U.S. patent application number 09/725661 was filed with the patent office on 2001-11-29 for novel methods and compositions involving opioids and antagonists thereof.
Invention is credited to Farrar, John J..
Application Number | 20010047005 09/725661 |
Document ID | / |
Family ID | 26973877 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047005 |
Kind Code |
A1 |
Farrar, John J. |
November 29, 2001 |
Novel methods and compositions involving opioids and antagonists
thereof
Abstract
Novel methods and compositions comprising opioids and opioid
antagonists. In preferred embodiments, the methods and compositions
comprise opioids and peripheral mu opioid antagonist compounds. The
methods and compositions are particularly suitable for treating
and/or preventing side effects associated with opioids including,
for example, constipation, vomiting and/or nausea.
Inventors: |
Farrar, John J.; (Chester
Springs, PA) |
Correspondence
Address: |
David A. Cherry, Esquire
Woodcock Washburn Kurtz
Mackiewicz & Norris LLP
One Liberty Place-46th Floor
Philadelphia
PA
19103
US
|
Family ID: |
26973877 |
Appl. No.: |
09/725661 |
Filed: |
November 29, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09725661 |
Nov 29, 2000 |
|
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60304199 |
Apr 27, 2000 |
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Current U.S.
Class: |
514/282 ;
514/295; 514/326; 514/330 |
Current CPC
Class: |
A61K 31/454 20130101;
A61K 31/4748 20130101; A61K 31/4748 20130101; A61K 31/454 20130101;
A61K 31/485 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/485 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/282 ;
514/295; 514/326; 514/330 |
International
Class: |
A61K 031/485; A61K
031/4748; A61K 031/454 |
Claims
What is claimed is:
1. A method of preventing or treating a side effect associated with
an opioid comprising administering to a patient, in combination
with an effective amount of an opioid, an effective amount of a
compound of the following formula (I): 24wherein: R.sup.1 is
hydrogen or alkyl; R.sup.2 is hydrogen, alkyl or alkenyl; R.sup.3
is hydrogen, alkcyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or
aryl-substituted alkyl; R.sup.4 is hydrogen, alkyl or alkenyl; A is
OR.sup.5 or NR.sup.6R.sup.7; wherein: R.sup.5 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 25C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 26alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
2. A method according to claim 1 wherein the compound of formula
(I) is a trans 3,4-isomer.
3. A method according to claim 1 wherein RI is hydrogen; R.sup.2 is
alkyl; n is 1 or 2; R.sup.3 is benzyl, phenyl, cyclohexyl, or
cyclohexylmethyl; and R.sup.4 is alkyl.
4. A method according to claim 3 wherein A is OR.sup.5 in which
R.sup.5 is hydrogen or alkyl.
5. A method according to claim 3 wherein A is NR.sup.6R.sup.7 in
which R.sup.6 is hydrogen and R.sup.7 is alkylene substituted B
wherein B is C(O)W.
6. A method according to claim 5 wherein R.sup.7 is
(CH.sub.2).sub.q-B in which q is about 1 to about 3; and W is
OR.sup.10 in which R.sup.10 is hydrogen, alkyl, phenyl-substituted
alkyl, cycloalkyl or cycloalkyl-substituted alkyl.
7. A method according to claim 5 wherein W is NR.sup.11R.sup.12 in
which R.sup.11 is hydrogen or alkyl, and R.sup.12 is hydrogen,
alkyl or alkylene substituted C(.dbd.O)Y.
8. A method according to claim 7 wherein R.sup.12 is
(CH.sub.2).sub.mC(O)Y in which m is 1 to 3 and Y is OR.sup.18 or
NR.sup.19R.sup.20 wherein R.sup.18, R.sup.19 and R.sup.20 are
independently hydrogen or alkyl.
9. A method according to claim 5 wherein W is OE in which E is
CH.sub.2C(.dbd.O)D wherein D is OR.sup.15 or NR.sup.16R.sup.17 in
which R.sup.15 is hydrogen or alkyl, R.sup.16 is methyl or benzyl
and R.sup.17 is hydrogen.
10. A method according to claim 5 wherein W is OE in which E is
R.sup.13OC(.dbd.O)R.sup.14, wherein R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)-- and R.sup.14 is alkyl.
11. A method according to claim 1 wherein the configuration at
positions 3 and 4 of the piperidine ring is each R.
12. A method according to claim 1 wherein said compound is selected
from the group consisting of
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.2,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.3,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.2CH.sub.3-
, G--NH(CH.sub.2).sub.2C(O)NH.sub.2,
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3, G--NHCH.sub.2C(O)NH.sub.2,
G--NHCH.sub.2C(O)NHCH.sub.3, G--NHCH.sub.3C(O)NHCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH- .sub.3,
G--NH(CH.sub.2).sub.3C(O)NHCH.sub.3, G--NH(CH.sub.2).sub.2C(O)OH,
G--NH(CH.sub.2).sub.3C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)- NHCH.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2)-
.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub-
.2C(O)NH.sub.2, Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3,
Z--NHCH.sub.2C(O)OH, Z--NHCH.sub.2C(O)NH.sub.2,
Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2,
Z-NBCH.sub.2C(O)OCH.sub.2CH(CH.sub- .3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2C(O)OH, Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3,
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3,
Z--NHCH.sub.2C(O)O(CH.sub.2).sub- .4CH.sub.3,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)O--(4-methoxycyclohexyl),
Z--NHCH.sub.2C(O)OCH.sub.2C(O)- NHCH.sub.2(C.sub.6H.sub.5) or
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein: Q represents
27
13. A method according to claim 12 wherein said compound is
selected from the group consisting of
(3R,4R,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3)- .sub.2,
(+)--Z--NHCH.sub.2C(O)OH, (-)--Z--NHCH.sub.2C(O)OH,
(3R,4R,R)--Z--NHCH.sub.2C(O)--OCH.sub.2CH(CH.sub.3).sub.2, (3
S,4S,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2, (3
S,4S,R)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub.2(C.sub.6 H.sub.5) or
(3R,4R)-G--NH(CH.sub.2).sub.3C(O)OH.
14. A method according to claim 13 wherein said compound is
selected from thle group consisting of (+)--Z--NHCH.sub.2C(O)OH and
(-)--Z--NHCH.sub.2C(O)OH.
15. A method according to claim 14 wherein said compound is
(+)--Z--NHCH.sub.2C(O)OH.
16. A method according to claim 1 wherein said compound is a
substantially pure stereoisomer.
17. A method according to claim 1 wherein said compound is a
peripheral mu opioid antagonist.
18. A method according to claim 1 wherein said opioid is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
19. A method according to claim 18 wherein said opioid is selected
from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
20. A method according to claim 1 wherein said side effect is
selected from the group consisting of constipation, nausea and
vomiting
21. A method according to claim 20 wherein said side effect is
constipation.
22. A method according to claim 20 wherein said side effect is
nausea.
23. A method according to claim 20 wherein said side effect is
vomiting.
24. A method according to claim 1 wherein said opioid and said
compound of formula (I) are in a single dosage unit form.
25. A method of preventing or treating a side effect associated
with an opioid comprising administering to a patient an effective
amount of an opioid in combination with an effective amount of a
peripheral mu opioid antagonist compound.
26. A method according to claim 25 wherein said peripheral mu
opioid antagonist compound is selected from the group consisting of
a piperidine-N-alkylcarboxylate, a quaternary morphinan, an opium
alkaloid derivative and a quaternary benzomorphan compound.
27. A method according to claim 26 wherein said peripheral mu
opioid antagonist compound is a piperidine-N-alkylcarboxylate
compound.
28. A method according to claim 27 wherein said
piperidine-N-alkylcarboxyl- ate compound has the following formmula
(I): 28wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen,
alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4is
hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 29C(.dbd.O)W or NR.sup.3R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 30alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
29. A method according to claim 26 wherein said peripheral mu
opioid antagonist compound is a quaternary morphinan compound.
30. A method according to claim 29 wherein said quaternary
morphinan compound is a quaternary salt of a compound selected from
the group consisting of N-methylnaltrexone, N-methylnaloxone,
N-methylnalorphine, N-diallylnormorphine, N-allyllevallorphan and
N-methylnalmefene.
31. A method according to claim 26 wherein said peripheral mu
opioid antagonist compound is an opium alkaloid derivative.
32. A method according to claim 31 wherein said opium alkaloid
derivative has the following formula (III) or (IV): 31wherein: R is
alkyl, cycloalkyl-substituted alkyl, aryl, aryl-substituted alkyl
or alkenyl; Z is hydrogen or OH; R' is X'--J(L)(T), wherein: J is
alkylene or alkenylene; L is hydrogen, amino, or alkyl optionally
substituted with CO.sub.2H, OH or phenyl; and T is CO.sub.2H,
SO.sub.3H, amnino or guanidino; X' is a direct bond or C(.dbd.O);
and R" is NH--J(L)(T) or guanidino; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
33. A method according to claim 32 wherein R is
C.sub.1-C.sub.3alkyl, allyl or cyclopropylmethyl; Z is OH; J is
C.sub.1-C.sub.5alkylene, C.sub.2-C.sub.6alkylene interrupted by an
oxygen atom, or C.sub.2-C.sub.5alkenylene; L is hydrogen or amino;
and T is CO.sub.2H or guanidino.
34. A method according to claim 33 wherein R is cyclopropylmethyl,
R' is C(.dbd.O)(CH.sub.2).sub.2CO.sub.2H,
C(.dbd.O)(CH.sub.2).sub.3CO.sub.2H, C(.dbd.O)CH.dbd.CHCO.sub.2H,
C(.dbd.O)CH.sub.2OCH.sub.2CO.sub.2H,
C(.dbd.O)CH(NH.sub.2)(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2,
C(.dbd.O)CU(NH.sub.2)CH.sub.2CO.sub.2H or CH.sub.2CO.sub.2H and R"
is NHCH.sub.2CO.sub.2H.
35. A method according to claim 26 wherein said peripheral mu
opioid antagonist compound is a quaternary benzomorphan
compound.
36. A method according to claim 35 wherein said quaternary
benzomorphan compound has the following formula (V): 32where:
R.sup.24 is hydrogen or acyl; and R.sup.25 is alkyl or alkenyl; or
a stereoisomer, prodrug, or pharmaceutically acceptable salt,
hydrate or N-oxide thereof.
37. A method according to claim 36 wherein R.sup.24 is hydrogen or
C.sub.1-C.sub.2 acyl and R.sup.25 is C.sub.1-C.sub.3 alkyl or
C.sub.2-C.sub.3 alkenyl.
38. A method according to claim 37 wherein R.sup.24 is hydrogen or
acetoxy and R.sup.25 is propyl or allyl.
39. A method according to claim 36 wherein the quaternary
benzomorphan compound is selected from the group consisting of
2'-hydroxy-5,9-dirnethy- l-2,2-diallyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-pro- pyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromid-
e and
2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromi-
de.
40. A method according to claim 25 wherein said opioid is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
41. A method according to claim 40 wherein said opioid is selected
from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
42. A method according to claim 25 wherein said side effect is
selected from the group consisting of constipation, nausea and
vomiting.
43. A method according to claim 42 wherein said side effect is
constipation.
44. A method according to claim 42 wherein said side effect is
nausea.
45. A method according to claim 42 wherein said side effect is
vomiting.
46. A method according to claim 25 wherein said opioid and said
peripheral mu opioid antagonist are in a single dosage unit
form.
47. A method of treating or preventing pain comprising
administering to a patient an effective amount of an opioid, in
combination with an effective amount of a compound of the following
formula (I): 33wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is
hydrogen, alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl,
aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4
is hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 34C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 35alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
48. A method according to claim 47 wherein the compound of formula
(I) is a trans 3,4-isomer.
49. A method according to claim 47 wherein R.sup.1 is hydrogen;
R.sup.2 is alkyl; n is 1 or 2; R.sup.3 is benzyl, phenyl,
cyclohexyl, or cyclohexylmethyl; and R.sup.4 is alkyl.
50. A method according to claim 49 wherein A is OR.sup.5 in which
R.sup.5 is hydrogen or alkyl.
51. A method according to claim 50 wherein A is NR.sup.6R.sup.7 in
which R.sup.6 is hydrogen and R.sup.7 is alkylene substituted B
wherein B is C(O)W.
52. A method according to claim 51 wherein R.sup.7 is
(CH.sub.2).sub.q-B in which q is about 1 to about 3; and W is
OR.sup.10 in which R.sup.10 is hydrogen, alkyl, phenyl-substituted
alkyl, cycloalkyl or cycloalkyl-substituted alkyl.
53. A method according to claim 51 wherein W is NR.sup.11R.sup.12
in which R.sup.11 is hydrogen or alkyl, and R.sup.12 is hydrogen,
alkyl or alkylene substituted C(.dbd.O)Y.
54. A method according to claim 53 wherein R.sup.12 is
(CH.sub.2).sub.mC(O)Y in which m is 1 to 3 and Y is OR.sup.18 or
NR.sup.19R.sup.20 wherein R.sup.18, R.sup.19 and R.sup.20 are
independently hydrogen or alkyl.
55. A method according to claim 51 wherein W is OE in which E is
CH.sub.2C(.dbd.O)D wherein D is OR.sup.15 or NR.sup.16R.sup.17 in
which R.sup.15 is hydrogen or alkyl, R.sup.16 is methyl or benzyl
and R.sup.17 is hydrogen.
56. A method according to claim 51 wherein W is OE in which E is
R.sup.13OC(.dbd.O)R.sup.14, wherein R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)-- and R.sup.14 is alkyl.
57. A method according to claim 47 wherein the configuration at
positions 3 and 4 of the piperidine ring is each R.
58. A method according to claim 47 wherein said compound is
selected from the group consisting of
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.2,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.3,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.2CH.sub.3-
, G--NH(CH.sub.2).sub.2C(O)NH.sub.2,
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3, G--NHCH.sub.2C(O)NH.sub.2,
G--NHCH.sub.2C(O)NHCH.sub.3, G--NHCH.sub.3C(O)NHCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH- .sub.3,
G--NH(CH.sub.2).sub.3C(O)NHCH.sub.3, G--NH(CH.sub.2).sub.2C(O)OH,
G--NH(CH.sub.2).sub.3C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.1l))C(O)- NHCH.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2)-
.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub-
.2C(O)NH.sub.2, Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3,
Z--NHCH.sub.2C(O)OH, Z--NHCH.sub.2C(O)NH.sub.2,
Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.su- b.3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2C(O)OH, Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3,
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3,
Z--NHCH.sub.2C(O)O(CH.sub.2).sub- .4CH.sub.3,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)O--(4-methoxycyclohexyl),
Z--NHCH.sub.2C(O)OCH.sub.2C(O)- NHCH.sub.2(C.sub.6H,) or
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein: Q represents
36
59. A method according to claim 58 wherein said compound is
selected from the group consisting of
(3R,4R,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3)- .sub.2,
(+)--Z--NHCH.sub.2C(O)OH, (-)--Z--NHCH.sub.2C(O)OH,
(3R,4R,R)--Z--NHCH.sub.2C(O)--OCH.sub.2CH(CH.sub.3).sub.2,
(3S,4S,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,(3S,4S,R)--Z--NHC-
H.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub- .2(C.sub.6 H.sub.5) or
(3R,4R)-G--NH(CH.sub.2).sub.3C(O)OH.
60. A method according to claim 59 wherein said compound is
selected from the group consisting of (+)--Z--NHCH.sub.2C(O)OH and
(-)--Z--NHCH.sub.2C(O)OH.
61. A method according to claim 60 wherein said compound is
(+)--Z--NHCH.sub.2C(O)OH.
62. A method according to claim 47 wherein said compound is a
substantially pure stereoisomer.
63. A method according to claim 47 wherein said compound is a
peripheral mu opioid antagonist.
