U.S. patent application number 13/879908 was filed with the patent office on 2013-10-31 for 6-amido derivatives of 4, 5-a epoxymorphinans for the treatment of pain.
This patent application is currently assigned to MEMORIAL SLOAN-KETTERING CANCER CENTER. The applicant listed for this patent is Susruta Majumdar, Gavril Pasternak. Invention is credited to Susruta Majumdar, Gavril Pasternak.
Application Number | 20130289060 13/879908 |
Document ID | / |
Family ID | 45975852 |
Filed Date | 2013-10-31 |
United States Patent
Application |
20130289060 |
Kind Code |
A1 |
Pasternak; Gavril ; et
al. |
October 31, 2013 |
6-AMIDO DERIVATIVES OF 4, 5-a EPOXYMORPHINANS FOR THE TREATMENT OF
PAIN
Abstract
Compounds of formula: ##STR00001## in which R.sup.4 is chosen
from substituted phenyl, optionally substituted naphthylene,
optionally substituted anthracene and optionally substituted
aromatic heterocycle, are useful as analgesics.
Inventors: |
Pasternak; Gavril; (New
York, NY) ; Majumdar; Susruta; (Stamford,
CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pasternak; Gavril
Majumdar; Susruta |
New York
Stamford |
NY
CT |
US
US |
|
|
Assignee: |
MEMORIAL SLOAN-KETTERING CANCER
CENTER
New York
NY
|
Family ID: |
45975852 |
Appl. No.: |
13/879908 |
Filed: |
October 19, 2011 |
PCT Filed: |
October 19, 2011 |
PCT NO: |
PCT/US11/56827 |
371 Date: |
April 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61394481 |
Oct 19, 2010 |
|
|
|
Current U.S.
Class: |
514/282 ;
435/7.21; 546/44 |
Current CPC
Class: |
A61K 51/0455 20130101;
C07D 489/08 20130101; A61P 25/04 20180101; G01N 33/9486
20130101 |
Class at
Publication: |
514/282 ; 546/44;
435/7.21 |
International
Class: |
C07D 489/08 20060101
C07D489/08 |
Goverment Interests
FEDERALLY SPONSORED RESEARCH
[0002] The following invention was made with government support
under contracts numbers DA02615, DA06241 and DA00220R01 awarded by
the National Institutes of Health (NIH). The Government has certain
rights in this invention.
Claims
1. A compound of formula I ##STR00016## wherein R.sup.1 is chosen
from (a) C.sub.2-C.sub.10 hydrocarbon other than cyclopropylmethyl;
and (b) --CH.sub.2-Het, wherein Het is a five- or six-membered
heterocycle; R.sup.2 is chosen from hydrogen,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)oxaalkyl, and
(C.sub.1-C.sub.6)acyloxaalky; R.sup.3 is chosen from hydrogen and
(C.sub.1-C.sub.6)alkyl; R.sup.4 is chosen from (a) phenyl
substituted at other than 2 or 6 with from one to three
substituents chosen from amino, bromo, chloro, iodo, hydroxy,
nitro, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
(b) optionally substituted naphthylene; (c) optionally substituted
anthracene; (d) optionally substituted aromatic heterocycle;
R.sup.8 is chosen from hydrogen and (C.sub.1-C.sub.6)alkyl;
R.sup.10 is optionally substituted phenyl, optionally substituted
aromatic heterocycle or optionally substituted non-aromatic oxygen
or sulfur heterocycle; wherein the substituents on naphthylene,
anthracene, heterocycle or R.sup.10 are chosen independently from
halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)acyl and (C.sub.1-C.sub.3)alkoxy.
2. A compound according to claim 1 wherein R.sup.1 is
cyclobutylmethyl or allyl; R.sup.3 is hydrogen or methyl; R.sup.4
is chosen from (a) phenyl substituted at other than 2 or 6 with
from one to three substituents chosen from amino, bromo, chloro,
iodo, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (b) optionally substituted
naphthylene; (c) optionally substituted anthracene; (d) aromatic
heterocycle chosen from pyridine, thiophene, furan and pyrrole
optionally substituted with from one to three substituents chosen
from bromo, chloro, iodo, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy and (C.sub.1-C.sub.3)alkoxy; and
R.sup.8 is hydrogen.
3. A compound of formula II ##STR00017## wherein R.sup.2 is chosen
from hydrogen, (C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)oxaalkyl,
and (C.sub.1-C.sub.6)acyloxaalkyl; R.sup.3 is chosen from hydrogen
and (C.sub.1-C.sub.6)alkyl; R.sup.4a is chosen from ##STR00018##
wherein R.sup.5a is chosen from amino, bromo, chloro, iodo, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.2-C.sub.3)alkoxy and R.sup.10;
##STR00019## wherein R.sup.6a is chosen from hydroxy, nitro, cyano,
(C.sub.2-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; ##STR00020## wherein R.sup.5
is chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
and R.sup.6b is chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10,
or, taken together, R.sup.5 and R.sup.6b are alkylenedioxy, with
the proviso that both R.sup.5 and R.sup.6b are not chloro or
fluoro; ##STR00021## wherein R.sup.5b is chosen from bromo, chloro,
iodo, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; R.sup.6 is chosen from
hydrogen, halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; R.sup.7 is chosen from
halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; and (e) napthylene
substituted with from one to three substituents chosen from
halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (f) anthracene optionally
substituted with from one to three substituents chosen from
halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (g) aromatic heterocycle
other than unsubstituted pyridine, quinoline or isoquinoline,
optionally substituted with from one to three substituents chosen
from halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; R.sup.8 is chosen from
hydrogen and (C.sub.1-C.sub.6)alkyl; and R.sup.10 is optionally
substituted phenyl, optionally substituted aromatic heterocycle or
optionally substituted non-aromatic oxygen or sulfur heterocycle;
wherein the substituents on naphthylene, anthracene, heterocycle or
R.sup.10 are independently chosen from halogen, hydroxy, nitro,
cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)acyl and
(C.sub.1-C.sub.3)alkoxy.
4. A compound according to claim 1 wherein the amide substituent at
the oxymorphone 6 position is in the .beta. configuration and
R.sup.8 is hydrogen: ##STR00022##
5. A compound according to claim 4 wherein R.sup.2 is H.
6. A compound according to claim 4 wherein R.sup.2 is chosen from
CH.sub.3, acetyl, acetoxymethyl,
--CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3 and
--CH.sub.2C(.dbd.O)OCH.sub.3.
7. A compound according to claim 4 wherein R.sup.3 is H.
8. A compound according to claim 4 wherein R.sup.3 is CH.sub.3.
9. A compound according to claim 4 wherein R.sup.4 is ##STR00023##
wherein R.sup.5a is chosen from bromo, chloro, iodo,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.2-C.sub.3)alkoxy and R.sup.10.
10. A compound according to claim 9 wherein R.sup.5a is chosen from
bromo, chloro, iodo, trifluoromethyl, trifluoromethoxy and
R.sup.10, and R.sup.10 is chosen from phenyl, furanyl and
thiophenyl optionally substituted with one to three substituents
independently chosen from halogen, methyl, trifluoromethyl,
methoxy, trifluoromethoxy and acetyl.
11. A compound according to claim 4 wherein R.sup.4 is ##STR00024##
wherein R.sup.5 is chosen from halogen, nitro, cyano, methyl,
trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl,
furanyl; and R.sup.6b is chosen from halogen, nitro, cyano, methyl,
trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl,
furanyl, with the proviso that both R.sup.5 and R.sup.6b are not
phenyl or heteroaryl.
12. A compound according to claim 11 wherein R.sup.4 is
3,4-diiodophenyl.
13. A compound according to claim 2 wherein the amide substituent
at the oxymorphone 6 position is in the .beta. configuration and
R.sup.4 is phenyl substituted at other than 2 or 6 with from one to
three substituents chosen from bromo, chloro, iodo, hydroxy, nitro,
cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and
R.sup.10.
14. A compound according to claim 13 wherein R.sup.4 is phenyl
substituted at the 3- and 4-positions with two substituents chosen
independently from bromo, chloro, iodo, methyl, trifluoromethyl,
methoxy and trifluoromethoxy.
15. A compound according to claim 14 wherein R.sup.1 is allyl;
R.sup.2 is H; R.sup.3 is hydrogen and R.sup.4 is
3,4-diiodophenyl.
16. A compound according to claim 13 wherein R.sup.4 is phenyl
substituted at the 3- or 4-position with a substituent chosen from
bromo, chloro, iodo, methyl, trifluoromethyl, methoxy,
trifluoromethoxy and R.sup.10, and R.sup.10 is chosen from phenyl,
furanyl and thiophenyl optionally substituted with one to three
substituents independently chosen from halogen, methyl,
trifluoromethyl, methoxy, trifluoromethoxy, methylenedioxy and
acetyl.
17. A compound according to claim 10 wherein R.sup.4 is
3-iodophenyl.
18. A compound according to claim 2 wherein the amide substituent
at the oxymorphone 6 position is in the .beta. configuration and
R.sup.4 is optionally substituted quinoline.
19.-21. (canceled)
22. A method for reducing pain comprising administering to a
subject suffering from pain an amount of a compound according to
claim 1 effective to reduce pain.
23.-25. (canceled)
26. A method for assaying for the kappa3 receptor comprising
exposing a tissue to a radiolabeled compound according to claim 1,
rinsing said tissue and measuring the amount and/or location of
said radiolabeled compound in said tissue.
27. A method for assaying for an opioid-like receptor comprising
exposing a labeled compound according to claim 12 to a source of
receptor in vitro or in vivo, and measuring the amount and/or
location of said labeled compound bound to the receptor.
28.-30. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
application 61/394,481, filed Oct. 19, 2010, the entire contents of
which are incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The invention relates to opioid receptor binding 6-amido
derivatives of 4,5a-epoxymorphinans. The compounds are useful as
analgesics.
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., methadone, buprenorphine and naltrexone) in humans
work by triggering .mu. opioid receptors in the central nervous
system (CNS) and by crossing the blood-brain barrier. However, as
there are .mu. opioid receptors outside the CNS, these opiates
usually cause unwanted peripheral side effects. Often, the
peripheral side effects manifest themselves in the gastrointestinal
(GI) tract and the respiratory system. For instance, prolonged
morphine administration often causes constipation, and prolonged
morphine administration ultimately causes life-threatening
respiratory depression in patients. Other side effects appear to
arise from the central action of morphine-like compounds. These
central side effects of .mu. ligands include physical dependence
(addiction) and sedation. Thus, a drug that is able to treat
symptoms of pain, but not cause some or all of the peripheral and
central side effects, would be most valuable.
