U.S. patent application number 14/598028 was filed with the patent office on 2015-05-07 for methods of preventing and treating gastrointestinal dysfunction.
The applicant listed for this patent is Adolor Corporation. Invention is credited to David D. Christ, Deanne D. Garver, David Jackson, William K. Schmidt, Bruce A. Wallin.
Application Number | 20150126554 14/598028 |
Document ID | / |
Family ID | 34636584 |
Filed Date | 2015-05-07 |
United States Patent
Application |
20150126554 |
Kind Code |
A1 |
Christ; David D. ; et
al. |
May 7, 2015 |
METHODS OF PREVENTING AND TREATING GASTROINTESTINAL DYSFUNCTION
Abstract
Methods of preventing and treating gastrointestinal dysfunction,
particularly postoperative ileus and post-partum ileus, in a
patient undergoing surgery or other biological stress by
administering 4-aryl-piperidine derivatives are disclosed.
Inventors: |
Christ; David D.; (Newark,
DE) ; Wallin; Bruce A.; (Haverford, PA) ;
Garver; Deanne D.; (Downingtown, PA) ; Schmidt;
William K.; (Davis, CA) ; Jackson; David;
(Cape Coral, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Adolor Corporation |
Exton |
PA |
US |
|
|
Family ID: |
34636584 |
Appl. No.: |
14/598028 |
Filed: |
January 15, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10999054 |
Nov 29, 2004 |
8946262 |
|
|
14598028 |
|
|
|
|
60526851 |
Dec 4, 2003 |
|
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Current U.S.
Class: |
514/327 ;
514/331 |
Current CPC
Class: |
A61K 31/445 20130101;
A61K 9/0053 20130101; A61K 31/451 20130101 |
Class at
Publication: |
514/327 ;
514/331 |
International
Class: |
A61K 31/451 20060101
A61K031/451; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating or preventing non-opioid induced
gastrointestinal dysfunction in a patient undergoing surgery,
comprising the step of: administering to said patient in need
thereof about 0.5 mg/day to about 18 mg/day of an effective amount
of at least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof; in a manner so as to obtain a pharmacokinetic profile
wherein the free concentration in the plasma of said patient of
said 4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
sufficient to achieve substantially saturate the .mu. opioid
receptors in the gastrointestinal tract of said patient; wherein
said patient is not receiving chronic or periodic exogenous
opioids; wherein said gastrointestinal dysfunction is postoperative
ileus; and wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
2. A method of treating or preventing gastrointestinal dysfunction
in a patient undergoing surgery, comprising the step of:
administering to said patient an effective amount of at least one
4-aryl-piperidine derivative or a stereoisomer, a prodrug, a
pharmaceutically acceptable salt, a hydrate, a solvate, an acid
salt hydrate, an N-oxide or an isomorphic crystalline form thereof;
in a manner so as to obtain a pharmacokinetic profile wherein the
plasma or whole blood concentration of 4-aryl-piperidine of said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof reaches a
maximum concentration from about 30 minutes to about 120 minutes
prior to said surgery; wherein said gastrointestinal dysfunction is
postoperative ileus; and wherein said 4-aryl-piperidine derivative
is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
3. A method of treating or preventing gastrointestinal dysfunction
in a patient undergoing surgery, comprising the step of:
administering to said patient an effective amount of at least one
4-aryl-piperidine derivative or a stereoisomer, a prodrug, a
pharmaceutically acceptable salt, a hydrate, a solvate, an acid
salt hydrate, an N-oxide or an isomorphic crystalline form thereof;
in a manner so as to obtain a pharmacokinetic profile wherein the
plasma or whole blood concentration of 4-aryl-piperidine of said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof reaches a
maximum concentration from about 30 minutes to about 120 minutes
after said administration; wherein said gastrointestinal
dysfunction is postoperative ileus; and wherein said
4-aryl-piperidine derivative is
[[24[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylprop-
anoyl]aminolacetic acid.
