U.S. patent application number 11/205354 was filed with the patent office on 2006-02-09 for method for decreasing opioid metabolism.
This patent application is currently assigned to Rensselaer Polytechnic Institute. Invention is credited to Mark P. Wentland.
Application Number | 20060030580 11/205354 |
Document ID | / |
Family ID | 22922766 |
Filed Date | 2006-02-09 |
United States Patent
Application |
20060030580 |
Kind Code |
A1 |
Wentland; Mark P. |
February 9, 2006 |
Method for decreasing opioid metabolism
Abstract
8-Substituted-2,6-methano-3-benzazocines of general streucture I
in which A is --CH.sub.2--OH, --CH.sub.2NH.sub.2,
--NHSO.sub.2CH.sub.3, ##STR1## and Y is O, S or NOH are useful as
analgesics, anti-diarrheal agents, anticonvulsants, antitussives
and anti-addiction medications. ##STR2## 8-Carboxamides,
thiocarboxamides, hydroxyamidines and formamides are preferred.
Inventors: |
Wentland; Mark P.; (Menands,
NY) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
Rensselaer Polytechnic
Institute
Troy
NY
|
Family ID: |
22922766 |
Appl. No.: |
11/205354 |
Filed: |
August 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10987527 |
Nov 12, 2004 |
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11205354 |
Aug 17, 2005 |
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10409803 |
Apr 9, 2003 |
6887998 |
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10987527 |
Nov 12, 2004 |
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10305287 |
Nov 26, 2002 |
6784187 |
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10409803 |
Apr 9, 2003 |
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PCT/US01/45581 |
Oct 31, 2001 |
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10305287 |
Nov 26, 2002 |
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60244438 |
Oct 31, 2000 |
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Current U.S.
Class: |
514/295 ; 546/44;
546/97 |
Current CPC
Class: |
A61P 1/06 20180101; A61P
25/00 20180101; A61P 25/14 20180101; A61P 25/30 20180101; A61P
25/04 20180101; A61P 25/34 20180101; C07D 491/18 20130101; C07D
489/10 20130101; A61P 11/00 20180101; C07D 221/22 20130101; C07D
221/26 20130101; A61P 43/00 20180101; A61P 37/06 20180101; A61P
11/14 20180101; A61P 1/12 20180101; C07D 405/06 20130101; A61P 9/10
20180101; C07D 489/08 20130101; A61P 25/32 20180101; A61P 17/04
20180101; A61P 3/04 20180101; A61P 25/28 20180101; C07D 489/02
20130101; A61P 25/36 20180101; A61P 13/02 20180101; C07D 489/12
20130101; A61P 1/00 20180101; A61P 3/00 20180101; C07D 489/00
20130101; A61P 25/02 20180101; A61K 31/485 20130101; A61P 29/00
20180101; A61P 25/08 20180101; C07D 401/04 20130101 |
Class at
Publication: |
514/295 ;
546/044; 546/097 |
International
Class: |
A61K 31/485 20060101
A61K031/485; C07D 221/22 20060101 C07D221/22 |
Goverment Interests
STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH
[0002] This invention was made with Government support under
Contract No. RO1 DA12180, awarded by the National Institutes of
Health. Accordingly, the U.S. Government has certain rights in this
invention.
Claims
1-31. (canceled)
32. A method for treating a disease or condition by altering a
response mediated by an opioid receptor comprising bringing into
contact with said opioid receptor a compound having the formula
##STR34## wherein A is chosen from --CH.sub.2-Z,
--NHSO.sub.2-(loweralkyl), ##STR35## Q is chosen from O, S and
NR.sup.17; Y is chosen from O, S, NR.sup.17 and NOH; Z is chosen
from OH, SH and NH.sub.2; R.sup.1 is chosen from hydrogen, lower
alkoxy, phenyl and --NHR.sup.8; R.sup.8 is chosen from hydrogen,
--OH, --NH.sub.2 and --CH.sub.2R.sup.15; R.sup.15 is chosen from
hydrogen, alkyl, aryl, substituted aryl and alkyl substituted with
alkoxy, amino, alkylamino or dialkylamino; R.sup.16 is chosen from
hydrogen and NH.sub.2; and R.sup.17 is chosen from hydrogen, alkyl,
aryl and benzyl; and B represents an appropriate residue such that
an existing compound ##STR36## alters a response mediated by said
opioid receptor with the proviso that said existing compound cannot
be: (a) cyclazocine converted to --NHCHO; (b) naltrexone or
oxymorphone converted to --NHSO.sub.2CH.sub.3; (c)
levo-methylmorphinan converted to
levo-(methylmorphinan-3-yl)phenylmethanone; or (d) dextro
N-benzylnormetazocine converted to dextro
N-[1-benzyl-6,11-dimethylbenzomorphan-8-yl] methanesulfonamide.
33. A method according to claim 31 wherein said disease or
condition is chosen from the group consisting of pain, pruritis,
diarrhea, irritable bowel syndrome, gastrointestinal motility
disorder, obesity, respiratory depression, convulsions, coughing,
hyperalgesia and drug addiction.
34-50. (canceled)
51. A method according to claim 31 wherein A is chosen from the
group consisting of: --COOCH.sub.3, -COOEt, --CONH.sub.2,
--C(.dbd.S)NH.sub.2, --C(O)NHOH, --C(O)NHNH.sub.2, --CONHCH.sub.3,
-CONHBn, --CONHCH.sub.2(4-MeOC.sub.6H.sub.4),
2-(4,5-dihydroimidazolyl), --C(.dbd.NOH)NH.sub.2,
--CH.sub.2NH.sub.2, CH.sub.2OH, --COC.sub.6H.sub.5, --CN,
--C(.dbd.NOH)C.sub.6H.sub.5, --NHCHO, --NHCHS and
--NHSO.sub.2CH.sub.3.
52. A method according to claim 51 wherein A is chosen from the
group consisting of: --CONH.sub.2, --C(.dbd.S)NH.sub.2,
--C(.dbd.NOH)NH.sub.2, and --NHCHO.
53. A method according to claim 33 wherein said disease or
condition is obesity or drug addiction.
54. A method according to claim 53 wherein said drug addiction is
chosen from alcohol addiction, nicotine addiction, cocaine
addiction and heroin addiction.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of copending U.S.
application Ser. No. 10/987,527, filed Nov. 12, 2004, which was a
continuation of U.S. application Ser. No. 10/409,803, filed Apr. 9,
2003, now U.S. Pat. No. 6,887,998, which was a divisional of Ser.
No. 10/305,287, filed Nov. 26, 2002, now U.S. Pat. No. 6,784,187.
U.S. Ser. No. 10/305,287 was a continuation-in-part of PCT
International application PCT/USO1/45581, filed Oct. 31, 2001, and
published under PCT Article 21(2) in English on May 10, 2002, as WO
02/36573. PCT US01/45581 claimed benefit from U.S. provisional
application 60/244,438, filed Oct. 31, 2000. The entire contents of
each of the prior applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0003] The invention relates to opioid receptor binding compounds
containing carboxaamides, formamides, thiocarboxamides and
hydroxyamidines. The compounds are useful as analgesics,
anti-diarrheal agents, anticonvulsants, antitussives, anti-cocaine,
and anti-addiction medications.
