U.S. patent application number 15/239754 was filed with the patent office on 2017-02-16 for selective opioid compounds.
The applicant listed for this patent is Alkermes, Inc.. Invention is credited to Derrick Arnelle, Reginald L. Dean, III, Daniel Deaver, Mark Todtenkopf.
Application Number | 20170042882 15/239754 |
Document ID | / |
Family ID | 40955699 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170042882 |
Kind Code |
A1 |
Arnelle; Derrick ; et
al. |
February 16, 2017 |
Selective Opioid Compounds
Abstract
The present invention relates to compounds of Formula I or II,
or pharmaceutically acceptable salts, esters, or prodrugs thereof:
##STR00001## which relates to mophinan compounds useful as .mu.,
.delta. and/or .kappa. receptor opioid compounds and
pharmaceuticals containing same that may be useful for mediating
analgesia, combating drug addiction, alcohol addiction, drug
overdose, mental illness, bladder dysfunctions, neurogenic bladder,
interstitial cystitis, urinary incontinence, premature ejaculation,
inflammatory pain, peripherally mediated and neuropathic pain,
cough, lung edema, diarrhea, cardiac disorders, cardioprotection,
depression, and cognitive, respiratory, diarrhea, irritable bowel
syndrome and gastro-intestinal disorders, immunomodulation, and
anti-tumor agents.
Inventors: |
Arnelle; Derrick;
(Arlington, MA) ; Deaver; Daniel; (Franklin,
MA) ; Dean, III; Reginald L.; (Boxborough, MA)
; Todtenkopf; Mark; (Franklin, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkermes, Inc. |
Waltham |
MA |
US |
|
|
Family ID: |
40955699 |
Appl. No.: |
15/239754 |
Filed: |
August 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14695184 |
Apr 24, 2015 |
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15239754 |
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13693662 |
Dec 4, 2012 |
9040552 |
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14695184 |
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12371334 |
Feb 13, 2009 |
8354534 |
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13693662 |
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61028780 |
Feb 14, 2008 |
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61087295 |
Aug 8, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/12 20180101; A61P
25/28 20180101; A61P 29/00 20180101; A61P 1/00 20180101; A61P 1/10
20180101; A61P 1/04 20180101; A61P 9/00 20180101; A61P 25/00
20180101; C07D 471/08 20130101; A61P 25/32 20180101; C07D 489/08
20130101; A61P 1/16 20180101; A61K 45/06 20130101; A61P 25/18
20180101; A61K 31/485 20130101; A61P 13/10 20180101; A61P 19/00
20180101; A61P 37/06 20180101; A61P 25/16 20180101; A61P 25/24
20180101; A61P 37/08 20180101; A61P 25/30 20180101; A61P 25/34
20180101; A61P 43/00 20180101; A61P 3/04 20180101; A61P 35/00
20180101; A61P 31/12 20180101; A61P 9/12 20180101; A61P 13/00
20180101; A61P 1/18 20180101; A61P 9/10 20180101; A61K 31/4748
20130101; A61P 1/08 20180101; A61P 31/04 20180101; A61P 15/00
20180101; A61P 25/04 20180101; A61P 11/00 20180101; A61P 37/00
20180101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of preventing or treating a condition or disease
associated with binding opioid receptors in a patient in need
thereof, comprising the step of: administering to said patient a
composition comprising an effective amount of a compound of Formula
I or II: ##STR00031## or its geometric isomers, enantiomers,
diastereomers, racemates, pharmaceutically acceptable salts,
prodrugs and solvates thereof, wherein: R.sub.1 is selected from
the group consisting of: hydrogen, halogen, OR.sub.a, SR.sub.a,
S(O)R.sub.a, SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c,
SO.sub.2NR.sub.bR.sub.c, NR.sub.b-Q-R.sub.c, CN,
(C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a, CH.sub.2OR.sub.a,
CH.sub.2NR.sub.bR.sub.c, heteroaryl, and substituted heteroaryl;
R.sub.a, R.sub.b, R.sub.c are each independently selected from: (i)
hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted
heteroaryl; (iii) heterocyclic or substituted heterocyclic; and
(iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms
selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl,
substituted --C.sub.2-C.sub.8 alkenyl, or substituted
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms
selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, or
substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12
cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl;
alternatively, R.sub.b and R.sub.c are taken together to form a
heterocyclic or substituted heterocyclic; Q is absent or selected
from (C.dbd.O), (SO.sub.2), (C.dbd.NH), (C.dbd.S), or (CONR.sub.a);
W is O, S, NOR.sub.a or NR.sub.a; R.sub.2 is independently selected
from the group consisting of hydrogen, halogen, OR.sub.a, SR.sub.a,
NR.sub.bR.sub.c; alternatively, R.sub.1 and R.sub.2 are taken
together to form a heteroaryl, substituted heteroaryl, heterocyclic
or substituted heterocylic; R.sub.3 is independently selected from
the group consisting of: (v) hydrogen; (vi) aryl; substituted aryl;
heteroaryl; substituted heteroaryl; (vii) heterocyclic or
substituted heterocyclic; and (viii) --C.sub.1-C.sub.8 alkyl,
--C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each
containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or
N; substituted --C.sub.1-C.sub.8 alkyl, substituted
--C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl
each containing 0, 1, 2, or 3 or more heteroatoms selected from O,
S or N; --C.sub.3-C.sub.12 cycloalkyl, or substituted
--C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or
substituted --C.sub.3-C.sub.12 cycloalkenyl; R.sub.4 is hydrogen,
OR.sub.a, or NR.sub.b-Q.sup.1-R.sub.c, where Q.sup.1 is absent or
selected from (C.dbd.O) or (SO.sub.2); R.sub.5 is selected from the
group consisting of: hydrogen, halogen, SR.sub.a, S(O)R.sub.a,
SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c, SO.sub.2NR.sub.bR.sub.c,
NR.sub.b-Q-R.sub.c, CN, (C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a,
CH.sub.2OR.sub.a, CH.sub.2NR.sub.bR.sub.c, heteroaryl, and
substituted heteroaryl; Y is hydrogen, lower akyl, or lower alkoxy;
V.sub.1 is C.dbd.O, SO.sub.2, C.sub.1-C.sub.6 alkylene, substituted
alkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene;
V.sub.2 is absent, alkylene, substituted alkylene, C.sub.2-C.sub.6
alkenylene, C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl,
aryl or C.dbd.O; V.sub.3 is absent, alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene;
heterocyclic, heteroaryl, aryl or C.dbd.O; V.sub.4 is absent,
alkylene, substituted alkylene, C.sub.2-C.sub.6 alkenylene,
C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl, aryl or
C.dbd.O; n is 1, 2, 3 or 4; wherein each repeating unit can be the
same or different; Z is hydrogen, NR.sub.bR.sub.c,
(C.dbd.W)NR.sub.bR.sub.c, NR.sub.a(C.dbd.W)NR.sub.bR.sub.c,
(C.dbd.W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl;
alternatively, ##STR00032## can be selected from the group
consisting of natural or unnatural amino acids and peptidomimetics;
and denotes a carbon-carbon single or double bond.
2. The method according to claim 1, wherein the binding antagonizes
the activity of the opioid receptors.
3. The method according to claim 1, wherein the condition or
disease is pain, gastrointestinal dysfunction, or ileus.
4. The method of claim 3, wherein the ileus is post-operative
ileus.
5. A method according to claim 3, wherein the condition is pain and
the composition further comprises an effective amount of an
opioid.
6. The method according to claim 2, wherein the compound binds to
the opioid receptors.
7. The method according to claim 6, wherein the .mu. opioid
receptors are located in the central nervous system.
8. The method according to claim 6, wherein the .mu. opioid
receptors are located peripherally to the central nervous
system.
9. The method according to claim 2, wherein the compound does not
substantially cross the blood-brain barrier.