SUMMARY OF THE INVENTION
[0005] The compounds of the invention are useful as analgesics
having lessened liability for constipation and respiratory
depression.
[0006] In one aspect, the invention relates to compounds of formula
I:
##STR00002##
wherein [0007] R.sup.1 is chosen from
[0008] (a) C.sub.2-C.sub.10 hydrocarbon other than
cyclopropylmethyl; and
[0009] (b) --CH.sub.2-Het, wherein Het is a five- or six-membered
heterocycle; [0010] R.sup.2 is chosen from hydrogen,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)oxaalkyl, and
(C.sub.1-C.sub.6)acyloxaalky; [0011] R.sup.3 is chosen from
hydrogen and (C.sub.1-C.sub.6)alkyl; [0012] R.sup.4 is chosen from
[0013] (a) phenyl substituted at other than 2 or 6 with from one to
three substituents chosen from amino, bromo, chloro, iodo, hydroxy,
nitro, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
[0014] (b) optionally substituted naphthylene; [0015] (c)
optionally substituted anthracene; [0016] (d) optionally
substituted aromatic heterocycle; [0017] R.sup.8 is chosen from
hydrogen and (C.sub.1-C.sub.6)alkyl; [0018] R.sup.10 is optionally
substituted phenyl, optionally substituted aromatic heterocycle or
optionally substituted non-aromatic oxygen or sulfur heterocycle;
[0019] wherein the substituents on naphthylene, anthracene,
heterocycle or R.sup.10 are chosen independently from halogen,
hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)acyl and (C.sub.1-C.sub.3)alkoxy.
[0020] In another aspect, the invention relates to a compound of
formula II:
##STR00003##
wherein R.sup.4a is chosen from
##STR00004##
wherein R.sup.5a is chosen from bromo, chloro, iodo, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.2-C.sub.3)alkoxy and
R.sup.10;
##STR00005##
wherein R.sup.5a is chosen from hydroxy, nitro, cyano,
(C.sub.2-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10;
##STR00006##
wherein R.sup.5 is chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
and R.sup.6b is chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10,
or, taken together, R.sup.5 and R.sup.6b are alkylenedioxy, with
the proviso that both R.sup.5 and R.sup.6b are not chloro or
fluoro;
##STR00007##
wherein R.sup.5b is chosen from bromo, chloro, iodo, hydroxy,
nitro, cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
R.sup.6 is chosen from hydrogen, halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
R.sup.7 is chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10;
and (e) napthylene substituted with from one to three substituents
chosen from halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (f) anthracene optionally
substituted with from one to three substituents chosen from
halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (g) aromatic heterocycle
other than unsubstituted pyridine, quinoline or isoquinoline,
optionally substituted with from one to three substituents chosen
from halogen, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10.
[0021] In another aspect, the invention relates to a pharmaceutical
composition comprising at least one compound of the formula above
and a pharmaceutically acceptable carrier.
[0022] In another aspect, the invention relates to a method for
reducing pain comprising administering to a subject suffering from
pain an amount of a compound described above effective to reduce
pain.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Analgesic compounds of the invention fall into two primary
classes: compounds of general formula II, in which R.sup.1 is
cyclopropylmethyl, and compounds of general formula I, in which
R.sup.1 is not cyclopropylmethyl. The compounds of general formula
I include a series in which R.sup.1 is allyl and one in which
R.sup.1 is cyclobutylmethyl. When R.sup.1 is --CH.sub.2-Het, Het
may be tetrahydrofuranyl.
[0024] In one aspect, the invention relates to compounds of formula
I:
##STR00008##
[0025] Some embodiments of the invention can be represented by the
formula:
##STR00009##
which is a subset of formula I. In these compounds, R.sup.1 is
cyclobutylmethyl or allyl; R.sup.2 is chosen from hydrogen,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)oxaalkyl, and
(C.sub.1-C.sub.6)acyloxaalky; R.sup.3 is hydrogen or methyl;
R.sup.4 is chosen from (a) phenyl substituted at other than 2 or 6
with from one to three substituents chosen from bromo, chloro,
iodo, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10; (b) optionally substituted
naphthylene; (c) optionally substituted anthracene; (d) aromatic
heterocycle chosen from pyridine, thiophene, furan and pyrrole
optionally substituted with from one to three substituents chosen
from bromo, chloro, iodo, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy and (C.sub.1-C.sub.3)alkoxy; R.sup.8 is
hydrogen; and R.sup.10 is optionally substituted phenyl, optionally
substituted aromatic heterocycle or optionally substituted
non-aromatic oxygen or sulfur heterocycle; wherein the substituents
on naphthylene, anthracene, heterocycle or R.sup.10 are chosen
independently from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)acyl and (C.sub.1-C.sub.3)alkoxy.
[0026] In some embodiments of the compounds of formula II, R.sup.4a
is (g), an aromatic heterocycle other than unsubstituted pyridine,
quinoline or isoquinoline, optionally substituted with from one to
three substituents chosen from halogen, hydroxy, nitro, cyano,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10.
In these embodiments R.sup.4a may also be other than pyridine
monosubstituted with bromine, chlorine, methyl, methoxy or cyano.
In these embodiments R.sup.4a may also be other than unsubstituted
pyrimidine, cinnoline quinazoline or pyridazine.
[0027] In some embodiments, the amide substituent at the
oxymorphone 6 position is in the .beta. configuration and R.sup.8
is hydrogen:
##STR00010##
[0028] In some embodiments R.sup.2 is hydrogen; in others R.sup.2
is chosen from CH.sub.3, acetyl, acetoxymethyl,
--CH.sub.2OC(.dbd.O)C(CH.sub.3).sub.3 and
--CH.sub.2C(.dbd.O)OCH.sub.3.
[0029] In some embodiments, R.sup.3 is hydrogen; in others R.sup.3
is methyl.
[0030] In some embodiments, R.sup.4 or R.sup.4a is
##STR00011##
In some of these embodiments, R.sup.5a is chosen from bromo,
chloro, iodo, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.2-C.sub.3)alkoxy and R.sup.10.
In narrower embodiments, R.sup.5a is chosen from bromo, chloro,
iodo, trifluoromethyl, trifluoromethoxy and R.sup.10, and R.sup.10
is chosen from phenyl, furanyl and thiophenyl optionally
substituted with one to three substituents independently chosen
from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy,
methylenedioxy and acetyl. In some embodiments R.sup.5a is iodo,
either in its normal isotopic ratio or in a ratio enriched in
.sup.125I. In other embodiments, R.sup.4 or R.sup.4a is
##STR00012##
wherein R.sup.5 is chosen from halogen, nitro, cyano, methyl,
trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl,
furanyl; and R.sup.6b is chosen from halogen, nitro, cyano, methyl,
trifluoromethyl, trifluoromethoxy, methoxy, phenyl, thiophenyl and
furanyl. In one embodiment, R.sup.4 or R.sup.4a is
3,4-diiodophenyl, which also may be enriched in .sup.125I.
[0031] In one embodiment, the amide substituent at the oxymorphone
6 position is in the .beta. configuration and R.sup.4 is phenyl
substituted at other than 2 or 6 with from one to three
substituents chosen from bromo, chloro, iodo, hydroxy, nitro,
cyano, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, (C.sub.1-C.sub.3)alkoxy and R.sup.10.
In a narrower embodiment, R.sup.1 is cyclobutylmethyl or allyl;
R.sup.3 is hydrogen or methyl; R.sup.8 is hydrogen; the amide
substituent at the oxymorphone 6 position is in the .beta.
configuration and R.sup.4 is phenyl substituted at other than 2 or
6 with from one to three substituents chosen from bromo, chloro,
iodo, hydroxy, nitro, cyano, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.3)alkoxy and R.sup.10. A preferred subgenus is that
in which R.sup.4 is phenyl substituted at the 3- and 4-positions
with two substituents chosen independently from bromo, chloro,
iodo, methyl, trifluoromethyl, methoxy and trifluoromethoxy. An
example is the compound in which R.sup.1 is allyl; R.sup.2 is H;
R.sup.3 and R.sup.8 are hydrogen and R.sup.4 is 3,4-diiodophenyl.
In another preferred subgenus, R.sup.4 is phenyl substituted at the
3- or 4-position with a substituent chosen from bromo, chloro,
iodo, methyl, trifluoromethyl, methoxy, trifluoromethoxy and
R.sup.10. R.sup.10 may be chosen from phenyl, furanyl and
thiophenyl optionally substituted with one to three substituents
independently chosen from halogen, methyl, trifluoromethyl,
methoxy, trifluoromethoxy, methylenedioxy and acetyl. In general,
it appears that compounds in which R.sup.4 is substituted phenyl do
not exhibit useful analgesic activity when the substituents are at
2 and/or 6.
[0032] In another embodiment, the amide substituent at the
oxymorphone 6 position is in the .beta. configuration and R.sup.4
is optionally substituted quinoline. In some embodiments, R.sup.1
is allyl; R.sup.2 is H; R.sup.3 and R.sup.8 are hydrogen and
R.sup.4 is optionally substituted quinoline.
[0033] As described above, R.sup.8 is chosen from hydrogen and
(C.sub.1-C.sub.6)alkyl. Preferred compounds are those in which
R.sup.8 is hydrogen or methyl.
[0034] Pharmaceutical compositions in accord with the invention
comprise a pharmaceutically acceptable carrier and a compound as
described above.
[0035] The compounds described above may be employed in a method
for reducing pain. The method comprises administering to a subject
suffering from pain an amount of a compound above effective to
reduce pain. In the treatment of pain, the pain may be reduced
without substantial reduction of intestinal motility and/or without
substantial respiratory depression. The term "substantial" is
intended to mean that the intestinal motility or respiration rate
is reduced by at least 50% at a dose that is the analgesic
ED.sub.50 for a naive subject. The compounds may also be employed
in a method for reducing pain in a .mu.-opioid-dependent patient.
The compounds may also be employed in assays for the kappa3
receptor; radioiodinated compounds are particularly useful for this
assay.