BACKGROUND OF THE INVENTION
[0004] Opiates have been the subject of intense research since the
isolation of morphine in 1805, and thousands of compounds having
opiate or opiate-like activity have been identified. Many opioid
receptor-interactive compounds including those used for producing
analgesia (e.g., morphine) and those used for treating drug
addiction (e.g., naltrexone and cyclazocine) in humans have limited
utility due to poor oral bioavailability and a very rapid clearance
rate from the body. This has been shown in many instances to be due
to the presence of the 8-hydroxyl group (OH) of
2,6-methano-3-benzazocines, also known as benzomorphans [(e.g.,
cyclazocine and EKC (ethylketocyclazocine)] and the corresponding
3-OH group in morphinanes (e.g., morphine). ##STR3## The high
polarity of these hydroxyl groups retards oral absorption of the
parent molecules. Furthermore, the 8-(or 3-)OH group is prone to
sulfonation and glucuronidation (Phase II metabolism), both of
which facilitate rapid excretion of the active compounds, leading
to disadvantageously short half-lives for the active compounds.
Unfortunately, the uniform experience in the art of the past
seventy years has been that removal or replacement of the 8-(or
3-)OH group has lead to pharmacologically inactive compounds.
SUMMARY OF THE INVENTION
[0005] We have now found that the 8-(or 3-)hydroxyl group may be
replaced by a number of small, polar, neutral residues, such as
carboxamide, thiocarboxamide, hydroxyamidine and formamide groups.
Not only do the benzomorphan, morphinan carboxamides have
unexpectedly high affinity for opioid receptors, compounds
containing these groups in place of OH are far less susceptible to
Phase II metabolism and are generally more orally bioavailable. The
compounds of the invention are therefore useful as analgesics,
anti-pruritics, anti-diarrheal agents, anticonvulsants,
antitussives, anorexics and as treatments for hyperalgesia, drug
addiction, respiratory depression, dyskinesia, pain (including
neuropathic pain), irritable bowel syndrome and gastrointestinal
motility disorders. Drug addiction, as used herein, includes
alcohol and nicotine addiction. There is evidence in the literature
that the compounds may also be useful as anti-retroviral agents,
immunosuppressants and antiinflammatories and for reducing ischemic
damage (and cardioprotection), for improving learning and memory,
and for treating urinary incontinence.
[0006] In one aspect, the invention relates to
2,6-methano-3-benzazocine-8-carboxamides and
2,6-methano-3-benzazocine-8-carboxylate esters of formula: ##STR4##
wherein [0007] A is chosen from --CH.sub.2-Z, --CN,
--NHSO.sub.2-(lower alkyl), ##STR5## [0008] Q is chosen from O, S
and NR.sup.17; [0009] Y is chosen from O, S, NR.sup.17 and NOH;
[0010] Z is chosen from OH, SH, CN and NH.sub.2; [0011] R.sup.1 is
chosen from hydrogen, lower alkoxy, phenyl and --NHR.sup.8; [0012]
R.sup.2 and R.sup.2a are both hydrogen or taken together R.sup.2
and R.sup.2a are .dbd.O; [0013] R.sup.3 is chosen from hydrogen,
lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;
[0014] R.sup.4 is chosen from hydrogen, hydroxy, amino, lower
alkoxy, C.sub.1-C.sub.20 alkyl and C.sub.1-C.sub.20 alkyl
substituted with hydroxy or carbonyl; [0015] R.sup.5 is lower
alkyl; [0016] R.sup.6 is lower alkyl; [0017] R.sup.7 is chosen from
hydrogen and hydroxy; or together R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 may form from one to three rings, said rings having
optional additional substitution; [0018] R.sup.8 is chosen from
hydrogen, --OH, --NH.sub.2 and --CH.sub.2R.sup.15; [0019] R.sup.15
is chosen from hydrogen, alkyl, aryl, substituted aryl and alkyl
substituted with alkoxy, amino, alkylamino or dialkylamino; [0020]
R.sup.16 is chosen from hydrogen and NH.sub.2; and [0021] R.sup.17
is chosen from hydrogen, alkyl, aryl and benzyl; with the provisos
that, (1) when R.sup.2 and R.sup.2a are hydrogen, R.sup.3 is
hydrogen or cyclopropyl, R.sup.4 is hydroxy, and together R.sup.5,
R.sup.6 and R.sup.7 form two rings substituted with a
spirodioxolane, A cannot be --COOCH.sub.3 or NHSO.sub.2CH.sub.3;
(2) when R.sup.2 and R.sup.2a are hydrogen, R.sup.3 is hydrogen or
cyclopropyl, R.sup.4 is hydroxy, and together R.sup.5, R.sup.6 and
R.sup.7 form the ring system of oxymorphone and naltrexone, A
cannot be NHSO.sub.2CH.sub.3; (3) when R.sup.2, R.sup.2a, R.sup.4
and R.sup.7 are hydrogen, R.sup.3 is cyclopropyl and R.sup.5 and
R.sup.6 are methyl, A cannot be --NHC(O)H. The explicit provisos
exclude oxymorphone and naltrexone-3-sulfonamides, which were
disclosed as having no activity in vitro or in vivo [McCurdy et al.
Org. Lett. 2, 819-821 (2000)]; and cyclazocine formamide, which was
disclosed as an intermediate in a synthesis in U.S. Pat. Nos.
3,957,793; 4,032,529 and 4,205,171. Additionally, when A is --CN,
R.sup.7 must be hydroxyl. When R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 form one to three rings, it is preferred that none of the
rings formed by R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is aryl or
heteroaryl.
[0022] Subclasses of the foregoing structure include:
II. 2,6-methano-3-benzazocines of the structure shown above, in
which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 do not form additional
rings;
[0023] III. morphinans in which R.sup.5 and R.sup.6 form one ring:
##STR6## IV. morphinans in which R.sup.5, R.sup.6 and R.sup.7 form
two rings: ##STR7## and V. morphinans wherein R.sup.4 and R.sup.11
form an additional sixth ring, which may be saturated or
unsaturated but not fully aromatic: ##STR8## or ##STR9## In
addition to the major subclasses, there are compounds such as
##STR10## which the person of skill recognizes as closely related
to the major subclasses, but which defy easy description in a
common Markush structure.
[0024] In another aspect, the invention relates to a method for
preparing a second compound that interacts with an opioid receptor
when a first compound that interacts with an opioid receptor is
known. When the first compound contains a phenolic hydroxyl, the
method comprises converting the phenolic hydroxyl to a residue
chosen from the group described as the variable A above.
[0025] In another aspect, the invention relates to a method for
decreasing the rate of metabolism of a compound that interacts at
an opioid receptor. When the first compound contains a phenolic
hydroxyl, the method comprises converting the phenolic hydroxyl to
a residue chosen from the group described as the variable A
above.
[0026] In another aspect, the invention relates to methods for
inhibiting, eliciting or enhancing responses mediated by an opioid
receptor comprising:
(a) providing a first compound that inhibits, elicits or enhances
an opioid receptor response;
(b) preparing a second compound that interacts with an opioid
receptor by converting a phenolic hydroxyl group on the first
compound to a residue described as A above; and
(c) bringing the second compound into contact with the opioid
receptor.
[0027] In another aspect, the invention relates to a method for
treating a disease by altering a response mediated by an opioid
receptor. The method comprises bringing into contact with the
opioid receptor a compound having the formula ##STR11## wherein B
represents the appropriate residue of a known compound of formula
##STR12## and the known compound of that formula alters a response
mediated by an opioid receptor.
