U.S. patent application number 15/078027 was filed with the patent office on 2016-07-14 for delta opioid receptor agonist compounds.
The applicant listed for this patent is VERSI GROUP, LLC. Invention is credited to KESTUTIS P. BICIUNAS, KWEN-JEN CHANG, SHYI-TAI JAN, KLIM KING, ROBERT W. MCNUTT, WILLIAM PENDERGAST.
Application Number | 20160200689 15/078027 |
Document ID | / |
Family ID | 23354077 |
Filed Date | 2016-07-14 |
United States Patent
Application |
20160200689 |
Kind Code |
A1 |
CHANG; KWEN-JEN ; et
al. |
July 14, 2016 |
DELTA OPIOID RECEPTOR AGONIST COMPOUNDS
Abstract
Compositions and methods for treatment of sexual dysfunctions by
administering to a subject a pharmaceutical composition comprising
a delta opioid receptor agonist in an amount effective to delay the
onset of ejaculation in the subject during sexual stimulation.
Inventors: |
CHANG; KWEN-JEN; (CHAPEL
HILL, NC) ; KING; KLIM; (CHAPEL HILL, NC) ;
BICIUNAS; KESTUTIS P.; (DURHAM, NC) ; MCNUTT; ROBERT
W.; (DURHAM, NC) ; PENDERGAST; WILLIAM;
(DURHAM, NC) ; JAN; SHYI-TAI; (CARY, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VERSI GROUP, LLC |
Gladstone |
NJ |
US |
|
|
Family ID: |
23354077 |
Appl. No.: |
15/078027 |
Filed: |
March 23, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14503758 |
Oct 1, 2014 |
9296707 |
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15078027 |
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14042893 |
Oct 1, 2013 |
8865721 |
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14503758 |
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13439948 |
Apr 5, 2012 |
8551998 |
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14042893 |
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10335764 |
Jan 2, 2003 |
8575169 |
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13439948 |
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10282411 |
Oct 29, 2002 |
7030124 |
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10335764 |
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60345216 |
Jan 2, 2002 |
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60337887 |
Nov 2, 2001 |
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60340084 |
Oct 29, 2001 |
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Current U.S.
Class: |
514/255.04 ;
544/396 |
Current CPC
Class: |
A61K 31/445 20130101;
A61K 31/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/495 20130101; A61P 15/10 20180101; A61K 38/33 20130101;
A61K 31/445 20130101; A61K 31/495 20130101; A61K 38/33 20130101;
A61K 31/519 20130101; A61K 31/519 20130101; A61P 15/00 20180101;
A61K 2300/00 20130101; C07D 241/04 20130101; A61K 2300/00
20130101 |
International
Class: |
C07D 241/04 20060101
C07D241/04 |
Claims
1. A delta opioid receptor agonist compound having the following
structure: ##STR00044##
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-hydroxybenzyl)-N,N-diethylbenzamide
2. The delta opioid receptor agonist compound of claim 1 wherein
the compound is combined with a pharmaceutically acceptable
solution.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of and claims priority
from copending U.S. patent application Ser. No. 14/503,758, filed
on Oct. 1, 2014, now U.S. Pat. No. 9,296,707, which in turn claims
priority to U.S. patent application Ser. No. 14/042,893, filed on
Oct. 1, 2013, now U.S. Pat. No. 8,865,721, which in turn claims
priority to U.S. patent application Ser. No. 13/439,948, now U.S.
Pat. No. 8,551,998, which in turn claims priority to U.S. patent
application Ser. No. 10/335,764, now U.S. Pat. No. 8,575,169, which
in turns claimed priority from U.S. Provisional Patent Application
No. 60/345,216 filed on Jan. 2, 2002 and is a Continuation-in-Part
application of co-pending U.S. patent application Ser. No.
10/282,411 filed on Oct. 29, 2002, now U.S. Pat. No. 7,030,124,
which in turn claimed priority to U.S. Provisional Patent
Application No. 60/337,887 filed on Nov. 2, 2001 and U.S.
Provisional Patent Application No. 60/340,084, filed on Oct. 29,
2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to compositions and methods of
treatment for sexual dysfunctions, and more particularly, to the
treatment of premature ejaculation in male subjects by
administration of delta receptor agonist compound(s), optionally in
combination with other agents.
[0004] 2. Description of the Related Art
[0005] Premature ejaculation is one of the most common male sexual
dysfunctions, estimated to affect up to 40% of men, irrespective of
age. Premature ejaculation is defined as a persistent or recurrent
ejaculation with minimal sexual stimulation before, on or shortly
after penetration. Although premature ejaculation is common, there
is some disagreement on its precise cause and treatment.
[0006] The reasons for premature ejaculation are generally thought
to include a malfunction of the repressor center due to the fatigue
of nervous transmission, hypersensitivity of a specific site due to
genital disorders, hormonal disorders, physical problems and the
like. It is believed that the premature ejaculation is generally
caused by a complex interaction of the above-mentioned reasons or
by a loss of cooperation among the related sexual nerve
centers.
[0007] Premature ejaculation has been treated with psychotherapy
and drug therapy. Psychotherapy requires sexual training for a long
period of time, which involves discussions and cooperation with a
physician and the patient and his partner. However, since
psychotherapy necessitates a long period of time for the doctor,
patient and partner to work together in order to be effective, its
success rate is low. That is, changes in living style, external
stress, etc., undermine its success such that the problem is never
solved or it reoccurs. Therefore, drug therapy is now more widely
used since time restrictions are not as great.
[0008] Methods for treating premature ejaculation by systemic
administration of several different antidepressant compounds have
been described in U.S. Pat. Nos. 5,151,448 and 5,276,042. However,
these drugs may not be effective for all patients, and the side
effects of these drugs can halt treatment or impair patient
compliance. Disease states or adverse interactions with other drugs
may contraindicate the use of these compounds or require lower
dosages that may not be effective to delay the onset of
ejaculation. Additionally, the stigma of mental illness associated
with antidepressant therapy can discourage patients from beginning
or continuing such treatments.
[0009] Administration of the antidepressant fluoxetine has been
claimed to treat premature ejaculation (U.S. Pat. No. 5,151,448).
However, the administration of fluoxetine has many undesired
aspects. Patients with hepatic or renal impairments may not be able
to use fluoxetine due to its metabolism in the liver and excretion
via the kidney. Systemic events during fluoxetine treatment
involving the lungs, kidneys or liver have occurred, and death has
occurred from overdoses. In addition, side effects of oral
fluoxetine administration include hair loss, nausea, vomiting,
dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia,
drowsiness, fatigue, headache, tremors, dizziness, convulsions,
sweating and skin rashes. Fluoxetine interacts with a range of
drugs, often by impairing their metabolism by the liver.
[0010] U.S. Pat. No. 5,276,042 describes the administration of
paroxetine for the treatment of premature ejaculation. Paroxetine
is predominantly excreted in the urine, and decreased doses are
recommended in patients with hepatic and renal impairments.
Paroxetine cannot be given to patients undergoing treatment with a
monoamine oxidase inhibitor. Side effects from oral administration
of paroxetine include hyponatremia, asthenia, sweating, nausea,
decreased appetite, oropharynx disorder, somnolence, dizziness,
insomnia, tremors, anxiety, impaired micturition, weakness and
paresthesia.
[0011] Other therapies include the application of local anesthetics
for blunting the sensitivity of the sexual peripheral nerve.
However, local anesthetics, such as lidocaine ointment or spray,
may induce vasoconstriction, which may lead to transient erectile
failure, and can be transferred to sexual partners thereby
decreasing their sensitivity and pleasure as well.
[0012] Thus, present day drug therapy cannot successfully solve the
problems associated with premature ejaculation. Accordingly there
is a need for a method of treating premature ejaculation that
requires no specialized psychological therapy, can be used
conveniently and without embarrassment, and does not involve the
problems associated with prior therapeutic methods.
SUMMARY OF THE INVENTION
[0013] The present invention relates in one aspect to a method of
treating premature ejaculation by administering to a subject a
pharmaceutical composition comprising a delta opioid receptor
agonist in an amount effective to delay the onset of ejaculation
during sexual stimulation. The delta opioid receptor agonist is
either peptidic or non-peptidic. The pharmaceutical formulation may
further comprise an additional active agent, e.g., Viagra.RTM.
(sildenafil citrate), Prozac.RTM. (fluoxetine), vasoactive agents
and combination of two or more thereof
[0014] One aspect of the present invention provides a method for
delaying the onset of ejaculation in a subject during sexual
stimulation comprising administering to the subject an effective
amount of at least one compound of the formulae:
##STR00001##
[0015] wherein: [0016] Ar.sup.1 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 may include
thiophenyl, thiazolyl, furanyl, pyrrolyl, phenyl, or pyridyl, and
having on a first carbon atom thereof a substituent Y and on a
second ring carbon thereof a substituent R.sup.1,
[0017] Y is selected from the group consisting of: [0018] hydrogen;
[0019] halogen; [0020] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl; [0021] C.sub.1-C.sub.6 haloalkyl;
[0022] C.sub.1-C.sub.6 alkoxy; [0023] C.sub.3-C.sub.6 cycloalkoxy;
[0024] 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; [0025] sulfoxides of the formula
SOR.sup.8 where R.sup.8 is the same as above; [0026] sulfones of
the formula SO.sub.2R.sup.8 where R.sup.8 is the same as above;
[0027] nitrile; [0028] C.sub.1-C.sub.6 acyl; [0029]
alkoxycarbonylamino (carbamoyl) of the formula NHCO.sub.2R.sup.8
where R.sup.8 is the same as above; [0030] carboxylic acid, or an
ester, amide, or salt thereof; [0031] 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; [0032] 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
[0033] sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above; [0034] Z is selected
from the group consisting of: [0035] hydrogen, hydroxy and carboxy
and esters thereof; [0036] alkoxy-carboxylic acid, --OCH.sub.3COOH,
--ORCOOH; [0037] alkoxy, carboxyalkoxy, hydroxymethyl, and esters
thereof; and amino, carboxamides and sulfonamides thereof; [0038] G
is carbon or nitrogen; [0039] R.sup.1 is hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl; [0040] R.sup.2 is is hydrogen, halogen, or C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl; [0041]
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; [0042] R.sup.6 is selected
from the group consisting of: [0043] hydrogen; [0044]
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl; [0045] C.sub.3-C.sub.6 cycloalkyl; [0046] arylalkyl having
C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl moieties; [0047]
alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 alkyl
moieties; [0048] C.sub.2-C.sub.4 cyanoalkyl; [0049] C.sub.2-C.sub.4
hydroxyalkyl; [0050] aminocarbonylalkyl having a C.sub.1-C.sub.4
alkyl moiety; and [0051] 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 or hydroxy, [0052] or R.sup.6 is
[0052] ##STR00002## [0053] and Ar.sup.2 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 carbon atom thereof a substituent X, [0054] wherein X
is selected from the group consisting of a halogen (fluorine,
bromine, chlorine, iodine), hydrogen, hydroxy and esters thereof,
carboxy and esters thereof; [0055] C1-C4 carbosy alkyl and esters
thereof; alkyl carboxylic acid, carboxylic acid, alkoxy,
hydroxymethyl, and esters thereof; and [0056] amino, and
carboxamides and sulfonamides thereof; and [0057] R.sup.7 is is
hydrogen or fluorine;
##STR00003##
[0057] wherein [0058] 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. [0059] 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; [0060]
R.sub.5 is hydrogen, hydroxy, C.sub.1-3 alkoxy, thiol or alkylthio;
[0061] 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; [0062]
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, [0063] or R.sub.6 is a para or meta
[0063] ##STR00004## group [0064] 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, [0065] R.sub.7
is hydrogen, straight or branched C.sub.1-8 alkyl or halogen;
[0065] ##STR00005## [0066] wherein, [0067] R.sub.1 and R.sub.2, 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. [0068]
R.sub.3 and R.sub.4, can be the same or different, are each
hydrogen, linear or branched C.sub.1-6 alkyl; [0069] R.sub.5 is
hydroxy, C.sub.1-6 alkoxy, thiol or alkylthio; [0070] R.sub.6 is a
--C(Z)--R.sub.8 group, wherein 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, [0071] or R.sub.6 is
[0071] ##STR00006## group [0072] wherein 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;
##STR00007##
[0072] wherein [0073] A is N or C--X wherein [0074] X is H or
C.sub.1-4 alkyl; [0075] G is C--Y wherein [0076] Y is H or
C.sub.1-4 alkyl; B is an optional C.sub.1-6 hydrocarbyl group,
optionally substituted; L is an optional C.sub.1-6 hydrocarbyl
group, optionally substituted; and wherein A, B, and L in
combination with the N constitute a first ring structure which has
from 5-7 atoms in the ring; further wherein: either D is H or a
C.sub.1-10 hydrocarbyl group, or D is a C.sub.1-10 hydrocarbyl
group linked to B or L to form a second ring structure which
includes the N of the first ring structure, which second ring
structure is fused to the first ring structure and which second
ring structure has from 5-7 atoms in the ring; E is a phenyl group
substituted by at least one or more of hydroxy, C.sub.1-4 alkoxy,
or NH.sub.2SO.sub.2--C.sub.1-4 alkylene; F represents a combination
of a phenyl group and a heterocyclic group, wherein [0077] the
phenyl group is positioned intermediate (in between) G and the
heterocyclic group; [0078] the phenyl group is fused to the
heterocyclic group or is linked directly to the heterocyclic group
or is attached via a spacer group to the heterocyclic group,
wherein the spacer group is any one of C.sub.1-4 alkylene, carbonyl
or SO.sub.2; and the heterocyclic group is substituted by at least
one or more of: a --COOH group, a bio-isostere of a --COOH group, a
biolabile ester derivative of a --COOH group, a C.sub.1-10
hydrocarbyl group comprising one or more --COOH groups, a
C.sub.1-10 hydrocarbyl group comprising one or more bio-isosteres
of a --COOH group, or a C.sub.1-10 hydrocarbyl group comprising one
or more biolabile ester derivatives of a --COOH group; and
pharmaceutically acceptable esters and salts of compounds
(I)-(IV).
[0079] The pharmaceutical composition of the present invention may
comprises an amount effective to treat sexual dysfunction with at
least one a delta opioid receptor agonist described in the
following references, the contents of which are incorporated by
reference herein in their entireity for all purposes: [0080] Chang
et al. U.S. Pat. No. 5,658,908 issued Aug. 19, 1997; [0081] Chang
et al. U.S. Pat. No. 5,681,830 issued Oct. 28, 1997; [0082] Chang
et al. U.S. Pat. No. 5,552,404 issued Sep. 3, 1996; [0083] Chang et
al. U.S. Pat. No. 5,574,159 issued Nov. 12, 1996; [0084] Chang et
al. U.S. Pat. No. 5,854,249 issued Dec. 29, 1998; [0085] Chang et
al. U.S. Pat. No. 5,807,858 issued Sep. 15, 1998; [0086] Chang et
al. U.S. Pat. No. 5,985,880 issued Nov. 16, 1999; [0087] Chang et
al. U.S. Pat. No. 6,300,332 issued Oct. 9, 2001; [0088] WO 0146263;
[0089] U.S. Pat. No. 6,130,222; [0090] U.S. Pat. No. 6,187,792;
[0091] WO 0174804; [0092] WO 9852929; [0093] WO 0174805; and [0094]
WO 0174806.
[0095] In another aspect of the invention, a pharmaceutical
composition is provided for carrying out the methods of the
invention. The pharmaceutical composition comprises an effective
amount of a delta opioid receptor agonist as provided herein, a
pharmacologically acceptable carrier, and optionally another active
agent. Other types of components may be incorporated into the
composition as well, e.g., excipients, surfactants, preservatives,
stabilizers, chelating agents and the like, as will be appreciated
by those skilled in the art of pharmaceutical composition
preparation and drug delivery.
[0096] Administration of the pharmaceutical composition is carried
out within the context of a predetermined dosing regime such that
the delta opioid receptor agonist is effective in the treatment of
premature ejaculation.
[0097] Delivery of the pharmaceutical compositions may be
accomplished through any route effective to provide relief from
premature ejaculation, including, oral, rectal, topical,
sub-lingual, mucosal, nasal, ophthalmic, subcutaneous,
intramuscular, intravenous, transdermal, spinal, intrathecal,
intra-articular, intra-arterial, sub-arachnoid, bronchial,
lymphatic, transurethral, intracavernosal injection and urethral
suppository administration.
[0098] Yet another aspect of the present invention relates to
damping male sexual response or diminishing sexual libido in a
subject by administering to the subject in need thereof, an
effective amount of a delta opioid receptor agonist.
[0099] 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
[0100] FIG. 1 is a longitudinal cross-sectional view of an electric
bipolar rectal probe used for inducing ejaculation, according to
one embodiment of the present invention.
[0101] FIG. 2 illustrates the dependence of ejaculation on the
oscillating frequency of the stimulating electricity.
[0102] FIG. 3 illustrates the suppression effects of delta
selective agonist SNC-80 in delaying electrically stimulated
ejaculation.
[0103] FIG. 4 illustrates that the suppression effects of SNC-80
were abolished by introduction of NTI, a delta opioid receptor
antagonist.
DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS
THEREOF
[0104] Delta opioid receptors are present in the central and
peripheral nervous systems of many species, including man. The
delta opioid receptor has been identified as having a role in many
bodily functions, such as circulatory and pain systems,
immunomodulatory activities, and gastrointestinal disorders.
[0105] Agonists are agents that recognize and bind to the delta
receptors thereby affecting biochemical and/or physiological
pathways. One of the major neuronal effects of opioid receptor
activation is blocking the release and liberation of
neurotransmitters. The neurotransmitter adrenaline is liberated by
postganglic sympathetic nerve, which initiates the contraction of
smooth muscle surrounding the seminal vesicle and prostate gland
that leads to semen emission. Likewise, the parasympathetic nerve
liberates a neurotransmitter that initiates contraction of the
bulbocarvernous muscle surrounding the penis, which leads to
forcible ejection of semen from the urethra. While not wishing to
be bound by any specific mechanism of action, it is believed that
the activation of the delta opioid receptor leads to inhibiting the
release of adrenaline or acetylcholine from sympathetic and
parasympathetic nerve endings, and consequently prevents smooth
muscle from contraction with a concomitant delay of ejaculation. It
is noteworthy to point out that heretofore no reference appears in
the literature about any possible use of delta opioid receptor
agonists, either peptidic or non-peptidic, in treatment of
premature ejaculation.
DEFINITIONS
[0106] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular drug
delivery systems. It is also to be understood that the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting.
[0107] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0108] The terms "active agent," as used herein means a chemical
material or compound which, when administered to an organism (human
or animal) induces a desired pharmacologic effect. Included are
derivatives and analogs of those compounds or classes of compounds
specifically mentioned which also induce the desired pharmacologic
effect.
[0109] The terms "transurethral," "intraurethral" and "urethral" to
specify the mode of administration as used herein are used
interchangeably to refer to delivery of the drug into the urethra
such that the drug contacts and passes through the wall of the
urethra.
[0110] The term "intracavernosal" as used herein means another mode
of drug administration and involves injection into one or both
corpora of the corpora cavernosal tissues of the penis.
[0111] By the term "transdermal" delivery, applicants intend to
include both transdermal (or "percutaneous") and transmucosal
administration, i.e., delivery by passage of a drug through the
skin or mucosal tissue and into the bloodstream.
[0112] The term "topical administration" is used in its
conventional sense to mean delivery of a topical drug or
pharmacologically active agent to the skin or mucosa.
[0113] "Carriers" or "vehicles" as used herein means carrier
materials suitable for drug administration. Carriers and vehicles
useful herein include any such materials known in the art, e.g.,
any liquid, gel, solvent, liquid diluent, solubilizer, or the like,
which is nontoxic and which does not interact with other components
of the composition in a deleterious manner.
[0114] By an "effective" amount of a drug or pharmacologically
active agent is meant a nontoxic but sufficient amount of the drug
or agent to provide the desired effect.
[0115] Active Agents for Treating Premature Ejaculation
[0116] In order to carry out the method of the invention, at lease
one delta opioid receptor agonist is administered to male subject
with a history of premature ejaculation. In a first embodiment,
suitable delta opioid receptor agonists that can be administered to
treat premature ejaculation include, but are not limited to; [0117]
deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH.sub.2); [0118]
deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-HH.sub.2); [0119]
Biphalin; [0120] DADLE [D-Ala.sup.2, D-Leu.sup.5] enkephalin;
[0121] [D-Ser.sup.e, Leu.sup.5]enkephalil-Thr; [0122]
[D-Pen.sup.2,D-Pen.sup.5]-enkephalin; [0123] compounds of the
formulae:
##STR00008##
[0123] wherein: [0124] Ar.sup.1 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 may include
thiophenyl, thiazolyl, furanyl, pyrrolyl, phenyl, or pyridyl, and
having on a first carbon atom thereof a substituent Y and on a
second ring carbon thereof a substituent R.sup.1, [0125] Y is
selected from the group consisting of: [0126] hydrogen; [0127]
halogen; [0128] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; [0129] C.sub.1-C.sub.6 haloalkyl; [0130]
C.sub.1-C.sub.6 alkoxy; [0131] C.sub.3-C.sub.6 cycloalkoxy; [0132]
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; [0133] sulfoxides of the formula SOR.sup.8
where R.sup.8 is the same as above; [0134] sulfones of the formula
SO.sub.2R.sup.8 where R.sup.8 is the same as above; [0135] nitrile;
[0136] C.sub.1-C.sub.6 acyl; [0137] alkoxycarbonylamino (carbamoyl)
of the formula NHCO.sub.2R.sup.8 where R.sup.8 is the same as
above; [0138] carboxylic acid, or an ester, amide, or salt thereof;
[0139] 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; [0140] 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 [0141]
sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above; [0142] Z is selected from the
group consisting of: [0143] hydrogen, hydroxy and carboxy and
esters thereof; [0144] alkoxy, carboxyalkoxy, alkoxy-carboxylic
acid, hydroxymethyl, and esters thereof; and [0145] amino,
carboxamides and sulfonamides thereof; [0146] G is carbon or
nitrogen; [0147] R.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl; [0148]
R.sup.2 is hydrogen, halogen, or C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl; [0149] 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; [0150] R.sup.6 is selected
from the group consisting of: [0151] hydrogen; [0152]
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl; [0153] C.sub.3-C.sub.6 cycloalkyl; [0154] arylalkyl having
C.sub.5-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl moieties; [0155]
alkoxyalkyl having C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 alkyl
moieties; [0156] C.sub.2-C.sub.4 cyanoalkyl; [0157] C.sub.2-C.sub.4
hydroxyalkyl; [0158] aminocarbonylalkyl having a C.sub.1-C.sub.4
alkyl moiety; and [0159] 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 or hydroxy, [0160] or R.sup.6 is
[0160] ##STR00009## [0161] and Ar.sup.2 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 carbon atom thereof a substituent X, [0162] wherein X
is selected from the group consisting of a halogen (fluorine,
bromine, chlorine, iodine), hydrogen, hydroxy, and esters thereof;
carboxy and esters thereof; C.sub.1-C.sub.4 carboxyalkyl and esters
thereof; alkoxy, alkyl carboxylic acid, carboxylic acid,
hydroxymethyl, and esters thereof; and amino, and carboxamides and
sulfonamides thereof; and [0163] R.sup.7 is hydrogen or
fluorine;
##STR00010##
[0163] wherein [0164] 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. [0165] 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; [0166]
R.sub.5 is hydrogen, hydroxy, C.sub.1-3 alkoxy, thiol or alkylthio;
[0167] 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; [0168]
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, [0169] or R.sub.6 is a para or meta
[0169] ##STR00011## group [0170] 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, [0171] R.sub.7
is hydrogen, straight or branched C.sub.1-8 alkyl or halogen;
##STR00012##
[0171] wherein, [0172] R.sub.1 and R.sub.2, 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. [0173] R.sub.3 and
R.sub.4, can be the same or different, are each hydrogen, linear or
branched C.sub.1-6 alkyl; [0174] R.sub.5 is hydroxy, C.sub.1-6
alkoxy, thiol or alkylthio; [0175] R.sub.6 is a --C(Z)--R.sub.8
group, wherein 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, [0176] or
R.sub.6 is a meta or para
[0176] ##STR00013## group [0177] wherein 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; and
##STR00014##
[0177] wherein [0178] A is N or C--X wherein [0179] X is H or
C.sub.1-4 alkyl; [0180] G is C--Y wherein [0181] Y is H or
C.sub.1-4 alkyl; B is an optional C.sub.1-6 hydrocarbyl group,
optionally substituted; L is an optional C.sub.1-6 hydrocarbyl
group, optionally substituted; and wherein A, B, and L in
combination with the N constitute a first ring structure which has
from 5-7 atoms in the ring; further wherein: either D is H or a
C.sub.1-10 hydrocarbyl group, or D is a C.sub.1-10 hydrocarbyl
group linked to B or L to form a second ring structure which
includes the N of the first ring structure, which second ring
structure is fused to the first ring structure and which second
ring structure has from 5-7 atoms in the ring; E is a phenyl group
substituted by at least one or more of hydroxy, C.sub.1-4 alkoxy,
or NH.sub.2SO.sub.2--C.sub.1-4 alkylene; F represents a combination
of a phenyl group and a heterocyclic group, wherein [0182] the
phenyl group is positioned intermediate (in between) G and the
heterocyclic group; [0183] the phenyl group is fused to the
heterocyclic group or is linked directly to the heterocyclic group
or is attached via a spacer group to the heterocyclic group,
wherein the spacer group is any one of C.sub.1-4 alkylene, carbonyl
or SO.sub.2; and the heterocyclic group is substituted by at least
one or more of: a --COOH group, a bio-isostere of a --COOH group, a
biolabile ester derivative of a --COOH group, a C.sub.1-10
hydrocarbyl group comprising one or more --COOH groups, a
C.sub.1-10 hydrocarbyl group comprising one or more bio-isosteres
of a --COOH group, or a C.sub.1-10 hydrocarbyl group comprising one
or more biolabile ester derivatives of a --COOH group; and
pharmaceutically acceptable esters and salts of the compounds
(I)-(IV).