DEFINITIONS
[0036] Throughout this specification the terms and substituents
retain their definitions.
[0037] Alkyl is intended to include linear or branched, or cyclic
hydrocarbon structures and combinations thereof. A combination
would be, for example, cyclopropylmethyl. 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.
[0038] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon
atoms of a straight, branched, or 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.
[0039] 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. 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. As used herein aryl and
heteroaryl refer to residues in which one or more rings are
aromatic, but not all need be.
[0040] Arylalkyl means an aryl ring attached to an alkyl residue in
which the point of attachment to the parent structure is through
the alkyl. 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.
[0041] C.sub.2 to C.sub.10 hydrocarbon means a linear, branched, or
cyclic residue comprised of hydrogen and carbon as the only
elemental constituents and includes alkyl, cycloalkyl,
polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof.
Examples include benzyl, phenethyl, cyclohexylmethyl,
cyclopropylmethyl, cyclobutylmethyl, allyl, camphoryl and
naphthylethyl.
[0042] Unless otherwise specified, the term "carbocycle" is
intended to include ring systems in which the ring atoms are all
carbon but of any oxidation state. Thus (C.sub.3-C.sub.10)
carbocycle refers to both non-aromatic and aromatic systems,
including such systems as cyclopropane, benzene and cyclohexene;
(C.sub.8-C.sub.12) carbopolycycle refers to such systems as
norbornane, decalin, indane and naphthalene. Carbocycle, if not
otherwise limited, refers to monocycles, bicycles and
polycycles.
[0043] 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 include pyrrolidine, pyrazole, pyrrole,
imidazole, indole, quinoline, isoquinoline, tetrahydroisoquinoline,
benzofuran, benzodioxan, benzodioxole (commonly referred to as
methylenedioxyphenyl, when occurring as a substituent), tetrazole,
morpholine, thiazole, pyridine, pyridazine, pyrimidine, pyrazine,
thiophene, furan, oxazole, oxazoline, isoxazole, dioxane,
tetrahydrofuran and the like.
[0044] As used herein, the term "optionally substituted" may be
used interchangeably with "unsubstituted or substituted". The term
"substituted" refers to the replacement of one or more hydrogen
atoms in a specified group with a specified radical. For example,
substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to
alkyl, aryl, cycloalkyl, or heterocyclyl wherein one or more H
atoms in each residue are replaced with halogen, haloalkyl, alkyl,
acyl, alkoxyalkyl, hydroxyloweralkyl, carbonyl, phenyl, heteroaryl,
benzenesulfonyl, hydroxy, loweralkoxy, haloalkoxy, oxaalkyl,
carboxy, alkoxycarbonyl [--C(.dbd.O)O-alkyl], alkoxycarbonylamino
[HNC(.dbd.O)O-alkyl], carboxamido [--C(.dbd.O)NH.sub.2],
alkylaminocarbonyl [--C(.dbd.O)NH-alkyl], cyano, acetoxy, nitro,
amino, alkylamino, dialkylamino, (alkyl)(aryl)aminoalkyl,
alkylaminoalkyl (including cycloalkylaminoalkyl),
dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy,
mercapto, alkylthio, sulfoxide, sulfone, sulfonylamino,
alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy,
acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl,
phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino,
oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido,
benzyloxyphenyl, and benzyloxy. "Oxo" is also included among the
substituents referred to in "optionally substituted"; it will be
appreciated by persons of skill in the art that, because oxo is a
divalent radical, there are circumstances in which it will not be
appropriate as a substituent (e.g. on phenyl). In one embodiment,
1, 2 or 3 hydrogen atoms are replaced with a specified radical. In
the case of alkyl and cycloalkyl, more than three hydrogen atoms
can be replaced by fluorine; indeed, all available hydrogen atoms
could be replaced by fluorine.
[0045] 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. It will be apparent that
certain chiral centers are specified in compounds set forth in the
claims. In these cases, the chiral centers that are not specified
encompass both configurations; those that are specified encompass
only the specified configuration. 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.
[0046] As used herein, and as would be understood by the person of
skill in the art, the recitation of "a compound"--unless expressly
further limited--is intended to include salts of that compound. In
a particular embodiment, the term "compound of formula I" refers to
the compound or a pharmaceutically acceptable salt thereof.
[0047] The compounds of the invention may exist as salts, i.e.
cationic species. The term "pharmaceutically acceptable salt"
refers to salts whose counter ion (anion) derives from
pharmaceutically acceptable non-toxic acids including inorganic
acids and organic acids. Suitable pharmaceutically acceptable acids
for salts of the compounds of the present invention include, for
example, acetic, adipic, alginic, ascorbic, aspartic,
benzenesulfonic (besylate), benzoic, boric, butyric, camphoric,
camphorsulfonic, carbonic, citric, ethanedisulfonic,
ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric,
glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric,
hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic,
laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic,
naphthylenesulfonic, nitric, oleic, pamoic, pantothenic,
phosphoric, pivalic, polygalacturonic, salicylic, stearic,
succinic, sulfuric, tannic, tartaric acid, teoclatic,
p-toluenesulfonic, and the like.
[0048] It will be recognized that the compounds of this invention
can exist in radiolabeled form, i.e., the compounds may contain one
or more atoms containing an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Alternatively, a plurality of molecules of a single structure may
include at least one atom that occurs in an isotopic ratio that is
different from the isotopic ratio found in nature. Radioisotopes of
hydrogen, carbon, phosphorous, fluorine, chlorine and iodine
include .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N,
.sup.35S, .sup.18F, .sup.36Cl, .sup.125I, .sup.124I and .sup.131I
respectively. Compounds that contain those radioisotopes and/or
other radioisotopes of other atoms are within the scope of this
invention. Tritiated, i.e. .sup.3H, and carbon-14, i.e., .sup.14C,
radioisotopes are particularly preferred for their ease in
preparation and detectability. Compounds that contain isotopes
.sup.11C, .sup.13N, .sup.15O, .sup.124I and .sup.18F are well
suited for positron emission tomography. Radiolabeled compounds of
formulae I and II of this invention and prodrugs thereof can
generally be prepared by methods well known to those skilled in the
art. Conveniently, such radiolabeled compounds can be prepared by
carrying out the procedures disclosed in the Examples and Schemes
by substituting a readily available radiolabeled reagent for a
non-radiolabeled reagent.
[0049] Although this invention is susceptible to embodiment in many
different forms, preferred embodiments of the invention are 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 genera I and II
that are not already in the possession of the public.
[0050] While it may be possible for the compounds of formula I or
II to be administered as the raw chemical, it is preferable to
present them as a pharmaceutical composition. According to a
further aspect, the present invention provides a pharmaceutical
composition comprising a compound of formula I or II or a
pharmaceutically acceptable salt or solvate thereof, together with
one or more pharmaceutically carriers thereof and optionally one or
more other therapeutic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof. The compositions may be formulated for oral, topical or
parenteral administration. For example, they may be given
intravenously, intraarterially, subcutaneously, and directly into
the CNS--either intrathecally or intracerebroventricularly.
[0051] Formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous
and intraarticular), rectal and topical (including dermal, buccal,
sublingual and intraocular) administration. The compounds are
preferably administered orally or by injection (intravenous or
subcutaneous). The precise amount of compound administered to a
patient will be the responsibility of the attendant physician.
However, the dose employed will depend on a number of factors,
including the age and sex of the patient, the precise disorder
being treated, and its severity. Also, the route of administration
may vary depending on the condition and its severity. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. In general, the formulations are prepared by uniformly
and intimately bringing into association the active ingredient with
liquid carriers or finely divided solid carriers or both and then,
if necessary, shaping the product into the desired formulation.
[0052] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as a solution or a
suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0053] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine a mixture of the powdered compound moistened
with an inert liquid diluent. The tablets may optionally be coated
or scored and may be formulated so as to provide sustained, delayed
or controlled release of the active ingredient therein.
[0054] Formulations for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient.
Formulations for parenteral administration also include aqueous and
non-aqueous sterile suspensions, which may include suspending
agents and thickening agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in a freeze-dried (lyophilized) condition
requiring only the addition of a sterile liquid carrier, for
example saline, phosphate-buffered saline (PBS) or the like,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0055] Formulations for rectal administration may be presented as a
suppository with the usual carriers such as cocoa butter or
polyethylene glycol.
[0056] Formulations for topical administration in the mouth, for
example buccally or sublingually, include lozenges comprising the
active ingredient in a flavoured basis such as sucrose and acacia
or tragacanth, and pastilles comprising the active ingredient in a
basis such as gelatin and glycerin or sucrose and acacia.
[0057] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.
[0058] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations of this invention
may include other agents conventional in the art having regard to
the type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0059] As used herein, "treatment" or "treating," or "palliating"
or "ameliorating" are used interchangeably herein. These terms
refers to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a
prophylactic benefit. By therapeutic benefit is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological systems associated
with the underlying disorder such that an improvement is observed
in the patient, notwithstanding that the patient may still be
afflicted with the underlying disorder. For prophylactic benefit,
the compositions may be administered to a patient at risk of
developing a particular disease, or to a patient reporting one or
more of the physiological systems of a disease, even though a
diagnosis of this disease may not have been made.
Abbreviations
[0060] The following abbreviations and terms have the indicated
meanings throughout:
Ac=acetyl Boc=t-butyloxy carbonyl
BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate Bu=butyl c-=cyclo DCM=dichloromethane=methylene
chloride=CH.sub.2Cl.sub.2 DIEA=diisopropylethylamine
DMF=N,N-dimethylformamide
[0061] DMSO=dimethyl sulfoxide DOR=delta opioid receptor
EtOAc=ethyl acetate EtOH=ethanol GC=gas chromatography HOAc=acetic
acid KOR=kappa opioid receptor Me=methyl MOR=mu opioid receptor
MTBE=methyl t-butyl ether PEG=polyethylene glycol Ph=phenyl
PhOH=phenol rt=room temperature sat'd=saturated s-=secondary t- or
tent-=tertiary TBDMS=t-butyldimethylsilyl TFA=trifluoroacetic acid
THF=tetrahydrofuran TMS=trimethylsilyl tosyl=p-toluenesulfonyl
Pharmacological and Behavioral Assays
[0062] Receptor-Binding Assays: Competition-binding assays in
MOR-CHO (mu), DOR-CHO (delta) and KOR-CHO (kappa) were performed at
25.degree. C. in 50 mM potassium phosphate buffer, pH 7.4,
containing 5 mM magnesium sulfate (only in the case of CHO-MOR).