[0028] In another aspect, the invention relates to processes for
converting opioid-binding phenols or phenols on a benzomorphan or
morphinane to a carboxamide. The carboxamide conversion processes
comprise either:
(a) reacting the phenol with a reagent to convert it to a group
displaceable by CN.sup..theta.;
(b) reacting that group with Zn(CN).sub.2 in the presence of a
Pd(0) catalyst to provide a nitrile; and
(c) hydrolyzing the nitrile to a carboxamide; or:
(a) reacting the phenol with a reagent to convert the phenol to a
triflate;
(b) reacting the triflate with carbon monoxide and ammonia in the
presence of a Pd(II) salt and a Pd(0) catalyst to provide a
carboxamide; or
(a) reacting the phenol with a reagent to convert the phenol to a
triflate;
(b) reacting the triflate with carbon monoxide and
hexamethyldisilazane in the presence of a Pd(II) salt and a Pd(0)
catalyst to provide a silylated carboxamide precursor; and
(c) hydrolyzing the silylated carboxamide precursor to provide a
carboxamide.
[0029] Similar processes convert phenols to amidines and thioamides
by reacting the foregoing nitrile with hydroxylamine to produce a
hydroxyamidine or reacting the foregoing carboxamide with a
pentavalent phosphorus-sulfur reagent to produce a thioamide. For
the purpose of the invention an "opioid-binding phenol" is one that
exhibits binding at an opioid receptor below 25 nM.
DETAILED DESCRIPTION OF THE INVENTION
[0030] From many years of SAR studies, it is known that the
hydroxyl of morphinans and benzomorphans interacts with a specific
site in the opiate receptor. Previous exploration of the tolerance
of this site for functional groups other than phenolic hydroxyls
has almost uniformly resulted in the complete or near-complete loss
of opioid binding. We have now surprisingly found that the hydroxyl
can be replaced with one of several bioisosteres. Although a fairly
wide range of primary and secondary carboxamides, as well as
carboxylates, aminomethyl, hydroxymethyl and even dihydroimidazolyl
exhibit binding in the desired range below 25 nanomolar, optimal
activity is observed with a carboxamido, thiocarboxamido,
hydroxyamidino or formamido group.
[0031] Since the hydroxyl functionality of benzomorphans and
morphinans can be chemically converted to an amide by a simple,
flexible and convenient route described below, and since
thiocarboxamido, hydroxyamidino and formamido compounds are also
easily synthesized as described below, the door is opened to
improving the bioavailability of virtually any of the known and new
therapeutic agents that rely on opioid binding for their activity.
Moreover, since the receptor seems to tolerate some variation
beyond the .alpha.-carbon of A, one may contemplate further
modulating receptor specificity, affinity and tissue distribution
by varying the properties of the alkyl or aryl substituents on A.
Preferred residues A are --COOCH.sub.3, -COOEt, --CONH.sub.2,
--C(.dbd.S)NH.sub.2, --C(O)NHOH, --C(O)NHNH.sub.2, --CONHCH.sub.3,
-CONHBn, --CONHCH.sub.2(4-MeOC.sub.6H.sub.4),
2-(4,5-dihydroimidazolyl), --C(.dbd.NOH)NH.sub.2,
--CH.sub.2NH.sub.2, CH.sub.2OH, --COC.sub.6H.sub.5,
--C(.dbd.NOH)C.sub.6H.sub.5, --NHCHO, --NHCHS and
--NHSO.sub.2CH.sub.3. When R.sup.7 is hydroxyl, A may also be --CN.
Most preferred are --CONH.sub.2, --C(.dbd.S)NH.sub.2,
--C(.dbd.NOH)NH.sub.2, and --NHCHO.
[0032] It is known in the art that compounds that are .mu., .delta.
and .kappa. agonists exhibit analgesic activity; compounds that are
selective .mu. agonists exhibit anti-diarrheal activity and are
useful in treating dyskinesia; .mu. antagonists and .kappa.
agonists are usefuil in treating heroin, cocaine, alcohol and
nicotine addiction; .kappa. agonists are also anti-pruritic agents
and are useful in treating hyperalgesia. Recently it has been found
[Peterson et al. Biochem. Pharmacol. 61, 1141-1151 (2001)] that
.kappa. agonists are also useful in treating retroviral infections.
In general, the dextrorotatory isomers of morphinans of type III
above are useful as antitussives and anticonvulsants.
[0033] Additional diseases and conditions for which opioid agonists
and antagonists are known to be useful include irritable bowel
syndrome, gastrointestinal motility disorder, obesity and
respiratory depression. Certain opioids (e.g. fentanyl and
derivatives) are useful as anesthetics, i.e., they alter the state
of consciousness.
[0034] Opioid receptor ligands having known high affinity are shown
in the following charts 1 and 2. Replacement of OH in these
compounds produces compounds that exhibit similar activity and
better bioavailability. ##STR13## ##STR14## ##STR15## ##STR16##
##STR17## ##STR18## ##STR19## ##STR20## Other opioid receptor
ligands are described in Aldrich, J. V. "Analgesics" in Burger's
Medicinal Chemistry and Drug Discovery, M. E. Wolff ed., John Wiley
& Sons 1996, pages 321-44, the disclosures of which are
incorporated herein by reference.
[0035] We have examined the opioid receptor binding of a series of
analogs of known compounds that interact at opioid receptors in
which the OH is replaced by the R-group shown in Tables 1-4. The
standards are shown in Table 5. The affinities of the compounds of
the invention were determined in guinea pig brain cells by the
method described in Wentland et al. Biorgan. Med. Chem. Lett. 9.
183-187 (2000). Alternatively, where noted, the affinities of the
compounds of the invention were determined in cloned human
receptors in Chinese hamster ovary cells by the method described by
Xu et al [Synapse 39, 64-69 (2001)]. CHO cell membranes, expressing
the human .mu., .delta., or .kappa. opioid receptor, were incubated
with 12 different concentrations of the compounds in the presence
of receptor-specific radioligands at 25.degree. C., in a final
volume of 1 ml of 50 mM Tris-HCl, pH 7.5. Nonspecific binding was
determined using 1 .mu.M naloxane. Data are the mean
value.+-.S.E.M. from three experiments, performed in triplicate.
TABLE-US-00001 TABLE 1 Cyclazocine subseries ##STR21## ex-
[.sup.3H] [.sup.3H] [.sup.3H] am- DAMGO Naltrindole U69,593 ple A =
(.mu.) (.delta.) (.kappa.) 4b (+)CONH.sub.2 63 .+-. 5.4 570 .+-. 50
67 .+-. 1.6 5 C(.dbd.S)NH.sub.2 0.22 .+-. 4.0 .+-. 0.48 0.67 .+-.
0.01 0.02 6 CONHOH 12 .+-. 0.32 210 .+-. 40 6.9 .+-. 0.61 7
CONHNH.sub.2 60 .+-. 9.3 450 .+-. .A-inverted.62 19 .+-. 1.4 8
CONHCH.sub.3 24 .+-. 1.6 63 .+-. 4.1 2.6 .+-. 0.19 9
CONHCH.sub.2C.sub.6H.sub.5 20 .+-. 2.2 140 .+-. 18 78 .+-. 7.6 10
CONHCH.sub.2(4-MeOC.sub.6H.sub.4) 19 .+-. 1.5 150 .+-. 17 110 .+-.
3.1 11 CONHCH.sub.2CH.sub.2N(CH.sub.3).sub.2 26 .+-. 2.9 350 .+-.
