U.S. patent application number 12/098899 was filed with the patent office on 2008-08-14 for compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds.
Invention is credited to Michael J. Bishop, Kwen-Jen Chang, Robert W. McNutt, Hugh O. Pettit.
Application Number | 20080193383 12/098899 |
Document ID | / |
Family ID | 25390891 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080193383 |
Kind Code |
A1 |
Chang; Kwen-Jen ; et
al. |
August 14, 2008 |
COMPOSITIONS AND METHODS FOR REDUCING RESPIRATORY DEPRESSION AND
ATTENDANT SIDE EFFECTS OF MU OPIOID COMPOUNDS
Abstract
A method of reducing, treating or preventing drug-mediated
respiratory depression, muscle rigidity, or nausea/vomiting in an
animal, incident to the administration to said animal of a mixed
delta/mu opioid agonist or a respiratory depression-mediating drug,
comprising administering to the animal receiving said drug an
effective amount of a delta receptor agonist compound. Preferred
examples of such delta receptor agonist compound include
diarylmethyl piperazine compounds and diarylmethyl piperidine
compounds, and pharmaceutical compositions thereof, having utility
in medical therapy for reducing respiratory depression associated
with certain analgesics, such as mu opiates.
Inventors: |
Chang; Kwen-Jen; (Chapel
Hill, NC) ; McNutt; Robert W.; (Durham, NC) ;
Pettit; Hugh O.; (Cary, NC) ; Bishop; Michael J.;
(Durham, NC) |
Correspondence
Address: |
MOORE & VAN ALLEN PLLC
P.O. BOX 13706
Research Triangle Park
NC
27709
US
|
Family ID: |
25390891 |
Appl. No.: |
12/098899 |
Filed: |
April 7, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11184762 |
Jul 19, 2005 |
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12098899 |
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09974004 |
Oct 9, 2001 |
6919350 |
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11184762 |
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09352308 |
Jul 12, 1999 |
6300332 |
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09974004 |
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08887312 |
Jul 3, 1997 |
5985880 |
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09352308 |
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08658726 |
Jun 5, 1996 |
5807858 |
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08887312 |
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Current U.S.
Class: |
424/9.2 |
Current CPC
Class: |
A61K 31/40 20130101;
A61P 11/00 20180101; A61P 43/00 20180101; A61K 31/485 20130101;
A61K 31/496 20130101; C07D 295/155 20130101; A61P 11/16 20180101;
A61K 31/485 20130101; A61K 31/00 20130101; A61P 25/00 20180101;
A61K 31/55 20130101; A61K 31/445 20130101; A61K 2300/00 20130101;
A61K 31/495 20130101; C07D 295/096 20130101; A61K 31/495 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/9.2 |
International
Class: |
A61K 49/00 20060101
A61K049/00 |
Claims
1. A screening method to determine the level of respiratory
depression caused by an opioid receptor agonist test compound
having mu, delta or mixed mu/delta receptor activity, the method
comprising: (a) providing a test model mammal implanted with a
catheter for introduction of a testing compound; (b) placing an
electrode on an outer surface of the mammal, wherein the electrode
monitors O.sub.2 and CO.sub.2 levels; (c) administering a first
control compound exhibiting suppression of respiratory depression
to the mammal and determining the level of respiratory depression;
(d) administering a second control compound that exhibits
anti-suppression of respiratory depression relative to the first
control compound to the mammal, wherein the second control compound
is a mixed mu/delta receptor opioid agonist, wherein the mixed
mu/delta opioid receptor agonist is selected from compounds of the
formula: ##STR00014## wherein: Ar is a 5- or 6-member carbocyclic
or heterocyclic aromatic ring with atoms selected from the group
consisting of carbon, nitrogen, oxygen and sulfur, and having on a
first carbon atom thereof a substituent Y and on a second ring
carbon thereof a substituent R.sup.1; Y is selected from the group
consisting of: hydrogen; halogen; C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6
haloalkyl; C.sub.1-C.sub.6 alkoxy; C.sub.3-C.sub.6 cycloalkoxy;
sulfides of the formula SR.sup.8 where R.sup.8 is C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a C.sub.5-C.sub.10
aryl moiety and an C.sub.1-C.sub.6 alkyl moiety, or
C.sub.5-C.sub.10 aryl; sulfoxides of the formula SOR.sup.8 where
R.sup.8 is the same as above; sulfones of the formula
SO.sub.2R.sup.8 where R.sup.8 is the same as above; nitrile;
C.sub.1-C.sub.6 acyl; alkoxycarbonylamino (carbamoyl) of the
formula NHCO.sub.2R.sup.8 where R.sup.8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof; aminomethyl
of the formula CH.sub.2NR.sup.9R.sup.10 where R.sup.9 and R.sup.10
may be the same or different, and may be hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 methoxyalkyl,
C.sub.3-C.sub.6 cycloalkyl, or C.sub.5-C.sub.10 aryl, or R.sup.9
and R.sup.10 together may form a ring of 5 or 6 atoms, the ring
atoms selected from the group consisting of N and C; carboxamides
of the formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are
the same as above, or C.sub.2-C.sub.30 peptide conjugates thereof,
and sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above; Z is selected from the
group consisting of: hydroxyl, and esters thereof; hydroxymethyl,
and esters thereof; and amino, and carboxamides and sulfonamides
thereof; G is nitrogen; R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl; R.sup.3, R.sup.4
and R.sup.5 may be the same or different, and are independently
selected from hydrogen and methyl, and wherein at least one of
R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject to the proviso
that the total number of methyl groups does not exceed two, or any
two of R.sup.3, R.sup.4 and R.sup.5 together may form a bridge of 1
to 3 carbon atoms; R.sup.6 is selected from the group consisting
of: hydrogen; C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; C.sub.3-C.sub.6 cycloalkyl; arylalkyl
having C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl moieties;
alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 alkyl
moieties; C.sub.2-C.sub.4 cyanoalkyl; C.sub.2-C.sub.4 hydroxyalkyl;
aminocarbonylalkyl having a C.sub.1-C.sub.4 alkyl moiety; and
R.sup.12COR.sup.13, where R.sup.12 is C.sub.1-C.sub.4 alkylene, and
R.sup.13 is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy; and
R.sup.7 is hydrogen or fluorine, or a pharmaceutically acceptable
ester or salt thereof; (e) determining level of respiratory
depression reversal for use as a comparative combined control; (f)
providing a test compound; (g) repeating steps a to c and then
administering the test compound to a mammal to determine the level
of respiratory depression and compare to the level determined for
the comparative combined control.
2. The screening method according to claim 1, wherein the second
control compound is
(+)-3-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide.
3. The screening method according to claim 1, wherein the first
control compound is alfentanil.
4. The screening method according to claim 1, wherein the first and
second control compound are administered simultaneously and the
level of respiratory depression is determined and compared to that
of the first control compound alone.
5. The screening method according to claim 1, wherein the first
control compound is selected from the group consisting of alcohol,
aldesleukin, alfentanil, bremazocine, buprenorphine, butorphanol,
chloropromazine, clozapine, codeine, dantrolene, diazepam,
dihydrocodeine, etorphine, fentanyl, flurazepam, heroin,
hydrocodone, hydromorphone, ketamine, larazepam, levallorphen,
levorphanol, meperidine, methadone, methohexital, mitomycin,
morphine, nalbuphine, opium, oxazepam, oxycodone, oxymorphone,
pentazocine, phenobarbital, porfimer, propoxyphene, resperidone,
sufentanil, temazepam, thiopental, thiorzadine, tramadol,
trimethaphan, and zolpidem.
6. The screening method according to claim 1, wherein the second
control compound is
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide or a pharmaceutically
acceptable salt thereof.
7. The screening method according to claim 1, wherein the second
control compound is selected from the group consisting of:
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide;
4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydro-
xybenzyl)benzamide;
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1
piperazinyl)-3-hydroxybenzyl)benzamide;
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piper-
azinyl)benzyl)benzamide;
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxybenzyl)-N-ethyl-N-methyl-benzamide;
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol;
(.+-.)--N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,-
4,5-trimethyl-1-piperazinyl)benzyl)-benzamide;
(+)-4-(((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide;
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-p-
iperazinyl)benzyl)phenol;
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-
-1-piperazinyl)benzyl)phenol;
(.+-.)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-4-(methylsulfonyl)benzyl)-phenol;
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
(+)-4-(((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
(-)-4-(((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
(.+-.)-3-((.alpha.R*)--((2S*,
5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxbenzyl)benzamide;
(.+-.)-4-((.alpha.R*)--((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybe-
nzyl)-N,N-diethyl-benzamide;
(.+-.)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzy-
l)-N,N-diethylbenzamide;
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenz-
yl)-N,N-diethyl-benzamide; and pharmaceutically acceptable salts
thereof.
8. The screening method according to claim 1, wherein the second
control compound is selected from the group consisting of:
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide;
cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybe-
nzyl)-N,N-diethyl-benzamide; and acceptable salts thereof.
9. A screening method to determine the level of respiratory
depression caused by an opioid receptor agonist test compound
having mu, delta or mixed mu/delta receptor activity, the method
comprising: (a) administering a first control compound exhibiting
suspression of respiratory depression to a mammal and determining
the level of respiratory depression; (b) administering a second
control compound that exhibits anti-suspression of respiratory
depression relative to the first control compound to the mammal,
wherein the second control compound is a mixed mu/delta receptor
opioid agonist, wherein the mixed mu/delta opioid receptor agonist
is selected from compounds of the formula: ##STR00015## wherein: Ar
is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with
atoms selected from the group consisting of carbon, nitrogen,
oxygen and sulfur, and having on a first carbon atom thereof a
substituent Y and on a second ring carbon thereof a substituent
R.sup.1; Y is selected from the group consisting of: hydrogen;
halogen; C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6 haloalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.3-C.sub.6 cycloalkoxy; sulfides of the formula
SR.sup.8 where R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
arylalkyl having a C.sub.5-C.sub.10 aryl moiety and an
C.sub.1-C.sub.6 alkyl moiety, or C.sub.5-C.sub.10 aryl; sulfoxides
of the formula SOR.sup.8 where R.sup.8 is the same as above;
sulfones of the formula SO.sub.2R.sup.8 where R.sup.8 is the same
as above; nitrile; C.sub.1-C.sub.6 acyl; alkoxycarbonylamino
(carbamoyl) of the formula NHCO.sub.2R.sup.8 where R.sup.8 is the
same as above; carboxylic acid, or an ester, amide, or salt
thereof; aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C; carboxamides of the formula
CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same as
above, or C.sub.2-C.sub.30 peptide conjugates thereof; and
sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above; Z is selected from the group
consisting of: hydroxyl, and esters thereof; hydroxymethyl, and
esters thereof; and amino, and carboxamides and sulfonamides
thereof; G is nitrogen; R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl; R.sup.3, R.sup.4
and R.sup.5 may be the same or different, and are independently
selected from hydrogen and methyl, and wherein at least one of
R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject to the proviso
that the total number of methyl groups does not exceed two, or any
two of R.sup.3, R.sup.4 and R.sup.5 together may form a bridge of 1
to 3 carbon atoms; R.sup.6 is selected from the group consisting
of: hydrogen; C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; C.sub.3-C.sub.6 cycloalkyl; arylalkyl
having C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl moieties;
alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 alkyl
moieties; C.sub.2-C.sub.4 cyanoalkyl; C.sub.2-C.sub.4 hydroxyalkyl;
aminocarbonylalkyl having a C.sub.1-C.sub.4 alkyl moiety; and
R.sup.12COR.sup.13, where R.sup.12 is C.sub.1-C.sub.4 alkylene, and
R.sup.13 is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy; and
R.sup.7 is hydrogen or fluorine, or a pharmaceutically acceptable
ester or salt thereof, (c) determining level of respiratory
depression reversal for use as a comparative combined control; (d)
providing a test compound; (e) repeating step a and then
administering the test compound to a mammal to determine the level
of respiratory depression and compare to the level determined for
the comparative combined control.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of copending U.S. patent application
Ser. No. 11/184,762 filed on Jul. 19, 2005 which is a divisional
application of U.S. patent application Ser. No. 09/974,004 filed on
Oct. 9, 2001 and issued on Jul. 19, 2005 as U.S. Pat. No.
6,919,350, which claims priority to U.S. patent application Ser.
No. 09/352,308 filed Jul. 12, 1999 and issued Oct. 9, 2001 as U.S.
Pat. No. 6,300,332, which claims priority to U.S. patent
application Ser. No. 08/887,312 filed Jul. 3, 1997 and issued on
Nov. 16, 1999 as U.S. Pat. No. 5,985,880, which is a
continuation-in-part of U.S. patent application Ser. No.
08/658,726, filed Jun. 5, 1996 and issued on Sep. 15, 1998 as U.S.
Pat. No. 5,807,858. The disclosures of the following applications
are hereby incorporated herein by reference in their entirety: U.S.
patent application Ser. No. 08/658,726 filed Jun. 5, 1996; U.S.
patent application Ser. No. 08/169,879 filed Dec. 17, 1993; U.S.
patent application Ser. No. 08/098,333 filed Jul. 30, 1993; U.S.
patent application Ser. No. 08/430,677 filed Apr. 28, 1995;
International Patent Application no. PCT/GB93/00216 filed Feb. 2,
1993; Great Britain patent application 9202238.3 filed 3 Feb. 1992;
and all applications from which they claim priority, or from which
priority is claimed.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Technology
[0003] This invention relates generally to methods for reducing,
treating, reversing or preventing drug-mediated respiratory
depression, such as may be directly or indirectly caused by use of
various bioactive compositions, including anesthetics,
barbiturates, analgesics, etc. The invention further relates to
diarylmethyl piperazine compounds and diarylmethyl piperidine
compounds, and pharmaceutical compositions thereof, having utility
in medical therapy especially for reducing respiratory depression
associated with certain analgesics, such as mu opiates. This
invention additionally relates to diarylmethyl piperazine compounds
and diarylmethyl piperidine compounds having utility in assays for
determining the respiratory reducing characteristics of other
bioactive compounds, including other diarylmethyl piperazine
compounds and other diarylmethyl piperidine compounds.
[0004] 2. Background of Related Art
[0005] In the study of opioid biochemistry, a variety of endogenous
opioid compounds and non-endogenous opioid compounds has been
identified. In this effort, significant research has been focused
on understanding the mechanism of opioid drug action, particularly
as it relates to cellular and differentiated tissue opiate
receptors.
[0006] Opioid drugs typically are classified by their binding
selectivity in respect of the cellular and differentiated tissue
receptors to which a specific drug species binds as a ligand. These
receptors include mu (.mu.), delta (.delta.), sigma (.sigma.) and
kappa (.kappa.) receptors.
[0007] The well-known narcotic opiates, such as morphine and its
analogs, are selective for the opiate mu receptor. Mu receptors
mediate analgesia, respiratory depression, and inhibition of
gastrointestinal transit. Kappa receptors mediate analgesia and
sedation. Sigma receptors mediate various biological
activities.
[0008] Diarylmethyl piperazine compounds and diarylmethyl
piperidine compounds having utility, for example, as analgesics,
are disclosed in International Publication WO93/15062, which is
incorporated by reference herein in its entirety. The present
application provides for the use of compounds of such general type
to treat or prevent respiratory depression.
[0009] Campa, M. J., et al., "Characterization of .delta. Opioid
Receptors in Lung Cancer Using a Novel Nonpeptidic Ligand," Cancer
Research 56, 1965-1701, Apr. 1, 1996, describes binding of
[.sup.3H]
(+)-4-[(.alpha.-R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-dieth-ylbenzamide with membranes prepared from
various small cell lung cancer cells.
[0010] There is a continuing need in the art for methods of
preventing or treating respiratory depression associated with the
use of various bioactive compositions, e.g., certain analgesics,
anaesthetics, and barbiturates, which effect respiratory
depression, either directly or indirectly.
[0011] There is also a continuing need for improved opioid
compounds, particularly compounds which can reduce respiratory
depression associated with the use of certain analgesics, such as
mu opiate analgesic compounds, when such improved opioid compounds
are administered contemporaneously with or sequential to the
administration of the respiratory depression-mediating
analgesic.