[0184] 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
diarylmethylpiperazine delta opioid receptor agonist 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 diarylmethylpiperazine delta
opioid receptor agonist for its intended utility; and (iv) alkyl
groups including linking or bridge moieties, e.g., heteroatoms such
as nitrogen, oxygen, sulfur, etc.
[0185] 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
diarylmethylpiperazine delta opioid receptor agonist for its
intended utility. Examples of substituents for substituted aryl
groups include hydrogen, 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.
[0186] The active agent may be administered in the form of a
pharmaceutically acceptable salt, ester, amide or prodrug or
combination thereof. Salts, esters, amides and prodrugs of the
active agents may be prepared using standard procedures known to
those skilled in the art of synthetic organic chemistry and
described, for example, by J. March, Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, 4th Ed. (New York:
Wiley-Interscience, 1992). For example, acid addition salts are
prepared from the free base (typically wherein the neutral form of
the drug has a neutral --NH.sub.2 group) using conventional means,
involving reaction with a suitable acid. Generally, the base form
of the active agent is dissolved in a polar organic solvent such as
methanol or ethanol and the acid is added thereto. The resulting
salt either precipitates or may be brought out of solution by
addition of a less polar solvent. Suitable acids for preparing acid
addition salts include both organic acids, e.g., acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic
acid, malonic acid, succinic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids,
e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like. An acid addition salt may be
reconverted to the free base by treatment with a suitable base.
Conversely, preparation of basic salts of acid moieties which may
be present on an active agent are prepared in a similar manner
using a pharmaceutically acceptable base such as sodium hydroxide,
potassium hydroxide, ammonium hydroxide, calcium hydroxide,
trimethylamine, or the like.
[0187] Examples of pharmaceutically acceptable salts 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 NR'.sub.4.sup.+ (wherein R' 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 hydroxyl group consist of
the anion of said compound in combination with a suitable cation
such as Na.sup.+, NH.sub.4.sup.+, or NR'.sub.4.sup.+ (wherein R' is
for example a C.sub.1-4 alkyl group).
[0188] Preparation of esters involves functionalization of hydroxyl
and/or carboxyl groups that may be present within the molecular
structure of the drug. The esters of hydroxyl groups are typically
acyl-substituted derivatives of free alcohol groups, i.e., moieties
which are derived from carboxylic acids of the formula RCOOH where
R is alkyl, and preferably is lower alkyl. Esters can be
reconverted to the free acids, if desired, by using conventional
hydrolysis procedures. Examples of pharmaceutically acceptable
esters include carboxylic acid esters of the hydroxyl group in the
compounds of the present invention 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). The esters of carboxyl groups within the
molecular structure of the drug are typically prepared from
C.sub.1-C.sub.4 alcohols (e.g., ethanol, propanol) or arylalkyl
alcohols (e.g., benzyl alcohols). Preparation of amides and
prodrugs can be carried out in an analogous manner.
[0189] Other derivatives and analogs of the active agents may be
prepared using standard techniques known to those skilled in the
art of synthetic organic chemistry, or may be deduced by reference
to the pertinent literature. In addition, chiral active agents may
be in isomerically pure form, or they may be administered as a
racemic mixture of isomers.
[0190] Pharmaceutical Formulations and Modes of Administration:
[0191] Depending on the intended mode of administration, the
pharmaceutical compositions may be in the form of solid, semi-solid
or liquid dosage forms, such as, for example, tablets,
suppositories, pills, capsules, powders, liquids, suspensions,
creams, ointments, lotions or the like, preferably in unit dosage
form suitable for single administration of a precise dosage. The
compositions include an effective amount of the delta opioid
receptor agonist in combination with a pharmaceutically acceptable
carrier, if desired, and, in addition, may include other
pharmaceutical agents, adjuvants, diluents, buffers, etc. The
amount of active agent administered will, of course, be dependent
on the subject being treated, the subject's weight, the manner of
administration and the judgment of the prescribing physician.
[0192] For solid compositions, conventional nontoxic solid carriers
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talc, cellulose,
glucose, sucrose, magnesium carbonate, and the like. Liquid
pharmaceutically administrable compositions can, for example, be
prepared by dissolving, dispersing, etc., an active compound as
described herein and optionalpharmaceutical adjuvants in an
excipient, such as, for example, water, saline, aqueous dextrose,
glycerol, ethanol, and the like, to thereby form a solution or
suspension. If desired, the pharmaceutical composition to be
administered may also contain minor amounts of nontoxic auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents and the like, for example, sodium acetate, sorbitan
monolaurate, triethanolamine sodium acetate, triethanolamine
oleate, etc. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington: the Science and Practice of Pharmacy,
19.sup.th Ed. (Easton, Pa.: Mack Publishing Co., 1995).
[0193] For oral administration, the composition will generally take
the form of a tablet or capsule, or may be an aqueous or nonaqueous
solution, suspension or syrup. Tablets and capsules are preferred
oral administration forms. Tablets and capsules for oral use will
generally include one or more commonly used carriers such as
lactose and cornstarch. Lubricating agents, such as magnesium
stearate, are also typically added. When liquid suspensions are
used, the active agent may be combined with emulsifying and
suspending agents. If desired, flavoring, coloring and/or
sweetening agents may be added as well. Other optional components
for incorporation into an oral formulation herein include, but are
not limited to, preservatives, suspending agents, thickening
agents, and the like.
[0194] Parenteral administration, if used, is generally
characterized by injection. Injectable formulations can be prepared
in conventional forms, either as liquid solutions or suspensions,
solid forms suitable for solubilization or suspension in liquid
prior to injection, or as emulsions. Preferably, sterile injectable
suspensions are formulated according to techniques known in the art
using suitable carriers, dispersing or wetting agents and
suspending agents. The sterile injectable formulation may also be a
sterile injectable solution or a suspension in a nontoxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils, fatty esters or polyols are conventionally
employed as solvents or suspending media. A more recently revised
approach for parenteral administration involves use of a slow
release or sustained release system, such that a constant level of
dosage is maintained.
[0195] Intracavernosal injection can be carried out by use of a
syringe any other suitable device. The injection is made on the
dorsum of the penis by placement of the needle to the side of each
dorsal vein and inserting it deep into the corpora.
[0196] The active agent can be administered in a pharmaceutical
formulation suitable for transurethral drug delivery. The
formulation contains one or more selected carriers or excipients,
such as water, silicone, waxes, petroleum jelly, polyethylene
glycol ("PEG"), propylene glycol ("PG"), liposomes, sugars such as
mannitol and lactose, and/or a variety of other materials, with
polyethylene glycol and derivatives thereof particularly
preferred.
[0197] Depending on the delta opioid receptor agonist administered,
it may be desirable to incorporate a transurethral permeation
enhancer in the urethral dosage form. Examples of suitable
transurethral permeation enhancers include dimethylsulfoxide
("DMSO"), dimethyl formamide ("DMF"), N,N-dimethylacetamide
("DMA"), decylmethylsulfoxide ("C.sub.10 MSO"), polyethylene glycol
monolaurate ("PEGML"), glycerol monolaurate, lecithin, the
1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.), SEPA.RTM. (available from Macrochem Co., Lexington,
Mass.), alcohols (e.g., ethanol), detergents (such as
Tergitol.RTM., Nonoxynol-9.RTM. and TWEEN-80.RTM.) and the
like.
[0198] Transurethral formulations may additionally include one or
more enzyme inhibitors effective to inhibit drug-degrading enzymes
that may be present in the urethra. Such enzyme inhibiting
compounds may be determined by those skilled in the art by
reference to the pertinent literature and/or using routine
experimental methods. Additional optional components include
excipients, preservatives (e.g., antioxidants), chelating agents,
solubilizing agents (e.g., surfactants), and the like, as will be
appreciated by those skilled in the art of drug formulation
preparation and delivery.
[0199] Transurethral drug administration can be carried out in a
number of different ways using a variety of urethral dosage forms.
For example, the composition can be introduced into the urethra
from a flexible tube, squeeze bottle, pump or aerosol spray. The
active agents may also be contained in coatings, pellets or
suppositories that are absorbed, melted or bioeroded in the
urethra. Urethral suppository formulations containing PEG or a PEG
derivative amay be used and may be formulated using conventional
techniques, e.g., compression molding heat molding or the like, as
will be appreciated by those skilled in the art and as described in
the pertinent literature and pharmaceutical texts. See, for
example, Remington, referenced above. The PEG or PEG derivative
preferably has a molecular weight Mw in the range of about 200 to
2500. Suitable polyethylene glycol derivatives include polyethylene
glycol fatty acid esters, for example, polyethylene glycol
monostearate, polyethylene glycol sorbitan esters, e.g.,
polysorbates, and the like. It is also preferred that urethral
suppositories contain one or more solubilizing agents effective to
increase the solubility of the active agent in the PEG or other
transurethral vehicle. The solubilizing agent may be a nonionic,
anionic, cationic or amphoteric surfactant.
[0200] It may be desirable to deliver the active agent in a
urethral dosage form, which provides for controlled or sustained
release of the active agent. In such a case, the dosage form
typically comprises a biocompatible, biodegradable material,
typically a biodegradable polymer. Examples of such polymers
include polyester, polyalkylcyanoacrylate, polyorthoester,
polyanhydride, albumin, gelatin and starch. These and other
polymers can be used to provide biodegradable microparticles that
enable controlled and sustained drug release, which in turn will
minimize the required dosing frequency.
[0201] The compounds of the invention may also be delivered through
the skin or muscosal tissue using conventional transdermal drug
delivery systems, i.e., transdermal "patches" wherein the agent is
typically contained within a laminated structure that serves as a
drug delivery device to be affixed to the body surface. In such a
structure, the pharmaceutical composition is typically contained in
a layer, or "reservoir," underlying an upper backing layer. The
laminated device may contain a single reservoir, or it may contain
multiple reservoirs. In one embodiment, the reservoir comprises a
polymeric matrix of a pharmaceutically acceptable contact adhesive
material that serves to affix the system to the skin during drug
delivery. Examples of suitable skin contact adhesive materials
include, but are not limited to, polyethylenes, polysiloxanes,
polyisobutylenes, polyacrylates, polyurethanes, and the like.
Alternatively, the active agent-containing reservoir and skin
contact adhesive are present as separate and distinct layers, with
the adhesive underlying the reservoir which, in this case, may be
either a polymeric matrix as described above, or it may be a liquid
or gel reservoir, or may take some other form. The backing layer in
these laminates, which serves as the upper surface of the device,
functions as the primary structural element of the laminated
structure and provides the device with much of its flexibility. The
material selected for the backing layer should be substantially
impermeable to the active agent and any other materials that are
present.
[0202] Alternatively, the pharmaceutical compositions of the
invention may be administered in the form of suppositories for
rectal administration. These can be prepared by mixing the agent
with a suitable nonirritating excipient which is solid at room
temperature but liquid at the rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols. The suppository
will preferably, although not necessarily, be on the order of 2 to
20 mm, preferably 5 to 10 mm in length and less than about 5 mm,
preferably less than about 2 mm in width. The weight of the
suppository form will typically be in the range of approximately 1
mg to 50 mg. However, it will be appreciated by those skilled in
the art that the size of the suppository can and will vary,
depending on the potency of the active agent, the nature of the
composition, and other factors.
[0203] The pharmaceutical compositions of the invention may also be
administered by nasal aerosol or inhalation. 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. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, propellants such
as fluorocarbons or nitrogen, and/or other conventional
solubilizing or dispersing agents.
[0204] The delta opioid receptor agonists of the present invention
may be included in formulations for topical drug delivery, such as
in ointments and creams. Ointments are semisolid preparations that
are typically based on petrolatum or other petroleum derivatives.
Creams containing the selected active agent, are, as known in the
art, viscous liquid or semisolid emulsions, either oil-in-water or
water-in-oil. Cream bases are water-washable, and contain an oil
phase, an emulsifier and an aqueous phase. The oil phase, also
sometimes called the "internal" phase, is generally comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol;
the aqueous phase usually, although not necessarily, exceeds the
oil phase in volume, and generally contains a humectant. The
emulsifier in a cream formulation is generally a nonionic, anionic,
cationic or amphoteric surfactant. The specific ointment or cream
base to be used, as will be appreciated by those skilled in the
art, is one that will provide for optimum delivery of the active
agent. As with other carriers or vehicles, an ointment base should
be inert, stable, nonirritating and nonsensitizing.
[0205] 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.
[0206] 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.
[0207] The pharmaceutical formulations discussed above may further
contain one or more pharmacologically active agents in addition to
the delta opioid receptor agonists, such as vasodilators.
[0208] The compounds contemplated by the invention include those
set forth above, as well as physiologically functional derivatives
thereof. By "physiologically functional derivative" is meant a
pharmaceutically acceptable salt, ether, ester or salt of an ether
or ester of the compounds set forth above or any other compound
which, upon administration to the recipient, is capable of
providing (directly or indirectly) the said compound or an active
metabolite or residue thereof.
[0209] The amount of delta opioid receptor agonist administered,
and the dosing regimen used, will, of course, be dependent on the
particular delta opioid receptor agonist selected, the age and
general condition of the subject being treated, the severity of the
subject's condition, and the judgment of the prescribing physician.
Generally, the daily dosage when administered locally will be less
than the dosage normally given in conjunction with systemic modes
of administration, and typically, the delta agonist will be
administered one to four times daily or, with some active agents,
just prior to intercourse. Alternatively, a large initial loading
dose can be used to achieve effective levels of the active agent
and can be followed by smaller doses to maintain those levels. A
typical daily dose of an active agent as administered locally is
generally in the range of approximately 0.1 to 100 mg/kg body
weight of the recipient. Depending on the half-life of the delta
opioid receptor agonist and the availability via the chosen route
of administration, the dosing regimen can be modulated in order to
achieve satisfactory control of the onset of ejaculation.
[0210] 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 condition
involved, as readily determinable within the skill of the art,
suitable therapeutic doses of the compounds of the invention, for
each of the appertaining compositions described herein, and for
achievement of therapeutic benefit in treatment of each of the
conditions described herein, will preferably in the range of 10
micrograms (.mu.g) to 500 milligrams (mg) per kilogram body weight
of the recipient per day, more preferably in the range of 50 .mu.g
to 75 mg per kilogram body weight per day, and most preferably in
the range of 1 mg to 50 mg per kilogram body weight per day. The
desired dose is may be presented as two, three, four, five, six, or
more sub-doses administered at appropriate intervals throughout the
day.
[0211] 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. 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 compounds of the present 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.
[0212] Kits
[0213] The invention also encompasses a kit for patients to carry
out the present method of treating premature ejaculation. The kit
contains the pharmaceutical composition to be administered, a
device for administering the pharmaceutical composition (e.g., a
transurethral drug delivery device such as a syringe, a transdermal
patch), a container, preferably sealed, for housing the active
agent and delivery device during storage and prior to use, and
instructions for carrying out drug administration in an effective
manner. The formulation may consist of the delta opioid receptor
agonist in unit dosage form. The kit may contain multiple
formulations of different dosages of the same agent. The
instructions may be in written or pictograph form, or can be on
recorded media including audio tape, video tape, or the like.
[0214] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the foregoing description as well as the examples
which follow are intended to illustrate and not limit the scope of
the invention. Other aspects, advantages and modifications within
the scope of the invention will be apparent to those skilled in the
art to which the invention pertains.
[0215] The following examples are illustrative of synthetic
procedures that may be advantageously utilized to make compounds of
the present invention.
[0216] 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. NMR spectra were obtained on a variety of instruments
ranging from 200 to 600 MHz in field strength. HPLC analyses were
performed with a Waters liquid chromatography system equipped with
a 700 Satellite WISP, 600E System Controller and a 991 Photodiode
Array. 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.).
Mass spectra were performed by various contractual sources using
chemical ionization (CI), electrospray (ES), or fast-atom
bombardment (FAB) instrumentation. Optical rotations were obtained
with a Perkin-Elmer 241 polarimeter. Analytical thin layer
chromatography was performed on E. Merck glass plates pre-coated
with silica gel GF (250 microns). Elemental analyses were performed
by Atlantic Microlab, Norcross, Ga.
Example 1
4-((alpha-S)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-
-diethylbenzamide
[0217] 4-Carboxybenzaldehyde (150 g, 100 mmol) was added to a 250
mL, 3-necked round bottom flask and stirred under nitrogen in 110
mL of toluene. Thionyl chloride (8.75 mL, 120 mmol) was added to
the mixture, followed by the addition of 6 drops of DMF. A reflux
condenser fitted with a calcium chloride drying tube was placed on
the flask. The reaction was placed in an oil bath and heated at a
bath temperature maintained below 120.degree. C. The mixture was
allowed to reflux for 1 hour after a clear solution was obtained
and then cooled to room temperature. The solution was diluted with
anhydrous toluene, and all volatiles were removed under vacuum.
[0218] The crude acid chloride was dissolved in 200 mL of dry
tetrahydrofuran and cooled in an ice/water bath. Diethylamine
(31.35 mL, 300 mmol) in 70 mL of dry tetrahydrofuran was added
dropwise via an addition funnel. The cloudy solution was allowed to
warm to room temperature over 1 hour and stirred overnight. Water
was added and the product was extracted with dichloromethane. The
organic layer was washed with water and saturated sodium chloride
solution, dried over sodium sulfate, and the solvent was removed
under vacuum. 3-Formyl-N,N-diethylbenzamide (17.72 g) was obtained
as a light golden oil (86% unchromatographed yield). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta.1.04-1.18 (m, 6H); 3.17-3.45 (m,
4H); 7.65-7.66 (m, 2H); 7.85 (s, 1H); 7.93-7.94 (m, 1H); 10.03 (s,
1H).
[0219] 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 with adjustment of
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 1M 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 10M sodium hydroxide, with
cooling to maintain temperature below 40 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.
[0220] 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.
[0221] 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 C
for 30 minutes. The solution was filtered, and the filter cake was
washed 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. NMR (300
MHz, DMSO-d.sub.6): .delta. 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3
Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz,
1H); 2.6-2.8 (m, 4H); 3.33 (dd, J.sub.1=5 Hz, J.sub.2=14 Hz, 1H);
5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8 (m, 1H).
[0222] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South
Plainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot
(.about.60 C) 95% ethanol (16 L) and racemic
trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) was added in
several portions (caution: exothermic). The hot solution was seeded
with crystals of the diastereoisomerically pure salt (obtained from
a previous small-scale resolution) and cooled to room temperature
over 2-3 hours. The solution was slowly stirred for 2 days at room
temperature. The resulting salt was collected by filtration, washed
twice with 95% ethanol, and dried under vacuum to give 826.5 g of a
white solid (47%). The process was repeated with a second batch of
the di-p-toluoyl-D-tartaric acid and racemic
trans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).
[0223] The total of 1695 g of salt was divided into three batches
and each batch was recrystallized twice in the following fashion.
The salt was dissolved in refluxing 95% ethanol (.about.2.7 L/100 g
of salt), and approximately half of the ethanol was removed by
distillation. (Note: vigorous stirring was necessary during
distillation to prevent crystallization on the vessel wall.) The
hot solution was seeded with crystals of the pure diastereomeric
salt, cooled to room temperature, and stirred slowly for 2 days
before collecting the salt by filtration. (Note: a subsequent
experiment suggested that crystallization time can be reduced from
2 days to 8 hours.) The total amount recovered was 1151 g. The salt
was dissolved in 3 L of 2 M aqueous sodium hydroxide, and the
aqueous solution was extracted with four 1 L portions of
dichloromethane. The organic extracts were combined, dried over
sodium sulfate, and solvent removed by rotary evaporation
(temperature <20.degree. C.) to give 293 g (29% based on racemic
weight) of (2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil.
[.alpha.].sub.D.sup.20=-55.1 (abs. ethanol, c=1.2). The
trifluoroacetamide of the product was prepared with trifluoroacetic
anhydride and analyzed by chiral capillary gas chromatography
(Chiraldex B-PH column, 20 m.times.0.32 mm, Advanced Separation
Technologies Inc., Whippany, N.J., 120.degree. C.) indicating an
enantiopurity of >99% ee (retention time of desired enantiomer,
11.7 min; other enantiomer, 10.7 min).