Specific binding was defined as the difference between total
binding and nonspecific binding, determined in the presence of 8
.mu.M levallorphan. 125I-SMGP1 (IBNtxA) was used as the universal
radioligand to determine the relative affinity of drugs in
MOR1-CHO, KOR1-CHO and DOR1-CHO. Protein concentrations were
generally 20-40 .mu.g/mL, incubation times were 150 minutes for all
assays. (Majumdar et al., Bioorg Med Chem. Lett. 2011, 21(13),
4001-4004). Kappa3 opioid receptor competition binding assays were
carried out in whole brain membrane homogenates, performed at
25.degree. C. in 50 mM potassium phosphate buffer, pH 7.4,
containing 5 mM magnesium sulfate for 90 minutes in presence of 100
nM CTAP, 100 nM U50488h and 100 nM DPDPE. .sup.125I-SMGP1 was used
as the radioligand in the assays, typically 500 micrograms of
protein and 0.15 nM of the radioligand was used in a 0.5 mL assay.
Specific binding was defined as the difference between total
binding and nonspecific binding, determined in the presence of 1
.mu.M levallorphan. Protein concentration was determined as
described by Lowry et al. [J Biol Chem 1951, 193, 265-275; (1951)]
using bovine serum albumin as the standard. Kd, Bmax, and Ki values
were calculated by nonlinear regression analysis (GraphPadPrism).
We have observed that compounds that bind with the kappa3 site and
that exhibit K.sub.i less than 100 nM exhibit useful analgesia, and
compounds that are selective for kappa3 exhibit improved
side-effect profiles. The "kappa3 opioid receptor" as referred to
herein is the receptor first characterized by Clark et al. [J.
Pharmacol. Exp. Ther. 251, 461-468 (1989)]. This receptor appears
to be the same receptor which has been alternately referred to as
the kappa2b receptor by Rothman et al. [Peptides 11, 311-331
(1990)]. In any event, it can be characterized by the high affinity
binding (K.sub.i<1 nM) for levallorphan, ketocyclazocine and
SMGP1 and low affinity for morphine (K.sub.i>1 .mu.M),
norbinaltorphimine (K.sub.i>50 nM) and DADL (K.sub.i>50
nM).
[0063] Tail Flick Analgesia Assays: Male CD-i mice (25-35 g;
Charles River Breeding Laboratories, Wilmington, Mass.) were
maintained on a 12-hr light/dark cycle with Purina rodent chow and
water available ad libitum. Mice were housed in groups of five
until testing. Analgesia was determined using the radiant heat
tail-flick technique [D'Amour and Smith, J. Pharmacol. Exp. Ther.
72: 74-79 (1941)]. For the tail-flick assay, the latency to
withdraw the tail from a focused light stimulus was measured
electronically using a photocell. Baseline latencies (2.0-3.0 sec)
were determined before experimental treatments for all animals as
the mean of two trials. Post-treatment tail-flick latencies were
determined as indicated for each experiment, and a maximal latency
of 10 sec for tail-flick was used to minimize tissue damage. All
experiments were replicated at least twice with each group in each
experiment containing at least 10 mice and the combined results of
all replications presented. Compounds with an ED.sub.50 less than
10 mg/kg are preferred because the potency allows for smaller
dosages, but higher ED.sub.50's are possible.
[0064] Gastrointestinal motility assay: Gastrointestinal transit
was determined as described by Paul and Pasternak [Eur. J.
Pharmacol. 149 (1988), pp. 403-404.)]. In brief, after withholding
food for 8 hours, animals received the indicated drug and then were
given a charcoal meal (0.2 mL; 10% of purified charcoal and 2.5% of
gum tragacanth, w/v) by gavage and were sacrificed 30 min later.
The distance traveled by the charcoal meal was then measured and
reported in centimeters.
[0065] Conditional place preference/Aversion and Locomotor
activity: The testing apparatus consisted of two compartments of
equal size separated by a wall with a guillotine-style door
(MedAssociates ENV-512 insert). One compartment was surrounded by
white walls and had a rod floor, while the other had black walls
and a grid floor. Infrared photobeams lining the floor of the
compartments were used to track the location of the mouse at all
times; this data was used to calculate the total distance traveled
by the animal using MedAssociates Activity Monitor software. This
data is expressed as the distance each animal traveled following
each drug injection divided by the average distance traveled by
that animal following saline injection.
[0066] For 2 days prior to testing, the animal cages were brought
to the testing room for 3 hours for habituation to the environment.
On the pre-conditioning test day, animals are placed in one chamber
and allowed to explore both sides freely for 20 minutes. Their
baseline preferences for each compartment are calculated; in the
place preference experiment, the side in which they spend more time
in initially is assigned to saline, while the opposite side is
designated as the drug-paired side. For place aversion, the
initially preferred side is paired with drug, while the other side
is assigned to saline. During the conditioning phase of the
experiment, animals are allowed to habituate to the experimental
room for 1 hour prior to each session. Animals are injected on
alternating days for 8 days with either drug or saline and
restricted to one compartment for 20 minutes so that they learn to
associate a treatment condition with a specific compartment. On the
post-conditioning testing day, animals are placed in the side
paired with saline and allowed to freely explore both compartments
for 20 minutes. The time spent in each compartment
post-conditioning is calculated and subtracted from the amount of
time spent in each compartment pre-conditioning to determine the
change in each animals' preference due to conditioning.
[0067] Determination of LD.sub.50: Lethality was determined 60
minutes after the administration of test compound (250 mg/kg) to
groups of mice (n=8). See Gistrak et al. The Journal of
Pharmacology and Experimental Therapeutics. 251, 469-476
(1989).
[0068] Tolerance studies: Groups of mice (n=10) were treated with
either morphine (6 mg/kg s.c.) or test compound (1 mg/kg s.c.)
twice daily for 5 days. Tail-flick latencies were determined before
and 30 minutes after each injection. See Gistrak et al. (1989) op.
cit. Effects of Chronic administration: Mice were pelleted with
morphine pellets (75 mg free base; NIDA) and tested for analgesia
on Day 1 and 3. On Day 3 they also were tested with test compound
(1 mg/kg, s.c.) for analgesia and with naloxone (1 mg/kg, s.c.) to
precipitate withdrawal. A separate group of mice received test
compound alone as a control for its analgesia in the
morphine-tolerant mice. Similarly, a group of mice (n=10) were made
tolerant to test compound by twice daily injections to 1 mg/kg,
s.c. for 10 days. On Day 10 they also were tested with test
compound (1 mg/kg, s.c.) for analgesia and with naloxone (1 mg/kg,
s.c.) and levallorphan (1 mg/kg) to precipitate withdrawal. Animals
were evaluated for signs of diarrhea and jumping. See Gistrak et
al. (1989) op. cit.
[0069] Respiratory Depression assessment: The MouseOx Pulse
Oximeter system (Starr Life Sciences, Pittsburgh, Pa.) was used to
assess respiratory rate in awake, freely-moving, adult male CD1
mice. For 30 minutes, each animal was habituated to the device
using a blank collar, after which the oximeter collar was placed on
the animal. A five-second average breath rate was assessed at 5
minute intervals. A baseline for each animal was obtained over a 25
minute period prior to drug injection; beginning 15 minutes
post-injection, measurements were then taken for a period of 35
minutes. Groups of mice (n=5) were treated subcutaneously with
either morphine or test compound and breath rates were measured for
both sets. At doses that are five times the ED.sub.50 of each
compound, i.e. 2.5 mg/kg for SMGP1 and 20 mg/kg for morphine,
morphine showed 50% respiratory depression whereas SMGP1 showed no
statistically significant depression as compared to saline.
[0070] Representative results of these studies are outlined in
Table 1.