51 44 .+-. 11 12 CONH(CH.sub.2).sub.3N(CH.sub.3).sub.2 370 .+-. 54
3000 .+-. 230 310 .+-. 64 13 2-(4,5-H.sub.2)-imidazolyl 23 .+-. 1.9
55 .+-. 5.1 11 .+-. 0.69 14 C(.dbd.NOH)NH.sub.2 3.8 .+-. 0.42 16
.+-. 0.67 0.90 .+-. 0.15 15 CH.sub.2NH.sub.2 31 .+-. 5.4 390 .+-.
47 17 .+-. 2.9 16 CH.sub.2OH 21 .+-. 2.0 210 .+-. 29 7.6 .+-. 0.80
17 COC.sub.6H.sub.5 33 .+-. 0.90 490 .+-. 43 19 .+-. 2.6 18
C(.dbd.NOH)C.sub.6H.sub.5 86 .+-. 3.8 180 .+-. 15 7.2 .+-. 0.40 38
CH.sub.2CN 3.3 .+-. 1.5.sup.a 2000 .+-. 685.sup.a 2.9 .+-.
0.36.sup.a 39 CH(N.dbd.OH) 18 .+-. 1.8.sup.a 140 .+-. 15.sup.a 0.73
.+-. 0.03.sup.a 19 NHCHO 1.9 .+-. 0.14 37 .+-. 3.9 0.85 .+-. 0.080
19a (-)NHCHO 1.1 .+-. 0.04 9.8 .+-. 0.28 0.49 .+-. 0.012 19b
(+)NHCHO 2300 .+-. >10,000 900 .+-. 8.7 180 20 NHCHS 0.76 .+-.
16 .+-. 0.30 0.63 .+-. 0.15 0.09 21 NHSO.sub.2CH.sub.3 15 .+-. 1.2
780 .+-. 170 21 .+-. 1.5 36 NHCONH.sub.2 20 .+-. 0.66 90 .+-. 12 15
.+-. 1.4 37 NHCSNH.sub.2 10 .+-. 1.7.sup.a 440 .+-. 72.sup.a 4.0
.+-. 0.54.sup.a .sup.adata from chinese hamster ovary rather than
guinea pig brain
[0036] TABLE-US-00002 TABLE 2 Keto subseries: ##STR22## ex- am-
[.sup.3H]DAMGO [.sup.3H]Naltrindole [.sup.3H]U69,593 ple A = (.mu.)
(.delta.) (.kappa.) 22 CN(KC) 680 .+-. 61 3400 .+-. 410 59 .+-.
0.77 23 CONH.sub.2(KC) 1.4 .+-. 0.07 20 .+-. 2.3 1.8 .+-. 0.10 24
CONH.sub.2(EKC) 1.2 .+-. 0.12 9.8 .+-. 0.50 0.70 .+-. 0.08 40
NHCHO(EKC) 6.1 .+-. 0.83 52 .+-. 3.4 1.2 .+-. 0.11
[0037] TABLE-US-00003 TABLE 3 Merz subseries ##STR23## ex-
[.sup.3H] am- DAMGO [.sup.3H]Naltrin- [.sup.3H]U69,593 ple A =
(.mu.) dole(.delta.) (.kappa.) 25 (-)-(2''S)-8-OH 0.19 .+-. 0.01
3.6 .+-. 0.40 0.09 .+-. 0.01 26 (-)-(2''S)-8-CONH.sub.2 0.052 .+-.
2.0 .+-. 0.15 0.089 .+-. 0.013 0.004 27 (-)-(2''R)-8-OH 4.0 .+-.
0.54 67 .+-. 4.3 1.5 .+-. 0.07 28 (-)-(2''R)-8-CONH.sub.2 2.9 .+-.
0.17 34 .+-. 0.10 2.8 .+-. 0.24 29 (-)-(2''S)-8-CH.sub.2NH.sub.2 28
.+-. 2.3 300 .+-. 27 18 .+-. 1.9
[0038] TABLE-US-00004 TABLE 4 Other Series ##STR24## ##STR25##
##STR26## ##STR27## ##STR28## ##STR29## ##STR30## ex- [.sup.3H]
[.sup.3H] am- [.sup.3H]DAMGO Naltrindole U69,593 ple A = (.mu.)
(.delta.) (.kappa.) 30 CONH.sub.2(morphine) 34 .+-. 1.8 1900 .+-.
81 2000 .+-. 97 31 CONHCH.sub.3(morphine) 440 .+-. 9.2 >10,000
>10,000 32 CONH.sub.2(naltrexone) 1.9 .+-. 0.21 110 .+-. 8.1 22
.+-. 0.85 33 CO.sub.2Et(naltrexone) 24 .+-. 1.7 970 .+-. 155 16
.+-. 0.70 41 (-)NHCHO 4.1 .+-. 0.40.sup.a 280 .+-. 7.6.sup.a 2.3
.+-. (naltrexone) 0.044.sup.a 34 CONH.sub.2(naltrindole) 47 .+-.
2.7 0.33 .+-. 0.04 99 .+-. 7.9 35 CONH.sub.2 2.3 .+-. 0.29 7.3 .+-.
0.61 4.3 .+-. 0.05 (buprenorphine) 42 CONH.sub.2(nalbuphine) 3.8
.+-. 0.62.sup.a 150 .+-. 82.sup.a 0.46 .+-. 0.04.sup.a 43 CN(7-OH)
0.35 .+-. 0.092.sup.a 82 .+-. 24.sup.a 2.6 .+-. 0.21.sup.a 44
CONH2(butorphanol) 0.15 .+-. 0.019.sup.a 14 .+-. 2.1.sup.a 0.39
.+-. 0.057.sup.a
[0039] TABLE-US-00005 TABLE 5 Standards [.sup.3H]DAMGO
[.sup.3H]Naltrindole [.sup.3H]U69,593 (.mu.) (.delta.) (.kappa.)
(.+-.)-Cyclazocine 0.32 .+-. 0.02 1.1 .+-. 0.04 0.18 .+-. 0.020
(.+-.)-Cyclazocine .sup. 0.16 .+-. 0.01 .sup.a .sup. 2.0 .+-. 0.22
.sup.a .sup. 0.07 .+-. 0.01 .sup.a (+)-Cyclazocine 360 .+-. 16 1100
.+-. 63 76 .+-. 8.2 (-)-Cyclazocine 0.10 .+-. 0.03 0.58 .+-. 0.06
0.052 .+-. 0.009 (.+-.)-EKC 0.78 .+-. 0.10 3.4 .+-. 0.41 0.62 .+-.
0.11 (.+-.)-ketocyclazocine 3.3 .+-. 0.66 .sup. 20 .+-. 2.7.sup.
1.0 .+-. 0.24 (.+-.)-ketocyclazocine 1.7 .+-. 0.21 .sup.a.sup. 130
.+-. 14 .sup.a.sup. .sup. 1.0 .+-. 0.019 .sup.a naltrexone (3-OH)
0.17 .+-. 0.03 .sup. 11 .+-. 1.1.sup. 0.31 .+-. 0.03 naltrindole
(3-OH) 13 .+-. 1.1 0.13 .+-. 0.02 4.6 .+-. 0.23 buprenorphine 0.98
.+-. 0.11 0.72 .+-. 0.10 0.90 .+-. 0.11 nalbuphine 1.6 .+-. 0.37
.sup.a.sup. 580 .+-. 80 .sup.a.sup. 3.0 .+-. 0.63 .sup.a.sup.
butorphanol 0.12 .+-. 0.058 .sup.a.sup. .sup. 12 .+-. 3.8 .sup.a
0.22 .+-. 0.023 .sup.a.sup.
