U.S. patent application number 11/184522 was filed with the patent office on 2005-12-22 for arylpiperazines having activity at the serotonin 1a receptor.
Invention is credited to Godfrey, Alexander Glenn, Kohlman, Daniel Timothy, O'Toole, John Cunningham, Xu, Yao-Chang, Zhang, Tony Yantao.
Application Number | 20050282817 11/184522 |
Document ID | / |
Family ID | 27371593 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050282817 |
Kind Code |
A1 |
Godfrey, Alexander Glenn ;
et al. |
December 22, 2005 |
Arylpiperazines having activity at the serotonin 1A receptor
Abstract
A series of aryl piperazine compounds are effective
pharmaceuticals for the treatment of conditions related to or
affected by the serotonin 1.sub.A receptor; the compounds are
particularly effective antagonists at that receptor, and are
particularly useful for alleviating the symptoms of nicotine and
tobacco withdrawal.
Inventors: |
Godfrey, Alexander Glenn;
(Greenwood, IN) ; Kohlman, Daniel Timothy;
(Indianapolis, IN) ; O'Toole, John Cunningham;
(Indianapolis, IN) ; Xu, Yao-Chang; (Fishers,
IN) ; Zhang, Tony Yantao; (Indianapolis, IN) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
27371593 |
Appl. No.: |
11/184522 |
Filed: |
July 19, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11184522 |
Jul 19, 2005 |
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10613798 |
Jul 2, 2003 |
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6946579 |
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10613798 |
Jul 2, 2003 |
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10022045 |
Dec 18, 2001 |
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6645967 |
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10022045 |
Dec 18, 2001 |
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09753645 |
Jan 3, 2001 |
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6358958 |
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09753645 |
Jan 3, 2001 |
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09208553 |
Dec 9, 1998 |
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6239135 |
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60069722 |
Dec 16, 1997 |
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60069791 |
Dec 16, 1997 |
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60089589 |
Jun 17, 1998 |
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Current U.S.
Class: |
514/252.13 ;
514/255.03 |
Current CPC
Class: |
C07C 45/29 20130101;
A61P 25/00 20180101; C07C 45/59 20130101; A61P 15/10 20180101; C07C
49/563 20130101; C07C 49/583 20130101; C07C 49/563 20130101; C07C
49/86 20130101; C07C 49/583 20130101; C07C 49/577 20130101; C07C
49/583 20130101; C07D 213/74 20130101; C07C 49/563 20130101; C07C
49/583 20130101; A61P 25/06 20180101; C07D 295/108 20130101; A61P
25/22 20180101; C07C 45/515 20130101; A61K 31/495 20130101; A61K
31/496 20130101; A61P 3/04 20180101; A61P 25/20 20180101; A61P
25/18 20180101; C07C 45/515 20130101; C07C 45/59 20130101; C07C
45/004 20130101; A61P 9/00 20180101; C07C 45/29 20130101; A61P
25/28 20180101; C07C 49/86 20130101; A61P 9/12 20180101; A61P 25/30
20180101; C07C 45/40 20130101; C07C 45/004 20130101; C07C 45/68
20130101; C07C 49/577 20130101; C07D 295/088 20130101; A61P 43/00
20180101; A61P 25/24 20180101; C07D 295/104 20130101; A61P 1/00
20180101; C07C 45/68 20130101; A61P 25/34 20180101; C07C 45/59
20130101; C07C 45/40 20130101; C07C 45/68 20130101; C07C 49/563
20130101 |
Class at
Publication: |
514/252.13 ;
514/255.03 |
International
Class: |
A61K 031/496; A61K
031/495 |
Claims
We claim:
1. A method for treating obesity, the method comprising
administering to a patient in need of such treatment of an
effective amount of a compound of the formula: 25wherein Ar' is a
mono or bicyclic aryl or heteroaryl radical substituted with one to
three substituents selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylth- io; R.sup.2 is
phenyl, naphthyl or (C.sub.3-C.sub.12)cycloalkyl substituted with
one or two substituents selected from the group consisting of
hydrogen (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.3 is selected from the group consisting of hydrogen
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylth- io, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
X is --(C.dbd.O)--; or a pharmaceutically acceptable salt,
racemate, optical isomer or solvate thereof.
2. The method of claim 1, wherein Ar' is phenyl substituted with
(C.sub.1-C.sub.6)alkoxy.
3. The method of claim 1, wherein R.sup.2 is phenyl or
(C.sub.3-C.sub.12)cycloalkyl.
4. The method of claim 1, wherein the compound has a formula:
26
5. The method of claim 1, wherein the pharmaceutically acceptable
salt is a dihydrochloride salt or a monohydrochloride salt.
6. The method of claim 1, wherein the pharmaceutically acceptable
salt is selected from the group consisting of an oxalate salt, a
maleate salt, and a phosphate salt.
7. A method for treating sexual dysfunction, the method comprising
administering to a patient in need of such treatment of an
effective amount of a compound of the formula: 27wherein Ar' is a
mono or bicyclic aryl or heteroaryl radical substituted with one to
three substituents selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylth- io; R.sup.2 is
phenyl, naphthyl or (C.sub.3-C.sub.12)cycloalkyl substituted with
one or two substituents selected from the group consisting of
hydrogen (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.3 is selected from the group consisting of hydrogen
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylth- io, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
X is --(C.dbd.O)--; or a pharmaceutically acceptable salt,
racemate, optical isomer or solvate thereof.
8. The method of claim 7, wherein Ar' is phenyl substituted with
(C.sub.1-C.sub.6)alkoxy.
9. The method of claim 7, wherein R.sup.2 is phenyl or
(C.sub.3-C.sub.12)cycloalkyl.
10. The method of claim 7, wherein the compound has a formula:
28
11. The method of claim 7, wherein the pharmaceutically acceptable
salt is a dihydrochloride salt or a monohydrochloride salt.
12. The method of claim 7, wherein the pharmaceutically acceptable
salt is selected from the group consisting of an oxalate salt, a
maleate salt, and a phosphate salt.
13. A method for treating an eating disorder, the method comprising
administering to a patient in need of such treatment of an
effective amount of a compound of the formula: 29wherein Ar' is a
mono or bicyclic aryl or heteroaryl radical substituted with one to
three substituents selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylth- io; R.sup.2 is
phenyl, naphthyl or (C.sub.3-C.sub.12)cycloalkyl substituted with
one or two substituents selected from the group consisting of
hydrogen (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
R.sup.3 is selected from the group consisting of hydrogen
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylth- io, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or halo;
X is --(C.dbd.O)--; or a pharmaceutically acceptable salt,
racemate, optical isomer or solvate thereof.
14. The method of claim 13, wherein Ar' is phenyl substituted with
(C.sub.1-C.sub.6)alkoxy.
15. The method of claim 13, wherein R.sup.2 is phenyl or
(C.sub.3-C.sub.12)cycloalkyl.
16. The method of claim 13, wherein the compound has a formula:
30
17. The method of claim 13, wherein the pharmaceutically acceptable
salt is a dihydrochloride salt or a monohydrochloride salt.
18. The method of claim 13, wherein the pharmaceutically acceptable
salt is selected from the group consisting of an oxalate salt, a
maleate salt, and a phosphate salt.
Description
CROSS REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 10/613,798 filed Jul. 2, 2003, which is a division of U.S.
application Ser. No. 10/022,045 filed Dec. 18, 2001, now U.S. Pat.
No. 6,645,967, which is a division of U.S. application Ser. No.
09/753,645 filed Jan. 3, 2001, now U.S. Pat. No. 6,358,958, which
is a division of U.S. application Ser. No. 09/208,553 filed Dec. 9,
1998, now U.S. Pat. No. 6,239,135, which claims the benefit of U.S.
Provisional Application Nos. 60/069,722 filed Dec. 16, 1997,
60/069,791 filed Dec. 16, 1997 and 60/089,589 filed Jun. 17,
1998.
FIELD OF THE INVENTION
[0002] The present invention belongs to the fields of pharmacology
and medicinal chemistry, and provides new pharmaceuticals which are
useful for the treatment of diseases which are caused or affected
by disorders of the serotonin-affected neurological systems,
particularly those relating to the 1.sub.A receptor.
BACKGROUND OF THE INVENTION
[0003] Pharmaceutical researchers have discovered in recent years
that the neurons of the brain which contain monoamines are of
extreme importance in a great many physiological processes which
very strongly affect many psychological and personality-affecting
processes as well. In particular, serotonin (5-hydroxytryptamine;
5-HT) has been found to be a key to a very large number of
processes which affect both physiological and psychological
functions. Drugs which influence the function of serotonin in the
brain are accordingly of great importance and are now used for a
surprisingly large number of different therapies.
[0004] The early generations of serotonin-affecting drugs tended to
have a variety of different physiological functions, considered
from both the mechanistic and therapeutic points of view. More
recently, it has become possible to study the function of drugs at
individual receptors in vitro or ex vivo, and it has also been
realized that therapeutic agents with a single mechanism of action
are often advantageous to the patient. Accordingly, the objective
of research now is to discover not only agents which affect only
functions of serotonin, but agents which affect only a single
function of serotonin, at a single identifiable receptor.
[0005] The present invention provides compounds which have highly
selective activity as antagonists of the serotonin 1.sub.A
receptor.
SUMMARY OF THE INVENTION
[0006] The present invention provides a series-of new aryl
piperazine compounds, methods of using them for pharmaceutical
purposes, and pharmaceutical compositions whereby the compounds may
be conveniently administered.
[0007] The invention also provides methods of antagonizing, the
5HT-1.sub.A receptor, and therapeutic methods which are related to
their effect on the 5HT-1.sub.A receptor. Such methods of treatment
include, particularly, methods of alleviating the symptoms caused
by withdrawal or partial withdrawal from the use of tobacco or of
nicotine, comprising the administration to a patient in need of
such treatment of a compound of Formula I 1
[0008] wherein
[0009] Ar' is a mono- or bi-cyclic aryl or heteroaryl radical
substituted with one to three substituents selected from the group
consisting of hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylthio,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkylhalo, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkenyl or halo;
[0010] R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylthio;
[0011] R.sup.2 is phenyl, naphthyl or (C.sub.3-C.sub.12)cycloalkyl
substituted with one or two substituents selected from the group
consisting of hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylthio,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkylhalo, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkenyl or halo;
[0012] R.sup.3 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylth- io, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylhalo,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkenyl or
halo;
[0013] X is --C(.dbd.O)--, --CHOH-- or --CH.sub.2--;
[0014] or a pharmaceutically acceptable salt, racemate, optical
isomer or solvate thereof.
[0015] Further, such therapeutic methods include methods of
treatment of anxiety, depression, hypertension, cognitive
disorders, psychosis, sleep disorders, gastric motility disorders,
sexual dysfunction, brain trauma, memory loss, eating disorders and
obesity, substance abuse, obsessive-compulsive disease, panic
disorder and migraine.
[0016] A further treatment method provided by the present invention
is a method for potentiating the action of a serotonin reuptake
inhibitor, comprising administering to a patient an effective
amount of a compound of Formula I in combination with the serotonin
reuptake inhibitor.
[0017] More specifically, the present invention provides compounds
of formula Ia; 2
[0018] or the pharmaceutically acceptable salts thereof.
[0019] The compounds of formula Ia are enclosed within the scope of
the compounds of Formula I and are therefore useful for the methods
described herein for Formula I. For example, the present invention
provides methods of antagonizing, the 5HT-1.sub.A receptor, and
therapeutic methods which are related to their effect on the
5HT-1.sub.A receptor. Such methods of treatment include,
particularly, methods of alleviating the symptoms caused by
withdrawal or partial withdrawal from the use of tobacco or of
nicotine, comprising the administration to a patient in need of
such treatment, an effective amount of a compound of formula Ia.
Further, such therapeutic methods include methods of treatment of
anxiety, depression, hypertension, cognitive disorders, psychosis,
sleep disorders, gastric motility disorders, sexual dysfunction,
brain trauma, memory loss, eating disorders and obesity, substance
abuse, obsessive-compulsive disease, panic disorder and
migraine.
[0020] In addition, the present invention provides a method for
potentiating the action of a serotonin reuptake inhibitor,
comprising administering to a patient an effective amount of a
compound of formula Ia in combination with the serotonin reuptake
inhibitor.
[0021] The invention further provides a method-of assisting a
patient in ceasing or reducing their use of tobacco or nicotine
comprising administering to a patient an effective amount of a
compound of the Formula I or formula Ia.
[0022] This invention also encompasses novel processes for the
synthesis of the compounds of formula I and formula Ia, the
synthesis of novel intermediates thereof, and further encompasses
novel intermediates per se.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0023] In the present document, all descriptions of concentrations,
amounts, ratios and the like will be expressed in weight units
unless otherwise stated. All temperatures are in degrees
Celsius.
[0024] The Compounds
[0025] It is believed that the general description of the compounds
above is sufficient to explain their nature to the skilled reader;
attention to the Examples which follow is also encouraged. Some
additional description will be provided to assure that no
misunderstanding occurs.
[0026] In the general description, the general chemical terms are
all used in their normal and customary meanings. For example, the
small alkyl and alkoxy groups, such as (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy groups include, depending on the size of
the groups, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl,
pentyl, 3-methylbutyl, hexyl, and branched hexyl groups, and the
corresponding alkoxy groups, as may be allowed by the individually
named groups. Where a number of possible substituent groups are
permitted on a group, such as the one to three alkyl, alkoxy or
halo groups permitted on an Ar group, it will be understood by the
reader that only substitution which is electronically and
sterically feasible is intended.