TABLE-US-00001 TABLE 1 ##STR00013## Tail flick analgesia K.sub.i
(nM) ED.sub.50 Compd R.sub.1 R.sub.2 R.sub.3 R.sub.4.sup.a MOR KOR
DOR kappa.sub.3 (mg/kg) SMGP1 --CH.sub.2cPropyl H H Ph--3I 0.11
0.03 0.24 0.16 0.53 SMGP 2 --CH.sub.3 H H Ph--3I 0.97 47.22 2.45
41.22 >10 SMGP 3 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3I 0.22 0.08
2.55 0.25 0.57 SMGP 4 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3I.sup.b
5.07 12.16 7.642 8.46 5.0 SMGP 5 --CH.sub.2CH.sub.2CH.sub.3 H H
Ph--3I 60 SMGP 6 --CH.sub.2cButyl H H Ph--3I 0.88 0.67 2.38 11.44
SMGP 7 --Bz H H Ph--3I SMGP 8 --CH.sub.2CH.dbd.CH.sub.2 CH.sub.3 H
Ph--3I >100 >100 >100 >100 >10 SMGP 9
--CH.sub.2C.sub.3H.sub.5 CH.sub.3 H Ph--3I SMGP10 --CH.sub.3
CH.sub.3 H Ph--3I SMGP11 --CH.sub.2CH.dbd.CH.sub.2 COCH.sub.3 H
Ph--3I SMGP12 --CH.sub.2CH.dbd.CH.sub.2 CH.sub.2OCCH.sub.3 H Ph--3I
SMGP13 --CH.sub.2CH.dbd.CH.sub.2 CH.sub.2OCCH.sub.3 H Ph--3I SMGP14
--CH.sub.2CH.dbd.CH.sub.2 CH.sub.2OCOC(CH.sub.3).sub.3 H Ph--3I
SMGP15 --CH.sub.2CH.dbd.CH.sub.2 H CH.sub.3 Ph--3I SMGP16
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--2I 1.56 1 22.8 29 >10 SMGP17
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--4I 0.11 0.28 3.36 0.64 0.16
SMGP18 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3F 0.47 2.05 18.19 8.09
3.24 SMGP19 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3Cl 1.15 0.52 4.87
5.49 2.3 SMGP20 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3Br 3.85 1.58
23.37 2.05 1.36 SMGP21 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--H 4.03
14.27 60.78 5.82 5 SMGP22 --CH.sub.2CH.dbd.CH.sub.2 H H
Ph--3CH.sub.3 0.29 1.62 8.24 8.98 2 SMGP23
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--3CF.sub.3 0.85 0.22 2.96 9.32
0.26 SMGP24 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3OCH.sub.3 0.18 4.97
17.22 1.64 0.1 SMGP25 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3NH.sub.2
0.43 0.4 36 7.62 >10 SMGP26 --CH.sub.2CH.dbd.CH.sub.2 H H
Ph--3N(CH.sub.3).sub.2 6.39 34.9 51.35 10.79 >10 SMGP27
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--3OH 0.23 2.75 11.25 5.21 10.3
SMGP28 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--3NO.sub.2 1.41 1.51 18.13
4.53 6.79 SMGP29 --CH.sub.2CH.dbd.CH.sub.2 H H Ph--4OCF.sub.3 0.66
3.16 17.88 7.43 0.82 SMGP30 --CH.sub.2CH.dbd.CH.sub.2 H H
Ph--4OC.sub.4H.sub.9 >10 SMGP31 --CH.sub.2CH.dbd.CH.sub.2 H H
Ph-4Boronic >10 acid pinacol ester SMGP32
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--4CH.sub.2- tButyl SMGP33
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--4Si(OC.sub.2H.sub.5).sub.3 SMGP34
--CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4-I,I 0.5 0.05 0.12 0.004 0.05
SMGP35 --CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4,5-I,I,I SMGP36
--CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4-O.sub.2C.sub.2H.sub.4 >10
SMGP37 --CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4-O.sub.2CH.sub.2 >10
SMGP38 --CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4-(OC.sub.2H.sub.5).sub.2
SMGP39 --CH.sub.2CH.dbd.CH.sub.2 H H Ph-3,4-
(OC.sub.2H.sub.4CF.sub.3).sub.2 SMGP40 --CH.sub.2CH.dbd.CH.sub.2 H
H Ph--Ph 0.95 25.79 19.15 7.17 12.5 SMGP41
--CH.sub.2CH.dbd.CH.sub.2 H H C.sub.14H.sub.10 0.74 1.29 5.51 6.64
1.47 SMGP42 --CH.sub.2CH.dbd.CH.sub.2 H H Ph-cHexane 1.55 49.78
45.05 7.22 >10 SMGP43 --CH.sub.2CH.dbd.CH.sub.2 H H PhCH.sub.2Ph
SMGP44 --CH.sub.2CH.dbd.CH.sub.2 H H PhOPh SMGP45
--CH.sub.2CH.dbd.CH.sub.2 H H Anthracene SMGP46
--CH.sub.2CH.dbd.CH.sub.2 H H Ph--Ph--Ph SMGP47
--CH.sub.2CH.dbd.CH.sub.2 H H 2-Quinoline 0.2 0.5 150 0.01 0.04
SMGP48 --CH.sub.2CH.dbd.CH.sub.2 H H Ph- 4Benzofuran SMGP49
--CH.sub.2CH.dbd.CH.sub.2 H H Ph- 4Thiophene SMGP50
--CH.sub.2CH.dbd.CH.sub.2 H H Ph- 4Benzopyrrole SMGP51
--CH.sub.2CH.dbd.CH.sub.2 H H Ph-4(2-Furan) >10 SMGP52
--CH.sub.2CH.dbd.CH.sub.2 H H Ph-4(2- Thiophene) SMGP53
--CH.sub.2CH.dbd.CH.sub.2 H H Ph-4(2-Pyrrole) SMGP54
--CH.sub.2CH.dbd.CH.sub.2 H H CH.sub.3 20.46 >100 >100
>100 >10 SMGP55 --CH.sub.2CH.dbd.CH.sub.2 H H C.sub.6H.sub.13
9.5 9.15 32.2 29.65 >10 SMGP56 --CH.sub.2CH.dbd.CH.sub.2 H H
C.sub.12H.sub.25 0.61 9.35 32.2 29.65 >10 SMGP57
--CH.sub.2CH.dbd.CH.sub.2 H H cHexane 11.54 17.9 >100 30.17
>10 SMGP58 --CH.sub.2CH.dbd.CH.sub.2 H H Adamantane 6.5 7.1
>100 30.27 >10 SMGP59 --CH.sub.2CH.dbd.CH.sub.2 H H
Ph-4-SCH.sub.3 0.8 3.67 15.87 4.08 5.43 .sup.aBeta isomer
.sup.bAlpha isomer
[0071] Compound SMGP1, which had both high affinity and high
selectivity for kappa3 receptors, was examined more extensively.
Compound SMGP1 is a very potent analgesic in mice, having a potency
greater than morphine. However, the pharmacology of the drug
differed from morphine in a number of important criteria. Naloxone
is an effective antagonist, capable of reversing morphine and
virtually all the clinically used opiates. However, naloxone was
far less potent in reversing the analgesia elicited by SMGP1, and a
series of antagonists selective against traditional mu, delta,
kappa1 and ORL1 drugs were inactive. Levallorphan is an opioid
antagonist structurally analogous to the opioid agonist
levorphanol. Like levorphanol, levallorphan has high affinity for
the kappa3 site. Thus, it was not surprising that levallorphan
effectively reversed the analgesic actions of compound 1. This
confirms the opioid nature of the response. Chronic administration
of morphine rapidly leads to a diminished response, or
tolerance.
[0072] Compound SMGP1 also showed some tolerance with chronic
administration, although it appeared more slowly than that seen
with morphine. However, SMGP1 showed no cross tolerance to
morphine. When given to highly morphine tolerant mice, SMGP1 showed
a normal analgesic response. Following chronic administration, all
animals administered morphine show prompt and dramatic signs of
withdrawal, a measure of physical dependence, when challenged with
an antagonist. In contrast, chronic administration of SMGP1 led to
no physical dependence. Naloxone did not precipitate withdrawal,
which was expected since it also did not reverse the analgesia at
this dose and had poor affinity for the binding site. However,
levallorphan also did not precipitate withdrawal despite its
ability to reverse analgesia, clearly distinguishing SMGP1 from
clinically available opioids. Unlike other kappa drugs currently
available clinically, SMGP1 could be used in conjunction with
traditional opiates regardless of how long a patient had been
taking them, i.e. they could be used to reduce pain in a
.mu.-opioid-dependent patient. The effect of SMGP1 on the
inhibition of gastrointestinal transit was minimal. This is in
marked contrast to morphine. Based upon these observations, a
person of skill would conclude that SMGP1 would have minimal
constipation liability.
[0073] Compounds of the invention may be synthesized via the
following general route:
##STR00014##
[0074] This synthesis may be extended for compounds in which
R.sup.2 is other than hydrogen:
##STR00015##
[0075] Detailed descriptions of the synthesis of representative
compounds of the invention follow:
General Procedures: All reactions were carried out under positive
nitrogen atmosphere with a magnetic stirrer at ambient temperatures
using oven dried glassware. .sup.1H-NMR were taken on a 500 MHz
Bruker instrument using CDCl.sub.3 as solvent. Silica gel (230-400
mesh) was used in column chromatography.
[0076] The ketone at the 6-position of the three opiates was
transformed to an amine (Opiate-NH.sub.2) by reductive amination
using NaBH.sub.3CN and NH.sub.4OAc to yield a mixture of beta and
alpha isomers. The beta and alpha isomers were purified by column
chromatography. In a parallel synthesis, substituted carboxylic
acids were converted to N-succinimidyl ester by reacting it with
N-hydroxysuccinimide in presence of DCC and THF. The corresponding
activated ester was then reacted with the beta or alpha isomer of
the Opiate-NH.sub.2 in presence of DIEA and DCM. The aroyl amido
derivatives of opiates were then purified by column chromatography.
Alternatively, the substituted carboxylic acids were directly
coupled to the Opiate-NH.sub.2 using BOP and DIEA in DCM to give
3,6-diaroylated derivatives. The 3,6-diaroyl opiate derivatives
were then subjected to basic hydrolysis with K.sub.2CO.sub.3 to
yield 6-aroyl derivatives of naltrexamine, naloxamine and
oxymorphanamine.
[0077] Reductive amination of naltrexone, naloxone and oxymorphone
was carried out using a literature protocol published by Portoghese
and co-workers (J Med Chem 1977(20), 8, 1100). Typically, 10 g of
opiate (30 mmol), was stirred with NH.sub.4OAc (22 g, 0.3 mol, 10
eqv) in 40 mL dry methanol for 10 minutes at room temperature.
NaBH.sub.3CN (1.31 g, 21 mmol, 0.7 eqv) in 5 mL dry methanol was
then added to the reaction mixture and contents stirred overnight.
The reaction was quenched by addition of 10 mL 1N NaOH, the
solvents were evaporated on a rotavapor at 40.degree. C. The
residue was then extracted with 30 mL DCM three times; the organic
extracts were combined and washed with 25 mL water. The organic
extracts were dried over Na.sub.2SO.sub.4 and concentrated to a
white solid, which was purified by silica gel column
chromatography. The reaction gave a mixture of alpha and beta
isomers. The respective isomers were isolated by column
chromatography using 87:10:3 of EtOAc:MeOH:NH.sub.4OH as the
eluent. The beta isomer had a higher R.sub.f than the alpha isomer
on a TLC plate and eluted first when the mixture was subjected to
column chromatography. Yields for beta isomer were about 2.5-3 g
(25-30%). NMR peaks of the compounds matched the literature
values.
[0078] N-hydroxysuccinimide (NHS) esters of substituted carboxylic
acids were synthesized as follows: Substituted carboxylic acid (7.8
mmol), NHS (1 g, 8.6 mmol, 1.1 eqv), DCC (1.79 g, 8.6 mmol, 1.1
eqv) in 20 mL dry THF were stirred overnight. The white suspension
was filtered and the clear filterate was evaporated on a rotavapor
at 40.degree. C. The white solid seen was purified by column
chromatography using EtOAc/hexanes as eluents. A singlet at
.delta.2.9 integrating to 4 protons in .sup.1H-NMR and
corresponding to four protons of succinimide was seen in all NHS
esters of substituted carboxylic acids. Yields were about
80-100%.