[0012] It is an object of the present invention to provide a
bioactive compound which when administered contemporaneously with
analgesics, anesthetics, barbiturates and other drugs which cause
respiratory depression, acts to markedly attenuate such respiratory
depression side effects.
SUMMARY OF THE INVENTION
[0013] The present invention relates to methods of treating,
reducing or preventing respiratory depression in an animal, e.g., a
human or non-human mammal, comprising administering to such animal
an effective amount of a composition comprising a delta receptor
angonist, optionally further including a mu receptor agonist
compound.
[0014] Illustrative examples of suitable delta receptor agonist
compounds that may be co-administered in accordance with the
invention include, but are not limited to: [0015]
(+)-4-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide; [0016]
[D-Pen.sup.2,D-Pen.sup.5]-(enkephalin); [0017] deltorphin I; [0018]
deltorphin II;
[0019] the compounds disclosed in International Patent Application
Publication WO96/36620 published 21 Nov. 1996 for "Diaryldiamine
Derivatives and Their Use as Delta Opioid (ant)-agonists," the
disclosure of which is hereby incorporated herein by reference;
and
[0020] the compounds disclosed in International Patent Application
Publication WO97/10230 published 20 Mar. 1997 for
"Diarylalkenylamine Derivatives," the disclosure of which is hereby
incorporated herein by reference.
[0021] Particularly preferred delta agonist compounds from among
the foregoing illustrative compounds include
##STR00001## [0022]
(+)-4-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide, and [0023]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide (and,
independently, each of the component isomers thereof, viz., [0024]
(+)-4-((.alpha.R)-.alpha.-((2R*,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, and
(-)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfonamide).
[0025] The composition that is co-administered with the bioactive
agent mediating respiratory depression may further include a mu
receptor agonist such as morphine, fentanyl, alfentanil and their
analogs, or the mu receptor agonists disclosed in U.S. patent
application Ser. No. 08/284,445 and U.S. patent application Ser.
No. 08/285,313, the disclosures of which hereby are incorporated
herein by reference, including compounds therein displaying
predominantly mu receptor agonist character, as well as compounds
therein disclosed displaying mixed mu/delta receptor agonism.
Examples of compounds displaying such mixed mu/delta agonist
character include by way of example the following compounds:
##STR00002##
[0026] The compounds mediating respiratory depression, as mentioned
above, include various analgesics, and aesthetics, and
barbiturates, such as for example morphine, fentanyl, midazolam,
meperidine, sufentanil and codeine.
[0027] Thus, the invention contemplates co-administration with drug
agents mediating respiratory depression, of delta receptor agonist
compounds, optionally with further co-administration of mu receptor
agonist agents, or simply compounds displaying mixed mu
receptor/delta receptor agonist character, in an amount effective
to combat, e.g., significantly attenuate, and preferably
substantially eliminate, the respiratory depression incident to the
use of the respiratory depression-mediating agent.
[0028] The invention therefore has broad utility in surgical and
clinical care applications, to combat the unwanted respiratory
depression side effect incident to the use of such commonly used
drugs as morphine and fentanyl.
[0029] Illustrative of a preferred class of delta agonist compounds
which may be usefully employed in the broad practice of the present
invention are delta agonist compounds of the formula:
##STR00003##
wherein:
[0030] Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic
ring with atoms selected from the group consisting of carbon,
nitrogen, oxygen and sulfur, and having on a first carbon atom
thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1,
[0031] Y is selected from the group consisting of: [0032] hydrogen;
[0033] halogen; [0034] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl; [0035] C.sub.1-C.sub.6 haloalkyl;
[0036] C.sub.1-C.sub.6 alkoxy; [0037] C.sub.3-C.sub.6 cycloalkoxy;
[0038] sulfides of the formula SR.sup.8 where R.sup.8 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a
C.sub.5-C.sub.10 aryl moiety and an C.sub.1-C.sub.6 alkyl moiety,
or C.sub.5-C.sub.10aryl; [0039] sulfoxides of the formula SOR.sup.8
where R.sup.8 is the same as above; [0040] sulfones of the formula
SO.sub.2R.sup.8 where R.sup.8 is the same as above; [0041] nitrile;
[0042] C.sub.1-C.sub.6 acyl; [0043] alkoxycarbonylamino (carbamoyl)
of the formula NHCO.sub.2R.sup.8 where R.sup.8 is the same as
above; [0044] carboxylic acid, or an ester, amide, or salt thereof;
[0045] aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 [0046] hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C; [0047] carboxamides of the formula
CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same as
above, or C.sub.2-C.sub.30 peptide conjugates thereof; and [0048]
sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above;
[0049] Z is selected from the group consisting of: [0050] hydroxyl,
and esters thereof; [0051] hydroxymethyl, and esters thereof; and
[0052] amino, and carboxamides and sulfonamides thereof; [0053] G
is carbon or nitrogen; [0054] R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; [0055] R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl; R.sup.2,
R.sup.4 and R.sup.5 may be the same or different, and are
independently selected from hydrogen and methyl, and wherein at
least one of R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject
to the proviso that the total number of methyl groups does not
exceed two, or any two of R.sup.3, R.sup.4 and R.sup.5 together may
form a bridge of 1 to 3 carbon atoms;
[0056] R.sup.6 is selected from the group consisting of: [0057]
hydrogen; [0058] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; [0059] C.sub.3-C.sub.6 cycloalkyl; [0060]
arylalkyl having C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl
moieties; [0061] alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and
C.sub.1-C.sub.4 alkyl moieties; [0062] C.sub.2-C.sub.4 cyanoalkyl;
[0063] C.sub.2-C.sub.4 hydroxyalkyl; [0064] aminocarbonylalkyl
having a C.sub.1-C.sub.4 alkyl moiety; and [0065]
R.sup.12COR.sup.13, where R.sup.12 is C.sub.1-C.sub.4 alkylene, and
R.sup.13 is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy;
and
[0066] R.sup.7 is hydrogen or fluorine,
or a pharmaceutically acceptable ester or salt thereof.
[0067] In addition to methods of treating, reducing or preventing
respiratory depression, the present invention also contemplates
methods for screening and characterizing opioid compounds that
reduce, treat or prevent respiratory depression.
[0068] The methods for screening such opioid compounds (i.e.,
opioid compounds that reduce, treat or prevent respiratory
depression, referred to here as respiratory depression-suppressing
compounds) comprise conducting activity reversal assays of
candidate respiratory depression-suppressing compounds in receptor
tissue to determine if such candidate compounds transductionally
mediate a respiratory depression effect in response to a
respiration-depressing composition. Such activity reversal assays
are conducted comparatively, in the absence and in the presence of
an anti-suppression compound of formula (I), i.e., a compound
combating the respiratory depression-suppressing effect and
allowing such respiratory depression to take place. If the activity
of the candidate compound is markedly reversed in the receptor
system by the presence of the anti-suppression compound of formula
(I), the assay is positive for the candidate respiratory
depression-suppressing compound, indicating its potential
bioefficacy for supressing respiratory depression effects incident
to the use of other therapeutic agents.
[0069] The anti-suppression compound of formula (I) employed in the
above-described screen assay is preferably selected from those of
the group consisting of: [0070]
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; [0071]
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide; [0072]
cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybe-
nzyl)-N,N-diethyl-benzamide; and acceptable salts thereof.
[0073] In such context, the term "acceptable" in reference to
suitable salt species of the particular identified compounds, means
salts which are effective to mediate suppression of respiratory
depression effects.
[0074] Further, the present invention provides pharmaceutical
compositions comprising a combination of an effective amount of an
opiate analgesic and an effective amount of a composition for
combating the respiratory depression effect of a respiratory
depression-mediating agent.
[0075] The respiratory depression-combating agent comprise at least
one delta receptor agonist compound.
[0076] The delta agonist compound employed in the invention may
also exhibit mu receptor agonism (i.e., such compound may have
mixed mu/delta receptor agonist character) or the respiratory
depression-combating composition of the invention may include
different compounds, one or more of which exhibits delta receptor
agonist character, and one or more different ones of which exhibit
mu receptor agonist character.
[0077] As a still further alternative, the respiratory
depression-combating composition of the invention may utilize two
or more compounds, each of which has a varying mu/delta receptor
agonist activity character.
[0078] In a specific embodiment, the invention contemplates as the
respiratory depression-combating compound, a compound of formula
(I) for reducing, treating or preventing respiratory depression
which would otherwise be effected by an administered opiate
analgesic.
[0079] Additionally, the present invention provides the following
particularly preferred compounds, which can be included, for
example, in a pharmaceutical composition containing a compound and
a pharmaceutically acceptable carrier, and can be used, for
example, in a form suitable for injectable or spinal
administration, to combat respiratory depression incident to the
use of analgesic or anesthetic agents. The particularly preferred
compounds are as follows: [0080]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; [0081]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide; [0082]
4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydro-
xybenzyl)benzamide; [0083]
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)benzamide; [0084]
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piper-
azinyl)benzyl)benzamide; [0085]
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxybenzyl)-N-ethyl-N-methyl-benzamide; [0086]
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol; [0087]
3-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol; [0088] (.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5
S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenz-
enesulfonamide; [0089]
(+)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; [0090]
(-)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfonamide); [0091]
(.+-.)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trim-
ethyl-1-piperazinyl)benzyl)-benzamide; [0092]
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; and pharmaceutically
acceptable salts thereof.
[0093] These preferred compounds of the invention have utility in
medical therapy, in particular for reducing, treating or preventing
respiratory depression associated with certain analgesics, such as
mu opiates.
[0094] Various other aspects, features and embodiments of the
invention will be more fully apparent from the ensuing disclosure
and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0095] FIG. 1A shows the effect of the positive isomer of the delta
agonist BW373U86 on respiratory depression induced by the mu
agonist, alfenta.
[0096] FIG. 1B shows the effect of the delta agonist BW373U86 on
analgesia induced by the mu agonist, alfenta.
[0097] FIG. 2A shows the analgesic and respiratory depression
effects of 3290W93 and fentanyl in rats, plotted at 4 minute time
points at which times peak effects were observed following drug
administration.
[0098] FIG. 2B shows the analgesic and respiratory depression
effects of 3290W93 and fentanyl in rats, plotted at 8 minute time
points.
DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS
THEREOF
[0099] The vast majority of currently used high potency analgesics,
including morphine, fentanyl, meperidine, sufentanil, codeine and
naltrindole, are mu receptor binding compounds. As is well
established, these compounds, while highly efficacious for
mediating analgesia, have accompanying side effects, including
respiratory depression. The use of delta agonist compounds
according to the present invention may prevent, reduce, attenuate
or even eliminate or reverse conditions in which analgesia induces
respiratory depression, such as the respiratory depressing side
effects normally attendant to the use of mu receptor binding
compounds.
[0100] The present invention therefore provides, inter alia,
methods of reducing, treating or preventing respiratory depression
using respiratory depression-combating agents including delta
agonist compound(s). Such delta agonist compounds may as mentioned
exhibit mixed mu/delta receptor agonist character, or be provided
with other receptor binding agents exhibiting mu receptor agonism.
The compositions of the invention therefore may be co-administered
with drugs or other bioactive agents which mediate respiratory
depression, so that the respiratory depression effects of such drug
or bioactive agent are at least partially attenuated.
[0101] The delta agonist compounds which may be usefully employed
in such compositions include delta agonist compounds and
pharmaceutical compositions comprising a combination of an
effective amount of an opiate analgesic and an amount of a delta
agonist compound effective for reducing, treating or preventing
respiratory depression. The use of delta agonist compounds for
combating respiratory depression, and in combination pharmaceutical
compositions, are more fully discussed below.
[0102] Preferably, the delta agonist compound reduces, treats or
prevents respiratory depression without affecting analgesia desired
from opiate analgesic agents, such as mu opiate analgesic
agents.
[0103] Delta agonist compounds potentially useful in the broad
practice of the present invention variously include:
I. [D-Pen.sup.2,D-Pen.sup.5]-(enkephalin); II. deltorphin I; III.
deltorphin II; IV. delta agonist compounds of the formula:
##STR00004##
wherein:
[0104] Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic
ring with atoms selected from the group consisting of carbon,
nitrogen, oxygen and sulfur, and having on a first carbon atom
thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1,
[0105] Y is selected from the group consisting of: [0106] hydrogen;
[0107] halogen; [0108] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl; [0109] C.sub.1-C.sub.6 haloalkyl;
[0110] C.sub.1-C.sub.6 alkoxy; [0111] C.sub.3-C.sub.6 cycloalkoxy;
[0112] sulfides of the formula SR.sup.8 where R.sup.8 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a
C.sub.5-C.sub.10 aryl moiety and an C.sub.1-C.sub.6 alkyl moiety,
or C.sub.5-C.sub.10 aryl; [0113] sulfoxides of the formula
SOR.sup.8 where R.sup.8 is the same as above; [0114] sulfones of
the formula SO.sub.2R.sup.8 where R.sup.8 is the same as above;
[0115] nitrile; [0116] C.sub.1-C.sub.6 acyl; [0117]
alkoxycarbonylamino (carbamoyl) of the formula NHCO.sub.2R.sup.8
where R.sup.8 is the same as above; [0118] carboxylic acid, or an
ester, amide, or salt thereof; [0119] aminomethyl of the formula
CH.sub.2NR.sup.9R.sup.10 where R.sup.9 and R.sup.10 may be the same
or different, and may be hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
hydroxyalkyl, C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6
cycloalkyl, or C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10
together may form a ring of 5 or 6 atoms, the ring atoms selected
from the group consisting of N and C; [0120] carboxamides of the
formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same
as above, or C.sub.2-C.sub.30 peptide conjugates thereof; and
[0121] sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above;
[0122] Z is selected from the group consisting of: [0123] hydroxyl,
and esters thereof; [0124] hydroxymethyl, and esters thereof; and
[0125] amino, and carboxamides and sulfonamides thereof, [0126] G
is carbon or nitrogen; [0127] R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; [0128] R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl; R.sup.3,
R.sup.4 and R.sup.5 may be the same or different, and are
independently selected from hydrogen and methyl, and wherein at
least one of R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject
to the proviso that the total number of methyl groups does not
exceed two, or any two of R.sup.3, R.sup.4 and R.sup.5 together may
form a bridge of 1 to 3 carbon atoms;
[0129] R.sup.6 is selected from the group consisting of: [0130]
hydrogen; [0131] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; [0132] C.sub.3-C.sub.6 cycloalkyl; [0133]
arylalkyl having C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl
moieties; [0134] alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and
C.sub.1-C.sub.4 alkyl moieties; [0135] C.sub.2-C.sub.4 cyanoalkyl;
[0136] C.sub.2-C.sub.4 hydroxyalkyl; [0137] aminocarbonylalkyl
having a C.sub.1-C.sub.4 alkyl moiety; and [0138]
R.sup.12COR.sup.13, where R.sup.12 is C.sub.1-C.sub.4 alkylene, and
R.sup.13 is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy;
and
[0139] R.sup.7 is hydrogen or fluorine,
or a pharmaceutically acceptable ester or salt thereof; V. delta
agonist compounds of the formula:
##STR00005##
[0140] in which,
[0141] R.sub.1 and R.sub.2, which can be the same or different, are
each hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkenyl, C.sub.4-6 cycloalkylalkyl,
C.sub.3-6 alkenyl, C.sub.3-5 alkynyl, aryl, aralkyl or furan-2 or
3-yl alkyl or may form together a C.sub.3-7 alkyl ring which may be
interrupted by oxygen. [0142] R.sub.3 and R.sub.4, which can be the
same or different, are each hydrogen, linear or branched C.sub.1-6
alkyl, or R.sub.4 is oxygen forming with the carbon atom to which
is attached a C.dbd.O group; [0143] R.sub.5 is hydrogen, hydroxy,
C.sub.1-3 alkoxy, thiol or alkylthio; [0144] R.sub.6 is phenyl,
halogen, NH.sub.2 or a para or meta --C(Z)-R.sub.8 group, in which
Z is oxygen or sulphur;
[0145] R.sub.8 is C.sub.1-8-alkyl, C.sub.1-8-alkoxy or
NR.sub.9R.sub.10, wherein R.sub.9 and R.sub.10, which may be the
same or different, are hydrogen, straight or branched C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6
alkenyl, aryl or aralkyl, [0146] or R.sub.6 is a para or metal
##STR00006##
[0146] group
[0147] in which R.sub.11 and R.sub.12 which may the same or
different are hydrogen, straight or branched C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl,
aryl, aralkyl or an optionally substituted heterocyclic ring, and Z
is as defined above; and, [0148] R.sub.7 is hydrogen, straight or
branched C.sub.1-8 alkyl or halogen; and VI. delta agonist
compounds of the formula:
##STR00007##
[0149] in which,
[0150] R.sub.1 and R.sub.2, which can be the same or different, are
each hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkenyl, C.sub.4-6 cycloalkylalkyl,
C.sub.3-6 alkenyl, C.sub.3-5 alkynyl, aryl, aralkyl or furan-2 or
3-yl alkyl or may form together a C.sub.3-7 alkyl ring which may be
interrupted by oxygen.