10. The method of treating or preventing a side effect associated
with an opioid, comprising the step of: administering to a patient
in need thereof, a composition comprising an effective amount of a
compound of Formula I or II: ##STR00033## or its geometric isomers,
enantiomers, diastereomers, racemates, pharmaceutically acceptable
salts, prodrugs and solvates thereof, wherein: R.sub.1 is selected
from the group consisting of: hydrogen, halogen, OR.sub.a,
SR.sub.a, S(O)R.sub.a, SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c,
SO.sub.2NR.sub.bR.sub.c, NR.sub.b-Q-R.sub.c, CN,
(C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a, CH.sub.2OR.sub.a,
CH.sub.2NR.sub.bR.sub.c, heteroaryl, and substituted heteroaryl;
R.sub.a, R.sub.b, R.sub.c are each independently selected from: (v)
hydrogen; (vi) aryl; substituted aryl; heteroaryl; substituted
heteroaryl; (vii) heterocyclic or substituted heterocyclic; and
(viii) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms
selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl,
substituted --C.sub.2-C.sub.8 alkenyl, or substituted
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms
selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, or
substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12
cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl;
alternatively, R.sub.b and R.sub.c are taken together to form a
heterocyclic or substituted heterocyclic; Q is absent or selected
from (C.dbd.O), (SO.sub.2), (C.dbd.NH), (C.dbd.S), or (CONR.sub.a);
W is O, S, NOR.sub.a or NR.sub.a; R.sub.2 is independently selected
from the group consisting of hydrogen, halogen, OR.sub.a, SR.sub.a,
NR.sup.bR.sup.c; alternatively, R.sub.1 and R.sub.2 are taken
together to form a heteroaryl, substituted heteroaryl, heterocyclic
or substituted heterocylic; R.sub.3 is independently selected from
the group consisting of: (ix) hydrogen; (x) aryl; substituted aryl;
heteroaryl; substituted heteroaryl; (xi) heterocyclic or
substituted heterocyclic; and (xii) --C.sub.1-C.sub.8 alkyl,
--C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each
containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or
N; substituted --C.sub.1-C.sub.8 alkyl, substituted
--C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl
each containing 0, 1, 2, or 3 or more heteroatoms selected from O,
S or N; --C.sub.3-C.sub.12 cycloalkyl, or substituted
--C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or
substituted --C.sub.3-C.sub.12 cycloalkenyl; R.sub.4 is hydrogen,
OR.sub.a, or NR.sub.b-Q.sup.1-R.sub.c, where Q.sup.1 is absent or
selected from (C.dbd.O) or (SO.sub.2); R.sub.5 is selected from the
group consisting of: hydrogen, halogen, SR.sub.a, S(O)R.sub.a,
SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c, SO.sub.2NR.sub.bR.sub.c,
NR.sub.b-Q-R.sub.c, CN, (C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a,
CH.sub.2OR.sub.a, CH.sub.2NR.sub.bR.sub.c, heteroaryl, and
substituted heteroaryl; Y is hydrogen, lower akyl, or lower alkoxy;
V.sub.1 is C.dbd.O, SO.sub.2, C.sub.1-C.sub.6 alkylene, substituted
alkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene;
V.sub.2 is absent, alkylene, substituted alkylene, C.sub.2-C.sub.6
alkenylene, C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl,
aryl or C.dbd.O; V.sub.3 is absent, alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene;
heterocyclic, heteroaryl, aryl or C.dbd.O; V.sub.4 is absent,
alkylene, substituted alkylene, C.sub.2-C.sub.6 alkenylene,
C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl, aryl or
C.dbd.O; n is 1, 2, 3 or 4; wherein each repeating unit can be the
same or different; Z is hydrogen, NR.sub.bR.sub.c,
(C.dbd.W)NR.sub.bR.sub.c, NR.sub.a(C.dbd.W)NR.sub.bR.sub.c,
(C.dbd.W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl;
alternatively, ##STR00034## can be selected from the group
consisting of natural or unnatural amino acids and peptidomimetics;
and denotes a carbon-carbon single or double bond.
11. The method according to claim 10, wherein the opioid is
endogenous.
12. The method according to claim 10, wherein the opioid is
exogenous.
13. The method according to claim 10, wherein the composition
further comprises an effective amount of at least one opioid.
14. The method according to claim 10, wherein the side effect is
selected from the group consisting of constipation, opioid-induced
bowel dysfunction, nausea, vomiting, and combinations thereof.
15. The method according to claim 10, wherein the administering
step occurs before, during or after a step of administering at
least one opioid.
16. The method according to claim 13, wherein the opioid is
alfentanil, buprenorphine, butorphanol, codeine, dezocine,
dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,
meperidine (pethidine), methadone, naloxone, naltrexone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, propiram,
propoxyphene, sufentanil, tramadol, or mixtures thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/695,184, filed Apr. 24, 2015, which is a continuation of
U.S. application Ser. No. 13/693,662, filed Dec. 4, 2012, now U.S.
Pat. No. 9,040,552, issued May 26, 2015, which is a divisional of
U.S. application Ser. No. 12/371,334, filed Feb. 13, 2009, now U.S.
Pat. No. 8,354,534, issued Jan. 15, 2013 and claims the benefit of
U.S. provisional application No. 61/028,780 filed Feb. 14, 2008 and
61/087,295 filed Aug. 8, 2008. The contents of the above
applications are incorporated herein by reference.
TECHNICAL FIELD
[0002] This invention relates to morphinan compounds useful as
.mu., .kappa. and/or .delta. receptor opioid compounds and
pharmaceuticals containing same that may be useful for mediating
analgesia, combating drug addiction, alcohol addiction, drug
overdose, mental illness, bladder dysfunctions, neurogenic bladder,
interstitial cystitis, urinary incontinence, premature ejaculation,
inflammatory pain, peripherally mediated and neuropathic pain,
cough, lung edema, diarrhea, cardiac disorders, cardioprotection,
depression, and cognitive, respiratory, diarrhea, irritable bowel
syndrome and gastro-intestinal disorders, immunomodulation, and as
anti-tumor agents.
BACKGROUND OF THE INVENTION
[0003] Opioid drugs typically target three types of endogenous
opioid receptors (i.e., .mu., .delta., and .kappa. receptors) in
biological systems. Many opiates, such as morphine, are .mu. opioid
agonists that are often used as analgesics for the treatment of
severe pain due to their activation of .mu. opioid receptors in the
brain and central nervous system (CNS). Opioid receptors are,
however, not limited to the CNS, and may be found in other tissues
throughout the body, i.e., peripheral to the CNS. A number of side
effects of opioid drugs may be caused by activation of these
peripheral receptors. For example, administration of .mu. opioid
agonists often results in intestinal dysfunction due to the large
number of receptors in the wall of the gut (Wittert, G., Hope, P.
and Pyle, D., Biochemical and Biophysical Research Communications,
1996, 218, 877-881; Bagnol, D., Mansour, A., Akil, A. and Watson,
S. J., Neuroscience, 1997, 81, 579-591). Specifically, opioids are
generally known to cause nausea and vomiting, as well as inhibition
of normal propulsive gastrointestinal function in animals and man
(Reisine, T., and Pasternak, G., Goodman & Gilman's The
Pharmacological Basis of Therapeutics, Ninth Edition, 1996,
521-555), resulting in side effects such as, for example,
constipation.
[0004] It would be of benefit to inhibit the natural activity of
endogenous opioids during and/or after periods of biological
stress, such as surgery and childbirth, so that ileus and related
forms of bowel dysfunction can be prevented and/or treated.
Currently, therapies for ileus include functional stimulation of
the intestinal tract, stool softeners, laxatives, lubricants,
intravenous hydration, and nasogastric decompression. These prior
art methods suffer from drawbacks, for example, as lacking
specificity for post-surgical or post-partum ileus. And these prior
art methods offer no means for prevention. If ileus could be
prevented, hospital stays, recovery times, and medical costs would
be significantly decreased, in addition to the benefit of
minimizing patient discomfort. Thus, drugs that selectively act on
opioid receptors in the gut would be ideal candidates for
preventing and/or treating post-surgical and post-partum ileus. Of
those, drugs that do not interfere with the effects of opioid
analgesics in the CNS would be of special benefit in that they
could be administered simultaneously for pain management with
limited side effects.
[0005] Peripheral opioid antagonists that do not cross the
blood-brain barrier into the CNS are known in the literature and
have been tested in relation to their activity on the GI tract. In
U.S. Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No.
5,159,081, and U.S. Pat. No. 5,270,328, peripherally selective
piperidine-N-alkylcarboxylate opioid antagonists are described as
being useful in the treatment of idiopathic constipation, irritable
bowel syndrome, and opioid-induced constipation. Some peripheral
.mu. antagonists derived from the structure naltrexone have been
reported in the literature (U.S. Pat. No. 4,806,556; Botros, et
al., J. Med. Chem. 1989, 32, 2068-2071). In addition, U.S. Pat. No.
4,176,186 describes quaternary derivatives of noroxymorphone (i.e.,
methylnaltrexone) that are said to prevent or relieve the
intestinal immobility side effect of narcotic analgesics without
reducing analgesic effectiveness. U.S. Pat. No. 5,972,954 describes
the use of methylnaltrexone, enteric-coated methylnaltrexone, or
other quaternary derivatives of noroxymorphone for preventing
and/or treating opioid- and/or nonopioid-induced side effects
associated with opioid administration.
[0006] General opioid antagonists, such as naloxone and naltrexone,
have also been implicated as being useful in the treatment of GI
tract dysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek,
M. J. Schaefer, R. A., Hahn, E. F., Fishman, J. Lancet, 1983, 1,
8319, 261 disclose naloxone and other morphinan-based opioid
antagonists (i.e., naloxone, naltrexone) for the treatment of
idiopathic gastrointestinal dysmotility. In addition, naloxone has
been shown to effectively treat non-opioid induced bowel
obstruction, implying that the drug may act directly on the GI
tract or in the brain (Schang, J. C., Devroede, G., Am. J.
Gastroenerol., 1985, 80, 6, 407). Furthermore, it has been
implicated that naloxone may provide therapy for paralytic ileus
(Mack, D. J. Fulton, J. D., Br. J. Surg., 1989, 76, 10, 1101).
However, it is well known that activity of naloxone and related
drugs is not limited to peripheral systems and may interfere with
the analgesic effects of opioid narcotics.
[0007] Despite recent advances in peripherally acting opioids,
there is still a need for more effective and safe opioid compounds,
with potent .mu., .kappa., and/or .delta. receptor agonist
activities that produce essentially no central mechanism side
effect, more particularly for the use in preventing or treating
undesirable side effects associated with administering exogenous
opioids with minimal impact on opioid agonist analgesia.
SUMMARY OF THE INVENTION
[0008] The present invention relates to derivatives of morphinans
and 3-carboxamido-6-amino-substituted 4,5 epoxymorphinans to target
modulation of opioid receptor activity outside of the CNS,
particularly those receptors associated with the gastrointestinal
tract, by reducing the lipid permeability of the drug either in the
gastrointestinal tract or at the blood-brain barrier (BBB).