[0079] Aroylations of naltrexamine, naloxamine and oxymorphonamine
were carried out as follows: Procedure I: Opiate-NH.sub.2 (200 mg,
0.6 mmol) was reacted with DIEA (116 ul, 0.66 mmol, 1.1 eqv) and
NHS esters of substituted carboxylic acids (0.66 mmol, 1.1 eqv) in
dry DCM (5 mL) for 2 h. The reaction was diluted to 20 mL with DCM
and washed with 5 mL water. The organic extracts were dried over
Na.sub.2SO.sub.4 and then concentrated to a white solid, which was
purified by silica gel column chromatography using 1-5% MeOH:DCM as
eluents. Yields of the target compounds were 50-75%.
[0080] Alternate procedure II: Opiate-NH.sub.2 (200 mg, 0.6 mmol)
was reacted with BOP (271 mg, 1.2 mmol, 2 eqv), DIEA (313 ul, 1.8
mmol, 3 eqv) and substituted carboxylic acid (1.2 mmol, 2 eqv) in
dry DCM (5 mL) for 2 h. The reaction mixture poured into a small
silica gel column and eluted with 100 mL EtOAc. The ethyl acetate
fraction was evaporated and a white solid was obtained. The solid
obtained was hydrolyzed in K.sub.2CO.sub.3 and MeOH. Briefly, the
contents, usually a white suspension were stirred with
K.sub.2CO.sub.3 (622 mg, 4.22 mmol, 7 eqv) and MeOH for 3 h. The
white suspension seen was filtered and the filterate concentrated
to a yellowish oil or a white solid. The oily residue or white
solid obtained was then purified by column chromatography using
1-5% MeOH: DCM as the eluent. Typical yields were around 65%.
[0081] Synthesis of individual embodiments:
[0082] SMGP1: Compound SMGP1 was synthesized according to the
general procedure (I) described above using .beta.-naltrexamine,
NHS ester of 3-iodobenzoic acid and DIEA in DCM. A white solid was
obtained. .sup.1H-NMR .delta.: 8.16 (s, 1H), 7.8-7.74 (m, 2H),
7.35-7.34 (d, 1H), 7.14-7.11 (m, 1H), 6.68-6.67 (d, 1H), 6.56-6.54
(d, 1H), 4.59 (d, 1H), 4.12 (m, 1H), 3.15-3.0 (m, 2H), 2.67-2.61
(m, 2H), 2.39-2.36 (m, 2H), 2.26-2.19 (m, 2H), 1.19 (m, 1H),
1.59-1.47 (m, 4H), 0.84 (m, 1H), 0.5 (m, 2H), 0.13 (m, 2H). ESI-MS
m/z: 573.2 (MH.sup.+).
[0083] SMGP2: Compound SMGP2 was synthesized according to the
general procedure (I) described above using .beta.-oxymorphanamine,
NHS ester of 3-iodobenzoic acid and DIEA in DCM. A white solid was
obtained. .sup.1H-NMR .delta.: 8.13 (s, 1H), 7.8-7.78 (d, 2H),
7.76-7.76 (d, 1H), 7.14-7.11 (m, 1H), 6.73-6.71 (d, 1H), 6.57-6.59
(d, 1H), 4.55 (d, 1H), 4.12 (m, 1H), 3.16-3.12 (m, 1H), 2.88 (m,
1H), 2.65-2.62 (m, 1H), 2.47 (m, 1H), 2.36 (s, 3H), 2.25-2.22 (m,
2H), 1.9-1.25 (m, 5H). ESI-MS m/z: 533.13 (MH.sup.+).
[0084] SMGP3: SMGP 3 was synthesized according to the general
procedure (I) described above using .beta.-naloxamine, NHS ester of
3-iodobenzoic acid and DIEA in DCM. A white solid was obtained.
Yield: 75%; .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.: 8.16 (s,
1H), 7.8 (d, J=8.9 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.15-7.11 (m,
1H), 6.69 (d, J=10.6 Hz, 1H), 6.57 (d, J=10.6 Hz, 1H), 5.8 (m, 1H),
5.23-5.16 (m, 2H), 4.57 (d, J=8.85 Hz, 1H), 4.13 (m, 1H), 3.14-1.2,
14H). .sup.13C NMR (600 MHz, CDCl.sub.3) .delta.: 165.4, 142.9,
140.3, 139.2, 136.4, 136.2, 135.2, 130.6, 130.1, 126.1, 124.7,
119.3, 118.1, 117.6, 94.3, 92.9, 70.2, 62.4, 57.8, 50.5, 47.3,
43.6, 31.5, 29.0, 23.2, 22.7 ppm. ESI-MS m/z: 559.1 (MH.sup.+).
HRMS calcd for C.sub.26H.sub.28N.sub.2O.sub.4I (MH+), 559.1094.
found, 559.1099.
[0085] SMGP4: SMGP4 was synthesized according to the general
procedure (I) described above using .alpha.-naloxamine, NHS ester
of 3-iodobenzoic acid and DIEA in DCM. A white solid was obtained.
Yield: 73%; .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.: 8.01 (s,
1H), 7.78 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.11 (t, J=7.8
Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.37 (d,
J=8.2 Hz, 1H), 5.80 (m, 1H), 5.18 (d, J=18.5 Hz, 1H,), 5.15 (d,
J=10.9 Hz, 1H), 4.74 (m, 2H), 3.50-1.00 (m, 15H) ppm. .sup.13C NMR
(600 MHz, CDCl.sub.3) .delta.: 165.5, 145.1, 140.3, 137.2, 136.6,
136.0, 135.2, 130.8, 130.1, 126.3, 125.9, 119.4, 118.0, 117.3,
94.2, 90.1, 69.7, 62.3, 58.1, 47.2, 46.7, 42.9, 33.3, 28.9, 23.0,
21.0 ppm. MS (ESI) m/z (%) 559 (MH+). HRMS calcd for
C.sub.26H.sub.28N.sub.2O.sub.4 I (MH+), 559.1094. found,
559.1107.
[0086] SMGP8: SMGP8 was synthesized according to the general
procedure (I) described above using 3-OMe-.beta.-naloxamine, NHS
ester of 3-iodobenzoic acid and DIEA in DCM. A white solid was
obtained. Yield: 36%; .sup.1H-NMR .delta.: 8.19 (s, 1H), 7.8 (m,
1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.75 (d, J=10 Hz, 1H), 6.66 (d,
J=10 Hz, 1H), 5.85 (m, 1H), 5.18 (m, 2H), 4.61 (d, 1H), 4.08 (m,
1H), 3.85 (s, 2H), 3.15-0.1 (m, 14H). MS (ESI) m/z (%) 573 (MH+).
HRMS calcd for C.sub.27H.sub.30N.sub.2O.sub.4I (MH+), 573.1250.
found, 573.1252.
[0087] SMGP16: SMGP16 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
2-iodobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 60%; .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 7.87 (d, J=8.35 Hz, 1H), 7.42 (d,
J=8.35, 1H), 7.38-7.36 (m, 1H), 7.11-7.08 (m, 1H), 6.75 (d, J=8.35,
1H), 6.6 (d, J=8.35, 1H), 6.41 (m, 1H), 5.78 (m, 1H), 5.14 (m, 2H),
4.51 (d, J=8.35, 1H), 4.17 (m, 1H), 3.49-1.26 (m, 14H). .sup.13C
NMR (600 MHz, CDCl.sub.3) .delta.: 169.2, 142.9, 142.2, 139.9,
139.6, 135.2, 131.1, 130.8, 128.3, 128.2, 124.8, 119.3, 118.0,
117.6, 93.2, 92.4, 70.2, 62.4, 57.7, 50.8, 47.5, 43.6, 31.0, 29.5,
23.5, 22.7 ppm. MS (ESI) m/z (%) 559 (MH+). HRMS calcd for
C.sub.26H.sub.28N.sub.2O.sub.4 I (MH+), 559.1094. found,
559.1115.
[0088] SMGP17: SMGP17 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
4-iodobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 43%; .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 7.78 (d, J=9.8 Hz, 2H), 7.53 (d,
J=9.8 Hz, 2H), 6.7 (d, J=9.8 Hz, 1H), 6.57 (d, J=9.8 Hz, 1H), 5.82
(m, 1H), 5.23-5.2 (m, 2H), 4.51 (d, J=8.2 Hz, 1H), 4.23 (m, 1H),
3.19-1.5 (m, 14H). .sup.13C NMR (600 MHz, Methanol-d4) .delta.
169.3, 143.8, 143.1, 139.0, 138.9, 135.1, 130.3, 130.0, 99.4, 91.9,
71.4, 64.7, 56.7, 53.3, 49.6, 47.7, 45.8, 31.1, 28.9, 24.6, 24.0
ppm. MS (ESI) m/z (%) 559 (MH+). HRMS calcd for
C.sub.26H.sub.28N.sub.2O.sub.4 I (MH+), 559.1094. found,
559.1099.
[0089] SMGP18: SMGP18 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3-fluorobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 70%, .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 7.59 (d, J=9.2 Hz, 1H), 7.55 (d,
J=9.2 Hz, 1H), 7.41-7.36 (m, 2H), 7.21-7.17 (m, 1H), 6.73 (d, J=9.2
Hz, 1H), 6.59 (d, J=10 Hz, 1H), 5.81 (m, 1H), 5.23-5.16 (m, 2H),
4.51 (d, J=9.2 Hz, 1H), 4.25 (m, 1H), 3.14-1.28 (m, 14H). MS (ESI)
m/z (%) 451 (MH+). HRMS calcd for C.sub.26H.sub.28N.sub.2O.sub.4F
(MH+), 451.2033. found, 451.2031.
[0090] SMGP19: SMGP19 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3-chlorobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 72%, .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 7.82 (s, 1H), 7.69 (d, J=7.85 Hz,
1H), 7.47 (d, J=7.85 Hz, 1H), 7.39-7.35 (m, 1H), 6.73 (d, J=8.05
Hz, 1H), 6.59 (d, J=8.05 Hz, 1H), 5.82-5.81 (m, 1H), 5.2-5.17 (m,
2H), 4.51-4.5 (d, J=5 Hz, 1H), 4.25 (m, 1H), 3.14-1.28 (m, 14H).
.sup.13C NMR (600 MHz, CDCl.sub.3) .delta. 165.7, 142.9, 139.2,
136.1, 135.2, 134.6, 131.5, 130.5, 129.8, 127.5, 125.1, 124.7,
119.3, 118.1, 117.6, 92.7, 70.3, 62.4, 57.8, 50.5, 47.2, 43.6,
31.6, 29.0, 23.2, 22.7 ppm. MS (ESI) m/z (%) 467 (MH+). HRMS calcd
for C.sub.26H.sub.28N.sub.2O.sub.4Cl (MH+), 467.1738. found,
467.1737.