[0151] R.sub.3 and R.sub.4, which can be the same or different, are
each hydrogen, linear or branched C.sub.1-6 alkyl; [0152] R.sub.5
is hydroxy, C.sub.1-6 alkoxy, thiol or alkylthio; [0153] R.sub.6 is
a --C(Z)-Rg group, in which Z is oxygen or sulphur, R.sub.8 is
C.sub.1-8-alkyl, C.sub.1-8-alkoxy or NR.sub.9R.sub.10, wherein
R.sub.9 and R.sub.10, which may be the same or different, are
hydrogen, straight or branched C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, aryl or
aralkyl,
[0154] or R.sub.6 is a
##STR00008##
group
[0155] in which R.sub.11 and R.sub.12 have the same meaning as
R.sub.9 and R.sub.10 or together form an optionally substituted
heterocyclic ring and Z is as defined above, and R.sub.7 is
hydrogen, straight or branched C.sub.1-8 alkyl or halogen.
[0156] An illustrative delta agonist compound from among the
foregoing illustrative compounds is:
##STR00009## [0157]
(+)-4-(((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethylbenzamide.
[0158] The composition that is co-administered with the bioactive
agent mediating respiratory depression may further include a mu
receptor agonist such as the mu receptor agonists disclosed in U.S.
patent application Ser. No. 08/284,445 and U.S. patent application
Ser. No. 08/285,313, including mu receptor agonist compounds, and
mixed mu/delta receptor agonist compounds such as:
##STR00010##
[0159] When the respiratory depression-combating compound utilized
in the practice of the invention does not affect analgesia, it can
be used in combination with an analgesic opiate agent, so that the
opiate agent produces its desired analgesic effect, but without the
occurrence of the respiratory depression that otherwise (i.e., in
the absence of the compound of formula (I)) would be produced by
such analgesic opiate agent. The invention therefore contemplates
the use of respiratory depression-combating compounds which mediate
analgesia themselves, as well as respiratory depression-combating
compounds which do not mediate analgesia.
[0160] In such combination of the opiate agent (or other
respiratory depression-mediating compound), and the respiratory
depression-combating compound, the dosage of the opiate agent for
inducing analgesia, and the dosage of the formula (I) compound for
reducing, treating or preventing respiratory depression, can be
independently determined. The separate control of dosages for these
two functions provides for greater flexibility in treating
individual patients. This separate control is one of the advantages
of the combination pharmaceutical compositions of the present
invention.
[0161] The combination pharmaceutical compositions of the invention
thus comprise a combination of (1) an effective amount of a
therapeutic agent having a respiratory depression (side) effect,
e.g., an opiate analgesic, and (2) an effective amount of a
compound, e.g., a compound of formula (I) below, for reducing,
treating or preventing respiratory depression.
[0162] Compounds of formula (I) are as follows:
##STR00011##
wherein:
[0163] Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic
ring with atoms selected from the group consisting of carbon,
nitrogen, oxygen and sulfur, and having on a first carbon atom
thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1,
[0164] Y is selected from the group consisting of: [0165] hydrogen;
[0166] halogen; [0167] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl; [0168] C.sub.1-C.sub.6 haloalkyl;
[0169] C.sub.1-C.sub.6 alkoxy; [0170] C.sub.3-C.sub.6 cycloalkoxy;
[0171] sulfides of the formula SR.sup.8 where R.sup.8 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a
C.sub.5-C.sub.10 aryl moiety and an C.sub.1-C.sub.6 alkyl moiety,
or C.sub.5-C.sub.10 aryl; [0172] sulfoxides of the formula
SOR.sup.8 where R.sup.8 is the same as above; [0173] sulfones of
the formula SO.sub.2R.sup.8 where R.sup.8 is the same as above;
[0174] nitrile; [0175] C.sub.1-C.sub.6 acyl; [0176]
alkoxycarbonylamino (carbamoyl) of the formula NHCO.sub.2R.sup.8
where R.sup.8 is the same as above; [0177] carboxylic acid, or an
ester, amide, or salt thereof; [0178] aminomethyl of the formula
CH.sub.2NR.sup.9R.sup.10 where R.sup.9 and R.sup.10 may be the same
or different, and may be hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
[0179] hydroxyalkyl, C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6
cycloalkyl, or C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10
together may form a ring of 5 or 6 atoms, the ring atoms selected
from the group consisting of N and C; [0180] carboxamides of the
formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same
as above, or C.sub.2-C.sub.30 peptide conjugates thereof; and
[0181] sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above;
[0182] Z is selected from the group consisting of: [0183] hydroxyl,
and esters thereof; [0184] hydroxymethyl, and esters thereof; and
[0185] amino, and carboxamides and sulfonamides thereof; [0186] G
is carbon or nitrogen; [0187] R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; [0188] R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl; R.sup.3,
R.sup.4 and R.sup.5 may be the same or different, and are
independently selected from hydrogen and methyl, and wherein at
least one of R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject
to the proviso that the total number of methyl groups does not
exceed two, or any two of R.sup.3, R.sup.4 and R.sup.5 together may
form a bridge of 1 to 3 carbon atoms;
[0189] R.sup.6 is selected from the group consisting of: [0190]
hydrogen; [0191] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; [0192] C.sub.3-C.sub.6 cycloalkyl; [0193]
arylalkyl having C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl
moieties; [0194] alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and
C.sub.1-C.sub.4 alkyl moieties; [0195] C.sub.2-C.sub.4 cyanoalkyl;
[0196] C.sub.2-C.sub.4 hydroxyalkyl; [0197] aminocarbonylalkyl
having a C.sub.1-C.sub.4 alkyl moiety; and [0198]
R.sup.12COR.sup.13, where R.sup.12 is C.sub.1-C.sub.4 alkylene, and
R.sup.13 is C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy;
and
[0199] R.sup.7 is hydrogen or fluorine,
or a pharmaceutically acceptable ester or salt thereof.
[0200] In preferred methods and pharmaceutical compositions of the
present invention, the substituents of the compound of formula (I)
for reducing, treating or preventing respiratory depression are as
follows.
[0201] Preferably, Ar is a 6-member carbocyclic aromatic (benzene)
ring and R.sup.1 is hydrogen.
[0202] In certain preferred methods, Y is a carboxamide of the
formula CONR.sup.9R.sup.10, and R.sup.9 and R.sup.10 preferably are
the same or different and are each hydrogen, C.sub.1 alkyl or
C.sub.2 alkyl, or together form a ring of five or six atoms,
thereby forming a pyrrolidinyl or piperidino ring. In other
preferred methods, Y is hydrogen or a sulfone of the formula
SO.sub.2R.sup.8 and R.sup.8 is preferably C.sub.1-C.sub.6
alkyl.
[0203] Furthermore, in preferred methods, G is N, R.sup.7 and
R.sup.2 are each hydrogen, and Z is hydroxyl.
[0204] Preferably, R.sup.6 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl and
C.sub.2-C.sub.6 alkynyl, and more preferably, R.sup.6 is selected
from the group consisting of hydrogen, methyl, propyl, allyl and
butenyl, and most preferably, R.sup.6 is allyl. In preferred
methods, R.sup.3, R.sup.4 and R.sup.5 are hydrogen or methyl, where
the total number of methyl groups is one or two, and most
preferably, R.sup.3 and R.sup.5 are both methyl, and R.sup.4 is
hydrogen.
[0205] Preferably, the compound for reducing, treating or
preventing respiratory depression is selected from the group
consisting of: [0206]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; [0207]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide; [0208]
4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydro-
xybenzyl)-benzamide; [0209]
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)benzamide; [0210]
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piper-
azinyl)benzyl)benzamide; [0211]
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxybenzyl)-N-ethyl-N-methyl-benzamide; [0212]
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol; [0213]
3-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol; [0214]
(.+-.)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trim-
ethyl-1-piperazinyl)benzyl)-benzamide; [0215]
(+)-4-((ccS)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydro-
xybenzyl)-N,N-diethyl-benzamide; [0216]
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-p-
iperazinyl)benzyl)phenol; [0217]
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-
-1-piperazinyl)benzyl)phenol; [0218] (.+-.)-3-((.alpha.R*)--((2R*,5
S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol;
[0219] (.+-.)-4-((.alpha.R*)--((2R*,5
S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenz-
enesulfonamide (and, independently, each of the component isomers
thereof); [0220]
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)benzyl)phenol; [0221]
(.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxbenzyl)benzamide; [0222]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5
S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
[0223]
(.+-.)-cis-4-.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydrox-
ybenzyl)-N,N-diethylbenzamide; [0224]
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenz-
yl)-N,N-diethyl-benzamide; and pharmaceutically acceptable salts
thereof.
[0225] Most preferably, the compound is [0226]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide; [0227]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; [0228]
(+)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfon-amide; or [0229]
(-)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, or a
pharmaceutically acceptable salt thereof.
[0230] In addition to methods of treating, reducing or preventing
respiratory depression, the present invention also provides methods
for screening and characterizing respiratory depression-suppressing
compounds, comprising conducting activity reversal assays of
candidate respiratory depression-suppressing compounds which in
receptor tissue transductionally mediate a respiratory depression
effect in response to a respiration-depressing composition.
[0231] The activity reversal assays are conducted comparatively, in
the absence and in the presence of an anti-suppression compound of
formula (I), to determine if the (respiratory depression)
suppressing activity of the candidate compound is markedly reversed
in the receptor system by the presence of the anti-suppression
compound of formula (I). If so, the assay indicates the candidate
respiratory depression-suppressing compound as possessing potential
bioefficacy for suppressing respiratory depression effects incident
to the use of other therapeutic agents.
[0232] Preferred anti-suppression compounds of formula (I) which
may be usefully employed in the above-discussed screen assay
include: [0233]
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; [0234]
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide; [0235]
cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybe-
nzyl)-N,N-diethyl-benzamide; and acceptable salts thereof.
[0236] Additionally, the present invention provides the following
preferred compounds of formula (I), which can be included, for
example, in a pharmaceutical composition containing the compound
and a pharmaceutically acceptable carrier.
[0237] These pharmaceutical compositions can be used, for example,
in a form suitable for injectable or spinal administration. The
above-referenced preferred compounds are as follows: [0238]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; [0239]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethyl-benzamide; [0240] 4-((.alpha.R)--
.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-benz-
amide; [0241] (.+-.)-3-((.alpha.R*)-.alpha.-((2
S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
[0242]
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl--
1-piperazinyl)benzyl)benzamide; [0243]
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxybenzyl)-N-ethyl-N-methyl-benzamide; [0244]
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
phenol; [0245]
(.+-.)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trim-
ethyl-1-piperazinyl)benzyl)benzamide; [0246]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; [0247]
(.+-.)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-dimethylbenzenesulfon-amide; [0248]
(-)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, [0249]
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethyl-benzamide; and pharmaceutically
acceptable salts thereof.
[0250] These preferred compounds of the invention have utility in
medical therapy, in particular for reducing, treating or preventing
respiratory depression associated with respiratory
depression-mediating drugs, including certain analgesics such as mu
opiate analgesics.
[0251] The respiratory depression-combating compositions of the
present invention may be formulated with the respiratory
depression-mediating agent, as a unitary composition.
Alternatively, the respiratory depression-combating compositions of
the present invention may be separately, independently administered
to a patient in need of same, to combat the respiratory depression
effects otherwise obtaining in use of the respiratory
depression-mediating agent, e.g., a respiratory depressant such as
morphine, fentanyl or the like. The invention contemplates the use
of any means and/or of modality of administration of the
respiratory depression-combating compositions of the invention, in
conjunction with the drug or bioactive agent mediating the
respiratory depression.
[0252] Compounds of the above general formula (I) exhibit binding
selectivity for receptor(s). Depending on the structure and
stereo-specificity of the particular formula (I) compounds, such
compounds may exhibit binding ability to receptor(s) selected from
the group consisting of delta receptors, mu receptors, kappa
receptors, sigma receptors, and combinations of such receptors.
[0253] Various compounds within general formula (I) exhibit delta
receptor agonist activity including reducing, treating or
preventing respiratory depression. Other compounds of formula (I)
exhibit delta receptor antagonist activity which are useful as
agonist conjugates for assay applications, for example, to identify
agonist species. Still other compounds within the general formula
exhibit mu receptor activity, and more particularly, in some
instances, mixed mu receptor/delta receptor activity.
[0254] In the case of delta receptor agonists, activity is
generally distinguished and measured by activity in the
electrically stimulated mouse vas deferens assay. Further,
empirical determinations utilizing compounds of the present
invention provide strong evidence of the existence of a delta
receptor subtype in the brain that is different from the delta
receptor in the mouse vas deferens.
[0255] In consequence of the existence of such delta receptor
subtypes, other receptor binding assays or screening techniques may
be employed as a further predictor of agonist or antagonist
activity for specific compounds of the present invention.
[0256] The compounds used in the methods and pharmaceutical
compositions of the present invention preferably have the following
in vitro profile according to the delta receptor IC.sub.50 and
mouse vas deferens ED.sub.50 tests described in Example 12.
Preferably, the IC.sub.50 is between about 0.01 and about 100 nM;
more preferably, the IC.sub.50 is less than about 100 nM; even more
preferably, the IC.sub.50 is less than about 10 nM; even more
preferably, the IC.sub.50 is less than about 2 nM, and most
preferably, the IC.sub.50 is less than about 1 nM. Preferably, the
mouse vas deferens ED.sub.50 is as high as possible; preferably,
greater than about 10 nM; more preferably, greater than about 30
nM; even more preferably, greater than about 50 nM; and most
preferably, greater than about 100 nM.
[0257] In general, it is preferred to have a ratio of
IC.sub.50:ED.sub.50 of about 1:10; and more preferably, about
1:100.
[0258] As used herein, in reference to the present invention, the
term "alkyl" is intended to be broadly construed as encompassing:
(i) alkyl groups of straight-chain as well as branched chain
character; (ii) unsubstituted as well as substituted alkyl groups,
wherein the substituents of substituted alkyl groups may include
any sterically acceptable substituents which are compatible with
such alkyl groups and which do not preclude the efficacy of the
diarylmethyl piperazine compound for its intended utility (examples
of substituents for substituted alkyl groups include halogen (e.g.,
fluoro, chloro, bromo, and iodo), amino, amido, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, nitro, hydroxy, etc.); (iii)
saturated alkyl groups as well as unsaturated alkyl groups, the
latter including groups such as alkenyl-substituted alkyl groups
(e.g., allyl, methallyl, propallyl, butenylmethyl, etc.),
alkynyl-substituted alkyl groups, and any other alkyl groups
containing sterically acceptable unsaturation which is compatible
with such alkyl groups and which does not preclude the efficacy of
the diarylmethyl piperazine compound for its intended utility; and
(iv) alkyl groups including linking or bridge moieties, e.g.,
heteroatoms such as nitrogen, oxygen, sulfur, etc.
[0259] As used herein, in reference to the present invention, the
term "aryl" is intended to be broadly construed as referring to
carbocyclic (e.g., phenyl, naphthyl) as well as heterocyclic
aromatic groups (e.g., pyridyl, thienyl, furanyl, etc.) and
encompassing unsubstituted as well as substituted aryl groups,
wherein the substituents of substituted aryl groups may include any
sterically acceptable substituents which are compatible with such
aryl groups and which do not preclude the efficacy of the
diarylmethyl piperazine compound for its intended utility. Examples
of substituents for substituted aryl groups include one or more of
halogen (e.g., fluoro, chloro, bromo, and iodo), amino, amido,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, nitro,
trifluoromethyl, hydroxy, hydroxyalkyl containing a C.sub.1-C.sub.4
alkyl moiety, etc.
