05 (m, 1H), 2.21 (s, 3H), 2.51 (m, 5H), 2.99
(s, 3H), 3.86 (m, 1H), 3.95 (m, 1H), 4.14 (m, 1H), 4.35 (m, 1H),
7.02 (m, 4H) 7.53 (m, 5H); mp 175-178.degree. C.; Anal calcd for
C.sub.23H.sub.26ClN.sub.3O.0.75H.sub.2O; C=67.47; H=6.77, N=10.26;
Cl=8.66; found C=67.58, H=6.79, N=10.34; Cl=8.78; [.alpha.].sub.D
+97.22.degree. (c=0.25, CH.sub.3OH).
[0070] Further elution gave as a second fraction 0.18 g (20%) of
solid which was characterized to be
3.beta.-(4-Methylphenyl)-2.alpha.-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane
which was recrystallized from ether/petroleum ether: .sup.1H NMR
(CDCl.sub.3) 1.77 (m, 2H), 2.0 (m, 4H), 2.25 (s, 3H), 2.47 (s, 3H),
3.33 (m, 2H), 3.51 (m, 1H), 3.69 (d of d, J=2.6, 12 Hz, 1H), 6.91
(m, 2H) 7.03 (m, 2H).7.45 (m, 2H), 7.45 (m, 3H), 7.89 (m, 2H); IR
(CHCL.sub.3) 3020, 1540, 1510, 1415, 1250, 1215. cm.sub.-1; Anal
calcd for C.sub.23H.sub.25N.sub.3O; C=76.85; H=7.01, N=11.69; found
C=76.60, H=7.12, N=11.55; [.alpha.].sub.D +40.73.degree. (c=0.28,
CHCl.sub.3).
Example 4
3.beta.-(4-Methylphenyl)-2.beta.-(5-methyl-1,3,4-oxadiazol-2-yl)-tropane
Hydrochloride (RTI-194)
[0071] Reaction of 0.65 g (2.5 mmol) of methyl acid as described
above for RTI-195 using 0.21 g (2.75 mmol) of N-acetic hydrazide
gave after work-up and Purification by flash column chromatography
[(75% (ether/triethylamine 9:1) in hexane] 0.29 g (39%) of pure
oxadiazole (RTI-194) which was recrystallized from ether/petroleum
ether: .sup.1H NMR (CDCl.sub.3) 1.75 (m, 3H), 2.18 (s, 3H), 2.22
(s, 3H), 2.25 (m, 2H), 2.35 (s, 3H), 2.56 (m, 1H), 3.24 (m, 1H),
3.4 (m, 2H), 3.47 (m, 1H) 7.0 (m, 4H); .sup.13C NMR (CDCl.sub.3)
11.06, 20.9, 25.08, 26.32, 34.11, 34.6, 41.83, 45.73, 61.97, 66.21,
127.11, 128.85, 135.85, 138.19, 162.5, 167.44; IR (CHCL.sub.3)
2950, 1590, 1510, 1450, 1350, 1215 cm.sup.-1; [.alpha.].sub.D
-108.47.degree. (c=0.14, CHCl.sub.3).
[0072] The-oxadiazole was converted into hydrochloride salt:
.sup.1H NMR (MeOD) 1.99 (m, 1H), 2.23 (s, 3H), 2.27 (s, 3H), 2.47
(m, 5H), 2.94 (s, 3H), 3.72 (m, 1H), 3.79 (m, 1H), 4.10 (m, 1H),
4.23 (m, 1H), 7.05 (m, 4H); mp 146.degree. C. (dec); Anal calcd for
C.sub.18H.sub.24ClN.sub.3O.0.5H.sub.2O; C=63.06; H=7.35, N=12.26;
Cl=10.34; found C=63.21, H=7.40, N=12.07; Cl=10.27; [.alpha.].sub.D
-43.05.degree. (c=0.15, CH.sub.3OH).
Example 5
3.beta.-(4-Chlorophenyl)-2.beta.-(5-phenyl-1,3,4-thiadiazol-2-yl)-tropane
Hydrochloride (RTI-200)
[0073] Reaction of 0.59 g (2 mmol) of
3.beta.-(4-Chlorophenyl)tropane-2.beta.-carboxylic acid as
described above for the preparation of amides gave after
purification of the crude by crystallizing from ethyl acetate/ether
0.52 g (66%) of pure
N-[3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxylic]-N'-benzoylhydrazi-
de: .sup.1H NMR (CDCl.sub.3) .delta. 1.76 (m, 3H), 2.24 (m, 2H),
2.41 (s, 3H), 2.51 (m, 1H), 2.68 (m, 1H), 3.18 (m, 1H), 3.44 (m,
2H), 7.22 (m, 4H), 7.46 (m, 3H), 7.78 (m, 2H), 9.02 (br s, 1H),
12.97 (br s, 1H); IR (CHCL.sub.3) 3385, 3035, 3000, 1620, 1570,
1485, 1450, 1215 cm.sup.-1.