Example 4 was tested several times independently to confirm the
K.sub.i's. Inspection of the results in Table 1 indicates not only
that affinity is preserved in the compounds of the invention, but
also that receptor selectivity can be modulated.
[0040] Antinociceptive activity is evaluated by the method
described in Jiang et al. [J. Pharmacol. Exp. Ther. 264, 1021-1027
(1993), page 1022]. Compound 4 was found to exhibit an ED.sub.50 of
0.21 nmol in the mouse acetic acid writhing test when administered
i.c.v. Its "parent" cyclazocine exhibited an ED.sub.50 of 2.9 nmol
i.c.v. The time courses in producing antinociception in the mouse
writhing test were compared for compound 4 and cyclazocine. Mice
were injected with 1.0 mg/kg of either compound 4 or cyclazocine,
given by i.p. administration. An increase in the duration of action
from ca. 2 hr to 15 hr was observed for compound 4 compared to
cyclazocine.
Definitions
[0041] Throughout this specification the terms and substituents
retain their definitions.
[0042] Alkyl is intended to include linear, branched, or cyclic
hydrocarbon structures and combinations thereof. Lower alkyl refers
to alkyl groups of from 1 to 6 carbon atoms. Examples of lower
alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl,
butyl, s-and t-butyl, cyclobutyl and the like. Preferred alkyl
groups are those of C.sub.20 or below. Cycloalkyl is a subset of
alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon
atoms. Examples of cycloalkyl groups include c-propyl, c-butyl,
c-pentyl, norbornyl and the like.
[0043] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon
atoms of a straight, branched, cyclic configuration and
combinations thereof attached to the parent structure through an
oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,
cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to
groups containing one to four carbons.
[0044] Aryl and heteroaryl mean a 5- or 6-membered aromatic or
heteroaromatic ring containing 0-3 heteroatoms selected from O, N,
or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring
system containing 0-3 heteroatoms selected from O, N, or S; or a
tricyclic 13- or 14-membered aromatic or heteroaromatic ring system
containing 0-3 heteroatoms selected from O, N, or S. Heteroaryl
refers to any maximally unsaturated heterocycle. The aromatic 6- to
14-membered carbocyclic rings include, e.g., benzene, naphthalene,
indane, tetralin, and fluorene and the 5- to 10-membered aromatic
heterocyclic rings include, e.g., imidazole, pyridine, indole,
thiophene, benzopyranone, thiazole, furan, benzimidazole,
quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine,
tetrazole and pyrazole.
[0045] Arylalkyl means an alkyl residue attached to an aryl ring.
Examples are benzyl, phenethyl and the like. Heteroarylalkyl means
an alkyl residue attached to a heteroaryl ring. Examples include,
e.g., pyridinylmethyl, pyrimidinylethyl and the like.
[0046] Heterocycle means a cycloalkyl or aryl residue in which one
to two of the carbons is replaced by a heteroatom such as oxygen,
nitrogen or sulfur. Heteroaryls form a subset of heterocycles.
Examples of heterocycles that fall within the scope of the
invention include pyrrolidine, pyrazole, pyrrole, indole,
quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran,
benzodioxan, benzodioxole (commonly referred to as
methylenedioxyphenyl, when occurring as a substituent), tetrazole,
morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene,
furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and
the like.
[0047] Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer
to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H
atoms in each residue are replaced with halogen, hydroxy,
loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl,
--NO.sub.2, --NR.sup.1R.sup.2; alkylthio, sulfoxide, sulfone,
acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy,
heteroaryloxy, or substituted phenyl, benzyl, heteroaryl, phenoxy,
benzyloxy, or heteroaryloxy.
[0048] Virtually all of the compounds described herein contain one
or more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)-- or (S)--. The
present invention is meant to include all such possible isomers, as
well as their racemic and optically pure forms. In general it has
been found that the levo isomer of morphinans and benzomorphans is
the more potent antinociceptive agent, while the dextro isomer may
be useful as an antitussive or antispasmodic agent. Optically
active (R)-- and (S)-- isomers may be prepared using chiral
synthons or chiral reagents, or resolved using conventional
techniques. When the compounds described herein contain olefinic
double bonds or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers. Likewise, all tautomeric forms are also
intended to be included. TABLE-US-00006 Abbreviations The following
abbreviations and terms have the indicated meanings throughout: Ac
= acetyl BNB = 4-bromomethyl-3-nitrobenzoic acid Boc = t-butyloxy
carbonyl Bu = butyl c- = cyclo DAMGO =
Tyr-ala-Gly-NMePhe-NHCH.sub.2OH DBU =
diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane = methylene
chloride = CH.sub.2Cl.sub.2 DEAD = diethyl azodicarboxylate DIC =
diisopropylcarbodiimide DIEA = N,N-diisopropylethyl amine DMAP =
4-N,N-dimethylaminopyridine DMF = N,N-dimethylformamide DMSO =
dimethyl sulfoxide DPPF = 1,1'-bis(diphenylphosphino)ferrocene DVB
= 1,4-divinylbenzene EEDQ =
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Fmoc =
9-fluorenylmethoxycarbonyl GC = gas chromatography HATU =
O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate HOAc = acetic acid HOBt = hydroxybenzotriazole
Me = methyl mesyl = methanesulfonyl MTBE = methyl t-butyl ether NMO
= N-methylmorpholine oxide PEG = polyethylene glycol Ph = phenyl
PhOH = phenol PfP = pentafluorophenol PPTS = pyridinium
p-toluenesulfonate PyBroP = bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate rt = room temperature sat'd = saturated s- =
secondary t- = tertiary TBDMS = t-butyldimethylsilyl TFA =
trifluoroacetic acid THF = tetrahydrofuran TMOF = trimethyl
orthoformate TMS = trimethylsilyl tosyl = p-toluenesulfonyl Trt =
triphenylmethyl U69,593 = ##STR31##
[0049] In the general processes described below, the preferred
reagent to convert a phenol to a group displaceable by
CN.sup..theta. is trifluoromethansulfonic anhydride, which is
usually employed in the presence of base. Other reagents are known
to persons of skill in the art to convert phenols to groups that
may be displaced by cyanide anion. The advantage of the
trifluoromethansulfonic anhydride procedure is that it allows
displacement under conditions that are mild enough to avoid
destruction of the rest of the molecule for most species of
interest. Other reagents are operable, but require more robust
substrates than may be of interest in a particular case. The
consideration of which to use is within the skill of the artisan. A
preferred Pd(0) catalyst for use in the displacement with zinc
cyanide is tetrakis(triphenylphosphine)palladium. In the direct
displacements with carbon monoxide and ammonia or an ammonia
equivalent, the preferred Pd(0) catalyst is generated in situ from
Pd(OAc).sub.2 or PdCl.sub.2 and
1,1'-bis(diphenylphosphino)ferrocene. Other Pd(0) ligands include
DPPF, DPPP, triphenylphosphine, 1,3-bis(diphenylphosphino)propane,
BINAP and xantphos. The preferred pentavalent phosphorus-sulfur
reagents for converting carboxamides to thiocarboxamides are
Lawesson's reagent and phosphorus pentasulfide.