[0260] The compounds contemplated by the invention include those of
formula (I) per se, as well as physiologically functional
derivatives thereof.
[0261] By "physiologically functional derivative" is meant a
pharmaceutically acceptable salt, ether, ester or salt of an ether
or ester of the compound of formula (I) or any other compound
which, upon administration to the recipient, is capable of
providing (directly or indirectly) the said compound of formula (I)
or an active metabolite or residue thereof. Phenolic
C.sub.1-C.sub.6 alkyl ethers are a sub-class of physiologically
functional derivatives of the compounds of formula (I).
[0262] In enantiomeric forms, compounds of the invention include
individual enantiomers of the compounds of formula (I) in single
species form substantially free of the corresponding enantiomer, as
well as in admixture (in mixtures of enantiomeric pairs and/or in
mixtures of multiple enantiomer species).
[0263] A sub-class of compounds within the scope of formula (I) are
the pharmaceutically acceptable esters and salts thereof.
[0264] Examples of pharmaceutically acceptable esters of the
invention include carboxylic acid esters of hydroxy groups in
compounds of formula (I) in which the non-carbonyl moiety of the
carboxylic acid portion of the ester grouping is selected from
straight or branched chain alkyl (e.g. n-propyl, t-butyl, n-butyl),
alkoxyalkyl (e.g. methoxymethyl), arylalkyl (e.g. benzyl),
aryloxyalky (e.g. phenoxymethyl), and aryl (e.g. phenyl); alkyl-,
aryl-, or arylalkylsulfonyl (e.g. methanesulfonyl); amino acid
esters (e.g. L-valyl or L-isoleucyl); dicarboxylic acid esters
(e.g. hemisuccinate); carbonate esters (e.g. ethoxycarbonyl);
carbamate esters (e.g. dimethylaminocarbonyl,
(2-aminoethyl)aminocarbonyl); and inorganic esters (e.g. mono-, di-
or triphosphate).
[0265] Examples of pharmaceutically acceptable salts of the
compounds of formula (I) and physiologically functional derivatives
thereof include salts derived from an appropriate base, such as an
alkali metal (for example, sodium, potassium), an alkaline earth
metal (for example, calcium, magnesium), ammonium and NX.sup.4+
(wherein X is C.sub.1-C.sub.4 alkyl). Pharmaceutically acceptable
salts of an amino group include salts of: organic carboxylic acids
such as acetic, lactic, tartaric, malic, lactobionic, fumaric, and
succinic acids; organic sulfonic acids such as methanesulfonic,
ethanesulfonic, isethionic, benzenesulfonic and p-toluenesulfonic
acids; and inorganic acids such as hydrochloric, hydrobromic,
sulfuric, phosphoric and sulfamic acids. Pharmaceutically
acceptable salts of a compound having a hydroxy group consist of
the anion of said compound in combination with a suitable cation
such as Na+, NH.sup.4+ or NX.sup.4+ (wherein X is for example a
C.sub.1-4 alkyl group).
[0266] For therapeutic use, salts of compounds of formula (I) will
be pharmaceutically acceptable, i.e., they will be salts derived
from a pharmaceutically acceptable acid or base. However, salts of
acids or bases which are not pharmaceutically acceptable may also
find use, for example, in the preparation or purification of a
pharmaceutically acceptable compound. All salts, whether or not
derived from a pharmaceutically acceptable acid or base, are within
the scope of the present invention.
[0267] As used herein, in reference to the present invention, the
term "hydrocarbyl" is intended to encompass a group containing only
carbon and hydrogen atoms, which may contain double or triple bonds
and which may be cyclic or aromatic in nature.
[0268] The compounds of the invention when used in pharmaceutical
or diagnostic applications desirably are prepared in substantially
pure enantiomer form, with an enantiopurity of at least 90%
enantiomeric excess (EE), preferably at least 95% EE, more
preferably at least 98% EE, and most preferably at least 99% EE.
Enantiomeric excess values provide a quantitative measure of the
excess of the percentage amount of a major isomer over the
percentage amount of a minor isomer which is present therewith, and
may be readily determined by suitable methods well-known and
established in the art, as for example chiral high pressure liquid
chromatography (HPLC), chiral gas chromatography (GC), nuclear
magnetic resonance (NMR) using chiral shift reagents, etc.
[0269] Subjects to be treated by the methods of the present
invention include both human and non-human animal (e.g., bird, dog,
cat, cow, horse) subjects, and are preferably mammalian subjects,
and most preferably human subjects.
[0270] Depending on the specific condition to be treated, animal
subjects may be administered compounds of formula (I) at any
suitable therapeutically effective and safe dosage, as may readily
be determined within the skill of the art, and without undue
experimentation.
[0271] In in vitro tests for agonist/antagonist activity, such as
receptor binding affinity tests, and inhibition of electrically
stimulated muscle twitch tests, compounds of the present invention
exhibit potency over a range of from nanomolar to micromolar
concentrations, depending on the specific compound employed.
[0272] In general, while the effective dosage of compounds of the
invention for therapeutic use may be widely varied in the broad
practice of the invention, depending on the specific application,
condition, or disease state involved, as readily determinable
within the skill of the art, suitable therapeutic doses of the
formula (I) compounds, for each of the appertaining compositions
described herein, and for achievement of therapeutic benefit in
treatment of each of the conditions described herein, will be in
the range of 10 micrograms (.mu.g) to 100 milligrams (mg) per
kilogram body weight of the recipient per day, preferably in the
range of 50 .mu.g to 75 mg per kilogram body weight per day, and
most preferably in the range of 100 .mu.g to 50 mg per kilogram
body weight per day. The desired dose is preferably presented as
two, three, four, five, six, or more sub-doses administered at
appropriate intervals throughout the day. These sub-doses may be
administered in unit dosage forms, for example, containing from 10
.mu.g to 1000 mg, preferably from 50 .mu.g to 500 mg, more
preferably from 50 .mu.g to 250 mg, and most preferably from 50
.mu.g to 10 mg of active ingredient per unit dosage form.
Alternatively, if the condition of the recipient so requires, the
doses may be administered as a continuous infusion.
[0273] The mode of administration and dosage forms will of course
affect the therapeutic amounts of the compounds which are desirable
and efficacious for the given treatment application.
[0274] For example, orally administered dosages typically are at
least twice, e.g., 2-10 times, the dosage levels used in parenteral
administration methods, for the same active ingredient. In oral
administration, dosage levels for delta receptor binding compounds
of the invention may be on the order of 5-200 mg/70 kg body
weight/day. In tablet dosage forms, typical active agent dose
levels are on the order of 10-100 mg per tablet.
[0275] The compounds of formula (I) may be administered per se as
well as in the form of pharmaceutically acceptable ethers, esters,
salts, and other physiologically functional derivatives
thereof.
[0276] The present invention also contemplates pharmaceutical
formulations, both for veterinary and for human medical use, which
comprise as the active agent one or more compound(s) of the
invention.
[0277] In such pharmaceutical formulations, the active agent
preferably is utilized together with one or more pharmaceutically
acceptable carrier(s) therefor and optionally any other therapeutic
ingredients. The carrier(s) must be pharmaceutically acceptable in
the sense of being compatible with the other ingredients of the
formulation and not unduly deleterious to the recipient thereof.
The active agent is provided in an amount effective to achieve the
desired pharmacological effect, as described above, and in a
quantity appropriate to achieve the desired daily dose.
[0278] The formulations include those suitable for parenteral as
well as non-parenteral administration, and specific administration
modalities include oral, rectal, topical, sub-lingual, mucosal,
nasal, ophthalmic, subcutaneous, intramuscular, intravenous,
transdermal, spinal, intrathecal, intra-articular, intra-arterial,
sub-arachnoid, bronchial, lymphatic, and intra-uterine
administration. Formulations suitable for parenteral administration
are preferred.
[0279] When the active agent is utilized in a formulation
comprising a liquid solution, the formulation advantageously may be
administered parenterally. When the active agent is employed in a
liquid suspension formulation or as a powder in a biocompatible
carrier formulation, the formulation may be advantageously
administered orally, rectally, or bronchially.
[0280] When the active agent is utilized directly in the form of a
powdered solid, the active agent may advantageously administered
orally. Alternatively, it may be administered bronchially, via
nebulization of the powder in a carrier gas, to form a gaseous
dispersion of the powder which is inspired by the patient from a
breathing circuit comprising a suitable nebulizer device.
[0281] In some applications, it may be advantageous to utilize the
active agent in a "vectorized" form, such as by encapsulation of
the active agent in a liposome or other encapsulant medium, or by
fixation of the active agent, e.g., by covalent bonding, chelation,
or associative coordination, on a suitable biomolecule, such as
those selected from proteins, lipoproteins, glycoproteins, and
polysaccharides.
[0282] The formulations comprising the active agent of the present
invention may conveniently be presented in unit dosage forms and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods generally include the step of bringing the
active compound(s) into association with a carrier which
constitutes one or more accessory ingredients. Typically, the
formulations are prepared by uniformly and intimately bringing the
active compound(s) into association with a liquid carrier, a finely
divided solid carrier, or both, and then, if necessary, shaping the
product into dosage forms of the desired formulation.
[0283] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, tablets, or lozenges, each containing a predetermined
amount of the active ingredient as a powder or granules; or a
suspension in an aqueous liquor or a non-aqueous liquid, such as a
syrup, an elixir, an emulsion, or a draught.
[0284] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine, with the active
compound being in a free-flowing form such as a powder or granules
which optionally is mixed with a binder, disintegrant, lubricant,
inert diluent, surface active agent, or discharging agent. Molded
tablets comprised of a mixture of the powdered active compound with
a suitable carrier may be made by molding in a suitable
machine.
[0285] A syrup may be made by adding the active compound to a
concentrated aqueous solution of a sugar, for example sucrose, to
which may also be added any accessory ingredient(s). Such accessory
ingredient(s) may include flavorings, suitable preservative, agents
to retard crystallization of the sugar, and agents to increase the
solubility of any other ingredient, such as a polyhydroxy alcohol,
for example glycerol or sorbitol.
[0286] Formulations suitable for parenteral administration
conveniently comprise a sterile aqueous preparation of the active
compound, which preferably is isotonic with the blood of the
recipient (e.g., physiological saline solution). Such formulations
may include suspending agents and thickening agents and liposomes
or other microparticulate systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose form.
[0287] Nasal spray formulations comprise purified aqueous solutions
of the active compounds with preservative agents and isotonic
agents. Such formulations are preferably adjusted to a pH and
isotonic state compatible with the nasal mucous membranes.
[0288] Formulations for rectal administration may be presented as a
suppository with a suitable carrier such as cocoa butter,
hydrogenated fats, or hydrogenated fatty carboxylic acids.
[0289] Ophthalmic formulations are prepared by a similar method to
the nasal spray, except that the pH and isotonic factors are
preferably adjusted to match that of the eye.
[0290] Topical formulations comprise the active compound dissolved
or suspended in one or more media, such as mineral oil, petroleum,
polyhydroxy alcohols, or other bases used for topical
pharmaceutical formulations.
[0291] Transdermal formulations may be prepared by incorporating
the active agent in a thixotropic or gelatinous carrier such as a
cellulosic medium, e.g., methyl cellulose or hydroxyethyl
cellulose, with the resulting formulation then being packed in a
transdermal device adapted to be secured in dermal contact with the
skin of a wearer.
[0292] In addition to the aforementioned ingredients, formulations
of this invention may further include one or more accessory
ingredient(s) selected from diluents, buffers, flavoring agents,
binders, disintegrants, surface active agents, thickeners,
lubricants, preservatives (including antioxidants), and the
like.
[0293] The compounds of formula (I) and pharmaceutically acceptable
esters, salts, and other physiologically functional derivatives
thereof, may be formed by the exemplary synthetic techniques
described in the aforementioned International Publication No.
WO93/15062.
[0294] The respiratory depression-combating compositions of the
present invention may also advantageously attenuate side effects of
drug agents other than respiratory depression. For example,
fentanyl also reduces muscle rigidity through mu receptor
activation. Such fentanyl-induced muscle rigidity can be inhibited
by a delta agonist compound such as
(.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-diethylbenzamide.
[0295] Moreover, such combination of mu agonist and delta agonist
compounds are synergistic, in selectively antagonizing each other's
adverse side effects. The compound
(.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-diethylbenzamide at high dosages may
induce seizure activity via delta receptor activation. The mu
agonist fentanyl, for example, has been shown to antagonize such
high dose seizure effect, while the delta agonist antagonizes the
respiratory depression and muscle rigidity side effects of
fentanyl. At the same time, the combination of such agonist
compounds results in an additive analgesic effect.
[0296] The nausea/vomiting effects of mu-opioid analgesics may also
be attenuated by the delta opioid agonist. The combination of mu-
and delta-opioid agonists or compounds possessing both mu- and
delta-opioid receptor activity may produce less nausea and vomiting
as compared to currently used mu-opioid analgesics.
[0297] The invention is further illustrated by the following
non-limiting examples.
[0298] Certain specifications and methods common to many of the
following examples relating to chemical synthesis are described in
the next paragraph.
[0299] Melting points were determined with a Thomas-Hoover
apparatus and are uncorrected. All chemical reagents were purchased
from Aldrich Chemical Company, Milwaukee, Wis., unless otherwise
specified. Commercial solvents were used without further
purification except tetrahydrofuran, which was distilled from
potassium metal. Nuclear magnetic resonance (NMR) spectra were
variously obtained with Perkin-Elmer R-24, Varian XL-200, or XL-300
spectrometers. HPLC analyses were performed with a Waters liquid
chromatography system equipped with a 700 Satellite WISP, 600E
System Controller and a 991 Photodiode Array detector, with either
a Cyclobond I column (4.6.times.250 mm, Advanced Separations
Technologies, Whippany, N.J.) or a .mu.-Bondapak C-18 column (125
.ANG., 3.9.times.300 mm, Waters Chromatography Division, Millipore
Corporation, Milford, Mass.) at a flow rate of 1 ml/min. Analytical
gas chromatography was performed on a Hewlett-Packard Series II
instrument, Model 5890 with flame ionization detector using helium
as the carrier gas (injector temperature, 225.degree. C.; detector
temperature, 250.degree. C.). Optical rotations were obtained with
a Perkin-Elmer 241 polarimeter. Mass spectra were performed by
Oneida Research Services, Whitesboro, N.Y. X-Ray crystallography
was performed by Molecular Structure Corporation, College Station,
Tex. Analytical thin layer chromatography was performed on Analtech
glass plates pre-coated with silica gel GF (250 microns), and
preparative thin layer chromatography on Analtech Uniplates
pre-coated with silica gel GF (1000 and 2000 microns). Elemental
analyses were performed by Atlantic Microlab, Norcross, Ga.
Example 1
(-)-4-(.alpha.R)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)-N,N-diethyl-benzamide
[0300] A mixture of 4-carboxybenzaldehyde (100 g, 0.66 mol), 1 L of
dimethylformamide and 2 L of dichloromethane was cooled in an ice
bath. Thionyl chloride (53 mL, 0.73 mol) was added dropwise while
stirring. After 18 hours at room temperature, the mixture was
cooled again and diethylamine (275 mL, 2.6 mol) was added dropwise.
After stirring at room temperature for one hour the solvent was
evaporated, and the residue was dissolved in aqueous 0.1 M sodium
hydroxide and extracted with ethyl acetate. The organic layers were
washed with water and brine, dried over sodium sulfate and
evaporated to give a yellow oil. Chromatography on silica gel with
ethanol (0-2%) in dichloromethane gave 44.2 g (32%) of
4-formyl-N,N-diethylbenzamide as a yellow oil.