[0027] The term "alkenyl" as used herein represents an unsaturated
branched or linear group having at least one double bond. Examples
of such groups include radicals such as vinyl, allyl, 2-butenyl,
3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl as well as dienes and trienes of
straight and branched chains.
[0028] The term "alkynyl" denotes such radicals as ethynyl,
propynyl, butynyl, pentynyl, hexynyl as well as di- and
tri-ynes.
[0029] The term "(C.sub.1-C.sub.6)alkylthio" defines a straight or
branched alkyl chain having one to six carbon atoms attached to the
remainder of the molecule by a sulfur atom. Typical
(C.sub.1-C.sub.6)alkylthio groups include methylthio, ethylthio,
propylthio, butylthio, pentylthio, hexylthio and the like.
[0030] The term "(C.sub.1-C.sub.6)alkylhalo" refers to alkyl
substituents having one or more independently selected halo atoms
attached at one or more available carbon atoms. These terms include
chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl,
3-bromopropyl, 2-bromopropyl, 3-chlorobutyl, 2,3-dichlorobutyl,
3-chloro-2-bromo-butyl, trichloromethyl, dichloroethyl,
1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl,
1,1-dichloropropyl, and the like. More preferred
(C.sub.1-C.sub.6)alkylhalo groups are trichloromethyl,
trichloroethyl, and trifluoromethyl. The most preferred
(C.sub.1-C.sub.6)alkylhalo is trifluoromethyl.
[0031] The term "(C.sub.3-C.sub.8)cycloalkyl" includes groups such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
and cyclooctyl. The term "(C.sub.3-C.sub.8)cycloalkyl" includes
(C.sub.3-C.sub.6)cycloalkyl.
[0032] The term "(C.sub.3-C.sub.8)cycloalkenyl" represents an
olefinically unsaturated ring having 3 to 8 carbon atoms including
groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. The term
"(C.sub.3-C.sub.8)cycloalkenyl" includes
(C.sub.3-C.sub.6)cycloalkenyl.
[0033] The term "aryl" represents phenyl or naphthyl.
[0034] The term "bicyclic" represents either an unsaturated or
saturated stable 7- to 12-membered bridged or fused bicyclic carbon
ring. The bicyclic ring may be attached at any carbon atom which
affords a stable structure. The term includes, but is not limited
to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
[0035] The term, "mono or bicyclic heteroaryl radical", refers to
radicals derived from monocyclic or polycyclic, aromatic nuclei
having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms
selected from the group consisting of nitrogen, oxygen or sulfur.
Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl,
pyrazolyl, imidazolyl, indolizinyl, isoquinolyl, benzothienyl,
isoindolizinyl, oxazolyl, indolyl, carbazolyl, norharmanyl,
azaindolyl, dibenzofuranyl, thianaphthenyl, dibenzothiophenyl,
indazolyl, imidazo(1.2-A)pyridinyl, anthranilyl, purinyl,
pyridinyl, phenylpyridinyl, pyrimidinyl, pyrazinyl, quinolinyl.
[0036] The terms "halo" or "halide" are used in the above formula
to refer to fluoro, chloro, bromo or iodo.
[0037] The term "aprotic solvent" refers to polar solvents of
moderately high dielectric constant which do not contain an acidic
hydrogen. Examples of common aprotic solvents are dimethylsulfoxide
(DMSO), dimethylformamide, sulfolane, tetrahydrofuran, diethyl
ether, methyl-t-butyl ether, or 1,2-dimethoxyethane.
[0038] The term "protic solvent" refers to a solvent containing
hydrogen that is attached to oxygen, and hence is appreciably
acidic. Common protic solvents include such solvents as water,
methanol, ethanol, 2-propanol, and 1-butanol.
[0039] The term "inert atmosphere" refers to reaction conditions in
which the mixture is covered with a layer of inert gas such as
nitrogen or argon.
[0040] As used herein, the term "Me" refers to a --CH.sub.3 group,
the term "Et" refers to a --CH.sub.2CH.sub.3 group and the term
"Pr" refers to a --CH.sub.2CH.sub.2CH.sub.3 group.
[0041] As used herein, the term "stereoisomer" refers to a compound
made up of the same atoms bonded by the same bonds but having
different three-dimensional structures which are not
interchangeable. The three-dimensional structures are called
configurations. As used herein, the term "enantiomer" refers to two
stereoisomers whose molecules are nonsuperimposable mirror images
of one another. As used herein, the term "optical isomer" is
equivalent to the term "enantiomer". The terms "racemate", "racemic
mixture" or "racemic modification" refer to a mixture of equal
parts of enantiomers. The term "chiral center" refers to a carbon
atom to which four different groups are attached.
[0042] The term "enantiomeric enrichment" as used herein refers to
the increase in the amount of one enantiomer as compared to the
other. A convenient method of expressing the enantiomeric
enrichment achieved is the concept of enantiomeric excess, or "ee",
which is found using the following equation: 1 ee = E 1 - E 2 E 1 +
E 2 .times. 100
[0043] wherein E.sup.1 is the amount of the first enantiomer and
E.sup.2 is the amount of the second enantiomer. Thus, if the
initial ratio of the two enantiomers is 50:50, such as is present
in a racemic mixture, and an enantiomeric enrichment sufficient to
produce a final ratio of 50:30 is achieved, the ee with respect to
the first enantiomer is 25%. However, if the final ratio is 90:10,
the ee with respect to the first enantiomer is 80%. An ee of
greater than 90% is preferred, an ee of greater than 95% is most
preferred and an ee of greater than 99% is most especially
preferred. Enantiomeric enrichment is readily determined by one of
ordinary skill in the art using standard techniques and procedures,
such as gas or high performance liquid chromatography with a chiral
column. Choice of the appropriate chiral column, eluent and
conditions necessary to effect separation of the enantiomeric pair
is well within the knowledge of one of ordinary skill in the art.
In addition, the enantiomers of compounds of formulas I or Ia can
be resolved by one of ordinary skill in the art using standard
techniques well known in the art, such as those described by J.
Jacques, et al., "Enantiomers, Racemates, and Resolutions", John
Wiley and Sons, Inc., 1981. Examples of resolutions include
recrystallization techniques or chiral chromatography.
[0044] The compounds of Formula I and formula Ia, as a class are
highly active, important and particularly useful in the treatment
methods of the present invention, but certain classes of the
compounds are preferred. The following paragraphs describe such
preferred classes. It will be understood that the preferred classes
are applicable both to the treatment methods and to the new
compounds of the present invention.
[0045] The reader will understand that the preferred classes of
compounds may be combined to form additional, broader or narrower
classes of preferred compounds.
[0046] a) Ar' is phenyl or pyridyl;
[0047] b) Ar' is naphthyl;
[0048] c) Ar' is pyrazinyl, pyrimidinyl, pyrrolyl, furyl, thienyl,
indolyl, purinyl, imidazolyl, pyrazolyl, indolizinyl, benzofuranyl,
isoquinolyl, quinolyl, benzothienyl or isoindolizinyl;
[0049] d) Ar' is optionally substituted with
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl;
[0050] e) Ar' is optionally substituted with
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy or halo;
[0051] f) R.sup.1 is hydrogen;
[0052] g) R.sup.1 is (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy;
[0053] h) R.sup.1 is (C.sub.1-C.sub.2)alkyl or
(C.sub.1-C.sub.2)alkoxy;
[0054] i) R.sup.2 is phenyl;
[0055] j) R.sup.2 is (C.sub.3-C.sub.8)cycloalkyl;
[0056] k) R.sup.2 is (C.sub.3-C.sub.6)cycloalkyl;
[0057] l) R.sup.2 is cyclohexyl;
[0058] m) R.sup.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy or halo;
[0059] n) R.sup.3 is (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy or halo;
[0060] o) X is --C.dbd.O;
[0061] p) X is --CHOH; and
[0062] q) X is --CH.sub.2.
[0063] r) formula Ia
[0064] s) the enantiomer of formula Ia wherein the
[.alpha.].sup.D.sub.20 in methanol is (+).
[0065] Since the compounds of this invention are basic in nature,
they accordingly react with any of a number of inorganic and
organic acids to form pharmaceutically acceptable acid addition
salts. Included within the scope of the invention are the mono- and
di-salts. Acids commonly employed to form such salts are inorganic
acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, phosphoric acid, and the like, and organic acids,
such as 2-toluenesulfonic acid, methanesulfonic acid, oxalic acid,
p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric
acid, benzoic acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caproate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, .beta.-hydroxybutyrate, glycollate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate and the like. Preferred
pharmaceutically acceptable salts are the monohydrochloride,
dihydrochloride, monohydrobromide, dihydrobromide, Formula
I/succinate(1:1), formula Ia/succinate(1:1), Formula I/succinate
2:1, formula Ia/succinate 2:1, phosphate, d-tartrate, 1-tartrate or
maleate. It is understood by one of ordinary skill that hydrates of
the free base or of the pharmaceutically acceptable salts are
included within the scope of the present invention.
[0066] Many of the compounds of Formula I, including formula Ia,
are optical isomers. For example, the compounds have an asymmetric
center (or chiral center) at the carbon atom to which R.sup.1 and X
are attached. However, when a compound of the present invention is
named without an indication of asymmetric form, any and all of the
possible asymmetric forms are intended. This invention is not
limited to any particular isomer but includes all possible
individual isomers and racemates.
[0067] The intermediates and final products may be isolated and
purified by conventional techniques, such as, purification with
chromatography using silica gel or recrystallization of crystalline
isolates.
[0068] It will be readily appreciated by the skilled artisan that
the starting materials which are not described are either
commercially available or can be readily prepared by known
techniques from commercially available starting materials. All
other reactants used to prepare the compounds in the instant
invention are commercially available.
[0069] The compounds of the invention are generally prepared
according to the following schemes. 3
[0070] Starting material (1) is treated with a base, preferably
potassium tert-butoxide, followed by alkylation with
2-bromomethyl-1,3-dioxolane. Other appropriate bases include sodium
hydride, sodium hydroxide, potassium hydroxide, potassium
carbonate, cesium carbonate and the like.
[0071] The reaction is preferably conducted in a solvent such as
dimethyl sulfoxide at a temperature of 15.degree. C. to reflux,
with a temperature of 45-55.degree. C. being most preferred, and is
substantially complete in 1 to 24 hours to prepare intermediate
(2).
[0072] Treatment of (2) with an acid, such as hydrochloric acid or
p-toluene-sulfonic acid in a suitable organic solvent, achieves
aldehyde (3). Generally, the reaction is conducted in a protic
solvent, such a mixture of aqueous acid and acetone, at
temperatures of from about 5.degree. to 75.degree. C., preferably
at ambient temperature.
[0073] Aldehyde (3) is coupled with the desired aryl piperidine (4)
by reductive amination to prepare (5). The reaction is preferably
conducted at ambient temperature in a non-reactive solvent such as
dichloroethane or methylene chloride in the presence of sodium
triacetoxyborohydride and is substantially complete in one to 24
hours. See for example A. F. Abdel-Magid, et al., J. Org. Chem.,
61, 3849 (1996).
[0074] Reduction of (5) is readily accomplished using a reducing
agent such as sodium borohydride or, preferably, diisobutylaluminum
hydride to prepare the hydroxy compound (6). The reaction is
preferably conducted in an organic solvent such as methylene
chloride at temperatures of from about -20.degree. C. to 0.degree.
C.
[0075] Further reduction of (6) to achieve product (7) may be
achieved by treatment with a reducing agent such as triethylsilane
or boron trifluoride (when R.sup.2 is phenyl or substituted phenyl)
or by treatment with an acid, such as hydrochloric acid or
trifluoroacetic acid, in an aprotic solvent such as
tetrahydrofuran, at ambient temperature to form the double bond,
followed by hydrogenation with, for example, hydrogen and palladium
on carbon.
[0076] Starting material (1) is either commercially available or
can be prepared by coupling (8) [See Nahm and Weinreb, Tetrahedron
Lett., 22, 3815, (1981)] and (9) as described in Scheme II, below.
4
[0077] M is a metallic salt, such as lithium or magnesium halide.
The reaction is preferably conducted under an inert atmosphere
preferably nitrogen, in an aprotic solvent, such as
tetrahydrofuran, at ambient temperatures.
[0078] More specifically, the compounds of formula Ia can be
prepared following the procedure described in Scheme III. All
substituents, unless otherwise indicated, are previously defined.
The reagents and starting materials are readily available to one of
ordinary skill in the art. 5
[0079] In Scheme III, step A, the ester of structure (10) is
treated with benzylmagnesium chloride or benzylmagnesium bromide
under standard conditions well known in the art to provide the
ketone of structure (11). For example, about 1.05 to about 1.1
equivalents of a suitable amine, such as dimethylamine is dissolved
in a suitable organic solvent, such as tetrahydrofuran (cooled to
about -5.degree. C.) under an inert atmosphere. The solution is
warmed to room temperature and 1.0 equivalents of the ester (10)
are added with stirring. Then approximately 1.0 to 1.05 equivalents
of benzylmagnesium chloride is slowly added to the solution,
maintaining the temperature at about 15-20.degree. C. with a
cooling bath during the addition. After addition is complete, the
reaction is stirred at room temperature for about 1 to 2 hours,
then cooled to less than 0.degree. C. and then carefully quenched
with a suitable acid, such as HCl. The quenched reaction is then
extracted with a suitable organic solvent, such as tert-butyl
methyl ether (hereinafter referred to as MTBE), the organic layers
are combined, dried over anhydrous magnesium sulfate, filtered and
concentrated to provide ketone (11). Ketone (11) can be purified by
techniques well known in the art, such as flash chromatography on
silica gel with a suitable eluent, such as ethyl acetate/hexane to
provide the purified material. Alternatively, the crude ketone (11)
can be carried on to step B.