Accordingly, the present invention provides a compound having a
general formula I or II:
##STR00002##
or its geometric isomers, enantiomers, diastereomers, racemates,
pharmaceutically acceptable salts, prodrugs and solvates thereof,
wherein: R.sub.1 is selected from the group consisting of:
hydrogen, halogen, OR.sub.a, SR.sub.a, S(O)R.sub.a,
SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c, SO.sub.2NR.sub.bR.sub.c,
NR.sub.b-Q-R.sub.c, CN, (C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a,
CH.sub.2OR.sub.a, CH.sub.2NR.sub.bR.sub.c, heteroaryl, and
substituted heteroaryl;
[0009] R.sub.a, R.sub.b, R.sub.c are each independently selected
from: [0010] (i) hydrogen; [0011] (ii) aryl; substituted aryl;
heteroaryl; substituted heteroaryl; [0012] (iii) heterocyclic or
substituted heterocyclic; and [0013] (iv) --C.sub.1-C.sub.8 alkyl,
--C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each
containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or
N; substituted --C.sub.1-C.sub.8 alkyl, substituted
--C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl
each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
--C.sub.3-C.sub.12 cycloalkyl, or substituted --C.sub.3-C.sub.12
cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted
--C.sub.3-C.sub.12 cycloalkenyl; [0014] alternatively, R.sub.b and
R.sub.c are taken together with the attached nitrogen atom to form
a heterocyclic or substituted heterocyclic;
[0015] Q is absent or selected from (C.dbd.O), (SO.sub.2),
(C.dbd.NH), (C.dbd.S), or (CONR.sub.a);
[0016] W is O, S, NOR.sub.a or NR.sub.a;
R.sub.2 is independently selected from the group consisting of
hydrogen, halogen, OR.sub.a, SR.sub.a, NR.sup.bR.sup.c;
alternatively, R.sub.1 and R.sub.2 are taken together with the
carbon they attached to form a heteroaryl, substituted heteroaryl,
heterocyclic or substituted heterocylic; R.sub.3 is independently
selected from the group consisting of: [0017] (i) hydrogen; [0018]
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
[0019] (iii) heterocyclic or substituted heterocyclic; and [0020]
(iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 or more
heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8
alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted
--C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 or more
heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl,
or substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12
cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl;
R.sub.4 is hydrogen, OR.sub.a, or NR.sub.b-Q.sup.1-R.sub.c, where
Q.sup.1 is absent or selected from (C.dbd.O) or (SO.sub.2); R.sub.5
is selected from the group consisting of: hydrogen, halogen,
SR.sub.a, S(O)R.sub.a, SO.sub.2R.sub.a, S(O)NR.sub.bR.sub.c,
SO.sub.2NR.sub.bR.sub.c, NR.sub.b-Q-R.sub.c, CN,
(C.dbd.W)NR.sub.bR.sub.c, C(O)OR.sub.a, CH.sub.2OR.sub.a,
CH.sub.2NR.sub.bR.sub.c, heteroaryl, and substituted heteroaryl; Y
is hydrogen, lower akyl, or lower alkoxy; V.sub.1 is C.dbd.O,
SO.sub.2, C.sub.1-C.sub.6 alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene; V.sub.2 is
absent, alkylene, substituted alkylene, C.sub.2-C.sub.6 alkenylene,
C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl, aryl or
C.dbd.O; V.sub.3 is absent, alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene;
heterocyclic, heteroaryl, aryl or C.dbd.O; V.sub.4 is absent,
alkylene, substituted alkylene, C.sub.2-C.sub.6 alkenylene,
C.sub.2-C.sub.6 alkynylene; heterocyclic, heteroaryl, aryl or
C.dbd.O; n is 1, 2, 3 or 4; wherein each repeating unit can be the
same or different; Z is hydrogen, NR.sub.bR.sub.c,
(C.dbd.W)NR.sub.bR.sub.c, NR.sub.a(C.dbd.W)NR.sub.bR.sub.c,
(C.dbd.W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl;
alternatively,
##STR00003##
[0020] can be selected from the group consisting of natural or
unnatural amino acids and peptidomimetics; and denotes a
carbon-carbon single or double bond.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The foregoing and other objects, features and advantages of
the invention will be apparent from the following more particular
description of preferred embodiments of the invention, as
illustrated in the accompanying drawings in which like reference
characters refer to the same parts throughout the different views.
The drawings are not necessarily to scale, emphasis instead being
placed upon illustrating the principles of the invention.
[0022] FIG. 1: Inhibition of morphine blockade of PGE.sub.2-induced
diarrhea by compound-12.
[0023] FIG. 2: Inhibition of morphine blockade of PGE.sub.2-induced
diarrhea by compound-13.
DETAILED DESCRIPTION OF THE INVENTION
[0024] A first embodiment of the invention is a compound
represented by Formula I or II as described above, or a
pharmaceutically acceptable salts, esters or prodrugs thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient.
[0025] In one embodiment of the invention are compounds represented
by Formula III or IV:
##STR00004##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, where n, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
Y, V.sub.1, V.sub.2, V.sub.3, V.sub.4 and Z are as defined
above.
[0026] In one embodiment of the invention are compounds represented
by Formula V:
##STR00005##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, where A.sub.1 is absent, C.sub.1-C.sub.6 alkylene,
substituted alkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6
alkynylene; A.sub.2 hydrogen, NR.sub.bR.sub.c,
(C.dbd.W)NR.sub.bR.sub.c, NR.sub.a(C.dbd.W)NR.sub.bR.sub.c,
(C.dbd.W)OH, heteroaryl or substituted heteroaryl; and n, R.sub.3,
V.sub.1, V.sub.3, V.sub.4, W, R.sub.a, R.sub.b, R.sub.c and Z are
as defined above. In one example,
##STR00006##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0027] In one embodiment of the invention are compounds represented
by Formula VI:
##STR00007##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, wherein R.sub.30 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkenyl, heterocyclic or substituted heterocyclic; where
A.sub.1 is absent, C.sub.1-C.sub.6 alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene; A.sub.2
hydrogen, NR.sub.bR.sub.c, (C.dbd.W)NR.sub.bR.sub.c,
NR.sub.a(C.dbd.W)NR.sub.bR.sub.c, (C.dbd.W)OH, heteroaryl or
substituted heteroaryl; and n, R.sub.3, V.sub.1, V.sub.3, V.sub.4,
W, R.sub.a, R.sub.b, R.sub.c and Z are as defined above. In one
example,
##STR00008##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0028] In one embodiment of the invention are compounds represented
by Formula VII:
##STR00009##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, wherein X.sup.- is counterion selected from the group
consisting of halide, sulfate, phosphate, nitrate, and
anionic-charged organic species; R.sub.30, and R.sub.31 are
independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl,
heterocyclic or substituted heterocyclic; where A.sub.1 is absent,
C.sub.1-C.sub.6 alkylene, substituted alkylene, C.sub.2-C.sub.6
alkenylene, C.sub.2-C.sub.6 alkynylene; A.sub.2 hydrogen,
NR.sub.bR.sub.c, (C.dbd.W)NR.sub.bR.sub.c,
NR.sub.a(C.dbd.W)NR.sub.bR.sub.c, (C.dbd.W)OH, heteroaryl or
substituted heteroaryl; and n, R.sub.3, V.sub.1, V.sub.3, V.sub.4,
W, R.sub.a, R.sub.b, R.sub.c and Z are as defined above. In one
example,
##STR00010##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0029] In one embodiment of the invention are compounds represented
by Formula VIII:
##STR00011##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, where A.sub.1 is absent, C.sub.1-C.sub.6 alkylene,
substituted alkylene, C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6
alkynylene; A.sub.2 hydrogen, NR.sub.bR.sub.c,
(C.dbd.W)NR.sub.bR.sub.c, NR.sub.a(C.dbd.W)NR.sub.bR.sub.c,
(C.dbd.W)OH, heteroaryl or substituted heteroaryl; and n, R.sub.3,
V.sub.1, V.sub.3, V.sub.4, W, R.sub.a, R.sub.b, R.sub.c and Z are
as defined above. In one example,
##STR00012##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0030] In one embodiment of the invention are compounds represented
by Formula IX:
##STR00013##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, wherein R.sub.30 is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkenyl, heterocyclic or substituted heterocyclic; A.sub.1 is
absent, C.sub.1-C.sub.6 alkylene, substituted alkylene,
C.sub.2-C.sub.6 alkenylene, C.sub.2-C.sub.6 alkynylene; A.sub.2
hydrogen, NR.sub.bR.sub.c, (C.dbd.W)NR.sub.bR.sub.c,
NR.sub.a(C.dbd.W)NR.sub.bR.sub.c, (C.dbd.W)OH, heteroaryl or
substituted heteroaryl; n, Y, V.sub.1, V.sub.3, V.sub.4, W,
R.sub.a, R.sub.b, R.sub.c and Z are as defined above. In one
example
##STR00014##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0031] In one embodiment of the invention are compounds represented
by Formula X:
##STR00015##
or a pharmaceutically acceptable salt, ester or prodrug thereof,
alone or in combination with a pharmaceutically acceptable carrier
or excipient, wherein X.sup.- is counterion selected from the group
consisting of halide, sulfate, phosphate, nitrate, and
anionic-charged organic species; R.sub.30 and R.sub.31 are
independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl,
heterocyclic or substituted heterocyclic; where A.sub.1 is absent,
C.sub.1-C.sub.6 alkylene, substituted alkylene, C.sub.2-C.sub.6
alkenylene, C.sub.2-C.sub.6 alkynylene; A.sub.2 hydrogen,
NR.sub.bR.sub.c, (C.dbd.W)NR.sub.bR.sub.c,
NR.sub.a(C.dbd.W)NR.sub.bR.sub.c, (C.dbd.W)OH, heteroaryl or
substituted heteroaryl; and n, R.sub.3, V.sub.1, V.sub.3, V.sub.4,
W, R.sub.a, R.sub.b, R.sub.c and Z are as defined above. In one
example,
##STR00016##
is selected from the group consisting of lysine (K), arginine (R),
histidine (H), aspartic acid (D), glutamic acid (E) or combinations
thereof.