[0301] A solution of 3-bromophenol (500 g, 2.89 mol),
tert-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole
(500 g, 7.22 mol) in 500 mL of dimethylformamide was stirred
overnight at room temperature. The reaction solution was poured
into 3000 mL of water and extracted with two 2000 mL portions of
diethyl ether. The combined ether extracts were dried over sodium
sulfate and the solvent removed to give 846 g of
3-(bromophenoxy)-tert-butyldimethylsilane as a pale yellow liquid.
NMR (300 MHz, CDCl.sub.3): .delta. 0.2 (s, 6H); 1.0 (s, 9H); 6.75
(m, 1H); 7.0 (br s, 1H); 7.1 (m, 2H).
[0302] 3-(Bromophenoxy)-tert-butyldimethylsilane (61.7 g, 0.21 mol)
was dissolved in 500 mL of dry tetrahydrofuran under nitrogen and
cooled to -78.degree. C. A solution of 1.6 M n-butyllithium in
hexane (132 mL, 0.21 mol) was added dropwise at a rate to maintain
the temperature below -70.degree. C. The reaction was stirred for
thirty minutes after the addition was complete and the cold
solution was transferred via cannula to another vessel containing a
cold (-78.degree. C.) solution of 4-formyl-N,N-diethylbenzamide
(44.1 g, 0.21 mol), from above, in 500 mL of dry tetrahydrofuran
under nitrogen. The transfer rate was monitored to maintain the
temperature below -70.degree. C. After stirring for one hour at
-78.degree. C., the reaction was quenched with saturated aqueous
ammonium chloride, warmed to room temperature and diluted with
diethyl ether. The ether layer was washed with water and brine,
dried over sodium sulfate and evaporated to give a yellow oil.
Chromatography on silica gel with ethanol (0-1%) in dichloromethane
gave 45.4 g (52%) of
4-(3-(tert-butyldimethylsilyloxy)-.alpha.-hydroxybenzyl)-N,N-diethylbenza-
mide as a white solid.
[0303] NMR (200 MHz, CDCl.sub.3) .delta.: 0.15 (s, 6H); 1.0 (s,
9H); 1.2 (br m, 6H); 2.8 (br s, 1H); 3.25 (br m, 2H); 3.5 (br m,
2H); 5.75 (s, 1H); 6.75 (d, J=8 Hz, 1H); 6.85 (s, 1H); 7.95 (d, J=8
Hz, 1H); 7.2 (t, J=8 Hz, 1H); 7.35 (AB q, J=8 Hz, 4H).
[0304] Thionyl chloride (5.3 mL, 0.075 mol) was added to a solution
of the benzhydryl alcohol from above (19.75 g, 0.048 mol) in 350 mL
of dichloromethane. After stirring at room temperature overnight
the solvent was evaporated, the residue was redissolved in toluene
and again evaporated to drive off excess thionyl chloride and
afford crude
4-(3-(tert-butyldimethylsilyloxy)-.alpha.-chlorobenzyl)-N,N-diethylbenzam-
ide.
[0305] The crude benzhydryl chloride (approximately 0.047 mol),
(2R,5R)-2,5-dimethylpiperazine (6.0 g, 0.53 mol), prepared from
L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.)
as described in J. Org. Chem. 50: 4909-13 (1985), sodium iodide
(9.0 g, 0.06 mol), and disopropylethylamine (14.19 g, 0.11 mol)
were heated to reflux in acetonitrile (300 mL) under nitrogen for
four hours. The acetonitrile was evaporated. The residue was
dissolved in ethyl acetate (0.5 L) and washed with water. The
organic phase was dried over sodium sulfate and concentrated in
vacuo. The residue was dissolved in dichloromethane and purified on
a short column of silica gel with ethanol (5%) in dichloromethane
to provide a 1:1 mixture of two benzhydrylpiperazine
diastereomers.
[0306] The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9
mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL
(18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium
carbonate and stirred at room temperature under nitrogen for 2
days. The reaction solution was poured into ice water/ethyl acetate
and separated. The organic layer was dried over sodium sulfate, and
concentrated in vacuo. The residue was dissolved in a small amount
of dichloromethane and placed on a column of silica gel. The
diastereomers were separated by elution with a stepwise gradient of
ethanol in dichloromethane. The first isomer was eluted with 1.3%
ethanol in dichloromethane, and the second isomer was obtained with
1.6% ethanol in dichloromethane. Fractions containing the second
isomer were combined and the solvent removed in vacuo to give 1.44
g of
4-(.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-
-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown
oil.
[0307] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.12 (s, 6H); 0.89 (m,
12H); 0.93 (d, J=6.5 Hz, 3H); 1.05 (br s, 6H); 2.13 (app t, J=10.4
Hz, 1H); 2.25-2.37 (m, 3H); 2.55 (dd, partially obscured by DMSO,
1H); 2.71 (dd, J1=8.2 Hz, J2=14.2 Hz, 1H); 2.82 (br d, J=6.2 Hz,
1H); 3.12 (br s, 2H); 3.19 (m, obscured by water, 1H); 3.36 (br s,
2H); 4.55 (s, 1H); 5.08 (d, J=10.8 Hz, 1H), 5.14 (d, J=21.5 Hz,
1H); 5.72-5.83 (m, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.99 (s, 1H); 7.00
(d, J=8.1 Hz, 1H); 7.12 (t, J=7.9 Hz, 1H); 7.23 (d, J=8.2 Hz, 2H);
7.33 (d, J=8.2 Hz, 2H).
[0308] The brown oil (1.05 g, 1.9 mmol) was dissolved in 8 mL of
acetonitrile with 0.53 g (2.9 mmol) of tetraethylammonium fluoride
dihydrate and stirred for 30 minutes at room temperature. After
evaporation of solvent, the residue was redissolved in 1N
hydrochloric acid and diethyl ether. The aqueous phase was
separated and neutralized to pH 8 with 1N sodium hydroxide
solution. The product was extracted using dichloromethane and
washed with brine. The organic phase was dried over sodium sulfate
and the solvent removed to give 0.69 g of
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide.
[0309] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.95 (d, J=5.4 Hz, 3H);
1.00 (d, J=5.4 Hz, 3H); 1.13 (br s, 6H); 2.19 (app t, J=10.0 Hz,
1H); 2.26-2.41 (m, 3H); 2.55 (m, partially obscured by DMSO, 1H);
2.81 (dd, J1=7.9 Hz, J2=14.1 Hz, 1H); 2.89 (br d, J=6.2 Hz, 1H);
3.21 (br s, 2H); 3.21 (m, obscured, 1H); 3.39 (br s, 2H); 4.54 (s,
1H); 5.17 (d, J=11.3 Hz, 1H), 5.22 (d, J=19.6 Hz, 1H); 5.82-5.96
(m, 1H); 6.60 (d, J=7.8 Hz, 1H); 6.93 (m, 2H); 7.11 (t, J=7.9 Hz,
1H); 7.31 (d, J=7.9 Hz, 2H); 7.52 (d, J=7.9 Hz, 2H); 9.39 (s,
1H).
[0310] Mass spectrum (CI-CH.sub.4) m/z: 436 (M+1,12%), 282 (100%),
153 (3%). [.alpha.].sub.D.sup.20=-27.8.degree. (ethanol,
c=1.2).
[0311] A portion of the free amine (0.100 g) was dissolved in
ethanol and titrated with ethanolic hydrogen chloride to pH 4.0,
followed by precipitation with diethyl ether from dichloromethane
to give 0.089 g of the monohydrochloride salt as a hygroscopic
beige powder. Calculations for C.sub.27H.sub.37N.sub.3O.sub.2HCl
0.75H.sub.2O: C, 66.78, H, 8.20; N, 8.65 Cl, 7.30. Found: C, 66.90;
H, 8.05; N, 8.69; Cl, 7.13.
Example 2
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethyl-benzamide
[0312] The first isomer to elute from the column of Example 1 was
obtained as 1.39 g of a brown oil.
[0313] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.11 (s, 6H); 0.86 (d,
J=6.8 Hz, 3H); 0.88 (m, 9H); 0.94 (d, J=6.8 Hz, 3H); 1.02 (br s,
6H); 2.14 (app t, J=10.7 Hz, 1H); 2.25-2.38 (m, 3H); 2.55 (dd,
partially obscured by DMSO, 1H); 2.73 (dd, J1=7.4 Hz, J2=13.9 Hz,
1H); 2.84 (br s, 1H); 3.13 (br s, 2H); 3.28 (m, obscured by water,
1H); 3.34 (br s, 2H); 4.55 (s, 1H); 5.09 (d, J=11.3 Hz, 1H), 5.14
(d, J=19.9 Hz, 1H); 5.74-5.84 (m, 1H); 6.63 (d, J=7.8 Hz, 1H); 6.90
(s, 1H); 7.02 (d, J=7.6 Hz, 1H); 7.13 (t, J=7.8 Hz, 1H); 7.23 (d,
J=8.1 Hz, 2H); 7.47 (d, J=8.1 Hz, 2H).
[0314] The brown oil (0.95 g, 1.73 mmol) was dissolved in 8 mL of
acetonitrile with 0.48 g (2.6 mmol) of tetraethylammonium fluoride
dihydrate and stirred for 30 minutes at room temperature. After
evaporation of solvent, the residue was redissolved in 1N
hydrochloric acid and diethyl ether. The aqueous phase was
separated and neutralized to pH 8 with 1N sodium hydroxide
solution. The product was extracted using dichloromethane, then
washed with brine. The organic phase was dried over sodium sulfate
and the solvent removed to give 0.64 g. of
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide.
[0315] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.89 (d, J=5.8 Hz, 3H);
0.98 (d, J=5.8 Hz, 3H); 1.08 (br s, 6H); 2.10-2.43 (m, 4H); 2.56
(m, partially obscured by DMSO, 1H); 2.78 (dd, J.sub.1=7.7 Hz,
J2=14.4 Hz, 1H); 2.97 (br d, J=6.0 Hz, 1H); 3.17-3.43 (m, 5H); 4.51
(s, 1H); 5.13 (d, J=8.6 Hz, 1H), 5.19 (d, J=15.6 Hz, 1H); 5.75-5.88
(m, 1H); 6.57 (d, J=6.8 Hz, 1H); 6.88 (m, 2H); 7.04 (t, J=7.7 Hz,
1H); 7.27 (d, J=8.0 Hz, 2H); 7.50 (d, J=8.0 Hz, 2H); 9.34 (s, 1H).
Mass spectrum (CI-CH4) m/z: 436 (M+1, 23%), 282 (100%), 153 (4%).
[.alpha.].sub.D.sup.20=-27.3.degree. (ethanol, c=1.2).
[0316] A portion of the free amine (0.100 g) was dissolved in
ethanol and titrated with ethanolic hydrogen chloride to pH 4.0,
followed by precipitation with diethyl ether from dichloromethane
to give 0.075 g of the monohydrochloride salt as a hygroscopic
off-white powder. Calculations for
C.sub.27H.sub.37N.sub.3O.sub.2HCl 0.5H.sub.2O: C, 67.41, H, 8.17;
N, 8.73 Cl, 7.37. Found: C, 67.16; H, 8.18; N, 8.81; Cl, 7.26.
Example 3
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide
[0317]
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.075 g, 0.17 mmol,
Example 1) was dissolved in toluene (10 mL), added to a 3-neck
flask containing Lindlar's catalyst (0.071 g, ca. 0.033 mmol Pd)
and stirred for 3.5 hours under a hydrogen atmosphere. The solution
was filtered through celite, the solvent was evaporated under
vacuum, and the residue was purified on silica gel with 5% ethanol
in dichloromethane to give 0.065 g. of
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethylbenzamide as a light-brown solid.
[0318] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.75-1.41 (m, 17H);
2.10-2.43 (m, 4H); 2.56 (m, partially obscured by DMSO, 1H); 2.87
(m, 1H); 3.03-3.52 (m, 6H); 4.50 (s, 1H); 6.57 (d, J=7.4 Hz, 1H);
6.91 (m, 2H); 7.07 (t, J=7.9 Hz, 1H); 7.27 (d, J=7.7 Hz, 2H); 7.48
(d, J=7.7 Hz, 2H); 9.33 (s, 1H).
[0319] Mass spectrum (C1-CH4) m/z: 438 (M+1, 5%), 282 (100%), 155
(4%). [.alpha.].sub.D.sup.20=-37.5.degree. (ethanol, c=1.2).
[0320] A portion of the free amine (0.055 g) was dissolved in
ethanol and titrated with ethanolic hydrogen chloride to pH 4.0,
followed by precipitation with diethyl ether from dichloromethane
to give 0.045 g of the monohydrochloride salt as a hygroscopic
beige powder. Calculations for C.sub.27H.sub.39N.sub.3O.sub.2HCl
0.5H.sub.2O: C, 67.13, H, 8.55; N, 8.70. Found: C, 67.23; H, 8.55;
N, 8.49.
Example 4
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide
[0321]
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.200 g, 0.46 mmol,
Example 2) was dissolved in toluene (10 mL) and stirred for 4 hours
under a hydrogen atmosphere. The solution was filtered through
celite to give 0.182 g of crude product. The phenol was reprotected
as follows to improve chromatographic resolution. A mixture of
crude product (0.18 g), tert-butylchlorodimethylsilane (0.93 g),
and imidazole (0.070 g) in 10 mL of acetonitrile was stirred
overnight at room temperature. The reaction solution was poured
into 100 mL of water and extracted with two 50 mL portions of
dichloromethane. The combined extracts were dried over sodium
sulfate and the solvent removed. The residue was purified on a
column of silica gel with ethanol (0-4%) in dichloromethane to give
0.085 g of
4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-(te-
rt-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a
light-brown solid.
[0322] The material (0.080 g) was dissolved in acetonitrile (5 mL)
and treated with tetraethylammonium fluoride dihydrate (0.040 g).
After 30 minutes the solvent was removed under reduced pressure.
The residue was dissolved in 1N hydrochloric acid (5 mL) and washed
two times with diethyl ether. The aqueous phase was then adjusted
to pH 9 with 1N sodium hydroxide solution and extracted with
dichloromethane. The dichloromethane extracts were combined, dried
over sodium sulfate, and the solvent removed under reduced pressure
to give 0.056 g of
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-
-hydroxybenzyl)-N,N-diethylbenzamide as a light-brown solid.
[0323] NMR (300 MHz, DMSO-d.sub.6): .delta. 0.72-1.41 (m, 17H);
1.95-2.34 (m, 4H); 2.56 (m, partially obscured by DMSO, 1H); 2.91
(m, 1H); 3.02-3.48 (m, 6H); 4.47 (s, 1H); 6.56 (br s, 1H); 6.83 (m,
2H); 7.05 (m, 1H); 7.24 (d, J=6.5 Hz, 2H); 7.46 (d, J=6.5 Hz, 2H);
9.31 (s, 1H). Mass spectrum (CI-CR.sub.4) m/z: 438 (M+1, 12%), 282
(100%), 155 (4%). [.alpha.].sub.D.sup.20=-36.7.degree. (ethanol,
c=1.3).
[0324] The free amine (0.044 g) was dissolved in ethanol and
titrated with ethanolic hydrogen chloride to pH 4.0, followed by
precipitation with diethyl ether from dichloromethane to give 0.031
g of the monohydrochloride salt as a hygroscopic off-white powder.
Calculations for C.sub.27H.sub.39N.sub.3O.sub.2HCl H2O: C, 65.90,
H, 8.60; N, 8.54 Found: C, 65.72; H, 8.41; N, 8.52.
Example 5
4-((.alpha.R)-.alpha.-(2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydrox-
ybenzyl)-benzamide
[0325] 3-(Bromophenoxy)-tert-butyldimethylsilane (146 g, 0.51 mol,
Example 1, infra) was dissolved in dry tetrahydrofuran under
nitrogen and cooled to -78.degree. C. A solution of 1.6 M
n-butyllithium in hexane (318 mL, 0.51 mol) was added dropwise at a
rate to maintain temperature below -70.degree. C. The reaction was
stirred for 30 minutes after the addition was complete, and the
cold solution was transferred to another vessel containing a cold
(-78.degree. C.) solution of 4-bromobenzaldehyde (94.3 g, 0.51 mol)
in 1000 mL of dry tetrahydrofuran under nitrogen. The transfer rate
was monitored to maintain reaction temperature below -70.degree. C.