64. A method according to claim 47 wherein said opioid is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
65. A method according to claim 64 wherein said opioid is selected
from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
66. A method according to claim 47 wherein said opioid and said
compound of formula (I) are in a single dosage unit form.
67. A method of treating or preventing pain comprising
administering to a patient an effective amount of an opioid in
combination with an effective amount of a peripheral mu opioid
antagonist compound.
68. A method according to claim 67 wherein said peripheral mu
opioid antagonist compound is selected from the group consisting of
a piperidine-N-alkylcarboxylate, a quaternary morphinan, an opium
alkaloid derivative and a quaternary benzomorphan compound.
69. A method according to claim 68 wherein said peripheral mu
opioid antagonist compound is a piperidine-N-alkylcarboxylate
compound.
70. A method according to claim 69 wherein said
piperidine-N-alkylcarboxyl- ate compound has the following formula
(I): 37wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen,
alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4
is hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 38C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 39alklene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16 R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
71. A method according to claim 68 wherein said peripheral mu
opioid antagonist compound is a quaternary morphinan compound.
72. A method according to claim 71 wherein said quaternary
morphinan compound is a quaternary salt of a compound selected from
the group consisting of N-methylnaltrexone, N-methylnaloxone,
N-methylnalorphine, N-diallylnormorphine, N-allyllevallorphan and
N-methylnalmefene.
73. A method according to claim 68 wherein said peripheral mu
opioid antagonist compound is an opium alkaloid derivative.
74. A method according to claim 73 wherein said opium alkaloid
derivative has the following formula (III) or (IV): 40wherein: R is
alkyl, cycloalkyl-substituted alkyl, aryl, aryl-substituted alkyl
or alkenyl; Z is hydrogen or OH; R' is X'--J(L)(T), wherein: J is
alkylene or alkenylene; L is hydrogen, amino, or alkyl optionally
substituted with CO.sub.2H, OH or phenyl; and T is CO.sub.2H,
SO.sub.3H, amino or guanidino; X' is a direct bond or C(.dbd.O);
and R" is NH--J(L)(T) or guanidino; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
75. A method according to claim 74 wherein R is
C.sub.1-C.sub.3alkyl, allyl or cyclopropylmethyl; Z is OH; J is
C.sub.1-C.sub.5alkylene, C.sub.2-C.sub.6alkylene interrupted by an
oxygen atom, or C.sub.2-C.sub.5alkenylene; L is hydrogen or amino;
and T is CO.sub.2H or guanidino.
76. A method according to claim 75 wherein R is cyclopropylmethyl,
R' is C(.dbd.O)(CH.sub.2).sub.2CO.sub.2H,
C(.dbd.O)(CH.sub.2).sub.3CO.sub.2H, C(.dbd.O)CH.dbd.CHCO.sub.2H,
C(.dbd.O)CH.sub.2OCH.sub.2CO.sub.2H,
C(.dbd.O)CH(NH.sub.2)(CH.sub.2).sub.3NHC(=NH)NH.sub.2,
C(.dbd.O)CH(NH.sub.2)CH.sub.2CO.sub.2H or CH.sub.2CO.sub.2H and R"
is NHCH.sub.2CO.sub.2H.
77. A method according to claim 68 wherein said peripheral mu
opioid antagonist compound is a quaternary benzomorphan
compound.
78. A method according to claim 77 wherein said quaternary
benzomorphan compound has the following formula (V): 41where:
R.sup.24 is hydrogen or acyl; and R.sup.25 is alkyl or alkenyl; or
a stereoisomer, prodrug, or pharmaceutically acceptable salt,
hydrate or N-oxide thereof.
79. A method according to claim 78 wherein R.sup.24 is hydrogen or
C.sub.1-C.sub.2 acyl and R.sup.25 is C.sub.1-C.sub.3 alkyl or
C.sub.2-C.sub.3 alkenyl.
80. A method according to claim 79 wherein R.sup.24 is hydrogen or
acetoxy and R.sup.25 is propyl or allyl.
81. A method according to claim 78 wherein the quaternary
benzomorphan compound is selected from the group consisting of
2'-hydroxy-5,9-dimethyl- -2,2-diallyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-prop- yl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromid-
e and
2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromi-
de.
82. A method according to claim 67 wherein said opioid and said
peripheral mu opioid antagonist compound are in a single dosage
unit form.
83. A pharmaceutical composition comprising an effective amount of
an opioid and an effective amount of a compound of the following
formula (I): 42wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is
hydrogen, alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl,
aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4
is hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 43C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 44alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
84. A composition according to claim 83 wherein the compound of
formula (I) is a trans 3,4-isomer.
85. A composition according to claim 83 wherein R' is hydrogen;
R.sup.2 is alkyl; n is 1 or 2; R.sup.3 is benzyl, phenyl,
cyclohexyl, or cyclohexylmethyl; and R.sup.4 is alkyl.
86. A composition according to claim 85 wherein A is OR.sup.5 in
which R.sup.5 is hydrogen or alkyl.
87. A composition according to claim 85 wherein A is
NR.sup.6R.sup.7 in which R.sup.6 is hydrogen and R.sup.7 is
alkylene substituted B wherein B is C(O)W.
88. A composition according to claim 87 wherein R.sup.7 is
(CH.sub.2).sub.q-B in which q is about 1 to about 3; and W is
OR.sup.10 in which R.sup.10 is hydrogen, alkyl, phenyl-substituted
alkyl, cycloalkyl or cycloalkyl-substituted alkyl.
89. A composition according to claim 87 wherein W is
NR.sup.11R.sup.12 in which R.sup.11 is hydrogen or alkyl, and
R.sup.12 is hydrogen, alkyl or alkylene substituted C(.dbd.O)Y.
90. A composition according to claim 89 wherein R.sup.12 is
(CH.sub.2),C(O)Y in which m is 1 to 3 and Y is OR.sup.18 or
NR.sup.19R.sup.20 wherein R.sup.18, R.sup.19 and R.sup.20 are
independently hydrogen or alkyl.
91. A composition according to claim 87 wherein W is OE in which E
is CH.sub.2C(.dbd.O)D wherein D is OR.sup.15 or NR.sup.16R.sup.17
in which R.sup.15 is hydrogen or alkyl, R.sup.16 is methyl or
benzyl and R.sup.17 is hydrogen.
92. A composition according to claim 87 wherein W is OE in which E
is R.sup.13OC(.dbd.O)R.sup.14, wherein R.sup.13 is --CH(CH.sub.3)--
or --CH(CH.sub.2CH.sub.3)-- and R.sup.14 is alkyl.
93. A composition according to claim 83 wherein the configuration
at positions 3 and 4 of the piperidine ring is each R.
94. A composition according to claim 83 wherein said compound is
selected from the group consisting of
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)O- H,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.-
2,Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.3,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.2CH.sub.3-
, G--NH(CH.sub.2).sub.2C(O)NH.sub.2,
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3, G--NHCH.sub.2C(O)NH.sub.2,
G--NHCH.sub.2C(O)NHCH.sub.3, G--NHCH.sub.3C(O)NHCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH- .sub.3,
G--NH(CH.sub.2).sub.3C(O)NHCH.sub.3, G--NH(CH.sub.2).sub.2C(O)OH,
G--NH(CH.sub.2).sub.3C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)- NHCH.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2)-
.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub-
.2C(O)NH.sub.2, Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3,
Z--NHCH.sub.2C(O)OH, Z--NHCH.sub.2C(O)NH.sub.2,
Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.su- b.3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2C(O)OH, Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3,
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3,
Z--NHCH.sub.2C(O)O(CH.sub.2).sub- .4CH.sub.3,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)O--(4-methoxycyclohexyl),
Z--NHCH.sub.2C(O)OCH.sub.2C(O)- NHCH.sub.2(C.sub.6H.sub.5) or
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein: 45
95. A composition according to claim 94 wherein said compound is
selected from the group consisting of
(3R,4R,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.s- ub.3).sub.2,
(+)--Z--NHCH.sub.2C(O)OH, (-)--Z--NHCH.sub.2C(O)OH,
(3R,4R,R)--Z--NHCH.sub.2C(O)--OCH.sub.2CH(CH.sub.3).sub.2,
(3S,4S,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,(3S,4S,R)--Z--NHC-
H.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub- .2(C.sub.6 H.sub.5) or
(3R,4R)-G--NH(CH.sub.2).sub.3C(O)OH.
96. A composition according to claim 95 wherein said compound is
selected from the group consisting of (+)--Z--NHCH.sub.2C(O)OH and
(-)--Z--NHCH.sub.2C(O)OH.
97. A composition according to claim 96 wherein said compound is
(+)--Z--NHCH.sub.2C(O)OH.
98. A composition according to claim 83 wherein said compound is a
substantially pure stereoisomer.
99. A composition according to claim 83 wherein said opioid is
selected from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
100. A composition according to claim 99 wherein said opioid is
selected from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
101. A composition according to claim 83 which is in a single
dosage unit form.
102. A pharmaceutical composition comprising an effective amount of
an opioid, an effective amount of a peripheral mu opioid
antagonist, and a pharmaceutically acceptable carrier.
103. A composition according to claim 102 wherein said peripheral
mu opioid antagonist compound is selected from the group consisting
of a piperidine-N-alkylcarboxylate, a quaternary morphinan, an
opium alkaloid derivative and a quaternary benzomorphan
compound.
104. A composition according to claim 103 wherein said peripheral
mu opioid antagonist compound is a piperidine-N-alkylcarboxylate
compound.
105. A composition according to claim 104 wherein said
piperidine-N-alkylcarboxylate compound has the following formula
(I): 46wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen,
alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4
is hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 47C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 48alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
106. A composition according to claim 103 wherein said peripheral
mu opioid antagonist compound is a quaternary morphinan
compound.
107. A composition according to claim 106 wherein said quaternary
morphinan compound is a quaternary salt of a compound selected from
the group consisting of N-methylnaltrexone, N-methylnaloxone,
N-methylnalorphine, N-diallylnormorphine, N-allyllevallorphan and
N-methylnalmefene.
108. A composition according to claim 103 wherein said peripheral
mu opioid antagonist compound is an opium alkaloid derivative.
109. A composition according to claim 103 wherein said opium
alkaloid derivative has the following formula (III) or (IV):
49wherein: R is alkyl, cycloalkyl-substituted alkyl, aryl,
aryl-substituted alkyl or alkenyl; Z is hydrogen or OH; R' is
X'--J(L)(T), wherein: J is alkylene or alkenylene; L is hydrogen,
amino, or alkyl optionally substituted with CO.sub.2H, OH or
phenyl; and T is CO.sub.211, SO.sub.3H, amino or guanidino; X' is a
direct bond or C(.dbd.O); and R" is NH--J(L)(T) or guanidino; or a
stereoisomer, prodrug, or pharmaceutically acceptable salt, hydrate
or N-oxide thereof.
110. A composition according to claim 109 wherein R is
C.sub.1-C.sub.3alkyl, allyl or cyclopropyhnethyl; Z is OH; J is
C.sub.1-C.sub.5alkylene, C.sub.2-C.sub.6alkylene interrupted by an
oxygen atom, or C.sub.2-C.sub.5alkenylene; L is hydrogen or amino;
and T is CO.sub.2H or guanidino.
111. A composition according to claim 110 wherein R is
cyclopropylmethyl, R' is C(.dbd.O)(CH.sub.2).sub.2CO.sub.2H,
C(.dbd.O)(CH.sub.2).sub.3CO.sub- .2H, C(.dbd.O)CH.dbd.CHCO.sub.2H,
C(.dbd.O)CH.sub.2OCH.sub.2CO.sub.2H,
C(.dbd.O)CH(NH.sub.2)(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2,
C(.dbd.O)CH(NH.sub.2)CH.sub.2CO.sub.2H or CH.sub.2CO.sub.2H and R"
is NHCH.sub.2CO.sub.2H.
112. A composition according to claim 103 wherein said peripheral
mu opioid antagonist compound is a quaternary benzomorphan
compound.
113. A composition according to claim 112 wherein said quatemary
benzomorphan compound has the following formula (V): 50where:
R.sup.24 is hydrogen or acyl; and R.sup.25 is alkyl or alkenyl; or
a stereoisomer, prodrug, or pharmaceutically acceptable salt,
hydrate or N-oxide thereof.
114. A composition according to claim 113 wherein R.sup.24 is
hydrogen or C.sub.1-C.sub.2 acyl and R.sup.25 is C.sub.1-C.sub.3
alkyl or C.sub.2-C.sub.3 alkenyl.
115. A composition according to claim 114 wherein R.sup.24 is
hydrogen or acetoxy and R.sup.25 is propyl or allyl.
116. A composition according to claim 113 wherein the quatemary
benzomorphan compound is selected from the group consisting of
2'-hydroxy-5,9-dimethyl-2,2-diallyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-propyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-
-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-
-n-propyl-2-propargyl-6,7-benzomorphanium-bromide and
2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide.
117. A composition according to claim 102 wherein said opioid is
selected from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
118. A composition according to claim 117 wherein said opioid is
selected from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
119. A composition according to claim 102 which is in a single
dosage unit form.
120. A pharmaceutical kit comprising one or more containers
containing pharmaceutical dosage units comprising an effective
amount of an opioid and an effective amount of a compound of the
following formula (I): 51wherein: R.sup.1 is hydrogen or alkyl;
R.sup.2 is hydrogen, alkyl or alkenyl; R.sup.3 is hydrogen, alkyl,
alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
R.sup.4 is hydrogen, alkyl or alkenyl; A is OR.sup.5 or
NR.sup.6R.sup.7; wherein: R.sup.5 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 52C(.dbd.O)W or NR.sup.8R?; wherein;
R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl, alkenyl,
cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 53alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
121. A kit according to claim 120 wherein the compound of formula
(I) is a trans 3,4-isomer.
122. A kit according to claim 120 wherein R.sup.1 is hydrogen;
R.sup.2 is alkyl; n is 1 or 2; R.sup.3 is benzyl, phenyl,
cyclohexyl, or cyclohexylmethyl; and R.sup.4 is alkyl.
123. A kit according to claim 122 wherein A is OR.sup.5 in which
R.sup.5 is hydrogen or alkyl.
124. A kit according to claim 122 wherein A is NR.sup.6R.sup.7 in
which R.sup.6 is hydrogen and R.sup.7 is alkylene substituted B
wherein B is C(O)W.
125. A kit according to claim 124 wherein R.sup.7 is
(CH.sub.2).sub.q-B in which q is about 1 to about 3; and W is
OR.sup.10 in which R.sup.10 is hydrogen, alkyl, phenyl-substituted
alkyl, cycloalkyl or cycloalkyl-substituted alkyl.
126. A kit according to claim 124 wherein W is NR.sup.11R.sup.12 in
which R.sup.11 is hydrogen or alkyl, and R.sup.12 is hydrogen,
alkyl or alkylene substituted C(.dbd.O)Y.
127. A kit according to claim 126 wherein R.sup.12 is
(CH.sub.2).sub.mC(O)Y in which m is 1 to 3 and Y is OR.sup.18 or
NR.sup.19R.sup.20 wherein R.sup.18, R.sup.19 and R.sup.20 are
independently hydrogen or alkyl.
128. A kit according to claim 124 wherein W is OE in which E is
CH.sub.2C(.dbd.O)D wherein D is OR.sup.15 or NR.sup.16R.sup.17 in
which R.sup.15 is hydrogen or alkyl, R.sup.16 is methyl or benzyl
and R.sup.17 is hydrogen.
129. A kit according to claim 124 wherein W is OE in which E is
R.sup.13OC(.dbd.O)R.sup.14, wherein R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)-- and R.sup.14 is alkyl.
130. A kit according to claim 120 wherein the configuration at
positions 3 and 4 of the piperidine ring is each R.