[0050] It may happen that residues in the substrate of interest
require protection and deprotection during the conversion of the
phenol to the desired bioisostere. Terminology related to
"protecting", "deprotecting" and "protected" functionalities occurs
throughout this application. Such terminology is well understood by
persons of skill in the art and is used in the context of processes
which involve sequential treatment with a series of reagents. In
that context, a protecting group refers to a group which is used to
mask a functionality during a process step in which it would
otherwise react, but in which reaction is undesirable. The
protecting group prevents reaction at that step, but may be
subsequently removed to expose the original functionality. The
removal or "deprotection" occurs after the completion of the
reaction or reactions in which the functionality would interfere.
Thus, when a sequence of reagents is specified, as it is in the
processes of the invention, the person of ordinary skill can
readily envision those groups that would be suitable as "protecting
groups". Suitable groups for that purpose are discussed in standard
textbooks in the field of chemistry, such as Protective Groups in
Organic Synthesis by T. W. Greene [John Wiley & Sons, New York,
1991], which is incorporated herein by reference.
[0051] The compounds of the invention are synthesized by one of the
routes described below: ##STR32## ##STR33##
Chemical Syntheses
[0052] Proton NMR [Varian Unity-500 (500 MHz) NMR] data, direct
insertion probe (DIP) chemical ionization mass spectra (Shimadzu
GC-17A GC-MS mass spectrometer), and infrared spectra (Perkin-Elmer
Paragon 1000 FT-IR spectrophotometer) were consistent with the
assigned structures of all test compounds and intermediates.
.sup.1H NMR multiplicity data are denoted by s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
Coupling constants are in hertz. Carbon, hydrogen, and nitrogen
elemental analyses for all novel targets were performed by
Quantitative Technologies Inc., Whitehouse, N.J., and were within
.+-.0.4% of theoretical values except as noted; the presence of
water was conformed by proton NMR. Melting points were determined
on a Meltemp capillary melting point apparatus and are uncorrected.
Optical rotation data were obtained from a Perkin-Elmer 241
polarimeter. Reactions were generally performed under a N.sub.2
atmosphere. Amines used in the Pd-catalyzed amination reactions and
racemic-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP) were
purchased from Aldrich Chemical Company and used as received unless
otherwise indicated. Tris(dibenzylideneacetone) dipalladium (0)
[Pd.sub.2(dba).sub.3], Pd(OAc).sub.2,
1,1'-bis(diphenylphosphino)ferrocene (DPPF), were purchased from
Strem Chemicals, Incorporated. Toluene and Et.sub.2O were distilled
from sodium metal. THF was distilled from sodium/benzophenone
ketyl. Pyridine was distilled from KOH. Methylene chloride was
distilled from CaH.sub.2. DMF and DMSO were distilled from
CaH.sub.2 under reduced pressure. Methanol was dried over
3.+-.(**') molecular sieves prior to use. Silica gel (Bodman
Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for
flash column chromatography.
[0053] (.+-.)-3
-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano--
3-benzazocin-8-carbonitrile [1]. The triflate [36] of cyclazocine
[35] (470 mg, 1.166 mmol), obtained by the method of Wentland et
al. [Bioorgan. Med. Chem. Lett. 9,183-187 (2000)], was dissolved in
20 mL DMF and Zn(CN).sub.2 (272.6 mg, 2.322 mmol) and
Pd(PPh.sub.3).sub.4 (53.9 mg, 0.0466 mmol) were added. After
heating in 120.degree. C. for 2 h, the reaction was allowed to stir
at 25.degree. C. overnight. A mixture of EtOAc and NaHCO.sub.3
solution was then added. The organic phase was washed with brine
and then dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to dryness. Flash column chromatography gave
1 as a colorless oil (260 mg, 80%). .sup.1H-NMR (500 MHz,
CDCl.sub.3) d 7.52 (b,1H), 7.37 (dd, J=7.8, 1.5 Hz, 1H), 7.14 (d,
J=8.1, 1H), 3.15 (m, 1H), 2.96 (d, J=19.0 Hz, 1H), 2.66-2.74 (m,
2H), 2.45 (m, 1H), 2.30 (m, 1H), 1.84-1.98 (m, 3H), 1.38 (s, 3H),
1.29 (m, 1H), 0.85 (m, 1H), 0.82 (d, J=7.1 Hz, 3H), 0.51 (m, 2H),
0.10 (m, 2H). IR (film) 2961, 2918, 2225 cm-.sup.-1. CI-MS, m/z
(relative intensity) 281 (M+1, 100%). Anal. Calcd. for
C.sub.19H.sub.24N.sub.20.125H.sub.2O: C 80.78, H 8.59, N 9.92.
Found: C 80.75, H 8.63, N 9.89.
[0054]
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimeth-
yl-2,6-methano-3-benzazocin-8-carboxamide [4]. Compound 1 (80 mg,
0.286 mmol) was dissolved in about 1 mL t-butyl alcohol. KOH (58.8
mg, 1.05 mmol) was then added. The reaction mixture was stirred at
reflux for about 20 min and the solvent was evaporated and
CH.sub.2Cl.sub.2 and MeOH and NaCl solution were added. The organic
phase was washed with brine and then dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to dryness to
give 4 as white foam (80 mg, 95%). .sup.1H-NMR (500 MHz,
CD.sub.3OD) d 7.81 (m, 1H), 7.62 (m, 1H), 7.17 (m, 1H), 3.22 (m,
1H), 3.04 (m, 1H), 2.66-2.82 (m, 2H), 2.50 (m, 1H), 2.35 (m, 1H),
1.86-1.98 (m, 3H), 1.34 (s, 3H), 1.36 (m, 1H), 0.88 (m, 1H), 0.84
(d, J=7.0 Hz, 3H), 0.54 (m, 2H), 0.16 (m, 2H) . .sup.13C-NMR (500
MHz, CD.sub.3OD) d 172.71, 143.32, 142.34, 133.01, 128.61, 126.61,
126.18, 60.67, 58.09, 46.92, 42.74, 42.38, 37.69, 25.92, 25.07,
14.62, 9.67, 4.64, 4.52. IR (film) 1654.2 cm.sup.-1. CI-MS, m/z
(relative intensity) 299 (M+1, 100%). Anal. Calcd. for
C.sub.19H.sub.26N.sub.2O0.25H.sub.2O: C 75.37, H 8.76, N 9.26.
Found: C 75.27, H 9.02, N 9.03.
[0055]
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimeth-
yl-2,6-methano-3-benzazocin-8-carboxamide [1] (alternate
procedure). A flask containing triflate 36 (100 mg), Pd(OAc).sub.2
(10.2 mg), and 1,1'-bis(diphenylphosphino)ferrocene(DPPF, 25 mg)
was purged with argon. The argon was replaced with gaseous CO and
the reaction vessel was closed to the atmosphere. Dry DMSO (1.25
mL) was added via syringe and gaseous ammonia was added to the
resulting mixture via a canula. A balloon was used to keep the
additional volume contained. The mixture was stirred for 17 h at
70.degree. C. followed by cooling to 25.degree. C. The reaction
mixture was diluted with water and the product was extracted into
ethyl acetate. The organic extracts was washed with aqueous
NaHCO.sub.3 and dried (Na.sub.2SO.sub.4). Concentration of the
solvent in vacuo gave 90 mg of a crude product. This material was
purified via flash chromatography (25:1:0.1
--CH.sub.2Cl.sub.2:MeOH: conc NH.sub.4OH) to provide 47 mg (65.3%)
of compound 4.