[0080] In Scheme III, step B, ketone (11) is alkylated with
bromoacetaldehyde diethyl acetal, and then iodomethane, under
conditions well known in the art to provide compound of structure
(12). For example, ketone (11) is dissolved in a suitable organic
solvent, such as methyl sulfoxide and treated with about 1.05 to
about 1.1 equivalents of a suitable base, such as potassium
tert-butoxide. The reaction is stirred for about 15 to 30 minutes
and about 1.0 to about 1.05 equivalents of bromoacetaldehyde
diethyl acetal is added dropwise to the reaction. One of ordinary
skill in the art would readily appreciate that bromoacetaldehyde
dimethyl acetal, bromoacetaldehyde ethylene acetal and the like may
be used in place of the corresponding diethyl acetal. The reaction
mixture is then heated to about 50.degree. C. for about 2 to 2.5
hours. The reaction mixture is then cooled with an ice/water bath
and about 2.2 equivalents of a suitable base, such as potassium
tert-butoxide is added. The reaction is allowed to stir for about
15 to 30 minutes with continued cooling and then about 1.5 to about
1.8 equivalents of iodomethane is added dropwise to the reaction
mixture keeping the temperature of the mixture below 41.degree. C.,
preferably below 21.degree. C. After addition is complete, the
reaction is warmed to room temperature and stirred for about 1 to 4
hours. The reaction mixture is then partitioned between water and a
suitable organic solvent, such as MTBE. The layers are separated
and the organic phase is washed with water, brine, dried over
anhydrous magnesium sulfate, filtered and concentrated under vacuum
to provide the compound (12).
[0081] In Scheme III, step C, compound (12) is hydrolyzed under
acidic conditions to provide aldehyde (13) in a manner analogous to
the procedure described in Scheme I. More specifically, for
example, compound (12) is dissolved in a suitable organic solvent,
such as acetone and treated with a suitable acid, such as
hydrochloric acid. The reaction mixture is stirred for about 1 to 3
hours at room temperature. The reaction mixture is then extracted
with a suitable organic solvent, such as ethyl acetate or methylene
chloride, the organic extracts are combined, washed with brine,
dried over anhydrous magnesium sulfate, filtered and concentrated
under vacuum to provide aldehyde (13). Aldehyde (13) can be
purified by techniques well known in the art, such as flash
chromatography on silica gel with a suitable eluent, such as ethyl
acetate/hexane. Alternatively, crude aldehyde (13) can be used
directly in step D.
[0082] In Scheme III, step D, aldehyde (13) is reductively
aminated, under conditions well known in the art, with piperazine
(14) to provide the compound of formula Ia in a manner analogous to
the procedure described in Scheme I. More specifically, for
example, aldehyde (13) is dissolved in a suitable organic solvent,
such as methylene chloride. To this solution is added about 1.1
equivalents of piperazine (14). Acetic acid may optionally be added
to aid in dissolution of the piperazine (14). Then about 1.2 to 1.3
equivalents of sodium triacetoxyborohydride is added and the
reaction is stirred at room temperature for about 3 to 5 hours. The
reaction is then quenched by addition of a suitable base, such as
aqueous sodium hydroxide to provide a pH of about 10 to about 12.
The quenched reaction is then extracted with a suitable organic
solvent, such as methylene chloride. The organic extracts are
combined, washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated under vacuum to provide the
compound of formula Ia. This material can then be purified by
techniques well known in the art, such as flash chromatography on
silica gel with a suitable eluent, such as ethyl
acetate/hexane.
[0083] The free base of formula Ia can be converted to the
corresponding pharmaceutically acceptable salts under standard
conditions well known in the art. For example, the free base of
formula Ia is dissolved in a suitable organic solvent, such as
methanol, treated with one equivalent of maleic or oxalic acid for
example, or two equivalents of hydrochloric acid for example, and
then concentrated under vacuum to provide the corresponding
pharmaceutically acceptable salt. The residue can then be purified
by recrystallization from a suitable organic solvent or organic
solvent mixture, such as methanol/diethyl ether.
[0084] In Scheme III, step E, the (+) enantiomer of formula Ia can
be separated from the (-) enantiomer using techniques and
procedures well known in the art, such as that described by J.
Jacques, et al., "Enantiomers, Racemates, and Resolutions", John
Wiley and Sons, Inc., 1981. For example, chiral chromatography with
a suitable organic solvent, such as ethanol/acetonitrile and
Chiralpak AD packing, 20 micron can also be utilized to effect
separation of the enantiomers.
[0085] In Scheme III, step F, the (+) enantiomer of formula Ia is
converted to its pharmaceutically acceptable salt, such as the
monohydrochloride, dihydrochloride, monohydrobromide,
dihydrobromide, formula Ia/succinate(1:1), formula Ia/succinate
2:1, phosphate, d-tartrate, l-tartrate or maleate salt, in a manner
analogous to the procedure described at the end of step D
above.
[0086] Alternatively, compounds of structure (5) can be prepared
following the procedure described in Scheme IV. All substituents,
unless otherwise indicated, are previously defined. The reagents
and starting materials are readily available to one of ordinary
skill in the art. 6
[0087] In Scheme IV, step A, aldehyde (15) is combined with a
suitable organometallic reagent (16) under conditions well known in
the art to provide alcohol (17). Examples of suitable
organometallic reagents include Grignard Reagents, alkyl lithium
reagents, alkyl zinc reagents, and the like. Grignard Reagents are
preferred. For examples of typical Grignard Reagents and reaction
conditions, see J. March, "Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure", 2.sup.nd Edition, McGraw-Hill, pages
836-841 (1977). More specifically, aldehyde (15) is dissolved in a
suitable organic solvent, such as tetrahydrofuran or toluene,
cooled to about -5.degree. C. and treated with about 1.1 to 1.2
equivalents of a Grignard reagent of formula (16) wherein M is MgCl
or MgBr. The reaction is allowed to stir for about 0.5 to 2 hours,
then quenched, and alcohol (17) is isolated. For example, the
reaction mixture is poured onto ice-cold 1N HCl, the quenched
mixture is extracted with a suitable organic solvent, such as
toluene, the organic extracts are dried either azeotropically or
over a suitable drying agent, such as anhydrous magnesium sulfate,
filtered and concentrated under vacuum to provide alcohol (17).
[0088] In Scheme IV, step B, alcohol (17) is oxidized under
standard conditions well know in the art, such as those described
by J. March, "Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure", 2.sup.nd Edition, McGraw-Hill, pages 1082-1084
(1977), to provide ketone (1). [Ketone (1) is the starting material
used in Scheme I above.]
[0089] For example, alcohol (17) is dissolved in a suitable organic
solvent, such as methylene chloride, the solution cooled with a wet
ice-acetone bath, and treated with 2.5 to 3.0 equivalents of
dimethyl sulfoxide. After stirring for about 30 minutes, the
reaction is then treated with about 1.8 equivalents of
P.sub.2O.sub.5. The reaction is allowed to stir for about 3 hours
and then, preferably, treated over about 30 minutes with about 3.5
equivalents of a suitable amine, such as triethylamine. The cooling
bath is then removed and the reaction is allowed to stir for about
8 to 16 hours. The ketone (1) is then isolated by standard
extraction techniques well known in the art. The above oxidation is
also performed using standard Swern Oxidation conditions which are
well known to one of ordinary skill in the art.
[0090] In Scheme IV, step C, ketone (1) is treated with a suitable
base followed by addition of the alkene (18), wherein X is a
suitable leaving group, to provide compound (19). For example,
ketone (1) is combined with an excess of alkene (18) in a suitable
organic solvent, such as tetrahydrofuran, and cooled with a wet ice
acetone bath. Examples of suitable leaving groups are Cl, Br, I,
tosylate, mesylate, and the like. Preferred leaving groups are Cl
and Br. About 1.1 equivalents of a suitable base is added and the
reaction is allowed to stir for about 2 hours at room temperature.
Examples of suitable bases are potassium tert-butoxide, sodium
hydride, NaN(Si(CH.sub.3).sub.3).sub.2, LDA,
KN(Si(CH.sub.3).sub.3).sub.2, NaNH.sub.2, sodium ethoxide, sodium
methoxide and the like. Potassium tert-butoxide is the preferred
suitable base. The reaction is then quenched with aqueous acid and
compound (19) is isolated by extraction with a suitable organic
solvent, such as heptane. The heptane extracts are washed with
sodium bicarbonate, dried over anhydrous magnesium sulfate,
filtered and concentrated under vacuum to provide compound
(19).
[0091] In Scheme IV, step D, compound (19) is treated with a
suitable oxidizing agent to provide aldehyde (3). [Aldehyde (3) is
also prepared in Scheme I.] Examples of suitable oxidizing agents
are ozone, NaIO.sub.4/Osmium catalyst, and the like. Ozone is the
preferred oxidizing agent. Examples of suitable oxidizing reagents
and conditions are described by J. March, "Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure", 2.sup.nd Edition,
McGraw-Hill, pages 1090-1096 (1977).
[0092] For example, compound (19) is dissolved in a suitable
organic solvent, such as methanol, a small amount of Sudan III is
added, and the solution is cooled to about -20.degree. C. Ozone is
bubbled into the solution for about 4 hours until the pink color
turns to a pale yellow color. Then Me.sub.2S is added to the
reaction mixture and the cooling bath is removed. Concentration of
the reaction mixture under vacuum provides the intermediate
dimethyl acetal of aldehyde (3). This dimethyl acetal is readily
hydrolyzed under standard acidic conditions to provide aldehyde
(3). Alternatively, direct acidic work-up of the crude reaction
mixture provides aldehyde (3). Alternatively, aldehyde (3) can be
obtained directly by ozonolysis of (19) in a non-acetal forming
solvent, such as methylene chloride.
[0093] In Scheme IV, step E, aldehyde (3) is reductively aminated
under conditions analogous to those described above in Scheme III,
step D, to provide compound (5). [Compound 5 is also prepared in
Scheme I.]
[0094] Scheme V provides an alternative synthesis for the
preparation of compound (5). All substituents, unless otherwise
indicated, are previously defined. The reagents and starting
materials are readily available to one of ordinary skill in the
art. 7
[0095] In Scheme V, step A, aldehyde (3) is condensed with
piperidine (4) under standard conditions well known in the art to
provide the enamine (20). For example, about 1.05 equivalents of
aldehyde (3) dissolved in a suitable organic solvent, such as
isopropyl acetate or isopropanol, is added to neat piperazine (4),
free base. Additional organic solvent is added to produce a slurry
and the reaction is stirred for about 1 to 2 hours. The enamine
(20) is then isolated by standard techniques, such as collection by
filtration.
[0096] In Scheme V, step B, the enamine (20) is hydrogenated under
conditions well known by one of ordinary skill in the art to
provide compound (5). For example, enamine (20) is combined with a
suitable organic solvent, such as isopropyl alcohol and a catalytic
amount of 5% palladium on carbon in a Parr bottle. The mixture is
placed under 50 psi of hydrogen and shaken for about 2 days at room
temperature. The slurry is then filtered to remove catalyst and the
filtrate is concentrated to provide compound (5).
[0097] The following examples represent typical syntheses of the
compounds of Formula I and formula Ia as described generally above.
These examples are illustrative only and are not intended to limit
the invention in any way. The reagents and starting materials are
readily available to one of ordinary skill in the art. As used
herein, the following terms have the meanings indicated: "aq"
refers to aqueous; "eq" refers to equivalents; "g" refers to grams;
"mg" refers to milligrams; "L" refers to liters; "mL" refers to
milliliters; ".mu.L" refers to microliters; "mol" refers to moles;
"mmol" refers to millimoles; "psi" refers to pounds per square
inch; "min" refers to minutes; "h" refers to hours; ".degree. C."
refers to degrees Celsius; "TLC" refers to thin layer
chromatography; "HPLC" refers to high performance liquid
chromatography; "R.sub.f" refers to retention factor; "R.sub.t"
refers to retention time; ".delta." refers to part per million
down-field from tetramethylsilane; "THF" refers to tetrahydrofuran;
"DMF" refers to N,N-dimethylformamide; "IPA" refers to isopropyl
alcohol; "iPrOAc" refers to isopropyl acetate; "AcOH" refers to
acetic acid; "HRMS" refers to high resolution mass spectrometry;
"Et.sub.3N" refers to triethylamine; "LDA" refers to lithium
diisopropyl amide; "RT" refers to room temperature; "SRI" refers to
serotonin reuptake inhibitor; "aq" refers to aqueous; and "MTBE"
refers to tert-butyl methyl ether.
EXAMPLE 1
[0098] 8
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine
oxalate
A. Preparation of 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane
[0099] To a stirred suspension of sodium hydride (61.25 mmol) in
150 mL of dimethylformamide at 0.degree. C. under nitrogen was
added dropwise a solution of deoxybenzoin (50.96 mmol) in 150 mL of
tetrahydrofuran. The mixture was stirred at 0.degree. C. for 1 hour
and room temperature for 1 hour. To the mixture
2-bromomethyl-1,3-dioxolane (60.55 mmol) and catalyst potassium
iodide (6.0 mmol) were added. The mixture was heated to reflux for
13 hours. After cooling, diethyl ether (300 mL) and water (300 mL)
were added. The organic layer was separated and washed with water
(150 mL.times.2). Purification by flash chromatography using
hexanes and ethyl acetate gave
2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolan- e (8.18 g; 57%).