The reaction mixture was stirred for another 45 minutes at
-78.degree. C. and then quenched with 100 mL of saturated aqueous
ammonium chloride. After warming to room temperature, the mixture
was diluted with 2000 mL of diethyl ether and washed with 2000 mL
of water followed by 500 mL of saturated sodium chloride. The
ethereal solution was dried over sodium sulfate and the solvent
removed to give 197.2 g of crude
.alpha.-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl
alcohol as a yellow oil.
[0326] NMR (200 MHz, CDCl.sub.3): .delta. 0.2 (s, 6H); 0.9 (s, 6H);
5.7 (s, 1H); 6.75 (dd, J1=2 Hz, J2=8 Hz, 1H); 6.8 (br s, 1H); 6.9
(d, J=8 Hz, 1H); 7.15 (t, J=8 Hz, 1H); 7.25 and 7.45 (AB q, J=8 Hz,
4H).
[0327] The crude benzhydryl alcohol (53.2 g, 135 mmol) was
dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of
thionyl chloride was added dropwise. The solution was stirred
overnight at room temperature and the solvent was removed under
vacuum. The crude product was redissolved in 500 mL of toluene and
the solvent again was removed under vacuum to eliminate excess
thionyl chloride, providing crude
.alpha.-(4-bromophenyl)-3-(tert-butyldimethyl-silyloxy)benzyl
chloride as a dark oil.
[0328] NMR (200 MHz, CDCl.sub.3): .delta. 0.2 (s, 6H); 1.0 (s, 9H);
6.0 (s, 1H); 6.78 (dd, J1=1 Hz, J2=8 Hz, 1H); 6.9 (m, 2H); 7.2 (t,
J=8 Hz, 2H); 7.27 and 7.47 (AB q, J=8 Hz, 4H).
[0329] The crude benzhydryl chloride (approx. 42 mmol) was combined
with 9.55 g (84 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine,
prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals,
Philadelphia, Pa.) as described in J. Org. Chem. 50: 4909-13
(1985), and 30 mL of toluene and heated at reflux overnight under
nitrogen. The toluene was removed under vacuum, and the residue was
redissolved in diethyl ether and washed with 1.0 M sodium hydroxide
followed by saturated aqueous sodium chloride. The ether solution
was dried over sodium sulfate and the solvent removed to give a
dark oil. The product was purified by chromatography on silica gel
(Waters Prep 500) with 0.5-0.7% ethanol in dichloromethane with
0.1% triethylamine to give 8.01 g (39%) of
(2S,5S)-1-(4-bromo-.alpha.-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)--
2,5-dimethylpiperazine as a 1:1 mixture of diastereomers.
[0330] The purified benzhydrylpiperazine (1.51 g, 3.1 mmol) was
dissolved in 20 mL of dry tetrahydrofuran with 0.27 mL (3.2 mmol)
of allyl bromide and 1.6 g (15.5 mmol) of sodium carbonate and
heated at reflux overnight under nitrogen. The cooled reaction
solution was filtered and the solvent removed to give 1.62 g of
crude
(2S,5S)-1-allyl-4-(4-bromo-.alpha.-(3-(tert-butyldimethylsilyloxy)phenyl)-
benzyl)-2,5-dimethylpiperazine as a yellow oil.
[0331] NMR (200 MHz, CDCl.sub.3): .delta. 0.15 (s, 6H); 0.95-1.1
(m, 12H); 1.45 (m, 1H); 2.2-2.55 (m, 4H); 2.6 (m, 1H); 2.75-3.1 (m,
2H); 3.4 (m, 1H); 4.45 (s, 1H); 5.1-5.25 (m, 3H); 5.85 (m, 1H);
6.75 (d, J=8 Hz, 1H); 6.8-6.95 (m, 2H); 7.1 (m, 1H); 7.2-7.5 (m,
4H).
[0332] The product from above (1.40 g, 2.6 mmol) was dissolved in
10 mL of dry tetrahydrofuran and cooled to -78.degree. C. under
nitrogen. A solution of 1.6 M n-butyllithium in hexane (1.6 mL, 2.6
mmol) was added dropwise at a rate to maintain temperature below
-70.degree. C. After the orange solution was stirred an additional
30 minutes at low temperature, anhydrous carbon dioxide gas was
introduced into the reaction solution at a rate to maintain
temperature below -60.degree. C. Carbon dioxide addition was
stopped when the color of the reaction solution became a pale
yellow. The reaction was allowed to warm to room temperature with
stirring and the solvent was removed under vacuum. The residue was
redissolved in 50 mL of toluene and the solvent again removed under
vacuum in order to eliminate residual n-bromobutane. The reaction
provided 1.39 g of the lithium salt of
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(ter-
t-butyldimethylsilyloxy)benzyl)benzoic acid.
[0333] The lithium benzoate salt (1.39 g, 2.8 mmol) was dissolved
in dichloromethane and cooled to 0.degree. C. Thionyl chloride (0.3
mL, 4.2 mmol) was added dropwise. After stirring for two hours at
0.degree. C. concentrated ammonium hydroxide (6.0 mL) was added.
The resulting dark yellow slurry was allowed to warm to room
temperature and stirred for another hour. The reaction solution was
washed with water and dried over sodium sulfate. After removal of
the solvent, the residue was purified by chromatography on silica
gel with 1-3% methanol in dichloromethane to give 0.10 g of
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(ter-
t-butyldimethylsilyl-oxy)benzyl)benzamide as a yellow resin.
[0334] NMR (200 MHz, CDCl.sub.3): .delta. 0.15 (s, 6H); 0.95 (s,
9H); 0.97 (d, J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 2.2-2.5 (m, 4H);
2.65 (m, 1H); 2.8 (m, 1H); 3.0 (m, 1H); 3.5 (m, 1H); 4.55 (s, 1H);
5.1 (d, J=10 Hz, 1H); 5.2 (d, J=16 Hz, 1H); 5.85 (m, 1H); 6.1 (br
s, 2H); 6.65 (d, J=8 Hz, 1H); 6.9 (s, 1H); 6.95 (d, J=8 Hz, 1H);
7.1 (t, J=8 Hz, 1H); 7.55 and 7.7 (AB q, J=8 Hz, 4H).
[0335] The benzamide from above (0.10 g, 0.20 mmol) was dissolved
in 2 mL of acetonitrile with 60 mg (0.3 mmol) of tetraethylammonium
fluoride hydrate and stirred for 1 hour at room temperature. After
evaporation of the solvent, the residue was redissolved in
dichloromethane and washed with water (pH=8), then dried over
sodium sulfate and the solvent removed to give 90 mg of a beige
solid. The monohydrochloride salt was prepared by titration to pH
4.3 with ethanolic hydrogen chloride (approximately 0.2 M) followed
by precipitation with diethyl ether to give 49 mg of
4-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxy-benzyl)benzamide hydrochloride as a hygroscopic white powder.
Calculations for C.sub.23H.sub.29N.sub.3O.sub.2 HCl 1.5H.sub.2O: C,
62.36; H, 7.51; N, 9.49; Cl, 8.00. Found: C, 62.38; H, 7.42; N,
9.41; Cl, 8.10. Mass spec (CI-CH.sub.4): m/z 380 (M+1, 100%)
Example 6
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperaziny-
l)-3-hydroxybenzyl)-benzamide
[0336] A 12 L, 3-necked round bottom flask was charged with
trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been
recrystallized from toluene to mp=115-119.degree. C., and 600 mL of
water. The flask was cooled in an ice bath and a solution of
methanesulfonic acid (1290 g, 13.4 mol) in 600 mL of water was
added slowly with stirring and cooling to maintain the temperature
below 40.degree. C. The solution was cooled to 20.degree. C. and
800 mL of ethanol was added. A 500 mL addition funnel was filled
with 60% aqueous potassium acetate from a 2 L reservoir of the
solution, and potassium acetate was added to the reaction flask to
adjust the pH to 4.0. A second addition funnel was charged with a
solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of
tetrahydrofuran. The ethyl chloroformate and potassium acetate
solutions were simultaneously added dropwise at a rate to maintain
the reaction solution at pH 4.0.+-.0.1, with cooling as necessary
to maintain temperature at 25.degree. C. After addition of the
ethyl chloroformate was complete, the reaction was stirred for 1
hour with continued addition of potassium acetate solution to
maintain a pH of 4.0. The organic solvents were removed by
distillation under vacuum. The remaining aqueous solution was
washed with 1500 mL of ethyl acetate to remove any bis-carbamate
impurity. The ethyl acetate wash was extracted with two 500 mL
portions of 1 M hydrochloric acid to recover desired product. The
acid extracts were combined with the original aqueous solution and
the pH was adjusted to 11 by addition of 10 M sodium hydroxide,
with cooling to maintain temperature below 40.degree. C. The
aqueous solution was extracted with two 1500 mL portions of ethyl
acetate, the combined extracts were dried over magnesium sulfate,
and the solvent was removed to give 927 g (74%) ethyl
trans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.
[0337] A mixture of ethyl
trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl
bromide (328 mL, 3.80 mol), and sodium carbonate (440 g, 4.15 mol)
in 2500 mL of acetonitrile was heated at reflux for 1.5 hours. The
reaction was cooled to room temperature, filtered, and the solvent
removed under vacuum. The residue was dissolved in 4000 mL of
dichloromethane and washed with two 500 mL portions of 1 M sodium
hydroxide. The dichloromethane solution was dried over magnesium
sulfate and the solvent was removed to give 630 g (81%) of ethyl
trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.
[0338] Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate
(630 g, 2.78 mol) was added to a solution of 87% potassium
hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and
heated at reflux for 1.5 hours. Carbon dioxide evolution was
observed for the first 0.5-1 hour of heating. The reaction was
cooled below reflux temperature and 2000 mL of toluene was
carefully added. Ethanol was removed by azeotropic distillation at
105.degree. C., while adding an additional 4000 mL of toluene to
the reaction flask during the course of the distillation. After
collection of 9000 mL of distillate, the reaction was cooled to
100.degree. C. and 1000 mL of toluene was carefully added. The
solution was slowly cooled to 5.degree. C. and maintained at
5.degree. C. for 30 minutes. The solution was filtered, washing the
filter cake with an additional 1500 mL of toluene. The filtrate was
washed with 1000 mL of water, dried over magnesium sulfate, and the
solvent was removed to give 296 g (69%) of
trans-1-allyl-2,5-dimethylpiperazine as a dark liquid.
[0339] 3-(Bromophenoxy)-tert-butyldimethylsilane (155.2 g, 0.54
mol, Example 1, infra) was dissolved in 600 mL of dry
tetrahydrofuran, dried further over molecular sieves, then
transferred to a reaction flask and diluted to 1200 mL with dry
tetrahydrofuran and cooled to -78.degree. C. n-Butyllithium (310 mL
of a 1.6M solution in hexane) was added, while stirring under
nitrogen, at a rate to keep the temperature below -70.degree. C.
Stirring was continued at -78.degree. C. for 45 minutes. A solution
of 3-bromobenzaldehyde (100.0 g, 0.54 mol) in 900 mL of dry
tetrahydrofuran was added at a rate to keep the reaction
temperature below -70.degree. C.
[0340] After stirring for 30 minutes at -78.degree. C., the
reaction was quenched with 500 mL of saturated aqueous ammonium
chloride and allowed to warm to room temperature. The mixture was
diluted with water and diethyl ether and the ethereal layer was
washed with brine, dried over sodium sulfate and evaporated to give
216.2 g of a yellow oil. Chromatography on silica gel with
hexane:ethyl acetate (4-25%) gave 98.86 g (51%) of
.alpha.-(3-bromophenyl)-(3-(tert-butyldimethylsilyloxy)benzyl
alcohol as a yellow oil.
[0341] NMR (CDCl.sub.3, 200 MHz) .delta.: 0.2 (s, 6H); 0.95 (s,
9H); 2.3 (br s, 1H); 5.7 (s, 1H); 6.75 (d, J=8 Hz, 1H); 6.8 (s,
1H); 6.9 (d, J=8 Hz, 1H); 7.2 (m, 2H); 7.3 (d, J=8 Hz, 1H); 7.4 (d,
J=8 Hz, 1H); 7.5 (s, 1H).
[0342] Thionyl chloride (27.5 mL, 0.38 mol) was added dropwise to a
solution of the benzhydryl alcohol from above (98.9 g, 0.25 mol) in
500 mL of dichloromethane and the mixture was stirred overnight at
room temperature. The solvent was removed under vacuum, the residue
was redissolved in toluene, and the solvent was again removed under
vacuum to eliminate excess thionyl chloride to give 154 g of crude
.alpha.-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl
chloride as a brown oil.
[0343] NMR (CDCl.sub.3, 200 MHz) .delta.: 0.2 (s, 6H); 0.95 (s,
9H); 6.0 (s, 1H); 6.8-7.0 (m, 3H); 7.2-7.6 (m, 5H).
[0344] A mixture of the benzhydryl chloride from above (103.5 g,
0.25 mol) and trans-1-allyl-2,5-dimethylpiperazine (96.9 g, 0.63
mol) in 50 mL of toluene was heated at reflux overnight.
Acetonitrile (350 mL) and tetraethylammonium fluoride hydrate (75
g, 0.38 mol) were added to the cooled reaction mixture. After
stirring at room temperature for 30 minutes, the solvent was
removed under vacuum to give 344 g of a crude mixture of
diastereomers as a dark brown oil. Chromatography on silica gel
with dichloromethane:ethanol (99:1) gave 31.15 g of a brown solid
containing 95% of the less mobile diastereomer (RF=0.42 on silica
gel with dichloromethane:ethanol:ammonium hydroxide/95:5:1).
Crystallization from isopropanol gave 28.6 g (55% of theoretical
for one diastereomer) of
(.+-.)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-bromobenzyl)phenol as a white solid, mp 186-189.degree.
C.
[0345] NMR (DMSO-d.sub.6, 200 MHz) .delta.: 0.95 (d, J=6 Hz, 3H);
1.03 (d, J=6 Hz, 3H); 1.8 (dd, J1=6 Hz, J2=10 Hz, 1H); 2.1 (dd,
J1=6 Hz, J2=10 Hz, 1H); 2.4-2.6 (m, 3H); 2.7 (d, J=11 Hz, 1H); 2.8
(dd, J1=7 Hz, J2=14 Hz, 1H); 3.2 (dd, J1=6 Hz, J2=13 Hz, 1H); 4.9
(s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.7-5.9 (m,
1H); 6.6-6.8 (m, 3H); 7.0-7.4 (m, 4H); 7.55 (s, 1H); 9.35 (s,
1H).
[0346] The bromobenzene from above (3.22 g, 7.75 mmol) was
dissolved in 25 mL of dimethylformamide with cuprous cyanide (1.39
g, 15.5 mmol), and the reaction was heated at reflux for 3 days.
The reaction was cooled to room temperature and poured into 300 mL
aqueous 30% sodium cyanide. The mixture was extracted with 250 mL
of ethyl acetate. The solvent was to removed and the residue was
purified by chromatography on silica gel with ethanol (0-20%) in
dichloromethane to give 1.3 g (46%) of
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)benzonitrile, mp 169-171.degree. C.
Calculations for C.sub.23H.sub.27N.sub.30: C, 76.42; H, 7.53: N,
11.62. Found: C, 76.35; H, 7.54: N, 11.62.
[0347] Hydrogen peroxide (0.5 mL of a 30% by weight solution) was
added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL
of 10N aqueous sodium hydroxide and 3 mL of ethanol. The reaction
was exothermic with gas evolution and formation of a white
precipitate. After a few minutes, the mixture was carefully heated
under a reflux condenser in an oil bath at 60.degree. C. for three
hours. After cooling to room temperature, 6N aqueous hydrochloric
acid was added to adjust the pH to 8. The mixture was evaporated to
dryness under vacuum, and the residue was extracted between ethyl
acetate and pH 8 buffer solution. The organic layer was washed with
pH 8 buffer and brine, dried over sodium sulfate, and the solvent
was evaporated to give 0.42 g (79%) of
(.+-.)-3-(((.alpha.R*)--((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)benzamide as a bright yellow solid.