[0056]
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimet-
hyl-2,6-methano-3-benzazocin-8-carboxylic acid methyl ester [3]. A
modification of a known procedure (Cacchi, S.; Ciattini, P. G.;
Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27, 3931-3934) was
used in this preparation. Under an argon atmosphere, triethylamine
(0.30 mL, 2.15 mmol) was added to a mixture of the 8-triflate ester
of cyclazocine [36] (0.403 g, 1.0 mmol), palladium acetate (0.0068
g, 0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.00166 g,
0.03 mmol) and methanol (1 mL, 22.2 mmol) in DMF (1 mL). The
solution was purged with carbon monoxide for 15 min and stirred
under a CO balloon at 70.degree. C. for 5 h. The reaction mixture
was taken up in 20 mL of ethyl acetate and washed with saturated
sodium bicarbonate solution and water. The organic phase was dried
with sodium sulfate and evaporated to give crude product as a brown
oil. Chromatography on silica gel using
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (conc)/40:1:0.1 provided the
desired compound 3 (0.235 g, 86.6%) as a colorless oil: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta.7.93 (d, J=1.7 Hz, 1H), 7.76 (dd,
J.sub.1=1.7 Hz, J.sub.2=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.89
(s, 3H), 3.15 (m, 1H), 2.96 (d, J=19.0 Hz, 1H), 2.73 (d,J=6.1 Hz,
1H), 2.70 (m, 1H), 2.46 (dd, J.sub.1=7.3 Hz, J.sub.2=12.4 Hz, 1H),
2.31 (dd, J.sub.1=6.6 Hz, J.sub.2=12.4 Hz, 1H), 1.96 (m, 1H), 1.91
(m, 2H), 1.43 (s, 3H), 1.33 (m, 1H), 0.86 (m, 1H), 0.83 (d, J=7.1
Hz, 3H), 0.51 (d, J=8.1 Hz, 2H), 0.11 (m, 2H); IR (film) v.sub.max
2916, 1720, 1270 cm.sup.-1; MS (CI) m/z 314 (M+H).sup.+; Anal.
calc. for C.sub.20H.sub.27NO.sub.2: C, 76.64; H, 8.68; N, 4.47.
Found: C, 76.37; H, 8.93; N, 4.38.
[0057]
(.+-.)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dime-
thyl-2,6-methano-3-benzazocin-8-yl]-methanol [16]. Under a blanket
of N.sub.2 at 0.degree. C.,
(.+-.)-3-(cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-
-methano-3-benzazocin-8-carboxylic acid methyl ester [3] (0.1062 g,
0.34 mmol), LiA1H.sub.4 powder (0.0258 g, 0.68 mmol) and dry THF
(0.77 mL) were placed in a one-neck round bottom flask equipped
with condenser and stir bar. The ice/water bath was removed and the
reaction was stirred at reflux for 24 h. The mixture was cooled to
25.degree. C. and quenched by adding water dropwise until
effervescence ceased. The mixture was then treated with 10%
H.sub.2SO.sub.4 and stirred at 25.degree. C. for 3 hours. The
mixture then was extracted with diethyl ether (2.times.) and the
organic layer was dried (Na.sub.2SO.sub.4) and the solvent was
removed in vacuo. The crude product was purified by flash column
chromatography using CH.sub.2Cl.sub.2:MeOH/10:1 as eluent to
provide the desired product [16] (0.0557 g, 57%) as a light yellow
oil: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.7.24 (d, J=17 Hz,
1H), 7.10 (m, 1H), 7.08 (d, J=21.2 Hz, 1H), 4.64 (s, 2H), 3.14 (m,
1H), 2.91 (d, J=18.5 Hz, 1H), 2.68 (m, 2H), 2.47 (m, 1H), 2.31 (m,
1H), 1.92 (m, 6H), 1.34 (m, 3H), 0.84 (d, J=7.1 Hz), 0.50 (m, 2H),
0.11 (m, 2H); Anal. calc. for C.sub.19H.sub.27NO: C, 79.95; H,
9.53; N, 4.91. Found: C, 79.70; H, 9.50; N, 4.68.
[0058]
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-N-hydroxy-cis-6-
,11 -dimethyl-2,6-methano-3-benzazocin-8-carboxamidine [14]. A
modification of a known procedure (Jendralla, H.; Seuring, B.;
Herchen, J.; Kulitzscher, B.; Wunner, J. Tetrahedron 1995, 51,
12047-12068) was used in this preparation. A mixture of
(.+-.)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6--
methano-3-benzazocin-8-carbonitrile [1] (0.230 g, 0.82 mmol),
hydroxyamine hydrochloride (0.100 g, 1.44 mmol) and triethylamine
(0.30 mL, 2.15 mmol) in 1 mL of absolute ethanol was stirred at
reflux under an argon atmosphere for 5 h. The reaction mixture was
concentrated in vacuo and the residue was taken up in 15 mL of
CH.sub.2Cl.sub.2 and washed with water. The organic phase was dried
(Na.sub.2SO.sub.4) and evaporated to give crude product. Flash
column chromatography using CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
(conc)/25:1:0.1 provided the desired compound 14 (0.216 g, 84%) as
a white foam: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.9.48 (br s,
1H), 7.56 (d, J=1.5 Hz, 1H), 7.33 (dd, J.sub.1=1.5 Hz, J.sub.2=7.8
Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 4.84 (s, 2H), 3.19 (m, 1H), 2.94
(d, J=18.8 Hz, 1H), 2.72 (m, 2H), 2.48 (dd, J.sub.1=6.3 Hz,
J.sub.2=12.5 Hz, 1H), 2.34 (dd, J.sub.1=6.6 Hz, J.sub.2=12.5 Hz,
1H), 2.01 (m, 3H), 1.42 (s, 3H), 1.34 (d, J=11.4 Hz, 1H), 0.92 (m,
1H), 0.84 (d, J=6.8 Hz, 3H), 0.51 (m, 2H), 0.12 (m, 2H); IR (film)
v.sub.max 3365, 2921, 1634, 1577 cm.sup.-1; MS (CI) m/z 314
(M+H).sup.+; Anal. calc. for C.sub.19H.sub.27N.sub.3O: C, 72.81; H,
8.68; N, 13.47. Found: C, 72.96; H, 8.67; N, 13.18.