B. Preparation of 3-benzoyl-3-phenylpropionaldehyde
[0100] To 100 mL of acetone was added
2-(2'-benzoyl-2'-phenyl)ethyl-1,3-di- oxolane (8.85 mmol) and 100
mL of 2N hydrochloric acid solution. After the mixture was stirred
at room temperature for 7 hours, 100 mL of 2N sodium hydroxide was
added. Acetone was evaporated and the residue was extracted with
diethyl ether and hexanes (1:1, 100 mL.times.3). The combined
organic layer was dried (sodium sulfate), filtered and
concentrated. The residue was found to be rather pure material
(3-benzoyl-3-phenylpropional- dehyde) and therefore used for next
step.
C. Preparation of
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]pipe-
razine
[0101] The 3-benzoyl-3-phenylpropionaldehyde residue obtained from
Step B, above, (.about.8.85 mmol) was dissolved in 110 mL of
methylene chloride. To this solution was added
2-methoxyphenylpiperazine (10.61 mmol) and sodium
triacetoxyboranehydride, NaBH(OAc).sub.3, (10.61 mmol). The mixture
was stirred at room temperature for 3 hours. Aqueous workup
followed by flash chromatography gave pure product
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine
(3.48 g) in 95% yield for last two steps. One equivalent of oxalic
acid was added to the free base dissolved in methanol. The solvent
was evaporated and the product was dried under vacuum to form the
oxalate salt.
[0102] m.p.=161-163.degree. C.;
[0103] MS (m/e): 414 (M.sup.+)
EXAMPLE 2
[0104] 9
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine
oxalate
A. Preparation of Cyclohexyl Benzyl Ketone
[0105] To a stirred solution of N-methyl-N-methoxy
cyclohexanecarboxamide (7.42 mmol) in 30 mL of tetrahydrofuran at
0.degree. C. under nitrogen was added a solution of benzyl
magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol).
The mixture was stirred at 0.degree. C. for 30 minutes and at room
temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL)
were added. The organic layer was separated, dried, filtered, and
concentrated. Purification of the residue by flash chromatography
using hexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05
g) in 70% yield as oil.
B. Preparation of
2-(2'-cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane
[0106] Following the procedures described in the Example 1, Step A,
the reaction of cyclohexyl benzyl ketone (5.09 mmol) and
2-bromomethyl-1,3-dioxolane (7.63 mmol) in the presence of sodium
hydride (5.60 mmol) gave
2-(2'-cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane (0.86 g) in
59% yield.
C. Preparation of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde
[0107] Following the procedures described in the Example 1, Step B,
the reaction of
2-(2'-cyclohexanecarbonyl-2'-phenyl)ethyl-1,3-dioxolane (2.98 mmol)
with 1N hydrochloric acid gave
3-cyclohexanecarbonyl-3-phenylpropio- naldehyde as a crude product
in 100% yield.
D. Preparation of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl-
)propyl]piperazine
[0108] Following the procedures described in the Example 1, Step C,
the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39
mmol) and 2-methoxyphenylpiperazine (1.39 mmol) with sodium
triacetoxyboranehydride (1.80 mmol) gave pure product
1-(2-methoxyphenyl-4-[3-(cyclohexanecarbony-
l)-3-(phenyl)propyl]piperazine (464 mg) in 79% yield. The oxalate
salt was prepared as described above.
[0109] m.p.=149-151.degree. C.;
[0110] MS (m/e): 420 (M.sup.+)
EXAMPLE 3
[0111] 10
1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine
oxalate
[0112] Following the procedures described in the Example 1, Step C,
the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55
mmol) and 1-(2-pyridyl)piperazine (1.55 mmol) with sodium
triacetoxyboranehydride (2.0 mmol) gave pure product
1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(-
phenyl)propyl]piperazine (475 mg) in 78% yield. The oxalate salt
was prepared as described above.
[0113] m.p.=185-187.degree. C.;
[0114] MS (m/e): 391 (M.sup.+)
EXAMPLES 4
[0115] 11
1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine
dihydrochloride
[0116] Following the procedures described in the Example 1, Step C,
the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02
mmol) and 1-(2-ethoxyphenyl)piperazine (1.13 mmol) with sodium
triacetoxyboranehydride (1.33 mmol) gave pure product
1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine
(270 mg) in 52% yield. To a solution of free base in methanol was
added required amount of hydrochloric acid solution in diethyl
ether. The solvents were removed by reduced pressure, and the
product was dried under vacuum to give dihydrochloric acid
salt.
[0117] m.p.=180-183.degree. C.;
[0118] MS (m/e): 434 (M.sup.+).
EXAMPLE 5
[0119] 12
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine
oxalate
A. Preparation of 2-(2'-benzoyl-2'-phenyl)propyl-1,3-dioxolane
[0120] Following the procedures described in the Example 1, Step A,
the reaction of 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane (3.54
mmol) and iodomethane (10.62 mmol) in the presence of sodium
hydride (4.25 mmol) gave
2-(2'-benzoyl-2'-phenyl)propyl-1,3-dioxolane (0.60 g).
B. Preparation of 3-benzoyl-3-phenylbutyraldehyde
[0121] Following the procedures described in the Example 1, Step B,
the reaction of 2-(2'-benzoyl-2'-phenyl)propyl-1,3-dioxolane (0.60
g) with 3N hydrochloric acid gave 3-benzoyl-3-phenylbutyraldehyde
as a crude product (0.32 g).
C. Preparation of
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piper- azine
[0122] Following the procedures described in the Example 1, Step C,
the reaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and
1-(2-methoxyphenyl)piperazine (0.23 g) with sodium
triacetoxyboranehydride (0.33 g) gave-pure product
1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine (0.12
g). The oxalate salt was prepared as described above.
[0123] m.p.=192-193.degree. C.;
[0124] MS (m/e): 428 (M.sup.+)
EXAMPLE 6
[0125] 13
1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazin-
e dihydrochloride
[0126] Following the procedures described in the Example 1, Step C,
the reaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde
(2.52 mmol) and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with
sodium triacetoxyboranehydride (3.28 mmol) gave pure product
1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazi-
ne (770 mg) in 70% yield. The di-hydrochloric acid salt was
prepared as described above.
[0127] m.p.=193-194.degree. C.;
[0128] MS (m/e): 434 (M.sup.+).
EXAMPLE 7
[0129] 14
1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazin-
e dihydrochloride
[0130] Following the procedures described in the Example 1, Step C,
the reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde
(1.36 mmol) and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with
sodium triacetoxyboranehydride (1.77 mmol) gave pure product
1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazi-
ne (370 mg) in 67% yield. The di-hydrochloric acid salt was
prepared as described above.
[0131] m.p.=210-212.degree. C.;
[0132] MS (m/e): 406 (M.sup.+)
EXAMPLE 8
[0133] 15
1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazi-
ne oxalate
[0134] To a stirred solution of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbo-
nyl)-3-(phenyl)propyl]piperazine (0.11 g, 0.20 mmol) in methylene
chloride (10 mL) at -78.degree. C. under nitrogen was added
Dibal-H.TM. solution (0.89 mmol). The mixture was stirred at
-78.degree. C. for 1 hour and then slowly warmed to room
temperature for 16 hours. Workup followed by purification by flash
chromatography gave pure 1-(2-methoxyphenyl)-4-[4-(-
cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazine (0.086 g) in 78%
yield. The oxalate salt was prepared as described above.
[0135] m.p.=100-102.degree. C.;
[0136] MS (m/e): 422 (M.sup.+)
EXAMPLE 9
[0137] 16
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine
[0138] 17
Preparation of 2-phenyl-l-cyclohexane-ethan-1-one
[0139] Scheme III, step A: A 5 L reaction vessel was charged with
tetrahydrofuran (1.05 L) under an atmosphere of nitrogen. The
solution was cooled with an acetone/ice bath to about -5.degree. C.
Liquid dimethylamine (115.9 g, 2.57 mol) was then added through a
teflon addition tube. The cooling bath was removed and the solution
was allowed to warm to about 15-20.degree. C. Methyl
cyclohexanecarboxylate (341.7 g, 2.40 mol) was then added resulting
in a tea-colored solution. Then benzylmagnesium chloride (2.52 L of
a 2.0 M solution in THF, 246 mol) was slowly added at a rate to
complete addition in about 1.8 to about 2.2 hours. A cooling bath
was applied to maintain the temperature of the reaction mixture at
about 15-20.degree. C. during the addition. After the
benzylmagnesium chloride solution was added, the resulting slurry
was stirred at room temperature for about 1-2 hours. The reaction
mixture was then cooled to less than 0.degree. C. Concentrated HCl
(709.7 g, 7.2 mol) was combined with water (3.08 L)and the solution
was cooled to less than 5.degree. C. The dilute acid mixture was
added to a 22 L reaction vessel with an ice bath applied to the
vessel. The above-chilled reaction mixture was then slowly poured
into the chilled dilute acid solution with stirring. An extreme
exotherm occurs (Use Caution!). Addition rate of the-reaction
mixture should be controlled to maintain the temperature of the
quench solution below 45.degree. C. After addition of the reaction
mixture to the dilute acid solution, the quenched reaction mixture
was cooled to room temperature and the pH was adjusted to about 6.5
to 7.5 with a sufficient amount of concentrated HCl. The quenched
reaction mixture was extracted with MTBE (1.71 L). The layers were
separated and the organic layer was washed with a water/MTBE
mixture (1.03 L/1.37 L)followed by a second washing with a
water/MTBE mixture (1.03 L/1.03 L). The organic layers were
combined, washed with brine (683 mL), dried over anhydrous
magnesium sulfate (167 g), filtered and concentrated under vacuum.
The crude oil was dried under house vacuum for 5-16 hours to
provide crude 2-phenyl-1-cyclohexane-ethan-1-one (522.3 g). This
crude material was used in the next reaction without further
purification. 18
Preparation of
1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane
[0140] Scheme III, step B; 2-Phenyl-1-cyclohexane-ethan-1-one (8.26
g, 40.8 mmol)was combined with DMSO (45 mL) in a 3-necked, 250 mL
round bottom flask equipped with a magnetic stir bar,
thermocouple-digital thermometer unit and an addition funnel. To
the stirring solution was added potassium tert-butoxide (5.04 g,
44.9 mmol). A 16.degree. C. exotherm was observed and the yellow
solution became dark brown. The reaction mixture was stirred for an
additional 15 minutes after addition was complete, and then
bromoacetaldehyde diethyl acetal (8.26 g, 41.9 mmol) was added
dropwise via the addition funnel over approximately 10 minutes. The
reaction mixture was then heated at 50.degree. C. for 2 to 2.5
hours during which the reaction mixture became yellow. The reaction
mixture was then cooled with an ice/water bath to about 9.5.degree.
C. and potassium tert-butoxide (10.07 g, 89.7 mmol) was added
resulting in an exothermic reaction and change in color from yellow
to brown. With the cooling bath still in place, the reaction
mixture was stirred for an additional 15 minutes followed by
dropwise addition of iodomethane (10.26 g, 72.3 mmol, neat). The
temperature of the reaction mixture was maintained at or below
21.degree. C. Any exotherm during the iodomethane addition should
be maintained below 41-43.degree. C., which is the boiling point of
iodomethane. After addition was complete, the reaction mixture was
allowed to stir for 1 to 4 hours at room temperature. The reaction
mixture was then partitioned between MTBE (100 mL) and water (100
mL). The organic phase was washed with water (3.times.50 mL), brine
(50 mL), dried over anhydrous magnesium sulfate, suction filtered
and concentrated under vacuum to provide crude
1,1-diethoxy-3-phenyl-3-cycloh- exanecarbonyl-butane (13.6 g) as a
yellow oil. This crude material was used in the next reaction
without further purification. 19
Preparation of 1-cyclohexyl-2-phenyl-butan-1-one-4-al
[0141] Scheme III, step C;
1,1-Diethoxy-3-phenyl-3-cyclohexanecarbonyl-but- ane (74.4 g, 224
mmol) was dissolved in acetone (800 mL) followed by addition of 3.0
N HCl (800 mL). The reaction mixture was stirred for one hour at
room temperature. It was then concentrated under vacuum to less
than 1/2 its original volume and then extracted with methylene
chloride (800 mL). The organic extract was then washed with brine
(300 mL), dried over anhydrous magnesium sulfate, suction filtered
and concentrated under vacuum to provide crude
3-phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g). Alternatively,
the dried and filtered methylene chloride solution can be used
directly in the next step without concentration.
Preparation of the Final Title Compound,
1-(2-methoxyphenyl)-4-[3-(cyclohe-
xanecarbonyl)-3-(phenyl)butyl]piperazine
[0142] Scheme III, step D;
3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was
dissolved in methylene chloride (1650 mL) followed by addition of
1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246 mmol).
Acetic acid (41 mL) may optionally be added to turn the slurry into
a solution. To the stirred solution, sodium triacetoxyborohydride
(60.3 g, 284 mmol) was slowly added. A slight exotherm resulted and
a slurry was produced. The reaction mixture was stirred for an
additional 3 hours at room temperature. The reaction was then
quenched by addition of 2.0 N sodium hydroxide (1050 mL) producing
a pH of about 10 for the quenched reaction mixture. The mixture was
then extracted with methylene chloride (2 times, 1 L and 300 mL).