[0074] A solution of 0.4 g (1 mmol) of
N-[3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxylic]-N'-benzoyl-hydraz-
ide and 0.8 g (2 mmol) of Lawesson's reagent in 10 ml toluene was
refluxed for 4 h under nitrogen. The reaction mixture was cooled
and solvent removed in vacuo to give a yellow residue. To the
residue was added 3 g of silica gel and 10 ml of methylene
chloride, the resulting slurry was mixed properly and the solvent
removed in vacuo. The crude compound impregnated on silica gel was
loaded on a column and purified by flash column chromatography [50%
ether/triethylamine(9:1) in hexane] to obtain 0.23 g (58%) of pure
thiadiazole (RTI-200) which was further purified by recrystallizing
from ether: .sup.1H NMR (CDCl.sub.3) .delta. 1.75 (m, 3H), 2.20 (m,
3H), 2.32 (s, 3H), 3.30 (m, 3H), 3.78 (m, 1H), 6.86 (m, 2H), 7.08
(m, 2H), 7.43 (m, 3H), 7.97 (m, 2H); .sup.13C NMR 25.55, 25.88,
34.60, 36.09, 41.55, 49.73, 61.48, 65.33, 127.59, 128.28, 128.78,
128.88, 130.37, 130.88, 132.19, 139.27, 168-29, 169.56; IR
(CCl.sub.4) 2940, 1490, 1460, 1340, 1245, 1100, 1010 cm.sup.-1
[0075] The thiadiazole was converted into hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.06 (m, 1H), 2.53 (m, 5H), 2.97 (s,
3H), 3.92 (m, 1H), 4.17 (m, 2H), 4.39 (m, 1H), 7.11 (m, 2H), 7.26
(m, 2H), 7.51 (m, 3H), 7.79 (m, 2H); mp 165-170.degree. C.; Anal
calcd for C.sub.22H.sub.23Cl.sub.2N.sub.3S.0.75H.sub.2O; C=59.26,
H=5.54, N=9.42, Cl=15.90; S=7.19. found C=59.27, H=5.52, N=9.40,
Cl=15.99; S 7.09; [.alpha.].sub.D -42.81.degree. (c=0.16,
MeOH).
[0076] Further elution gave 0.08 g (21%) as a second fraction which
was characterized to be
3.beta.-(4-chlorophenyl)-2.alpha.-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane-
.
Example 6
3.beta.-(4-Methylphenyl)-2.beta.-(5-phenyl-1,3,4-thiadiazol-2-yl)-tropane
Hydrochloride (RTI-199)
[0077] Reaction of 0.65 g (2.5 mmol) of
3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxylic acid as
described above for preparation of amides gave after work up and
purification by flash column chromatography [(50% CMA-80 in
methylene chloride)] 0.48 g (51%) pure N-[3.beta.-(4-Methylphenyl)
Tropane-2.beta.-carboxylic]-N'-benzoyl-hydrazide which was further
purified by recrystallizing from ether/pet ether: .sup.1H NMR
(CDCl.sub.3) .delta. 1.75 (m, 3H), 2.20 (m, 2H), 2.27 (s, 3H), 2.42
(s, 3H), 2.51 (m, 1H), 2.67 (m, 1H), 3.18 (m, 1H), 3.47 (m, 2H),
7.11 (m, 4H), 7.48 (m, 3H), 7.81 (m, 2H), 9.06 (br s, 1H), 13.09
(br s, 1H); IR (CHCl.sub.3) 3385, 3045, 1625, 1570, 1460, 1420,
1100 cm.sup.-1;
[0078] Reaction of 0.29 g (0.75 mmol) of
N-[3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxylic]-N'-benzoyl-hydraz-
ide as described above for RTI-200 gave after work and purification
by flash chromatography [40% ether/triethylamine(9:1) in hexane]
0.16 g (58%) of pure thiadiazole (RTI-199): .sup.1H NMR
(CDCl.sub.3) .delta. 1.70 (m, 1H), 1.88 (m, 2H), 2.20 (s, 3H), 2.23
(m, 2H), 2.21 (s, 3H), 2.38 (m, 1H), 3.21 (m, 1H), 3.32 (m, 1H),
3.39 (m, 1H), 3.78 (m, 1H), 6.81 (m, 2H), 6.92 (m, 2H), 7.43 (m,
3H), 7.97 (m, 2H); .sup.13C NMR 20.98, 25.65, 25.95, 34.79, 36.25,
41.65, 50.05, 61.68, 65.49, 127.32, 127.65, 128.89, 128.95, 130.29,
131.11, 135.94, 137.68, 168.83, 169.45; IR (CCl.sub.4) 2935, 1510,
1450, 1250, 1120, 1100, 1060 cm.sup.-1
[0079] The thiadiazole was converted into hydrochloride salt;
.sup.1H NMR (MeOD) .delta. 1.95 (m, 1H), 2.17 (s, 3H), 2.41 (m,
5H), 2.89 (s, 3H), 3.76 (m, 1H), 4.05 (m, 2H), 4.30 (m, 1H), 4.22
(m, 1H), 6.89 (m, 2H), 6.99 (m, 2H), 7.39 (m, 3H), 7.67 (m, 2H); mp
180-185.degree. C.; Anal calcd for
C.sub.23H.sub.26ClN.sub.3S.H.sub.2O; C=65.62, H=6.46, N=9.98,
Cl=18.42; S=7.62. found C=65.57, H=6.63, N=9.91, Cl=18.24; S=7.55;
[.alpha.].sub.D -33.5.degree. (c=0.2, MeOH)
[0080] Further elution gave 0.04 g (15%) of a second fraction which
was characterized to be
3.beta.-(4-Methylphenyl)-2.alpha.(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane.
Example 7
3.beta.-(4-Chlorophenyl)-2.beta.-(5-phenyl-oxazol-2-yl)-tropane
Tartrate RTI-189)
[0081] Reaction of 0.73 g (2.5 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta. carboxylic acid as
described above for the preparation of amides gave after
purification by flash column chromatography (15% CMA 80 in
methylene chloride) 0.8 g (81%) of pure
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-N-(phenyacyl) carboxamide:
.sup.1H NMR (CDCl.sub.3) .delta. 1.71 (m, 3H), 2.19 (m, 2H), 2.39
(s, 3H), 2.46 (m, 1H), 2.58 (m, 1H), 3.13 (m, 1H), 3.43 (m, 2H),
4.74 (m, 2H), 7.13 (m, 4H), 7.49 (m, 2H), 7.59 (m, 1H), 7.96 (m,
2H), 10.57 (br s, 1H); IR (CHCl.sub.3) 3135, 3010, 2930, 1695,
1650, 1590, 1530, 1485, 1450, 1355, 1220 cm.sup.-1.