131. A kit according to claim 120 wherein said compound is selected
from the group consisting of
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.2,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.3,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.2CH.sub.3-
, G--NH(CH.sub.2).sub.2C(O)NH.sub.2,
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3, G--NHCH.sub.2C(O)NH.sub.2,
G--NHCH.sub.2C(O)NHCH.sub.3, G--NHCH.sub.3C(O)NHCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH- .sub.3,
G--NH(CH.sub.2).sub.3C(O)NHCH.sub.3, G--NH(CH.sub.2).sub.2C(O)OH,
G--NH(CH.sub.2).sub.3C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)- NHCH.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2)-
.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub-
.2C(O)NH.sub.2, Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3,
Z--NHCH.sub.2C(O)OH, Z--NHCH.sub.2C(O)NH.sub.2,
Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.su- b.3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2C(O)OH, Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3,
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3,
Z--NHCH.sub.2C(O)O(CH.sub.2).sub- .4CH.sub.3,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)O--(4-methoxycyclohexyl),
Z--NHCH.sub.2C(O)OCH.sub.2C(O)- NHCH.sub.2(C.sub.6H.sub.5) or
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein: 54
132. A kit according to claim 133 wherein said compound is selected
from the group consisting of 3R, 4R,
S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3- ) .sub.2,
(+)--Z--NHCH.sub.2C(O)OH, (-)--Z--NHCH.sub.2C(O)OH, (3R, 4R,
R)--Z--NHCH.sub.2C(O)--OCH.sub.2CH(CH.sub.3).sub.2,
(3S,4S,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3) .sub.2,
(3S,4S,R)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub.2(C.sub.6H.sub.5) or
(3R,4R)-G--NH(CH.sub.2).sub.3C(O)OH.
133. A kit according to claim 132 wherin said compopund is selected
from the group consisting of (+)--Z--NHCH.sub.2C(O)OH and
(-)--Z--NHCH.sub.2C(O)OH.
134. A kit according to claim 133 wherein said compound is
(+)--Z--NHCH.sub.2C(O)OH.
135. A kit according to claim 120 wherein said compound is a
substantially pure stereoisomer.
136. A kit according to claim 120 wherein said opioid is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
137. A kit according to claim 136 wherein said opioid is selected
from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
138. A kit according to claim 120 further comprising conventional
pharmaceutical kit components.
139. A pharmaceutical kit comprising one or more containers
containing pharmaceutical dosage units comprising an effective
amount of an opioid and an effective amount of a peripheral mu
opioid antagonist.
140. A kit according to claim 139 wherein said peripheral mu opioid
antagonist compound is selected from the group consisting of a
piperidine-N-alkylcarboxylate, a quaternary morphinan, an opium
alkaloid derivative and a quaternary benzomorphan compound.
141. A kit according to claim 140 wherein said peripheral mu opioid
antagonist compound is a piperidine-N-alkylcarboxylate
compound.
142. A kit according to claim 141 wherein said
piperidine-N-alkylcarboxyla- te compound has the following formula
(I): 55wherein: R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen,
alkyl or alkenyl; R.sup.3 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R.sup.4is
hydrogen, alkyl or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7;
wherein: R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.6
is hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring; B is 56C(.dbd.O)W or NR.sup.8R.sup.9;
wherein; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached, R.sup.8
and R.sup.9 form a heterocyclic ring; W is OR.sup.10,
NR.sup.11R.sup.12, or OE; wherein R.sup.10 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.11
is hydrogen or alkyl; R.sup.12 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic ring;
E is 57alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(--O)R.sup.14; wherein R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
wherein: R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.16
is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alk-yl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl; R.sup.17 is hydrogen or alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.16 and R.sup.17 form a heterocyclic ring; Y is OR.sup.18 or
NR.sup.19R.sup.20; wherein: R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R.sup.19
is hydrogen or alkyl; R.sup.20 is hydrogen, alkyl, alkenyl, aryl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring; R.sup.21 is
hydrogen or alkyl; and n is 0 to 4; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
143. A kit according to claim 140 wherein said peripheral mu opioid
antagonist compound is a quaternary morphinan compound.
144. A kit according to claim 143 wherein said quaternary morphinan
compound is a quaternary salt of a compound selected from the group
consisting of N-methylnaltrexone, N-methylnaloxone,
N-methylnalorphine, N-diallylnormorphine, N-allyllevallorphan and
N-methylnalmefene.
145. A kit according to claim 140 wherein said peripheral mu opioid
antagonist compound is an opium alkaloid derivative.
146. A kit according to claim 145 wherein said opium alkaloid
derivative has the following formula (III) or (IV): 58wherein: R is
alkyl, cycloalkyl-substituted alkyl, aryl, aryl-substituted alkyl
or alkenyl; Z is hydrogen or OH; R' is X'--J(L)(T), wherein: J is
alkylene or alkenylene; L is hydrogen, amino, or alkyl optionally
substituted with CO.sub.2H, OH or phenyl; and T is CO.sub.2H,
SO.sub.3H, amino or guanidino; X' is a direct bond or C(.dbd.O);
and R" is NH--J(L)(T) or guanidino; or a stereoisomer, prodrug, or
pharmaceutically acceptable salt, hydrate or N-oxide thereof.
147. A kit according to claim 146 wherein R is
C.sub.1-C.sub.3alkyl, allyl or cyclopropylmethyl; Z is OH; J is
C.sub.1-C.sub.5alkylene, C.sub.2-C.sub.6alkylene interrupted by an
oxygen atom, or C.sub.2-C.sub.5alkenylene; L is hydrogen or amino;
and T is CO.sub.2H or guanidino.
148. A kit according to claim 147 wherein R is cyclopropylmethyl,
R' is C(.dbd.O)(CH.sub.2).sub.2CO.sub.2H,
C(.dbd.O)(CH.sub.2).sub.3CO.sub.2H, C(.dbd.O)CH.dbd.CHC.sub.2H,
C(.dbd.O)CH.sub.2OCH.sub.2CO.sub.2H,
C(.dbd.O)CH(NH.sub.2)(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2,
C(.dbd.O)CH(NH.sub.2)CH.sub.2CO.sub.2H or CH.sub.2CO.sub.2H and R"
is NHCH.sub.2CO.sub.2H.
149. A kit according to claim 140 wherein said peripheral mu opioid
antagonist compound is a quaternary benzomorphan compound.
150. A kit according to claim 149 wherein said quaternary
benzomorphan compound has the following formula (V): 59where:
R.sup.24 is hydrogen or acyl; and R.sup.25 is alkyl or alkenyl; or
a stereoisomer, prodrug, or pharmaceutically acceptable salt,
hydrate or N-oxide thereof.
151. A kit according to claim 150 wherein R.sup.24 is hydrogen or
C.sub.1-C.sub.2 acyl and R.sup.25 is C.sub.1-C.sub.3 alkyl or
C.sub.2-C.sub.3 alkenyl.
152. A kit according to claim 151 wherein R.sup.24 is hydrogen or
acetoxy and R.sup.25 is propyl or allyl.
153. A kit according to claim 150 wherein the quaternary
benzomorphan compound is selected from the group consisting of
2'-hydroxy-5,9-dimethyl- -2,2-diallyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-prop- yl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide,
2'-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromid-
e and
2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromi-
de.
154. A kit according to claim 139 wherein said opioid is selected
from the group consisting of alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,
hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),
methadone, morphine, nalbuphine, oxycodone, oxymorphone,
pentazocine, propiram, propoxyphene, sufentanil and tramadol.
155. A kit according to claim 154 wherein said opioid is selected
from the group consisting of morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl and
tramadol.
156. A kit according to claim 139 further comprising conventional
pharmaceutical kit components.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel methods and
compositions comprising opioids and opioid antagonists. More
particularly, the present invention relates to novel methods and
compositions comprising opioids and peripheral mu opioid antagonist
compounds.
BACKGROUND OF THE INVENTION
[0002] It is well known that opioid drugs target three types of
endogenous opioid receptors (i.e., mu, delta and kappa receptors)
in biological systems. Most opioids, 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. A number of side effects of opioid drugs may
be caused by activation of these peripheral receptors.
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. It has been reported that acute
nausea or vomiting may occur in up to about 33% of patients who
receive oral narcotic analgesics and in up to about 80% of patients
who receive injectable narcotics following surgery or trauma. This
is due, at least in part, to direct effects of narcotics on the
gastrointestinal (GI) tract.
[0003] Opioid-induced side effects, such as nausea, vomiting, and
inhibited gastrointestinal propulsive activity remain serious
problems for patients being administered opioid analgesics for both
short term and long term pain management. Opioid antagonist
compounds that do not readily cross the blood-brain barrier
(peripherally acting drugs) have been tested for use in curbing
opioid-induced side effects. For instance, the peripheral mu opioid
antagonist compound methylnaltrexone and related compounds have
been suggested for use in curbing opioid-induced side effects in
patients. U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and
4,719,215 disclose the use of methylnaltrexone and related
compounds in controlling opioid-induced pruritus, nausea, and/or
vomiting. Additionally, methylnaltrexone has been shown to
effectively reduce the incidence of opioid-induced nausea and
pruritus as disclosed by Yuan, C. -S. et al. Drug and Alcohol
Dependence 1998, 52, 161. Similarly, U.S. Pat. Nos. 5,250,542,
5,434,171, 5,159,081, and 5,270,328, disclose peripherally
selective piperidine-N-alkylcarboxylate opioid antagonists as being
useful for the treatment of the opioid side effects constipation,
nausea or vomiting, as well as irritable bowel syndrome and
idiopathic constipation.
[0004] It is frequently the case that drugs have undesirable side
effects, and patients taking such drugs are often prescribed
additional drugs for countering these side effects. Thus, patients
may be required to take multiple doses of different drugs, causing
inconvenience and possible administration of incorrect doses. It
may therefore be desirable for multiple drugs to be combined as one
dose in a fixed ratio for ease of administration. Given that
nausea, vomiting, and inhibited gastrointestinal propulsive
activity are common side effects of opioid analgesics that
contribute to the discomfort of a patient receiving such therapy, a
need for a specific and effective side effect-relieving remedy is
present. As it is not readily evident to combine two or more drugs
for simultaneous administration, due to the complex nature of drug
interactions which are often undesirable and even fatal to the
patient, it is desirable to identify drug formulations that contain
compounds when taken simultaneously in pre-measured, fixed-dose
forms, resulting in safe alternative means for administering
multiple drugs. In the present invention, it has been found that
opioid analgesics, with their common undesirable side effects, are
optimal candidates for such formulations in combination with
peripheral mu opioid antagonist compounds. The methods and
formulations of the present invention are directed toward these, as
well as other, important ends.
SUMMARY OF THE INVENTION
[0005] Accordingly, the present invention is directed, in part, to
novel methods and compositions for treating and/or preventing side
effects that may be associated, for example, with the
administration of opioids. Specifically, in one embodiment, there
are provided methods of preventing or treating a side effect
associated with an opioid comprising administering to a patient, in
combination with an effective amount of an opioid, an effective
amount of a compound of the following formula (I): 1
[0006] wherein
[0007] R.sup.1 is hydrogen, alkyl or alkenyl;
[0008] R.sup.2 is hydrogen, alkyl or alkenyl;
[0009] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
[0010] R.sup.4 is hydrogen, alkyl or alkenyl;
[0011] A is OR.sup.5 or NR.sup.6R.sup.7; wherein:
[0012] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or ar yl-substituted alkyl;
[0013] R.sup.2 is hydrogen or alkyl;
[0014] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring;
[0015] B is 2
[0016] C(.dbd.O)W or NR.sup.8R.sup.9; wherein;
[0017] R.sup.8 is hydrogen or alkyl;
[0018] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl or aryl-substituted alkyl or, together with the nitrogen atom
to which they are attached, R.sup.8 and R.sup.9 form a heterocyclic
ring;
[0019] W is OR.sup.10, NR.sup.11R.sup.12, or OE; wherein
[0020] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0021] R.sup.11 is hydrogen or alkyl;
[0022] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic
ring;
[0023] E is 3
[0024] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0025] wherein
[0026] R.sup.13 is alkyl substituted alkylene;
[0027] R.sup.14 is alkyl;
[0028] D is OR.sup.15 or NR.sup.16R.sup.17;
[0029] wherein:
[0030] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0031] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl;
[0032] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached, R.sup.16 and R.sup.17 form a
heterocyclic ring;
[0033] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0034] wherein:
[0035] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0036] R.sup.19 is hydrogen or alkyl;
[0037] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring;
[0038] R.sup.21 is hydrogen or alkyl; and
[0039] n is 0 to 4;
[0040] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof.
[0041] Another embodiment of the invention relates to methods of
preventing or treating a side effect associated with an opioid
comprising administering to a patient an effective amount of an
opioid in combination with an effective amount of a peripheral mu
opioid antagonist compound.
[0042] Still another embodiment of the invention relates to methods
of treating or preventing pain comprising administering to a
patient an effective amount of an opioid, in combination with an
effective amount of a compound of the following formula (I): 4
[0043] wherein:
[0044] R.sup.1 is hydrogen or alkyl;
[0045] R.sup.2 is hydrogen, alkyl or alkenyl;
[0046] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
[0047] R.sup.4 is hydrogen, alkyl or alkenyl;
[0048] A is OR.sup.5 or NR.sup.6R.sup.7; wherein:
[0049] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0050] R.sup.6 is hydrogen or alkyl;
[0051] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring;
[0052] B is 5
[0053] C(.dbd.O)W or NR.sup.8R.sup.9; wherein;
[0054] R.sup.8 is hydrogen or alkyl;
[0055] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl or aryl-substituted alkyl or, together with the nitrogen atom
to which they are attached, R.sup.8 and R.sup.9 form a heterocyclic
ring;
[0056] W is OR.sup.10, NR.sup.11R.sup.12, or OE; wherein
[0057] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0058] R.sup.11 is hydrogen or alkyl;
[0059] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted aLkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic
ring;
[0060] E is 6
[0061] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(--O)R.sup.14;
[0062] wherein
[0063] R.sup.13 is alkyl substituted alkylene;
[0064] R.sup.14 is alkyl;
[0065] D is OR.sup.15 or NR.sup.16R.sup.17;
[0066] wherein:
[0067] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0068] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl;
[0069] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached, R.sup.16 and R.sup.17 form a
heterocyclic ring;
[0070] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0071] wherein:
[0072] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0073] R.sup.19 is hydrogen or alkyl;
[0074] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring;
[0075] R.sup.21 is hydrogen or alkyl; and
[0076] n is 0 to 4;
[0077] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof.
[0078] Yet another embodiment of the invention relates to methods
of treating or preventing pain comprising administering to a
patient an effective amount of an opioid in combination with an
effective amount of a peripheral mu opioid antagonist compound.
[0079] In another embodiment of the invention, there are provided
pharmaceutical compositions comprising an effective amount of an
opioid and an effective amount of a compound of the following
formula (I): 7
[0080] wherein:
[0081] R.sup.1 is hydrogen or alkyl;
[0082] R.sup.2 is hydrogen, alkyl or alkenyl;
[0083] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
[0084] R.sup.4 is hydrogen, alkyl or alkenyl;
[0085] A is OR.sup.5 or NR.sup.6R.sup.7; wherein:
[0086] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0087] R.sup.6 is hydrogen or alkyl;
[0088] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring;
[0089] B is 8
[0090] C(.dbd.O)W or NR.sup.8R.sup.9; wherein;
[0091] R.sup.8 is hydrogen or alkyl;
[0092] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl or aryl-substituted alkyl or, together with the nitrogen atom
to which they are attached, R.sup.8 and R.sup.9 form a heterocyclic
ring;
[0093] W is OR.sup.10, NR.sup.11R.sup.12, or OE; wherein
[0094] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0095] R.sup.11 is hydrogen or alkyl;
[0096] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic
ring;
[0097] E is 9
[0098] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0099] wherein
[0100] R.sup.13 is alkyl substituted alkylene;
[0101] R.sup.14 is alkyl;
[0102] D is OR.sup.15 or NR.sup.16R.sup.17;
[0103] wherein:
[0104] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0105] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituled alkyl;
[0106] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached, R.sup.16 and R.sup.17 form a
heterocyclic ring;
[0107] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0108] wherein:
[0109] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0110] R.sup.19 is hydrogen or alkyl;
[0111] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring;
[0112] R.sup.21 is hydrogen or alkyl; and
[0113] n is 0 to 4;
[0114] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof.