[0348] NMR (200 MHz, DMSO-d.sub.6) .delta.: 0.95 (d, J=6 Hz, 3H);
1.05 (d, J=6 Hz, 3H); 1.9 (m, 1H); 2.1 (m, 1H); 2.5-2.8 (m, 3H);
2.9 (m, 1H); 3.1 (m, 1H); 3.3 (br m, 1H); 4.9 (s, 1H); 5.1 (d, J=11
Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.8 (m, 1H); 6.6-6.8 (m, 3H); 7.1
(t, J=8 Hz, 1H); 7.2-7.45 (m, 2H); 7.55 (d, J=8 Hz, 1H); 7.65 (d,
J=8 Hz, 1H); 7.9 (m, 2H); 9.3 (br m, 1H).
[0349] The product was dissolved in absolute ethanol and converted
to the monohydrochloride salt by titration to pH 3 with ethanolic
hydrogen chloride. The salt was precipitated with diethyl ether,
and dried under vacuum to give 93 mg of a white powder.
Calculations for C.sub.23H.sub.29N.sub.3O.sub.2 HCl 0.6H.sub.2O: C,
64.73; H, 7.37; N, 9.85; Cl, 8.31. Found: C, 64.81; H, 7.26; N,
9.46; Cl, 8.09. Mass spec (CI-CH.sub.4): m/z 380 (M+1,76%); 379
(M+, 9%); 226 (39%); 153 (100%).
Example 7
N,N-Diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-pipera-
zinyl)benzyl)benzamide
[0350] Thionyl chloride (2.9 mL, 40.2 mmol) was added to a solution
of
4-(3-(tert-butyldimethylsilyloxy)-.alpha.-hydroxybenzyl)-N,N-diethylbenza-
mide (11.0 g, 26.8 mmol, Example 1, infra) in 150 mL of
dichloromethane. After stirring for one hour at room temperature,
the solvent was removed under vacuum. The residue was dissolved in
toluene and the solution evaporated under vacuum again to remove
excess thionyl chloride, repeating once more. The crude product was
dissolved in toluene (50 mL), and (2R,5R)-2,5-dimethylpiperazine,
prepared from D-Ala-D-Ala-diketopiperazine (Bachem Chemicals,
Philadelphia, Pa.) as described in J. Org. Chem. 50: 4909-13,
(1985), was added. The mixture was heated at reflux overnight under
nitrogen. The solvent was removed under vacuum, and the residue was
redissolved in ethyl acetate and washed with 1.0 M sodium hydroxide
and water. The organic layer was dried over sodium sulfate and the
solvent removed to give a dark oil. The crude product was dissolved
in 100 mL of acetonitrile, tetraethyl ammonium fluoride hydrate
(8.07 g, 39.6 mmol) was added, and the mixture was stirred at room
temperature for 30 minutes. The solvent was removed under vacuum.
The residue was dissolved in 100 mL of 1N aqueous hydrochloric acid
and 200 mL of diethyl ether. The aqueous layer was adjusted to pH 8
with 5M sodium hydroxide and extracted with dichloromethane (two
300 mL portions). The dichloromethane phase was dried over sodium
sulfate and evaporated to dryness to give 8.03 g of a brown solid.
Recrystallization from ethanol-hexane gave 1.37 g of
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piper-
azinyl)benzyl)benzamide (26% of theoretical yield for one
diastereomer).
[0351] NMR (200 MHz, CDCl.sub.3) .delta.: 0.95 (d, J=6 Hz, 3H);
1.05 (d, J=6 Hz, 3H); 1.0-1.3 (br m, 6H); 2.1 (t, J=11 Hz, 1H);
2.65 (dd, J1=3 Hz, J2=11 Hz, 1H); 2.75 (d, J=13 Hz, 1H); 3.0-3.4
(br m, 5H); 3.5 (br m, 2H); 4.5 (s, 1H); 6.65 (d, J=8 Hz, 1H); 6.8
(d, J=8 Hz, 1H); 6.9 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.3 (d, J=8 Hz,
2H); 7.5 (d, J=8 Hz, 2H).
[0352] Mass spec (CI-CH.sub.4) m/z 395 (M, 26%); 282 (100%); 113
(21%). Calculations for C.sub.24H.sub.33N.sub.3O.sub.2 0.5H.sub.2O:
C, 71.26; H, 8.47; N, 10.39. Found: C, 71.32; H, 8.46; N,
10.18.
Example 8
4-((.alpha.R)-.alpha.-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydro-
xybenzyl)-N-ethyl-N-methylbenzamide
[0353] Thionyl chloride (26 mL, 0.36 mol) was added dropwise to a
solution of 4-carboxybenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of
dichloromethane:N,N-dimethylformamide (4:1 mixture). The mixture
was stirred overnight at room temperature. Ethylmethylamine (75.0
g, 1.3 mol) was added dropwise, and stirring was continued at room
temperature for 90 minutes. The solvent was removed under vacuum,
the residue was dissolved in 500 mL of 0.1M sodium hydroxide, and
extracted with ethyl acetate. The organic phase was washed with
water, dried over sodium sulfate and evaporated under vacuum to
give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow
oil.
[0354] NMR (300 MHz, CDCl.sub.3) .delta.: 1.1 (m, 3H); 1.2 (m, 3H);
3.2 (m, 2H); 3.5 (m, 2H); 7.5 (d, J=8 Hz, 2H); 7.9 (d, J=8 Hz, 2H);
10.0 (s, 1H).
[0355] N-Ethyl-4-formyl-N-methylbenzamide (23.8 g, 0.12 mol) was
reacted with 3-(bromophenoxy)-tert-butyldimethylsilane and
n-butyllithium as described in Example 5 to give 19.6 g (40%)
4-(3-(tert-butyldimethylsilyloxy)-.alpha.-hydroxybenzyl)-N-ethyl-N-methyl-
benzamide as a colorless oil.
[0356] NMR (200 MHz, CD Cl.sub.3) .delta.: 0.1 (s, 6H); 0.95 (s,
9H); 1.1 (m, 3H); 2.9 and 3.0 (s, 3H); 3.05 (d, J=3 Hz, 1H); 3.3
(m, 1H); 6.95 (d, J=8 Hz, 1H); 7.1 (t, J=8 Hz, 1H); 7.25 (AB
quartet, J=8 Hz, 4H).
[0357] The benzhydryl alcohol (19.5 g, 0.049 mol) was treated with
thionyl chloride and (2S, 5S)-2,5-dimethylpiperazine as described
in Example 7 to give 8.13 g (34%) of a 1:1 mixture of
4-((.alpha.R)-.alpha.-((2S,5S)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzy-
l)-N-ethyl-N-methylbenzamide and
4-((.alpha.S)-.alpha.-((2S,5S)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzy-
l)-N-ethyl-N-methylbenz-amide as an off-white solid. After
chromatography on silica gel (Waters Prep 500) with
dichloromethane:ethanol:triethylamine (100:0.5:0.1), 0.95 g of
4-((.alpha.R)-.alpha.-((2S,5S)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzy-
l)-N-ethyl-N-methylbenzamide, the less mobile diastereomer, was
obtained.
[0358] The product (0.77 g, 1.55 mmol) was treated with allyl
bromide (0.14 mL, 1.6 mmol) as described in Example 5 to give 0.71
g of a light beige solid which was dissolved in 25 mL of
acetonitrile and treated with tetraethylammonium fluoride hydrate
(0.40 g) at room temperature for 30 minutes. The solvent was
evaporated under vacuum and the residue was dissolved in diethyl
ether and 1N aqueous hydrochloric acid. The aqueous layer was
adjusted to pH 8 with 10N sodium hydroxide and extracted with
dichloromethane, dried over sodium sulfate and evaporated under
vacuum to give 0.51 g of
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydr-
oxybenzyl)-N-ethyl-N-methylbenzamide as a white solid.
[0359] NMR (200 MHz, CDCl.sub.3) .delta.: 0.95 (d, J=6 Hz, 6H); 1.2
(br m, 3H); 2.1-2.5 (m, 4H); 2.6 (m, 1H); 2.7-2.95 (m, 2H); 3.25
(br m, 1H); 3.4 (m, 1H); 3.55 (br m, 1H); 4.45 (s, 1H); 5.1-5.2 (m,
2H); 5.8 (m, 1H); 6.6 (d, J=8 Hz, 1H); 6.9 (d, J=8 Hz, 1H); 6.95
(s, 1H); 7.05 (t, J=8 Hz, 1H); 7.25 (d, J=8 Hz, 2H); 7.35 (d, J=8
Hz, 2H).
[0360] Conversion to the monohydrochloride salt as described in
Example 6 gave 0.42 g of a white solid. Calculations for
C.sub.26H.sub.35N.sub.3O.sub.2HCl 0.75H.sub.2O: C, 66.22; H, 8.02:
Cl, 7.52; N, 8.91.
[0361] Found: C, 65.96; H, 8.02; Cl, 7.54; N, 8.92.
[.alpha.].sub.D.sup.20=+9.80 (abs ethanol, c=1.5). Mass spec
(CI-CH.sub.4) m/z: 422 (M+1, 53%); 268 (25%); 153 (100%).
Example 9
3-((.alpha.R)-.alpha.-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)benzyl)p-
henol and 3-((.alpha.S)-.alpha.-((2S,
5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol
[0362] A solution of
(2S,5S)-1-allyl-4-(4-bromo-.alpha.-(3-(tert-butyldimethyl-silyloxy)phenyl-
)-benzyl)-2,5-dimethylpiperazine (0.37 g, 0.7 mmol, Example 5,
infra) in 50 mL dry tetrahydrofuran was cooled to -78.degree. C.
n-Butyllithium (0.44 mL of a 1.6M solution in hexanes) was added
dropwise. After stirring at -78.degree. C. for 10 minutes,
saturated aqueous ammonium chloride (10 mL) was added. The mixture
was warmed to room temperature and diluted with diethyl ether and
water. The ethereal layer was dried over sodium sulfate and
evaporated to give a light yellow oil, which was purified by
preparative thin layer chromatography to give 0.23 g of a yellow
glass. The product was dissolved in acetonitrile and treated with
tetraethylammonium fluoride hydrate for 30 minutes. The solvent was
evaporated under vacuum, and the residue was dissolved in 1N
hydrochloric acid and extracted with diethyl ether. The aqueous
layer was adjusted to pH 8 with aqueous sodium hydroxide, extracted
with dichloromethane, the organic layer dried over sodium sulfate
and the solvent removed to give 0.16 g of a 1:1 isomeric mixture of
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
-phenol and
3-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-benzyl-
)phenol as a yellow oil.
[0363] NMR (200 MHz, CDCl.sub.3) .delta.: 0.9-1.2 (m, 6H); 2.2-2.8
(m, 5H); 2.8-3.2 (m, 2H); 3.4 (m, 1H); 4.5 (s, 0.5H); 4.6 (s,
0.5H); 5.1-5.25 (m, 2H); 5.8 (m, 1H); 6.6 (d, J=8 Hz, 1H); 6.7-7.5
(m, 8H). A portion of the product (40 mg) was dissolved in absolute
ethanol and titrated to pH 4 with ethanolic hydrogen chloride.
Diethyl ether was added to precipitate the monohydrochloride salt
as a white solid. After drying under vacuum at 65.degree. C.
overnight, 25 mg of salt was obtained. Calculations for
C.sub.22H.sub.28N.sub.2O HCl 0.75H.sub.2O: C, 68.12; H, 7.58; N,
7.16. Found: C, 68.38; H, 7.95; N, 7.25.
Example 10
(.+-.)-N,N-Diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trime-
thyl-1-piperazinyl)benzyl)-benzamide
[0364]
4-(3-(tert-Butyldimethylsilyloxy)-.alpha.-hydroxybenzyl)-N,N-diethy-
lbenzamide (Example 1, infra) was treated with thionyl chloride and
trans-2,5-dimethylpiperazine as described in Example 5. The crude
mixture of diastereomers was purified by chromatography on silica
gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine
(100:0.25:0.1). The less mobile isomer (1.28 g, 2.5 mmol) was
dissolved in acetonitrile and treated with tetraethylammonium
fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give 0.46 g
of
(.+-.)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,5-dimeth-
yl-1-piperazinyl)benzyl)benzamide as a white solid, mp
175-177.degree. C.
[0365] NMR (200 MHz, DMSO-d.sub.6) .delta.: 0.85 (d, J=6 Hz, 3H);
1.1-1.2 (m, 9H); 1.45 (m, 1H); 2.2 (m, 2H); 2.5 (m, 1H); 2.6 (m,
1H); 2.8 (m, 2H); 3.2-3.6 (m, 4H); 5.25 (s, 1H); 6.6 (d, J=8 Hz,
1H); 6.75 (d, J=8 Hz, 1H); 6.8 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.25
(d, J=8 Hz, 2H); 7.4 (d, J=8 Hz, 2H); 9.25 (s, 1H).
[0366] A mixture of the product (0.31 g, 0.78 mmol), 96% formic
acid (0.12 mL, 3.1 mmol) and 37% aqueous formaldehyde (0.06 mL, 2.3
mmol) was heated in an oil bath at 80.degree. C. overnight. The
cooled reaction mixture was dissolved in 3 mL of 6N hydrochloric
acid and extracted with diethyl ether. The aqueous layer was
adjusted to pH 8 with 10N sodium hydroxide, and extracted with
dichloromethane. The organic layer was dried over sodium sulfate
and evaporated to give a brown oil. The crude product was purified
by preparative thin layer chromatography with
dichloromethane:ethanol:ammonium hydroxide (95:5:1) to give 0.160 g
of a yellow oil. Crystallization from ethyl acetate gave 0.105 g of
(O)--N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,
5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)benzamide as a white
solid, mp 220-221.degree. C.
[0367] NMR (200 MHz, CDCl.sub.3) .delta.: 0.9 (d, J=6 Hz, 3H); 1.15
(d, J=6 Hz, 3H); 1.2 (br m, 6H); 1.85 (m, 1H); 2.0-2.3 (m, 2H); 2.2
(s, 3H); 2.5-2.8 (m, 3H); 3.3 (br m, 2H); 3.6 (br m, 2H); 5.25 (s,
1H); 6.6 (d, J=8 Hz. 1H); 6.8 (d, J=8 Hz, 1H); 6.85 (s, 1H); 7.05
(t, J=8 Hz, 1H); 7.15 (d, J=8 Hz, 2H); 7.35 (d, J=8 Hz, 2H). Mass
spec (CI-CH.sub.4) m/z 410 (M+1). Calculations for
C.sub.25H.sub.35N.sub.2O.sub.2: C, 73.31; H, 8.61; N, 10.26. Found:
C, 73.11; H, 8.65; N, 10.25.
Example 11
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethylbenzamide
[0368] The procedure described in Example 1 was followed using
(2S,5S)-2,5-dimethylpiperazine to give
4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(ter-
t-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide (1.51 g).
Chromatography on silica gel with dichloromethane:ethanol (1-2%)
gave 0.27 g (27% of theoretical for one diastereomer) of the less
mobile isomer. Treatment with tetraethylammonium fluoride in
acetonitrile as in Example 1 gave 0.18 g (85%) of
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide as a white solid.
[0369] NMR (200 MHz, DMSO-d.sub.6) .delta.: 0.85 (d, J=6 Hz, 3H);
0.95 (d, J=6 Hz, 3H); 1.1 (br m, 6H); 2.1-2.6 (m, 5H); 2.6-2.95 (m,
2H); 3.0-3.5 (br m, 5H); 4.5 (s, 1H); 5.1 (d, J=8 Hz, 1H); 5.2 (d,
J=14 Hz, 1H); 5.85 (m, 1H); 6.8 (d, J=8 Hz, 1H); 6.9 (m, 2H); 7.1
(t, J=8 Hz, 1H); 7.25 (d, J=8 Hz, 2H); 7.5 (d, J=8 Hz, 2H); 9.25
(s, 1H). Mass spec (CI) m/z: 436 (M+1, 74%); 282 (100%); 153 (7%).
[.alpha.].sub.D.sup.20=+21.6.degree. (abs ethanol, c=1.1).
[0370] The monohydrochloride salt was prepared as in Example 1 to
give 0.148 g of a white powder. Calculations for
C.sub.27H.sub.37N.sub.3O.sub.2HCl H.sub.2O: C, 66.17; H, 8.24; N,
8.57; Cl, 7.23. Found: C, 66.36; H, 8.16; N, 8.66; Cl, 7.33.