The organic extracts were combined, washed successively with 1.0 N
HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL),
dried over anhydrous magnesium sulfate, filtered and concentrated
under vacuum to provide the final title compound as a thick
oil;
[0143] UV (MeOH): .lambda..sub.max=243 nm, .epsilon..sub.243=7110;
.lambda..sub.max=281 nm, .epsilon..sub.281=3200
[0144] IR (CDCl.sub.3, cm.sup.-1) 2937, 2856, 2836, 1698, 1499,
1451, 1377, 1316, 1242, 1029
[0145] .sup.1H NMR (300 MHz, DMSO) .delta. 7.75 (2H, m), 7.55 (2H,
m), 6.93 (3H, m), 6.85 (2H, m), 3.75 (3H, s), 2.90 (4H, m), 2.43
(4H, m), 2.08 (5H, m), 1.5 (10H, m), 1.05 (3H, m)
[0146] .sup.13C NMR (300 MHz, DMSO) .delta. 214.18, 151.94, 141.25,
141.23, 128.45, 126.85, 126.74, 122.22, 120.79,. 117.81, 111.97,
55.28, 54.54, 53.67, 53.13, 50.01, 45.30, 33.75, 30.44, 30.12,
25.21, 24.98, 24.93, 19.94.
[0147] Anal. Calcd for C.sub.28H.sub.38N.sub.2O.sub.2: C, 77.38; H,
8.81; N, 6.45. Found: C, 76.44; H, 8.89; N, 6.01.
Preparation of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine maleate
[0148]
1-(2-Methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]pipe-
razine (prepared directly above) was dissolved in warm methanol (50
mL) followed by addition of maleic acid (26.8 g) and MTBE (200 mL).
This mixture was concentrated to a paste and then redissolved by
addition of methanol (approximately 15 mL) and MTBE (200 mL). The
mixture was seeded and an additional amount of MTBE (300 mL) was
added once crystallization was initiated. The mixture was suction
filtered, and the solid rinsed with MTBE and vacuum dried for 5
hours at 40.degree. C. to provide the title compound (122 g).
[0149] In addition, one of ordinary skill in the art could prepare
the title compound,
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)-
butyl]piperazine, in a manner analogous to the procedures described
above, from 3-cyclohexanecarbonyl-3-phenylbutyraldehyde and
1-(2-methoxyphenyl)piperazine as described generally in Scheme
V.
Preparation of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine 2HCl
[0150] The title compound is prepared by one of ordinary skill in
the art, in a manner analogous to preparation of the above maleate
salt, from the free base and hydrochloric acid to provide a white
solid; mp(DSC)=192.81.degree. C.
Preparation of
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(pheny-
l)butyl]piperazine and
(-)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)--
3-(phenyl)butyl]piperazine
[0151] Scheme III, step E:
[0152] Materials:
[0153] Chiralpak AD Bulk packing, 20 micron
[0154] Acetonitrile
[0155] 3A alcohol
[0156] Prochrom 8 cm column
[0157] Prochrom LC-80 system/collection system
[0158] Column Preparation: A ProChem LC-80 automated system with an
8.times.19 cm Prochrom column (ProChem, 5622 West 73.sup.rd Street,
Indianapolis, Ind. 46278) is slurry packed using approximately 500
g Chiralpak AD (Chiral Technologies, 730 Springdale Drive, Exton,
Pa. 19341) in propanol (1 L). An eluent containing approximately 5%
3A alcohol in acetonitrile was prepared. Column flow rate was 155
mL/min and the detector was set at 280 nm. The racemic
1-(2-methoxyphenyl)-4-[3-(cyc-
lohexanecarbonyl)-3-(methyl)-3(phenyl)propyl]piperazine (25 g) was
dissolved in acetonitrile (50 mL). Approximately 3 g of this
solution was weighed into a flask and diluted with acetonitrile (50
mL). This solution was then pumped onto the column to begin
separation of the (+) and (-) enantiomers of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)b-
utyl]piperazine. Fractions were then collected with the (-)
enantiomer eluting first. Approximate total cycle time is 15
minutes.
[0159] The enantiomeric excess of the two separated isomers was
determined under the following conditions:
[0160] Column: 46.times.15 cm Chiralcel OH--H
[0161] Eluent: 3% ethanol in Heptane containing 0.2%
dimethylamine
[0162] Flow rate: 0.6 mL/min
[0163] Temperature: ambient
[0164] uv: 280 nm
[0165] % ee for the (-) enantiomer 96.4%.
[0166] % ee for the (+) enantiomer 96.6%.
Preparation of
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(pheny-
l)butyl]piperazine dihydrochloride
[0167] Scheme III, step F:
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbon-
yl)-3-(phenyl)butyl]piperazine (15.0 g, 34.5 mmol, prepared above)
was diluted with methanol (40 mL). To this solution was added HCl
(9.58 g of a 26.3% solution in methanol, 69.0 mmol). The mixture
began to form gelatinous-looking crystals and set up solid within
minutes. To this mixture was added with vigorous stirring, diethyl
ether (100 mL). The white solid was collected by suction filtration
and then dried under vacuum at 45.degree. C. for two days to
provide the title compound (13.4 g, 76%) as a white solid;
mp(DSC)=195.58.degree. C.
[0168] IR (CDCl.sub.3, cm.sup.-1) 2976, 2939, 1700, 1502, 1462,
1451, 1267, 1243, 1021;
[0169] .sup.1H NMR (300 MHz, DMSO) .delta. 7.40 (2H, m), 73.1 (3H,
m) 7.03 (3H, M) 6.90 (1H, m) 3.78 (3H, s) 3.49 (4H, m) 3.16 (5H, m)
2.64 (1H, m) 2.40 (3H, m) 1.56 (3H, s) 1.46 (4H, m) 1.11 (5H, m)
0.86 (1H, m);
[0170] .sup.13C NMR (300 MHz, DMSO) .delta. 213.46, 151.84, 139.56,
138.12, 128.72, 127.37, 126.86, 124.29, 120.85, 118.71, 112.29,
55.48, 54.06, 52.20, 50.78, 50.57, 46.93, 45.14, 30.31, 30.16,
25.15, 24.91, 24.89, 19.15;
[0171] HRMS calcd for C.sub.28H.sub.39N.sub.2O.sub.2 (MH.sup.+)
435.3012, found 435.3018.
[0172] [.alpha.].sup.25.sub.D=+76.53.degree. (c=1, MeOH), ee 99.3%
(Chiral HPLC)
Preparation of
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(pheny-
l)butyl]piperazine monohydrochloride
[0173] Scheme III, step F:
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbon-
yl)-3-(phenyl)butyl]piperazine (6.05 g, 13.9 mmol) was diluted with
MTBE (120 mL) followed by addition of HCl (2.2 M solution in
isopropanol, 6.3 mL, 13.9 mmol, prepared from 0.80 g of HCl gas in
10 mL of isopropanol). The mixture formed an oil/solid mixture
which upon further stirring yielded a uniformly crystalline
material. The mixture was suction-filtered and rinsed with MTBE to
provide a white solid which was dried under vacuum at 45.degree. C.
(5.74 g, 96.2% ee).
[0174]
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]-
piperazine monohydrochloride can be prepared in an analogous manner
as above from an equivalent of concentrated aqueous HCl in place of
the gaseous HCl.
Alternative Preparation of
1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)--
3-(phenyl)butyl]piperazine
[0175] 20
Preparation of 1-Cyclohexyl-2-phenylpropanol
[0176] Scheme IV, step A: To a solution of cyclohexylmagnesium
chloride (50 mmol) in 25 mL of Et.sub.2O and 40 mL of THF at
-5.degree. C. was added a solution of 2-phenylpropanaldehyde (5.36
g, 40 mmol) in 10 mL of THF. The reaction mixture exothermed to
5.degree. C. After stirring at room temperature for 75 min, the
solution was poured onto ice cold 1 N HCl, extracted with toluene,
dried over MgSO.sub.4, and concentrated to give the title compound
as a colorless oil (6.15 g, 70%): .sup.1H NMR (d.sup.6-DMSO):
.delta. 7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH),
4.17-4.51 (br s, 1H, --OH), 3.23-3.33 (m, 1H, R.sub.2CHOH), 2.78
(dq, J=7.0 Hz, J=7.1 Hz, 1H, --CH(CH.sub.3)Ph), 1.23-1.83 (m, 6H,
cyclohexyl CH), 1.20 (d, J=6.9 Hz, 3H, --CH(CH.sub.3)Ph), 0.88-1.18
(m, 5H, cyclohexyl CH). 21
Preparation of Cyclohexyl 1-phenylethyl ketone
[0177] Scheme IV, step B: DMSO (118 mL, 1.6674 mol) was added
dropwise to a solution of 126.42 g (0.579 mol) of
1-cyclohexyl-2-phenylpropanol in 1737 mL of CH.sub.2Cl.sub.2
(cooled in a wet ice acetone bath). After 29 min, 147.93 g (1.0422
mol) of P.sub.2O.sub.5 was added. After 11 min, the cooling bath
was removed. An aliquot quenched with Et.sub.3N showed complete
reaction within 3 h at RT. The reaction mixture was cooled in a wet
ice acetone bath. Et.sub.3N (282 mL, 2.0265 mol) was added dropwise
to the cooled reaction mixture over a 30 min period. The cooling
bath was removed and the mixture was stirred overnight at RT. The
reaction mixture was quenched by dropwise addition of 500 mL of 3 N
HCl (aq) (pH=0). After shaking in separatory funnel, the aqueous
phase was removed. The organic phase was washed with 500 mL of 3 N
HCl (aq) (pH=0), washed twice with 1 L of 10% K.sub.2CO.sub.3 (aq)
(pH=12; 12), washed three times with 500 mL of NaOCl (aq) solution,
washed with 1 L of water, washed with 1 L of 25% NaCl (aq), dried
over MgSO.sub.4, gravity filtered and concentrated under vacuum
with dry ice trap to collect Me.sub.2S. An amber oil of the title
compound (107.01 g, 85.437%) was obtained;
[0178] .sup.1H NMR (d.sup.6-DMSO): .delta. 7.30-7.37 (m, 2H, phenyl
CH), 7.21-7.28 (m, 3H, phenyl CH), 4.08 (q, J=6.9 Hz, 1H,
--CH(CH.sub.3)Ph), 2.40-2.49 (m, 1H, cyclohexyl CH), 1.82-1.84 (m,
1H, cyclohexyl --CH.sub.2), 1.67-1.69 (m, 1H, cyclohexyl
--CH.sub.2), 1.52-1.63 (m, 1H, cyclohexyl --CH.sub.2), 1.34-1.43
(m, 1H, cyclohexyl --CH.sub.2), 1.26 (d, J=6.9 Hz, 3H,
--CH(CH.sub.3)Ph), 1.01-1.24 (m, 4H, cyclohexyl --CH.sub.2). 22
Preparation of 2-phenyl-2-methyl-4-pentenoyl cyclohexane
[0179] Scheme IV, step C; A solution of 31.39 g (0.2797 mol) of
t-BuOK in 100 mL of THF was added dropwise to a solution of 55.00 g
(0.2543 mol) of cyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052
mol) of allyl bromide in 136 mL of THF (cooled in a wet ice acetone
bath). THF washings (16 mL) were added to the reaction mixture. The
cooling bath was removed after addition. After reaction completion
(2 h), the reaction mixture was quenched with 300 mL of 1 N HCl
(pH=0) and extracted with 300 mL of heptane. The heptane extract
was washed with 10% NaHCO.sub.3 (aq) (pH=9), dried over MgSO.sub.4,
gravity filtered and concentrated under vacuum to afford 59.70 g
(91.58%) of title compound as an amber oil: .sup.1H NMR
(d.sup.6-DMSO): .delta. 7.32-7.42 (m, 2H, phenyl CH), 7.24-7.31 (m,
3H, phenyl CH), 5.34-5.47 (m, 1H, --CH.dbd.CH.sub.2), 5.02 (dd,
J=17.1 Hz, J=2.1 Hz, 1H, --CH.dbd.CH--H (trans)), 4.97 (ddd, J=10.2
Hz, J=2.2 Hz, J=1.0 Hz, 1H, --CH.dbd.CH--H (cis, W-coupling)), 2.66
(ddd, J=14.2 Hz, J=6.9 Hz, J=1.0 Hz, 1H,
--CH.sub.2CH.dbd.CH.sub.2), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz, J=1.0
Hz, 1H, --CH.sub.2CH.dbd.CH.sub.2), 2.38-2.49 (m, 1H, cyclohexyl
CH), 1.48-1.69 (m, 4H, cyclohexyl --CH.sub.2), 1.46 (s, , 3H,
--CH(CH.sub.3)Ph), 1.36-1.44 (m, 1H, cyclohexyl --CH.sub.2),
0.82-1.36 (m, 5H, cyclohexyl --CH.sub.2). 23
Preparation of
4-Cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde
[0180] Scheme IV, step D: Ozone was bubbled through a cloudy
mixture of 56.50 g (0.2204 mol) of 2-phenyl-2-methyl-4-pentenoyl
cyclohexane and a small amount (.about.10 mg) of Sudan III in 220
mL of MeOH (cooled in a dry ice acetone bath at -20.degree. C.) for
4 h until pink color turned to pale yellow color. After all of the
olefin was consumed, Me.sub.2S (50 mL) was added to reaction
mixture. The cooling bath was removed. The exotherm rose to
38.degree. C. and mixture was cooled in cooling bath until there
was no exotherm. Then the cooling bath was removed and the mixture
was stirred overnight. The reaction solution was concentrated under
vacuum with dry ice trap to collect excess Me.sub.2S to afford
83.65 g of crude 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde
dimethyl acetal as a pink oil:
[0181] .sup.1H NMR (d.sup.6-DMSO): .delta. 7.34-7.39 (m, 2H, phenyl
CH) , 7.24-7.30 (m, 3H, phenyl CH), 3.99 (dd, J=4.2 Hz, J=5.9 Hz,
1H, CH(OCH.sub.3).sub.2), 3.14 (s, 3H, CH(OCH.sub.3).sub.2), 3.06
(s, 3H, CH(OCH.sub.3).sub.2) 2.34-2.43 (m, 1H, cyclohexyl CH),
2.10-2.20 (m, 2H, --CH.sub.2CH(OCH.sub.3).sub.2), 1.55-1.67 (m, 1H,
cyclohexyl --CH.sub.2), 1.53 (s, 3H, R.sub.2C(CH.sub.3)Ph),
0.80-1.52 (m, 9H, cyclohexyl --CH.sub.2).