[0224] A solution of 4-formyl-N,N-diethylbenzamide (4.105 g, 20
mmol), benzotriazole (2.38 g, 20 mmol) and
(2R,5S)-1-allyl-2,5-dimethylpiperazine (3.085 g, 20 mmol) in
toluene (200 mL) was heated under reflux with azeotropic removal of
water for 2.5 h. The volume of the reaction mixture was reduced to
approximately 75 mL by distillation. Anhydrous tetrahydrofuran (50
mL) was added to the solution under nitrogen, and the reaction was
stirred during the addition of phenylmagnesium bromide (1.0 M in
tetrahydrofuran, 40 mL, 40 mmol). The reddish brown suspension was
stirred at ambient temperature for 1 h and quenched with saturated
aqueous ammonium chloride solution (10 mL). The yellow suspension
was stirred for 15 min, and anhydrous magnesium sulfate (10 g)
added. The suspension was stirred for a further 15 min and
filtered. The filter cake was washed with tetrahydrofuran, and the
combined filtrate and washings were evaporated to a thick oil. The
residue was partitioned between ethyl acetate (400 mL) and aqueous
sodium hydroxide solution (1.0 M, 100 mL). The organic layer was
separated and washed successively with 1M-NaOH (3.times.100 mL),
water (100 mL) and saturated aqueous sodium chloride solution (100
mL). The ethyl acetate solution was extracted with 1.0 M HCl
(2.times.25 mL), and the combined acid extracts were basified to pH
10 with 10 M aqueous NaOH. The oily aqueous suspension was
extracted with methylene chloride (2.times.25 mL) and the organic
layer dried over anhydrous magnesium sulfate. The methylene
chloride solution was evaporated to dryness, and the
semi-crystalline residue crystallized from ethyl acetate to yield
the title compound (1.84 g, 21.9%). Calc. for
C.sub.27H.sub.37N.sub.3O 0.15 H.sub.2O C, 76.79; H, 8.90; N, 9.95.
Found C, 76.79; H, 8.85; N, 9.87% .sup.1H NMR ((CD.sub.3).sub.2SO,
500 MHz); .delta. 0.94 (d, J=6.2 Hz, 3H); 1.09 (d, J=6.2 Hz, 3H,
partially obscured by br m, 6H); 1.80 (m, 1H); 2.09 (dd, J=11, 7
Hz, 1H); 2.50 (br m, 1H, partially obscured by DMSO); 2.72 (dd,
J=11, 2.8 Hz, 1H); 2.84 (dd, J=14, 7 Hz, 1H); 3.16 (dd, J=14, 5.2
Hz, 1H); 3.28 (br m, 3H); 5.10 (s, 1H), overlapped by 5.09 (d,
J=10.6 Hz, 1H); 5.16 (dd, J=17, 1.4 Hz, 1H); 5.79 (m, 1H); 7.28 (m,
5H); 7.38 (m, 2H); 7.42 (d, J=8 Hz, 2H).
Example 2
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)benzyl)-N,N-diethyl-
benzamide
[0225] The compound of Example 1 was de-allylated by the method of
Genet [J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron
Letters, 36, 1267-1270 (1995)] as follows. A solution of
4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,-
N-diethylbenzamide (Example 1, 8.392 g, 20 mmol) and thiosalicylic
acid (3.70 g, 24 mmol) in anhydrous tetrahydrofuran (50 mL) was
stirred under nitrogen for 3 h at room temperature with a catalyst
solution prepared by dissolution of
bis(dibenzylidineacetone)palladium (575 mg, 1.0 mmol) and
1,4-bis(diphenylphosphino)butane (426 mg, 1.0 mmol) in
tetrahydrofuran (10 mL). The reaction mixture was evaporated to
dryness, the residue dissolved in a mixture of ethyl acetate/ether
(1:3, 300 mL) and extracted with 5% sodium carbonate solution
(2.times.300 mL). The organic layer was diluted with two volumes of
pentane and extracted with 3M-hydrochloric acid (6.times.50 mL).
The aqueous solution was filtered to remove suspended solid and the
pH adjusted to 12 with 5-M NaOH. The resulting oily suspension was
extracted with methylene chloride (2.times.125 mL) and the combined
organic extracts dried over anhydrous sodium sulfate and evaporated
to dryness. The residue was crystallized from ethyl acetate to
yield fine white needles of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethy-
lbenzamide (3.46 g). The product showed a single spot on thin layer
chromatography (silica gel, EM60F.sub.264, 4% NH.sub.4OH/10% EtOH
in ethyl acetate, R.sub.f=0.47). .sup.1H NMR (CDCl.sub.3, 600 MHz);
.delta. 0.93 (d, J=6.3 Hz, 3H); 1.12 (br m, 3H); 1.20 (d, J=6.1 Hz,
3H); 1.24 (br m, 3H); 1.55 (dd, J=9.7, 11.3 Hz, 1H, partially
obscured by br m, 2H); 2.33 (m, 1H); 2.68 (m, 2H); 2.89 (m, 1H);
2.92 (dd, J=12.1, 3.1 Hz, 1H); 3.29 (br m, 2H); 3.54 (br m, 2H);
5.38 (s, 1H); 7.14 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.46 (d,
J=7.8 Hz, 2H).
Example 3
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0226] A solution of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethy-
lbenzamide (1.898 g, 5.0 mmol) in 25 mL acetonitrile was added to
sodium iodide (75 mg, 0.5 mmol) and stirred during the addition of
triethylamine (2.5 mL, 1.815 g, 17.94 mmol), followed by
3-fluorobenzyl bromide (1.227 mL, 1.89 g, 10.0 mmol). An immediate
turbidity was observed on addition of the 3-fluorobenzyl bromide,
thickening to a copious white precipitate over one hour. The flask
was sealed under nitrogen and the suspension stirred overnight at
room temperature. The reaction mixture was evaporated to dryness
and and the residue was partitioned between ethyl acetate (40 mL)
and saturated sodium bicarbonate solution (10 mL). The supernatant
organic layer was separated and the aqueous layer extracted further
with ethyl acetate (2.times.40 mL). The combined organic extracts
were dried over anhydrous sodium sulfate and evaporated to a pale
yellow solid which was dissolved in ethyl acetate (.about.7.5 mL)
and applied to an intermediate (4.times.15 cm) Biotage silica
column. Elution with ethyl acetate gave fractions containing the
product, as evidenced by t.l.c. (silica, EM60F.sub.254, 100% EtOAc,
R.sub.f=0.78) were evaporated to dryness and dried at room
temperature and 2 mm Hg to yield the title compound as white
crystals (2.372 g, 97.3%). Calc. for C.sub.31H.sub.38FN.sub.3O: C,
76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.89; N, 8.51;
F, 3.90% .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.06 (d, J=6.1
Hz, 3H); 1.15 (d, J=6.1 Hz, 3H, partially overlapped by br m, 3H);
1.22 (br m, 3H); 1.94 (dd, J=10.8, 8.1 Hz, 1H); 2.02 (dd, J=10.7,
8.2 Hz, 1H); 2.57 (br m, 2H); 2.67 (m, 2H); 3.18 (d, J=13.8 Hz,
1H); 3.28 (br m, 2H); 3.53 (br m, 2H); 3.87 (d, J=13.5 Hz, 1H);
5.15 (s, 1H); 6.90 (br t, J=8.2 Hz, 1H); 7.04 (m, 2H); 7.21 (m,
3H); 7.30 (m, 5H); 7.46 (d, J=8.0 Hz, 2H).
[0227] Also prepared from
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethy-
lbenzamide (Example 2) by an essentially similar procedure to
Example 3 were:
Example 4
4-((alpha-S)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,-
N-diethylbenzamide
[0228] (71.8%). Calc. for C.sub.31H.sub.39N.sub.3O: C, 79.28; H,
8.37; N, 8.95. Found C, 79.05; H, 8.34; N, 8.91% .sup.1H NMR
(CDCl.sub.3, 500 MHz); .delta. 1.09 (d, J=6.2 Hz, 3H); 1.12 (d,
J=6.1 Hz, 3H); both doublets partially overlapped by br m, 3H);
1.24 (br m, 3H); 1.72 (m, 1H); 1.93 (m, 1H); 2.02 (dd, J=9.3, 8.4
Hz, 1H); 2.55 (m, 2H); 2.66 (dd, J=11.1, 2.4 Hz, 1H); 2.70 (dd,
J=11, 2.5 Hz, 1H); 3.18 (d, J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.55
(br m, 2H); 3.92 (d, J=13.1 Hz, 1H); 5.18 (s, 1H); 7.20 (d, J=7.4
Hz, 2H, partially overlapped by m, 1H); 7.30 (m, 9H); 7.47 (d, J=8
Hz, 2H).
Example 5
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0229] (68.9%). Calc. for C.sub.31H.sub.38FN.sub.3O: C, 76.35; H,
7.85; N, 8.62; F, 3.90. Found C, 76.35; H, 8.02; N, 8.60; F, 3.81%
.sup.1H NMR (CDCl.sub.3, 600 MHz); .delta. 1.09 (d, J=6.1 Hz, 3H);
1.13 (d, J=6.1 Hz, 3H); (both doublets overlapped by br m, 3H);
1.24 (br m, 3H); 1.90 (br t, J=10.4 Hz, 1H); 2.08 (dd, J=10.9, 8.6
Hz, 1H); 2.56 (br m, 2H); 2.66 (dd, J=11.5, 2.7 Hz, 1H); 2.73 (dd,
J=11.1, 2.4 Hz, 1H); 3.28 (br m, 2H); 3.34 (d, J=13.8 Hz, 1H); 3.54
(br m, 2H); 3.88 (d, J=13.8 Hz, 1H); 5.19 (s, 1H); 7.00 (br t,
J=9.1 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.19 (m, 3H); 7.29 (m, 5H);
7.37 (br t, J=7.1 Hz, 1H); 7.46 (d, J=8.1 2H).
Example 6
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-pyridylmethyl)-1-piperazinyl-
)benzyl)-N,N-diethylbenzamide
[0230] (69.7%). Calc. for C.sub.30H.sub.38N.sub.4O 0.15 H.sub.2O:
C, 76.12; H, 8.16; N, 11.84. Found C, 76.14; H, 8.36; N, 11.70%.
.sup.1H NMR (CDCl.sub.3, 600 MHz); .delta. 1.05 (d, J=6.1 Hz, 3H);
1.11 (d, J=6.2 Hz, 3H; overlapped by br m, 3H); 1.24 (br m, 3H);
1.96 (br t, J=10.0 Hz, 1H); 2.08 (dd, J=7.8, 4.1 Hz, 1H); 2.59 (br
d, J=4.9 Hz, 2H); 2.68 (m, 2H); 3.21 (d, J=14.0 Hz, 1H); 3.27 (br
m, 2H); 3.54 (br m, 2H); 3.86 (d, J=14.2 Hz, 1H); 5.13 (s, 1H);
7.23 (d, J=7.4 Hz, 2H); 7.24 (d, J=5.6 Hz, 2H); 7.29 (d, J=8.2 Hz,
2H, partially obscuring doublet, 1H); 7.34 (br t, J=7.4 Hz, 2H);
7.46 (d, J=8.1 2H); 8.49 (d, J=5.9 Hz, 2H).
Example 7
4-((alpha-S)-alpha-((2S,5R)-4-(3-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0231] (75.8%). Calc. for C.sub.31H.sub.38ClN.sub.3O: C, 73.86; H,
7.60; N, 8.34; Cl, 7.03. Found C, 73.86; H, 7.68; N, 8.37; Cl,
7.01% .sup.1H NMR (CDCl.sub.3, 600 MHz); .delta. 1.06 (d, J=6.2 Hz,
3H); 1.12 (d, J=6.1 Hz, 3H, overlapping br m, 3H); 1.23 (br m, 3H);
1.94 (br t, J=9.5 Hz, 1H); 2.01 (dd, J=11.1, 8.2 Hz, 1H); 2.56 (m,
2H); 2.67 (dt, J=10.5, 2.4 Hz, 2H); 3.15 (d, J=13.5 Hz, 1H); 3.28
(br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=13.5 Hz, 1H); 5.15 (s, 1H);
7.19 (m, 5H); 7.29 (m, 4H); 7.33 (br t, J=7.4 Hz, 2H); 7.46 (d,
J=8.1 Hz, 2H).
Example 8
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-methoxybenzyl)-1-piperazinyl-
)benzyl)-N,N-diethylbenzamide
[0232] (72.44%). Calc. for C.sub.32H.sub.41N.sub.3O.sub.2: C,
76.92; H, 8.27; N, 8.41. Found C, 76.98; H, 8.38; N, 8.42%. .sup.1H
NMR (CDCl.sub.3, 600 MHz); .delta. 1.07 (d, J=6.2 Hz, 3H); 1.11 (d,
J=6.1 Hz, 3H, overlapping br m, 3H); 1.23 (br m, 3H); 1.91 (br t,
J=10.2 Hz, 1H); 1.99 (dd, J=11.0, 8.6 Hz, 1H); 2.52 (br m, 2H);
2.64 (dd, J=11.5, 2.6 Hz, 1H); 2.68 (dd, J=11.1, 2.6 Hz, 1H); 3.13
(d, J=12.9 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.79 (s, 3H);
3.85 (d, J=13.5 Hz, 1H); 5.17 (s, 1H); 6.82 (d, J=8.5 Hz, 2H); 7.19
(d, J=8.3 Hz, 4H); 7.29 (m, 5H); 7.46 (d, J=8.1 Hz, 2H).
Example 9
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-trifluor-
omethylsulfonyloxybenzyl)-N,N-diethylbenzamide
[0233] A solution of 3-bromophenol (400 g, 2.31 mol),
tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole
(346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred
overnight at room temperature. The reaction solution was poured
into 2000 mL of water and the layers were separated. The organic
layer was washed with 1N aqueous sodium hydroxide solution
(3.times.1500 mL) and water (2.times.1500 mL) before passing
through a pad of silica gel (400 g, silica 60, 230-400 mesh). The
silica gel was washed with dichloromethane (2.times.500 mL), the
filtrates were combined and the solvent removed under reduced
pressure to give 669 g (98.4%) of
3-(bromophenoxy)-tert-butyldimethylsilane as a clear pale yellow
liquid. NMR (300 MHz, CDCl.sub.3): .quadrature. 0.2 (s, 6H); 1.0
(s, 9H); 6.75 (m, 1H); 7.0 (br s, 1H); 7.1 (m, 2H).
[0234] 3-tert-Butyldimethylsilyloxyphenylmagnesium bromide was
formed by the slow addition of a mixture
3-bromophenoxy-tert-butyldimethylsilane (27.3 g, 92.6 mmol) and
dibromoethane (3.45 g, 18.4 mmol) in 100 mL of inhibitor-free
anhydrous tetrahydrofuran to a solution of magnesium turnings (3.57
g, 147 mmol) in 200 mL of inhibitor-free anhydrous tetrahydrofuran
at reflux. After stirring for one hour at reflux the light brown
clear mixture was cooled to room temperature.
[0235] 4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was
dissolved/suspended in toluene (1200 mL, dimethylformamide (0.15
mL) added and the suspension stirred during the dropwise addition
of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction
mixture was heated to reflux under nitrogen and stirred for 2 h,
during which time much, but not all of the aldehydo-acid passed
into solution. A further quantity of thionyl chloride (20 mL, 32.6
g, 0.27 mol) was added and reflux continued overnight. The clear
reaction mixture was evaporated, and the residue dissolved in
anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an
ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5
equivalents)) was added dropwise to the stirred solution. The
ice-bath was removed and stirring continued for 2.5 h. The reaction
mixture was filtered to remove the white crystalline diethylamine
hydrochloride by-product. The crystals were washed with ethyl
acetate (2.times.600 mL), and the washings set aside. The
tetrahydrofuran filtrate was evaporated, and the residue dissolved
in the ethyl acetate washings. The solution was washed sequentially
with 1 M-hydrochloric acid (2.times.600 mL), water 2.times.300 mL),
dilute sodium carbonate solution (saturated: H.sub.2O, 1:1,
2.times.600 mL), water (2.times.300 mL) and saturated sodium
chloride solution (300 mL). The organic layer was separated, dried
over anhydrous sodium sulfate and evaporated to yield
4-formyl-N,N-diethylbenzamide as a pale brown oil which was used
without further purification. (Yield 115.7 g, 84%)
[0236] In a 1000 mL round bottom flask fitted with a condenser and
Dean-Stark trap were combined 4-formyl-N,N-diethylbenzamide (9.50
g, 46.3 mmol), benzotriazole (5.51 g, 46.3 mmol), and
(2R,5S)-1-allyl-2,5-dimethylpiperazine (7.15 g, 46.3 mmol,
Chirotech Technology, Ltd., Cambridge, England) with 400 mL of
toluene. The reaction was heated to reflux under nitrogen until no
additional water was observed in the trap (ca. 2 hours). The
reaction was cooled to room temperature and concentrated under
vacuum to leave a volume of approximately 50 mL. Anhydrous
tetrahydrofuran (100 mL) was added to the flask under nitrogen with
stirring to dissolve all residue. The solution of benzotriazole
adduct was added to the solution of
3-tert-butyldimethylsilyloxyphenylmagnesium bromide (above) at room
temperature via double-ended needle. After stirring for 2 hours,
the reaction was quenched by addition of 20 mL of saturated aqueous
ammonium chloride. Anhydrous magnesium sulfate was added and the
reaction was filtered. Solvent was removed under vacuum and the
residue was redissolved in 800 mL of ethyl acetate. The ethyl
acetate solution was washed with 4.times.200 mL of 1 M sodium
hydroxide, 200 mL of water, and 200 mL of saturated aqueous sodium
chloride. The organic layer was dried over anhydrous magnesium
sulfate and the solvent was removed to give 32.7 g of dark oil. The
oil was dissolved in 250 mL of tetrahydrofuran and 250 mL of 3 M
hydrochloric acid and stirred for 2 hours at room temperature. The
reaction solution was extracted with 3.times.250 mL of 2:1 diethyl
ether/ethyl acetate. Ethyl acetate (300 mL) was added to the
aqueous layer and pH was adjusted to 8 with aqueous sodium
hydroxide. Layers were separated and the aqueous portion was
extracted with another 3.times.300 mL of ethyl acetate. The
combined organic extracts were washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, and the solvent was
removed under vacuum to give 12.4 g of brown residue. The residue
was purified by chromatography on 300 g of silica gel, eluting with
a gradient of 1-15% ethanol in dichloromethane, to give 5.54 g of
4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)-N,N-diethylbenzamide as a colorless gum (27% from
4-formyl-N,N-diethylbenzamide).
[0237]
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethylbenzamide hydrochloride (0.97 g, 2.0 mmol)
was dissolved in methylene chloride (10 mL) under nitrogen and
triethylamine (0.919 mL, 0.667 g, 6.6 mmol) was added followed by
N-phenyl bis(trifluoromethanesulfonimide) (0.785 g, 2.2 mmol). The
reaction mixture was stirred at room temperature overnight and
evaporated to dryness. The residue was dissolved in ethyl acetate
(20 mL) and extracted with 5% sodium carbonate solution (2.times.15
mL). The organic layer was separated, dried over anhydrous sodium
sulfate and evaporated to yield a viscous amber oil. The residue
was dissolved in methylene chloride (5 mL), applied to a column of
silica gel (4.times.30 cm), and eluted with ethanol/methylene
chloride (2:98 v/v). Pure fractions containing desired product, as
evidenced by t.l.c. (silica gel, EM60F.sub.254, 2% NH.sub.4OH in
ethyl acetate, R.sub.f=0.78) were evaporated to dryness to yield
4-((alpha-R)-alpha-((2
S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxyben-
zyl)-N,N-diethylbenzamide (0.72 g) as a yellow/amber oil. .sup.1H
NMR (CDCl.sub.3, 500 MHz); .delta. 1.00 (d, J=6.2 Hz, 3H); 1.12 (br
m, 3H); 1.21 (d, J=6.1 Hz, 3H); 1.25 (br m, 3H); 1.83 (t, J=10.6
Hz, 1H); 2.60 (m, 3H); 2.91 (dd J=11.4, 2.7, 1H); 3.02 (m, 1H);
3.18 (br s, 2H); 3.28 (br m, 2H); 3.46 (dd, J=13.7, 5.5 Hz, 1H);
3.55 (br m, 2H); 5.25 (m, 2H); 5.31 (s, 1H); 5.88 (m, 1H); 7.02 (d,
J=7.7 Hz, 1H); 7.05 (s, 1H); 7.23 (m, 2H); 7.32 (d, J=8.1 Hz, 2H);
7.40 (d, J=8.1 Hz, 2H); 7.46 (t, J=7.9 Hz, 1H).
Example 10
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethyls-
ulfonyloxybenzyl)-N,N-diethylbenzamide
[0238] The compound of Example 9 was de-allylated by the method of
Genet [J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron
Letters, 36, 1267-1270 (1995)] as follows.
[0239] A solution of
4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluo-
romethylsulfonyloxybenzyl)-N,N-diethylbenzamide (Example 9, 0.72 g,
1.286 mmol) and thiosalicylic acid (234.7 mg, 1.522 mmol) in
anhydrous tetrahydrofuran (4 mL) was stirred under nitrogen for 3 h
at room temperature with a catalyst solution prepared by
dissolution of bis(dibenzylidineacetone)palladium (36.46 mg, 0.0634
mmol) and 1,4-bis(diphenylphosphino)butane (27.04 mg, 0.0634 mmol)
in tetrahydrofuran (0.5 mL). The reaction mixture was evaporated to
dryness, the residue was dissolved in a mixture of ethyl
acetate/ether (1:3, 20 mL) and extracted with 5% sodium carbonate
solution (2.times.15 mL). The organic layer was diluted with two
volumes of pentane and extracted with 3M-hydrochloric acid
(5.times.4 mL). The aqueous solution was adjusted to pH 9-10 with
concentrated ammonia solution and extracted with methylene chloride
(3.times.10 mL). The combined organic extracts were dried over
anhydrous sodium sulfate and evaporated to yield
4-((alpha-R)-alpha-((2
S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxy
[0240] benzyl)-N,N-diethylbenzamide as a brittle pale yellow foam
(0.63 g). The product showed a single spot on thin layer
chromatography (silica gel, EM60F.sub.264, 2% NH.sub.4OH in ethyl
acetate, R.sub.f=0.33). .sup.1H NMR (CDCl.sub.3, 500 MHz); .delta.
0.95 (d, J=6 Hz, 3H); 1.13 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.26
(br m, 3H); 1.50 (t, J=9.7 Hz, 1H); 2.31 (m, 1H); 2.64 (dd J=11.3,
2.5, 1H); 2.71 (m, 1H); 2.95 (m, 1H); 3.29 (br m, 2H); 3.56 (br m,
2H); 5.43 (s, 1H); 7.04 (m, 1H); 7.21 (d, J=7.7, 1H); 7.24 (dd,
J=8.2, 2.2 Hz, 1H); 7.34 (d, J=8.2 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H);
7.48 (t, J=8 Hz, 1H).
Example 11
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-diethylbenzamide
[0241]
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoro-
methylsulfonyloxy-benzyl)-N,N-diethylbenzamide (Example 10, 527.6
mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL) with sodium
iodide (30 mg, 0.2 mmol). The suspension was stirred during the
addition of triethylamine (800 .mu.L, 580.8 mg, 5.74 mmol),
followed by 4-fluorobenzyl bromide (249 .mu.L, 378 mg, 2.0 mmol).