[0115] Still another embodiment of the invention relates to
pharmaceutical compositions comprising an effective amount of an
opioid, an effective amount of a peripheral mu opioid antagonist,
and a pharmaceutically acceptable carrier.
[0116] Yet another embodiment of the invention relates to
pharmaceutical kits comprising one or more containers containing
pharmaceutical dosage units comprising an effective amount of an
opioid and an effective amount of a compound of the following
formula (I): 10
[0117] wherein:
[0118] R.sup.1 is hydrogen or alkyl;
[0119] R.sup.2 is hydrogen, alkyl or alkenyl;
[0120] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
[0121] R.sup.4 is hydrogen, alkyl or alkenyl;
[0122] A is OR.sup.5 or NR.sup.6R.sup.7; wherein:
[0123] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0124] R.sup.6 is hydrogen or alkyl;
[0125] R.sup.7is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring;
[0126] B is 11
[0127] C(.dbd.O)W or NR.sup.8R.sup.9; wherein;
[0128] R.sup.8 is hydrogen or alkyl;
[0129] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl or aryl-substituted alkyl or, together with the nitrogen atom
to which they are attached, R.sup.8 and R.sup.9 form a heterocyclic
ring;
[0130] W is OR.sup.10, NR.sup.11R.sup.12, or OE; wherein
[0131] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0132] R.sup.11 is hydrogen or alkyl;
[0133] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic
ring;
[0134] E is 12
[0135] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0136] wherein
[0137] R.sup.13 is alkyl substituted alkylene;
[0138] R.sup.14 is alkyl;
[0139] D is OR.sup.15 or NR.sup.16R.sup.17;
[0140] wherein:
[0141] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0142] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted
alkyl, cycloalkyl, cycloalkenyt, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl;
[0143] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached, R.sup.16 and R.sup.17 form a
heterocyclic ring;
[0144] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0145] wherein:
[0146] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0147] R.sup.19 is hydrogen or alkyl;
[0148] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring;
[0149] R.sup.21 is hydrogen or alkyl; and
[0150] n is 0 to 4;
[0151] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof.
[0152] Still another embodiment of the invention relates to
pharmaceutical kits comprising one or more containers containing
pharmaceutical dosage units comprising an effective amount of an
opioid and an effective amount of a peripheral mu opioid
antagonist.
[0153] These and other aspects of the invention will become more
apparent from the following detailed description.
BRIEF DESCRIPTION OF THE DRAWING
[0154] FIG. 1 is a graphical representation of studies on the
inhibition of the slowing of gut motility employing compositions
and methods according to an embodiment of the present
invention.
[0155] FIGS. 2A and 2B are graphical representations of studies on
the inhibition of nausea and vomiting employing methods according
to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0156] As employed above and throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0157] "Alkyl" refers to an aliphatic hydrocarbon group which may
be straight, branched or cyclic having from 1 to about 10 carbon
atoms in the chain, and all combinations and subcombinations of
ranges therein. "Branched" refers to an alkyl group in which a
lower alkyl group, such as methyl, ethyl or propyl, is attached to
a linear alkyl chain. In certain preferred embodiments, the alkyl
group is a C.sub.1-C.sub.5 alkyl group, i.e., a branched or linear
alkyl group having from 1 to about 5 carbons. In other preferred
embodiments, the alkyl group is a C.sub.1-C.sub.3 alkyl group,
i.e., a branched or linear alkyl group having from 1 to about 3
carbons. Exemplary alkyl groups include methyl, ethyl, n-propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, nonyl and decyl. "Lower alkyl" refers to an alkyl
group having 1 to about 6 carbon atoms. Preferred alkyl groups
include the lower alkyl groups of 1 to about 3 carbons.
[0158] "Alkenyl" refers to an alkyl group containing at least one
carbon-carbon double bond and having from 2 to about 10 carbon
atoms in the chain, and all combinations and subcombinations of
ranges therein. In certain preferred embodiments, the alkenyl group
is a C.sub.2-C.sub.10 alkyl group, i.e., a branched or linear
alkenyl group having from 2 to about 10 carbons. In other preferred
embodiments, the alkenyl group is a C.sub.2-C.sub.6 alkenyl group,
i.e., a branched or linear alkenyl group having from 2 to about 6
carbons. In still other preferred embodiments, the alkenyl group is
a C.sub.3-C.sub.10 alkenyl group, i.e., a branched or linear
alkenyl group having from about 3 to about 10 carbons. In yet other
preferred embodiments, the alkenyl group is a C.sub.2-C.sub.5
alkenyl group, i.e., a branched or linear alkenyl group having from
2 to about 5 carbons. -Exemplary alkenyl groups include, for
example, vinyl, propenyl, butenyl, pentenyl hexenyl, heptenyl,
octenyl, nonenyl and decenyl groups.
[0159] "Alkylene" refers to a straight or branched bivalent
aliphatic hydrocarbon group having from 1 to about 6 carbon atoms,
and all combinations and subcombinations of ranges therein. The
alkylene group may be straight, branched or cyclic. Exemplary
alkylene groups include, for example, methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--) and propylene
(--(CH.sub.2).sub.3--). There may be optionally inserted along the
alkylene group one or more oxygen, sulphur or optionally
substituted nitrogen atoms, wherein the nitrogen substituent is
alkyl as described previously. Preferred alkylene groups have from
about 1 to about 4 carbons.
[0160] "Alkenylene" refers to an alkylene group containing at least
one carbon-carbon double bond. Exemplary alkenylene groups include,
for example, ethenylene (--CH.dbd.CH--) and propenylene
(--CH.dbd.CHCH.sub.2--). Preferred alkenylene groups have from 2 to
about 4 carbons.
[0161] "Cycloalkyl" refers to any stable monocyclic or bicyclic
ring having from about 3 to about 10 carbons, and all combinations
and subcombinations of ranges therein. In preferred embodiments,
the cycloalkyl group is a C.sub.3-C.sub.8 cycloalkyl group, i.e., a
cycloalkyl group having from about 3 to about 8 carbons, with
C.sub.3-C.sub.6 cycloalkyl groups, i.e., cycloalkyl groups having
from about 3 to about 6 carbons being more preferred. The
cycloalkyl group may be optionally substituted with one or more
cycloalkyl group substituents. Preferred cycloalkyl group
substituents include alkyl, preferably C.sub.1-C.sub.3 alkyl,
alkoxy, preferably C.sub.1-C.sub.3 alkoxy, or halo. Exemplary
cycloalkyl groups include, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
[0162] "Cycloalkyl-substituted alkyl" refers to a linear alkyl
group, preferably a lower alkyl group, substituted at a terminal
carbon with a cycloalkyl group, preferably a C.sub.3-C.sub.8
cycloalkyl group. Typical cycloalkyl-substituted alkyl groups
include cyclohexylmethyl, cyclohexylethyl, cyclopentylethyl,
cyclopentylpropyl, cyclopropylmethyl and the like.
[0163] "Cycloalkenyl" refers to an olefinically unsaturated
cycloalkyl group having from about 4 to about 10 carbons, and all
combinations and subcombinations of ranges therein. In preferred
embodiments, the cycloalkenyl group is a C.sub.5-C.sub.8
cycloalkenyl group, i.e., a cycloalkenyl group having from about 5
to about 8 carbons.
[0164] "Alkoxy" refers to an alkyl-O-- group where alkyl is as
previously described. Exemplary alkoxy groups include, for example,
methoxy, ethoxy, propoxy, butoxy and heptoxy.
[0165] "Alkoxy-alkyl" refers to an alkyl-O-alkyl group where alkyl
is as previously described.
[0166] "Acyl" means an alkyl-CO-- group wherein alkyl is as
previously described. Preferred acyl groups comprise lower alkyl
groups, such as alkyl of about 1 to about 3 carbons. Exemplary acyl
groups include acetyl, propanoyl, 2-methylpropanoyl, butanoyl and
palmitoyl.
[0167] "Aryl" refers to an aromatic carbocyclic radical containing
from about 6 to about 10 carbons, and all combinations and
subcombinations of ranges therein. The phenyl group may be
optionally substituted with one or two or more aryl group
substituents. Preferred aryl group substituents include alkyl
groups, preferably C.sub.1-C.sub.2 alkyl groups. Exemplary aryl
groups include phenyl and naphthyl.
[0168] "Aryl-substituted alkyl" refers to an linear alkyl group,
preferably a lower alkyl group, substituted at a terminal carbon
with an optionally substituted aryl group, preferably an optionally
substituted phenyl ring. Exemplary aryl-substituted alkyl groups
include, for example, phenylmethyl, phenylethyl and
3-(4-methylphenyl)propyl.
[0169] "Heterocyclic" refers to a monocyclic or multicylic ring
system carbocyclic radical containing from about 4 to about 10
members, and all combinations and subcombinations of ranges
therein, wherein one or more of the members is an element other
than carbon, for example, nitrogen, oxygen or sulfur. The
heterocyclic group may be aromatic or nonaromatic. Exemplary
heterocyclic groups include, for example, pyrrole and piperidine
groups.
[0170] "Halo" refers to fluoro, chloro or bromo.
[0171] "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 benefitted by its administration. In the
case, for example, of opioids, the term "side effect" may
preferably refer to such conditions as, for example, constipation,
nausea and/or vomiting.
[0172] "Effective amount" refers to an amount of a compound as
described herein that may be therapeutically effective to inhibit,
prevent or treat the symptoms of particular disease, disorder or
side effect. Such diseases, disorders and side effects include, but
are not limited to, those pathological conditions associated with
the administration of opioids (for example, in connection with the
treatment and/or prevention of pain), wherein the treatment or
prevention comprises, for example, inhibiting the activity thereof
by contacting cells, tissues or receptors with compounds of the
present invention. Thus, for example, the term "effective amount",
when used in connection with opioids, for example, for the
treatment of pain, refers to the treatment and/or prevention of the
painful condition. The term "effective amount", when used in
connection with peripheral mu opioid antagonist compounds, refers
to the treatment and/or prevention of side effects typically
associated with opioids including, for example, such side effects
as constipation, nausea and/or vomiting.
[0173] "In combination with", "combination therapy" and
"combination products" refer, in certain embodiments, to the
concurrent administration to a patient of opioids and peripheral mu
opioid antagonists, including, for example, the compounds of
formula (I). When administered in combination, each component may
be administered at the same time or sequentially in any order at
different points in time. Thus, each component may be administered
separately but sufficiently closely in time so as to provide the
desired therapeutic effect.
[0174] "Dosage unit" refers to physically discrete units suited as
unitary dosages for the particular individual to be treated. Each
unit may contain a predetermined quantity of active compound(s)
calculated to produce the desired therapeutic effect(s) in
association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention may be
dictated by (a) the unique characteristics of the active
compound(s) and the particular therapeutic effect(s) to be
achieved, and (b) the limitations inherent in the art of
compounding such active compound(s).
[0175] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0176] "Pharmaceutically acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and the like.
[0177] Certain acidic or basic compounds of the present invention
may exist as zwitterions. All forms of the compounds, including
free acid, free base and zwitterions, are contemplated to be within
the scope of the present invention.
[0178] "Patient" refers to animals, including mammals, preferably
humans.
[0179] The present invention is directed to methods and
pharmaceutical compositions involving opioid compounds. As
discussed above, such opioid compounds may be useful, for example,
in the treatment and/or prevention of pain. However, as also
discussed above, undesirable side effects including, for example,
constipation, nausea and vomiting, as well as other side effects,
may frequently occur in patients receiving opioid compounds. By
virtue of the methods and compositions of the present invention,
effective and desirable inhibition of undesirable side effects that
may be associated with opioid compounds may be advantageously
achieved. Accordingly, combination methods and compositions, where
opioids are combined or co-administered with suitable peripheral mu
opioid antagonist compounds, may afford an efficacy advantage over
the compounds and agents alone.
[0180] In this connection, as discussed above, patients are often
administered opioids for the treatment, for example, of painful
conditions. However, as noted above, undesirable side effects such
as, for example, constipation, nausea and/or vomiting, may result
from opioid administration. These undesirable side effects may act
as a limiting factor in connection with the amount of opioid that
may be administered to the patient. That is, the amount of opioid
capable of being administered to the patient may be limited due to
the undesired occurrence of the aforementioned side effects. The
limited amounts of opioid that may be administered to a patient
may, in turn, result in a disadvantageously diminished degree of
pain alleviation. The present combination methods and compositions
may be used to advantageously increase the amount of opioid
administered to a patient, thereby obtaining enhanced pain
alleviation, while reducing, minimizing and/or avoiding undesirable
side effects that may be associated with the opioid. The peripheral
mu opioid antagonists employed in the methods and compositions of
the present invention preferably have substantially no central
nervous system activity and, accordingly, desirably do not affect
the pain killing efficacy of the opioid.
[0181] While not intending to be bound by any theory or theories of
operation, it is contemplated that opioid side effects, such as
constipation, vomiting and nausea, may result from undesirable
interaction of the opioid with peripheral mu receptors.
Administration of a mu opioid antagonist according to the methods
of the present invention may block interaction of the opioid
compounds with the mu receptors, thereby preventing and/or
inhibiting the side effects.
[0182] In accordance with the present invention, there are provided
methods which comprise administering to a patient, inter alia, an
opioid compound. A wide variety of opioids are available which may
be suitable for use in the present methods and compositions.
Generally speaking, it is only necessary that the opioid provide
the desired effect (for example, pain alleviation), and be capable
of being incorporated into the present combination products and
methods (discussed in detail below). In preferred embodiments, the
present methods and compositions may involve an opioid which is
selected from alfentanil, buprenorphine, butorphanol, codeine,
dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine (pethidine), methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, propiram,
propoxyphene, sufentanil and/or tramadol. More preferably, the
opioid is selected from morphine, codeine, oxycodone, hydrocodone,
dihydrocodeine, propoxyphene, fentanyl and/or tramadol.
[0183] The opioid component of the present compositions may further
include 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 disclosures of which are hereby
incorporated herein by reference, in their entirety.
[0184] In addition, the opioid component may further include 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.
[0185] Other opioids, optional conventional opioid components, and
optional compounds for enhancing the analgesic potency of the
opioid and/or for reducing analgesic tolerance development, that
may be employed in the methods and compositions of the present
invention, in addition to those exemplified above, would be readily
apparent to one of ordinary skill in the art, once armed with the
teachings of the present disclosure.
[0186] In preferred form, the methods of the present invention may
further involve administering to a patient a compound which is a mu
peripheral opioid antagonist compound.
[0187] The term peripheral designates that the compound acts
primarily on physiological systems and components external to the
central nervous system, i.e., the compound preferably does not
readily cross the blood-brain barrier. In preferred form, the
peripheral mu opioid antagonist compounds employed in the methods
of the present invention exhibit high levels of activity with
respect to gastrointestinal tissue, while exhibiting reduced, and
preferably substantially no, central nervous system (CNS) activity.
The term "substantially no CNS activity", as used herein, means
that less than about 20% of the pharmacological activity of the
peripheral mu opioid antagonist compounds employed in the present
methods is exhibited in the CNS. In preferred embodiments, the
peripheral mu opioid antagonist compounds employed in the present
methods exhibit less than about 15% of their pharmacological
activity in the CNS, with less than about 10% being more preferred.