[0182] To a solution of 82.65 g (66.29 g, 0.2177 mol) of
4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal
in 539 mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After
reaction completion (2 h), the mixture was concentrated to 426.5 g
(or 1/3 volume) of residue (RT-40.degree. C.). The residue
contained mostly water (pH=0) and was extracted twice with 300 mL
of MTBE. The MTBE extract was washed with 300 mL of 25% NaCl (aq),
dried over MgSO.sub.4, gravity filtered and concentrated to afford
54.92 g (97.65%) of title compound as a pink oil: .sup.1H NMR
(d.sup.6-DMSO): .delta. 9.54 (t, J=2.0 Hz, 1H, --CHO), 7.36-7.45
(m, 2H, phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6
Hz, J=1.9 Hz, 1H, CH.sub.2CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H,
CH.sub.2CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 (s, 3H,
R.sub.2C(CH.sub.3)Ph), 0.85-1.66 (m, 10H, cyclohexyl
--CH.sub.2).
Preparation of Final Title Compound
1-(2-methoxyphenyl)-4-[3-(cyclohexanec-
arbonyl)-3-(phenyl)butyl]piperazine
[0183] Scheme IV, step E: To a slurry of 13.72 g (0.05310 mol) of
4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde and 11.57 g
(0.05058 mol) of 1-(2'-methoxyphenyl)piperazine hydrochloride in
391 mL of CH.sub.2Cl.sub.2 was added 9.7 mL of AcOH to make the
reaction mixture homogeneous. To the reaction solution was added
slowly 14.63 g (0.06904 mol) of NaBH(OAc).sub.3. After stirring
over 4 days (reaction should be complete within 2-5 h), 200 mL of
1N HCl (aq) was added to quench reaction mixture (pH=1). The
mixture was extracted with 200 mL of CH.sub.2Cl.sub.2. The
CH.sub.2Cl.sub.2 extract was washed again with 200 mL of 1N HCl
(aq) (pH=1). Both HCl (aq) washes were combined and saved. The
organic extract was washed with 200 mL of 1N NaOH (aq) (pH=14). An
emulsion formed and was broken up by addition of 100 mL of water
and 100 mL of MTBE. The organic phase was washed again with 200 mL
of 1N NaOH (aq) (pH=14) and washed with 200 mL of 25% NaCl (aq),
dried over MgSO.sub.4, gravity filtered and concentrated to afford
22.74 g of crude title compound as an amber oil. HPLC analysis
against pure standard showed that crude product oil has 13.66 g
(61.71%) of title compound.
[0184] To the combined HCl wash was added 28.44 g of NaOH (s) to
make mixture basic (pH=14). The cloudy mixture was extracted twice
with 100 mL of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts were
combined, washed with 25% NaCl (aq), dried over MgSO.sub.4, gravity
filtered and concentrated to afford 1.86 g of amber oil residue
that contained 0.096 g (total=62.15%) of title compound and 1.05 g
(10.8% recovery) of 1-(2'-methoxyphenyl)piperazine.
[0185] .sup.1H NMR (d.sup.6-DMSO): .delta. 7.35-7.43 (m, 2H, phenyl
CH), 7.26-7.32 (m, 3H, phenyl CH), 6.89-6.96 (m, 2H, phenyl CH),
6.83-6.88 (m, 2H, phenyl CH), 3.76 (s, 3H, OCH.sub.3), 2.80-3.03
(m, 4H, piperazine CH.sub.2), 2.34-2.49 (m, 4H, piperazine
CH.sub.2), 1.91-2.24 (m, 4H), 1.52-1.62 (m, 2H, cyclohexyl
CH.sub.2), 1.51 (s, 3H, R.sub.2C(CH.sub.3)Ph), 1.34-1.48 (m, 2H,
cyclohexyl --CH.sub.2), 1.13-1.27 (m, 4H, cyclohexyl --CH.sub.2),
1.00-1.10 (m, 2H, cyclohexyl --CH.sub.2), 0.83-1.00 (m, 1H,
cyclohexyl --CH.sub.2).
Alternative Preparation of Final Title Compound
[0186] 24
Preparation of Enamine
[0187] Scheme V, step A: To a solution of 25.00 g (0.1093 mol) of
1-(2'-methoxyphenyl)piperazine hydrochloride in 42 mL of water was
added 14.5 mL (0.109 mol) of concentrated (29.4%) NH.sub.4OH (aq)
(pH=9). The mixture was extracted twice with 250 mL of 1:1 (v/v) of
THF:toluene. The organic extracts were combined, dried over
MgSO.sub.4, gravity filtered and concentrated to afford 20.17 g
(96.00%) of 1-(2'-methoxyphenyl)pipera- zine as a pale green oil:
.sup.1H NMR (d.sup.6-DMSO): d 6.90-6.97 (m, 2H, phenyl CH),
6.83-6.90 (m, 3H, phenyl CH), 3.77 (s, 3H, OCH.sub.3), 2.77-2.91
(m, 8H, piperazine CH.sub.2), 2.49-2.53 (m, 1H, NH). A solution of
9.55 g (0.0370 mol) of
4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehy- de in 10 mL of
iPrOAc was added to 6.77 g (0.0352 mol) of neat
1-(2'-methoxyphenyl)piperazine. The mixture turned turbid, and then
turned to a solid mass when 10 mL of iPrOAc was added. The solid
was slurried with 45 mL of iPrOAc. After 1.5 h, reaction was
complete. The solid was vacuum filtered and washed with 10 mL of
iPrOAc and air dried to afford 9.81 g (64.4%) of pure enamine as an
off-white powder. The filtrate was concentrated to afford 6.40 g of
crude enamine;
[0188] .sup.1H NMR (d.sup.6-DMSO): .delta. 7.31-7.43 (m, 2H, phenyl
CH), 7.20-7.31 (m, 3H, phenyl CH), 6.82-7.04 (m, 4H, phenyl CH),
6.06 (d, J=14.2 Hz, 1H, CR.sub.3CH=CH NR.sub.2(trans)), 4.98 (d,
J=14.2 Hz, 1H, CR.sub.3CH.dbd.CH NR.sub.2(trans)), 3.80 (s, 3H,
OCH.sub.3), 2.93-3.15 (m, 8H, piperazine CH.sub.2), 2.38-2.49 (m,
1H, cyclohexyl CH), 1.59-1.72 (m, 2H, cyclohexyl CH.sub.2),
1.47-1.59 (m, 2H, cyclohexyl --CH.sub.2), 1.40 (s, 3H,
R.sub.2C(CH.sub.3)Ph), 1.21-1.34 (m, 3H, cyclohexyl --CH.sub.2),
1.03-1.21 (m, 2H, cyclohexyl --CH.sub.2), 0.83-1.03 (m, 1H,
cyclohexyl --CH.sub.2).
[0189] Preparation of Final Title Compound
[0190] Scheme V, step B: To 5.35 g (0.00101 mol) of 5% Pd/C in a
500 mL Parr bottle chilled in an ice bath was added 8.68 g (0.0201
mol) of above-formed enamine. To the solid mixture was added 40 mL
of IPA cooled in a freezer (-22.degree. C.). H.sub.2 was introduced
at 50 psi and mixture was shaken for 2 day at RT to complete
reaction. The black slurry was vacuum filtered and concentrated to
afford 8.70 g of a colorless oil. The Pd/C catalyst was washed with
50 mL of IPA with stirring. The black slurry was vacuum filtered.
The filtrate was combined with 8.70 g of residue and concentrated
to afford 10.03 g of the final title compound as a colorless
oil.
[0191] Additional compounds included with the scope of the present
invention, which can be prepared by one of ordinary skill in the
art in a manner analogous to the procedures described above, are as
follows:
[0192] 10)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine dihydrobromide;
[0193] 11)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine monohydrobromide;
[0194] 12)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine succinate, 1:1;
[0195] 13)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine succinate, 2:1;
[0196] 14)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine phosphate;
[0197] 15)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine d-tartrate; 16)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexaneca-
rbonyl)-3-(phenyl)butyl]piperazine 1-tartrate;
[0198] 17)
(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)bu-
tyl]piperazine maleate;
[0199] Serotonin 1A Receptor Activity
[0200] The compounds of the present invention are selective
antagonists at the serotonin 1A receptor. Previously known
compounds with 1A receptor activity typically have the disadvantage
of possessing other central nervous system activities as well. It
is now well understood by pharmacologists and physicians that
pharmaceuticals which have a single physiological activity, or
which are much more active in the desired activity than in their
other activities, are much more desirable for therapy than are
compounds (pindolol for example) which have multiple activities at
about the same dose.
[0201] Many other known serotonin receptor 1A antagonists typically
have .alpha.-adrenergic, .beta.-adrenergic or dopamine-2 activity
as well, and are therefore nonselective for 1A activity.
[0202] The 5-HT.sub.1A receptor binding potency of the present
compounds has been measured by a modification of the binding assay
described by Taylor, et al. (J. Pharmacol. Exp. Ther., 236,
118-125, 1986); and Wong, et al., Pharm. Biochem. Behav., 46,
173-77 (1993). Membranes for the binding assay were prepared from
male Sprague-Dawley rats (150-250 g). The animals were killed by
decapitation, and the brains were rapidly chilled and dissected to
obtain the hippocampi. Membranes from the hippocampi were either
prepared that day, or the hippocampi were stored frozen
(-70.degree.) until the day of preparation. The membranes were
prepared by homogenizing the tissue in 40 volumes of ice-cold
Tris-Hydrochloric acid buffer (50 mM, pH 7.4 at 22.degree.) using a
homogenizer for 15 seconds, and the homogenate was centrifuged at
39800.times.g for 10 minutes. The resulting pellet was then
resuspended in the same buffer, and the centrifugation and
resuspension process was repeated three additional times to wash
the membranes. Between the second and third washes the resuspended
membranes were incubated for 10 minutes at 37.degree. to facilitate
the removal of endogenous ligands. The final pellet was resuspended
in 67 mM Tris-Hydrochloric acid, pH 7.4, to a concentration of 2 mg
of tissue original wet weight/200 .mu.l. This homogenate was stored
frozen (-70.degree.) until the day of the binding assay. Each tube
for the binding assay had a final volume of 800 .mu.l and contained
the following: Tris-Hydrochloric acid (50 mM), pargyline (10
.mu.M), CaCl.sub.2 (3 mM), [.sup.3H]8-OH-DPAT (1.0 nM), appropriate
dilutions of the drugs of interest, and membrane resuspension
equivalent to 2 mg of original tissue wet weight, for a final pH of
7.4. The assay tubes were incubated for either 10 minutes or 15
minutes at 37.degree., and the contents were then rapidly filtered
through GF/B filters (pretreated with 0.5% polyethylenimine),
followed by four one-ml washes with ice-cold buffer. The
radioactivity trapped by the filters was quantitated by liquid
scintillation spectrometry, and specific [.sup.3H]8-OH-DPAT binding
to the 5-HT.sub.1A sites was defined as the difference between
[.sup.3H]8-OH-DPAT bound in the presence and absence of 10 .mu.M
5-HT.
[0203] IC.sub.50 values, i.e., the concentration required to
inhibit 50% of the binding, were determined from 12-point
competition curves using nonlinear regression (SYSTAT, SYSTAT,
Inc., Evanston, Ill.). IC.sub.50 values were converted to K.sub.i
values using the Cheng-Prusoff equation (Biochem. Pharmacol., 22,
3099-3108 (1973). All experiments were performed in triplicate.
[0204] Additional binding assays of some of the present compounds
have been carried out by an assay method which uses a cloned cell
line which expresses the serotonin 1A receptor, rather than the
hippocampal membranes. Such cloned cell lines have been described
by Fargin, et al., J. Bio. Chem., 264, 14848-14852 (1989), Aune, et
al., J. Immunology, 151, 1175-1183 (1993), and Raymond, et al.,
Naunyn-Schmiedeberg's Arch. Pharmacol., 346, 127-137 (1992).
Results from the cell line assay are substantially in agreement
with results from the hippocampal membrane assay.
[0205] 5HT.sub.1a Antagonist, in vivo Tests
[0206] a) 5HT.sub.1a Antagonism Subcutaneous Test
[0207] Compounds were tested over a range of subcutaneous doses for
activity in blocking the 8-OH-DPAT induced behaviors and
hypothermia. Lower lip retraction (LLR) and flat body posture (FBP)
were recorded in male Sprague Dawley rats (.about.250 grams from
Harlan Sprague Dawley). Both LLR and FBP were measured on a scale
of 0-3 (Wolff et al, 1997). In the LLR behavioral assay, "0"
indicated normal lip position; "1" indicated a slight separation of
the lips; "2" indicated that the lips were open with some teeth
visible; "3" indicated that the lips were fully open with all the
front teeth exposed. In the FBP assay, a score of "0" indicated
normal body posture; "1" indicated that the stomach was on the
floor with the back in its normal rounded position; "2" indicated
that the stomach was on the floor with the back straightened and
rising from the shoulders to the hips; "3" indicated that the
stomach was pressed into the floor and the back was flattened with
the shoulders and hips even. Core body temperature was recorded by
rectal probe inserted 5.0 cm immediately after the behavioral
measures. Rats were injected subcutaneous with compound (at 0, 0.3,
1.0 and 3.0 mg/kg) 35 minutes before scoring and the 8-OH-DPAT (0.1
mg/kg subcutaneous) was injected 20 minutes before scoring.