The reaction mixture was sealed under nitrogen and stirred
overnight at room temperature. The reaction mixture was evaporated
to dryness and and the residue dissolved in ethyl acetate (10 mL).
The organic solution was washed with saturated aqueous sodium
bicarbonate solution (2.times.5 mL) and saturated sodium chloride
solution (5 mL), dried over anhydrous sodium sulfate and evaporated
to a golden oil (a single spot on silica gel, EM60F.sub.264, 2%
NH.sub.4OH in ethyl acetate, R.sub.f=0.86). This intermediate
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (608.9
mg) was used without further purification. The oil was dissolved in
ethanol (8 mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5
mL, 12.5 mmol) was added. The reaction mixture was stirred at room
temperature for 3.5 h and the ethanol was removed by evaporation.
The oily suspension of the sodium salt was clarified by the
addition of water (7.5 mL), and the pH of the solution was adjusted
to 8.5-9 by the passage of gaseous carbon dioxide (from dry ice).
The copious white precipitate was collected by filtration, washed
well with water, and dried under vacuum (2 mm Hg) at room
temperature overnight to yield 4-((alpha-R)-alpha-((2
S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-
-diethylbenzamide as a white solid (423.6 mg, 84%). Calc. for
C.sub.31H.sub.38FN.sub.3O.sub.2C, 73.93; H, 7.61; N, 8.34. Found C,
73.91; H, 7.65; N, 8.21% .sup.1H NMR (CDCl.sub.3, 600 MHz); .delta.
1.05 (d, J=6.3 Hz, 3H); 1.07 (d, J=6.3 Hz, 3H); 1.11 (br m, 3H);
1.25 (br m, 3H); 1.97 (m, 2H); 2.53 (br m, 1H); 2.57 (br m, 1H);
2.61 (dd, J=9, 2.6 Hz, 1H); 2.65 (dd, J=9, 2.4 Hz, 1H); 3.14 (d,
J=13 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.87 (d, J=13 Hz,
1H); 5.13 (s, 1H); 6.62 (s, 1H); 6.70 (m, 2H); 6.96 (t, J=8.5 Hz,
2H); 7.13 (t, J=7.8 Hz, 1H); 7.24 (m, 2H); 7.28 (d, J=8.2 Hz, 2H);
7.43 (d, J=8.1 Hz, 2H).
Example 12
4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-
benzyl)-N,N-diethylbenzamide
[0242] This compound was prepared from
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-
sulfonyloxybenzyl)-N,N-diethylbenzamide (Example 10) by a procedure
similar to that of Example 11 (88.5%). Calc. for
C.sub.31H.sub.39N.sub.3O.sub.2 0.9 H.sub.2O: C, 74.19; H, 8.19; N,
8.37. Found C, 74.20; H, 7.88; N, 8.25%. .sup.1H NMR (CDCl.sub.3,
300 MHz); .delta. 1.03 (d, J=6.1 Hz, 3H); 1.09 (d, J=6.1 Hz, 3H);
1.12 (br m, 3H); 1.24 (br m, 3H); 1.99 (m, 2H); 2.53 (br m, 2H);
2.60 (dd, J=9, 2 Hz, 1H); 2.65 (dd, J=9, 2 Hz, 1H); 3.17 (d, J=13
Hz, 1H); 3.29 (br m, 2H); 3.55 (br m, 2H); 3.95 (d, J=13 Hz, 1H);
5.13 (s, 1H); 6.55 (s, 1H); 6.64 (m, 2H); 7.10 (t, J=7.7 Hz, 2H);
7.13 (m, 1H); 7.24 (m, 5H); 7.45 (d, J=8.1 Hz, 2H).
Example 13
4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-d-
imethylpiperazin-1-ylmethyl)benzoic acid
[0243]
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoro-
methylsulfonyloxy-benzyl)-N,N-diethylbenzamide (Example 10, 844 mg,
1.6 mmol) in acetonitrile (8 mL) was added to sodium iodide (45 mg,
0.3 mmol) and stirred during the addition of triethylamine (1.0 mL,
726 mg, 7.17 mol), followed by methyl 4-(bromomethyl benzoate
(916.3 mg, 4.0 mmol). The reaction mixture was sealed under
nitrogen and stirred at ambient temperature for 5 days. The solvent
was removed by evaporation and the residue was partitioned between
ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate
solution (3 mL). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3.times.10 mL). The
combined organic extracts were dried over anhydrous sodium sulfate
and evaporated to dryness. The residue was dissolved in ethyl
acetate (5 mL) and applied to an intermediate (4.times.15 cm)
Biotage silica column and eluted with ethyl acetate. Fractions
containing the product, as evidenced by t.l.c. (silica,
EM60F.sub.254, 100% EtOAc, Rf=0.74) were evaporated to dryness and
dried at room temperature and 2 mm Hg to yield methyl
4-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-(trifluoromethylsulfonylox-
y)phenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoate as a
rigid white foam. The solid (1.09 g, 1.615 mmol) was dissolved in
ethanol (10 mL) and sodium hydroxide solution (2.5 M, 6.46 mL,
16.16 mmol) was added in approximately 1 mL aliquots. The slightly
turbid reaction mixture clarified about 5 min after the last
addition to yield a yellow solution which was stirred for 16 h at
ambient temperature. The solution was diluted with an equal volume
of water and the ethanol was removed by evaporation along with an
estimated 50% of the aqueous volume. The pH of the solution was
adjusted to 4 with 3 M hydrochloric acid, to yield a flocculent
white solid, which was collected by filtration and washed sparingly
with cold water. After removal of granular solid from the filter,
the remaining small amount of gummy material was removed from the
filter, sonicated with water (.about.1 mL) to yield a fine solid
that was collected by filtration. After drying at room temperature
and 5 mm Hg, both samples were shown to be identical by HPLC
(Zorbax C-8, isocratic 40% 0.01 M NH.sub.4OAc in MeOH, 3 min:
gradient to 100% MeOH, 45 min: isocratic MeOH 5 min. 1.0 mL/min:
.lamda..sub.obs=210 nm, Rt=10.58 min) and combined to yield the
title compound (888 mg, 85.9% from 4-((alpha-R)-alpha-((2
S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyl
oxybenzyl)-N,N-diethylbenzamide). Calc. for
C.sub.32H.sub.39N.sub.3O.sub.4 1.5 NaCl 1.6 H.sub.2O: C, 59.48; H,
6.58; N, 6.50. Found C, 59.50; H, 6.45; N, 6.32% .sup.1H NMR
((CD.sub.3).sub.2SO+20% v/v 1-M NaOD in D.sub.2O, 300 MHz); .delta.
0.93 (d, J=6.0 Hz, 3H); 0.98 (d, J=5.9 Hz, 3H; both doublets
overlapping br m, 6H); 1.9 (m, 2H); 2.54 (m, 2H, partially obscured
by DMSO); 3.13 (br m, 2H); 3.22 (d, J=14.2 Hz, 1H); 3.34 (br m,
2H); 3.71 (d, J=14.0 Hz, 1H); 4.66 (s, 1H); 5.97 (d, J=6.9 Hz, 1H);
6.16 (d, J=7.9, 1H); 6.23 (s, 1H); 6.72 (t, J=7.7 Hz, 1H); 7.16 (d,
J=7.8 Hz, 4H); 7.38 (d, J=8.1 Hz, 2H); 7.72 (d, J=8.1 Hz, 2H). Mass
spectrum: (ESI-, DP-120V, MeOH); m/z: 529.0, (M+, 100%); 528,
((M-1)+, 57%); 512.6, ((M-17)+, 95%).
Example 14
3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethyl-
aminocarbonyl)benzyl)phenoxyacetic acid
[0244] Sodium hydride (60% dispersion in oil, 250 mg (150 mg NaH,
6.25 mmol)) was washed with anhydrous tetrahydrofuran (2.times.5
mL) and anhydrous tetrahydrofuran (10 mL) was added as supernatant.
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-Dimethyl-1-piperazinyl)-3-hydroxy-
benzyl)-N,N-diethylbenzamide hydrochloride (435 mg, 1.0 mmol,
prepared in Example 9) was dissolved in the stirred suspension, and
when effervescence had subsided, sodium iodide (15 mg, 0.1 mmol)
was added. Methyl chloroacetate (350 uL, 434 mg, 4 mmol) was added
to the stirred suspension under nitrogen and the reaction was
stirred overnight at ambient temperature. The reaction mixture was
partially neutralized by the passage of carbon dioxide gas (from
dry ice), then glacial acetic acid added until the suspension
showed a pH of 5 as measured by moistened indicator strips. The
reaction mixture was evaporated to dryness, and the residue
partitioned between ethyl acetate (10 mL) and 1 M HCl (5 mL). The
organic layer was extracted with 1 M HCl (2.times.3 mL) and the pH
of the combined acidic extracts was adjusted to 8 with saturated
sodium carbonate solution. The oily aqueous suspension was
extracted with ethyl acetate (3.times.10 mL) and the combined
organic extracts were dried over anhydrous sodium sulfate. The
solution was evaporated to a yellow gum. The residue was dissolved
in ethyl acetate and applied to an intermediate (4.times.15 cm)
silica gel Biotage column and eluted with 10% ethanol in ethyl
acetate. Fractions containing the product, as evidenced by t.l.c.
(silica, EM60F.sub.254, 10% EtOH in EtOAc, R.sub.f=0.52) were
evaporated to dryness and dried at room temperature and 2 mm Hg to
yield methyl
3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethy-
laminocarbonyl)benzyl)phenoxyacetate as a clear pale yellow gum.
The residue was dissolved in ethanol (4 mL) and aqueous sodium
hydroxide solution (2.5-M, 1.0 mL, 2.5 mmol) and stirred at room
temperature for 6 h. The solution was evaporated to remove the bulk
of the ethanol, and water (5 mL) added. Evaporation was continued
until approximately 4 mL of solution remained, a further 8 mL of
water added, and the solution was evaporated to approximately half
its volume to ensure complete removal of ethanol. A small amount of
suspended solid was removed by filtration, and the pH of the
solution was adjusted to 6 with 3 M HCl. The solution was
evaporated to dryness and the residue evaporated several times with
absolute ethanol to ensure removal of water. The residue was
extracted with ethanol (3.times.20 mL) and the combined ethanol
extracts were filtered and evaporated to dryness. The gummy residue
was triturated with ethyl acetate (5 mL), filtered, evaporated, and
dried under high vacuum to yield
3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)--
4-(diethylaminocarbonyl)benzyl)phenoxyacetic acid as a brittle
white foam (52 mg, 9.5%). Calc. for C.sub.29H.sub.39N.sub.3O.sub.4
0.9 NaCl 0.5 H.sub.2O: C, 63.45; H, 7.20; N, 7.65. Found C, 63.83;
H, 7.19; N, 7.25% .sup.1H NMR (0.1-M NaOD in D.sub.2O, 300 MHz);
.delta. 0.86 (d, J=6.3 Hz, 3H); 0.94 (t, J=7.1 Hz, 3H); 1.01 (d,
J=6.1 Hz, 3H); 1.09 (t, J=7.2 Hz, 3H); 1.81 (t, J=11.3 Hz, 1H);
2.09 (t, J=11.2 Hz, 1H); 2.43 (m, 2H); 2.73 (m, 3H); 3.13 (q, J=7.1
Hz, 2H); 3.25 (dd, J=13.5, 5.8 Hz, 1H); 3.38 (q, J=7.2 Hz, 2H);
4.32 (s, 2H); 5.09 (s, 1H): 5.14 (d, J=7.8 Hz, 1H); 5.24 (s, 1H);
5.74 (m, 1H); 6.73 (s, 1H); 6.80 (s, 2H); 7.21 (m, 3H); 7.32 (d,
J=8.2 Hz, 2H). Mass spectrum: (ESI-, -5 KV, MeOH); m/z: 493, (M+,
25%); 492.5, ((M-1)+, 100%).
Example 15
3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-(diethy-
lamino carbonyl)benzyl)phenoxyacetic acid
[0245] Alkylation of
4-((alpha-R)-alpha-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydrox-
ybenzyl)-N,N-diethylbenzamide (Example 12) with ethyl iodoacetate,
and subsequent hydrolysis of the ester as in Example 14 gave the
title compound (84.6%) .sup.1H NMR (0.1-M NaOD in CD.sub.3OD, 300
MHz); .delta. 1.10 (d, J=5.0 Hz, 3H); 1.11 (d, J=5.8 Hz, 3H; both
doublets superimposed on m, 3H); 1.23 (m, 3H); 2.03 (m, 2H); 2.57
(m, 2H); 2.69 (m, 2H); 3.30 (m, 3H, superimposed on br m, 2H); 3.88
(d, J=13.1 Hz, 1H); 4.35 (s, 2H); 5.16 (s, 1H): 6.83 (m, 2H); 6.88
(s, 1H); 7.25 (m, 8H); 7.52 (d, J=8.1 Hz, 2H). Mass spectrum:
(PFAB, glycerol matrix subtracted): m/z: 544.8, ((M+1)+, 82%).
Example 16
3-((alpha-R)-4-(Diethylaminocarbonyl)-alpha-((2S,5R)-2,5-dimethyl-4-(4-flu-
oro-benzyl)-1-piperazinyl)benzyl)phenoxyacetic acid
[0246] By an essentially similar procedure to that of Example 15,
3-((alpha-R)-4-(diethylaminocarbonyl)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fl-
uorobenzyl)-1-piperazinyl)-benzyl)phenoxyacetic acid was made from
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-hydroxybenzyl)-N,N-diethylbenzamide (product from Example 11).
Calc. for C.sub.33H.sub.40FN.sub.3O.sub.4 0.6 NaCl 1.2 H.sub.2O: C,
64.10; H, 6.91; N, 6.80; F, 3.07. Found C, 64.19; H, 6.91; N, 6.49;
F, 3.06%. .sup.1H NMR (D.sub.2O, 300 MHz); .delta. 0.95 (t, J=6.6
Hz, 3H); 1.04 (d, J=6.1 Hz, 3H); 1.09 (d, J=6.3 Hz, 3H superimposed
on 1.102 (t, J=7.2 Hz, 3H)); 2.10 (br m, 1H); 2.58 (br m, 1H); 2.79
(br t, J=10.8 Hz, 1H); 2.93 (br d, J=12.5 Hz, 1H); 3.14 (d, J=6.5
Hz, 1H, superimposed on m, 2H); 3.39 (d, J=7.3 Hz, 1H, superimposed
on m, 3H); 4.00 (m, 1H); 4.40 (s, 2H); 5.33 (br s, 1H): 6.76 (br m,
1H) overlapping 6.83 (m, 2H); 7.10 (m, 2H); 7.22 (m, 3H); 7.37 (m,
4H). Mass spectrum (PFAB, glycerol matrix subtracted); m/z: 562.1,
(M+, 82%); 340.2 ((M-222)+, 40%); 109.0 (C.sub.7H.sub.6F+,
100%).
Example 17
N,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl-
)(3-hydroxyphenyl)methyl)benzamide
[0247] 3-Carboxybenzaldehyde (15.01 g, 100 mmol) was added to a 250
mL, 3-necked round bottom flask and stirred under nitrogen in 110
mL of toluene. Thionyl chloride (8.75 mL, 120 mmol) was added to
the mixture, followed by the addition of 6 drops of DMF. A reflux
condenser fitted with a calcium chloride drying tube was placed on
the flask. The reaction was placed in an oil bath and heated at a
bath temperature maintained below 120.degree. C. The mixture was
allowed to reflux for 1 hour after a clear solution was obtained
and then cooled to room temperature. The solution was diluted with
anhydrous toluene, and all volatiles were removed under vacuum.
[0248] The crude acid chloride was dissolved in 200 mL of dry
tetrahydrofuran and cooled in an ice/water bath. Triethylamine
(27.88 mL, 200 mmol) in 70 mL of dry tetrahydrofuran was added
dropwise via an addition funnel, followed by diethylamine (10.45
mL, 100 mmol). The cloudy solution was allowed to warm to room
temperature over 1 hour and stirred overnight. Water was added and
the product was extracted with dichloromethane. The organic layer
was washed with water and saturated sodium chloride solution and
dried over sodium sulfate, and the solvent was removed under
vacuum. 3-Formyl-N,N-diethylbenzamide (17.72 g) was obtained as a
light golden oil (86% unchromatographed yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 1.04-1.18 (m, 6H); 3.17-3.45 (m, 4H);
7.65-7.66 (m, 2H); 7.85 (s, 1H); 7.93-7.94 (m, 1H); 10.03 (s,
1H).
[0249] 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 with adjustment of
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.
[0250] 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.
[0251] 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 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
C and 1000 mL of toluene was carefully added. The solution was
slowly cooled to 5 C and maintained at 5.degree. C. for 30 minutes.
The solution was filtered, and the filter cake was washed 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. NMR (300 MHz, DMSO-d.sub.6): .delta. 0.87 (d, J=6.3
Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m,
1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd, J.sub.1=5
Hz, J.sub.2=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,
1H) 5.8 (m, 1H).
[0252] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South
Plainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot
(.about.60 C) 95% ethanol (16 L) and racemic
trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) was added in
several portions (caution: exothermic). The hot solution was seeded
with crystals of the diastereoisomerically pure salt (obtained from
a previous small-scale resolution) and cooled to room temperature
over 2-3 hours. The solution was slowly stirred for 2 days at room
temperature. The resulting salt was collected by filtration, washed
twice with 95% ethanol, and dried under vacuum to give 826.5 g of a
white solid (47%). The process was repeated with a second batch of
the di-p-toluoyl-D-tartaric acid and racemic
trans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).
[0253] The total of 1695 g of salt was divided into three batches
and each batch was recrystallized twice in the following fashion.
The salt was dissolved in refluxing 95% ethanol (.about.2.7 L/100 g
of salt), and approximately half of the ethanol was removed by
distillation. (Note: vigorous stirring was necessary during
distillation to prevent crystallization on the vessel wall.) The
hot solution was seeded with crystals of the pure diastereomeric
salt, cooled to room temperature, and stirred slowly for 2 days
before collecting the salt by filtration. (Note: a subsequent
experiment suggested that crystallization time can be reduced from
2 days to 8 hours.) The total amount recovered was 1151 g. The salt
was dissolved in 3 L of 2 M aqueous sodium hydroxide, and the
aqueous solution was extracted with four 1 L portions of
dichloromethane. The organic extracts were combined, dried over
sodium sulfate, and solvent removed by rotary evaporation
(temperature <20.degree. C.) to give 293 g (29% based on racemic
weight) of (2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil.
[.alpha.].sub.D.sup.20=-55.1 (abs. ethanol, c=1.2). The
trifluoroacetamide of the product was prepared with trifluoroacetic
anhydride and analyzed by chiral capillary gas chromatography
(Chiraldex B-PH column, 20 m.times.0.32 mm, Advanced Separation
Technologies Inc., Whippany, N.J., 120.degree. C.) indicating an
enantiopurity of >99% ee (retention time of desired enantiomer,
11.7 min; other enantiomer, 10.7 min).
[0254] 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 either 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).
[0255] 3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide was
formed by the slow addition of 2.7 M n-butyllithium in heptane (150
mL, 405 mmol) to a solution of
3-bromophenoxy-tert-butyldimethylsilane (123.44 g, 429 mmol) in 500
mL anhydrous tetrahydrofuran at -70.degree. C. After stirring 45
min. this cold solution was siphoned under nitrogen into a slurry
of magnesium bromide etherate (110.62 g, 428 mmol) in 650 mL
anhydrous tetrahydrofuran at room temperature, and stirred for 45
min.
[0256] 2R,5S-1-allyl-2,5-dimethylpiperazine (2.31 g, 15 mmol),
benzotriazole (1.80 g, 15.15 mmol, 1.01 eq., Aldrich), and
3-formyl-N,N-diethylbenzamide (3.08 g, 15 mmol) were mixed in 150
mL of dry toluene with two drops of triethylamine. The mixture was
placed in an oil bath maintained below 140.degree. C. (bath
temperature). The flask was attached to a Dean-Stark trap and
reflux condenser to allow the azeotropic removal of water. The
mixture was refluxed for 2-3 hours, under a nitrogen atmosphere,
then the majority of the toluene was removed under reduced
pressure. The crude adduct was used in the following procedure
without isolation.
[0257] The crude benzotriazole adduct was dissolved in .about.20 mL
of anhydrous tetrahydrofuran under nitrogen and added to a solution
of 3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide (1.75
equiv.) via a double-ended needle. After stirring under nitrogen at
room temperature for 2 hours, the reaction was quenched with 6-8 mL
of saturated ammonium chloride solution. Having stirred this for
about half an hour, a generous amount of anhydrous magnesium
sulfate was added. Filtering and concentrating the solution under
reduced pressure gave the crude product contaminated with
benzotriazole. This residue was dissolved in ethyl acetate and
extracted with 10% aqueous NaOH solution three times to remove most
of the benzotriazole. The organic layer was washed with saturated
sodium chloride solution, dried over sodium sulfate/magnesium
sulfate, and the ethyl acetate was removed under reduced
pressure.
[0258] The t-butyldimethylsilyl protecting group was removed by
dissolving the residue in 80 mL of tetrahydrofuran and adding 80 mL
of 3N aqueous HCl at room temperature. The solution warmed upon
acid addition. The mixture was stirred for 90 minutes at room
temperature. The reaction was concentrated under reduced pressure
to remove most of the organic solvent. The residue was partitioned
between water and a solution of diethyl ether:ethyl acetate/3:2.
The acidic aqueous layer was extracted twice with a solution of
diethyl ether:ethyl acetate/3:2. The aqueous layer was adjusted to
pH=2 using aqueous NaOH solution, at which point cloudiness
persisted and a dark oil began to precipitate. Methylene chloride
(.about.100 mL) was added and stirred briskly. This was separated
and the aqueous layer was again extracted with 100 mL methylene
chloride. Water (100 mL) was added to the combined organic
extracts, and while stirring vigorously, was adjusted to pH=9 using
aqueous NaOH solution. The organic layer was separated and the
aqueous layer was again extracted with 100 mL methylene chloride.