4. A method according to claim 1, 2, or 3, further comprising the
step of administering at least one opioid to said patient.
5. A method according to claim 4, wherein said 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered to said patient from about
30 minutes prior to surgery to less than about 120 minutes prior to
said administration of said opioid.
6. A method according to claim 1, 2, or 3, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered to said patient from about 30 minutes prior to surgery
to less than about 120 minutes prior to surgery.
7. A method according to claim 1, 2, or 3, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered orally.
8. A method according to claim 1, 2, or 3, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered parenterally.
9. A method according to claim 8, wherein said 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered intravenously.
10. A method according to claim 1, 2, or 3, wherein said
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid is in hydrate form.
11. A method according to claim 10, wherein said
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid dihydrate.
12. A method according to claim 11, wherein said compound is a
substantially pure stereoisomer.
13. A method according to claim 12, wherein said
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid is
[[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-
-3-phenylpropanoyl]amino]acetic acid dihydrate.
14. A method of treating or preventing gastrointestinal dysfunction
in a patient undergoing surgery, comprising the step of:
administering to said patient an effective amount of at least one
4-aryl-piperidine derivative or a stereoisomer, a prodrug, a
pharmaceutically acceptable salt, a hydrate, a solvate, an acid
salt hydrate, an N-oxide or an isomorphic crystalline form thereof;
in a manner so as to obtain a pharmacokinetic profile wherein the
free concentration in the plasma of said patient of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof is sufficient to substantially saturate the .mu. opioid
receptors in the gastrointestinal tract of said patient; wherein
said gastrointestinal dysfunction is postoperative ileus; and
wherein said 4-aryl-piperidine derivative is a compound of formula
(IA): ##STR00023## wherein: 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 aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.4 is hydrogen, alkyl or alkenyl; A is
OR.sup.5 or NR.sup.6R.sup.7; R.sup.5 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.6 is hydrogen or alkyl; R.sup.7 is hydrogen,
alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, aralkyl, B, or alkylene substituted 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 ##STR00024## C(.dbd.O)W or
NR.sup.8R.sup.9; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen,
alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,
heteroaryl, or heteroarylalkyl, or aralkyl 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;
R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or
aralkyl; R.sup.11 is hydrogen or alkyl; R.sup.12 is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, heteroarylalkyl, aralkyl 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 ##STR00025## alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl; R.sup.16 is hydrogen,
alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
aralkyl, 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; R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.19 is hydrogen or alkyl; R.sup.20 is
hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl, 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; n is 0 to
4; and p is 0 or 1.
15. A method of treating or preventing gastrointestinal dysfunction
in a patient undergoing surgery, comprising the step of:
administering to said patient an effective amount of at least one
4-aryl-piperidine derivative or a stereoisomer, a prodrug, a
pharmaceutically acceptable salt, a hydrate, a solvate, an acid
salt hydrate, an N-oxide or an isomorphic crystalline form thereof;
in a manner so as to obtain a pharmacokinetic profile wherein the
plasma or whole blood concentration of 4-aryl-piperidine of said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof reaches a
maximum concentration from about 30 minutes to about 120 minutes
prior to said surgery; wherein said gastrointestinal dysfunction is
postoperative ileus; and wherein said 4-aryl-piperidine derivative
is a compound of formula (IA): ##STR00026## wherein: 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,
aralkyl, heteroaryl, or heteroarylalkyl; R.sup.4 is hydrogen, alkyl
or alkenyl; A is OR.sup.5 or NR.sup.6R.sup.7; R.sup.5 is hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted
alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.6 is hydrogen or alkyl; R.sup.7 is hydrogen,
alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted 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 ##STR00027## C(.dbd.O)W or
NR.sup.8R.sup.9; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen,
alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,
heteroaryl, or heteroarylalkyl 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; R.sup.10 is
hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or
aralkyl; R.sup.11 is hydrogen or alkyl; R.sup.12 is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, heteroarylalkyl, 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
##STR00028## alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl; R.sup.16 is hydrogen,
alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
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; R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.19 is hydrogen or alkyl; R.sup.20 is
hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl 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; n is 0 to
4; and p is 0 or 1.