[0371] The more mobile isomer from the chromatography was also
isolated (0.22 g, 22% of theoretical for one diastereomer) and
treated with tetraethylammonium fluoride to give 0.090 g (53%) of
(+)-4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide as a white solid.
[0372] NMR (200 MHz, DMSO-d.sub.6) .delta.: 0.85 (d, J=6 Hz, 3H);
0.95 (d, J=6 Hz, 3H); 1.1 (br m, 6H); 2.1-2.5 (m, 5H); 2.8 (m, 1H);
3.0 (m, 1H); 3.05-3.5 (br m, 5H); 4.5 (s, 1H); 5.1 (d, J=10 Hz,
1H); 5.2 (d, J=15 Hz, 1H); 5.8 (m, 1H); 6.6 (d, J=8 Hz, 1H); 6.85
(s, 1H); 6.9 (d, J=8 Hz, 1H); 7.1 (t, J=8 Hz, 1H); 7.3 (d, J=8 Hz,
2H); 7.5 (d, J=8 Hz, 2H); 9.25 (s, 1H). Mass spec (CI) m/z: 436
(M+1, 3.7%); 282 (100%); 153 (3%). [.alpha.].sub.D.sup.20=+28.70
(abs ethanol, c=2.3).
[0373] The monohydrochloride salt was prepared as in Example 1 to
give 0.061 g of a white powder. Calculations for
C.sub.27H.sub.37N.sub.3O.sub.2HCl 0.75H.sub.2O: C, 66.78; H, 8.20;
N, 8.65; Cl, 7.30.
[0374] Found: C, 66.55; H, 8.07; N, 8.63; Cl, 7.35.
Example 12
In Vitro Delta Opioid Receptor Activity
[0375] Selected compounds of the present invention, identified
below with reference to the appertaining synthesis Examples hereof,
were evaluated for in vitro delta opioid receptor affinity in rat
brain membranes (Delta Receptor IC.sub.50) and delta opioid agonist
potency in the mouse vas deferens (Mouse Vas Deferens ED.sub.50).
The assay procedures used for such determinations of delta receptor
activity are set out below.
[0376] In vitro bioassays: Vasa deferentia were removed from mice
and suspended between platinum electrodes with 0.5 g of tension in
organ bath chambers containing a modified Krebs' buffer of the
following composition (millimolar): NaCl, 118; KCl, 4.75;
CaCl.sub.2, 2.6; KH.sub.2PO.sub.4, 1.20; NaHCO.sub.3, 24.5; and
glucose, 11. The buffer was saturated with 95% O.sub.2/5% CO.sub.2
and kept at 37.degree. C. Tissues were stimulated at supramaximal
voltage with 10 Hz pulse trains for 400 msec.; train interval 10
seconds; and 0.5 msec pulse duration. The percentage inhibition of
the electrically induced muscle contractions was determined for the
compounds at varying cumulative concentrations. The ED.sub.50
values were extrapolated from curves showing the dose concentration
plotted against the response (Lord, et al., Nature 267, 495,
(1977)).
[0377] Inhibition of receptor binding: Rat (Sprague-Dawley) brain
membranes were prepared and binding assays were performed at
24.degree. C. for 90 minutes as described by Chang, et al. (J.
Biol. Chem. 254, 2610 (1979) and Mol. Pharmacol. 16, 91 (1979))
with a filtration method (GF/C filter). Delta receptor binding
assays were performed with
(.sup.3H)-(+)-4-((.alpha.-R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-p-
iperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.1 nM), having
an activity of .about.48 Ci/mmole, or with .sup.3H-[D-Pen.sup.2,
D-Pen.sup.5-(enkephalin)] (13H-DPDPE, 0.1 nM) having an activity of
.about.50 Ci/mmole. Non-specific binding was determined in the
presence of 1 mM of the unlabeled ligand. The potency of compounds
in inhibiting the binding of
(3H)-(+)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperaz-
inyl)-3-hydroxy-benzyl)-N,N-diethylbenzamide or .sup.3H-DPDPE was
determined as the concentration which reduced the binding of the
labeled compounds by 50 percent (Delta Receptor IC.sub.50).
[0378] The following compounds of the invention were also
tested.
Compound 12:
[0379]
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trime-
thyl-1-piperazinyl)benzyl)phenol
Compound 13:
[0379] [0380]
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-
-1-piperazinyl)benzyl)phenol
Compound 14:
[0380] [0381]
(+)N,N-Diethyl-4-(3-hydroxy-(.alpha.S)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-
-piperazinyl)benzyl)-benzamide
Compound 15:
[0381] [0382]
N,N-diethyl-4-(3-hydroxy-(.alpha.R)-.alpha.-((2R,5R)-2,4,5-trimethyl-1-pi-
perazinyl)benzyl)benzamide (see, for example, International
Publication WO 93/15062, Example 13 for the synthesis of this
compound)
Compound 16:
[0382] [0383]
N-ethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2S,5S)-2,4,5-trimethyl-1-pipera-
zinyl)benzyl)-N-methyl-benzamide
Compound 17:
[0383] [0384]
cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybe-
nzyl)-N,N-diethyl-benzamide (see, for example, International
Publication WO 93/15062, Example 11 for the synthesis of this
compound)
Compound 18:
[0384] [0385]
(.+-.)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazin-
yl)-4-(methylsulfonyl)benzyl)-phenol (see, for example,
International Publication WO 93/15062, Example 55 for the synthesis
of this compound)
Compound 19:
[0385] [0386]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-Allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide (see, for
example, International Publication WO 93/15062, Example 56 for the
synthesis of this compound)
Compound 20:
[0386] [0387]
(.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazin-
yl)benzyl)phenol (see, for example, International Publication WO
93/15062, Example 10 for the synthesis of this compound)
Compound 21:
[0387] [0388]
(.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazin-
yl)-3-hydroxbenzyl)benzamide (see, for example, International
Publication WO 93/15062, Example 4 for the synthesis of this
compound)
Compound 22:
[0388] [0389]
(.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-Dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)-N,N-diethylbenzamide (see, for example, International
Publication WO 93/15062, Example 15 for the synthesis of this
compound)
Compound 23:
[0389] [0390]
(.+-.)-cis-4-(.alpha.-(4-Allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzy-
l)-N,N-diethylbenzamide
Compound 24:
[0390] [0391]
cis-4-(.alpha.-(3,5-Dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenz-
yl)-N,N-diethylbenzamide
[0392] Results are shown in Table A below, with the compounds
described in Examples 1-11 being listed as Compounds 1-11,
respectively.
TABLE-US-00001 TABLE A In Vitro Delta Opioid Receptor Activity of
Compounds of the Invention Delta Receptor Mouse Vas Compound
IC.sub.50 (nM) Deferens ED.sub.50 (nM) 1 2.sup.a 43 2 1.sup.a -- 3
-- -- 4 -- >1,000 5 1.6 260 6 4.0 25 7 1.1 560 8 0.86 30 9 1.5
450 10 1.1 90 11 -- -- 12 1.2 250 13 0.8 200 14 2 pA.sub.2 =
7.1.sup.b 15 2.8 pA.sub.2 = 7.0.sup.b 16 3.1 pA.sub.2 = 7.2.sup.b
17 1.5 pA.sub.2 = 8.2.sup.c 18 1.3 250 19 2.6 37 20 1.3 78 21 1.6
44 22 0.7 4400 23 3.3 42 24 2.8 20 .sup.aCompounds 1 and 2 were
assayed against
(.sup.3H)-(+)-4-((.alpha.-R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-p-
iperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. Compounds 5-24
were assayed against .sup.3H-[D-Pen.sup.2,
D-Pen.sup.5]-(enkephalin). .sup.b, .sup.c Antagonist potency
(pA.sub.2 value) as determined by Schild analysis, according to
Arunlakshana et al., Brit. J. Pharmacol. 14: 48-58 (1979), of data
for blockade of inhibitory effect of [D-Ala.sup.2, D-Leu.sup.5]
enkephalin (.sup.b) or
(.+-.)-4-((.alpha.-R*)-.alpha.-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazi-
nyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (.sup.c) on electrically
stimulated muscle contraction in the mouse vas deferens.
Example 13
Effects of the Compounds of Example 1 and Example 2 on Alfentanil
Induced Analgesia and Respiratory Depression in Rats
[0393] Analgesia was assayed in rats using the tail pinch test with
simultaneous monitoring of capillary blood gases (pCO.sub.2 and
pO.sub.2) using a transcutaneous electrode. Male Sprague Dawley
rats (groups of six animals) were anesthetized with 2% isoflurane
(J. A. Webster, Inc., Sterling, Mass.), and a cannula was implanted
into the right external jugular vein. A small patch of skin was
shaved on the back of the animals and a fixation ring was attached
using VetBond adhesive (3M Corp., Minneapolis, Minn.). The
transcutaneous electrode of a TCM3 TINATM blood gas monitor system
(Radiometer-Copenhagen, Copenhagen, Denmark) was attached to the
fixation ring and the rats were allowed to recover from the
anesthetic for 1 hour. The mu-opioid analgesic alfentanil (Janssen
Pharmaceuticals, Inc., Titusville, N.J.) was administered by
continuous infusion via i.v. cannula at a dose of 6 .mu.g/kg/min
with concurrent administration of delta-opioid test compounds.
Analgesia was assayed before and during dosing using the tail pinch
test. An artery clamp was placed on the tail one inch from the tip
for a maximum of 20 seconds. Rats were observed for nociceptive
responses of vocalization or painful body movements. The elapsed
time to elicit a pain response was recorded as the tail pinch
latency in seconds. Blood gases were monitored continuously
throughout the test session.
[0394] After 15 minutes of infusion, the alfentanil dose of 6
.mu.g/kg/min produced a maximum analgesic effect as indicated by a
tail pinch latency of 20 seconds. Respiratory depression was
measured at an average of 30% increase in pCO.sub.2 level (above
preinfusion baseline). Concurrent infusion of the compound of
Example 1 at a dose of 60 .mu.g/kg/min partially reversed the
respiratory depression to a pCO.sub.2 level of 22% above baseline.
Increasing the dose of the compound of Example 1 to 120
.mu.g/kg/min produced a further improvement in respiratory
depression to 17% above baseline. Tail pinch latency remained
unaffected by treatment with the compound of Example 1.
[0395] When the compound of Example 2 was infused at a dose of 60
.mu.g/kg/min concurrently with alfentanil (6 .mu.g/kg/min) and the
compound of Example 1 (60 .mu.g/kg/min), the effects of the
compound of Example 1 were blocked and respiratory depression
increased to a pCO.sub.2 level of 33% above baseline. Analgesia
remained unaffected, with tail pinch latency continuing to be at
the maximum of 20 seconds. In separate experiments, administration
of the compound of Example 1 alone or the compound of Example 2
alone produced no analgesic effect and no effect on blood pCO.sub.2
levels.
Example 14
[0396] A series of experiments were carried out to determine the
effects of delta agonists on respiratory depression and analgesia
induced by i.v. infusions of alfenta or fentanyl, very potent mu
agonists. Two different methods were used to measure respiratory
depression effects. The first method analyzed rat blood gases for
pCO.sub.2 levels. Rat blood samples were drawn and analyzed for
CO.sub.2 content following a continuous i.v. infusion of alfenta (6
mg/min) and an i.v. bolus injection of various doses of the
selective delta agonist, BW373U86:
##STR00012## [0397]
(+)-4-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide.
[0398] As an indication of respiratory depression, blood CO.sub.2
levels were observed to increase as a result of alfenta
administration. The key finding in the experiment, however, was
that BW373U86 dose dependently reduced the level of pCO.sub.2 seen
following the alfenta infusion. Results are depicted in FIGS. 1A
and 1B.
[0399] FIGS. 1A and 1B show the effect of the positive isomer of
the delta agonist BW373U86 on analgesia and respiratory depression
induced by the mu agonist, alfenta. (+)373U86 blocks the
respiratory depression (as shown by FIG. 1A), but not the analgesia
induced by alfenta (as shown by FIG. 1B). The negative isomer of
373U86 does not have any significant effects on alfenta-induced
respiratory depression (data not shown). All doses of BW373U86 are
plotted in the analgesia graph, however some points cannot be seen
because the symbols are overlapping.
[0400] Analgesia was also assessed with a tail-pinch method at the
same time points that blood was drawn. Most importantly, BW373U86
did not significantly affect the analgesia produced by alfenta
(FIG. 1B). Overall, the data indicate that BW373U86, or other delta
agonists, are useful clinically in intraoperative, postoperative
and chronic pain applications to attenuate the respiratory
depression and maintain the analgesic effects of mu opioid receptor
analgesics.
[0401] A second method was used to quantify respiratory depression
effects in subsequent studies. These studies utilized a
transcutaneous pO.sub.2/pCO.sub.2 non-invasive monitoring system
(Radiometer Copenhagen). The system monitors O.sub.2 and CO.sub.2
levels through an electrode that is adhered to the outside skin
surface. These systems are typically used on infants in hospital
critical care centers and were adapted for use with rats for the
present studies. Rats were implanted with a catheter in the right
external jugular vein under 2% isoflurane anesthesia. Subjects were
allowed to recover for 1 hr and then were placed in plastic
restraining cages. Testing began after baseline measures of
pCO.sub.2 and pO.sub.2 were obtained over a 15 min period.
[0402] Both fentanyl (a strong mu-receptor analgesic agent) and
3290W93 (a compound with mixed delta and mu receptor activity),
whose chemical structure is shown below:
##STR00013##
were found to produce high levels of analgesia. Results are
depicted in FIGS. 2A and 2B.
[0403] FIGS. 2A and 2B show comparative analgesic and respiratory
depression effects of 3290W93 and fentanyl in rats. Effects are
plotted at 4 (FIG. 2A) and 8 (FIG. 2B) minute time points at which
peak effects were observed following drug administration. A greater
separation between analgesic and respiratory depressant effects
occurred following 3290W93 administration than was observed
following fentanyl administration.
[0404] However, whereas fentanyl produced high levels of
respiratory depression, 3290W93 did not substantially increase
respiratory depression except at high doses. The ED.sub.50 values
in rats for fentanyl and 3290W93 to produce analgesia were 0.0031
and 0.08 mg/kg (i.v.), respectively. The ED.sub.50 values for
fentanyl and 3290W93 to produce respiratory depression are 0.014
and 2.0 mg/kg (i.v.), respectively. The therapeutic ratio
(respiratory depression ED50 divided by analgesia ED50) for
fentanyl and 3290W93 are 4.5 and 25, respectively. These data
indicate that the mixed delta/mu agonist 3290W93 has a five times
greater separation between analgesic and respiratory depressant
effects than does fentanyl.
[0405] As shown in FIGS. 1 and 2, a delta receptor agonist can
selectively block effects produced by the mu opioid receptor
agonists alfenta and fentanyl. Typically, mu agonists produce a
substantial beneficial effect of analgesia and many adverse side
effects, such as respiratory depression, nausea, addiction and
dependence. The ability to use delta receptor compounds to block
the unwanted side effects of mu agonists permits physicians to
increase the administration of analgesics because of reduced
concerns about respiratory depression. Patients experience less
pain after an operation and require less postoperative care by
hospital staff. The overall lifestyle of patients taking mu opioids
may be significantly improved with the concurrent use of delta
receptor compounds.
[0406] In addition to the delta agonist compounds described
specifically above, the compounds disclosed in International Patent
Publications WO96/36620 and WO97/10230 may advantageously be
employed in the broad practice of the present invention, to
antagonistically modulate the respiratory depression effects
incident to the use of morphine, fentanyl and other analgesics,
aesthetics and barbiturates, as well as any other opioid receptor
therapeutic agents which mediate respiratory depression as an
effect of their physiological activity.
[0407] While the invention has been illustratively described herein
with respect to various illustrative aspects, features and
embodiments, it will be appreciated that numerous variations,
modifications and other embodiments are possible in the practice of
the present invention, and the invention therefore is to be broadly
construed as encompassing all such variations, modifications and
other embodiments, within its spirit and scope.
* * * * *