The combined methylene chloride extract was dried over sodium
sulfate/magnesium sulfate, and the solvent was evaporated under
reduced pressure. The crude material was chromatographed on a
silica gel column (20-25 g of silica gel per gram of crude
material) eluting first with methylene chloride, then with 20%
ethyl acetate in methylene chloride to remove the less polar
contaminant. Then, the column was eluted with a solution of ethyl
acetate containing 2% ammonium hydroxide (solution A) in a gradient
with methylene chloride (solution B), quickly increasing in
polarity from 25% to 100% (solution A in B). The desired fractions
were combined and the solvent was removed under reduced pressure. A
10:1 mixture of diastereomers (approx. 2.01 g) was obtained. Pure
product was obtained by crystallization from a hot solution of
ethyl acetate (5-10 mL) followed by slow addition of heptane (10-20
mL) and gradual cooling to give 1.35 g of
(+)-3-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide as an off-white crystalline
solid with >98% isomeric purity (as determined by NMR). NMR (400
MHz, DMSO-d.sub.6): .delta. 0.91 (d, J=6.2 Hz, 3H); 0.99 (br s,
3H); 1.05 (d, J=6.2 Hz, 3H); 1.09 (br s, 3H); 1.84 (dd, J.sub.1=7.3
Hz, J.sub.2=10.9 Hz, 1H); 2.06 (dd, J.sub.1=7.3 Hz, J.sub.2=10.9
Hz, 1H); 2.48 (m, 1H); 2.51 (dd, J.sub.1=2.7 Hz, J.sub.2=10.9 Hz,
1H); 2.58 (br s, 1H); 2.70 (dd, J.sub.1=2.7 Hz, J.sub.2=10.9 Hz,
1H); 2.81 (dd, J.sub.1=7.0 Hz, J.sub.2=13.9 Hz, 1H); 3.12 (br s,
2H); 3.15 (dd, J.sub.1=5.1 Hz, J.sub.2=13.9 Hz, 1H); 3.38 (br s,
2H); 4.97 (br s, 1H); 5.07 (d, J=10.2 Hz, 1H), 5.14 (d, J=16.9 Hz,
1H); 5.70-5.82 (m, 1H); 6.64 (dd, J.sub.1=2.1 Hz, J.sub.2=8.0 Hz,
1H); 6.65 (s, 1H); 6.68 (d, J=7.7 Hz, 1H); 7.11 (t, J=8.0 Hz, 1H);
7.14 (d, J=7.6 Hz, 1H); 7.30 (s, 1H); 7.33 (t, J=7.6 Hz, 1H); 7.39
(d, J=8.0 Hz, 1H); 9.31 (s, 1H).
[0259] 3-((R)-((2
S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl
benzamide (4.35 g, 10 mmol),
N-phenylbis(trifluoromethanesulfonimide) (3.82 g, 10.7 mmol), and
triethylamine (3.1 mL, 22 mmol) were dissolved in 75 mL
dichloromethane and stirred overnight at room temperature under
nitrogen. After concentrating under reduced pressure, the residue
was dissolved in 100 mL ethyl acetate and washed with
Na.sub.2CO.sub.3 solution (3.times.100 mL), water (1.times.100 mL),
and brine (1.times.100 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 6.01 g (10.59
mmol) of 3-((alpha-R)-alpha-((2
S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybe-
nzyl)-N,N-diethylbenzamide as a viscous, golden yellow oil.
[0260] The allyl group was removed using Pd(dba)2/DPPB in the
presence of thiosalicylic acid by the method of Genet [J. P. Genet,
S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270
(1995)]. The reaction was concentrated and the residue was
dissolved in 50 mL ethyl acetate and 100 mL diethyl ether. After
washing this with Na.sub.2CO.sub.3 solution (3.times.100 mL) and
water (1.times.100 mL), the organic solution was extracted with 3 N
HCl (3.times.20 mL) and 1 N HCl (1.times.20 mL). The acidic extract
was adjusted to pH 8.5 using NaOH solution and extracted with
dichloromethane (3.times.25 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 4.39 g (8.32
mmol) of
3-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-
-sulfonyloxybenzyl)-N,N-diethylbenzamide as a viscous, deep
amber-orange colored oil.
[0261] The above free amine (0.70 g, 1.33 mmol) and
3-hydroxybenzaldehyde (0.32 g, 2.66 mmol) were placed in a 50 mL
flask and sealed under nitrogen with 15 mL of tetrahydrofuran and
83.75 .quadrature.l of acetic acid (1.46 mmol, 1.10 equiv.). The
solution was stirred at room temperature for 20 minutes, and then
sodium triacetoxyborohydride (0.56 g, 2.66 mmol) was added and
stirred for 4 hours. The reaction solution was concentrated under
reduced pressure. Ethanol (15 mL) and 10 mL of 10% NaOH solution
was added to the residue and the reaction was stirred for 30
minutes. The ethanol was removed under vacuum. Water (25 mL) and
ethyl acetate (25 mL) were added to the residue, and the pH was
adjusted to 8.5 using 6 N HCl. The ethyl acetate layer was
separated and the aqueous layer was extracted again with ethyl
acetate (2.times.25 mL). The combined ethyl acetate extract was
dried (Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (EtOAc/CH.sub.2Cl.sub.2) to give 0.52 g (1.04 mmol) of the
desired product as a white amorphous solid. The white powdery solid
was precipitated from ethyl acetate/hexanes. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz); .delta. 0.99 (d, J=6.3 Hz, 3H); 1.02 (d,
J=6.3 Hz, 3H, both doublets partially overlapped by br m, 3H); 1.08
(br m, 3H); 1.92 (m, 1H); 1.98 (m, 1H); 2.51 (m, 2H); 2.60 (m, 2H);
3.11 (d, J=13.8 Hz, 1H, overlapping br m, 2H); 3.30 (br m, 2H,
partially obscured by H.sub.2O); 3.67 (d, J=13.5 Hz, 1H); 4.97 (s,
1H); 6.56 (d, J=7.8 Hz, 1H); 6.67 (m, 4H); 7.03 (t, J=7.8 Hz, 1H);
7.13 (m, 2H); 7.36 (m, 4H); 9.18 (s, 1H); 9.32 (s, 1H). MS: 502.1
(M+1, 100%). Calculated for C.sub.31H.sub.39N.sub.3O.sub.3.0.20
C.sub.4H.sub.8O.sub.2.0.40 C.sub.6H.sub.14: C, 74.18; H, 8.41; N,
7.59. Found: C, 74.25; H, 8.36; N, 7.61.
Example 18
(-)-4-(.alpha.R)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)-N,N-diethyl-benzamide
[0262] 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.
[0263] 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, CDC.sub.l3): .delta. 0.2 (s, 6H); 1.0 (s, 9H); 6.75
(m, 1H); 7.0 (br s, 1H); 7.1 (m, 2H).
[0264] 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.
[0265] 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).
[0266] 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.
[0267] 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 diisopropylethylamine (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.
[0268] 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.
[0269] 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, J.sub.1=8.2 Hz, J.sub.2=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).
[0270] 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.
[0271] 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, J.sub.1=7.9 Hz, J.sub.2=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).
[0272] Mass spectrum (CI--CH.sub.4) m/z: 436 (M+1.12%), 282 (100%),
153 (3%). [.alpha.].sub.D.sup.2=-27.8.degree. (ethanol, c=1.2).
[0273] 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
0.75 H.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 19
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethyl-benzamide
[0274] The first isomer to elute from the column of Example 1 was
obtained as 1.39 g of a brown oil.
[0275] 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, J.sub.1=7.4 Hz,
J.sub.2=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).
[0276] 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.
[0277] 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,
J.sub.2=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).
[0278] 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 0.5 H.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 20
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide
[0279]
(-)-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.
[0280] 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). Mass spectrum (CI--CH4) m/z: 438
(M+1, 5%), 282 (100%), 155 (4%).
[.alpha.].sub.D.sup.20=-37.5.degree. (ethanol, c=1.2).
[0281] 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
0.5 H.sub.2O: C, 67.13; H, 8.55; N, 8.70. Found: C, 67.23; H, 8.55;
N, 8.49.
Example 21
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3--
hydroxybenzyl)-N,N-diethylbenzamide
[0282]
(-)-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.
[0283] 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.
[0284] 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--CH.sub.4) m/z: 438 (M+1, 12%), 282
(100%), 155 (4%). [.alpha.].sub.D.sup.20=-36.7.degree. (ethanol,
c=1.3).
[0285] 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 H.sub.2O: C,
65.90; H, 8.60; N, 8.54 Found: C, 65.72; H, 8.41; N, 8.52.
Example 22
4-((.alpha.R)-.alpha.-(2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydrox-
ybenzyl)-benzamide
[0286] 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-butyl dimethyl silyloxy)benzyl
alcohol as a yellow oil.
[0287] NMR (200 MHz, CDCl.sub.3): .delta. 0.2 (s, 6H); 0.9 (s, 6H);
5.7 (s, 1H); 6.75 (dd, J.sub.1=2 Hz, J.sub.2=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).
[0288] 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-butyl dimethyl silyloxy)benzyl
chloride as a dark oil.
[0289] NMR (200 MHz, CDCl.sub.3): .delta. 0.2 (s, 6H); 1.0 (s, 9H);
6.0 (s, 1H); 6.78 (dd, J.sub.1=1 Hz, J.sub.2=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).
[0290] 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.
[0291] 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.
[0292] 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).
[0293] 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.
[0294] 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-butyldimethylsilyloxy)benzyl)benzamide as a yellow resin.
[0295] 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).
[0296] 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.2HCl 1.5 H.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 23
(-)-3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)p-
henol
[0297] 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).
[0298] 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 with adjustment of
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 1M 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 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.
[0299] 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.
[0300] 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 l 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 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
C and 1000 mL of toluene was carefully added. The solution was
slowly cooled to 5 C and maintained at 5 C for 30 minutes. The
solution was filtered, and the filter cake was washed 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. NMR (300 MHz, DMSO-d.sub.6): .delta. 0.87 (d, J=6.3
Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m,
1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd, J.sub.1=5
Hz, J.sub.2=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,
1H) 5.8 (m, 1H).
[0301] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South
Plainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot
(-60.degree. C.) 95% ethanol (16 L) and racemic
trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) was added in
several portions (caution: exothermic). The hot solution was seeded
with crystals of the diastereoisomerically pure salt (obtained from
a previous small-scale resolution) and cooled to room temperature
over 2-3 hours. The solution was slowly stirred for 2 days at room
temperature. The resulting salt was collected by filtration, washed
twice with 95% ethanol, and dried under vacuum to give 826.5 g of a
white solid (47%). The process was repeated with a second batch of
the di-p-toluoyl-D-tartaric acid and racemic
trans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).
[0302] The total of 1695 g of salt was divided into three batches
and each batch was recrystallized twice in the following fashion.
The salt was dissolved in refluxing 95% ethanol (.about.2.7 L/100 g
of salt), and approximately half of the ethanol was removed by
distillation. (Note: vigorous stirring was necessary during
distillation to prevent crystallization on the vessel wall.) The
hot solution was seeded with crystals of the pure diastereomeric
salt, cooled to room temperature, and stirred slowly for 2 days
before collecting the salt by filtration. (Note: a subsequent
experiment suggested that crystallization time can be reduced from
2 days to 8 hours.) The total amount recovered was 1151 g. The salt
was dissolved in 3 L of 2 M aqueous sodium hydroxide, and the
aqueous solution was extracted with four 1 L portions of
dichloromethane. The organic extracts were combined, dried over
sodium sulfate, and solvent removed by rotary evaporation
(temperature <20.degree. C.) to give 293 g (29% based on racemic
weight) of (2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil.
[.alpha.].sub.D.sup.20=-55.1 (abs. ethanol, c=1.2). The
trifluoroacetamide of the product was prepared with trifluoroacetic
anhydride and analyzed by chiral capillary gas chromatography
(Chiraldex B-PH column, 20 m.times.0.32 mm, Advanced Separation
Technologies Inc., Whippany, N.J., 120.degree. C.) indicating an
enantiopurity of >99% ee (retention time of desired enantiomer,
11.7 min; other enantiomer, 10.7 min).
[0303] 3-Phenoxy-tert-butyldimethylsilane magnesium bromide was
formed by the slow addition of 2.7 M n-butyllithium in heptane (150
mL, 405 mmol) to a solution of
bromophenoxy-tert-butyldimethylsilane (123.44 g, 429 mmol) in 500
mL anhydrous tetrahydrofuran at -70.degree. C. After stirring 45
min. this cold solution was siphoned under nitrogen into a slurry
of magnesium bromide etherate (110.62 g, 428 mmol) in 650 mL
anhydrous tetrahydrofuran at room temperature, and stirred for 45
min.
[0304] Thiophene-3-carboxaldehyde (29.09 g, 259 mmol),
benzotriazole (30.91 g, 259 mmol), and
(2R,5S)-1-allyl-2,5-trans-dimethylpiperazine (40.01 g, 259 mmol)
were dissolved in 250 mL toluene and heated to a gentle reflux. The
water-toluene azeotrope was collected in a Dean-Stark trap over the
course of 2.5 hours. The remaining solvent was removed under
vacuum. The residue was dissolved in 150 mL anhydrous
tetrahydrofuran and added to a solution of
3-phenoxy-tert-butyldimethylsilane magnesium bromide in anhydrous
tetrahydrofuran (1150 mL, 0.35 M) under a nitrogen atmosphere.
[0305] The reaction was stirred at room temperature for 2 hours and
then quenched by the addition of 25 mL saturated NH.sub.4Cl
solution. Anhydrous magnesium sulfate (.about.5 g) and Celite
(.about.10 g) were added. The mixture was stirred and filtered, and
the solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate and washed first with 0.5 N NaOH
solution (5.times.200 mL) and then with brine (1.times.200 mL). The
solution was dried (Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated
under reduced pressure.
[0306] The dark residue was dissolved in 250 mL anhydrous
acetonitrile and tetraethyl-ammonium fluoride dihydrate (72.26 g,
390 mmol) was added. After stirring for 90 min. the reaction was
concentrated and the residue was dissolved in 200 mL ethyl acetate.
The mixture was extracted with dilute NaHCO.sub.3 solution
(3.times.200 mL) and with water (1.times.200 mL). The organic layer
was diluted with 200 mL diethyl ether and extracted with 10% citric
acid solution (8.times.200 mL). The combined aqueous extracts was
adjusted to pH 8.5 using 50% NaOH solution and extracted with
dichloromethane (3.times.200 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The resulting tan solid (53.25 g, 155 mmol) was
crystallized twice from 225 mL of 2:1/isopropanol: water to yield
fluffy, white needle crystals (34.14 g, 99.7 mmol),
[.alpha..quadrature.].sub.D.sup.20=-8.33.degree. (abs. ethanol,
c=1.0).
[0307] .sup.1H NMR (500 MHz, d.sub.6-DMSO): .delta.9.32 (s, 1H),
7.44 (dd, J=3.2, 4.9 Hz, 1H), 7.15 (s, 1H), 7.13 (t, J=8.25 Hz,
1H), 6.98 (d, J=4.9 Hz, 1H), 6.66-6.70 (m, 3H), 5.73-5.81 (m, 1H),
5.15 (d, J=17.1 Hz, 1H), 5.09 (d, J=10.5 Hz, 1H), 5.02 (s, 1H),
3.20 (br d, J=10.2 Hz, 1H), 2.78 (dd, J=7.3, 7.5 Hz, 1H), 2.68 (dd,
J=2.6, 11.3 Hz, 1H), 2.59 (dd, J=1, 9.3 Hz, 1H), 2.44 (br s, 2H),
2.02 (t, J=8.6 Hz, 1H), 1.81 (t, J=8.1 Hz, 1H), 1.09 (d, J=6 Hz,
3H), 0.91 (d, J=6 Hz, 3H). Calculated for
C.sub.20H.sub.26N.sub.2OS: C, 70.14; H, 7.65; N, 8.18; S, 9.36%.
Found: C, 70.19; H, 7.58; N, 8.12; S, 9.33%.
Example 24
3-((S)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phen-
ol
[0308] 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 either 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..quadrature.0.2 (s, 6H); 1.0 (s,
9H); 6.75 (m, 1H); 7.0 (br s, 1H); 7.1 (m, 2H).
[0309] 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 with adjustment of
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.
[0310] 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.
[0311] 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, and the
filter cake was washed 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. NMR (300
MHz, DMSO-d.sub.6): .delta. 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3
Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz,
1H); 2.6-2.8 (m, 4H); 3.33 (dd, J.sub.1=5 Hz, J.sub.2=14 Hz, 1H);
5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8 (m, 1H).
[0312] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South
Plainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot
(-60.degree. C.) 95% ethanol (16 L) and racemic
trans-1-allyl-2,5-dimethylpiperazine (500 g, 3.2 mol) was added in
several portions (caution: exothermic). The hot solution was seeded
with crystals of the diastereoisomerically pure salt (obtained from
a previous small-scale resolution) and cooled to room temperature
over 2-3 hours. The solution was slowly stirred for 2 days at room
temperature. The resulting salt was collected by filtration, washed
twice with 95% ethanol, and dried under vacuum to give 826.5 g of a
white solid (47%). The process was repeated with a second batch of
the di-p-toluoyl-D-tartaric acid and racemic
trans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).
[0313] The total of 1695 g of salt was divided into three batches
and each batch was recrystallized twice in the following fashion.
The salt was dissolved in refluxing 95% ethanol (.about.2.7 L/100 g
of salt), and approximately half of the ethanol was removed by
distillation. (Note: vigorous stirring was necessary during
distillation to prevent crystallization on the vessel wall.) The
hot solution was seeded with crystals of the pure diastereomeric
salt, cooled to room temperature, and stirred slowly for 2 days
before collecting the salt by filtration. (Note: a subsequent
experiment suggested that crystallization time can be reduced from
2 days to 8 hours.) The total amount recovered was 1151 g. The salt
was dissolved in 3 L of 2 M aqueous sodium hydroxide, and the
aqueous solution was extracted with four 1 L portions of
dichloromethane. The organic extracts were combined, dried over
sodium sulfate, and solvent removed by rotary evaporation
(temperature <20.degree. C.) to give 293 g (29% based on racemic
weight) of (2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil.
[.alpha.].sub.D.sup.20=-55.1 (abs. ethanol, c=1.2). The
trifluoroacetamide of the product was prepared with trifluoroacetic
anhydride and analyzed by chiral capillary gas chromatography
(Chiraldex B-PH column, 20 m.times.0.32 mm, Advanced Separation
Technologies Inc., Whippany, N.J., 120.degree. C.) indicating an
enantiopurity of >99% ee (retention time of desired enantiomer,
11.7 min; other enantiomer, 10.7 min).
[0314] 3-Phenoxy-tert-butyldimethylsilane magnesium bromide was
formed by the slow addition of 2.7 M n-butyllithium in heptane (150
mL, 405 mmol) to a solution of
3-bromophenoxy-tert-butyldimethylsilane (123.44 g, 429 mmol) in 500
mL anhydrous tetrahydrofuran at -70.degree. C. After stirring 45
min. this cold solution was siphoned under nitrogen into a slurry
of magnesium bromide etherate (110.62 g, 428 mmol) in 650 mL
anhydrous tetrahydrofuran at room temperature, and stirred for 45
min.
[0315] Thiophene-3-carboxaldehyde (29.09 g, 259 mmol),
benzotriazole (30.91 g, 259 mmol), and
(2R,5S)-1-allyl-2,5-trans-dimethylpiperazine (40.01 g, 259 mmol)
were dissolved in 250 mL toluene and heated to a gentle reflux. The
water-toluene azeotrope was collected in a Dean-Stark trap over the
course of 2.5 hours. The remaining solvent was removed under
vacuum. The residue was dissolved in 150 mL anhydrous
tetrahydrofuran and added to a solution of
3-phenoxy-tert-butyldimethylsilane magnesium bromide in anhydrous
tetrahydrofuran (1150 mL, 0.35 M) under a nitrogen atmosphere.
[0316] The reaction was stirred at room temperature for 2 hours and
then quenched by the addition of 25 mL saturated NH.sub.4Cl
solution. Anhydrous magnesium sulfate (.about.5 g) and Celite
(.about.10 g) were added. The mixture was stirred and filtered, and
the solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate and washed first with 0.5 N NaOH
solution (5.times.200 mL) and then with brine (1.times.200 mL). The
solution was dried (Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated
under reduced pressure.
[0317] The dark residue was dissolved in 250 mL anhydrous
acetonitrile and tetraethyl-ammonium fluoride dihydrate (72.26 g,
390 mmol) was added. After stirring for 90 min. the reaction was
concentrated and the residue was dissolved in 200 mL ethyl acetate.
The mixture was extracted with dilute NaHCO.sub.3 solution
(3.times.200 mL) and with water (1.times.200 mL). The organic layer
was diluted with 200 mL diethyl ether and extracted with 10% citric
acid solution (8.times.200 mL). The combined aqueous extracts was
adjusted to pH 8.5 using 50% NaOH solution and extracted with
dichloromethane (3.times.200 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The resulting tan solid (53.25 g, 155 mmol) was
crystallized twice from 225 mL of 2:1/isopropanol: water to yield
fluffy, white needle crystals (34.14 g, 99.7 mmol) of
3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phen-
ol.
[0318] .sup.1H NMR (500 MHz, d.sub.6-DMSO): .delta..quadrature.9.32
(s, 1H), 7.44 (dd, J=3.2, 4.9 Hz, 1H), 7.15 (s, 1H), 7.13 (t,
J=8.25 Hz, 1H), 6.98 (d, J=4.9 Hz, 1H), 6.66-6.70 (m, 3H),
5.73-5.81 (m, 1H), 5.15 (d, J=17.1 Hz, 1H), 5.09 (d, J=10.5 Hz,
1H), 5.02 (s, 1H), 3.20 (br d, J=10.2 Hz, 1H), 2.78 (dd, J=7.3, 7.5
Hz, 1H), 2.68 (dd, J=2.6, 11.3 Hz, 1H), 2.59 (dd, J=1, 9.3 Hz, 1H),
2.44 (br s, 2H), 2.02 (t, J=8.6 Hz, 1H), 1.81 (t, J=8.1 Hz, 1H),
1.09 (d, J=6 Hz, 3H), 0.91 (d, J=6 Hz, 3H). Calculated for
C.sub.20H.sub.26N.sub.2OS: C, 70.14; H, 7.65; N, 8.18; S, 9.36%.
Found: C, 70.19; H, 7.58; N, 8.12; S, 9.33%.
[0319] 3-((S)-((2
S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol
(8.56 g, 25 mmol), N-phenyltrifluoromethanesulfonimide (9.86 g,
27.6 mmol), and triethylamine (8.0 mL, 57.1 mmol) were dissolved in
75 mL dichloromethane and stirred overnight at room temperature
under nitrogen. After concentrating under reduced pressure, the
residue was dissolved in 150 mL ethyl acetate and washed with
Na.sub.2CO.sub.3 solution (3.times.150 mL), water (1.times.100 mL),
and brine (1.times.100 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 11.8 g (24.8
mmol) of a viscous, light yellow oil.
[0320] The allyl portion was removed using Pd(dba).sub.2/DPPB in
the presence of thiosalicylic acid by the method of Genet [J. P.
Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36,
1267-1270 (1995)]. The reaction was concentrated and the residue
was dissolved in 50 mL ethyl acetate and 100 mL diethyl ether.
After washing this with Na.sub.2CO.sub.3 solution (3.times.150 mL)
and water (1.times.100 mL), the organic solution was extracted with
3 N HCl (2.times.20 mL) and 1 N HCl (2.times.20 mL). The acidic
extract was adjusted to pH 8.5 using NaOH solution and extracted
with dichloromethane (3.times.50 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 8.83 g (20.3
mmol) of a viscous, light amber oil.
[0321] The above free amine (1.09 g, 2.5 mmol) was combined with
anhydrous sodium carbonate powder (1.50 g, 14.1 mmol), 10 mL
anhydrous acetonitrile, and benzyl bromide (0.33 mL, 2.75 mmol).