16. A method of treating or preventing gastrointestinal dysfunction
in a patient undergoing surgery, comprising the step of:
administering to said patient an effective amount of at least one
4-aryl-piperidine derivative or a stereoisomer, a prodrug, a
pharmaceutically acceptable salt, a hydrate, a solvate, an acid
salt hydrate, an N-oxide or an isomorphic crystalline form thereof;
in a manner so as to obtain a pharmacokinetic profile wherein the
plasma or whole blood concentration of 4-aryl-piperidine of said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof reaches a
maximum concentration from about 30 minutes to about 120 minutes
after said administration; wherein said gastrointestinal
dysfunction is postoperative ileus; and wherein said
4-aryl-piperidine derivative is a compound of formula (IA):
##STR00029## wherein: 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, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.4 is hydrogen, alkyl or alkenyl; A is
OR.sup.5 or NR.sup.6R.sup.7; R.sup.5 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.6 is hydrogen or alkyl; R.sup.7 is hydrogen,
alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted 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 ##STR00030## C(.dbd.O)W or
NR.sup.8R.sup.9; R.sup.8 is hydrogen or alkyl; R.sup.9 is hydrogen,
alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl,
cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl,
heteroaryl, or heteroarylalkyl 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; R.sup.10 is
hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or
aralkyl; R.sup.11 is hydrogen or alkyl; R.sup.12 is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, heteroarylalkyl, 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
##STR00031## alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14; R.sup.13 is alkyl substituted
alkylene; R.sup.14 is alkyl; D is OR.sup.15 or NR.sup.16R.sup.17;
R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl; R.sup.16 is hydrogen,
alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
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; R.sup.18 is hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl; R.sup.19 is hydrogen or alkyl; R.sup.20 is
hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl 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; n is 0 to
4; and p is 0 or 1.
17. A method according to claim 14, 15, or 16, further comprising
the step of administering at least one opioid to said patient.
18. A method according to claim 17, wherein said 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered to said patient from about
30 minutes to less than about 120 minutes prior to said
administration of said opioid.
19. A method according to claim 14, 15, or 16, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered to said patient from about 30 minutes to less than
about 120 minutes prior to surgery.
20. A method according to claim 14, 15, or 16, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered orally.
21. A method according to claim 14, 15, or 16, wherein said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered parenterally.
22. A method according to claim 21, wherein said 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered intravenously.
23. A method according to claim 14, 15, or 16, wherein the compound
of formula (IA) is a trans 3,4-isomer.
24. A method according to claim 14, 15, or 16, 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.
25. A method according to claim 14, 15, or 16, wherein: A is
OR.sup.5; and R.sup.5 is hydrogen or alkyl.
26. A method according to claim 14, 15, or 16, wherein: A is
NR.sup.6R.sup.7; R.sup.6 is hydrogen; R.sup.7 is alkylene
substituted B; and B is C(O)W.
27. A method according to claim 14, 15, or 16, wherein: R.sup.7 is
(CH.sub.2).sub.q--B; q is about 1 to about 3; W is OR.sup.10; and
R.sup.10 is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl
or cycloalkyl-substituted alkyl.
28. A method according to claim 14, 15, or 16, wherein: W is
NR.sup.11R.sup.12 R.sup.11 is hydrogen or alkyl; and R.sup.12 is
hydrogen, alkyl or alkylene substituted C(.dbd.O)Y.
29. A method according to claim 14, 15, or 16, wherein: R.sup.12 is
(CH.sub.2).sub.mC(O)Y; m is 1 to 3; Y is OR.sup.18 or
NR.sup.19R.sup.20; and R.sup.18, R.sup.19 and R.sup.20 are
independently hydrogen or alkyl.