[0082] A solution of 0.725 g (1.83 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-N(phenyacyl)carboxamide in
6 ml POCl.sub.3 was heated at 125.degree. C. under nitrogen for 2
hours. The reaction mixture was cooled and poured into ice and
rendered basic to pH 7-8 using concentrated NH.sub.4OH. To the ice
cold aqueous layer was added 10 ml brine and extracted thrice with
10 ml methylene chloride. The organic layers were combined dried
(NaSO.sub.4), filtered, and the solvent removed in vacuo to 0.63 g
crude oxazole. Purification of the crude by flash column
chromatography [(40% (ether/triethylamine 9:1) in hexane] gave 0.34
g (49%) of pure oxazole (RTI-189) which was further purified by
recrystallizing from ether/petroleum ether: .sup.1H NMR
(CDCl.sub.3) 1.79 (m, 3H), 2.22 (s, 3H), 2.27 (m, 2H), 2.66 (m,
1H), 3.27 (m, 1H), 3.40 (m, 2H), 3.53 (m, 1H), 7.11 (s, 1H), 7.16
(s, 4H) 7.31 (m, 5H); IR (CHCl.sub.3) 2950, 1540, 1490, 1445, 1350,
1120, 1090 CM-1; [.alpha.].sub.D -70.37.degree. (c=0.19,
CHCl.sub.3).
[0083] The oxazole was converted into tartrate salt: .sup.1H NMR
(MeOD) 2.14 (m, 1H), 2.54 (m, 5H), 2.96 (s, 3H), 3.75 (m, 2H), 4.12
(m, 1H), 4.25 (m, 1H), 4.41 (s, 2H), 7.05 (m, 2H), 7.29 (m, 7H),
7.45 (s, 1H), 7.43 (s, 1H); mp 126.degree. C. (dec); Anal calcd for
C.sub.27H.sub.29ClN.sub.2O.sub.7.0.75H.sub.2O; C=59.78; H=5.67,
N=5.16; Cl=6.54; found C=59.78, H=5.58, N=4.93; Cl=6.31;
[.alpha.].sub.D +101.43.degree. (c=0.21, CH.sub.3OH).
Example 8
3.beta.-(4-Methylphenyl)-2.beta.-(5-phenyl-oxazol-2-yl)-tropane
Tartrate (RTI-178)
[0084] Reaction of 0.52 g (2 mmol) of
3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxylic acid as
described above for preparation of amides gave after work up and
purification by flash column chromatography (15% CMA in methylene
chloride) 0.54 g (72%) of pure
3.beta.-(4-Methylphenyl)-tropane-2.beta.-N-(phenyacyl) carboxamide:
.sup.1H NMR (CDCl.sub.3) .delta. 1.73 (m, 3H), 2.14 (m, 2H), 2.26
(s, 3H), 2.40 (s, 3H), 2.47 (m, 1H), 2.59 (m, 1H), 3.14 (m, 1H),
3.42 (m, 2H), 4.74 (m, 2H), 7.05 (m, 4H), 7.48 (m, 2H), 7.59 (m,
2H), 7.97 (m, 2H), 10.62 (br s, 1H); IR (CHCl.sub.3) 3155, 3005,
2930, 1690, 1650, 1520, 1450, 1355, 1215 cm.sup.-1
[0085] Reaction of 0.5 g (1.33 mmol) of
3.beta.-(4-Methylphenyl)-tropane-2.beta.-N-(phenyacyl)carboxamide
as described above for RTI-189 gave after workup and purification
by flash column chromatography [(40% (ether/triethylamine 9:1) in
hexane] 0.1 g (31%) RTI-158 as a first fraction. Further elution
gave 0.19 g (42%) of pure oxazole RTI-178: .sup.1H NMR (CDCl.sub.3)
1.8 (m, 3H), 2.18 (m, 2H), 2.21 (s, 3H), 2.22 (s, 3H), 2.67 (m,
1H), 3.28 (m, 1H), 3.42 (m, 2H), 3.53 (m, 1H), 6.98 (m, 2H), 7.11
(m, 3H), 7.30 (m, 5H).
[0086] The oxazole was crystallized as the tartrate salt: .sup.1H
NMR (MeOD) 1.99 (m, 1H), 2.19 (s, 3H), 2.54 (m, 5H), 2.95 (s, 3H),
3.74 (m, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.4 (s, 2H), 6.91 (m,
2H), 7.0 (m, 2H), 7.25 (m, 2H), 7.33 (m, 3H), 7.43 (s, 1H); mp
175-181 C; Anal calcd for C.sub.28H.sub.32N.sub.2O.sub.7.1H.sub.2O;
C=63.87; H=6.51, N=5.32; found C=64.21, H=6.40, N=5.19;
[.alpha.].sub.D -104.04.degree. (c=0.6, CH.sub.3OH).