In even more preferred embodiments, the peripheral mu opioid
antagonist compounds employed in the present methods exhibit less
than about 5% of their pharmacological activity in the CNS, with
about 0% (i.e., no CNS activity) being still more preferred.
[0188] In more preferred embodiments, the present methods involve
the administration to a patient of a mu peripheral opioid
antagonist compound that is a piperidine-N-alkylcarboxylate
compound. Preferred piperidine-N-alkylcarboxylate opioid antagonist
compounds include, for example, the compounds disclosed in U.S.
Pat. Nos. 5,250,542; 5,159,081; 5,270,328; and 5,434,171, the
disclosures of which are hereby incorporated herein by reference,
in their entireties. A particularly preferred class of
piperidine-N-alkylcarboxylate opioid antagonist compounds include
those having the following formula (I): 13
[0189] wherein:
[0190] R.sup.1 is hydrogen or alkyl;
[0191] R.sup.2 is hydrogen, alkyl or alkenyl;
[0192] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl or aryl-substituted alkyl;
[0193] R.sup.4 is hydrogen, alkyl or alkenyl;
[0194] A is OR.sup.5 or NR.sup.6R.sup.7; wherein:
[0195] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0196] R.sup.6 is hydrogen or alkyl;
[0197] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl,
aryl-substituted alkyl, or alkylene substitued B or, together with
the nitrogen atom to which they are attached, R.sup.6 and R.sup.7
form a heterocyclic ring;
[0198] B is 14
[0199] C(.dbd.O)W or NR.sup.8R.sup.9; wherein;
[0200] R.sup.8 is hydrogen or alkyl;
[0201] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl or aryl-substituted alkyl or, together with the nitrogen atom
to which they are attached, R.sup.8 and R.sup.9 form a heterocyclic
ring;
[0202] W is OR.sup.10, NR.sup.11R.sup.12, or OE; wherein
[0203] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0204] R.sup.11 is hydrogen or alkyl;
[0205] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aryl-substituted alkyl or alkylene
substituted C(.dbd.O)Y or, together with the nitrogen atom to which
they are attached, R.sup.11 and R.sup.12 form a heterocyclic
ring;
[0206] E is 15
[0207] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0208] wherein
[0209] R.sup.13 is alkyl substituted alkylene;
[0210] R.sup.14 is alkyl;
[0211] D is OR.sup.15 or NR.sup.16R.sup.17;
[0212] wherein:
[0213] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0214] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl;
[0215] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached, R.sup.16 and R.sup.17 form a
heterocyclic ring;
[0216] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0217] wherein:
[0218] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl;
[0219] R.sup.19 is hydrogen or alkyl;
[0220] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or,
together with the nitrogen atom to which they are attached,
R.sup.19 and R.sup.20 form a heterocyclic ring;
[0221] R.sup.2l is hydrogen or alkyl; and
[0222] n is 0 to about 4;
[0223] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof
[0224] In the above formula (I), R.sup.1 is hydrogen or alkyl. In
preferred embodiments, R.sup.1 is hydrogen or C.sub.1-C.sub.5alkyl.
In even more preferred embodiments, R.sup.1 is hydrogen.
[0225] In the above formula (I), R.sup.2 is hydrogen, alkyl or
alkenyl. In preferred embodiments, R.sup.2 is hydrogen,
C.sub.1-C.sub.5alkyl or C.sub.2-C.sub.6alkenyl. Also in preferred
embodiments, R.sup.2 is alkyl, with C.sub.1-C.sub.3alkyl being more
preferred.
[0226] In the above formula (I), R.sup.3 is hydrogen, alkyl,
alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl. In
preferred embodiments, R.sup.3 is hydrogen, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.10alkenyl, phenyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkyl-su- bstituted
C.sub.1-C.sub.3alkyl or phenyl-substituted C.sub.1-C.sub.3 alkyl.
In more preferred embodiments, R.sup.3 is benzyl, phenyl,
cyclohexyl, or cyclohexylmethyl.
[0227] In the above formula (I), R.sup.4 is hydrogen, alkyl or
alkenyl. In preferred embodiments, R.sup.4 is hydrogen,
C.sub.1-C.sub.5alkyl or C.sub.2-C.sub.6alkenyl. In more preferred
embodiments, R.sup.4 is C.sub.1-C.sub.3alkyl, with methyl being
even more preferred.
[0228] In the above formula (I), A is OR.sup.5 or
NR.sup.6R.sup.7.
[0229] In the above formula (I), R.sup.5 is hydrogen, alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aryl-substituted alkyl. In
preferred embodiments, R.sup.5 is hydrogen, C.sub.1-C.sub.10alkyl,
C.sub.2-C.sub.10alkenyl, cycloalkyl, C.sub.5-C.sub.8cycloalkenyl,
cycloalkyl-substituted C.sub.1-C.sub.3 alkyl,
C.sub.5-C.sub.8cycloalkenyl- -substituted C.sub.1-C.sub.3alkyl, or
phenyl-substituted C.sub.1-C.sub.3alkyl. Also in preferred
embodiments, R.sup.5 is hydrogen or alkyl, with
C.sub.1-C.sub.3alkyl being more preferred.
[0230] In the above formula (I), R.sup.6 is hydrogen or alkyl.
Preferably, R.sup.6 is hydrogen or C.sub.1-C.sub.3alkyl. Even more
preferably, R.sup.6 is hydrogen.
[0231] In the above formula (I), R.sup.7 is hydrogen, alkyl,
alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aryl-substituted
alkyl, aryl-substituted alkyl or alkylene substituted B. In
preferred embodiments, R.sup.7 is hydrogen, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.10alkenyl, phenyl, cycloalkyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkenyl,
C.sub.5-C.sub.8cycloalkenyl-substituted C.sub.1-C.sub.3alkyl,
phenyl-substituted C.sub.1-C.sub.3alkyl or (CH.sub.2).sub.q-B. In
more preferred embodiments, R.sup.7 is (CH.sub.2).sub.q-B.
[0232] In certain alternative embodiments, in the above formula
(I), R.sup.6 and R.sup.7 form, together with the nitrogen atom to
which they are attached, a heterocyclic ring.
[0233] The group B in the definition of R.sup.7 is 16
[0234] C(.dbd.O)W or NR.sup.8R.sup.9. In preferred embodiments, B
is C(.dbd.O)W.
[0235] The group R.sup.8 in the definition of B is hydrogen or
alkyl. In preferred embodiments, R.sup.8 is hydrogen or
C.sub.1-C.sub.3alkyl.
[0236] The group R.sup.9 in the definition of B is hydrogen, alkyl,
alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aryl or aryl-substituted alkyl. In
preferred embodiments, R.sup.9 is hydrogen, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.10alkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, cycloalkyl, C.sub.5-C.sub.8cycloalkenyl,
C.sub.5-C.sub.8cycloalkenyl-subs- tituted C.sub.1-C.sub.3alkyl,
phenyl or phenyl-substituted C.sub.1-C.sub.3alkyl.
[0237] In certain alternative embodiments, in the definition of B,
R.sup.8 and R.sup.9 form, together with the nitrogen atom to which
they are attached, a heterocyclic ring.
[0238] The group W in the definition of B is OR.sup.10,
NR.sup.11R.sup.12 or OE.
[0239] The group R.sup.10 in the definition of W is hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl.
In preferred embodiments, R.sup.10 is hydrogen,
C.sub.1-C.sub.10alkyl, C.sub.2-C.sub.10alkenyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkenyl-- substituted
C.sub.1-C.sub.3alkyl, or phenyl-substituted C.sub.1-C.sub.3alkyl.
Also in preferred embodiments, R.sup.10 is hydrogen, alkyl,
preferably C.sub.1-C.sub.5alkyl, phenyl-substituted alkyl,
preferably phenyl-substituted C.sub.1-C.sub.2alkyl, cycloalkyl or
cycloalkyl-substituted alkyl, preferably
C.sub.5-C.sub.6cycloalkyl-substi- tuted C.sub.1-C.sub.3alkyl.
[0240] The group R.sup.11 in the definition of W is hydrogen or
alkyl. In preferred embodiments, R.sup.11 is hydrogen or
C.sub.1-C.sub.3alkyl.
[0241] The group R.sup.12 in the definition of W is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aryl-substituted alkyl or alkylene-substituted C(.dbd.O)Y. In
preferred embodiments, R.sup.12 is hydrogen, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.10alkenyl, phenyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkenyl-substituted
C.sub.1-C.sub.3alkyl, phenyl-substituted C.sub.1-C.sub.3alkyl, or
alkylene-substituted C(.dbd.O)Y. Also in preferred embodiments,
R.sup.12 is hydrogen, alkyl, preferably C.sub.1-C.sub.3alkyl or
(CH.sub.2).sub.mC(O)Y, where m is 1 to 4.
[0242] The group Y in the definition of R.sup.12 is OR.sup.18 or
NR.sup.19R.sup.20.
[0243] In certain alternative embodiments, in the definition of W,
R.sup.12 and R.sup.13 form, together with the nitrogen atom to
which they are attached, a heterocyclic ring.
[0244] The group E in the definition of W is 17
[0245] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14. In preferred embodiments, E is 18
[0246] (CH.sub.2).sub.m(C.dbd.O)D (where m is as defined above), or
--R.sup.13OC(.dbd.O)R.sup.14.
[0247] The group R.sup.13 in the definition of E is alkyl
substituted alkylene. In preferred embodiments, R.sup.13 is
C.sub.1-C.sub.3alkyl substituted methylene. In more preferred
embodiments, R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)--.
[0248] The group R.sup.14 in the definition of E is alkyl. In
preferred embodiments, R.sup.14 is C.sub.1-C.sub.10alkyl.
[0249] The group D in the definition of E is D is OR.sup.15 or
NR.sup.16R.sup.17.
[0250] The group R.sup.15 in the definition of D is hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl.
In preferred embodiments, R.sup.15 is hydrogen,
C.sub.1-C.sub.10alkyl, C.sub.2-C.sub.10alkenyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkenyl-- substituted
C.sub.1-C.sub.3alkyl, or phenyl-substituted C.sub.1-C.sub.3alkyl.
Also in preferred embodiments, R.sup.15 is hydrogen or alkyl, with
C.sub.1-C.sub.3alkyl being more preferred.
[0251] The group R.sup.16 in the definition of D is hydrogen,
alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl or
cycloalkenyl-substituted alkyl. In preferred embodiments, R.sup.16
is hydrogen, C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.10alkenyl,
phenyl, phenyl-substituted C.sub.1-C.sub.3alkyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-C.sub.8cycloalkenyl-substituted
C.sub.1-C.sub.3alkyl. In even more preferred embodiments, R.sup.16
is methyl or benzyl.
[0252] The group R.sup.17 in the definition of D is hydrogen or
alkyl. In preferred embodiments, R.sup.17 is hydrogen or
C.sub.1-C.sub.3 alkyl. In even more preferred embodiments, R.sup.17
is hydrogen.
[0253] In certain alternative embodiments, in the definition of D,
R.sup.16 and R.sup.17 form, together with the nitrogen atom to
which they are attached, a heterocyclic ring.
[0254] The group R.sup.18 in the definition of Y is hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl.
In preferred embodiments, R.sup.18 is hydrogen,
C.sub.1-C.sub.10alkyl, C.sub.2-C.sub.10alkenyl, cycloalkyl,
C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted C.sub.1-C.sub.3
alkyl, C.sub.5-C.sub.8cycloalkenyl- -substituted
C.sub.1-C.sub.3alkyl, or phenyl-substituted C.sub.1-C.sub.3alkyl.
In more preferred embodiments, R.sup.18 is hydrogen or
C.sub.1-C.sub.3alkyl.
[0255] The group R.sup.19 in the definition of Y is hydrogen or
alkyl. In preferred embodiments, R.sup.19 is hydrogen or
C.sub.1-C.sub.3alkyl.
[0256] The group R.sup.20 in the definition of Y is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or
aryl-substituted alkyl. In preferred embodiments, R.sup.20 is
hydrogen, C.sub.1-C.sub.10alkyl, C.sub.3-C.sub.10alkenyl, phenyl,
cycloalkyl, C.sub.5-C.sub.8cycloalkenyl, cycloalkyl-substituted
C.sub.1-C.sub.3alkyl, C.sub.5-Cgcycloalkenyl-subst- ituted
C.sub.1-C.sub.3alkyl, or phenyl-substituted C.sub.1-C.sub.3alkyl.
In more preferred embodiments, R.sup.20 is hydrogen or
C.sub.1-C.sub.3alkyl.
[0257] In certain alternative embodiments, in the definition of Y,
R.sup.19 and R.sup.20 form, together with the nitrogen atom to
which they are attached, a heterocyclic ring.
[0258] The group R.sup.21 in the definition of B is hydrogen or
alkyl. Preferably, R.sup.21 is hydrogen or C.sub.1-C.sub.3alkyl.
Even more preferably, R.sup.21 is hydrogen.
[0259] In the above formula (I), n is 0 to about 4. In preferred
embodiments, n is about 1 or 2.
[0260] In the above definition of R.sup.7, q is about I to about 4.
In preferred embodiments, q is about I to about 3.
[0261] In the above definition of E, m is about 1 to about 4. In
preferred embodiments, m is about 1 to about 3.
[0262] The compounds of formula (I) can occur as the trans and cis
stereochemical isomers by virtue of the substituents at the 3- and
4-positions of the piperidine ring, and such stereochemical isomers
are within the scope of the claims. The term "trans", as used
herein, refers to R.sup.2 in position 3 being on the opposite side
from the methyl group in position 4, whereas in the "cis" isomer
R.sup.2 and the 4-methyl are on the same side of the ring. In the
methods of the present invention, the compounds employed may be the
individual stereoisomers, as well as mixtures of stereoisomers. In
the most preferred embodiments, the methods of the present
invention involve compounds of formula (I) wherein the group
R.sup.2 at the 3-position is situated on the opposite side of the
ring, i.e., trans to the methyl group in the 4-position and on the
same side of the ring. These trans isomers can exist as the
3R,4R-isomer, or the 3S,4S-isomer.
[0263] The terms "R" and "S" are used herein as commonly used in
organic chemistry to denote specific configuration of a chiral
center. The term "R" refers to "right" and refers that
configuration of a chiral center with a clockwise relationship of
group priorities (highest to second lowest) when viewed along the
bond toward the lowest priority group. The term "S" or "left"
refers to that configuration of a chiral center with a
counterclockwise relationship of group priorities (highest to
second lowest) when viewed along the bond toward the lowest
priority group. The priority of groups is based upon their atomic
number (heaviest isotope first). A partial list of priorities and a
discussion of stereochemistry is contained in the book: The
Vocabulary of Organic Chemistry, Orchin, et al., John Wiley and
Sons Inc., page 126 (1980), which is incorporated herein by
reference in its entirety.
[0264] Preferred piperidine-N-alkylcarboxylate compounds for use in
the methods of the present invention are those of formula (I) in
which the configuration of substituents on the piperidine ring is
3R and 4R.
[0265] When R.sup.3 is not hydrogen, the carbon atom to which
R.sup.3 is attached is asymmetric.
[0266] As such, this class of compounds can further exist as the
individual R or S stereoisomers at this chiral center, or as
mixtures of stereoisomers, and all are contemplated within the
scope of the present invention. Preferably, a substantially pure
stereoisomer of the compounds of this invention is used, i.e., an
isomer in which the configuration at the chiral center to which
R.sup.3 is attached is R or S, i.e., those compounds in which the
configuration at the three chiral centers is preferably 3R, 4R, S
or 3R, 4R, R.
[0267] Furthermore, other asymmetric carbons can be introduced into
the molecule depending on the structure of A. As such, these
classes of compounds can exist as the individual R or S
stereoisomers at these chiral centers, or as mixtures of
stereoisomers, and all are contemplated as being within the scope
of methods of the present invention.