30. A method according to claim 14, 15, or 16, wherein: W is OE; E
is CH.sub.2C(.dbd.O)D; D is OR.sup.15 or NR.sup.16R.sup.17;
R.sup.15 is hydrogen or alkyl; R.sup.16 is methyl or benzyl; and
R.sup.17 is hydrogen.
31. A method according to claim 14, 15, or 16, wherein: W is OE; E
is R.sup.13OC(.dbd.O)R.sup.14; R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)--; and R.sup.14 is alkyl.
32. A method according to claim 14, 15, or 16, wherein p is 1.
33. A method according to claim 14, 15, or 16, wherein the
configuration at positions 3 and 4 of the piperidine ring is each
R.
34. A method according to claim 14, 15, or 16, 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.3,
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.2C(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.sub.3).sub.2,
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5),
Z--NH(CH.sub.2)C(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) and
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; wherein: Q represents
##STR00032## G represents ##STR00033## and Z represents
##STR00034##
35. A method according to claim 34, wherein said compound is
selected from the group consisting of: (+)-Z--NHCH.sub.2C(O)OH,
(-)-Z--NHCH.sub.2C(O)OH,
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub.2(C.sub.6H.sub.5) and
(3R,4R)-G-NH(CH.sub.2).sub.3C(O)OH.
36. A method according to claim 35, wherein said compound is
selected from the group consisting of: (+)-Z--NHCH.sub.2C(O)OH, and
(-)-Z--NHCH.sub.2C(O)OH.
37. A method according to claim 36, wherein said compound is
selected from the group consisting of: (+)-Z--NHCH.sub.2C(O)OH.
38. A method according to claim 35, wherein said compound is
Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH.
39. A method according to claim 38, wherein said compound is
(3R,4R, S)-Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH.
40. A method according to claim 14, 15, or 16, wherein said
compound is a substantially pure stereoisomer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Application No.
60/526,851 filed Dec. 4, 2003, the entire disclosure of which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to methods of
preventing and treating gastrointestinal (GI) dysfunction. More
specifically, the present invention relates to methods of
preventing and treating gastrointestinal dysfunction, particularly
postoperative ileus and post-partum ileus, in a patient undergoing
surgery or other biological stress, by administering
4-aryl-piperidine derivatives.
BACKGROUND OF THE INVENTION
[0003] It is well known that opioid drugs target three types of
endogenous opioid receptors (i.e., .mu., .delta., .kappa.
receptors) in biological systems. Many opiates, such as morphine,
are mu opioid agonists that are often used as analgesics for the
treatment of severe pain due to their activation of mu opioid
receptors in the brain and central nervous system (CNS). Opioid
receptors are, however, not limited to the CNS, and may be found in
other tissues throughout the body. A number of side effects of
opioid drugs may be caused by activation of these peripheral
receptors. For example, administration of mu opioid agonists often
results in intestinal dysfunction due to the large number of
receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle,
D., Biochemical and Biophysical Research Communications, 1996, 218,
877-881; Bagnol, D., Mansour, A., Akil, A. and Watson, S. J.,
Neuroscience, 1997, 81, 579-591). Specifically, opioids are
generally known to cause nausea and vomiting as well as inhibition
of normal propulsive gastrointestinal function in animals and man
(Reisine, T., and Pasternak, G., Goodman & Gilman's The
Pharmacological Basis of Therapeutics Ninth Edition, 1996, 521-555)
resulting in side effects such as, for example, constipation.