The reaction was stirred overnight at room temperature under
nitrogen, and then concentrated under reduced pressure. The residue
was suspended in 15 mL ethanol, 10 mL of 10% NaOH solution was
added, and the reaction was stirred for 1 hour. The ethanol was
removed under vacuum and the residue was partitioned between water
and dichloromethane. The solution was adjusted to pH 8.5 using 3 N
HCl, separated and extracted again with dichloromethane (2.times.25
mL). The solution was dried (Na.sub.2SO.sub.4/MgSO.sub.4) and
concentrated under reduced pressure. The residual oil was purified
by chromatography on silica gel (2% NH.sub.4OH in
EtOAc/CH.sub.2Cl.sub.2) to give 0.81 g (1.93 mmol) of
3-((S)-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phe-
nol as a white foam.
[0322] .sup.1H NMR (500 MHz, d.sub.6-DMSO): .delta. 9.33 (s, 1H),
7.45 (dd, J=3, 4.9 Hz, 1H), 7.25-7.36 (m, 4H), 7.17-7.21 (m, 2H),
7.13 (t, J=7.8 Hz, 1H), 6.99 (d, J=4.9 Hz, 1H), 6.66-6.71 (m, 3H),
5.00 (s, 1H), 3.81 (d, J=13.2 Hz, 1H), 3.15 (d, J=12.9 Hz, 1H),
2.65 (dd, J=2.6, 11.2 Hz, 1H), 2.58 (dd, J=2.4, 11 Hz, 1H), 2.42
(br s, 1H), 1.86-1.94 (m, 2H), 1.02 (d, J=5.7 Hz, 3H), 1.01 (d,
J=5.7 Hz, 3H). MS: 393 (M+1, 100%), 189 (32%). Calculated for
C.sub.24H.sub.28N.sub.2OS 0.3 C.sub.4H.sub.8O: C, 72.24; H, 7.31;
N, 6.69; S, 7.65%. Found: C, 72.23; H, 7.24; N, 6.74; S, 7.74%.
[0323] This material was converted to the hydrochloride salt and
precipitated from CH.sub.2Cl.sub.2/Et.sub.2O as an amorphous, white
solid. Calculated for C.sub.24H.sub.28N.sub.2OS 0.3
C.sub.4H.sub.10O.1.3 HCl: C, 65.49; H, 7.04; N, 6.06; S, 6.94; Cl,
9.97%. Found: C, 65.70; H, 7.34; N, 6.09; S, 6.97; Cl, 9.95%.
Example 25
3-((S)-((2S,5R)-4-(2,6-Difluorobenzyl)-2,5-dimethyl-1-piperazinyl)(3-thien-
yl) methyl)phenol
[0324] The compound of this Example was prepared by following the
synthesis procedure as described in Example 24 using
2,6-difluorobenzyl bromide.
[0325] The free base was obtained as an off-white foam in 84% yield
from
3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phen-
ol.
[0326] .sup.1H NMR (500 MHz, d.sub.6-DMSO): .delta. 9.31 (s, 1H);
7.45 (dd, J=3.0, 4.9 Hz, 1H); 7.35-7.38 (m, 1H); 7.13 (s, 1H); 7.12
(t, J=7.7 Hz, 1H); 7.05 (t, J=7.8 Hz, 1H); 7.02-7.07 (m, 1H); 6.96
(d, J=4.9 Hz, 1H); 6.66 (br d, J=8.0 Hz, 2H); 6.64 (br s, 1H); 5.02
(s, 1H); 3.83 (d, J=12.6 Hz, 1H); 3.26 (d, J=7.4 Hz, 1H); 2.58-2.62
(m, 2H); 2.50 (m, 1H--obscured by DMSO peak); 2.45 (m, 1H); 2.32
(m, 1H); 1.97 (t, J=9.2 Hz, 1H); 1.77 (m, 1H); 1.05 (d, J=6.0 Hz,
3H); 1.01 (d, J=6.0 Hz, 3H).
[0327] This material was converted to the hydrochloride salt and
precipitated from CH.sub.2Cl.sub.2/Et.sub.2O as an amorphous,
off-white solid. Calculated for C.sub.24H.sub.26F.sub.2N.sub.2OS
0.1 C.sub.4H.sub.10O.0.6 H.sub.2O.1.05 HCl: C, 60.43; H, 6.07; N,
5.78; S, 6.61; Cl, 7.68%. Found: C, 60.33; H, 6.02; N, 5.71; S,
6.46; Cl, 7.55%. MS: 429 (M+1, 100%), 189 (11%).
Example 26
(+)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-
-(3-fluorophenyl)-N-methylbenzamide
[0328] 3-Fluoro-N-methylaniline was prepared from 3-fluoroaniline
using a modified reductive amination. First,
1-hydroxymethylbenzotriazole was prepared by adding 37% aqueous
formaldehyde to benzotriazole at 40.degree. C. in a 1:1 ratio and
cooling to room temperature to precipitate the product. After
filtration the hydroxymethylbenzotriazole (125 g) was heated to
reflux in toluene with 3-fluoroaniline (92.2 g). Water was removed
azeotropically using a Dean-Stark trap. After three hours, the
mixture was cooled to room temperature, then refrigerated for
several hours to complete precipitation. The white crystalline
solid was collected by filtration, yielding 174.2 g (86.6%) of
1-((3-fluoroanilino)methyl)-1H-benzotriazole.
[0329] 1-((3-Fluoroanilino)methyl)-1H-benzotriazole (173.9 g) was
slurried in dry tetrahydrofuran. Sodium borohydride (32.5 g) was
added portionwise to the mixture at room temperature. After
addition was complete, the mixture was heated at reflux for 4
hours. The solution was cooled and poured slowly into 400 mL of 5 M
hydrochloric acid with ice and stirred for 1 hour at room
temperature. The solution pH was adjusted to 9-10 using 10 M sodium
hydroxide solution. The product was extracted using diethyl ether.
The ether extracts were washed successively with 1 M sodium
hydroxide solution, saturated sodium chloride solution, and water.
The organic phase was dried over sodium sulfate and evaporated
under reduced pressure to yield 87.5 g (97%) of
3-fluoro-N-methylaniline as a colorless oil. [NMR (200 MHz,
DMSO-d.sub.6): .delta. 2.76 (s, 3H); 3.41 (br s, 1H); 6.59-6.92 (m,
3H); 7.27 (q, J=8.0 Hz, 1H)].
[0330] 3-Carboxybenzaldehyde was slurried in thionyl chloride (6
mL). A reflux condenser fitted with a calcium chloride drying tube
was placed on the flask. The reaction was placed in an oil bath and
heated at a bath temperature maintained below 100.degree. C. The
mixture was allowed to reflux until a clear solution was obtained
and for 5-10 additional minutes before cooling to room temperature.
The solution was diluted with anhydrous toluene, and all volatiles
were removed under vacuum.
[0331] The crude acid chloride was dissolved in dichloromethane and
cooled in an ice/water bath. Triethylamine (6 mL) was added
dropwise via an addition funnel, followed by
N-methyl-3-fluoroaniline (1.83 g) in dichloromethane. The cloudy
solution was allowed to warm to room temperature over 1 hour. Water
was added and the product was extracted with dichloromethane. The
organic layer was washed with water and saturated sodium chloride
solution and dried over sodium sulfate, and the solvent was removed
under vacuum. N-(3-Fluorophenyl)-3-formyl-N-methylbenzamide (3.20
g) was obtained as a light golden oil (93% unchromatographed
yield). [NMR (300 MHz, DMSO-d.sub.6): .delta. 3.38 (s, 3H);
6.94-7.02 (m, 2H); 7.18-7.29 (m, 2H); 7.46 (t, J=7.7 Hz, 1H) 7.55
(d, J=7.6 Hz, 1H); 7.81 (m, 2H); 9.90 (s, 1H)].
[0332] 2R,5S-1-Allyl-2,5-dimethylpiperazine (as prepared in Example
1, 1.28 g, 8.3 mMol.), benzotriazole (1.00 g, 8.4 mMol., 1.01 eq.,
Aldrich), and N-(3-fluorophenyl)-3-formyl-N-methylbenzamide (2.14
g, 8.3 mMol.) were mixed in 80 mL of dry toluene with one drop of
triethylamine. The mixture was placed in an oil bath maintained
below 140.degree. C. (bath temperature. The flask was attached to a
Dean-Stark trap and reflux condenser to allow the azeotropic
removal of water. The mixture was refluxed for 2-3 hours, under a
nitrogen atmosphere, then the majority of the toluene was removed
under reduced pressure. The crude adduct was used in the following
procedure without isolation.
[0333] The crude benzotriazole adduct was dissolved in .about.10 mL
of tetrahydrofuran and added to a solution of
3-phenoxy-tert-butyldimethylsilane magnesium bromide (as prepared
in Example 17, 1.75 equiv.) via a double-ended needle. After
stirring under nitrogen at room temperature for 2 hours, the
reaction was quenched with 3-4 mL of saturated ammonium chloride
solution. Having stirred this for about half an hour, a generous
amount of anhydrous magnesium sulfate was added. Filtering and
concentrating the solution under reduced pressure gave the crude
silyl ether contaminated with benzotriazole by-product. This
residue was dissolved in ethyl acetate and extracted with 10%
aqueous NaOH solution three times to remove most of the
benzotriazole. The organic layer was washed with saturated sodium
chloride solution, dried over sodium sulfate/magnesium sulfate, and
the ethyl acetate was removed under reduced pressure.
[0334] The t-butyldimethylsilyl protecting group was removed by
dissolving the residue in 40 mL of tetrahydrofuran and adding 40 mL
of 3N aqueous HCl at room temperature. The solution warmed upon
acid addition. The mixture was stirred for 90 minutes at room
temperature. The reaction was concentrated under reduced pressure
to remove most of the organic solvent. The residue was partitioned
between water and a solution of diethyl ether:ethyl acetate/3:2.
The acidic aqueous layer was extracted twice with a solution of
diethyl ether:ethyl acetate/3:2.
[0335] The aqueous layer was adjusted to pH=2 using aqueous NaOH
solution, at which point cloudiness persisted and a dark oil began
to precipitate. Methylene chloride (.about.100 mL) was added and
stirred briskly. This was separated and the aqueous layer was again
washed with more methylene chloride. The combined organic extract
was partitioned with water, and while stirring vigorously was
adjusted to pH=9 using aqueous NaOH solution. This was then
separated and the aqueous layer was again washed with more
methylene chloride.
[0336] The combined extract was dried over sodium sulfate/magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
crude material was chromatographed on silica gel column (roughly
20-25 g of silica gel per gram of crude material) eluting first
with methylene chloride, then with 20% ethyl acetate in methylene
chloride to remove the less polar contaminant. Then, the column was
eluted with a solution of ethyl acetate containing 2% ammonium
hydroxide (solution A) in a gradient with methylene chloride
(solution B), quickly increasing in polarity from 25% to 100%
(solution A in B).
[0337] The desired fractions were combined and the solvent was
removed under reduced pressure. A 10:1 mixture of diastereomers
(approx. 2.6 g) was obtained. Pure product was obtained by
crystallization from a hot solution of ethyl acetate (5-10 mL)
followed by slow addition of heptane (10-20 mL) and gradual cooling
to give 1.78 g of (+)-3-((.alpha.R)-.alpha.-((2
S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophe-
nyl)-N-methylbenzamide as an off-white crystalline solid
(m.p.=144-145.degree. C.) with >98% isomeric purity (as
determined by NMR). NMR (200 MHz, DMSO-d.sub.6): .delta. 0.84 (d,
J=6.0 Hz, 3H); 0.97 (d, J=5.9 Hz, 3H); 1.69 (dd, J.sub.1=7.7 Hz,
J.sub.2=10.7 Hz, 1H); 2.01 (dd, J.sub.1=7.4 Hz, J.sub.2=10.7 Hz,
1H); 2.28 (br. d, J=8.3 Hz, 1H); 2.40-2.52 (m, 2H); 2.67 (br d,
J=10.5 Hz, 1H); 2.82 (dd, J.sub.1=7.6 Hz, J.sub.2=13.2 Hz, 1H);
3.17 (br. d, J=14.0 Hz, 1H); 3.34 (s, 3H); 4.80 (s, 1H); 5.10 (d,
J=10.1 Hz, 1H); 5.17 (d, J=17.3 Hz, 1H); 5.70-5.84 (m, 1H); 6.42
(d, J=7.1 Hz, 1H); 6.56 (s, 1H); 6.65 (d, J=8.3 Hz, 1H); 6.90-7.32
(m, 9H); 9.31 (s, 1H). Mass spectrum (CI--CH.sub.4) m/z: 488 (m+1,
100%), 334 (39%), 153 (87%). [.alpha.].sub.D.sup.20=+4.9.degree.
(abs. ethanol, c=1.2).
Example 27
3-((R)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-
-fluorophenyl)-N-methylbenzamide
[0338] 3-((R)-((2
S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluoro
phenyl)-N-methylbenzamide (Example 26, 4.88 g, 10 mmol),
N-phenyltrifluoromethane-sulfonimide (3.82 g, 10.7 mmol), and
triethylamine (3.1 mL, 22 mmol) were dissolved in 75 mL
dichloromethane and stirred overnight at room temperature under
nitrogen. After concentrating under reduced pressure, the residue
was dissolved in 100 mL ethyl acetate and washed with
Na.sub.2CO.sub.3 solution (3.times.100 mL), water (1.times.100 mL),
and brine (1.times.100 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 6.1 g (9.8
mmol) of a viscous, golden yellow oil.
[0339] The allyl portion was removed using Pd(dba).sub.2/DPPB in
the presence of thiosalicylic acid by the method of Genet [J. P.
Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36,
1267-1270 (1995)]. The reaction was concentrated and the residue
was dissolved in 50 mL ethyl acetate and 100 mL diethyl ether.
After washing this with Na.sub.2CO.sub.3 solution (3.times.100 mL)
and water (1.times.100 mL), the organic solution was extracted with
3 N HCl (3.times.20 mL) and 1 N HCl (1.times.20 mL). The acidic
extract was adjusted to pH 8.5 using NaOH solution and extracted
with dichloromethane (3.times.25 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 4.44 g (7.6
mmol) of a viscous, deep amber-orange colored oil.
[0340] The above free amine (0.867 g, 1.5 mmol) was combined with
anhydrous sodium carbonate powder (0.81 g, 7.64 mmol), 10 mL
anhydrous acetonitrile, and benzyl bromide (0.20 mL, 1.68 mmol).
The reaction was stirred overnight at room temperature under
nitrogen, and then concentrated under reduced pressure. The residue
was suspended in 15 mL ethanol, 10 mL of 10% NaOH solution was
added, and the reaction was stirred for 30 minutes. The ethanol was
removed under vacuum and the residue was partitioned between water
and dichloromethane. The solution was adjusted to pH 8.5 using 3 N
HCl, separated and extracted again with dichloromethane (2.times.25
mL). The solution was dried (Na.sub.2SO.sub.4/MgSO.sub.4) and
concentrated under reduced pressure. The residual oil was purified
by chromatography on silica gel (2% NH.sub.4OH in
EtOAc/CH.sub.2Cl.sub.2) to give 0.44 g (0.82 mmol) of the desired
product as a white foam.
[0341] .sup.1H NMR (500 MHz, d.sub.6-DMSO): .delta. 9.32 (s, 1H),
7.19-7.30 (m, 10H), 7.05-7.09 (m, 2H), 6.98 (dt, J=2.3, 8.4 Hz,
1H), 6.89 (dd, J=1.0, 8.0 Hz, 1H), 6.63 (dd, J=1.0, 8.0 Hz, 1H),
6.57 (br s, 1H), 6.43 (d, J=7.4 Hz, 1H), 4.77 (br s, 1H), 3.77 (d,
J=13.7 Hz, 1H), 3.36 (s, 3H), 3.21 (d, J=13.7 Hz, 1H), 2.59 (d,
J=9.0 Hz, 1H), 2.50 (m, 2H--obscured by DMSO peak), 2.35 (d, J=9.0
Hz, 1H), 1.92 (dd, J=7.4, 10.9 Hz, 1H), 1.74 (dd, J=7.4, 10.9 Hz,
1H), 0.99 (d, J=6.1 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H). MS: 538 (M+1,
100%), 334 (20%). Calculated for
C.sub.34H.sub.36FN.sub.3O.sub.2.0.15 C.sub.4H.sub.8O.sub.2.0.06
CH.sub.2Cl.sub.2: C, 74.88; H, 6.77; N, 7.56; F, 3.42%. Found: C,
74.72; H, 6.96; N, 7.38; F, 3.79%.
[0342] This material was converted to the hydrochloride salt and
precipitated from CH.sub.2Cl.sub.2/Et.sub.2O as an amorphous,
off-white solid. Calculated for C.sub.34H.sub.36FN.sub.3O.sub.2.0.1
C.sub.4H.sub.10O.1.1 HCl 0.1 H.sub.2O: C, 70.39; H, 6.58; N, 7.16;
Cl, 6.64%. Found: C, 70.41; H, 6.56; N, 7.13; Cl, 6.60%.
Example 28
3-((R)-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybe-
nzyl)-N-(3-fluoro-phenyl)-N-methylbenzamide
[0343] The compound of this Example was prepared by following the
synthesis procedure as described in Example 27 using 4-fluorobenzyl
bromide.
[0344] The free base was obtained as an off-white foam in 58% yield
from
3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-
-fluorophenyl)-N-methylbenzamide.
[0345] .sup.1H NMR (600 MHz, d.sub.6-DMSO): .delta. 9.29 (s, 1H),
7.16-7.29 (m, 7H), 7.02-7.10 (m, 4H), 6.97 (dt, J=2.3, 8.4 Hz, 1H),
6.88 (dd, J=1.2, 8.0 Hz, 1H), 6.61 (dd, J=1.2, 8.0 Hz, 1H), 6.55
(br s, 1H), 6.42 (br d, J=7.3 Hz, 1H), 4.74 (br s, 1H), 3.71 (br d,
J=13.0 Hz, 1H), 3.34 (s, 3H), 3.19 (br d, J=13.0 Hz, 1H), 2.56 (d,
J=9.0 Hz, 1H), 2.48 (m, 2H--obscured by DMSO peak), 2.32 (d, J=9.0
Hz, 1H), 1.90 (dd, J=7.2, 11.1 Hz, 1H), 1.72 (dd, J=7.2, 11.1 Hz,
1H), 0.97 (d, J=6.1 Hz, 3H), 0.90 (d, J=6.1 Hz, 3H). MS: 556 (M+1,
100%), 334 (26%).
[0346] This material was converted to the hydrochloride salt and
precipitated from CH.sub.2Cl.sub.2/Et.sub.2O as an amorphous,
off-white solid. Calculated for
C.sub.34H.sub.35F.sub.2N.sub.3O.sub.2.0.5 H.sub.2O 0.95 HCl: C,
68.14; H, 6.21; N, 7.01; Cl, 5.62%. Found: C, 68.17; H, 6.27; N,
6.91; Cl, 5.63%.
Example 29
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-
-3-methoxybenzyl)-N,N-diethylbenzamide
[0347] Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH,
10 mmol)) was washed with pentane (2.times.7 mL), and
tetrahydrofuran (10 mL) was added. The product from Example 11,
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.007 g, 2.0 mmol) was
dissolved in the stirred suspension, and when effervescence had
subsided, methyl iodide (249 .delta.L, 568 mg, 4 mmol) was added.
The reaction mixture was sealed under nitrogen and stirred for 6 h
at ambient temperature. The reaction mixture was evaporated to
dryness, and the residue was partitioned between ethyl acetate (15
mL) and water (5 mL). The organic layer was separated, the aqueous
portion extracted with ethyl acetate (2.times.10 mL) and the
combined organic extracts were dried over anhydrous sodium sulfate.
The organic solution was evaporated to a pale yellow gum, which on
trituration and sonication with pentane yielded
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid
(0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc.
for C.sub.32H.sub.40FN.sub.3O.sub.2 0.25 H.sub.2O: C, 73.60; H,
7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%
.sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.09 (d, J=6.2 Hz, 6H,
superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br
m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H);
3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H);
6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26
(m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Example 30
N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3-hydroxybenzyl)-2,5-dimethylpiperazin-1-yl-
](3-methoxyphenyl)methyl]benzamide
[0348] The title compound was made in identical fashion to the
compound of Example 17, with the exception that 3-methoxyphenyl
magnesium bromide was substituted for
3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide. Calc. for
C.sub.32H.sub.41N.sub.3O.sub.3.HCl: C, 66.98; H, 7.75; N, 7.32; Cl,
6.80. Found: C, 66.92; H, 7.64; N, 7.21; Cl, 6.61.
Example 31
N,N-Diethyl-3-{(R)-(3-hydroxyphenyl)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dime-
thylpiperazin-1-yl]methyl}benzamide
[0349] The title compound was made in identical fashion to the
compound of Example 17, with the exception that
3-methoxybenzaldehyde was substituted for 3-hydroxybenzaldehyde.
Calc. for C.sub.32H.sub.41N.sub.3O.sub.3.HCl.H.sub.2O: C, 67.41; H,
7.78; N, 7.37; Cl, 6.22. Found: C, 66.80; H, 7.73; N, 7.21; Cl,
6.63.
Example 32
(3-{(2R,5S)-4-[(R)-(3-Diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-
-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid
[0350] 3-Hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dissolved in
25 mL of dry tetrahydrofuran under nitrogen with 3.5 g of potassium
carbonate and 3.01 g (18.0 mmol) of ethyl bromoacetate. The
reaction was heated at reflux for 6 hr, then cooled to room
temperature and filtered from inorganic salts. The filtrate was
evaporated, redissolved in 30 mL of methylene chloride, washed with
2.times.15 mL of water, and dried over sodium sulfate. Evaporation
of solvent gave 2.92 of ethyl 3-formylphenoxyacetate as a yellow
oil.
[0351]
3-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoro-
methyl-sulfonyloxybenzyl)-N,N-diethylbenzamide (0.79 g, 1.5 mmol,
as made in Example 17) and ethyl 3-formylphenoxyacetate (0.62 g,
3.0 mmol) were placed in a 50 mL flask and sealed under nitrogen
with 15 mL of tetrahydrofuran and 100 mg of acetic acid. The
solution was stirred at room temperature for 20 minutes, and then
sodium triacetoxyborohydride (0.96 g, 4.00 mmol) was added and the
reaction was stirred overnight. The reaction mixture was diluted
with 100 mL of ethyl acetate, washed with aqueous sodium carbonate
and brine, and dried over anhydrous sodium sulfate. Evaporation of
solvent gave 1.2 g of yellow oil. The crude diester was purified by
chromatography on silica gel with 20% ethyl acetate in methylene
chloride to give 0.56 g of ethyl
(3-{(2R,5S)-4-[(R)-(3-diethylcarbamoylphenyl)-(3-trifluoromethylsulfonylo-
xyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetate.
The product was dissolved in 8 mL of 95% ethanol with 80 mg of
sodium hydroxide and stirred overnight. The ethanol was evaporated
and the aqueous solution was extracted with 2.times.2 mL of 1:1
diethyl ether/ethyl acetate. Dilute hydrochloric acid was added
dropwise to the aqueous layer to give maximum precipitate, which
was collected by filtration. The collected yellow solid was
triturated with a mixture of diethyl ether (4 mL), methanol (4 mL),
hexane (2 mL), and ethyl acetate (1.5 mL) and filtered. The
remaining solid was collected by filtration and dissolved in 5 mL
of methylene chloride. Diethyl ether was added with stirring to
precipitate the product, which was collected by filtration and
dried to give 277 mg of
(3-{(2R,5S)-4-[(R)-(3-diethylcarbamoylphenyl)-(3-hydroxyphenyl)-methyl]-2-
,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid as a white
solid. Calc. for C.sub.33H.sub.41N.sub.3O.sub.51.4
CH.sub.2Cl.sub.2: C, 60.89; H, 6.51; N, 6.19. Found: C, 60.98; H,
6.56; N, 6.23.