[0059] (.+-.)-3
-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano--
3-benzazocin-8-thiocarboxamide [5]. A modification of a known
procedure (Varma R. S.; Kumar, D. Organic Lett. 1999, 1, 697-700)
was used in this preparation. A mixture of
(+)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-met-
hano-3-benzazocin-8-carboxamide [4] (0.0298 g, 0.1 mmol) and
Lawsson's reagent (0.0320 g, 0.08 mmol) in 1 mL of toluene was
sealed in a glass tube under an argon atmosphere. The glass tube
was put in a microwave oven and irradiated for 7 min. Additional
Lawsson's reagent (0.0160 g, 0.04 mmol) was added and the reactants
was allowed to be irradiated for additional 7 min. The reaction
mixture was taken up in 10 mL of CH.sub.2Cl.sub.2 and washed with
water. The organic phase was dried with sodium sulfate and
evaporated to give crude product. Chromatography on silica gel
using CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (conc)/40:1:0.1 the provided
desired compound 5 (0.022 g, 70.1%) as a yellow crystalline solid:
mp 171-173.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta.7.78 (d, J=1.9 Hz, 1H), 7.64 (brs, 1H), 7.60(dd, J.sub.1=1.9
Hz, J.sub.2=8.1 Hz, 1H), 7.19 (brs, 1H), 7.09 (d, J=8.1 Hz, 1H),
3.16 (m, 1H), 2.95 (d, J=19.0 Hz, 1H), 2.70 (m, 2H), 2.46 (dd,
J.sub.1=6.1 Hz, J.sub.2=12.4 Hz, 1H), 2.32 (dd, J.sub.1=6.3 Hz,
J.sub.2=12.4 Hz, 1H), 1.92 (m, 3H), 1.43 (s, 3H), 1.34 (m, 1H),
0.85 (m, 1H), 0.83 (d, J=7.1 Hz, 3H), 0.51 (m, 2H), 0.10 (m, 2H);
IR (film) v.sub.max 3172, 2920, 1617, 1424 cm.sup.-1; MS (CI) m/z
315 (M+H).sup.+; Anal. calc. for C.sub.19H.sub.26N.sub.2S0.75
H.sub.2O: C, 69.58; H, 8.45; N, 8.54. Found: C, 69.54; H, 8.15; N,
8.26.
[0060]
(.+-.)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dime-
thyl-2,6-methano-3-benzazocin-8-yl]-methylamine [15].
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6--
methano-3-benzazocin-8-carbonitrile [1] (0.154 g, 0.55mmol) was
dissolved in Et.sub.2O (1.1 mL) to obtain a 0.5 M solution. This
solution was added dropwise via syringe to a vigorously stirred
solution of 1.0 M LiA1H.sub.4 in Et.sub.2O (1.1 mL, 1.1 mmol) at
0.degree. C. After stirring at room temperature for 10 min, water
was added dropwise to quench the reaction. The resulting solution
was then extracted with EtOAc several times and the combined EtOAc
layers were dried (Na.sub.2SO.sub.4), and filtered. The solvent was
removed in vacuo and the residue purified by flash column
chromatography (CH.sub.2Cl.sub.2:MeOH:Et.sub.3N/10:1:0.2) to yield
the desired product 15 (0.105 g, 67%) as a brown oil: .sup.1H NMR
(500 MHz, CDCl3) .delta.7.16 (s, 1H), 7.04 (m, 2H), 3.82 (s, 2H),
3.16 (s, 1H), 2.91 (d, J=8.3 Hz, 1H), 2.70 (m, 2H), 2.49 (m, 1H),
2.34 (m, 1H), 1.92 (m, 5H), 1.39 (m, 4H), 0.85 (m, 4H), 0.51 (d,
J=7.6 Hz, 2H), 0.11 (m, 2H); IR (film) <.sub.max 3075, 2962,
2917, 2814, 1574, 1499, 1462, 1428, 1380, 1333, 1218, 1101, 1075,
1018, 963 cm.sup.-1; Anal. calc. for
C.sub.19H.sub.28N.sub.20.5H.sub.2O: C, 77.77; H, 9.96; N, 9.54.
Found: C, 78.18; H, 10.17; N, 9.39.
[0061]
(.+-.)-N-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-di-
methyl-2,6-methano-3-benzazocin-8-yl]-formamide [19]. A
modification of a known procedure (Chakrabarty, M.; Khasnobis, S.;
Harigaya, Y.; Kinda, Y. Synthetic Comm. 2000, 30, 187-200.) was
used in this preparation.
(.+-.)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6--
methano-3-benzazocin-8-amine [37] (0.091 g, 0.337 mmol) was treated
with 96% formic acid (20 mL) and was heated at 100.degree. C. for
14 h. The solution was then poured onto crushed ice and basified
with solid NaHCO.sub.3. The organic material was extracted into
EtOAc (3.times.) and the extracts were washed with water and dried
(Na.sub.2SO.sub.4). After concentration in vacuo, the crude product
was purified by flash column chromatography
(CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH/10:1:0.05) to yield the desired
product 19 as a brown oil (0.065 g, 65%): .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.8.62 (d, J=11.5 Hz, 0.5H, CHO of one rotomer),
8.34 (d, J=1.7 Hz, 0.5H, CHO of other rotomer), 8.17 (d, J=10.5 Hz,
0.5H, NH of one rotomer), 7.57 (br s, 0.5H, NH of other rotomer),
7.36 (m, 1H), 7.04 (m, 1H), 6.89 (m, 1H), 3.15 (m, 1H), 2.90 (m,
1H), 2.72 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.95 (m, 3H), 1.32
(m, 4H), 0.85 (m, 4H), 0.51 (m, 2H), 0.11 (m, 2H); IR (film)
v.sub.max 3265, 2963, 2922, 1694, 1682, 1614, 1538, 1503, 1462,
1402, 1380, 1311, 1218, 1100, 1074, 1020, 964, 888, 808 cm.sup.-1;
MS (CI) m/z 299 (M+H).sup.+; Anal. calc. for
C.sub.19H.sub.26N.sub.2O0.125H.sub.2O: C, 75.90; H, 8.88; N, 9.32.
Found: C, 76.00; H, 8.95; N, 9.13.
[0062] The remaining compounds of Table 1 were prepared in similar
fashion, except Example 8, which was made by the CO/palladium
route, but with a slight variation using 2.0 M CH.sub.3NH.sub.2 in
THF, rather than gaseous CH.sub.3NH.sub.2, and DMF rather than
DMSO; mp=155-156.degree. C.; 25.6% yield. 24-[the
(.+-.)-8-CONH.sub.2 analogue of ethylketocyclazocine (R.sup.2 and
R.sup.2a=O; R.sup.6=Et)] was made by the nitrile hydrolysis route,
mp=194-196.degree. C.; Step 1-89.1%, Step 2-81.4%. 23-[the
(.+-.)-8-CONH.sub.2 analogue of ketocyclazocine (R.sup.2 and
R.sup.2a=O; R.sup.6=Me)] was made by the nitrile hydrolysis route,
mp=206-207.degree. C.; Step 1-99.7%, Step 2-94.2%. It was also made
by the CO/Pd route in 34.7% yield.
[0063] In general, the chemistry described above works in the
presence of the variety of functional groups found on known core
structures. The exceptions would be morphine and congeners having a
free 6-OH, which can be protected by a TBDPS (t-butyldiphenylsilyl)
group [see Wentland et al J. Med. Chem. 43, 3558-3565 (2000)].
[0064] The compound identified as Example 43 in table 4 was
prepared by treating the nitrile of nalbuphine with an excess of
potassium hydroxide in t-butanol as described for example 4 above.
Hydrolysis of the nitrile appears to have proceeded more slowly
than elimination and ring opening.
[0065] Although this invention is susceptible to embodiment in many
different forms, preferred embodiments of the invention have been
shown. It should be understood, however, that the present
disclosure is to be considered as an exemplification of the
principles of this invention and is not intended to limit the
invention to the embodiments illustrated. It may be found upon
examination that certain members of the claimed genus are not
patentable to the inventors in this application. In this event,
subsequent exclusions of species from the compass of applicants'
claims are to be considered artifacts of patent prosecution and not
reflective of the inventors' concept or description of their
invention; the invention encompasses all of the members of the
genus (I) that are not already in the possession of the public.
* * * * *