Example 9
3.beta.-(4-Chlorophenyl)-2.beta.-(5-phenylthiazol-2-yl)-tropane
Hydrochloride (RTI-219)
[0087] To a solution of 0.74 g (1.86 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-N-(phenyacyl)carboxamide
and 1.51 g (7.45 mmol) of Lawesson's reagent in 18 ml of toluene
was refluxed under N.sub.2 for 5 hours. The reaction mixture was
cooled and solvent removed in vacuo to give crude residue. To the
residue was added 3 g of silica gel and 10 ml of methylene
chloride, the resulting slurry was mixed properly and the solvent
removed in vacuo. The crude compound impregnated on silica gel was
loaded on a column and purified by flash column chromatography
[(40% (ether/triethylamine 9:1) in hexane] to give 0.21 g (30%) of
pure thiazole RTI-219: .sup.1H NMR (CDCl.sub.3) 1.61 (m, 1H), 1.82
(m, 2H), 2.22 (m, 2H), 2.34 (s, 3H), 2.39 (m, 1H), 3.28 (m, 2H),
3.39 (m, 1H), 3.49 (m, 1H), 6.8 (m, 2H) 7.07 (m, 2H).7.32 (m, 3H),
7.57 (m, 2H), 7.60 (s, 1H); .sup.13C NMR (MeOD) 25.51, 25.99,
35.01, 36.92, 41.72, 52.97, 61.58, 65.70, 126.45, 127.60, 128.13,
128.89, 129.05, 131.91, 132.43, 136.11, 139.91, 140.27, 168.97; IR
(CHCl.sub.3) 2945, 1590, 1485, 1445, 1350, 1125, 1090.
cm.sup.-1.
[0088] The thiazole was converted into hydrochloride salt: .sup.1H
NMR (MeOD) 1.99 (m, 1H), 2.51 (m, 5H), 2.93 (s, 3H), 3.79 (m, 2H),
4.15 (m, 1H), 4.28 (m, 1H), 7.02 (d, J=8.5 Hz, 2H) 7.21 (d, J=8.5
Hz, 2H), 7.39 (m, 5H), 8.06 (s, 1H); mp 228-230.degree. C.; Anal
calcd for C.sub.23H.sub.24ClN.sub.2S.H.sub.2O; C=61.47, H=5.83,
N=6.23, S=7.13, Cl=15.78; found C=61.61, H=5.76, N=6.20, S=7.51,
Cl=15.84; [.alpha.].sub.D +27.43.degree. (c=0.11, CH.sub.3OH).
Example 10
3.beta.-(4-Chlorophenyl)-2.beta.-(benzothiazol-2-yl)-tropane
Hydrochloride (RTI-202)
[0089] Reaction of 0.59 g (2 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxylic acid as
described above for preparation of amides gave after purification
of the crude by flash column chromatography (50% CMA-80 in
methylene chloride) 0.3 g (41%) of pure RTI-202 which was further
purified by recrystallizing from ether/hexane: .sup.1H NMR
(CDCl.sub.3) .delta. 1.65 (m, 1H), 1.87 (m, 2H), 2.24 (m, 2H), 2.34
(s, 3H), 2.41 (m, 1H), 3.28 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H),
6.8 (m, 2H), 6.81 (m, 2H), 7.29 (m, 2H), 7.70 (m, 1H), 7.84 (m,
1H); .sup.13C NMR (CDCl.sub.3) .delta.25.58, 26.07, 35.40, 36.95,
41.56, 53.09, 61.57, 65.47, 120.95, 122.42, 124.11, 125.20, 128.05,
129.03, 131.87, 136.72, 139.91, 151.33, 171.11; IR (CHCl.sub.3)
2940, 2795, 1495, 1445, 1305, 1130, 1105, 1015, 907 CM.sup.-1;
[.alpha.].sub.D -233.89.degree. (c=0.09, CHCl.sub.3).
[0090] The benzothiazole was converted into hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.02 (m, 1H), 2.43 (m, 4H), 2.89 (m,
1H), 2.98 (s, 3H), 3.90 (m, 2H), 4.23 (m, 1H), 4.34 (m, 1H), 7.02
(m, 2H), 7.13 (m, 2H), 7.45 (m, 2H), 7.81 (m, 1H), 8.16 (m, 1H); mp
140-150.degree. C. (dec); Anal calcd for
C.sub.21H.sub.22Cl.sub.2N.sub.2S.0.75H.sub.2O C=60.21, H=5.65,
N=6.69, Cl=16.93; S=7.65: found C=60.14, H=5.74, N=6.60, Cl=16.89;
S=7.71; [.alpha.].sub.D -1 72.49.degree. (c 0.28, MeOH).
Example 11
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-nitrile (RTI-161)
[0091] To a solution of 0.95 g (3.5 mmol) of
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-carboxamide in 20 ml dry
THF was added 0.56 ml (7 mmol) pyridine. To the resulting solution
at room temperature was added dropwise with stirring under nitrogen
0.35 ml (4.2 mmol) of trifluoroacetic anhydride. The reaction was
stirred at room temperature for 30 minutes, and quenched with 10 ml
water. The solvent was removed under vacuo and the residue was
taken in 10 ml saturated aqueous K.sub.2CO.sub.3 and extracted
thrice with 10 ml CHCl.sub.3. The organic layers were combined and
washed with 20 ml brine dried (NaSO.sub.4), filtered, and the
solvent removed in vacuo to give 0.26 g crude product. Purification
of the crude by flash column chromatography (10% CMA in methylene
chloride) gave 0.68 g (77%) of pure nitrile RTI-161 which was
recrystallized from methylene chloride and hexane: .sup.1H NMR
(CDCl.sub.3) .delta. 1.70 (m, 3H), 2.22 (m, 3H), 2.35 (s, 3H), 2.80
(m, 1H), 3.04 (m, 1H), 3.34 (m, 1H), 3.43 (m, 1H), 7.26 (m, 4H); IR
(CHCl.sub.3) 3700, 2950, 2225, 1490, 1470, 1090, 900 cm.sup.-1; mp
167-173.degree. C.; Anal calcd for
C.sub.15H.sub.18Cl.sub.2N.sub.2.0.75H.sub.2O; C=57.98, H=6.32
N=9.02, Cl=22.82; found C=58.22, H=6.12, N=8.48, Cl=22-89;
[.alpha.].sub.D -73.33.degree. (c=0.48, MeOH).