[0268] Preferred piperidine-N-alkylcarboxylate compounds for use in
the methods of the present invention include the following:
[0269] U--OCH.sub.2CH.sub.3; U--OH; G--OH;
U--NHCH.sub.2C(O)NHCH.sub.3; U--NHCH.sub.2C(O)NH.sub.2;
G--NHCH.sub.2C(O)NHCH.sub.3; U--NHCH.sub.2C(O)NHCH.sub.2CH.sub.3;
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH- .sub.3; G--NHCH.sub.2C(O)OH;
M--NHCH.sub.2C(O)NH.sub.2;
M--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5);
X--OCH.sub.2CH.sub.3; X--OH; X--NH(CH.sub.2).sub.2CH.sub.3;
Z--NH(CH.sub.2).sub.3C(O)OCH.sub.2C- H.sub.3; X--NHCH.sub.2C(O)OH;
Z--NH(CH.sub.2).sub.2N(CH.sub.3).sub.2;
Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3;
X--OCH.sub.2(C.sub.6H.sub.5)- ; X--N(CH.sub.3).sub.2;
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3;
Z--NH(CH.sub.2).sub.3C(O)NH.sub.2;
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.2CH.- sub.3;
X--OCH.sub.2C(O)OCH.sub.3; X--OCH.sub.2C(O)NHCH.sub.3; and
X--N(CH.sub.3)CH.sub.2C(O)CH.sub.2CH.sub.3; in which: 19
[0270] Particularly preferred piperidine-N-alkylcarboxylate
compounds for use in the methods of the present invention include
the following:
[0271] Z--OH; Z--NH(CH.sub.2).sub.2C(O)OH;
G--NH(CH.sub.2).sub.2C(O)NH.sub- .2;
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3; G--NHCH.sub.2C(O)NH.sub.2;
G--NHCH.sub.2C(O)NHCH.sub.2CH.sub.3;
G--NH(CH.sub.2).sub.3C(O)NHCH.sub.3; G--NH(CH.sub.2).sub.2C(O)OH;
G--NH(CH.sub.2).sub.3C(O)OH; X--NH.sub.2; X--NHCH(CH.sub.3).sub.2;
X--OCH.sub.2CH(CH.sub.3).sub.2; X--OCH.sub.2C.sub.6H.sub.5; X--OH;
X--O(CH.sub.2).sub.4CH.sub.3; X--O--(4-methoxycyclohexyl);
X--OCH(CH.sub.3)OC(O)CH.sub.3;
X--OCH.sub.2C(O)NHCH.sub.2(C.sub.6H.sub.5); M--NHCH.sub.2C(O)OH;
M--NH(CH.sub.2).sub.2C(O)OH; M--NH(CH.sub.2).sub.2C(O)NH.sub.2;
U-NHCH.sub.2C(O)OCH.sub.2CH.sub.3; and U-NHCH.sub.2C(O)OH; wherein
Z, G, X, M and U are as defined above.
[0272] Stated another way, in accordance with preferred embodiments
of the invention, the compound of formula (I) has the formula
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.su-
b.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.2,
Q--CH.sub.2CH.sub.2CH(C.su- b.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)-
NHCH.sub.2C(O)NHCH.sub.3,
Q--CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.su-
b.2C(O)NHCH.sub.2CH.sub.3, G--NH(CH.sub.2).sub.2C(O)NH.sub.2,
G--NH(CH.sub.2).sub.2C(O)NHCH.sub.3, G--NHCH.sub.2C(O)NH.sub.2,
G--NHCH.sub.2C(O)NHCH.sub.3, G--NHCH.sub.3C(O)NHCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)OCH.sub.2CH.sub.3,
G--NH(CH.sub.2).sub.3C(O)NHCH- .sub.3, G--NH(CH.sub.2).sub.2C(O)OH,
G--NH(CH.sub.2).sub.3C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NHCH.sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub.2C(O)OH,
Q--CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub.2C(O)NH.sub.-
2, Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3, Z--NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)NH.sub.2, Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2,
Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.su- b.3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2C(O)OH, Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3,
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3,
Z--NHCH.sub.2C(O)O(CH.sub.2).sub- .4CH.sub.3,
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3,
Z--NHCH.sub.2C(O)O--(4-methoxycyclohexyl),
Z--NHCH.sub.2C(O)OCH.sub.2C(O)- NHCH.sub.2(C.sub.6H.sub.5) or
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein Q, G and Z are
as defined above.
[0273] In even more preferred embodiments, the compound of formula
(I) has the formula
(3R,4R,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(+)--Z--NHCH.sub.2C(O)OH, (-)--Z--NHCH.sub.2C(O)OH,
(3R,4R,R)--Z--NHCH.sub.2C(O)--OCH.sub.2CH(CH.sub.3).sub.2,
(3S,4S,S)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2, (3
S,4S,R)--Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub.2(C.sub.6 H.sub.5) or
(3R,4R)-G--NH(CH.sub.2).sub.3C(O)OH, where Z and G are as defined
above. In still more preferred embodiments, the compound of formula
(I) has the formula (+)--Z--NHCH.sub.2C(O)OH or
(-)--Z--NHCH.sub.2C(O)OH where Z is as defined above.
[0274] Compounds of formula (I) that act locally on the gut, have
high potency, and are orally active are most preferred. A
particularly preferred embodiment of the present invention is the
compound (+)--Z--NHCH.sub.2C(O)OH, i.e., the compound of the
following formula (II). 20
[0275] The compound of formula (II) has low solubility in water
except at low or high pH conditions. Zwitterionic character may be
inherent to the compound, and may impart desirable properties such
as poor systemic absorption and sustained local affect on the gut
following oral administration.
[0276] In an alternate embodiment, the methods of the present
invention may involve administering to a patient a peripheral mu
opioid antagonist compound that is a quaternary morphinan compound.
Examples of quaternary morphinan compounds that may be suitable for
use in the methods of the present invention include, for example,
quaternary salts of N-methylnaltrexone, N-methylnaloxone,
N-methylnalorphine, N-diallylnormorphine, N-allyllevallorphan and
N-methylnalmefene.
[0277] In yet another alternate embodiment, the methods of the
present invention may involve administering to a patient a
peripheral mu opioid antagonist compound in the form of an opium
alkaloid derivative. The term "opium alkaloid derivative", as used
herein, refers to peripheral mu opioid antagonist compounds that
are synthetic or semi-synthetic derivatives or analogs of opium
alkaloids. In preferred form, the opium alkaloid derivatives
employed in the methods of the present invention exhibit high
levels of morphine antagonism, while exhibiting reduced, and
preferably substantially no, agonist activity. The term
"substantially no agonist activity", as used herein in connection
with the opium alkaloid derivatives, means that the maximal
response with respect to electrically stimulated guinea pig ileum,
at a concentration of 1 .mu.M, is about 60% or less relative to
morphine. In preferred embodiments, the opium alkaloid derivatives
employed in the present methods have a maximal response with
respect to guinea pig ileum, at a concentration of 1 .mu.M, of
about 50% or less relative to morphine, with a maximal response of
about 40% or less being more preferred. In even more preferred
embodiments, the opium alkaloid derivatives employed in the present
methods have a maximal response with respect to guinea pig ileum,
at a concentration of 1 .mu.M, of about 30% or less relative to
morphine, with a maximal response of about 20% or less being more
preferred. In still more preferred embodiments, the opium alkaloid
derivatives employed in the present methods have a maximal response
with respect to guinea pig ileum, at a concentration of 1 .mu.M, of
about 10% or less relative to morphine. In certain particularly
preferred embodiments, the opium alkaloid derivatives have a
maximal response with respect to guinea pig ileum, at a
concentration of 1 .mu.M, of about 0% (i.e., no response).
[0278] Suitable methods for determining maximal response of opium
alkaloid derivatives with respect to electrically stimulated guinea
pig ileum are described, for example, in U.S. Pat. Nos. 4,730,048
and 4,806,556, the disclosures of which are hereby incorporated
herein by reference, in their entireties.
[0279] In preferred form, the opium alkaloid derivatives employed
in the methods of the present invention have the following formulas
(III) or (IV): 21
[0280] wherein:
[0281] R is alkyl, cycloalkyl-substituted alkyl, aryl,
aryl-substituted alkyl or alkenyl;
[0282] Z is hydrogen or OH;
[0283] R' is X'-J(L)(T), wherein:
[0284] J is alkylene or alkenylene;
[0285] L is hydrogen, amino, or alkyl optionally substituted with
CO.sub.2H, OH or phenyl; and
[0286] T is CO.sub.2H, SO.sub.3H, amino or guanidino;
[0287] X' is a direct bond or C(.dbd.O); and
[0288] R" is NH--J(L)(T) or guanidino; or a stereoisomer, prodrug,
or pharmaceutically acceptable salt, hydrate or N-oxide
thereof.
[0289] In the compounds of formulas (III) and (IV) above, R is
alkyl, cycloalkyl-substituted alkyl, aryl, aryl-substituted alkyl
or alkenyl. In preferred embodiments, R is C.sub.1-C.sub.5alkyl,
C.sub.3-C.sub.6cycloaky- l-substituted alkyl, aryl, arylalkyl or
trans-C.sub.2-C.sub.5alkenyl. In more preferred embodiments, R is
C.sub.1-C.sub.3alkyl, allyl or cyclopropylmethyl, with
cyclopropylmethyl being even more preferred.
[0290] In the compounds of formulas (III) and (IV) above, Z is
hydrogen or OH. In preferred embodiments, Z is OH.
[0291] In the compounds of formulas (III) and (IV), R' is
X--J(L)(T) and R" is NH--J(L)(T) or guanidino.
[0292] In the definitions of R' and R", G is alkylene or
alkenylene. In preferred embodiments, J is C.sub.1-C.sub.5alkylene,
C.sub.2-C.sub.6alkylene interrupted by an oxygen atom, or
C.sub.2-C.sub.5alkenylene.
[0293] In the definitions of R' and R", L is hydrogen, amino, or
alkyl optionally substituted with CO.sub.2H, OH or phenyl. In
preferred embodiments, L is hydrogen, amino, or
C.sub.1-C.sub.5alkyl optionally substituted with CO.sub.2H, OH or
phenyl. In more preferred embodiments, L is hydrogen or amino.
[0294] In the definitions of R' and R", T is CO.sub.2H, SO.sub.3H,
amino or guanidino. In preferred embodiments, T is CO.sub.2H or
guanidino.
[0295] In the definition of R', X is a direct bond or
C(.dbd.O).
[0296] Preferred opioid alkaloid derivatives that may be employed
in the methods of the present invention include compounds of
formula (III) wherein R is cyclopropylmethyl, Z is OH, and R' is
selected from C(.dbd.O)(CH.sub.2).sub.2CO.sub.2H,
C(.dbd.O)(CH.sub.2).sub.3CO.sub.2H, C(.dbd.O)CH--CHCO.sub.2H,
C(.dbd.O)CH.sub.2OCH.sub.2CO.sub.2H,
C(.dbd.O)CH(NH.sub.2)(CH.sub.2).sub.3NHC(--NH)NH.sub.2 or
C(.dbd.O)CH(NH.sub.2)CH.sub.2CO.sub.2H. Also preferred are opioid
alkaloid derivatives of formula (III) wherein R is
cyclopropylmethyl, Z is OH, and R' is CH.sub.2CO.sub.2H. In other
preferred embodiments, the opioid alkaloid derivatives that may be
employed in the methods of the present invention include compounds
of formula (IV) wherein R is cyclopropylmethyl, Z is OH, and R" is
NHCH.sub.2CO.sub.2H.
[0297] Other opioid alkaloid derivatives that may be employed in
the methods of the present invention are described, for example, in
U.S. Pat. Nos. 4,730,048 and 4,806,556, the disclosures of which
are hereby incorporated herein by reference, in their
entireties.
[0298] In still another alternate embodiment, the methods of the
present invention may involve administering to a patient a
peripheral mu opioid antagonist compound in the form of a
quaternary benzomorphan compound. In preferred form, the quaternary
benzomorphan compounds employed in the methods of the present
invention exhibit high levels of morphine antagonism, while
exhibiting reduced, and preferably substantially no, agonist
activity. The term "substantially no agonist activity", as used
herein in connection with the quaternary benzomorphan compounds,
means that the maximal response with respect to electrically
stimulated guinea pig ileum, at a concentration of 1 .mu.M, is
about 60% or less relative to morphine. In preferred embodiments,
the quaternary benzomorphan compounds employed in the present
methods have a maximal response with respect to guinea pig ileum,
at a concentration of 1 .mu.M, of about 50% or less relative to
morphine, with a maximal response of about 40% or less being more
preferred. In even more preferred embodiments, the quaternary
benzomorphan compounds employed in the present methods have a
maximal response with respect to guinea pig ileum, at a
concentration of 1 .mu.M, of about 30% or less relative to
morphine, with a maximal response of about 20% or less being more
preferred. In still more preferred embodiments, the quaternary
benzomorphan compounds employed in the present methods have a
maximal response with respect to guinea pig ileum, at a
concentration of 1 .mu.M, of about 10% or less relative to
morphine. In certain particularly preferred embodiments, the
quaternary benzomorphan compounds have a maximal response with
respect to guinea pig ileum, at a concentration of 1 .mu.M, of
about 0% (i.e., no response).
[0299] In preferred-form, the quaternary benzomorphan compounds
employed in the methods of the present invention have the following
formula (V): 22
[0300] where:
[0301] R.sup.24 is hydrogen or acyl; and
[0302] R.sup.25 is alkyl or alkenyl;
[0303] or a stereoisomer, prodrug, or pharmaceutically acceptable
salt, hydrate or N-oxide thereof.
[0304] In the above formula (V), R.sup.24 is hydrogen or acyl. In
preferred embodiments, R.sup.24 is hydrogen or C.sub.1-C.sub.6
acyl. In more preferred embodiments, R.sup.24 is hydrogen or
C.sub.1-C.sub.2 acyl. In even more preferred embodiments, R.sup.24
is hydrogen or acetoxy, with hydrogen being still more
preferred.
[0305] In the above formula (V), R.sup.25 is alkyl or alkenyl. In
preferred embodiments, R.sup.25 is C.sub.1-C.sub.6 alkyl or
C.sub.2-C.sub.6 alkenyl. In even more preferred embodiments,
R.sup.25 is C.sub.1-C.sub.3 alkyl or C.sub.2-C.sub.3 alkenyl. In
still more preferred embodiments, R.sup.25 is propyl or allyl.
[0306] Preferred quaternary benzomorphan compounds that may be
employed in the methods of the present invention include the
following compounds of formula (V):
2'-hydroxy-5,9-dimethyl-2,2-diallyl-6,7-benzomorphanium-brom- ide;
2'-hydroxy-5,9-dimethyl-2-n-propyl-6,7-benzomorphan;
2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan;
2'-hydroxy-5,9-dimethyl-
-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide;
2'-hydroxy-5,9-dimethyl-2-
-n-propyl-2-propargyl-6,7-benzomorphanium-bromide; and
2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide.
[0307] Other quaternary benzomorphan compounds that may be employed
in the methods of the present invention are described, for example,
in U.S. Pat. No. 3,723,440, the disclosures of which are hereby
incorporated herein by reference, in their entirety.
[0308] Other mu opioid antagonist compounds which may be employed
in the methods and compositions of the present invention, in
addition to those exemplified above, would be readily apparent to
one of ordinary skill in the art, once armed with the teachings of
the present disclosure.
[0309] The compounds employed in the methods of the present
invention may exist in prodrug form. As used herein, "prodrug" is
intended to include any covalently bonded carriers which release
the active parent drug, for example, as according to formulas (I)
or (II) or other formulas or compounds employed in the methods of
the present invention in vivo when such prodrug is administered to
a mammalian subject. Since prodrugs are known to enhance numerous
desirable qualities of pharmaceuticals (e.g., solubility,
bioavailability, manufacturing, etc.) the compounds employed in the
present methods may, if desired, be delivered in prodrug form.