[0032] Representative compounds according to the invention are
those selected from the TABLE A below or its geometric isomers,
enantiomers, diastereomers, racemates, pharmaceutically acceptable
salts, prodrugs and solvates thereof:
TABLE-US-00001 TABLE A Compound No. Structure 1 ##STR00017## 2
##STR00018## 3 ##STR00019## 4 ##STR00020## 5 ##STR00021## 6
##STR00022## 7 ##STR00023## 8 ##STR00024## 9 ##STR00025## 10
##STR00026## 11 ##STR00027## 12 ##STR00028## 13 ##STR00029##
[0033] In one embodiment, the compound of the invention is
administered to antagonize the peripheral side effects of an
opioid, wherein the compound of the present invention does not
substantially cross the blood-brain barrier nor does it decrease
the beneficial activity of the opioid. The phrase "does not
substantially cross," as used herein, means that less than about
20% by weight of the compound employed in the present methods
crosses the blood-brain barrier, preferably less than about 15% by
weight, more preferably less than about 10% by weight, even more
preferably less than about 5% by weight and most preferably 0% by
weight of the compound crosses the blood-brain barrier. Selected
compounds can be evaluated for CNS penetration by determining
plasma and brain levels following I.V. administration.
[0034] In one embodiment of the present invention, the compositions
of the invention may further comprise at least one opioid. A wide
variety of opioids is available that may be suitable for use in the
present methods and compositions. In preferred embodiments, the
present methods and compositions may involve an opioid that is
selected from alfentanil, buprenorphine, diprenorphine, etorphine,
nalorphine, naltrindole, butorphanol, codeine, dezocine,
dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,
meperidine (pethidine), methadone, naltrexone, naloxone, nalmefene,
nalmexone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and/or tramadol.
More preferably, the opioid is selected from morphine, naltrexone,
naloxone, codeine, oxycodone, hydrocodone, dihydrocodeine,
propoxyphene, fentanyl, tramadol, and mixtures thereof.
[0035] The compounds of the invention may further comprise one or
more other active ingredients that may be conventionally employed
in analgesic and/or cough-cold-antitussive combination products.
Such conventional ingredients include, for example, aspirin,
acetaminophen, phenylpropanolamine, phenylephrine,
chlorpheniramine, caffeine, and/or guaifenesin. Typical or
conventional ingredients that may be included in the opioid
component are described, for example, in the Physicians' Desk
Reference, 1999, the disclosure of which is hereby incorporated
herein by reference, in its entirety.
[0036] In one embodiment, the compositions of the invention may
further comprise one or more compounds that may be designed to
enhance the analgesic potency of the opioid and/or to reduce
analgesic tolerance development. Such compounds include, for
example, dextromethorphan or other NMDA antagonists (Mao, M. J. et
al., Pain, 1996, 67, 361), L-364,718 and other CCK antagonists
(Dourish, C. T. et al., Eur. J. Pharmacol., 1988, 147, 469), NOS
inhibitors (Bhargava, H. N. et al., Neuropeptides, 1996, 30, 219),
PKC inhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther.,
1996, 277, 484), and dynorphin antagonists or antisera (Nichols, M.
L. et al., Pain, 1997, 69, 317). The disclosures of each of the
foregoing documents are hereby incorporated herein by reference, in
their entireties.
[0037] In one embodiment, the compounds of the invention can be
used in methods for preventing or treating post-operative or
opioid-induced ileus. In another embodiment, the compounds of the
invention can be used as as analgesics, anesthetics,
anti-pruritics, anti-diarrheal agents, anti-convulsants,
anti-tussives, and/or anorexics.
[0038] The compounds of the present invention may be used in
methods to bind .mu. opioid receptors. Such binding may be
accomplished by contacting the receptor with an effective amount of
the compound of the invention. The opioid receptors may be located
in the central nervous system or located peripherally to the
central nervous system or in both locations. Preferably, the
contacting step conducted in an aqueous medium, preferably at
physiologically relevant ionic strength, pH, and the like.
[0039] In one embodiment, the compounds are opioid receptor
agonists. In another embodiment, the compounds prevent or treat a
condition or disease caused by an opioid (either endogenous or
exogenous). In yet another embodiment, particularly where the
opioid are exogenous, the compounds of the invention preferably do
not substantially cross the blood-brain barrier.
[0040] In one embodiment, the compounds antagonize the activity of
the opioid receptors. In other preferred embodiments, the compounds
prevent or treat a condition or disease caused by a .delta.,
.kappa., or .mu. opioid (either endogenous or exogenous). In other
embodiment, particularly where the opioids are exogenous, the
compounds of the invention preferably do not substantially cross
the blood-brain barrier.
[0041] The compounds of the present invention may be used in
methods to antagonize opioid receptors, particularly where
undesirable symptoms or conditions are side effects of
administering exogenous opioids. Furthermore, the compounds of the
invention may be used to treat patients having disease states that
are ameliorated by binding opioid receptors or in any treatment
wherein temporary suppression of the .mu. opioid receptor system is
desired.
[0042] Such symptoms, conditions or diseases include the complete
or partial antagonism of opioid-induced sedation, confusion,
respiratory depression, euphoria, dysphoria, hallucinations,
pruritus (itching), increased biliary tone, increased biliary
colic, and urinary retention, ileus, emesis, and addiction
liability; prevention or treatment of opioid and cocaine
dependence; rapid opioid detoxification; treatment of alcoholism;
treatment of alcoholic coma; detection of opioid use or abuse
(pupil test); treatment of eating disorders; treatment of obesity;
treatment of post-concussional syndrome; adjunctive therapy in
septic, hypovolemic or endotoxin-induced shock; potentiation of
opioid analgesia (especially at ultra-low doses); reversal or
prevention of opioid tolerance and physical dependence (especially
at ultra-low doses); prevention of sudden infant death syndrome;
treatment of psychosis (especially wherein the symptoms are
associated with schizophrenia, schizophreniform disorder,
schizoaffective disorder, unipolar disorder, bipolar disorder,
psychotic depression, Alzheimer's disease, Parkinson's disease,
compulsive disorders, and other psychiatric or neurologic disorders
with psychosis as symptoms); treatment of dyskinesia, treatment of
autism; treatment of the endocrine system (including increased
release of leutinizing hormone, treatment of infertility,
increasing number of multiple births in animal husbandry, and male
and female sexual behavior); treatment of the immune system and
cancers associated with binding of the opioid receptors; treatment
of anxiolysis; treatment of diuresis; treatment and regulation of
blood pressure; treatment of tinnitus or impaired hearing;
treatment of epilepsy; treatment of cachexia; treatment of general
cognitive dysfunctions; and treatment of kleptomania.
[0043] The compounds of the present invention may also be used as
cytostatic agents, as antimigraine agents, as immunomodulators, as
immunosuppressives, as antiarthritic agents, as antiallergic
agents, as virucides, to treat diarrhea, antipsychotics, as
antischizophrenics, as antidepressants, as uropathic agents, as
antitussives, as antiaddictive agents, as anti-smoking agents, to
treat alcoholism, as hypotensive agents, to treat and/or prevent
paralysis resulting from traumatic ischemia, general
neuroprotection against ischemic trauma, as adjuncts to nerve
growth factor treatment of hyperalgesia and nerve grafts, as
anti-diuretics, as stimulants, as anti-convulsants, or to treat
obesity. Additionally, the present compounds may be used in the
treatment of Parkinson's disease as an adjunct to L-dopa for
treatment dyskinesia associated with the L-dopa treatment.
[0044] In certain embodiments, the compounds of the invention may
be used in methods for preventing or treating gastrointestinal
dysfunction, including, but not limited to, irritable bowel
syndrome, opioid-bowel dysfunction, colitis, post-operative and
opioid-induced emesis (nausea and vomiting), decreased gastric
motility and emptying, inhibition of small and/or large intestinal
propulsion, increased amplitude of non-propulsive segmental
contractions, constriction of sphincter of Oddi, increased anal
sphincter tone, impaired reflex relaxation with rectal distention,
diminished gastric, biliary, pancreatic or intestinal secretions,
increased absorption of water from bowel contents,
gastro-esophageal reflux, gastroparesis, cramping, bloating,
abdominal or epigastric pain and discomfort, constipation, and
delayed absorption of orally administered medications or nutritive
substances.
DEFINITIONS
[0045] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification and claims, unless
otherwise limited in specific instances, either individually or as
part of a larger group.
[0046] The term "peripheral" or "peripherally" designates that the
compound acts primarily on physiological systems and components
external to the central nervous system. In preferred form, the
peripheral opioid antagonist compounds employed in the methods of
the present invention exhibit high levels of activity with respect
to peripheral tissue, such as, gastrointestinal tissue, while
exhibiting reduced, and preferably substantially no CNS
activity.
[0047] The phrase "side effect" refers to a consequence other than
the one(s) for which an agent or measure is used, as the adverse
effects produced by a drug, especially on a tissue or organ system
other then the one sought to be benefited by its administration. In
the case, for example, of opioids, the term "side effect" may refer
to such conditions as, for example, respiratory depression, acute
sedation, constipation, opioid-induced bowel dysfunction, nausea
and/or vomiting.