Example 12
3.beta.-(4-Methylphenyl)-tropane-2.beta.-nitrile Hydrochloride
(RTI-158)
[0092] Reaction of 0.26 g (1 mmol) of
3.beta.-(4-Methylphenyl)-tropane-2.beta.-carboxamide as described
above for RTI-161 gave after work up and purification 0.16 g (67%)
of pure nitrile (RTI-158): .sup.1H NMR (CDCl.sub.3) .delta. 1.68
(m, 3H), 2.18 (m, 3H), 2.32 (s, 3H), 2.35 (s, 1H), 2.82 (m, 1H),
3.02 (m, 1H), 3.36 (m, 1H), 3.43 (m, 1H), 7.18 (m, 4H); IR
(CHCl.sub.3) 3675, 3000, 2950, 2200, 1600, 1510, 1450, 1350, 1220,
1100 cm.sup.-1.
[0093] The crude product was crystallized as the HCl salt: .sup.1H
NMR (MeOH) .delta. 2.08-2.58 (m, 9H), 2.92 (s, 3H), 3.54 (m, 1H),
3.69 (br s, 1H), 4.12 (br s, 1H), 4.29 (m, 1H), 7.21 (m, 4H); mp
270.degree. C. (dec.); Anal calcd for C.sub.16H.sub.21ClN.sub.2;
C=69.42, H=7.65 N=10.12, Cl=12.81; found C=69.31, H=7.70, N=10.12,
Cl=12.81; [.alpha.].sub.D -76.4.degree. (c=0.5, MeOH).
Example 13
3.beta.-(4-Chlorophenyl)-tropane-2.beta.-tetrazole (RTI-163)
[0094] To a solution of 0.13 g (0.5 mmol) of RTI-161 in 5 ml dry
THF was added 0.28 ml (5 mmol) azidotrimethylsilane and the mixture
was placed in a PTFE-lined autoclave. The solution was heated to
150.degree. C. for 24 hours in an oil bath. The reaction mixture
was cooled and transferred using MeOH. The solvent was removed in
vacuo to give a brownish residue. Purification of the crude by
flash column chromatography (20%-50% CMA in methylene chloride)
gave 0.05 g (33%) of pure tetrazole (RTI-163): .sup.1H NMR
(CDCl.sub.3+1 drop MeOD) .delta. 1.73 (m, 1H), 2.44-2.02 (m, 4H),
2.6 (m, 1H), 2.68 (s, 3H), 3.33 (m, 1H), 3.65 (m, 1H), 3.73 (m,
1H), 3.97 (m, 1H), 6.68 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz, 2H); mp
296-300.degree. C.; Anal calcd for
C.sub.15H.sub.18CIN.sub.5.0.75H.sub.2O; C=56.78, H=6.19 N=22.07,
Cl=11.17; found C=56.69, H=6.22, N=22.09, Cl=11.15; [.alpha.].sub.D
-124.94.degree. (c=0.39, MeOH).
Example 14
3.beta.-(4-Methylphenyl)-tropane-2.beta.-tetrazole Hydrochloride
(RTI-157)
[0095] Reaction of 0.12 g (0.5 mmol) of RTI-158 as described above
for RTI-163 gave after workup and purification of the crude by
flash column chromatography (100% CMA) 0.14 g (88%) of pure
tetrazole (RTI-157): .sup.1H NMR (CDCl.sub.3+1 drop MeOD) .delta.
1.8 (m, 1H), 2.14 (s, 3H), 2.35 (m, 5H), 2.71 (s, 3H), 3.36 (m,
1H), 3.75 (m, 2H), 4.02 (m, 1H), 6.48 (d, J=8 Hz, 2H), 6.82 (d, J=8
Hz, 2H).
[0096] The purified product was converted into HCl salt: .sup.1H
NMR (MeOD) .delta. 2.01 (m, 1H), 2.27 (s, 3H), 2.69 (m, 5H), 2.97
(s, 3H), 3.81 (m, 2H), 4.18 (m, 2H), 5.5 (s, 1H), 6.76 (d, J=8 Hz,
2H), 7.02 (d, J=8 Hz, 2H); mp 212**C (dec); Anal calcd for
C.sub.16H.sub.23Cl.sub.2N.sub.5.0.25H.sub.2O; C=53.26, H=6.56
N=19.41; found C=53.41, H=6.50, N=19.02; [.alpha.].sub.D
-110.97.degree. (c=0.16, MeOH).
Example 15
3-(4-Chlorophenyl)-2-(3-methylisoxazol-5-yl)tropane Hydrochloride
(RTI-165)
[0097] A solution of n-butyl lithium in hexane 5.9 ml (2.5 M. 14.6
mmol) was added to a stirred solution of acetone oxime 0.55 g (7.3
mmol) in dry THF (15 ml) at 0.degree. C. under nitrogen. After 1
hour, a solution of 1.65 g (5.62 mmol)
3.beta.-(4-Chlorophenyl)-2.beta.-(carbomethoxy)tropane in 10 ml dry
was added dropwise with stirring at 0.degree. C. The solution was
allowed to warm to room temperature over 18 hours. The mixture was
poured into a stirred solution of concentrated sulfuric acid (3.2
g) in THF (15 ml) and water (4 ml) and was heated under reflux for
1 hour. The cooled solution was made basic using saturated aqueous
K.sub.2CO.sub.3 (10 ml) and extracted thrice with 10 ml methylene
chloride. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and solvent removed in vacuo to give
1.8 g of crude isoxazole. Purification of the crude residue by
flash column chromatography (10% CMA in methylene chloride) gave
0.74 g (46%) of pure isoxazole RTI-165 which was further purified
by crystallization from methylene chloride/hexane: .sup.1H NMR
(CDCl.sub.3) .delta. 1.71 (m, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.24
(s, 3H), 3.20 (m, 2H), 3.32 (m, 2H), 6.18 (s, 1H), 6.9 (d, J=8 Hz,
2H), 7.14 (d, J=8, Hz, 2H); IR (CCl.sub.4) 2950, 1590, 1490, 1420,
1350, 1020, 910 cm.sup.-1; mp 154-156.degree. C.; Anal calcd for
C.sub.18H.sub.21N.sub.2OCl; C=68.28, H=6.68, N=8.84, Cl=11.19;
found C=68.22, H=6.69, N=8.87, Cl=11.19; [.alpha.].sub.D
-125.58.degree. (c=0.43, MeOH).