Thus, the present invention contemplates methods of delivering
prodrugs. Prodrugs of the compounds employed in the present
invention, for example formula (I), may be prepared by modifying
functional groups present in the compound in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound.
[0310] Accordingly, prodrugs include, for example, compounds
described herein in which a hydroxy, amino, or carboxy group is
bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino, or
carboxylic acid, respectively. Examples include, but are not
limited to, acetate, formate and benzoate derivatives of alcohol
and amine functional groups; and alkyl, carbocyclic, aryl, and
alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and
phenethyl esters, and the like.
[0311] The compounds employed in the methods of the present
invention may be prepared in a number of ways well known to those
skilled in the art. The compounds can be synthesized, for example,
by the methods described below, or variations thereon as
appreciated by the skilled artisan. All processes disclosed in
association with the present invention are contemplated to be
practiced on any scale, including milligram, gram, multigram,
kilogram, multikilogram or commercial industrial scale.
[0312] As discussed in detail above, compounds employed in the
present methods may contain one or more asymmetrically substituted
carbon atoms, and may be isolated in optically active or racemic
forms. Thus, all chiral, diastereomeric, racemic forms and all
geometric isomeric forms of a structure are intended, unless the
specific stereochemistry or isomeric form is specifically
indicated. It is well known in the art how to prepare and isolate
such optically active forms. For example, mixtures of stereoisomers
may be separated by standard techniques including, but not limited
to, resolution of racemic forms, normal, reverse-phase, and chiral
chromatography, preferential salt formation, recrystallization, and
the like, or by chiral synthesis either from chiral starting
materials or by deliberate synthesis of target chiral centers.
[0313] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Preferred protecting groups
include the benzyloxycarbonyl group and the tert-butyloxycarbonyl
group. Other preferred protecting groups that may be employed in
accordance with the present invention may be described in Greene,
T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis
2d. Ed., Wiley & Sons, 1991.
[0314] Piperidine-N-alkylcarboxylate compounds according to the
present invention may be synthesized employing methods taught, for
example, in U.S. Pat. Nos. 5,250,542, 5,434,171, 5,159,081, and
5,270,328, the disclosures of which are hereby incorporated herein
by reference in their entireties. For example, the
3-substituted-4-methyl-4-(3-hydroxy- or
alkanoyloxyphenyl)piperidine derivatives employed as starting
materials in the synthesis of the present compounds may be prepared
by the general procedure taught in U.S. Pat. No. 4,115,400 and U.S.
Pat. No. 4,891,379, the disclosures of which are hereby
incorporated herein by reference in their entireties. The starting
material for the synthesis of compounds described herein,
(3R,4R)-4-(3-hydroxypheny)-3,4-dimethylpiperidine, may be prepared
by the procedures described in U.S. Pat. No. 4,581,456, the
disclosures of which are hereby incorporated herein by reference,
in their entirety, but adjusted as described such that the
.beta.-stereochemistry is preferred.
[0315] The first step of the process may involves the formation of
the 3-alkoxyphenyllithium reagent by reacting 3-alkoxybromobenzene
with an alkyllithium reagent. This reaction may be performed under
inert conditions and in the presence of a suitable non-reactive
solvent such as dry diethyl ether or preferably dry
tetrahydrofuran. Preferred alkyllithium reagents used in this
process are n-butyllithium, and especially sec-butyllithium.
Generally, approximately an equimolar to slight excess of
alkyllithium reagent may be added to the reaction mixture. The
reaction may be conducted at a temperature of from about
-20.degree. C. and about -100.degree. C., more preferably from
about -50.degree. C. to about -55.degree. C.
[0316] Once the 3-alkoxyphenyllithium reagent has formed,
approximately an equimolar quantity of a 1-alkyl-4-piperidone may
be added to the mixture while maintaining the temperature between
-20.degree. C. and -100.degree. C. The reaction is typically
complete after about 1 to 24 hours. At this point, the reaction
mixture may be allowed to gradually warm to room temperature. The
product may be isolated by the addition to the reaction mixture of
a saturated sodium chloride solution to quench any residual lithium
reagent. The organic layer may be separated and further purified if
desired to provide the appropriate
1-alkyl-4-(3-alkoxyphenyl)piperidin- ol derivative.
[0317] The dehydration of the 4-phenylpiperidinol prepared above
may be accomplished with a strong acid according to well known
procedures. While dehydration occurs in various amounts with any
one of several strong acids such as hydrochloric acid, hydrobromic
acid, and the like, dehydration is preferably conducted with
phosphoric acid, or especially p-toluenesulfonic acid in toluene or
benzene. This reaction may be typically conducted under reflux
conditions, more generally from about 50.degree. C. and 150.degree.
C. The product thus formed may be isolated by basifying an acidic
aqueous solution of the salt form of the product and extracting the
aqueous solution with a suitable water immiscible solvent. The
resulting residue following evaporation can then be further
purified if desired.
[0318] The 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine
derivatives may be prepared by a metalloenamine alkylation. This
reaction is preferably conducted with n-butyllithium in
tetrahydroflran (THF) under an inert atmosphere, such as nitrogen
or argon. Generally, a slight excess of n-butyllithium may be added
to a stirring solution of the
1-alkyl-4-(3-alkoxyphenyl)-tetrahydropyridine in THF cooled to a
temperature in the range of from about is -50.degree. C. to about
0.degree. C., more preferably from about -20.degree. C. to
-10.degree. C. This mixture may be stirred for approximately 10 to
30 minutes followed by the addition of approximately from 1.0 to
1.5 equivalents of methyl halide to the solution while maintaining
the temperature of the reaction mixture below 0.degree. C. After
about 5 to 60 minutes, water may be added to the reaction mixture
and the organic phase may be collected. The product can be purified
according to standard procedures, but the crude product is
preferably purified by either distilling it under vacuum or
slurrying it in a mixture of hexane:ethyl acetate (65:35, v:v) and
silica gel for about two hours. According to the latter procedure,
the product may be then isolated by filtration followed by
evaporating the filtrate under reduced pressure.
[0319] The next step in the process may involve the application of
the Mannich reaction of aminomethylation to non-conjugated,
endocyclic enamines. This reaction is preferably carried out by
combining from about 1.2 to 2.0 equivalents of aqueous formaldehyde
and about 1.3 to 2.0 equivalents of a suitable secondary amine in a
suitable solvent. While water may be the preferred solvent, other
non-nucleophilic solvents, such as acetone and acetonitrile can
also be employed in this reaction. The pH of this solution may be
adjusted to approximately 3.0 to 4.0 with an acid that provides a
non-nucleophilic anion. Examples of such acids include sulfuric
acid, the sulfonic acids such as methanesulfonic acid and
p-toluenesulfonic acid, phosphoric acid, and tetrafluoroboric acid,
with sulfuric acid being preferred. To this solution may be added
one equivalent of a
1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine, typically
dissolved in aqueous sulfuric acid, and the pH of the solution may
be readjusted with the non-nucleophilic acid or a suitable
secondary amine. The pH is preferably maintained in the range of
from about 1.0 to 5.0, with a pH of about 3.0 to 3.5 being more
preferred during the reaction. The reaction is substantially
complete after about 1 to 4 hours, more typically about 2 hours,
when conducted at a temperature in the range of from about
50.degree. C. to about 80.degree. C., more preferably about
70.degree. C. The reaction may then be cooled to approximately
30.degree. C., and added to a sodium hydroxide solution. This
solution may then be extracted with a water immiscible organic
solvent, such as hexane or ethyl acetate, and the organic phase,
following thorough washing with water to remove any residual
formaldehyde, may be evaporated to dryness under reduced
pressure.
[0320] The next step of the process may involve the catalytic
hydrogenation of the prepared
1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetra-
hydropyridinemethanamine to the corresponding
trans-l-alkyl-3,4-dimethyl-4- -(3-alkoxyphenyl)piperidine. This
reaction actually occurs in two steps. The first step is the
hydrogenolysis reaction wherein the exo C-N bond is reductively
cleaved to generate the 3-methyltetrahydropyridine. In the second
step, the 2,3-double bond in the tetrahydropyridine ring is reduced
to afford the desired piperidine ring.
[0321] Reduction of the enamine double bond introduced the crucial
relative stereochemistry at the 3 and 4 carbon atoms of the
piperidine ring. The reduction generally does not occur with
complete stereoselectivity. The catalysts employed in the process
may be chosen from among the various palladium and preferably
platinum catalysts.
[0322] The catalytic hydrogenation step of the process is
preferably conducted in an acidic reaction medium. Suitable
solvents for use in the process include the alcohols, such as
methanol or ethanol, as well as ethyl acetate, tetrahydrofuran,
toluene, hexane, and the like.
[0323] Proper stereochemical outcome may be dependent on the
quantity of catalyst employed. The quantity of catalyst required to
produce the desired stereochemical result may be dependent upon the
purity of the starting materials in regard to the presence or
absence of various catalyst poisons.
[0324] The hydrogen pressure in the reaction vessel may not be
critical but can be in the range of from about 5 to 200 psi.
Concentration of the starting material by volume is preferably
around 20 mL of liquid per gram of starting material, although an
increased or decreased concentration of the starting material can
also be employed. Under the conditions specified herein, the length
of time for the catalytic hydrogenation may not be critical because
of the inability for over-reduction of the molecule. While the
reaction can continue for up to 24 hours or longer, it may not be
necessary to continue the reduction conditions after the uptake of
the theoretical two moles of hydrogen. The product may then be
isolated by filtering the reaction mixture for example through
infusorial earth, and evaporating the filtrate to dryness under
reduced pressure. Further purification of the product thus isolated
may not be necessary and preferably the diastereomeric mixture may
be carried directly on to the following reaction.
[0325] The alkyl substituent may be removed from the 1-position of
the piperidine ring by standard dealkylation procedures.
Preferably, a chloroformate derivative, especially the vinyl or
phenyl derivatives, may be employed and removed with acid. Next,
the prepared alkoxy compound may be dealkylated to the
corresponding phenol. This reaction may be generally carried out by
reacting the compound in a 48% aqueous hydrobromic acid solution.
This reaction may be substantially complete after about 30 minutes
to 24 hours when conducted at a temperature of from about
50.degree. C. to about 150.degree. C., more preferably at the
reflux temperature of the reaction mixture. The mixture may then be
worked up by cooling the solution, followed by neutralization with
base to an approximate pH of 8. This aqueous solution may be
extracted with a water immiscible organic solvent. The residue
following evaporation of the organic phase may then be used
directly in the following step.
[0326] The compounds employed as starting materials to the
compounds of the invention can also be prepared by brominating the
1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine
at the 3-position, lithiating the bromo compound thus prepared, and
reacting the lithiated intermediate with a methylhalide, such as
methyl bromide to provide the corresponding
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)tetrahyd-
ropyridinemethanamine. This compound may then be reduced and
converted to the starting material as indicated above.
[0327] As noted above, the compounds of the present invention can
exist as the individual stereoisomers. Preferably reaction
conditions are adjusted as disclosed in U.S. Pat. No. 4,581,456 or
as set forth in Example 1 of U.S. Pat. No. 5,250,542 to be
substantially stereoselective and provide a racemic mixture of
essentially two enantiomers. These enantiomers may then be
resolved. A procedure which may be employed to prepare the resolved
starting materials used in the synthesis of these compounds
includes treating a racemic mixture of
alkyl-3,4-dimethyl-4-(3-alkoxyphen- yl)piperidine with either (+)-
or (-)-ditoluoyl tartaric acid to provide the resolved
intermediate. This compound may then be dealkylated at the
1-position with vinyl chloroformate and finally converted to the
desired 4-(3-hydroxyphenyl)piperidine isomer.
[0328] As will be understood by those skilled in the art, the
individual enantiomers of the invention can also be isolated with
either (+) or (-) dibenzoyl tartaric acid, as desired, from the
corresponding racemic mixture of the compounds of the invention.
Preferably the (+)-trans enantiomer is obtained.
[0329] Although the (+)trans-3,4 stereoisomer is preferred, all of
the possible stereoiosmers of the compounds described herein are
within the contemplated scope of the present invention. Racemic
mixtures of the stereoisomers as well as the substantially pure
stereoisomers are within the scope of the invention. The term
"substantially pure", as used herein, refers to at least about 90
mole percent, more preferably at least about 95 mole percent and
most preferably at least about 98 mole percent of the desired
stereoisomer is present relative to other possible
stereoisomers.
[0330] Intermediates can be prepared by reacting a
3,4-alkyl-substituted-4- -(3-hydroxyphenyl)piperidine with a
compound of the formula LCH.sub.2(CH.sub.2),C.sub.1CHR.sup.3C(O)E
where L is a leaving group such as chlorine, bromine or iodine, E
is a carboxylic acid, ester or amide, and R.sup.3 and n are as
defined hereinabove. Preferably L may be chlorine and the reaction
is carried out in the presence of a base to alkylate the piperidine
nitrogen. For example 4-chloro-2-cyclohexylbutano- ic acid, ethyl
ester can be contacted with (3R,4R)-4-(3-hydroxyphenyl)-3,4-
-dimethylpiperidine to provide
4-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl- -1-piperidine]butanoic
acid, ethyl ester. Although the ester of the carboxylic acid may be
preferred, the free acid itself or an amide of the carboxylic acid
may be used.
[0331] In alternative synthesis, the substituted piperidine can be
contacted with a methylene alkyl ester to alkylate the piperidine
nitrogen. For example, 2-methylene-3-phenylproponic acid, ethyl
ester can be contacted with a desired piperidine to provide
2-benzyl-3-piperidinepr- opanoic acid ethyl ester.
[0332] Another synthetic route can involve the reaction of a
substituted piperidine with a haloalkylnitrile. The nitrile group
of the resulting piperidine alkylnitrile can be hydrolyzed to the
corresponding carboxylic acid.
[0333] With each of the synthetic routes, the resulting ester or
carboxylic acid can be reacted with an amine or alcohol to provide
modified chemical structures. In the preparation of amides, the
piperidine-carboxylic acid or -carboxylic acid ester may be reacted
with an amine in the presence of a coupling agent such as
dicyclohexylcarbodiimide, boric acid, borane-trimethylamine, and
the like. Esters can be prepared by contacting the
piperidine-carboxylic acid with the appropriate alcohol in the
presence of a coupling agent such as p-toluenesulfonic acid, boron
trifluoride etherate or N,N'-carbonyldiimidazole. Alternatively,
the piperidine-carboxylic acid chloride can be prepared using a
reagent such as thionyl chloride, phosphorus trichloride,
phosphorus pentachloride and the like. This acyl chloride can be
reacted with the appropriate amine or alcohol to provide the
corresponding amide or ester.
[0334] Opium alkaloid derivatives according to the present
invention may be synthesized employing methods taught, for example,
in U.S. Pat. Nos. 4,730,048 and 4,806,556, the disclosures of which
are hereby incorporated herein by reference in their entireties.
For example, opium alkaloid derivatives of formula (III) may be
prepared by attaching hydrophilic, ionizable moieties R' and R" to
the 6-amino group of naltrexamine (formula (III) where R is
(cyclopropyl)methyl, Z is OH and R! is H) or oxymorphamine (formula
(III) where R is CH.sub.3, Z is OH and R! is H). The opium alkaloid
derivatives of formula IV may be prepared by converting the
6-keto-group of oxymorphone (formula (VI) where R is CH.sub.3 and Z
is OH) or naltrexone (formula (VI) where R is (cyclopropyl)methyl
and Z is OH) to the ionizable, hydrophilic group (R"N.dbd.) by a
Schiff base reaction with a suitable amino-compound. 23
[0335] In a similar fashion, deoxy-opiates of formulae (III) and
(IV) wherein Z is hydrogen may be prepared from readily available
starting materials.