[0048] The term "unnatural amino acid" refers to any derivative of
a natural amino acid including D forms, and .alpha.- and
.beta.-amino acid derivatives. It is noted that certain amino
acids, e.g., hydroxyproline, that are classified as a non-natural
amino acid herein, may be found in nature within a certain organism
or a particular protein. Amino acids with many different protecting
groups appropriate for immediate use in the solid phase synthesis
of peptides are commercially available. In addition to the twenty
most common naturally occurring amino acids, the following examples
of non-natural amino acids and amino acid derivatives may be used
according to the invention (common abbreviations in parentheses):
.beta.-alanine (.beta.-ALA), .gamma.-aminobutyric acid (GABA),
2-aminobutyric acid (2-Abu), .alpha.,.beta.-dehydro-2-aminobutyric
acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC),
aminoisobutyric acid (Aib), 2-amino-thiazoline-4-carboxylic acid,
5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx),
8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun),
12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz),
3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid(4-Abz),
4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta),
aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid
(ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA),
para-aminophenylalanine (4-NH.sub.2-Phe), biphenylalanine (Bip),
para-bromophenylalanine (4-Br-Phe), ortho-chlorophenylalanine]
(2-Cl-Phe), meta-chlorophenylalanine (3-Cl-Phe),
para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine
(3-Cl-Tyr), para-benzoylphenylalanine (Bpa), tert-butylglycine
(TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg),
2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu),
3,4-dichlorophenylalanine (3,4-Cl.sub.2-Phe),
3,4-diflurorphenylalanine (3,4-F.sub.2-Phe), 3,5-diiodotyrosine
(3,5-I.sub.2-Tyr), ortho-fluorophenylalanine (2-F-Phe),
meta-fluorophenylalanine (3-F-Phe), para-fluorophenylalanine
(4-F-Phe), meta-fluorotyrosine (3-F-Tyr), homoserine (Hse),
homophenylalanine (Hfe), homotyrosine (Htyr), 5-hydroxytryptophan
(5-OH-Trp), hydroxyproline (Hyp), para-iodophenylalanine (4-1-Phe),
3-iodotyrosine (3-1-Tyr), indoline-2-carboxylic acid (Idc),
isonipecotic acid (Inp), meta-methyltyrosine (3-Me-Tyr),
1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal),
para-nitrophenylalanine (4-NO.sub.2-Phe), 3-nitrotyrosine
(3-NO.sub.2-Tyr), norleucine (Nle), norvaline (Nva), ornithine
(Orn), ortho-phosphotyrosine (H.sub.2PO.sub.3-Tyr),
octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen),
pentafluorophenylalanine (Fs-Phe), phenylglycine (Phg), pipecolic
acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU),
sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic),
and thiazolidine4-carboxylic acid (thioproline, Th). Additionally,
N-alkylatd amino acids may be used, as well as amino acids having
amine-containing side chains (such as Lys and Orn) in which the
amine has been acylated or or alkylated.
[0049] The term "peptide mimetic" or "peptidomimetic" means a
molecule able to mimic the biological activity of an amino acid or
peptide but is no longer peptidic in chemical nature. By strict
definition, a peptidomimetic is a molecule that no longer contains
any peptide bonds (that is, amide bonds between amino acids).
However, the term peptide mimetic is sometimes used to describe
molecules that are no longer completely peptidic in nature, such as
pseudo-peptides, semi-peptides and peptoids. Whether completely or
partially non-peptide, peptidomimetics according to this invention
provide a spatial arrangement of reactive chemical moieties that
closely resembles the three-dimensional arrangement of active
groups in the amino acid or peptide on which the peptidomimetic is
based. As a result of this similar active-site geometry, the
peptidomimetic has effects on biological systems, which are similar
to the biological activity of the amino acid or peptide.
[0050] The term "C.sub.1-C.sub.6 alkyl," or "C.sub.1-C.sub.8
alkyl," as used herein, refer to saturated, straight- or
branched-chain hydrocarbon radicals containing from one to six, or
from one to eight carbon atoms, respectively. Examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,
n-hexyl radicals; and examples of C.sub.1-C.sub.8 alkyl radicals
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl
radicals.
[0051] The term "C.sub.2-C.sub.6 alkenyl," or "C.sub.2-C.sub.8
alkenyl," as used herein, denote a group derived from a hydrocarbon
moiety, wherein the hydrocarbon moiety has at least one
carbon-carbon double bond and contains from two to six, or two to
eight, carbon atoms, respectively. Alkenyl groups include, but are
not limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
[0052] The term "C.sub.2-C.sub.6 alkynyl," or "C.sub.2-C.sub.8
alkynyl," as used herein, denote a group derived from a hydrocarbon
moiety, wherein the hydrocarbon moiety has at least one
carbon-carbon triple bond and contains from two to six, or two to
eight, carbon atoms, respectively.
[0053] Representative alkynyl groups include, but are not limited
to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl
and the like.
[0054] The term "C.sub.3-C.sub.8-cycloalkyl", or
"C.sub.3-C.sub.12-cycloalkyl," as used herein, denotes a group
derived from a monocyclic or polycyclic saturated carbocyclic ring
compound by the removal of a single hydrogen atom where the
saturated carbocyclic ring compound has from 3 ot 8, or from 3 to
12, ring atoms, respectively. Examples of
C.sub.3-C.sub.8-cycloalkyl include, but not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and
cyclooctyl; and examples of C.sub.3-C.sub.12-cycloalkyl include,
but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
[0055] The term "C.sub.3-C.sub.8-cycloalkenyl", or
"C.sub.3-C.sub.12-cycloalkenyl" as used herein, denote a group
derived from a monocyclic or polycyclic carbocyclic ring compound
having at least one carbon-carbon double bond, where the
carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring
atoms, respectively. Examples of C.sub.3-C.sub.8-cycloalkenyl
include, but not limited to, cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the
like; and examples of C.sub.3-C.sub.12-cycloalkenyl include, but
not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
[0056] The term "aryl," as used herein, refers to a mono-, bi-, or
tricyclic carbocyclic ring system having one or two aromatic rings
including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, idenyl and the like.
[0057] The term "arylalkyl," as used herein, refers to a
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl residue attached to
an aryl ring. Examples include, but are not limited to, benzyl,
phenethyl and the like.
[0058] The term "heteroaryl," as used herein, refers to a mono-,
bi-, or tri-cyclic aromatic radical or ring having from five to 15
ring atoms of which at least one ring atom is selected from S, O
and N; wherein any N or S contained within the ring may be
optionally oxidized. Heteroaryl includes, but is not limited to,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzooxazolyl, quinoxalinyl, and the like.
[0059] The term "heteroarylalkyl," as used herein, refers to a
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl residue residue
attached to a heteroaryl ring. Examples include, but are not
limited to, pyridinylmethyl, pyrimidinylethyl and the like.
[0060] The term "substituted" as used herein, refers to independent
replacement of one, two, or three or more of the hydrogen atoms
thereon with substituents including, but not limited to, --F, --Cl,
--Br, --I, --OH, protected hydroxy, --NO.sub.2, --CN, --NH.sub.2,
N.sub.3, protected amino, alkoxy, thioalkoxy, oxo,
-halo-C.sub.1-C.sub.12-alkyl, -halo-C.sub.2-C.sub.12-alkenyl,
-halo-C.sub.2-C.sub.12-alkynyl, -halo-C.sub.3-C.sub.12-cycloalkyl,
--NH--C.sub.1-C.sub.12-alkyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.2-C.sub.12-alkynyl, --NH--C.sub.3-C.sub.12-cycloalkyl,
--NH-aryl, --NH-heteroaryl, --NH -heterocycloalkyl, -dialkylamino,
-diarylamino, -diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkynyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-- heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkynyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkynyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkynyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkynyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkynyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkynyl,
--NHCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, --NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkynyl,
--NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)NH-aryl,
--NHC(O)NH-- heteroaryl, --NHC(O)NH-heterocycloalkyl,
NHC(S)NH.sub.2, --NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkynyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, --NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkynyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NH-heterocycloalkyl,
--NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkynyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)-aryl, --NHC(NH)--
heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkynyl,
--C(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --C(NH)NH-aryl, --C(NH)NH--
heteroaryl, --C(NH)NH-heterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkynyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl-SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkynyl,
--SO.sub.2NH--C.sub.3-C.sub.12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkynyl,
--NHSO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycloalkyl, polyalkoxyalkyl, polyalkoxy,
-methoxymethoxy, -methoxyethoxy, --SH, --S--C.sub.1-C.sub.12-alkyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.2-C.sub.12-alkynyl,
--S--C.sub.3-C.sub.12-cycloalkyl, --S-aryl, --S-heteroaryl,
--S-heterocycloalkyl, methylthiomethyl, or -L'-R', wherein L' is
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene, and R' is aryl, heteroaryl,
heterocyclic, C.sub.3-C.sub.12cycloalkyl or
C.sub.3-C.sub.12cycloalkenyl. It is understood that the aryls,
heteroaryls, alkyls, and the like can be further substituted. In
some cases, each substituent in a substituted moiety is
additionally optionally substituted with one or more groups, each
group can include --F, --Cl, --Br, --I, --OH, --NO.sub.2, --CN, or
--NH.sub.2 or the like.
[0061] In accordance with the invention, any of the aryls,
substituted aryls, heteroaryls and substituted heteroaryls
described herein, can be any type of aromatic group.
[0062] It is understood that any alkyl, alkenyl, alkynyl,
cycloalkyl and cycloalkenyl moiety described herein can also be an
aliphatic group, an alicyclic group or a heterocyclic group. An
"aliphatic group" is non-aromatic moiety that may contain any
combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,
nitrogen or other atoms, and optionally contain one or more units
of unsaturation, e.g., double and/or triple bonds. An aliphatic
group may be straight chained, branched or cyclic and preferably
contains between about 1 and about 24 carbon atoms, more typically
between about 1 and about 12 carbon atoms. In addition to aliphatic
hydrocarbon groups, aliphatic groups include, for example,
polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and
polyimines, for example. Such aliphatic groups may be further
substituted. It is understood that aliphatic groups may be used in
place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and
alkynylene groups described herein.