[0098] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.04 (s, 3H), 2.19 (m, 1H), 2.30 (m,
1H), 2.48 (m, 2H), 2.60 (m, 1H), 2.70 (m, 1H), 2.90 (s, 3H), 3.68
(m, 1H), 3.81 (m, 1H), 4.04 (m, 1H), 4.15 (m, 1H), 5.55 (s, 1H),
7.04 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H); mp>235.degree. C.
(dec); Anal calcd for C.sub.18H.sub.22Cl.sub.2N.sub.2O; C=61.19,
H=6.28, N=7.93, Cl=20.07; found c=60.98, H=6.38, N=7.91, Cl=19.96;
[.alpha.].sub.D -102.89.degree. (c=0.46, MeOH).
Example 16
3.beta.-(4-Methylphenyl)-2.beta.-(3-methylisoxazol-5-yl)tropane
Hydrochloride (RTI-171)
[0099] Reaction of 1.09 g (4 mmol) of
3.beta.-(4-Methylphenyl)-2.beta.-(carbomethoxy)tropane as described
above for RTI-165 gave after workup 1.21 g crude isoxazole.
Purification of the crude by flash column chromatography (15% CMA
in methylene chloride) gave 0.73 g (62%) pure isoxazole (RTI-171):
.sup.1H NMR (CDCl.sub.3) .delta. 1.73 (m, 3H), 2.11 (m, 3H), 2.17
(s, 3H), 2.23 (s, 3H), 2.25 (s, 3H), 3.20 (m, 2H), 3.32 (m, 2H),
6.13 (s, 1H), 6.97 (m, 4H); IR (CCl.sub.4) 2935, 2785, 1590, 1510,
1460, 1421, 1350, 1125, 1010, 910 cm.sup.-1.
[0100] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.01 (s, 3H), 2.24 (s, 3H), 2.32 (m,
2H), 2.42 (m, 4H), 2.81 (s, 3H), 3.61 (m, 1H), 3.78 (m, 1H), 4.03
(m, 1H) 4.15 (m, 1H), 5.45 (s, 1H), 6.96 (m, 4H); mp 277.degree.
C.; Anal calcd for C.sub.19H.sub.25ClN.sub.2O; C=68.55, H=7.57,
N=8.42, Cl=10.65; found C=68.65, H=7.62, N=8.42, Cl=10.56;
[.alpha.].sub.D -107.28.degree. (c=0.71, MeOH).
Example 17
3.beta.-(4-Iodophenyl)-2-(3-methylisoxazol-5-yl)tropane
Hydrochloride (RTI-180)
[0101] Reaction of 0.73 g (1.9 mmol) of
3.beta.-(4-Iodophenyl)-2.beta.-(carbomethoxy)tropane as described
above for RTI-165 gave after workup 0.77 g of crude isoxazole.
Purification of the crude by flash column chromatography (5% CMA80
in methylene chloride) gave 0.37 g (49%) of pure isoxazole RTI-180:
.sup.1H NMR (CDCl.sub.3) .delta. 1.71 (m, 3H), 2.12 (m, 3H), 2.18
(s, 3H), 2.24 (s, 3H), 3.17 (m, 2H), 3.33 (m, 2H), 6.18 (s, 1H),
6.74 (m, 2H), 7.49 (m, 2H); IR (CHCl.sub.3) 2940, 1600, 1485, 1450,
1420, 1355 cm.sup.-1.
[0102] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.11 (s, 3H), 2.50 (m, 6H), 2.89 (s,
3H), 3.70 (m, 1H), 3.90 (m, 1H), 4.14 (m, 1H), 4.22 (m, 1H), 5.66
(s, 1H), 6.96 (m, 2H), 7.56 (m, 2H); mp>235.degree. C. (dec);
Anal calcd for C.sub.18H.sub.22ClIN.sub.2O 0.25H.sub.2O C=48.12,
H=5.05, N=6.24, Cl=15.79; I=56.50; found C=47.84, H=5.05, N=6.19,
Cl=15.77; I=56.46; [.alpha.].sub.D -94.57.degree. (c=0.39,
MeOH).
Example 18
3.beta.-(4-Chlorophenyl)-2.beta.-(3-phenylisoxazol-5-yl)tropane
Hydrochloride (RTI-177)
[0103] Reaction of 1.18 g (4 mmol) of
3.beta.-(4-Chlorophenyl)-2.beta.-(carbomethoxy)tropane as described
above for RTI-165 gave after work up 1.46 g of crude isoxazole.
Purification of the crude by flash column chromatography [20%
(ether/triethylamine 9:1) in hexane] gave 0.75 g (50%) of pure
isoxazole RTI-177 which was further purified by crystallizing from
ether/petroleum ether: .sup.1H NMR (CDCl.sub.3) .delta. 1.74 (m,
3H), 2.22 (m, 3H), 2.27 (s, 3H), 3.24 (m, 2H), 3.36 (m, 2H), 6.80
(s, 1H), 6.94 (m, 2H), 7.12 (m, 2H), 7.40 (m, 3H), 7.76 (m, 2H); IR
(CHCl.sub.3) 2940, 1600, 1590, 1490, 1450, 1405, 1350
cm.sup.-1.