[0208] b) 5HT.sub.1a Agonist Subcutaneous Test
[0209] The compounds were also tested at a high dose of 10 mg/kg
subcutaneous alone to see if they induced 5HT.sub.1a agonist-like
hypothermia.
[0210] The potent serotonin 1A receptor activity of the present
compounds gives them a number of pharmaceutical and therapeutic
applications. One of those applications is a method of assisting
people who are dependent on the use of tobacco or nicotine to break
the habit.
[0211] Tobacco or Nicotine Withdrawal
[0212] It is well known that the chronic administration of nicotine
results in tolerance and, eventually, dependence. The use of
tobacco has become extremely widespread in all countries, despite
the well known adverse effects of the use of tobacco in all its
forms. Thus, it is clear that tobacco use is extremely
habit-forming, if not addictive, and that its use provides
sensations to the user which are pleasant and welcome, even though
the user is fully aware of the drastic long term ill effects of its
use.
[0213] Rather recently, vigorous campaigns against the use of
tobacco have taken place, and it is now common knowledge that the
cessation of smoking brings with it numerous unpleasant withdrawal
symptoms, which include irritability, anxiety, restlessness, lack
of concentration, lightheadedness, insomnia, tremor, increased
hunger and weight gain, and, of course, a craving for tobacco.
[0214] At the present time, probably the most widely used therapy
to assist the cessation of tobacco use is nicotine replacement, by
the use of nicotine chewing gum or nicotine-providing transdermal
patches. It is widely known, however, that nicotine replacement is
less effective without habit-modifying psychological treatment and
training.
[0215] The method of the present invention is broadly useful in
assisting persons who want to cease or reduce their use of tobacco
or nicotine. Most commonly, the form of tobacco use is smoking,
most commonly the smoking of cigarettes. The present invention is
also helpful, however, in assisting in breaking the habit of all
types of tobacco smoking, as well as the use of snuff, chewing
tobacco, etc. The present method is also helpful to those who have
replaced, or partially replaced, their use of tobacco with the use
of nicotine replacement therapy. Thus, such patients can be
assisted to reduce and even eliminate entirely their dependence on
nicotine in all forms.
[0216] It will be understood that the present invention is useful
for preventing or alleviating the withdrawal symptoms which afflict
patients who are trying to eliminate or reduce their use of tobacco
or nicotine. The common withdrawal symptoms of such people include,
at least, irritability, anxiety, restlessness, lack of
concentration, insomnia, nervous tremor, increased hunger and
weight gain, lightheadedness, and the craving for tobacco or
nicotine. The prevention or alleviation of such symptoms, when they
are caused by or occur in conjunction with ceasing or reducing the
patient's use of tobacco or nicotine is a desired result of the
present invention and an important aspect of it.
[0217] The present invention is carried out by administering an
effective amount of a compound of Formula I or formula Ia to a
patient who is in need of or carrying out a reduction or cessation
of tobacco or nicotine use.
[0218] As used herein, the term "patient" refers to a warm-blooded
animal, such as a mammal. Included within the term "patient" are
humans, dogs, rats, mice and the like. It is understood that the
preferred patient is a human.
[0219] An effective amount of a compound of Formula I or formula
Ia, is the amount, or dose, of the compound which provides the
desired effect in the patient under diagnosis or treatment. The
dose of compound of Formula I or formula Ia to be administered, is
effective over a wide dosage range, in general, it is from about 1
to about 200 mg/day; as usual, the daily dose may be administered
in a single bolus, or in divided doses, depending on the judgment
of the physician in charge of the case. A more preferred range of
doses is from about 5 to about 100 mg/day; other dosage ranges
which may be preferred in certain circumstances are from about 10
to about 50 mg/day; from about 5 to about 50 mg/day; from about 10
to about 25 mg/day; and a particularly preferred range is from
about 20 to about 25 mg/day. It will be understood that the dose
for a given patient is always to be set by the judgment of the
attending physician, and that the dose is subject to modification
based on the size of the patient, the lean or fat nature of the
patient, the characteristics of the particular compound chosen, the
intensity of the patient's tobacco habit, the intensity of the
patient's withdrawal symptoms, and psychological factors which may
affect the patient's physiological responses.
[0220] The effect of the compounds in alleviating the symptoms of
nicotine withdrawal was evaluated in rats by an auditory startle
test, which was carried out as follows.
[0221] Procedures for Nicotine Withdrawal Studies
[0222] Animals: Male Long Evans rats were individually housed in a
controlled environment on a 12 hour light-dark cycle and were given
free access to food (Purina Rodent Chow) and water. All treatment
groups contained 8-10 rats.
[0223] Chronic Nicotine Treatment: Rats were anesthetized with
halothane and Alzet.TM. osmotic minipumps (Alza Corporation, Palo
Alto, Calif., Model 2ML2) were implanted subcutaneously. Nicotine
ditartrate was dissolved in physiological saline. Pumps were filled
with either nicotine ditartrate (6 mg/kg base/day) or physiological
saline. Twelve days following implantation of pumps, rats were
anesthetized with halothane and the pumps were removed.
[0224] Auditory Startle Response: The sensory motor reactions
[auditory startle response (peak amplitude Vmax)] of individual
rats was recorded using San Diego Instruments startle chambers (San
Diego, Calif.). Startle sessions consisted of a 5-minute adaptation
period at a background noise level of 70.+-.3 dBA immediately
followed by 25 presentations of auditory stimuli (120.+-.2 dBA
noise, 50 ms duration) presented at 8-second intervals. Peak
startle amplitudes were then averaged for all 25 presentations of
stimuli for each session. Auditory startle responding was evaluated
daily at 24 hour intervals on days 1-4 following nicotine
withdrawal.
[0225] Combination with Reuptake Inhibitors
[0226] A further application of the compounds of Formula I or
formula Ia is their use in combination with a serotonin reuptake
inhibitor to further potentiate the action of those drugs by
increasing the availability of serotonin, as well as norepinephrine
and dopamine, in the brain of patients to whom the drug combination
is administered. Typical and appropriate serotonin reuptake
inhibitors (SRI) are fluoxetine, duloxetine, venlafaxine,
milnacipran, citalopram, fluvoxamine and paroxetine. Accordingly,
the present invention provides a method for potentiating the action
of a serotonin reuptake inhibitor, particularly one of the group
consisting of fluoxetine, duloxetine, venlafaxine, milnacipran,
citalopram, fluvoxamine and paroxetine, in increasing the
availability of serotonin, norepinephrine and dopamine in the
brain, comprising administering said serotonin reuptake inhibitor
in combination with a compound of Formula I or formula Ia. The
invention also provides pharmaceutical compositions which comprise
a serotonin reuptake inhibitor in combination with a compound of
Formula I or formula Ia, and a method of treating a pathological
condition which is created by or is dependent upon decreased
availability of serotonin, dopamine or norepinephrine, which method
comprises administering the same adjunctive therapy to a patient in
need of such treatment.
[0227] Fluoxetine,
N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylami- ne, is
marketed in the hydrochloride salt form, and as the racemic mixture
of its two enantiomers. U.S. Pat. No. 4,314,081 is an early
reference on the compound. Robertson, et al., J. Med. Chem., 31,
1412 (1988), taught the separation of the R and S enantiomers of
fluoxetine and showed that their activity as serotonin uptake
inhibitors is similar to each other. In this document, the word
"fluoxetine" will be used to mean any acid addition salt or the
free base, and to include either the racemic mixture or either of
the R and S enantiomers.
[0228] Duloxetine,
N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine- , is
usually administered as the hydrochloride salt and is the (+)
enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which
shows its high potency. The word "duloxetine" will be used here to
refer to any acid addition salt or the free base of the
molecule.
[0229] Venlafaxine is known in the literature, and its method of
synthesis and its activity as an inhibitor of serotonin and
norepinephrine uptake are taught by U.S. Pat. No. 4,761,501.
Venlafaxine is identified as compound A in that patent.
[0230] Milnacipran
(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxam- ide) is
taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as
its Example 4. The patent describes its compounds as
antidepressants. Moret, et al., Neuropharmacology 24, 1211-19
(1985), describe its pharmacological activities.
[0231] Citalopram,
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihy-
dro-5-isobenzofurancarbonitrile, is disclosed in U.S. Pat. No.
4,136,193 as a serotonin reuptake inhibitor. Its pharmacology was
disclosed by Christensen, et al., Eur. J. Pharmacol., 41, 153
(1977), and reports of its clinical effectiveness in depression may
be found in Dufour, et al., Int. Clin. Psychopharmacol., 2, 225
(1987), and Timmerman, et al., ibid., 239.
[0232] Fluvoxamine,
5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone
O-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225.
Scientific articles about the drug have been published by Claassen,
et al., Brit. J. Pharmacol., 60, 505 (1977); and De Wilde, et al.,
J. Affective Disord., 4, 249 (1982); and Benfield, et al., Drugs,
32, 313 (1986).
[0233] Paroxetine,
trans-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluo-
rophenyl)piperidine, may be found in U.S. Pat. Nos. 3,912,743 and
4,007,196. Reports of the drug's activity are in Lassen, Eur. J.
Pharmacol., 47, 351 (1978); Hassan, et al., Brit. J. Clin.
Pharmacol., 19, 705 (1985); Laursen, et al., Acta Psychiat. Scand.,
71, 249 (1985); and Battegay, et al., Neuropsychobiology, 13, 31
(1985).
[0234] All of the U.S. patents which have been mentioned above in
connection with compounds used in the present invention are
incorporated herein by reference.
[0235] In general, combinations and methods of treatment using
fluoxetine or duloxetine as the SRI are preferred.
[0236] It will be understood by the skilled reader that all of the
compounds used in the present invention are capable of forming
salts, and that the salt forms of pharmaceuticals are commonly
used, often because they are more readily crystallized and purified
than are the free bases. In all cases, the use of the
pharmaceuticals described above as salts is contemplated in the
description herein, and often is preferred, and the
pharmaceutically acceptable salts of all of the compounds are
included in the names of them.
[0237] The dosages of the drugs used in the present combination
must, in the final analysis, be set by the physician in charge of
the case, using knowledge of the drugs, the properties of the drugs
in combination as determined in clinical trials, and the
characteristics of the patient, including diseases other than that
for which the physician is treating the patient. General outlines
of the dosages, and some preferred dosages, are provided. Dosage
guidelines for some of the drugs will first be given separately; in
order to create a guideline for any desired combination, one would
choose the guidelines for each of the component drugs.
[0238] Fluoxetine: from about 1 to about 80 mg, once/day;
preferred, from about 10 to about 40 mg once/day; preferred for
bulimia and obsessive-compulsive disease, from about 20 to about 80
mg once/day;
[0239] Duloxetine: from about 1 to about 30 mg once/day; preferred,
from about 5 to about 20 mg once/day;
[0240] Venlafaxine: from about 10 to about 150 mg once-thrice/day;
preferred, from about 25 to about 125 mg thrice/day;
[0241] Milnacipran: from about 10 to about 100 mg once-twice/day;
preferred, from about 25 to about 50 mg twice/day;
[0242] Citalopram: from about 5 to about 50 mg once/day; preferred,
from about 10 to about 30 mg once/day;
[0243] Fluvoxamine: from about 20 to about 500 mg once/day;
preferred, from about 50 to about 300 mg once/day;
[0244] Paroxetine: from about 5 to about 100 mg once/day;
preferred, from about 50 to about 300 mg once/day.
[0245] In more general terms, one would create a combination of the
present invention by choosing a dosage of SRI according to the
spirit of the above guideline, and choosing a dosage of the
compound of Formula I or formula Ia in the ranges taught above.
[0246] The adjunctive therapy of the present invention is carried
out by administering a SRI together with a compound of Formula I or
formula Ia in any manner which provides effective levels of the two
compounds in the body at the same time. All of the compounds
concerned are orally available and are normally administered
orally, and so oral administration of the adjunctive combination is
preferred. They may be administered together, in a single dosage
form, or may be administered separately.
[0247] However, oral administration is not the only route or even
the only preferred route. For example, transdermal administration
may be very desirable for patients who are forgetful or petulant
about taking oral medicine. One of the drugs may be administered by
one route, such as oral, and the other may be administered by the
trans-dermal, percutaneous, intravenous, intramuscular, intranasal
or intrarectal route, in particular circumstances. The route of
administration may be varied in any way, limited by the physical
properties of the drugs and the convenience of the patient and the
caregiver.
[0248] It is particularly preferred, however, for the adjunctive
combination to be administered as a single pharmaceutical
composition, and so pharmaceutical compositions incorporating both
a SRI and a compound of Formula I or formula Ia are important
embodiments of the present invention. Such compositions may take
any physical form which is pharmaceutically acceptable, but orally
usable pharmaceutical compositions are particularly preferred. Such
adjunctive pharmaceutical compositions contain an effective amount
of each of the compounds, which effective amount is related to the
daily dose of the compounds to be administered. Each adjunctive
dosage unit may contain the daily doses of both compounds, or may
contain a fraction of the daily doses, such as one-third of the
doses. Alternatively, each dosage unit may contain the entire dose
of one of the compounds, and a fraction of the dose of the other
compound. In such case, the patient would daily take one of the
combination dosage units, and one or more units containing only the
other compound. The amounts of each drug to be contained in each
dosage unit depends on the identity of the drugs chosen for the
therapy, and other factors such as the indication for which the
adjunctive therapy is being given.