Example 33
(3-{(2R,5S)-4-[(R)-(3-Diethylcarbamoylphenyl)-(3-methoxyphenyl)methyl]-2,5-
-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid
[0352] The title compound was made from the compound of Example 30
by alkylating with methyl chloroacetate according to the procedure
of Example 14. Calc. for C.sub.34H.sub.43N.sub.3O.sub.5.0.65
CH.sub.2Cl.sub.2: C, 66.17; H, 7.10; N, 6.68. Found: C, 66.15; H,
7.49; N, 6.51.
Example 34
N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl-
](3-methoxyphenyl)methyl]benzamide
[0353] The title compound was made in identical fashion to the
compound of Example 17 by substituting 3-methoxyphenyl magnesium
bromide for 3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide
and by substituting 3-methoxybenzaldehyde for
3-hydroxybenzaldehyde. Calc. for C.sub.33H.sub.43N.sub.3O.sub.3.1.6
HCl: C, 67.40; H, 7.64; N, 7.15; Cl, 9.65. Found: C, 67.39; H,
7.66; N, 7.00; Cl, 9.61.
Example 35
4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperaziny-
l)-3-hydroxybenzyl)-N,N-diethylbenzamide
[0354] The title compound was made from
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-
sulfonyloxybenzyl)-N,N-diethylbenzamide (Example 10) by an
essentially identical procedure as Example 11, using
cyclopropylmethyl bromide as the alkylating agent. Calc. for
C.sub.33H.sub.43N.sub.3O.sub.3.0.75 H.sub.2O: C, 72.61; H, 8.81; N,
9.07. Found: C, 72.50; H, 8.56; N, 8.68.
Example 36
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-diethylbenzamide
[0355] A solution of
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-
-sulfonyloxybenzyl)-N,N-diethylbenzamide (3.522 g, 6.0 mmol,
Example 10) and sodium iodide (90 mg, 0.6 mmol) in acetonitrile (30
mL) was stirred during the addition of triethylamine (3.0 mL, 2.186
g, 21.6 mmol) followed by 3-fluorobenzyl bromide (1.472 mL, 2.268
g, 12.0 mmol). An immediate turbidity was observed, thickening to a
white crystalline precipitate as the reaction progressed. The
reaction mixture was sealed under nitrogen and stirred at room
temperature. After 18 h the solvent was removed by evaporation
under reduced pressure and the residue partitioned between ethyl
acetate (30 mL) and saturated sodium bicarbonate solution (10 mL).
The organic layer was separated and the aqueous portion further
extracted with ethyl acetate (3.times.15 mL). The combined extract
and washings were dried over sodium sulfate, the solution
evaporated to dryness and re-dissolved in ethyl acetate (.about.5
mL). The solution was applied to an intermediate (4.times.15 cm)
Biotage column and eluted with ethyl acetate, collecting fractions
of 20 mL. Fractions containing pure material as evidenced by thin
layer chromatography (silica, EM60F.sub.254, developed with ethyl
acetate, R.sub.f 0.9) were pooled and evaporated to yield a
yellow/orange oil (3.01 g). The oil was dissolved in ethanol (30
mL) and aqueous sodium hydroxide solution (10.0 mL, 2.5-M, 25 mmol)
was added. The initially cloudy suspension clarified to a yellow
solution that was set aside at room temperature for 3 h. The
mixture was evaporated under reduced pressure to remove ethanol,
and evaporation continued until condensation of water indicated
complete removal of ethanol. The cloudy suspension of the oily
sodium salt of the phenol was diluted to 20 mL with water to yield
a clear yellow solution. The pH of the strongly basic solution was
adjusted to 8.5-9 by passage of carbon dioxide gas (from dry ice)
to yield a dense white flocculent precipitate. The solid was
removed by filtration and washed thoroughly with cold water,
including twice re-slurrying of the precipitate on the sinter with
fresh water. The solid was air-dried on the sinter overnight, then
dried under vacuum at 1 mm Hg at room temperature to yield
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl-
)-3-hydroxybenzyl)-N,N-diethylbenzamide as a white solid (2.062 g,
67%) Calc. for C.sub.31H.sub.38FN.sub.3O.sub.2 0.5 H.sub.2O: C,
72.63; H, 7.67; N, 8.20; F, 3.71. Found C, 72.77; H, 7.52; N, 8.18;
F, 3.61%. .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.05 (d, J=5.9
Hz, 6H); 1.11 (br m, 3H); 1.23 (br m, 3H); 2.00 (m, 2H); 2.59 (br
m, 2H); 2.62 (d, J=11.4 Hz, 1H); 2.68 (d, J=11.0 Hz, 1H); 3.19 (d,
J=13.6 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.89 (d, J=13.9
Hz, 1H); 5.01 (s, 1H); 6.15 (v br s, 1H); 6.63 (s, 1H); 6.70 (m,
2H); 6.91 (t, J=8.8 Hz, 1H); 7.07 (m, 2H); 7.14 (t, J=7.8 Hz, 1H);
7.22 (m, 1H); 7.28 (d, J=8.2 Hz, 2H); 7.44 (d, J=8.1 Hz, 2H).
Example 37
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl-
)-benzyl)-N,N-diethylbenzamide
[0356] 4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in a
solution of 4-((alpha-S)-alpha-((2
S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (759
mg, 2.0 mmol, Example 2) and acetic acid in tetrahydrofuran (10
mL). Sodium triacetoxy borohydride (848 mg, -4 mmol) was added
portionwise over 5 min, then the reaction mixture sealed under
nitrogen and stirred overnight at room temperature. The reaction
mixture was evaporated to dryness and the residue partitioned
between water (6 mL) and ethyl acetate (20 mL). The aqueous
solution was further extracted with ethyl acetate (2.times.10 mL)
and the combined extract and washings diluted with an equal volume
of ether. The organic solution was extracted with 3M-HCl and the
acidic aqueous solution carefully neutralized, initially with
5M-NaOH, then saturated NaHCO.sub.3. At pH 4 the solution was
filtered through a 0.45 mM syringe filter to remove a small
quantity of an off-white gummy solid. The pH of the filtrate was
adjusted to 8.5 to precipitate a flocculent white solid which was
filtered off, washed well with cold water and dried overnight at 2
mm Hg at room temperature to yield
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-pipe-
razinyl)-benzyl)-N,N-diethylbenzamide (73.05%). Calc. for
C.sub.31H.sub.39N.sub.3O.sub.2 1.5H.sub.2O C, 72.62; H, 8.26; N,
8.20. Found C, 72.58; H, 7.83; N, 8.40% .sup.1H NMR (1% NaOD in
D.sub.2O, 300 MHz); .quadrature..quadrature.0.75 (br m, 3H); 0.81
(br d, J=7.3 Hz, 6H); 0.94 (br m, 3H); 1.71 (m, 1H); 1.84 (m, 1H);
2.29 (m, 2H); 2.49 (br m, 2H); 2.91 (m, 3H); 3.22 (m, 2H); 3.57 (br
m, 2H); 5.02 (s, 1H); 6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz,
2H); 7.01 (m, 7H); 7.17 (m, 2H).
Example 38
4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxyb-
enzyl)-N,N-diethylbenzamide
[0357] Alkylation of
4-((alpha-R)-alpha-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydrox-
ybenzyl)-N,N-diethylbenzamide (Example 12) with methyl iodide
according to the procedure of Example 29 gave the title compound.
Calc. for C.sub.32H.sub.41N.sub.3O.sub.2: C, 76.92; H, 8.27; N,
8.41. Found: C, 76.84; H, 8.34; N, 8.29.
Example 39
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-
-3-methoxybenzyl)-N,N-diethylbenzamide
[0358] 4-((alpha-R)-alpha-((2
S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,-
N-diethylbenzamide (from Example 10, 527.6 mg, 1.0 mmol) was
dissolved in acetonitrile (4.0 mL) and sodium iodide (15 mg, 0.1
mmol) added. The suspension was stirred during the addition of
triethylamine (500 .quadrature.L (363 mg), 3.59 mmol), followed by
2-fluorobenzyl bromide (241 .quadrature.L (378 mg), 2.0 mmol). The
reaction mixture was sealed under nitrogen and stirred overnight at
room temperature. The reaction mixture was evaporated to dryness
and partitioned between ethyl acetate (10 mL) and saturated aqueous
sodium bicarbonate solution (2.5 mL). The supernatant organic layer
was removed, and the aqueous portion washed with ethyl acetate
(3.times.10 mL). The combined organic extract and washings were
dried over anhydrous sodium sulfate and evaporated to a golden oil.
The residue was dissolved in ethyl acetate (7 mL), applied to a
pre-packed (Biotage) column and eluted with ethyl acetate. Pure
fractions containing desired product, as evidenced by t.l.c.
(silica gel, EM60F.sub.264, 100% ethyl acetate, R.sub.f=0.77) were
evaporated to dryness to yield the intermediate
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl-
)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (610
mg), as a yellow oil which was used without further purification.
The oil was dissolved in ethanol (7 mL) and aqueous 2.5 M (10%)
sodium hydroxide solution (5 mL, 12.5 mmol) was added. The reaction
mixture was set aside at room temperature for 5 h, then the ethanol
removed by evaporation. The oily suspension of the sodium salt was
clarified by the addition of water (5 mL), and the pH of the
solution adjusted to 9-10 by the passage of gaseous carbon dioxide
(from dry ice). The copious white precipitate was washed well with
water and dried under vacuum (2 mm Hg) at room temperature
overnight to yield 4-((alpha-R)-alpha-((2
S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-
-diethylbenzamide as a white solid (431 mg, 85.6%). Calc. for
C.sub.31H.sub.38FN.sub.3O.sub.2: C, 73.93; H, 7.61; N, 8.34; F,
3.77. Found C, 73.96; H, 7.67; N, 8.29; F, 3.75%. .sup.1H NMR
(CDCl.sub.3, 300 MHz); .delta. 1.05 (d, J=6.1 Hz, 3H); 1.09 (d, J=6
Hz, 3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.96 (t, J=10 Hz, 1H);
2.07 (t, J=10 Hz, 1H); 2.56 (br m, 2H); 2.60 (d, J=11 Hz, 1H); 2.72
(d, J=11 Hz, 1H); 3.29 (br m, 2H); 3.36 (d, J=14 Hz, 1H); 3.55 (br
m, 2H); 3.89 (d, J=14 Hz, 1H); 5.13 (s, 1H); 6.57 (s, 1H); 6.66 (d,
J=10 Hz, 2H); 7.00 (t, J=9 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.10
(t, J=8 Hz, 1H); 7.20 (m, 1H); 7.27 (d, J=8 Hz, 2H); 7.38 (t, J=7
Hz, 1H); 7.43 (d, J=7 Hz, 2H).
[0359]
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piper-
azinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was alkylated with
methyl iodide by a procedure essentially identical to that of
Example 29 to give
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl-
)-3-methoxybenzyl)-N,N-diethylbenzamide. Calc. for
C.sub.32H.sub.40FN.sub.3O.sub.2.0.1 H.sub.2O: C, 73.99; H, 7.80; N,
8.09; F, 3.66. Found: C, 73.98; H, 7.86; N, 8.00; F, 3.77.
Example 40
4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl-
]-N,N-dimethylbenzenesulfonamide
3-(t-Butyl-dimethylsilanyloxy)benzaldehyde
[0360] t-Butyldimethylchlorosilane (26.01 g; 172.56 mmol) was added
to a solution of 3-hydroxybenzaldehyde (20.7 g; 164.35 mmol) and
imidazole (27.97 g; 410.9 mmol) in chloroform (300 mL) under
nitrogen at 0.degree. C. The reaction was allowed to warm to room
temperature and stirred overnight. The reaction mixture was washed
with water (100 mL.times.3) and brine (100 mL), dried over
anhydrous sodium sulfate and concentrated to give crude product
(29.56 g), which was purified by column chromatography on silica
gel eluting with (i) pentane and (ii) 3% ethyl acetate in pentane
to give 3-(t-butyl-dimethylsilanyloxy)benzaldehyde (21.0 g; 54%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.93 (s, 1H), 7.45 (d,
1H, J=7.5 Hz), 7.38 (dd, 1H, J=7.5, 7.5 Hz), 7.31 (d, 1H, J=1.0
Hz), 7.09 (1H, dd, J=7.5, 1.0 Hz), 0.98 (s, 9H), 0.20 (s, 6H).
4-Iodo-N,N-dimethyl-benzenesulfonamide
[0361] Dimethylamine (100 mL of 2.0 M solution in tetrahydrofuran;
200 mmol) was added to a solution of 4-iodobenzenesulfonyl chloride
(54.76 g; 181 mmol) in pyridine (300 mL) at 0.degree. C. under
N.sub.2, followed by the addition of 4-N,N-dimethylaminopyridine
(15 mg). The reaction was allowed to warm to room temperature and
was stirred under N.sub.2 for 48 hrs. The reaction solution was
poured into 1.2 liter of water, and the precipitated product was
collected by filtration and rinsed with water (300 mL.times.2). The
solid was dissolved in ethyl acetate (500 mL) and washed with 5%
aqueous hydrochloric acid (300 mL.times.3), water (300 mL.times.2)
and brine (300 mL). The organic solution was dried over anhydrous
sodium sulfate and concentrated to give
4-iodo-N,N-dimethyl-benzenesulfonamide (49.46 g; 88%) as a white
solid, which was used in the next reaction without further
purification. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88 (d,
2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 2.69 (s, 3H).
4-{(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethyl-
silanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide
[0362] Part 1: Preparation of iminium intermediate: To a 3-neck
flask equipped with a Soxhlet extractor filled with 3 A molecular
sieves was added benzotriazole (618 mg; 5.19 mmol),
3-(t-butyl-dimethylsilanyloxy)benzaldehyde (1.227 g; 5.19 mmol),
(+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (961 mg; 6.23 mmol,
prepared by the method described in Example 1 for
(-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but using
di-p-toluoyl-L-tartaric acid as the resolving agent) and toluene
(150 mL). The solution was refluxed under N.sub.2 for 20 h. The
solution was cooled to room room temperature under N.sub.2.
[0363] Part 2: Preparation of Grignard reagent: Isopropylmagnesium
chloride (6.91 mL of 2.0 M solution in tetrahydrofuran; 13.82 mmol)
was added to a solution of 4-iodo-N,N-dimethylbenzenesulfonamide
(4.3 g; 13.82 mmol) at room temperature under N.sub.2 and stirred
for 20 minutes.
[0364] Part 3: The solution of Part 1 was added to the Grignard
reagent prepared in Part 2 dropwise via a syringe at room
temperature under N.sub.2 in a span of 35 minutes while the
reaction solution was stirred vigorously. The reaction was stirred
at room temperature overnight and quenched by the addition of
saturated aqueous ammonium chloride (10 mL). The resulting mixture
was diluted by the addition of ethyl acetate (120 mL) and water
(120 mL). The cloudy mixture was filtered thru a Celite.RTM. pad.
The filtrate was poured into a separate funnel. The organic layer
and water layer were separated. The organic layer was extracted
with 10% aqueous sodium hydroxide (75 mL.times.4), washed with
water (100 mL.times.3) and brine (100 mL), dried (sodium sulfate)
and concentrated to give crude product, which was purified by
silica gel chromatography conducted on CombiFlash.TM. Sq 16.times.
(gradient: 100% CH.sub.2Cl.sub.2 to 7% MeOH in CH.sub.2Cl.sub.2) to
give
4-{(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethy-
lsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide (1.3 g;
45%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.71 (d, 2H, J=8.0
Hz), 7.35 (d, 2H, J=8.0 Hz), 7.12 (dd, 1H, J=8.0, 8.0 Hz), 6.92 (s,
1H), 6.84 (d, 1H, J=8.0 Hz), 6.71 (d, 1H, J=8.0 Hz), 5.82 (1H, m),
5.23-5.11 (m, 3H), 3.35 (dd, 1H, J=14.0, 5.5 Hz), 2.88 (dd, 1H,
J=14.0, 8.0 Hz), 2.82 (dd, 1H, J=11.0, 3.0 Hz), 2.73 (s, 6H), 2.68
(dd, 1H, J=11.0, 2.5 Hz), 2.55 (m, 2H), 2.16 (dd, 1H, J=11.0, 8.5
Hz), 1.85 (dd, 1H, J=11.0, 9.0 Hz), 1.18 (d, 3H, J=6.0 Hz), 1.01
(d, 3H, J=6.0 Hz), 0.96 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H).
4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl-
]-N,N-dimethylbenzenesulfonamide
[0365] 3 N HCl (7 mL) was added to the solution of
4-{(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethy-
lsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide (1.3 g)
in tetrahydrofuran (15 mL). The mixture was stirred at room
temperature overnight. Water (15 mL) was added to the reaction. The
reaction mixture was extracted with diethyl ether (25 mL.times.3).
The remaining water layer was neutralized by 10% aqueous NaOH to
pH=8-9 and then extracted with ethyl acetate (30 mL.times.3). The
combined ethyl acetate layers were washed with water (20
mL.times.3) and brine (20 mL), dried over sodium sulfate and
concentrated to give 0.83 g of crude product. The crude product was
purified by silica gel chromatography conducted on CombiFlash.TM.
Sq 16.times. (gradient: 100% CH.sub.2Cl.sub.2 to 7% MeOH in
CH.sub.2Cl.sub.2) to give 4-[(R)-((2R,5S)-4-allyl-2,5-dimethyl
piperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide
(720 mg; 70%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.71 (d,
2H, J=8.5 Hz), 7.35 (d, 2H, J=8.5 Hz), 7.14 (dd, 1H, J=8.0, 8.0
Hz), 6.89 (bs, 1H), 6.85 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0, 2.5
Hz), 5.83 (1H, m), 5.24-5.12 (m, 3H), 3.32 (dd, 1H, J=13.5, 5.0
Hz), 2.86 (dd, 1H, J=13.5, 8.0 Hz), 2.78 (dd, 1H, J=11.5, 3.0 Hz),
2.72 (s, 6H), 2.65 (dd, 1H, J=11.0, 2.5 Hz), 2.51 (m, 2H), 2.14
(dd, 1H, J=11.5, 9.0 Hz), 1.81 (dd, 1H, J=11.0, 9.5 Hz), 1.16 (d,
3H, J=6.0 Hz), 0.98 (d, 3H, J=6.0 Hz); MS (FAB, glycerol) m/z: 444
(M.sup.++H), 290, 153. Found: C, 58.32; H, 6.66; N, 8.18. Calc.
(C.sub.24H.sub.33N.sub.3O.sub.3S 0.8 CH.sub.2Cl.sub.2): C, 58.23;
H, 6.82; N, 8.21.
Example 41
4-((alpha-S)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0366] 4-Carboxybenzaldehyde (100 g, 666 mmol) was added to a 2000
mL, 3-necked, round bottom flask and stirred under nitrogen in 1200
mL of toluene. Thionyl chloride (53.5 mL, 733 mmol) was added to
the mixture, followed by the addition of 0.15 mL of
dimethylformamide. A reflux condenser fitted with a calcium
chloride drying tube was placed on the flask. The reaction was
placed in an oil bath and heated at a bath temperature maintained
at 120.degree. C. The mixture was allowed to reflux for 1 hour
after a clear solution was obtained and then cooled to room
temperature. The solution was diluted with anhydrous toluene, and
all volatiles were removed under vacuum.
[0367] The crude acid chloride was dissolved in 1500 mL of dry
tetrahydrofuran and cooled in an ice/water bath. Diethylamine (173
mL, 1.67 mol, 2.5 equivalents) was added dropwise via an addition
funnel. The cloudy solution was allowed to warm to room temperature
over 1 hour and stirred overnight. The reaction mixture was
filtered to remove the white crystalline diethylamine hydrochloride
by-product. The crystals were washed with ethyl acetate
(2.times.600 mL). The tetrahydrofuran filtrate was evaporated, and
the residue was dissolved in the ethyl acetate washings. The
solution was washed sequentially with 1 M hydrochloric acid
(2.times.600 mL), water (2.times.300 mL), dilute sodium carbonate
solution (saturated: H.sub.2O, 1:1, 2.times.600 mL), water
(2.times.300 mL) and saturated sodium chloride solution (300 mL).
The organic layer was separated, dried over sodium sulfate, and the
solvent was removed under vacuum. 4-formyl-N,N-diethylbenzamide
(117.14 g) was obtained as a light yellow oil which was used
without further purification (85% crude yield). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 1.09-1.25 (m, 6H); 3.19-3.31 (d, J=6.4
Hz, 2H); 3.54-3.56 (d, J=6.6 Hz, 2H); 7.49-7.52 (d, J=8.1 Hz, 2H);
7.89-7.92 (d, J=8.2 Hz, 2H); 9.98 (s, 1H).
[0368] Phenylmagnesium bromide (1.0 M solution in tetrahydrofuran,
235 mL, 235 mmol) was slowly added to a flask containing a cold
(-78.degree. C.) solution of 4-formyl-N,N-diethylbenzamide (48.18
g, 235 mmol) in 500 mL of dry tetrahydrofuran under nitrogen. The
transfer rate was monitored to maintain reaction temperature below
.about.70.degree. C. The reaction was stirred for another 45
minutes at -78.degree. C. and then quenched with 45 mL of saturated
aqueous ammonium chloride. After warming to room temperature, the
mixture was diluted with 900 mL of diethyl ether and washed with
900 mL of water followed by 230 mL of saturated sodium chloride.
The ethereal solution was dried over sodium sulfate and the solvent
removed to give crude 4-(N,N-diethylcarbamoyl)benzhydryl alcohol as
a light yellow oil. Crude yield was .about.92%.
[0369] The 4-(N,N-diethylcarbamoyl)benzhydryl alcohol (61.35 g,
216.5 mmol) was dissolved in 1500 mL of dichloromethane and 23.69
mL (324.8 mmol) of thionyl chloride was added dropwise. The
reaction solution was stirred overnight at room temperature and the
solvent was removed under vacuum. The crude product was redissolved
in 800 mL of toluene and the solvent again was removed under vacuum
to eliminate excess thionyl chloride, providing crude
4-(N,N-diethylcarbamoyl)benzhydryl chloride as a dark oil. Crude
yield=100%.
[0370] The crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride (125
mmol) was dissolved in acetonitrile (300 mL). Sodium iodide (18.64
g, 125 mmol), diisopropylethylamine (32.65 mL, 187 mmol), and
(+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (19.23 g, 125 mmol,
prepared by the method described in Example 1 for
(-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but using
di-p-toluoyl-L-tartaric acid as the resolving agent) were added.
The mixture was stirred at reflux, under nitrogen, for 3 hours. The
acetonitrile was removed under reduced pressure, the reaction
mixture was poured into ethyl acetate (500 mL) and potassium
carbonate solution (150 mL of a 2M aqueous solution), and shaken.