[0104] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.35 (m, 6H), 2.84 (s, 3H), 3.73 (m,
1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.12 (s, 1H), 7.14 (m, 4H), 7.34
(m, 3H), 7.57 (m, 2H); mp 287.degree. C.; Anal calcd for
C.sub.23H.sub.24Cl.sub.21N.sub.2O.0.25H.sub.2O C=65.79, H=5.88,
N=6.67, Cl=16.89; found C=65.94, H=5.79, N=6.68, Cl=17.00;
[.alpha.].sub.D -97.5.degree. (c=0.28, MeOH).
Example 19
3.beta.-(4-Methylphenyl)-2.beta.-(3-phenylisoxazol-5-yl)tropane
Hydrochloride (RTI-176)
[0105] Reaction of 1.09 g (4 mmol) of
3.beta.-(4-Methylphenyl)-2.beta.-(carbomethoxy)tropane as described
above for RTI-165 gave after work up 1.56 g of crude isoxazole.
Purification of the crude by flash column chromatography [25%
(ether/triethylamine 9:1) in hexane] gave 1.1 g (77%) of pure
isoxazole RTI-176 which was further purified by crystallizing from
methylene chloride/hexane: .sup.1H NMR (CDCl.sub.3) .delta. 1.76
(m, 3H), 2.23 (m, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 3.23 (m, 2H),
3.36 (m, 2H), 6.74 (s, 1H), 6.93 (m, 4H), 7.41 (m, 3H), 7.76 (m,
2H); IR (CCl.sub.4) 2935, 1590, 1455, 1410, 1215 cm.sup.-1
[0106] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.08 (m, 1H), 2.15 (s, 3H), 2.45 (m,
5H), 2.84 (s, 3H), 3.68 (m, 1H), 3.88 (m, 1H), 4.07 (m, 1H), 4.22
(m, 1H), 5.97 (s, 1H), 7.0 (m, 4H), 7.33 (m, 3H), 7.54 (m, 2H); mp
270-295.degree. C. (dec); Anal calcd for
C.sub.24H.sub.27ClN.sub.2O; C=72.99, H=6.89, N=7.10, Cl=8.98; found
C=72.91, H=6.91, N=7.15, Cl=8.98; [.alpha.].sub.D -102.22 (c=0.68,
MeOH).
Example 20
3.beta.-(4-Iodophenyl)-2.beta.-(3-phenylisoxazol-5-yl)tropane
Hydrochloride (RTI-181)
[0107] Reaction of 0.73 g (1.9 mmol) of
3.beta.-(4-Iodophenyl)-2.beta.-(carbomethoxy)tropane as described
above for RTI-181 gave after workup 1.46 g of crude isoxazole.
Purification of the crude by flash column chromatography [20%
(ether/triethylamine 9:1) in hexane] gave 0.5 g (56%) of pure
isoxazole RTI-181 which was further purified by crystallizing from
methylene chloride/hexane: .sup.1H NMR (CDCl.sub.3) .delta. 1.72
(m, 3H), 2.15 (m, 2H), 2.28 (s, 3H), 3.22 (m, 2H), 3.35 (m, 2H),
6.74 (m, 2H), 6.79 (s, 1H), 7.44 (m, 5H), 7.75 (m, 2H); IR
(CHCl.sub.3) 2940, 1580, 1480, 1475, 1450, 1400, 1355, 1005
cm.sup.-1
[0108] The isoxazole was crystallized as the hydrochloride salt:
.sup.1H NMR (MeOD) .delta. 2.54 (m, 6H), 2.92 (s, 3H), 3.79 (m,
1H), 4.05 (m, 1H), 4.19 (m, 1H), 4.33 (m, 1H), 6.18 (s, 1H), 7.02
(m, 2H), 7.43 (m, 3H), 7.63 (m, 4H); mp>267.degree. C. (dec);
Anal calcd for C.sub.23H.sub.24ClIN.sub.2O.0.5H.sub.2O C=53.55,
H=4.89, N=5.43, Cl=13.75; I=49.21: found C=53.75, H=4.87, N=5.41,
Cl=13.68; I=48.95; [.alpha.].sub.D -91.11.degree. (c=0.43,
MeOH).
Example 21
Biochemistry of 3.beta.-(Substituted
phenyl)-2.beta.-(heterocyclic)tropanes
[0109] Inhibition of radioligand binding data at the dopamine,
serotonin, and norepinephrine transporters are listed in Table II,
III and IV.
TABLE-US-00004 TABLE II 3.beta.-(Substituted
phenyl)-2.beta.-(heterocyclic)tropanes A ##STR00116## IC.sub.50
(nM) Code DA NE 5-HT NE/DA 5-HT/DA Name Het X [.sup.3H]-WIN 35,428
[.sup.3H]-nisoxetine [.sup.3H]-paroxetine Ratio Ratio
RTI-163RTI-157 ##STR00117## ClCH.sub.3 911 .+-. 6.1 1557 .+-. 196
17,386 .+-. 2050 32,478 .+-. 2078 5456 .+-. 64 43,574 .+-. 5420 19
21 6 28 RTI-165RTI-171RTI-180 ##STR00118## ClCH.sub.3I 0.59 .+-.
0.040.93 .+-. 0.090.73 .+-. 0.04 181 .+-. 12 254 .+-. 31 67.9 .+-.