[0063] The term "alicyclic," as used herein, denotes a group
derived from a monocyclic or polycyclic saturated carbocyclic ring
compound. Examples include, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and
bicyclo [2.2.2]octyl. Such alicyclic groups may be further
substituted.
[0064] The term "heterocycloalkyl" and "heterocyclic" can be used
interchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or
7-membered ring or a bi- or tri-cyclic group fused system, where
(i) each ring contains between one and three heteroatoms
independently selected from oxygen, sulfur and nitrogen, (ii) each
5-membered ring has 0 to 1 double bonds and each 6-membered ring
has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms
may optionally be oxidized, (iv) the nitrogen heteroatom may
optionally be quaternized, (v) any of the above rings may be fused
to a benzene ring, and (vi) the remaining ring atoms are carbon
atoms which may be optionally oxo-substituted. Representative
heterocycloalkyl groups include, but are not limited to,
[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,
isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
Such heterocyclic groups may be further substituted to give
substituted heterocyclic.
[0065] It will be apparent that in various embodiments of the
invention, the substituted or unsubstituted alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl,
heteroarylalkyl, and heterocycloalkyl are intended to be monovalent
or divalent. Thus, alkylene, alkenylene, and alkynylene,
cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene,
hetoerarylalkylene and heterocycloalkylene groups are to be
included in the above definitions, and are applicable to provide
the formulas herein with proper valency.
[0066] The term "hydroxy activating group", as used herein, refers
to a labile chemical moiety which is known in the art to activate a
hydroxy group so that it will depart during synthetic procedures
such as in a substitution or elimination reactions. Examples of
hydroxy activating group include, but not limited to, mesylate,
tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
[0067] The term "activated hydroxy", as used herein, refers to a
hydroxy group activated with a hydroxy activating group, as defined
above, including mesylate, tosylate, triflate, p-nitrobenzoate,
phosphonate groups, for example.
[0068] The term "protected hydroxy," as used herein, refers to a
hydroxy group protected with a hydroxy protecting group, as defined
below, including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups.
[0069] The terms "halo" and "halogen," as used herein, refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0070] The compounds described herein contain one or more
asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)-
or (L)- for amino acids. The present invention is meant to include
all such possible isomers, as well as their racemic and optically
pure forms. Optical isomers may be prepared from their respective
optically active precursors by the procedures described herein, or
by resolving the racemic mixtures. The resolution can be carried
out in the presence of a resolving agent, by chromatography or by
repeated crystallization or by some combination of these
techniques, which are known to those skilled in the art. Further
details regarding resolutions can be found in Jacques, et al.,
Enantiomers, Racemates, and Resolutions (John Wiley & Sons,
1981). 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. The configuration of any carbon-carbon double bond
appearing herein is selected for convenience only and is not
intended to designate a particular configuration unless the text so
states; thus a carbon-carbon double bond depicted arbitrarily
herein as trans may be cis, trans, or a mixture of the two in any
proportion.
[0071] The term "subject" as used herein refers to a mammal. A
subject therefore refers to, for example, dogs, cats, horses, cows,
pigs, guinea pigs, and the like. Preferably the subject is a human.
When the subject is a human, the subject may be referred to herein
as a patient.
[0072] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts of the compounds formed by the process of the
present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art.
[0073] The term "hydroxy protecting group," as used herein, refers
to a labile chemical moiety which is known in the art to protect a
hydroxy group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the hydroxy
protecting group as described herein may be selectively removed.
Hydroxy protecting groups as known in the are described generally
in T. H. Greene and P. G., S. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
Examples of hydroxy protecting groups include benzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,
isopropoxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,
2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl,
chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,
benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl
ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl,
para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl),
tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl,
2,2,2-triehloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
methanesulfonyl, para-toluenesulfonyl, trimethylsilyl,
triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxy
protecting groups for the present invention are acetyl (Ac or
--C(O)CH.sub.3), benzoyl (Bz or --C(O)C.sub.6H.sub.5), and
trimethylsilyl (TMS or --Si(CH.sub.3).sub.3).
[0074] Berge, et al. describes pharmaceutically acceptable salts in
detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts
can be prepared in situ during the final isolation and purification
of the compounds of the invention, or separately by reacting the
free base function with a suitable organic acid. Examples of
pharmaceutically acceptable salts include, but are not limited to,
nontoxic acid addition salts e.g., salts of an amino group formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, maleic acid, tartaric acid, citric acid,
succinic acid or malonic acid or by using other methods used in the
art such as ion exchange. Other pharmaceutically acceptable salts
include, but are not limited to, adipate, alginate, ascorbate,
aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,
sulfonate and aryl sulfonate.
[0075] The term "amino protecting group," as used herein, refers to
a labile chemical moiety which is known in the art to protect an
amino group against undesired reactions during synthetic
procedures. After said synthetic procedure(s) the amino protecting
group as described herein may be selectively removed. Amino
protecting groups as known in the are described generally in T. H.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd edition, John Wiley & Sons, New York (1999). Examples of
amino protecting groups include, but are not limited to,
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl,
and the like.
[0076] As used herein, the term "pharmaceutically acceptable ester"
refers to esters of the compounds formed by the process of the
present invention which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include, but are not limited to, formates,
acetates, propionates, butyrates, acrylates and
ethylsuccinates.
[0077] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the compounds formed by the
process of the present invention which are, within the scope of
sound medical judgment, suitable for use in contact with the
tissues of humans and lower animals with undue toxicity,
irritation, allergic response, and the like, commensurate with a
reasonable benefit/risk ratio, and effective for their intended
use, as well as the zwitterionic forms, where possible, of the
compounds of the present invention. "Prodrug", as used herein means
a compound, which is convertible in vivo by metabolic means (e.g.
by hydrolysis) to afford any compound delineated by the formulae of
the instant invention. Various forms of prodrugs are known in the
art, for example, as discussed in Bundgaard, (ed.), Design of
Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et
al., (ed). "Design and Application of Prodrugs, Textbook of Drug
Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et
al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J.
of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and
Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975); and Bernard Testa & Joachim Mayer,
"Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry
And Enzymology," John Wiley and Sons, Ltd. (2002).
[0078] The term "acyl" includes residues derived from acids,
including but not limited to carboxylic acids, carbamic acids,
carbonic acids, sulfonic acids, and phosphorous acids. Examples
include aliphatic carbonyls, aromatic carbonyls, aliphatic
sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic
phosphates and aliphatic phosphates. Examples of aliphatic
carbonyls include, but are not limited to, acetyl, propionyl,
2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
[0079] The term "aprotic solvent," as used herein, refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
solvents are well known to those skilled in the art, and individual
solvents or mixtures thereof may be preferred for specific
compounds and reaction conditions, depending upon such factors as
the solubility of reagents, reactivity of reagents and preferred
temperature ranges, for example. Further discussions of aprotic
solvents may be found in organic chemistry textbooks or in
specialized monographs, for example: Organic Solvents Physical
Properties and Methods of Purification, 4th ed., edited by John A.
Riddick et al., Vol. II, in the Techniques of Chemistry Series,
John Wiley & Sons, N Y, 1986.
[0080] The terms "protogenic organic solvent" or "protic solvent"
as used herein, refer to a solvent that tends to provide protons,
such as an alcohol, for example, methanol, ethanol, propanol,
isopropanol, butanol, t-butanol, and the like. Such solvents are
well known to those skilled in the art, and individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of protogenic solvents may
be found in organic chemistry textbooks or in specialized
monographs, for example: Organic Solvents Physical Properties and
Methods of Purification, 4th ed., edited by John A. Riddick et al.,
Vol. II, in the Techniques of Chemistry Series, John Wiley &
Sons, N Y, 1986.
[0081] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable", as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and which maintains the integrity of the compound for a sufficient
period of time to be useful for the purposes detailed herein (e.g.,
therapeutic or prophylactic administration to a subject).
[0082] The synthesized compounds can be separated from a reaction
mixture and further purified by a method such as column
chromatography, high pressure liquid chromatography, or
recrystallization. Additionally, the various synthetic steps may be
performed in an alternate sequence or order to give the desired
compounds. In addition, the solvents, temperatures, reaction
durations, etc. delineated herein are for purposes of illustration
only and variation of the reaction conditions can produce the
desired bridged macrocyclic products of the present invention.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the compounds described herein include, for example, those
described in R. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective
Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991);
L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic
Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons
(1995).
[0083] The compounds of this invention may be modified by appending
various functionalities via synthetic means delineated herein to
enhance selective biological properties. Such modifications include
those which increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
Pharmaceutical Compositions
[0084] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator. The pharmaceutical compositions of this invention
can be administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), buccally, or as an
oral or nasal spray.
[0085] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0086] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0087] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose, any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0088] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0089] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide or
polylactide-co-glycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0090] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0091] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0092] In one embodiment, administration of the microparticles
comprising iloprost or another pharmaceutical agent to be
administered in addition to iloprost provides local or plasma
concentrations sustained at approximately constant values over the
intended period of release (e.g., up to 2 to 24 hours, to enable
dosing once, twice, three times, four times or more than four times
per day). The microparticle formulations may allow patients to take
treatments less frequently, and to receive more prolonged and
steadier relief.