[0336] The compounds of formula (V) may be synthesized employing
methods taught, for example, in U.S. Pat. No. 3,723,440, the
disclosures of which are hereby incorporated herein by reference in
their entirety.
[0337] The compounds employed in the methods of the present
invention including, for example, opioid and peripheral mu opioid
antagonist compounds, may be administered by any means that results
in the contact of the active agents with the agents' site or
site(s)of action in the body of a patient. The compounds may be
administered by any conventional means available for use in
conjunction with pharmaceuticals, either as individual therapeutic
agents or in a combination of therapeutic agents. For example, they
may be administered as the sole active agents in a pharmaceutical
composition, or they can be used in combination with other
therapeutically active ingredients.
[0338] The compounds are preferably combined with a pharmaceutical
carrier selected on the basis of the chosen route of administration
and standard pharmaceutical practice as described, for example, in
Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, Pa.,
1980), the disclosures of which are hereby incorporated herein by
reference, in their entirety.
[0339] Compounds of the present invention can be administered to a
mammalian host in a variety of forms adapted to the chosen route of
administration, e.g. orally or parenterally. Parenteral
administration in this respect includes administration by the
following routes: intravenous, intramuscular, subcutaneous,
intraocular, intrasynovial, transepithelial including transdermal,
ophthalmic, sublingual and buccal; topically including ophthalmic,
dermal, ocular, rectal and nasal inhalation via insufflation,
aerosol and rectal systemic.
[0340] The active compound may be orally administered, for example,
with an inert diluent or with an assimilable edible carrier, or it
may be enclosed in hard or soft shell gelatin capsules, or it may
be compressed into tablets, or it may be incorporated directly with
the food of the diet. For oral therapeutic administration, the
active compound may be incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. The amount of
active compound(s) in such therapeutically useful compositions is
preferably such that a suitable dosage will be obtained. Preferred
compositions or preparations according to the present invention may
be prepared so that an oral dosage unit form contains from about
0.1 to about 1000 mg of active compound.
[0341] The tablets, troches, pills, capsules and the like may also
contain one or more of the following: a binder, such as gum
tragacanth, acacia, corn starch or gelatin; an excipient, such as
dicalcium phosphate; a disintegrating agent, such as corn starch,
potato starch, alginic acid and the like; a lubricant, such as
magnesium stearate; a sweetening agent such as sucrose, lactose or
saccharin; or a flavoring agent, such as peppermint, oil of
wintergreen or cherry flavoring. When the dosage unit form is a
capsule, it may contain, in addition to materials of the above
type, a liquid carrier. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage
unit. For instance, tablets, pills, or capsules may be coated with
shellac, sugar or both. A syrup or elixir may contain the active
compound, sucrose as a sweetening agent, methyl and propylparabens
as preservatives, a dye and flavoring, such as cherry or orange
flavor. Of course, any material used in preparing any dosage unit
form is preferably pharmaceutically pure and substantially
non-toxic in the amounts employed. In addition, the active compound
may be incorporated into sustained-release preparations and
formulations.
[0342] The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compounds as free bases
or pharmacologically acceptable salts can be prepared in water
suitably mixed with a surfactant, such as hydroxypropylcellulose. A
dispersion can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof and in oils. Under ordinary conditions
of storage and use, these preparations may contain a preservative
to prevent the growth of microorganisms.
[0343] The pharmaceutical forms suitable for injectable use
include, for example, sterile aqueous solutions or dispersions and
sterile powders for the extemporaneous preparation of sterile
injectable solutions or dispersions. In all cases, the form is
preferably sterile and fluid to provide easy syringability. It is
preferably stable under the conditions of manufacture and storage
and is preferably preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier may be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycol and the like), suitable mixtures thereof, and
vegetable oils. The proper fluidity can be maintained, for example,
by the use of a coating, such as lecithin, by the maintenance of
the required particle size in the case of a dispersion, and by the
use of surfactants. The prevention of the action of microorganisms
may be achieved by various antibacterial and antifumgal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal
and the like. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. Prolonged
absorption of the injectable compositions may be achieved by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0344] Sterile injectable solutions may be prepared by
incorporating the active compounds in the required amounts, in the
appropriate solvent, with various of the other ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions may be prepared by incorporating the
sterilized active ingredient into a sterile vehicle which contains
the basic dispersion medium and the required other ingredients from
those enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation may include vacuum drying and the freeze drying
technique which yield a powder of the active ingredient, plus any
additional desired ingredient from the previously sterile-filtered
solution thereof.
[0345] The therapeutic compounds of this invention may be
administered to a patient alone or in combination with a
pharmaceutically acceptable carrier. As noted above, the relative
proportions of active ingredient and carrier may be determined, for
example, by the solubility and chemical nature of the compounds,
chosen route of administration and standard pharmaceutical
practice.
[0346] The dosage of the compounds of the present invention that
will be most suitable for prophylaxis or treatment will vary with
the form of administration, the particular compound chosen and the
physiological characteristics of the particular patient under
treatment. Generally, small dosages may be used initially and, if
necessary, increased by small increments until the desired effect
under the circumstances is reached. Generally speaking, oral
administration may require higher dosages.
[0347] The combination products of this invention, such as
pharmaceutical compositions comprising opioids in combination with
a peripheral mu opioid antagonist compound, such as the compounds
of formula (I), may be in any dosage form, such as those described
herein, and can also be administered in various ways, as described
herein. In a preferred embodiment, the combination products of the
invention are formulated together, in a single dosage form (that
is, combined together in one capsule, tablet, powder, or liquid,
etc.). When the combination products are not formulated together in
a single dosage form, the opioid compounds and the peripheral mu
opioid antagonist compounds may be administered at the same time
(that is, together), or in any order. When not administered at the
same time, preferably the administration of an opioid and a
peripheral mu opioid antagonist occurs less than about one hour
apart, more preferably less than about 30 minutes apart, even more
preferably less than about 15 minutes apart, and still more
preferably less than about 5 minutes apart. Preferably,
administration of the combination products of the invention is
oral, although other routes of administration, as described above,
are contemplated to be within the scope of the present invention.
Although it is preferable that the opioids and peripheral mu opioid
antagonists are both administered in the same fashion (that is, for
example, both orally), if desired, they may each be administered in
different fashions (that is, for example, one component of the
combination product may be administered orally, and another
component may be administered intravenously). The dosage of the
combination products of the invention may vary depending upon
various factors such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration, the age,
health and weight of the recipient, the nature and extent of the
symptoms, the kind of concurrent treatment, the frequency of
treatment, and the effect desired.
[0348] Although the proper dosage of the combination products of
this invention will be readily ascertainable by one skilled in the
art, once armed with the present disclosure, by way of general
guidance, where an opioid compounds is combined with a peripheral
mu opioid antagonist, for example, typically a daily dosage may
range from about 0.01 to about 100 milligrams of the opioid (and
all combinations and subcombinations of ranges therein) and about
0.001 to about 100 milligrams of the peripheral mu opioid
antagonist (and all combinations and subcombinations of ranges
therein), per kilogram of patient body weight. Preferably, the a
daily dosage may be about 0.1 to about 10 milligrams of the opioid
and about 0.01 to about 10 milligrams of the peripheral mu opioid
antagonist per kilogram of patient body weight. Even more
preferably, the daily dosage may be about 1.0 milligrams of the
opioid and about 0.1 milligrams of the peripheral mu opioid
antagonist per kilogram of patient body weight. With regard to a
typical dosage form of this type of combination product, such as a
tablet, the opioid compounds (e.g., morphine) generally may be
present in an amount of about 15 to about 200 milligrams, and the
peripheral mu opioid antagonists in an amount of about 0.1 to about
4 milligrams.
[0349] Particularly when provided as a single dosage form, the
potential exists for a chemical interaction between the combined
active ingredients (for example, an opioid and a peripheral mu
opioid antagonist compound). For this reason, the preferred dosage
forms of the combination products of this invention are formulated
such that although the active ingredients are combined in a single
dosage form, the physical contact between the active ingredients is
minimized (that is, reduced).
[0350] In order to minimize contact, one embodiment of this
invention where the product is orally administered provides for a
combination product wherein one active ingredient is enteric
coated. By enteric coating one or more of the active ingredients,
it is possible not only to minimize the contact between the
combined active ingredients, but also, it is possible to control
the release of one of these components in the gastrointestinal
tract such that one of these components is not released in the
stomach but rather is released in the intestines. Another
embodiment of this invention where oral administration is desired
provides for a combination He product wherein one of the active
ingredients is coated with a sustained-release material which
effects a sustained-release throughout the gastrointestinal tract
and also serves to minimize physical contact between the combined
active ingredients. Furthermore, the sustained-released component
can be additionally enteric coated such that the release of this
component occurs only in the intestine. Still another approach
would involve the formulation of a combination product in which the
one component is coated with a sustained and/or enteric release
polymer, and the other component is also coated with a polymer such
as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or
other appropriate materials as known in the art, in order to
further separate the active components. The polymer coating serves
to form an additional barrier to interaction with the other
component.
[0351] Dosage forms of the combination products of the present
invention wherein one active ingredient is enteric coated can be in
the form of tablets such that the enteric coated component and the
other active ingredient are blended together and then compressed
into a tablet or such that the enteric coated component is
compressed into one tablet layer and the other active ingredient is
compressed into an additional layer. Optionally, in order to
further separate the two layers, one or more placebo layers may be
present such that the placebo layer is between the layers of active
ingredients. In addition, dosage forms of the present invention can
be in the form of capsules wherein one active ingredient is
compressed into a tablet or in the form of a plurality of
microtablets, particles, granules or non-perils, which are then
enteric coated. These enteric coated microtablets, particles,
granules or non-perils are then placed into a capsule or compressed
into a capsule along with a granulation of the other active
ingredient.
[0352] These as well as other ways of minimizing contact between
the components of combination products of the present invention,
whether administered in a single dosage form or administered in
separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the
present disclosure.
[0353] 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 a
peripheral mu opioid antagonist compound, 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.TM. two-part container (available from
Abbott Labs, Chicago, Ill.), as desired. The opioid compound and
the peripheral mu opioid antagonist compound 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.
[0354] Compounds for use in the methods of the present invention,
including piperidine-N-alkylcarboxylate compounds of formula (I),
have been characterized in opioid receptor binding assays showing
preferential binding to mu opioid receptors. Studies in isolated
tissues (guinea pig and mouse vas deferens) have shown that these
compounds may act as antagonists with no measurable agonist
activity. Studies in animals have demonstrated that the present
compounds may reverse constipation in morphine-dependent mice when
administered orally or parenterally at very low doses, and do not
block the analgesic actions of morphine unless given in
hundred-fold or higher doses. Collectively, the data indicate that
the compounds described herein may have a very high degree of
peripheral selectivity.
EXAMPLES
[0355] The invention is further demonstrated in the following
examples. All of the examples are actual examples. The examples are
for purposes of illustration and are not intended to limit the
scope of the present invention.
Example 1
[0356] This example is directed to in vivo experiments in mice
which demonstrate the effectiveness of the combination methods and
products of the present invention.
[0357] In a mouse model of opioid-induced constipation (measured by
the charcoal meal transit time), the compound of formula (IT),
orally administered, prevented acute morphine-induced constipation.
A 3 mg/kg oral dose had a duration of action between 8 and 24
hours. Additional studies showed that the compound of formula (II)
was even more potent in reversing morphine-induced constipation in
chronic morphine treated mice. This establishes that the compound
of formula (II) is a gut-selective and peripherally-selective mu
antagonist compound. In addition, it is orally effective in
preventing or reversing morphine-induced constipation in mice.
[0358] The following examples are directed to in vivo experiments
in humans which demonstrates the effectiveness of the combination
methods and products of the present invention.
Example 2
[0359] A clinical study in man was an 8 subject multiple crossover
study of the effects of oral pre-treatment with placebo, 2.4 mg or
24 mg t.i.d. of the compound of formula (II) on slowing of gut
motility induced with 8 mg of b.i.d. of oral loperamide (a
peripheral mu opioid agonist). Both doses of the compound of
formula (II) prevented loperamide-induced slowing of gut motility
as shown in the graph illustrated in FIG. 1. The graph presents the
effects of 2.4 or 24 mg of the compound of formula (II) on colonic
transit time (in hours) following administration of loperamide. The
loperamide dose was constant in the three treatment groups. Since
both doses of the compound of formula (II) completely prevented
loperamide-induced increased colonic transit time, the effective
dose range of the compound of formula (II) may be well below the
lowest dose (2.4 mg t.i.d.) evaluated in the study.
Example 3
[0360] A Phase I study in 20 healthy volunteers demonstrated that a
4 mg oral dose of the compound of formula (II) blocked the effect
of intravenous morphine sulfate on upper gastrointestinal motility
(P<0.01). The compound of formula (II) also showed a trend
toward antagonizing morphine-induced nausea (P=0.07) indicating
that the compound of formula (II) may provide additional benefits
to patients experiencing common adverse side effects from morphine
or other opioids.
Example 4
[0361] A Phase I study in 11 volunteers demonstrated that a 3 mg
oral dose of the compound of formula (II) administered three times
daily for 4 days blocked the inhibition of gastrointestinal transit
produced by oral sustained-release morphin (MS Contin.RTM., 30 mg
twice daily) without antagonizing MS Contin.RTM. effects on pupil
size. Pupil size was used as a surrogate measure of the morphine's
analgesic activity.
Example 5
[0362] A double-blind Phase II clinical study in 24 young healthy
patients undergoing third molar extraction dental surgery showed
that the compound of formula (II) (4 mg total oral dose) did not
antagonize analgesia or pupil constriction produced by intravenous
morphine sulfate. No patients were withdrawn for adverse
effects.
Example 6
[0363] A 78 patient Phase II clinical study was conducted which
compared two doses (2 mg and 12 mg) of the compound of formula (II)
versus placebo in patients undergoing partial colectomy or simple
or radical hysterectomy surgical procedures. All patients in this
clinical study received morphine or meperidine infusions to treat
postoperative pain. Oral doses of compound (II) or placebo were
administered to block postsurgical opioid effects, including
postoperative nausea and vomiting. Results of this study comparing
patients receiving 12 mg of compound (II) and placebo are depicted
graphically in FIGS. 2A and 2B.
[0364] The intensity of nausea was evaluated by patients on a
100-point visual analog scale (VAS) with VAS=0 being no nausea and
VAS=100 being the worst nausea that a patient could imagine. The
highest VAS nausea score (worst nausea) recorded for each patient
was computed and the distributions of these maximum values were
compared among the treatment groups. Nearly 40% of the patients
receiving 12 mg per day of the compound of formula (II) exhibited
no nausea (highest VAS score=0), compared to approximately 25% of
the 2 mg per day group and just over 10% of the placebo group. The
overall treatment differences in the distributions were significant
when compared using a Kruskal-Wallis test (P=0.0184). The improved
outcomes observed in the 12 mg per day dose group are evident in
the pairwise comparisons based on the Wilcoxon rank sum tests. The
12 mg per day dose group had results that were statistically
significantly improved compared to the placebo dose (P=0.0072).
These results are further supported by noting that only 27% of the
12 mg per day dose group reported VAS scores over 20, compared to
63% of the placebo group and 67% of the 2 mg dose group (P=0.003
using the Mantel-Haenszel test for linear trend). No patients
experienced serious adverse side effects in this trial that were
judged by the clinical investigator to be related to the activity
of the compound of formula (II). None of the patients receiving the
compound of formula (II) experienced a reduction in postoperative
pain control, indicating the selectivity of the compound of formula
(II) for blocking opioid nausea and vomiting without blocking
analgesia.
[0365] These results demonstrate that the compound of formula (II)
blocked the adverse gastrointestinal effects of morphine or other
narcotic analgesics that were used for post-surgical pain
relief.
[0366] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0367] Various modification of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims.
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