[0091] SMGP20: SMGP20 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3-bromobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 70%; .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 7.96 (s, 1H), 7.72 (d, J=8.75 Hz,
1H), 7.61 (d, J=8.75 Hz, 1H), 7.31-7.28 (m, 1H), 7.24-7.22 (m, 1H),
6.72 (d, J=8.75 Hz, 1H), 6.58 (d, J=8.75 Hz, 1H), 5.8 (m, 1H),
5.23-5.16 (m, 2H), 4.52 (d, J=8.75 Hz, 1H), 4.18 (m, 1H), 3.14-1.5
(m, 14H). MS (ESI) m/z (%) 511 (MH+). HRMS calcd for
C.sub.26H.sub.28N.sub.2O.sub.4Br (MH+), 511.1232. found,
511.1250.
[0092] SMGP 21: SMGP 21 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, benzoic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 32%; .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta.: 7.82 (d, J=9.2 Hz, 2H), 7.51-7.42 (m, 3H), 7.20 (m, 1H),
6.74 (d, J=9.2 Hz, 1H), 6.59 (d, J=9.2 Hz, 1H), 5.82 (m, 1H),
5.23-5.17 (m, 2H), 4.5 (d, J=7.65 Hz, 1H), 4.26 (m, 1H), 3.13-1.25
(m, 14H). .sup.13C NMR (600 MHz, CDCl.sub.3) .delta. 166.9, 143.3,
139.2, 135.2, 134.5, 131.5, 130.7, 128.6, 127.0, 125.0, 119.2,
118.1, 117.5, 93.3, 70.2, 62.5, 57.8, 49.8, 47.2, 43.6, 31.7, 28.9,
23.2, 22.7 ppm. MS (ESI) m/z (%) 433 (MH+). HRMS calcd for
C.sub.26H.sub.29N.sub.2O.sub.4 (MH+), 433.2127. found,
433.2125.
[0093] SMGP 22: SMGP 22 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 3-toluic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 49%; .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta.: 7.67 (m, 2H), 7.51 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.71
(d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 5.82 (m, 1H), 5.23-5.17
(m, 2H), 4.55 (d, J=7.05 Hz, 1H), 4.06 (m, 1H), 3.36-1.5 (m, 16H).
.sup.13C NMR (600 MHz, CDCl.sub.3) .delta. 167.3, 143.1, 139.3,
138.4, 135.2, 134.4, 132.3, 130.7, 128.4, 127.8, 124.8, 123.9,
119.2, 118.1, 117.6, 93.3, 70.2, 62.5, 57.8, 50.2, 47.3, 43.6,
31.5, 29.1, 23.5, 22.7, 21.4 ppm. MS (ESI) m/z (%) 447 (MH+). HRMS
calcd for C.sub.27H.sub.31N.sub.2O.sub.4 (MH+), 447.2284. found,
447.2290.
[0094] SMGP 23: SMGP 23 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3-trifluorotoluic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 69%; .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta.: 8.01 (s, 3H), 8.0 (m, 1H), 7.89-7.88
(m, 1H), 7.65 (m, 1H), 7.45 (m, 1H), 6.62 (d, J=8.15 Hz, 1H), 6.5
(d, J=8.15 Hz, 1H), 5.78-5.74 (m, 1H), 5.2-5.13 (m, 2H), 4.67 (d,
J=6.15 Hz, 1H), 4.11-4.02 (m, 1H), 3.54-1.24 (m, 14H). .sup.13C NMR
(600 MHz, Methanol-d.sub.4) .delta. 165.7, 142.9, 139.2, 136.1,
135.2, 134.6, 131.5, 130.5, 129.8, 127.5, 125.1, 124.7, 119.3,
118.1, 117.6, 92.7, 70.3, 62.4, 57.8, 50.5, 47.2, 43.6, 31.6, 29.0,
23.2, 22.7 ppm. MS (ESI) m/z (%) 501 (MH+). HRMS calcd for
C.sub.27H.sub.28N.sub.2O.sub.4F.sub.3 (MH+), 501.2001. found,
501.2004.
[0095] SMGP 24: SMGP 24 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 3-anisic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 60%; .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta.: 7.56 (d, J=9 Hz, 1H), 7.39-7.26 (m, 3H), 7.0 (m, 1H), 6.72
(d, J=8.1 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 5.78-5.74 (m, 1H),
5.24-5.17 (m, 2H), 4.52 (d, J=6.2 Hz, 1H), 4.12-4.11 (m, 1H), 3.78
(s, 3H), 3.72-1.25 (m, 14H). .sup.13C NMR (600 MHz, Methanol-d4)
.delta. 170.0, 161.3, 143.8, 143.1, 136.9, 130.7, 127.9, 126.6,
121.8, 121, 120.5, 119.8, 118.6, 113.7, 91.9, 71.4, 64.7, 55.9,
53.2, 49.3, 47.6, 31.1, 29.0, 24.6, 24.1 ppm. MS (ESI) m/z (%) 463
(MH+). HRMS calcd for C.sub.27H.sub.31N.sub.2O.sub.5 (MH+),
463.2233. found, 463.2232.
[0096] SMGP 25: SMGP 25 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 3-amino
benzoic acid, BOP and DIEA in DCM followed by base hydrolysis. A
white solid was obtained. Yield: 30%; .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta.: 7.2-7.16 (m, 1H), 7.1 (d, J=7.95 Hz, 1H), 6.90
(d, J=7.95 Hz, 1H), 6.8 (d, J=7.95 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H),
6.69 (d, J=8.1 Hz, 1H), 5.81-5.8 (m, 1H), 5.19-5.16 (m, 2H), 4.46
(d, J=5.85 Hz, 1H), 4.21-4.19 (m, 1H), 3.48-1.22 (m, 16H). MS (ESI)
m/z (%) 448 (MH+). HRMS calcd for C.sub.26H.sub.30N.sub.3O.sub.4
(MH+), 448.2236. found, 448.2230.
[0097] SMGP 26: SMGP 26 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3-dimethylamino benzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 60%; .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta. 7.63 (s, 1H), 7.53 (d, J=6.0 Hz, 1H),
7.47 (t, J=6.8 Hz, 1H), 7.33 (dd, J=6.8, 1.8 Hz, 1H,), 6.77 (s,
1H), 6.76 (s, 1H), 5.93 (m, 1H), 5.68 (d, J=14.5 Hz, 1H,), 5.62 (d,
J=8.5 Hz, 1H), 4.81 (d, J=6.5 Hz, 1H), 3.95-1.55 (m, 23H) ppm. MS
(ESI) m/z (%) 476 (MH+). HRMS calcd for
C.sub.28H.sub.34N.sub.3O.sub.4 (MH+), 476.2549. found,
476.2544.
[0098] SMGP 27: SMGP 27 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 3-hydroxy
benzoic acid, BOP and DIEA in DCM followed by base hydrolysis. A
white solid was obtained. Yield: 39%; .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta.: 7.44 (m, 3H), 7.3-7.28 (m, 2H), 6.99 (d,
J=7.75 Hz, 1H), 6.71 (d, J=7.75 Hz, 1H), 6.6 (d, J=7.75 Hz, 1H),
5.82-5.8 (m, 1H), 5.22-5.17 (m, 2H), 4.51 (d, J=7.75 Hz, 1H), 4.062
(m, 1H), 3.51-1.51 (m, 14H). MS (ESI) m/z (%) 449 (MH+). HRMS calcd
for C.sub.26H.sub.29N.sub.2O.sub.5 (MH+), 449.2076. found,
449.2080.
[0099] SMGP 28: SMGP 28 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 3-nitro
benzoic acid, BOP and DIEA in DCM followed by base hydrolysis. A
white solid was obtained. Yield: 59%; .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta.: 8.68 (s, 1H), 8.36-8.34 (m, 1H), 8.22 (d,
J=11.8 Hz, 1H), 7.67-7.63 (m, 2H), 6.69 (d, J=11.8 Hz, 1H), 6.58
(d, J=11.8 Hz, 1H), 5.81 (m, 1H), 5.2-5.17 (m, 2H), 4.59 (d, J=9.8
Hz, 1H), 4.27 (m, 1H), 3.14-1.25 (m, 14H). MS (ESI) m/z (%) 478
(MH+). HRMS calcd for C.sub.26H.sub.28N.sub.3O.sub.6 (MH+),
479.1978. found, 478.1967.
[0100] SMGP 29: SMGP 29 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
4-(trifluoromethoxy)benzoic acid, BOP and DIEA in DCM followed by
base hydrolysis. A white solid was obtained. Yield: 79%;
.sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.: 7.87 (d, J=11.75 Hz,
1H), 7.44 (d, J=11.75 Hz, 1H), 7.24 (m, 2H), 6.72 (d, J=11.75 Hz,
1H), 6.58 (d, J=11.75 Hz, 1H), 5.81 (m, 1H), 5.23-5.16 (m, 2H),
4.53 (d, J=9.8 Hz, 1H), 4.24 (m, 1H), 3.33-1.28 (m, 14H). .sup.13C
NMR (600 MHz, Methanol-d4) .delta. 168.7, 152.8, 143.8, 143.2,
134.5, 130.6, 127.9, 126.6, 122.7, 121.8, 121.0, 119.7, 91.9, 71.4,
64.7, 56.7, 53.3, 48.3, 47.6, 31.1, 28.9, 24.6, 24.1 ppm. MS (ESI)
m/z (%) 517 (MH+). HRMS calcd for
C.sub.27H.sub.28N.sub.2O.sub.5F.sub.3 (MH+), 517.1950. found,
517.1956.
[0101] SMGP30: Compound SMGP30 was synthesized according to the
general procedure (II) described above using .beta.-naloxamine,
4-butoxybenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. .sup.1H-NMR .delta.:
7.77-7.75 (d, 2H), 7.22 (d, 1H), 6.88-6.86 (d, 2H), 6.73-6.71 (d,
1H), 6.57-6.55 (d, 1H), 5.79 (m, 1H), 5.22-5.15 (m, 2H), 4.52 (d,
1H), 4.17 (m, 1H), 3.99 (t, 2H), 3.47-0.97 (m, 21H) ESI-MS m/z:
503.24 (MH.sup.-).