[0249] As stated above, the benefit of the adjunctive therapy is
its ability to augment the increase in availability of serotonin,
norepinephrine and dopamine caused by the SRI compounds, resulting
in improved activity in treating the various conditions described
below in detail. The increase in availability of serotonin is
particularly important and is a preferred aspect of the invention.
Further, the invention provides a more rapid onset of action than
is usually provided by treatment with the SRI alone.
[0250] Preferred pathological conditions to be treated by the
present method of adjunctive therapy include depression, bulimia,
obsessive-compulsive disease and obesity. Another preferred
condition more specific to combinations including preferably
duloxetine but also venlafaxine and milnacipran is urinary
incontinence.
[0251] Depression in its many variations has recently become much
more visible to the general public than it has previously been. It
is now recognized as an extremely damaging disorder, and one that
afflicts a surprisingly large fraction of the population. Suicide
is the most extreme symptom of depression, but millions of people,
not quite so drastically afflicted, live in misery and partial or
complete uselessness, and afflict their families as well by their
affliction. The introduction of fluoxetine was a breakthrough in
the treatment of depression, and depressives are now much more
likely to be diagnosed and treated than they were only a decade
ago. Duloxetine is in clinical trials for the treatment of
depression.
[0252] Depression is often associated with other diseases and
conditions, or caused by such other conditions. For example, it is
associated with Parkinson's disease; with HIV; with Alzheimer's
disease; and with abuse of anabolic steroids. Depression may also
be associated with abuse of any substance, or may be associated
with behavioral problems resulting from or occurring in combination
with head injuries, mental retardation or stroke. Depression in all
its variations is a preferred target of treatment with the present
adjunctive therapy method and compositions.
[0253] Obsessive-compulsive disease appears in a great variety of
degrees and symptoms, generally linked by the patient's
uncontrollable urge to perform needless, ritualistic acts. Acts of
acquiring, ordering, cleansing and the like, beyond any rational
need or rationale, are the outward characteristic of the disease. A
badly afflicted patient may be unable to do anything but carry out
the rituals required by the disease. Fluoxetine is approved in the
United States and other countries for the treatment of
obsessive-compulsive disease and has been found to be
effective.
[0254] Obesity is a frequent condition in the American population.
It has been found that fluoxetine will enable an obese patient to
lose weight, with the resulting benefit to the patient's
circulation and heart condition, as well as general well being and
energy.
[0255] Urinary incontinence is classified generally as stress or
urge incontinence, depending on whether its root cause is the
inability of the sphincter muscles to keep control, or the
overactivity of the bladder muscles. Duloxetine controls both types
of incontinence, or both types at once, and so is important to the
many people who suffer from this embarrassing and disabling
disorder.
[0256] The present combination is useful for treating many other
diseases, disorders and conditions as well, as set out below. In
many cases, the diseases to be mentioned here are classified in the
International Classification of Diseases, 9th Edition (ICD), or in
the Diagnostic and Statistical Manual of Mental Disorders, 3rd
Version Revised, published by the American Psychiatric Association
(DSM). In such cases, the ICD or DSM code numbers are supplied
below for the convenience of the reader.
[0257] depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81,
293.82, 293.83, 310.10, 318.00, 317.00
[0258] migraine
[0259] pain, particularly neuropathic pain
[0260] bulimia, ICD 307.51, DSM 307.51
[0261] premenstrual syndrome or late luteal phase syndrome,
[0262] DSM 307.90
[0263] alcoholism, ICD 305.0, DSM 305.00 & 303.90
[0264] tobacco abuse, ICD 305.1, DSM 305.10 & 292.00
[0265] panic disorder, ICD 300.01, DSM 300.01 & 300.21
[0266] anxiety, ICD 300.02, DSM 300.00
[0267] post-traumatic syndrome, DSM 309.89
[0268] memory loss, DSM 294.00
[0269] dementia of aging, ICD 290
[0270] social phobia, ICD 300.23, DSM 300.23
[0271] attention deficit hyperactivity disorder, ICD 314.0
[0272] disruptive behavior disorders, ICD 312
[0273] impulse control disorders, ICD 312, DSM 312.39 &
312.34
[0274] borderline personality disorder, ICD 301.83, DSM 301.83
[0275] chronic fatigue syndrome
[0276] premature ejaculation, DSM 302.75
[0277] erectile difficulty, DSM 302.72
[0278] anorexia nervosa, ICD 307.1, DSM 307.10
[0279] disorders of sleep, ICD 307.4
[0280] autism
[0281] mutism
[0282] trichotillomania
[0283] Further, the compounds of Formula I or formula Ia are
particularly useful for alleviating the symptoms of smoking
cessation or nicotine withdrawal when administered in combination
with a serotonin reuptake inhibitor. The SRI's to be used in this
treatment method, and the administration methods and formulations,
are as described above. The use of the present compounds with SRI's
in patients striving to stop use of tobacco or nicotine provides
surprisingly complete alleviation of the usual painful and damaging
symptoms of such patients, including nervousness, irritability,
craving, excessive appetite, anxiety, depression in many forms,
inability to concentrate, and the like.
[0284] Therapeutic Applications
[0285] The compounds of Formula I or formula Ia are useful for
other important therapeutic purposes, as well as in combination
with SRIs and in nicotine withdrawal or smoking cessation cases. In
particular, the compounds are useful for antagonism at the
serotonin 1A receptor and accordingly are used for the treatment or
prevention of-conditions caused by or affected by excessive
activity of that receptor.
[0286] More particularly, the compounds of Formula I or formula Ia
are useful in the treatment of anxiety, depression, hypertension,
cognitive disorders, psychosis, sleep disorders, gastric motility
disorders, sexual dysfunction, brain trauma, memory loss, appetite
disorders and obesity, substance abuse, obsessive-compulsive
disease, panic disorder and migraine.
[0287] Anxiety and its frequent concomitant, panic disorder, may be
particularly mentioned in connection with the present compounds.
The subject is carefully explained by the Diagnostic and
Statistical Manual of Mental Disorders, published by the American
Psychiatric Association, which classifies anxiety under its
category 300.02. A further particularly noted disorder is
depression and the group of depression-related disorders, which are
discussed above in the discussion of adjunctive therapy with
SRIs.
[0288] Pharmaceutical Compositions
[0289] It is customary to formulate pharmaceuticals for
administration, to provide control of the dosage and stability of
the product in shipment and storage, and the usual methods of
formulation are entirely applicable to the compounds of Formula I
and formula Ia. Such compositions, comprising at least one
pharmaceutically acceptable carrier, are valuable and novel because
of the presence of the compounds of Formula I or formula Ia
therein. Although pharmaceutical chemists are well aware of many
effective ways to formulate pharmaceuticals, which technology is
applicable to the present compounds, some discussion of the subject
will be given here for the convenience of the reader.
[0290] The usual methods of formulation used in pharmaceutical
science and the usual types of compositions may be used, including
tablets, chewable tablets, capsules, solutions, parenteral
solutions, intranasal sprays or powders, troches, suppositories,
transdermal patches and suspensions. In general, compositions
contain from about 0.5% to about 50% of the compound in total,
depending on the desired dose and the type of composition to be
used. The amount of the compound of Formula I or formula Ia,
however, is best defined as the effective amount, that is, the
amount of the compound which provides the desired dose to the
patient in need of such treatment. The activity of the compounds do
not depend on the nature of the composition, so the compositions
are chosen and formulated solely for convenience and economy. Any
compound may be formulated in any desired form of composition. Some
discussion of different compositions will be provided, followed by
some typical formulations.
[0291] Capsules are prepared by mixing the compound with a suitable
diluent and filling the proper amount of the mixture in capsules.
The usual diluents include inert powdered substances such as starch
of many different kinds, powdered cellulose, especially crystalline
and microcrystalline cellulose, sugars such as fructose, mannitol
and sucrose, grain flours and similar edible powders.
[0292] Tablets are prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders.
[0293] A lubricant is necessary in a tablet formulation to prevent
the tablet and punches from sticking in the die. The lubricant is
chosen from such slippery solids as talc, magnesium and calcium
stearate, stearic acid and hydrogenated vegetable oils.
[0294] Tablet disintegrators are substances which swell when wetted
to break up the tablet and release the compound. They include
starches, clays, celluloses, algins and gums. More particularly,
corn and potato starches, methylcellulose, agar, bentonite, wood
cellulose, powdered natural sponge, cation-exchange resins, alginic
acid, guar gum, citrus pulp and carboxymethylcellulose, for
example, may be used, as well as sodium lauryl sulfate.
[0295] Enteric formulations are often used to protect an active
ingredient from the strongly acidic contents of the stomach. Such
formulations are created by coating a solid dosage form with a film
of a polymer which is insoluble in acidic environments, and soluble
in basic environments. Exemplary films are cellulose acetate
phthalate, polyvinyl acetate phthalate, hydroxypropyl
methylcellulose phthalate and hydroxypropyl methylcellulose acetate
succinate.
[0296] Tablets are often coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compounds may also be formulated as
chewable tablets, by using large amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now
well-established practice. Instantly dissolving tablet-like
formulations are also now frequently used to assure that the
patient consumes the dosage form, and to avoid the difficulty in
swallowing solid objects that bothers some patients.
[0297] When it is desired to administer the combination as a
suppository, the usual bases may be used. Cocoa butter is a
traditional suppository base, which may be modified by addition of
waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of
various molecular weights are in wide use, also.
[0298] Transdermal patches have become popular recently. Typically
they comprise a resinous composition in which the drugs will
dissolve, or partially dissolve, which is held in contact with the
skin by a film which protects the composition. Many patents have
appeared in the field recently. Other, more complicated patch
compositions are also in use, particularly those having a membrane
pierced with innumerable pores through which the drugs are pumped
by osmotic action.
[0299] The following typical formulae are provided for the interest
and information of the pharmaceutical scientist.
Formulation 1
[0300] Hard gelatin capsules are prepared using the following
ingredients:
1 Quantity (mg/capsule) Example 1 20 mg Starch, dried 200 mg
Magnesium stearate 10 mg Total 230 mg
Formulation 2
[0301] A tablet is prepared using the ingredients below:
2 Quantity (mg/capsule) Example 2 10 mg Cellulose, microcrystalline
400 mg Silicon dioxide, fumed 10 mg Stearic acid 5 mg Total 425
mg
[0302] The components are blended and compressed to form tablets
each weighing 425 mg.
Formulation 3
[0303] Tablets, each containing 10 mg of active ingredient, are
made as follows:
3 Example 3 10 mg Starch 45 mg Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg (as 10% solution in water) Sodium
carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg
Total 100 mg
[0304] The active ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous
solution containing polyvinyl-pyrrolidone is mixed with the
resultant powder, and the mixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. Sieve. The sodium
carboxymethyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 100 mg.
Formulation 4
[0305] Capsules, each containing 30 mg of active ingredient, are
made as follows:
4 Example 4 30 mg Starch 59 mg Microcrystalline cellulose 59 mg
Magnesium stearate 2 mg Total 150 mg
[0306] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 mesh U.S. sieve, and
filled into hard gelatin capsules in 150 mg quantities.
Formulation 5
[0307] Suppositories, each containing 5 mg of active ingredient,
are made as follows:
5 Example 5 5 mg Saturated fatty acid glycerides 2,000 mg Total
2,005 mg
[0308] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool.
Formulation 6
[0309] Suspensions, each containing 10 mg of active ingredient per
5 ml dose, are made as follows:
6 Example 6 10 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25
ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified
water to total 5 ml
[0310] The active ingredient is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethyl cellulose and syrup
to form a smooth paste. The benzoic acid solution, flavor and color
are diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
Formulation 7
[0311] An intravenous formulation may be prepared as follows:
7 Example 7 10 mg Isotonic saline 1,000 ml
Formulation 8
[0312] Hard gelatin capsules are prepared in a manner analogous to
formulation 1 using the following ingredients:
8 Quantity (mg/capsule) (+)-1-(2-Methoxyphenyl)-4-[3- 20 mg
(cyclohexanecarbonyl)-3- (phenyl)butyl]piperazine HCl Starch, dried
200 mg Magnesium stearate 10 mg Total 230 mg
Formulation 9
[0313] A tablet is prepared using the ingredients below:
9 Quantity (mg/capsule) (+)-1-(2-Methoxyphenyl)-4-[3- 10 mg
(cyclohexanecarbonyl)-3- (phenyl)butyl]piperazine HCl Cellulose,
microcrystalline 400 mg Silicon dioxide, fumed 10 mg Stearic acid 5
mg Total 425 mg
[0314] The components are blended and compressed to form tablets
each weighing 425 mg in a manner analogous to formulation 2.
Formulation 10
[0315] Tablets, each containing 10 mg of active ingredient, are
made as follows:
10 (+)-1-(2-Methoxyphenyl)-4-[3- 10 mg (cyclohexanecarbonyl)-3-
(phenyl)butyl]piperazine HCl Starch 45 mg Microcrystalline
cellulose 35 mg Polyvinylpyrrolidone 4 mg (as 10% solution in
water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg
Talc 1 mg Total 100 mg
[0316] The active ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous
solution containing polyvinyl-pyrrolidone is mixed with the
resultant powder, and the mixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. Sieve. The sodium
carboxymethyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 100 mg.
Formulation 11
[0317] Capsules, each containing 30 mg of active ingredient, are
made as follows in a manner analogous to formulation 4:
11 (+)-1-(2-Methoxyphenyl)-4-[3- 30 mg cyclohexanecarbonyl)-3-
(phenyl)butyl]piperazine HCl Starch 59 mg Microcrystalline
cellulose 59 mg Magnesium stearate 2 mg Total 150 mg
* * * * *