The organic phase was separated, washed with water and brine, dried
over solid potassium carbonate, and concentrated in vacuo to give
55.35 g (100% crude yield) of 4-((.alpha.R and
.alpha.S)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-
-diethylbenzamide as a 1:1 mixture of isomers, epimeric at the
benzhydryl carbon.
[0371] The allyl portion was removed using Pd(dba).sub.2/DPPB in
the presence of thiosalicylic acid by the method of Genet [J. P.
Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36,
1267-1270 (1995)]. The reaction was concentrated and the residue
was dissolved in 300 mL ethyl acetate and 600 mL diethyl ether.
After washing with Na.sub.2CO.sub.3 solution (3.times.300 mL) and
water (1.times.300 mL), the organic solution was diluted with
pentane (1500 mL) and extracted with 3 M HCl (5.times.80 mL) and 1
M HCl (3.times.100 mL), alternating with water (3.times.100 mL).
The combined aqueous extracts were filtered to remove a small
amount of suspended solid and the pH was adjusted to 12 using 5M
NaOH solution. The resulting oily suspension was extracted with
dichloromethane (3.times.300 mL). The combined organic solution was
dried (Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure to give 4-((.alpha.R and
.alpha.S)-.alpha.-((2R,5S)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethyl-
benzamide as a pale yellow solid (27.11 g, 71.43 mmol).
[0372] A solution of 4-((.alpha.R and
.alpha.S)-.alpha.-((2R,5S)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethyl-
benzamide (27.11 g, 71.43 mmol) in acetonitrile (450 mL) was added
to sodium iodide (1.07 g, 7.14 mmol) and stirred under nitrogen at
room temperature during the addition of triethylamine (35.84 mL,
26.02 g, 257 mmol), followed by 3-fluorobenzyl bromide (17.52 mL,
143 mmol). An immediate turbidity was observed on addition of the
fluorobenzyl bromide. The reaction mixture was stirred under
nitrogen overnight at room temperature. The solvent was removed by
evaporation and the residue was partitioned between 300 mL
methylene chloride and 300 mL saturated sodium bicarbonate
solution, followed by extraction with another 2.times.300 mL of
methylene chloride. The combined organic extracts were washed with
water (2.times.300 mL), and brine (300 mL), dried over
Na.sub.2SO.sub.4/MgSO.sub.4 and concentrated under reduced
pressure. The residual deep-red oil was purified by chromatography
on silica gel (12% EtOAc in CH.sub.2Cl.sub.2) to give 5.83 g (11.96
mmol) of
4-((.alpha.S)-.alpha.-((2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazi-
nyl)benzyl)-N,N-diethylbenzamide as a light yellow solid. The
benzhydryl epimer,
4-((.alpha.R)-.alpha.-((2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)-1--
piperazinyl)benzyl)-N,N-diethylbenzamide (5.46 g) and 11.25 g of
the epimer mixture were also obtained. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.06-1.28 (m, 12H); 1.95-2.07 (m, 2H);
2.59-2.72 (m, 4H); 3.22-3.55 (m, 5H); 3.81-3.86 (d, J=13.6 Hz, 1H);
5.11 (s, 1H); 6.87-6.88 (t, 1H); 7.03-7.44 (m, 12H). Calculated for
C.sub.31H.sub.38FN.sub.3O.0.20 EtOAc: C, 75.59; H, 7.90; N, 8.32;
F, 3.76. Found: C, 75.53; H, 7.82; N, 8.45; F, 3.69. HPLC: 91.85%
by Ace C-18 (34 initial 60% 0.01M NH.sub.4OAc in MeOH: gradient to
100% MeOH, 60 min: isocratic MeOH 5 min. 0.7 ml/min: .lamda.obs=210
nm, R.sub.t=63.4 min for title compound. The benzyhydryl R epimer
has R.sub.t=62 min.
Example 42
(+)-3-((.alpha.R)-.alpha.-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)benzoic acid
[0373] (+)-3-((R)-((2
S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophe-
nyl)-N-methylbenzamide (Example 26) was dissolved in 95% ethanol
containing 6% by weight of sodium hydroxide and heated at reflux
for 24 hours. The mixture was concentrated in vacuo to remove
ethanol. The residue was dissolved in water and the resulting
solution was adjusted to pH 5 with concentrated hydrochloric acid.
The solvent was removed in vacuo to give 3-((.alpha.R)-.alpha.-((2
S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic
acid as a mixture with sodium chloride. The crude acid was stirred
with a small volume of water and filtered. The solid in the filter
was washed with water and dried under vacuum to give
(+)-3-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3--
hydroxybenzyl)benzoic acid as a light beige solid. NMR
(DMSO-d.sub.6, 200 MHz) .delta.: 0.95 (d, J=6 Hz, 3H); 1.1 (d, J=6
Hz, 3H); 1.9 (ddd, J.sub.1=3 Hz, J.sub.2=7 Hz, J.sub.3=10 Hz, 1H);
2.1 (dd, J.sub.1=8 Hz, J.sub.2=10 Hz, 1H); 2.5 (m, 2H); 2.7-2.9 (m,
2H); 3.2 (m, 2H); 5.05 (d, J=12 Hz, .sup.1H); 5.2 (d, J=18 Hz, 1H);
5.8 (m, 1H); 6.7 (m, 3H); 7.1 (t, J=8 Hz, 1H); 7.4 (t, J=8 Hz, 1H);
7.65 (d, J=8 Hz, 1H); 7.8 (d, J=8 Hz, 1H); 8.0 (s, 1H); 9.4 (s,
1H). [.alpha.].sub.D.sup.20=+4.1.degree. (0.1 M aqueous sodium
hydroxide, c=1.09). Calc. for C.sub.23H.sub.28N.sub.2O.sub.3 0.75
H.sub.2O: C, 70.12; H, 7.55; N, 7.11. Found: C, 70.23; H, 7.35; N,
7.10. Mass spectrum (CI--CH.sub.4) m/e: 381 (M+1, 35%); 380 (M,
2%); 227 (28%); 155 (100%); 153 (83%).
[0374] The following Examples 43-45 may be made by methods
analogous to those described in the preceding Examples.
Example 43
(3-{(R)-(3-Diethylcarbamoylphenyl)-[(2S,5R)-4-(3-hydroxybenzyl)-2,5-dimeth-
ylpiperazin-1-yl]methyl}-phenoxy)acetic acid
Example 44
(3-{(R)-(3-Diethylcarbamoylphenyl)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimeth-
ylpiperazin-1-yl]methyl}-phenoxy)acetic acid
Example 45
(3-{(2R,5S)-4-[(R)-(3-Carboxymethoxyphenyl)-(3-diethylcarbamoylphenyl)meth-
yl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid
Example 46
[0375] To investigate the efficacy of delta opioid receptor
agonists as a treatment for premature ejaculation, intact conscious
male mice were electrically stimulated subsequent to the
administration of a delta opioid receptor agonist to determine if a
delay in ejaculation was observed when compared to administration
of a placebo
[0376] General Materials and Methods
[0377] Male, CD-1 mice (20-30 g) were housed in groups of ten (10)
in Plexiglas.RTM. chambers with food and water available before any
procedure. Animals were maintained on a 12 hour light/dark cycle in
a temperature-controlled animal colony. Studies were carried out in
accordance with the Guide for the Care and Use of Laboratory
animals as adopted and promulgated by the National Institutes of
Health.
[0378] An electric bipolar rectal probe, as shown in FIG. 1, was
used for stimulating the subjects. Specifically, the bipolar
electrode probe is an approximately 5 cm long tube having an outer
diameter of approximately 0.25 cm with an inner diameter of
approximately 0.08. In the center lumen of the elongated tubular
body 12 are embedded cathode 16 and anode 18, which are formed of a
conductive material, preferably platinum. The cathode 16 and anode
18 are connected at one end to external power supplying means (not
shown). Anode 18 extends at the other end all the way to one
extremity of the elongated body 12 and forming an anode terminal 22
at such extremity. Cathode 16 only extends to a middle portion of
the elongated body 12 and forming a cathode terminal 20 at such
middle portion. The cathode terminal 20 is preferably positioned
away from the anode terminal 22, at a distance of about 0.5 cm.
[0379] The testing delta opioid receptor agonist (SNC-80) was
purchased from Tocris Cookson, Inc., Ellisville, Mo., USA, and
dissolved in 5% dextrose injection solution. An equimolar amount of
aqueous hydrochloric acid was added when the manufacturer packaged
the compound in its base form. The placebo was 5% dextrose alone.
Each mouse was injected subcutaneously with 10 mg/kg of the SNC-80
compound or with 10 mg/kg of a placebo. 10 minutes after the
injection, the test mouse was subjected to electrostimulation. Ten
mice were tested for each dose level, the order of each mouse
receiving different doses was blinded and in a random manner.
[0380] During the testing the mouse was restrained in a cone bag
with rear legs extending from the bag. Excess fecal matter was
removed from the rectum and the above-discussed lubricated bipolar
electrode was inserted approximately 2.5 cm into the rectum. An
oscillating current of 40 Hz was utilized for electrical
stimulation starting at 3 volts with a gradual increase to 8 volts
by increments of 0.5 volts. The stimulation regime included 4
stimulating events for each voltage lasting 2 seconds with a rest
period of 2 seconds between stimulating events until ejaculation
occurred or the terminal voltage of 8 volts was reached. A white
coagulum ejaculate from the penis indicates a successful
ejaculation.
[0381] For the electroejaculation test, dose-response lines were
constructed as an accumulated ejaculation at a specified voltage. A
minimum of 10 mice was used at each dose level. Each dose response
was the average of two to three independent experiments. Students'
t-test was used to assess unpaired comparison, with p<0.06
indicating significance.
[0382] Electric stimulation was conducted on untreated mice to
determine effective ejaculation parameters relating to current
frequency and voltage. It was found that when 10 mice were
stimulated through the voltage program starting at 3 volts with a
gradual increase to 8 volts by increments of 0.5 volts, none of the
mice ejaculated if the current frequency was 20 Hz. When the
operating frequency increased from 30 to 70 Hz, the occurrence of
successful ejaculation, which is indicated by emission of a white
coagulum from the penis of the male mouse under stimulation, also
increases. When the operating frequency of the electric stimulation
was between 30 to 45 Hz, the ejaculation rate showed a linear
dependency on the frequency. When the operating frequency reached
60 Hz, all the mice ejaculated with a 100% ejaculation rate.
[0383] Testing was conducted on mice injected with SNC-80 or a
buffer vehicle for the control group. SNC-80 is a highly selective
delta receptor agonist which has been found to block the
contraction of mouse vas deferens smooth muscle in vitro which is
one of the tissue components in the ejaculation system. Each mouse
was subjected to electroejaculation at 40 Hz (starting at 3 volts
with a gradual increase to 8 volts by increments of 0.5 volts)
approximately 10 minutes after subcutaneous administration of
SNC-80 at different doses of 0, 0.1, 0.3 and 1 mg/kg. A minimum of
10 mice were used at each dose level. Each does response was the
average of two to three independent experiments .+-.SEM.
[0384] As shown in FIG. 3, when the frequency of the electric
stimulation was set at 40 Hz, a dose of 1 mg/kg of SNC-80
significantly reduced the occurrence of ejaculation in tested mice
as compared to that of the control group. This reduction of
ejaculation by SNC-80 is specific, as the compound works in a dose
dependent manner and the inhibitory effect diminished as the
concentration was reduced to 0.1 mg/kg.
Example 47
[0385] To determine if SNC-80 inhibits the ejaculation via specific
binding to delta opioid receptor, the effect of SNC-80 on
ejaculation was tested against the delta opioid selective
antagonist naltrindole (NTI). Subcutaneous injections of a control
vehicle (CTL), 0.5 mg/kg SNC-80, 0.5 mg/kg SNC-80 plus 0.1 mg/kg of
NTI and 0.1 mg/kg of NTI were administered to the mice. A minimum
of 10 mice was utilized for each dose level. Each dose response is
the average of two to three independent experiments .+-.SEM.
Electroejaculation stimulation was conducted 10 minutes after
injection at 35 Hz oscillating frequency, starting at 3 volts with
a gradual increase to 8 volts by increments of 0.5 volts. As shown
in FIG. 4, injection of 0.5 mg/kg of SNC-80 reduced the ejaculation
by a factor of at least 2. However, this inhibitory effect was
blocked by co-injection with 0.1 mg/kg of NTI. This result
demonstrated that blocking the delta opioid receptor by NTI
eliminated the effect of SNC-80 on ejaculation, indicating that
activation of the delta opioid receptor reduced the
electroejaculation in male mice. It is shown in FIG. 4 that
injections of just NTI, without any other active ingredient, did
not affect the ejaculation response.
Example 48
[0386] Further evidence showing that activation of the delta opioid
receptor leads to reduction in ejaculation is shown by using
additional delta opioid receptor agonists that were synthesized and
formulated by the inventors. Similar electroejaculation procedures
were used according to Examples 46 and 47 to determine the efficacy
in delayed ejaculation. All the compounds were found to be high
affinity delta opioid receptor agonists as judged by radioligand
competition binding and inhibition of contraction of mouse vas
defens in tissue bath. As shown in Table 1, the compounds displayed
an inhibitory effect on male ejaculation. These results further
elucidate an inhibitory role of delta opioid receptor activation in
ejaculation.
TABLE-US-00001 TABLE 1 EC.sub.50 Max. Optimal Exam- .mu. .delta.
.kappa. MVD.sup.1 ejaculation Dose.sup.2 ple (nM)* (nM)* (nM)*
(nM)** Inhibition (%) (mg/kg) 11 27.1 1.23 >100 2.8 30 5 12 1.45
0.123 68.7 4.4 28 5 14 162 11.1 >100 7.2 35 10 13 3470 5.69
>100 21.2 50 5 17 1.28 0.66 20.9 2.9 50 1 Binding affinity by
radio-ligand competition binding assay according to U.S. Pat. Nos.
5,985,880 and 5,807,858 the contents of which are herein
incorporated by reference. **Determined by in vitro inhibition of
electrically stimulated contraction of mouse vas deferens in the
tissue bath mouse vas deferens subcutaneous injection
Example 49
[0387] Additional formulations of delta opioid receptor agonists
were prepared and tested according to testing procedures set forth
in Examples 46 and 47. The compounds were administered orally and
the results are compiled in Table 2. The results show that the
delta opioid receptor agonists had an inhibitory effect on
ejaculation events of at least 33%.
TABLE-US-00002 TABLE 2 Effective Ejaculation Route of Ex. Dose
Inhibition Adminins- Compound No. (mg/kg) % tration
3-((alpha-R)-alpha-((2S,5R)- 14 0.01 45% oral
4-Allyl-2,5-dimethyl-1- piperazinyl)-4-(diethylamino-
carbonyl)benzyl)phenoxyacetic acid 3-((alpha-R)-alpha-((2S,5R)- 15
3 66% oral 4-Benzyl-2,5-dimethyl-1- piperazinyl)-4-(diethylamino-
carbonyl)benzyl) phenoxyacetic acid 4-((alpha-R)-alpha-((2S,5R)- 29
3 38% oral 2,5-Dimethyl-4-(4- fluorobenzyl)-1-piperazinyl)-
3-methoxybenzyl)-N,N- diethylbenzamide 4-(alpha-R)-alpha-((2S,5R)-
35 0.3 60% oral 4-(Cyclopropylmethyl)-2,5-
dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N- diethylbenzamide
4-((alpha-R)-alpha-((2S,5R)- 36 3 60% oral 2,5-Dimethyl-4-(3-
fluorobenzyl)-1-piperazinyl)- 3-hydroxybenzyl)-N,N-
diethylbenzamide 4-((alpha-S)-alpha-((2S,5R)- 37 3 50% oral
2,5-Dimethyl-4-(4- hydroxybenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide 4-(alpha-R)-alpha-((2S,5R)-4- 38 3 33%
oral Benzyl-2,5-dimethyl-1- piperazinyl)-3-methoxybenzyl)-
N,N-diethylbenzamide 4-((alpha-R)-alpha-((2S,5R)- 39 10 50% oral
2,5-Dimethyl-4-(2- fluorobenzyl)-1-piperazinyl)-
3-methoxybenzyl)-N,N- diethylbenzamide 4-[(R)-((2R,5S)-4-Allyl-2,5-
40 0.3 50% oral dimethylpiperazin-1-yl)(3-
hydroxyphenyl)methyl]-N,N- dimethylbenzenesulfonamide
4-((alpha-S)-alpha-((2R,5S)- 41 0.4 75% oral 2,5-Dimethyl-4-(3-
fluorobenzyl)-1-piperazinyl) benzyl)-N,N-diethylbenzamide
Example 50
[0388] Further evidence showing that activation of the delta opioid
receptor leads to reduction in ejaculation can be shown by using
additional delta opioid receptor agonists as set forth in Table 3
below. Similar electroejaculation procedures are used according to
Examples 46 and 47 to determine the efficacy in delaying
ejaculation. All the compounds have been found to be delta opioid
receptor agonists, and as such, the use of the compounds results in
inhibition of ejaculation in the testing subjects.
TABLE-US-00003 TABLE 3 EXAMPLE NO. STRUCTURE NAME 1 ##STR00015##
4-((alpha-S)-alpha-((2S,5R)-4-Allyl-
2,5-dimethyl-1-piperazinyl)benzyl)- N,N-diethylbenzamide 2
##STR00016## 4-((alpha-S)-alpha-((2S,5R)-2,5-
dimethyl-1-piperazinyl)benzyl)- N,N-diethylbenzamide 3 ##STR00017##
4-((alpha-S)-alpha-((2S,5R)-2,5- Dimethyl-4-(3-fluorobenzyl)-1-
piperazinyl)benzyl)-N,N- diethylbenzamide 4 ##STR00018##
4-((alpha-S)-alpha-((2S,5R)-4- Benzyl-2,5-dimethyl-1-piperazinyl)
benzyl)-N,N-diethylbenzamide 5 ##STR00019##
4-((alpha-S)-alpha-((2S,5R)-2,5- Dimethyl-4-(2-fluorobenzyl)-1-
piperazinyl)benzyl)-N,N- diethylbenzamide 6 ##STR00020##
4-((alpha-S)-alpha-((2S,5R)-2,5- Dimethyl-4-(4-pyridylmethyl)-1-
piperazinyl)benzyl)-N,N- diethylbenzamide 7 ##STR00021##
4-((alpha-S)-alpha-((2S,5R)-4-(3- Chlorobenzyl)-2,5-dimethyl-1-
piperazinyl)benzyl)-N,N- diethylbenzamide 8 ##STR00022##
4-((alpha-S)-alpha-((2S,5R)-2,5- Dimethyl-4-(4-methoxybenzyl)-1-
piperazinyl)benzyl)-N,N- diethylbenzamide 16 ##STR00023##
3-((alpha-R)-4- (Diethylaminocarbonyl)-alpha-((2S,
5R)-2,5-dimethyl-4-(4-fluorobenzyl)-
1-piperazinyl(benzyl)phenoxyacetic acid 18 ##STR00024##
(-)-4-(.alpha.R)-.alpha.-((2R,5R)-4-Allyl-2,5-
dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethyl- benzamide 19
##STR00025## (-)-4-(.alpha.S)-.alpha.-((2R,5R)-4-Allyl-2,5-
dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethyl- benzamide 20
##STR00026## (-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-Dimethyl-
4-propyl-1-piperazinyl)-3- hydroxybenzyl)-N,N- diethylbenzamide 21
##STR00027## (-)-4-(.alpha.S)-.alpha.-((2R,5R)-2,5-Dimethyl-
4-propyl-piperazinyl)-3- hydroxybenzyl)-N,N-diethyl- benzamide 22
##STR00028## 4-((.alpha.R)-.alpha.-(2S,5S)-4-Allyl-2,5-
dimethyl-1-piperazinyl)-3- hydroxybenzyl)-benzamide 23 ##STR00029##
(-)-3-((S)-((2S,5R)-4-Allyl-2,5- dimethyl-1-piperazinyl)(3-
thienyl)methyl)phenol 24 ##STR00030## 3-((S)-((2S,5R)-4-Benzyl-2,5-
dimethyl-1-piperazinyl)(3- thienyl)methyl)phenol 25 ##STR00031##
3-((S)-((2S,5R)-4-(2,6- Difluorobenzyl)-2,5-dimethyl-1-
piperazinyl)(3-thienyl)methyl)phenol 26 ##STR00032##
(+)-3-((R)-((2S,5R)-4-Allyl-2,5- dimethyl-1-piperazinyl)-3-
hydroxybenzyl)-N-(3-fluorophenyl)- N-methylbenzamide 27
##STR00033## 3-((R)-((2S,5R)-4-Benzyl-2,5-
dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N-(3-fluorophenyl)-
N-methylbenzamide 28 ##STR00034##
3-((R)-((2S,5R)-2,5-Dimethyl-4-(4- fluorobenzyl)-1-piperazinyl)-3-
hydroxybenzyl)-N-(3-fluorophenyl)- N-methylbenzamide 30
##STR00035## N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3- hydroxybenzyl)-2,5-
dimethylpiperazin-1-yl](3- methoxyphenyl)methyl]benzamide 31
##STR00036## N,N-Diethyl-3-{(R)-(3- hydroxyphenyl)-[(2S,5R)-4-(3-
methoxybenzyl)-2,5- dimethylpiperazin-1- yl]methyl}benzamide 32
##STR00037## (3-{(2R,5S)-4-[(R)-(3- Diethylcarbamoyl-phenyl)-(3-
hydroxyphenyl)methyl]-2,5-dimethyl-
piperazin-1-ylmethyl}-phenoxy)acetic acid 33 ##STR00038##
(3-{(2R,5S)-4-[(R)-(3- Diethylcarbamoylphenyl)-(3-
methoxyphenyl)methyl]-2,5- dimethylpiperazin-1-
ylmethyl}phenoxy)acetic acid 34 ##STR00039##
N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3- methoxybenzyl)-2,5-
dimethylpiperazin-1-yl](3- methoxyphenyl)methyl]benzamide 42
##STR00040## (+)-3-((alpha-R)-alpha-((2S,5R)-4-
Allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)benzoic acid 43
##STR00041## (3-{(R)-(3-Diethylcarbamoylphenyl)-
[(2S,5R)-4-(3-hydroxybenzyl)-2,5- dimethylpiperazin-1-yl]methyl}-
phenoxy)acetic acid 44 ##STR00042##
(3-{(R)-(3-Diethylcarbamoylphenyl)-
[(2S,5R)-4-(3-methoxybenzyl)-2,5- dimethylpiperazin-1-yl]methyl}-
phenoxy)acetic acid 45 ##STR00043## (3-{(2R,5S)-4-[(R)-(3-
Carboxymethoxyphenyl)-(3- diethylcarbamoylphenyl)methyl]-2,5-
dimethylpiperazin-1- ylmethyl}phenoxy)acetic acid
[0389] While the invention has been described herein in reference
to specific aspects, features and illustrative embodiments of the
invention, it will be appreciated that the utility of the invention
is not thus limited, but rather extends to and encompasses numerous
other aspects, features and embodiments. Accordingly, the claims
hereafter set forth are intended to be correspondingly broadly
construed, as including all such aspects, features and embodiments,
within their spirit and scope.
* * * * *