[0093] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0094] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0095] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0096] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0097] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0098] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0099] The total daily inhibitory dose of the compounds of this
invention administered to a subject in single or in divided doses
can be in amounts, for example, from 0.01 to 50 mg/kg body weight
or more usually from 0.1 to 25 mg/kg body weight. Single dose
compositions may contain such amounts or submultiples thereof to
make up the daily dose. In general, treatment regimens according to
the present invention comprise administration to a patient in need
of such treatment from about 10 mg to about 1000 mg of the
compound(s) of this invention per day in single or multiple
doses.
[0100] Suitable daily oral dosages for the compounds of the
inventions described herein are on the order of about 0.01 mg to
about 1,000 mg of each active agent described herein. Desirably,
each oral dosage contains from 0.01 to 1,000 mg/day, particularly
0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50,
75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000
milligrams/day of each active ingredient in the composition of the
present invention (e.g. each opioid antagonist and each
peripherally restricted opioid agonist) administered for the
treatment of a reward dysfunction disorder. The specific dose level
for any particular patient will vary depending upon a variety of
factors, including but not limited to, the activity of the specific
compound employed; the age, body weight, general health, sex and
diet of the patient; the time of administration; the rate of
excretion; drug combination; the severity of the particular disease
being treated; and the form of administration. Typically, in vitro
dosage-effect results provide useful guidance on the proper doses
for patient administration. Studies in animal models are also
helpful. The considerations for determining the proper dose levels
are well known in the art.
[0101] Dosing schedules may be adjusted to provide the optimal
therapeutic response. For example, administration can be one to
three times daily for a time course of one day to several days,
weeks, months, and even years, and may even be for the life of the
patient. Practically speaking, a unit dose of any given composition
of the invention or active agent can be administered in a variety
of dosing schedules, depending on the judgment of the clinician,
needs of the patient, and so forth. The specific dosing schedule
will be known by those of ordinary skill in the art or can be
determined experimentally using routine methods. Exemplary dosing
schedules include, without limitation, administration five times a
day, four times a day, three times a day, twice daily, once daily,
every other day, three times weekly, twice weekly, once weekly,
twice monthly, once monthly, and so forth.
[0102] The weight ratio of the active agents in the instant
combination therapy (e.g. an opioid antagonist and a peripherally
restricted opioid agonist) may be varied and will depend upon the
effective dose of each ingredient. Generally, an effective dose of
each will be used. Thus, for example, when an opioid antagonist is
combined with a peripherally restricted opioid agonist the weight
ratio of the opioid antagonist to the peripherally restricted
opioid will generally range from about 1000:1 to about 1:1000,
preferably about 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150,
175, 200, 225, 250, 500, 750, 850 and 1,000:1 to about 1:5, 10, 15,
20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500,
750, 850 and 1,000. Compositions of the agents in the combinations
of the present invention (e.g. an opioid antagonist and a
peripherally restricted opioid agonist) will generally also be
within the aforementioned range, but in each case, an effective
dose of each active ingredient should be used.
[0103] Pharmaceutical kits useful in, for example, the treatment of
pain, which comprise a therapeutically effective amount of an
opioid along with a therapeutically effective amount of the
morphinan compound of the invention, in one or more sterile
containers, are also within the ambit of the present invention.
Sterilization of the container may be carried out using
conventional sterilization methodology well known to those skilled
in the art. The sterile containers of materials may comprise
separate containers, or one or more multi-part containers, as
exemplified by the UNIVIAL.RTM. two-part container (available from
Abbott Labs, Chicago, Ill.), as desired. The opioid compound and
the compounds of the invention may be separate, or combined into a
single dosage form as described above. Such kits may further
include, if desired, one or more of various conventional
pharmaceutical kit components, such as for example, one or more
pharmaceutically acceptable carriers, additional vials for mixing
the components, etc., as will be readily apparent to those skilled
in the art. Instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, may also be included in the kit.
[0104] Unless otherwise defined, all technical and scientific terms
used herein are accorded the meaning commonly known to one with
ordinary skill in the art. All publications, patents, published
patent applications, and other references mentioned herein are
hereby incorporated by reference in their entirety.
ABBREVIATIONS
[0105] Abbreviations which have been used in the descriptions of
the schemes and the examples that follow are: [0106] ACN for
acetonitrile; [0107] Ac for acetyl; [0108] Boc for
tert-butoxycarbonyl; [0109] Bz for benzoyl; [0110] Bn for benzyl;
[0111] CDI for carbonyldiimidazole; [0112] dba for dibenzylidene
acetone; [0113] CDI for 1,1'-carbonyldiimidizole; [0114] DBU for
1,8-diazabicyclo[5.4.0]undec-7-ene; [0115] DCM for dichloromethane;
[0116] DIAD for diisopropylazodicarboxylate; [0117] DMAP for
dimethylaminopyridine; [0118] DMF for dimethyl formamide; [0119]
DMSO for dimethyl sulfoxide; [0120] dppb for diphenylphosphino
butane; [0121] EtOAc for ethyl acetate; [0122] HATU for
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate; [0123] iPrOH for isopropanol; [0124] NaHMDS
for sodium bis(trimethylsilyl)amide; [0125] NMO for
N-methylmorpholine N-oxide; [0126] MeOH for methanol; [0127] Ph for
phenyl; [0128] POPd for dihydrogen
dichlorobis(di-tert-butylphosphino)palladium(II); [0129] TBAHS for
tetrabutyl ammonium hydrogen sulfate; [0130] TEA for triethylamine;
[0131] THF for tetrahydrofuran; [0132] TPP for triphenylphosphine;
[0133] Tris for Tris(hydroxymethyl)aminomethane; [0134] BME for
2-mercaptoethanol; [0135] BOP for
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate; [0136] COD for cyclooctadiene; [0137] DAST for
diethylaminosulfur trifluoride; [0138] DABCYL for
6-(N-4'-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl-
)-(N,N-diisopropyl)-phosphoramidite; [0139] DCM for
dichloromethane; [0140] DIAD for diisopropyl azodicarboxylate;
[0141] DIBAL-H for diisobutylaluminum hydride; [0142] DIEA for
diisopropyl ethylamine; [0143] DMAP for N,N-dimethylaminopyridine;
[0144] DME for ethylene glycol dimethyl ether; [0145] DMEM for
Dulbecco's Modified Eagles Media; [0146] DMF for N,N-dimethyl
formamide; [0147] DMSO for dimethylsulfoxide; [0148] EDANS for
5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid; [0149] EDCI or
EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
[0150] EtOAc for ethyl acetate; [0151] HATU for O
(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; [0152] Hoveyda's Cat. for
Dichloro(o-isopropoxyphenylmethylene)
(tricyclohexylphosphine)ruthenium(II); [0153] KHMDS is potassium
bis(trimethylsilyl) amide; [0154] Ms for mesyl; [0155] EtOAc for
ethyl acetate; [0156] g for gram(s); [0157] h for hour(s); [0158]
NMM for N-4-methylmorpholine; [0159] PyBrOP for
Bromo-tri-pyrolidino-phosphonium hexafluorophosphate; [0160] Ph for
phenyl; [0161] RCM for ring-closing metathesis; [0162] RT for
reverse transcription; [0163] RT-PCR for reverse
transcription-polymerase chain reaction; [0164] TEA for triethyl
amine; [0165] TFA for trifluoroacetic acid; [0166] MeOH for
methanol; [0167] mg for milligram(s); [0168] min for minute(s);
[0169] MS for mass spectrometry; [0170] NMR for nuclear magnetic
resonance; [0171] rt for room temperature; [0172] THF for
tetrahydrofuran; [0173] TLC for thin layer chromatography; [0174]
TPP or PPh.sub.3 for triphenylphosphine; [0175] tBOC or Boc for
tert-butyloxy carbonyl; and [0176] Xantphos for
4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.
Synthetic Methods
[0177] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that illustrate the methods by which the compounds of the
invention may be prepared, which are intended as an illustration
only and not to limit the scope of the invention. Various changes
and modifications to the disclosed embodiments will be apparent to
those skilled in the art and such changes and modifications
including, without limitation, those relating to the chemical
structures, substituents, derivatives, formulations and/or methods
of the invention may be made without departing from the spirit of
the invention and the scope of the appended claims.
[0178] The morphinan compounds according to the present invention
may be synthesized employing methods taught, for example, in U.S.
Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No.
5,159,081, and U.S. Pat. No. 5,270,328, the disclosures of which
are hereby incorporated herein by reference in their entireties.
The optically active and commercially available naltrexone was
employed as starting material in the synthesis of the present
compounds may be prepared by the general procedure taught in U.S.
Pat. No. 3,332,950, the disclosure of which is hereby incorporated
herein by reference in its entirety.
[0179] Scheme 1 exemplified one method of preparing the compounds
of the invention.
##STR00030##
Biological Assays
[0180] The potencies of the compounds are determined by testing the
ability of a range of concentrations of each compound to inhibit
the binding of the non-selective opioid antagonist,
[.sup.3H]diprenorphine, to the cloned human .mu., .kappa., and
.delta. opioid receptors, expressed in separate cell lines.
IC.sub.50 values are obtained by nonlinear analysis of the data
using GraphPad Prism version 5.00 for Windows (GraphPad Software,
San Diego). K.sub.i values are obtained by Cheng-Prusoff
corrections of IC.sub.50 values.