[0102] SMGP34: SMGP34 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
3,4-diiodobenzoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 63%; .sup.1H-NMR
.delta.: 8.29 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.44 (d, J=9.1 Hz
1H), 6.7 (d, J=9.9 Hz, 1H), 6.66 (d, J=9.9 Hz, 1H), 5.85 (m, 1H),
5.18 (m, 2H), 4.61 (d, J=5 Hz, 1H), 4.08 (m, 1H), 3.85 (s, 2H),
3.15-0.1 (m, 14H). .sup.13C NMR (600 MHz, CDCl.sub.3) .delta.
164.9, 142.1, 139.3, 139.2, 137.9, 135.1, 130.4, 127.5, 124.5,
119.5, 118.2, 117.6, 112.1, 108.2, 92.4, 70.4, 62.4, 57.8, 51.4,
47.3, 43.6, 31.2, 29.5, 23.5, 22.7 ppm. MS (ESI) m/z (%) 685 (MH+).
HRMS calcd for C.sub.26H.sub.27N.sub.2O.sub.4I.sub.2 (MH+),
685.0060. found, 685.0052.
[0103] SMGP35: Compound SMGP35 was synthesized according to the
general procedure (I) described above using .beta.-naloxamine, NHS
ester of 3,4,5-triiodobenzoic acid, and DIEA in DCM. A white solid
was obtained. .sup.1H-NMR .delta.: 8.57 (s, 2H), 6.88-6.87 (d, 1H),
6.72-6.7 (d, 1H), 5.83-5.76 (m, 1H), 5.22-5.15 (m, 2H), 4.34 (d,
1H), 4.0 (m, 1H), 3.14-1.5 (m, 14H) ESI-MS m/z: 810.92
(MH.sup.+).
[0104] SMGP36: Compound SMGP36 was synthesized according to the
general procedure (I) described above using .beta.-naloxamine, NHS
ester of 1,4-benzodioxane-6-carboxylic acid, and DIEA in DCM. A
white solid was obtained. .sup.1H-NMR .delta.: 7.36 (s, 1H),
7.31-7.3 (d, 1H), 7.05-7.03 (d, 1H), 6.88-6.87 (d, 1H), 6.73-6.72
(d, 1H), 6.58-6.56 (d, 1H), 5.84-5.76 (m, 1H), 5.22-5.16 (m, 2H),
4.49-4.48 (d, 1H), 4.28-4.27 (m, 4H), 4.1 (m, 1H), 3.49-1.24 (m,
14H) ESI-MS m/z: 491.10 (MH.sup.+).
[0105] SMGP40: SMGP40 was synthesized according to the general
procedure (I) described above using .beta.-naloxamine, NHS ester of
biphenyl-4-carboxylic acid, and DIEA in DCM. A white solid was
obtained. Yield: 85%; .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.:
7.89 (d, J=8.15 Hz, 2H), 7.66-7.61 (m, 4H), 7.46 (m, 3H), 7.38 (m,
1H), 6.74 (d, J=8.15 Hz, 1H), 6.61 (d, J=8.15 Hz, 1H), 5.82-5.79
(m, 1H), 5.23-5.17 (m, 2H), 4.53-4.52 (d, J=5.15 Hz, 1H), 4.31-4.29
(m, 1H), 3.15-1.25 (m, 14H). .sup.13C NMR (600 MHz, CDCl.sub.3)
.delta. 166.7, 144.2, 143.2, 140.1, 139.2, 135.2, 133.1, 130.6,
128.9, 128.0, 127.6, 127.2, 119.2, 118.1, 117.6, 92.9, 70.2, 62.5,
57.8, 50.1, 47.2, 43.6, 31.7, 31.0, 28.9, 23.2, 22.7 ppm. MS (ESI)
m/z: 509.09 (MH.sup.+). HRMS calcd for
C.sub.32H.sub.33N.sub.2O.sub.4 (MH+), 509.2440. found,
509.2423.
[0106] SMGP41: SMGP41 was synthesized according to the general
procedure (I) described above using .beta.-naloxamine, NHS ester of
naphthalene-2-carboxylic acid, and DIEA in DCM.
[0107] A white solid was obtained. Yield: 89%; .sup.1H-NMR (500
MHz, CDCl.sub.3) .delta.:
[0108] .delta. 8.17 (s, 1H), 7.78-7.70 (m, 4H), 7.47 (t, J=7.5 Hz,
1H), 7.40 (t, J=7.5 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.1
Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 5.79 (m, 1H), 5.16 (m, 2H), 4.80
(m, 1H), 4.73 (d, J=4.3 Hz, 1H), 3.10-1.05 (m, 15H) ppm. .sup.13C
NMR (600 MHz, Methanol-d4) .delta. 170.0, 147.5, 140.4, 136.4,
134.0, 132.3, 130.1, 129.3, 129.1, 129.0, 128.8, 127.9, 125.1,
123.4, 121.0, 119.6, 89.7, 71.4, 71.0, 63.9, 57.0, 47.7, 47.2,
47.0, 31.8, 30.7, 24.6, 20.9 ppm. MS (ESI) m/z (%) 483 (MH+). HRMS
calcd for C.sub.30H.sub.31N.sub.2O.sub.4 (MH+), 483.2284. found,
483.2293.
[0109] SMGP42: Compound SMGP42 was synthesized according to the
general procedure (I) described above using .beta.-naloxamine, NHS
ester of 4-cyclohexylbenzoic acid, and DIEA in DCM. A white solid
was obtained. .sup.1H-NMR .delta.: 8.11-8.09 (d, 1H), 7.75-7.73 (d,
2H), 7.26 (d, 2H), 6.73-6.71 (d, 1H), 6.57-6.55 (d, 1H), 5.81 (m,
1H), 5.19 (m, 2H), 4.51 (d, 1H), 4.2 (m, 1H), 3.11-1.1 (m, 14H)
ESI-MS m/z: 515.35 (MH.sup.+).
[0110] SMGP54: SMGP54 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, acetic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 33%; .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 6.70 (d, J=8.2 Hz, 1H,), 6.56 (d, J=8.2 Hz, 1H), 5.96 (d,
J=9.2 Hz, 1H), 5.76 (m, 1H,), 5.18 (d, J=17.8 Hz, 1H,), 5.14 (d,
J=10.5 Hz, 1H,), 4.33 (d, J=6.5 Hz, 1H), 3.89 (m, 1H), 3.15-0.80
(m, 18H) ppm. MS (ESI) m/z (%) 371 (MH+). HRMS calcd for
C.sub.21H.sub.27N.sub.2O.sub.4 (MH+), 371.1971. found,
371.1965.
[0111] SMGP55: SMGP55 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, hexanoic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 50%; .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 6.71 (d, J=8.2 Hz, 1H,), 6.55 (d, J=8.2 Hz, 1H), 6.07 (d,
J=9.2 Hz, 1H), 5.77 (m, 1H), 5.18 (d, J=17.4 Hz, 1H), 5.14 (d,
J=10.1 Hz, 1H,), 4.34 (d, J=6.4 Hz, 1H), 3.91 (m, 1H), 3.15-0.80
(m, 26H) ppm. MS (ESI) m/z (%) 427 (MH+). HRMS calcd for
C.sub.26H.sub.35N.sub.2O.sub.4 (MH+), 427.2597. found,
427.2591.
[0112] SMGP56: SMGP56 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, dodecanoic
acid, BOP and DIEA in DCM followed by base hydrolysis. A white
solid was obtained. Yield: 35%; .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 6.71 (d, J=8.2 Hz, 1H), 6.55 (d, J=8.2 Hz, 1H,), 6.07 (d,
J=9.2 Hz, 1H,), 5.76 (m, 1H), 5.18 (d, J=17.4 Hz, 1H,), 5.14 (d,
J=10.1 Hz, 1H), 4.34 (d, J=6.4 Hz, 1H), 3.91 (m, 1H), 3.10-0.86 (m,
38H) ppm. MS (ESI) m/z (%) 511 (MH+). HRMS calcd for
C.sub.31H.sub.47N.sub.2O.sub.4 (MH+), 511.3536. found,
511.3550.
[0113] SMGP57: SMGP57 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine,
cyclohexanoic acid, BOP and DIEA in DCM followed by base
hydrolysis. A white solid was obtained. Yield: 33%; .sup.1H NMR
(500 MHz, CDCl.sub.3): .delta. 6.71 (d, J=8.1 Hz, 1H), 6.55 (d,
J=8.0 Hz, 1H), 6.14 (d, J=9.1 Hz, 1H), 5.77 (m, 1H), 5.18 (d,
J=17.4 Hz, 1H), 5.14 (d, J=10.0 Hz, 1H), 4.33 (d, J=6.1 Hz, 1H),
3.93 (m, 1H), 3.15-0.80 (m, 26H) ppm. .sup.13C NMR (600 MHz,
CDCl.sub.3) .delta. 176.0, 143.1, 139.5, 135.3, 130.8, 124.7,
119.1, 118.0, 117.6, 93.7, 70.1, 62.5, 57.7, 49.7, 47.3, 45.7,
43.6, 31.3, 29.7, 29.6, 29.3, 25.8, 25.7, 23.6, 22.7 ppm. MS (ESI)
m/z (%) 439 (MH+). HRMS calcd for C.sub.26H.sub.35N.sub.2O.sub.4
(MH+), 439.2597. found, 439.2602.
[0114] SMGP58: SMGP58 was synthesized according to the general
procedure (II) described above using .beta.-naloxamine, 1-Adamantyl
carboxylic acid, BOP and DIEA in DCM followed by base hydrolysis. A
white solid was obtained. Yield: 26%; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.: 6.71 (d, J=8.2 Hz, 1H,), 6.55 (d, J=8.2 Hz,
1H), 6.22 (d, J=9.5 Hz, 1H), 5.77 (m, 1H), 5.28 (s, 1H), 5.18 (d,
J=17.2 Hz, 1H), 5.14 (d, J=10.2 Hz, 1H), 4.31 (d, J=5.9 Hz, 1H),
3.97 (m, 1H), 3.15-0.76 (m, 29H) ppm. MS (ESI) m/z (%) 491 (MH+).
HRMS calcd for C.sub.30H.sub.39N.sub.2O.sub.4 (MH+), 491.2910.
found, 491.2912.
* * * * *