5.25 572 .+-. 58 3818 .+-. 346 36.4 .+-. 5.0 307 273 93 9704105 498
RTI-177RTI-176RTI-181 ##STR00119## ClCH.sub.3I 1.28 .+-. 0.181.58
.+-. 0.022.57 .+-. 0.14 504 .+-. 29 398 .+-. 18 868 .+-. 95 2418
.+-. 136 5110 .+-. 187 100 .+-. 9.0 393 251 337 18893234 39
RTI-189RTI-178 ##STR00120## ClCH.sub.3 19.7 .+-. 1.9835.4 .+-. 1.74
496 .+-. 42 677 .+-. 68 1116 .+-. 107 1699 .+-. 167 25 19 57 48
RTI-188RTI-195 ##STR00121## ClCH.sub.3 12.6 .+-. 1.0347.5 .+-. 4.76
929 .+-. 88 1310 .+-. 37 3304 .+-. 196 23,310 .+-. 822 73 28 262
491 RTI-194 ##STR00122## CH.sub.3 4.45 .+-. 0.12 253 .+-. 19 4885
.+-. 155 57 1098 RTI-200RTI-199 ##STR00123## ClCH.sub.3 15.3 .+-.
2.4335.9 .+-. 3.4 4142 .+-. 466 24,321 .+-. 3822 18,417 .+-. 1509
51,460 .+-. 4513 271 677 12031434 RTI-202 ##STR00124## Cl 1.37 .+-.
0.14 403 .+-. 30 1119 .+-. 120 294 817 RTI-219 ##STR00125## Cl 5.71
.+-. 0.36 8563 .+-. 824 10,342 .+-. 76 1500 1811
TABLE-US-00005 TABLE III Comparison of Transporter Binding
Potencies ##STR00126## IC.sub.50 (nM) DA RTI 5-HT [.sup.3H]WIN NE
No. R.sub.1 R.sub.2 [.sup.3H]Paroxetine 35,428 [.sup.3H]Nisoxetine
279 CH.sub.3 CH.sub.3 1.06 .+-. 0.39 5.98 .+-. 0.48 74.3 .+-. 3.8
353 C.sub.2H.sub.5 CH.sub.3 0.69 .+-. 0.07 331 .+-. 17 148 .+-. 9.2
Paro- 0.28 .+-. 0.02 623 .+-. 25 313 xetine* 5-HT = serotonin DA =
dopamine NE = norepinephrine *Aropax; Seroxat; see Merck Index.
TABLE-US-00006 TABLE IV 3.beta.-(Substituted
phenyl)-2.beta.-(substituted)tropanes ##STR00127## IC.sub.50 (nM)
Code DA NE 5-HT Name R X [.sup.3H]-WIN 35,428 [.sup.3H]-nisoxetine
[.sup.3H]-paroxetine RTI-93 CH.sub.2OH Cl 1.53 .+-. 0.15 43.8 .+-.
6.4 204 .+-. 16 RTI-99 CH.sub.2OH Br 1.49 .+-. 0.05 51 .+-. 4.6
RTI-100 CH.sub.2OH F 47 .+-. 4.6 4741 .+-. 335 RTI-101 CH.sub.2OH I
2.2 .+-. 0.19 26 .+-. 3.2 RTI-102 CO.sub.2H I 474 .+-. 57 43,400
.+-. 5500 1928 .+-. 120 RTI-103 CO.sub.2H Br 278 .+-. 43 17,400
.+-. 1400 3070 .+-. 208 RTI-104 CO.sub.2H F 2744 .+-. 141
>100.000 >100,00 RTI-105 CH.sub.2OAc Cl 1.60 .+-. 0.05 127
.+-. 5.9 143 .+-. 25 RTI-108 CH.sub.2Cl Cl 2.64 .+-. 0.31 129 .+-.
15 98 .+-. 8.7 RTI-123 CH.sub.2OCOC.sub.6H.sub.5 Cl 1.78 .+-. 0.09
393 .+-. 30 3.53 .+-. 0.58 RTI-131 CH.sub.2NH.sub.2 CH.sub.3 10.5
.+-. 1.7 120 .+-. 20 855 .+-. 52 RTI-132 CH.sub.2N(CH.sub.3).sub.2
CH.sub.3 3.48 .+-. 0.11 137 .+-. 11 208 .+-. 18 RTI-139 CH.sub.3 Cl
1.67 .+-. 0.13 57 .+-. 2.6 85 .+-. 9.3 RTI-145
CH.sub.2OCO.sub.2CH.sub.3 Cl 9.6 .+-. 0.42 1478 .+-. 96 2930 .+-.
181 RTI-158 CN CH.sub.3 57 .+-. 7.3 1624 .+-. 136 5095 .+-. 315
RTI-161 CN Cl 13.1 .+-. 0.76 2516 .+-. 253 1887 .+-. 134 RTI-164
CH.sub.2NHCH.sub.3 CH.sub.3 13.6 .+-. 2.03 280 .+-. 19 2246 .+-. 94
RTI-230 --C(CH.sub.3).dbd.CH.sub.2 Cl 1.28 .+-. 0.17 141 .+-. 16 57
.+-. 5.0 RTI-239 CH(CH.sub.3).sub.2 CH.sub.3 0.61 .+-. 0.07 35.6
.+-. 2.57 114 .+-. 3.69 RTI-240 CH(CH.sub.3).sub.2 Cl 1.38 .+-.
0.03 84.5 .+-. 3.09 38.4 .+-. 2.31 RTI-241 CH.sub.2CO.sub.2CH.sub.3
CH.sub.3 1.02 .+-. 0.06 124 .+-. 3.56 618 .+-. 28
[0110] This invention has been described in both generic terms, and
by reference to specific description. No specific description or
example is considered binding, unless so identified. Alternate
forms and methods will occur to those of ordinary skill in the art,
without the exercise of inventive faculty, and remain within the
scope of this invention, save as limited by the claims set forth
below.
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