Receptor Binding (In Vitro Assay)
[0181] The receptor binding method (DeHaven and DeHaven-Hudkins,
"Characterization of Opioid Receptors", Current Protocols in
Pharmacology (Eds. Enna S J and Williams M) 1.4.1-1.4.12, John
Wiley & Sons, Inc., New York (1998)) is a modification of the
method of Raynor, et al., Mol. Pharmacol. 45:330-334 (1994). Stable
cell lines expressing the individual full-length human mu, delta,
and kappa opioid receptor cDNAs were generated by transfecting 70%
confluent Chinese hamster ovary (CHO)-K1 cells in 35-mm dishes with
the appropriate cDNA construct. Cells harvested 72 h after
transfection were centrifuged at 1000 g for 10 min; resuspended in
50 mM TriszHCl, pH 7.8, containing 1 mM EGTA, 5 mM MgCl2, 10
mg/liter leupeptin, 10 mg/liter pepstatin A, 200 mg/liter
bacitracin, and 0.5 mg/liter aprotinin; and centrifuged as before.
The pellet was resuspended in the same buffer, and the cells were
homogenized using a Polytron homogenizer. The homogenate was
centrifuged at 48,000 g for 20 min at 4.degree. C., the membrane
pellet was resuspended at 1 mg protein/ml in the same buffer as
before, and the aliquots were stored at 80.degree. C. until use.
Experiments were conducted by incubating a final concentration of
25 to 100 mg of protein and 1 nM [3H]diprenorphine per tube with or
without cold drug in the buffer described above in a final assay
volume of 500 ml for 1 h at room temperature. After incubation at
room temperature for one hour, the samples were filtered through
GF/B filters that had been pre-soaked in a solution of 0.5% (w/v)
polyethylenimine and 0.1% (w/v) bovine serum albumin in water. The
filters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH
7.8 and radioactivity remaining on the filters determined by
scintillation spectroscopy. Nonspecific binding was determined by
the minimum values of the titration curves and was confirmed by
separate assay wells containing 10 .mu.M naloxone. K.sub.i values
were determined by Cheng-Prusoff corrections of IC.sub.50 values
derived from nonlinear regression fits of 12 point titration curves
using GraphPad Prism.RTM. version 5.00 for Windows (GraphPad
Software, San Diego, Calif.).
[0182] To determine the equilibrium dissociation constant for the
inhibitors (K.sub.i), radioligand bound (cpm) in the presence of
various concentrations of test compounds was measured. The
concentration to give half-maximal inhibition (IC.sub.50) of
radioligand binding was determined from a best nonlinear regression
fit to the following equation,
Y = Bottom + ( Top - Bottom ) 1 + 10 X - LogIC 50 ##EQU00001##
where Y was the amount of radioligand bound at each concentration
of test compound, Bottom was the calculated amount of radioligand
bound in the presence of an infinite concentration of test
compound, Top was the calculated amount of radioligand bound in the
absence of test compound, X was the logarithm of the concentration
of test compound, and Log IC.sub.50 was the log of the
concentration of test compound where the amount of radioligand
bound was half-way between Top and Bottom. The nonlinear regression
fit was performed using the program Prism.RTM. (GraphPad Software,
San Diego, Calif.). The K.sub.i values are then determined from the
EC.sub.50 values by the following equation,
Ki = EC 50 1 + [ ligand ] K d ##EQU00002##
where [ligand] was the concentration of radioligand and K.sub.d was
the equilibrium dissociation constant for the radioligand.
Opioid Receptor Mediated [.sup.5S] GTP.gamma.S Binding
[0183] The potencies of the antagonists were assessed by their
abilities to inhibit agonist-stimulated [.sup.35S]GTP.gamma.S
binding to membranes containing the cloned human .mu., .kappa., or
.delta. opioid receptors. The agonists used are loperamide for the
.mu. opioid receptor, U50488H for the .kappa. opioid receptor, and
BW373U86 for the .delta. opioid receptor.
[0184] To determine the IC.sub.50 value, which was the
concentration to give half-maximal inhibition of agonist-stimulated
[.sup.35S]GTP.gamma.S binding, the amount of [.sup.35S]GTP.gamma.S
bound in the presence of a fixed concentration of agonist and
various concentrations of antagonist was measured. The fixed
concentration of agonist is the EC.sub.80 for the agonist, which
was the concentration to give 80% of the relative maximum
stimulation of [.sup.35S]GTP.gamma.S binding. The IC.sub.50 value
was determined from a best nonlinear regression fit of the data to
the following equation,
Y = Bottom + ( Top - Bottom ) 1 + 10 X - LogIC 50 ##EQU00003##
where Y was the amount of [.sup.35S]GTP.gamma.S bound at each
concentration of antagonist, Bottom was the calculated amount of
[.sup.35S]GTP.gamma.S bound in the presence of an infinite
concentration of antagonist, Top was the calculated amount of
[.sup.35S]GTP.gamma.S bound in the absence of added antagonist, X
is the logarithm of the concentration of antagonist, and Log
IC.sub.50 was the logarithm of the concentration of antagonist
where the amount of [.sup.35S]GTP.gamma.S bound was halfway between
Bottom and Top. The nonlinear regression fit was performed using
GraphPad Prism.RTM. version 5.00 for Windows (GraphPad Software,
San Diego, Calif.).
Antagonism of Morphine-Inhibited Diarrhea in Mice (In Vivo
Assay)
[0185] Albino mice of either sex (Swiss-Webster) weighing 20-30 g
were used to determine the ability of an opioid antagonist to
antagonize morphine inhibition of prostaglandin E2 (PGE.sub.2)
induced diarrhea according to the method of Dajani et al. (1979).
Briefly, mice are treated at time 0 with morphine, 1 mg/kg s.c. and
an opioid antagonist, 60, 180, 240, 300, 360, 480, or 720 mg/kg
orally; or 3, 10, 30, 100 or 140 mg/kg i.p; or saline, 0.1 ml/10 gm
body weight orally or i.p. Mice are then treated at 30 min with
PGE.sub.2, 320 .mu.g/kg which consistently produced watery stools
in the absence of morphine. The pie-shaped cages were observed at
15 mins for the presence of absence of watery stools. Eleven to 24
mice were used per dose of an opioid antagonist for the oral and 6
are used for the i.p. routes. Data was analyzed using Fisher's
exact probability test (Siegel, 1956). These studies were repeated
using naltrexone, 0.005, 0.01, 0.05, 0.1, and 5 mg/kg i.p. and 0.5,
1, 2, and 4 mg/kg orally.
Antagonism of Morphine-Induced Antinocieption in Mice (in vivo
Assay)
[0186] Albino mice of either sex (Swiss-Webster) weighing 20-30 g
were used to determine the ability of an opioid antagonist to
antagonize morphine-induced antinocieption. Antinocieption was
measured using the hotplate method of Eddy et al. (1950; 1953). The
hot plate surface temperature was maintained at 55.degree. C. and
the test session was not allowed to go beyond 60 seconds.
[0187] Mice were tested for a non-drug baseline response at time 0.
After the test, mice are treated with morphine, 15 mg/kg i.p. and
15 minutes later are treated with an opioid antagonist, 10 and 30
mg/kg i.p. or saline, 0.1 ml/10 g body weight i.p followed by test
at 45 min. Ten mice were used per dose of an opioid antagonist. The
mean pretreatment response times were compared to the maximum
response times obtained after morphine administration. An increase
in response of 45 or more seconds was judged as antinocieption. A
statistically significant reduction in the morphine-related
response time was taken as a reversal of the morphine effect. The
number of mice demonstrating antinocieption on the hot plate test
after treatment with saline or an opioid antagonist 10 and 30 mg/kg
were compared using a one-way ANOVA. FIGS. 1 and 2 show the
inhibition of morphine blockade of PGE.sub.2-induced diarrhea by
compound-12.
Mouse Gastrointestinal Transit (GIT) Assay (In Vivo Assay)
[0188] Male Swiss-Webster mice (25-30 g) obtained from Charles
River Laboratories are used for all experiments. Mice are housed
5/cage in polycarbonate cages with food and water available ad
libitum. Mice are on a 12 hours light:dark schedule with lights on
at 6:30 a.m. All experiments are performed during the light cycle.
Mice are fasted the night before the experiment, with water
available ad libitum.
[0189] Mice are administered vehicle (water) or test compound (10
mg/kg) orally 2 or 6 hour before determination of GIT. Compounds
are administered in a volume of 0.1 ml/10 g of body weight.
Morphine (1-3 mg/kg) or vehicle (0.9% saline) is administered s.c.
35 minutes prior to determination of GIT. Ten minutes after the
morphine treatment, mice are administered 0.2 ml of a charcoal meal
orally. The charcoal meal consisted of a slurry of charcoal, flour,
and water in the following ratio (1:2:8, w:w:v). Twenty-five
minutes after receiving the charcoal meal, the mice are euthanized
with CO.sub.2 and the intestines are removed. GIT is determined
with GIT expressed as the % GIT by the following formula:
( distance to leading edge of charcoal meal ( cm ) ) ( total length
of the small intestine ( cm ) ) .times. 100 ##EQU00004##
[0190] For each compound a % Antagonism (% A) value is determined
for the 2 and 6 hour antagonist pretreatment. Using the mean % GIT
for each treatment group, % A is calculated using the following
formula:
1 = ( ( mean vehicle response - mean antagonist + morphine response
) ) ( mean vehicle response - mean morphine response ) .times. 100
##EQU00005##
Examples
[0191] The compounds and processes of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration only and not to limit the scope of
the invention. Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art and such
changes and modifications including, without limitation, those
relating to the chemical structures, substituents, derivatives,
formulations and/or methods of the invention may be made without
departing from the spirit of the invention and the scope of the
appended claims.
[0192] Although the invention has been described with respect to
various preferred embodiments, it is not intended to be limited
thereto, but rather those skilled in the art will recognize that
variations and modifications may be made therein which are within
the spirit of the invention and the scope of the appended
claims.
* * * * *