[0004] Recent evidence has indicated that naturally occurring
endogenous opioid compounds may also affect propulsive activity in
the gastrointestinal (GI) tract. Met-enkephalin, which activates mu
and delta receptors in both the brain and gut, is one of several
neuropeptides found in the GI tract (Koch, T. R., Carney, J. A.,
Go, V. L., and Szurszewski, J. H., Digestive Diseases and Sciences,
1991, 36, 712-728). Additionally, receptor knockout techniques have
shown that mice lacking mu opioid receptors may have faster GI
transit times than wild-type mice, suggesting that endogenous
opioid peptides may tonically inhibit GI transit in normal mice
(Schuller, A. G. P., King, M., Sherwood, A. C., Pintar, J. E., and
Pasternak, G. W., Society of Neuroscience Abstracts, 1998, 24,
524). Studies have shown that opioid peptides and receptors located
throughout the GI tract may be involved in normal regulation of
intestinal motility and mucosal transport of fluids in both animals
and man (Reisine, T., and Pasternak, G., Goodman & Gilman's The
Pharmacological Basis of Therapeutics Ninth Edition, 1996,
521-555). Other studies show that the sympathetic nervous system
may be associated with endogenous opioids and control of intestinal
motility (Bagnol, D., Herbrecht, F., Jule, Y., Jarry, T., and Cupo,
A., Regul. Pept., 1993, 47, 259-273). The presence of endogenous
opioid compounds associated with the GI tract suggests that an
abnormal physiological level of these compounds may lead to bowel
dysfunction.
[0005] It is a common problem for patients having undergone
surgical procedures, especially surgery of the abdomen, to suffer
from a particular bowel dysfunction called post-surgical (or
postoperative) ileus. "Ileus," as used herein, refers to the
obstruction of the bowel or gut, especially the colon. See, e.g.,
Dorland's Illustrated Medical Dictionary, p. 816, 27th ed. (W.B.
Saunders Company, Philadelphia 1988). Ileus should be distinguished
from constipation, which refers to infrequent or difficulty in
evacuating the feces. See, e.g., Dorland's Illustrated Medical
Dictionary, p. 375, 27th ed. (W.B. Saunders Company, Philadelphia
1988). Deus may be diagnosed by the disruption of normal
coordinated movements of the gut, resulting in failure of the
propulsion of intestinal contents. See, e.g., Resnick, J. Am. J. of
Gastroenterology, 1992, 751 and Resnick, J. Am. J. of
Gastroenterology, 1997, 92, 934. In some instances, particularly
following surgery, including surgery of the abdomen, the bowel
dysfunction may become quite severe, lasting for more than a week
and affecting more than one portion of the GI tract. This condition
is often referred to as post-surgical (or postoperative) paralytic
ileus and most frequently occurs after laparotomy (see Livingston,
E. H. and Passaro, E. D. Jr., Digestive Diseases and Sciences,
1990, 35, 121). Similarly, post-partum ileus is a common problem
for women in the period following childbirth, and is thought to be
caused by similar fluctuations in natural opioid levels as a result
of birthing stress.
[0006] Gastrointestinal dysmotility associated with post-surgical
ileus is generally most severe in the colon and typically lasts for
3 to 5 days. The administration of opioid analgesics to a patient
after surgery may often contribute to bowel dysfunction, thereby
delaying recovery of normal bowel function. Since virtually all
patients receive opioid analgesics, such as morphine or other
narcotics for pain relief after surgery, particularly major
surgery, current post-surgical pain treatment may actually slow
recovery of normal bowel function, resulting in a delay in hospital
discharge and increasing the cost of medical care.
[0007] Post-surgical ileus may also occur in the absence of
exogenous opioid agonists. It would be of benefit to inhibit the
natural activity of endogenous opioids during and/or after periods
of biological stress, such as surgery and childbirth, so that ileus
and related forms of bowel dysfunction can be prevented or treated.
Currently, therapies for ileus include functional stimulation of
the intestinal tract, stool softeners, laxatives, lubricants,
intravenous hydration, and nasogastric decompression. These prior
art methods suffer from drawbacks, for example, as lacking
specificity for post-surgical or post-partum ileus. And these prior
art methods offer no means for prevention. If ileus could be
prevented, hospital stays, recovery times, and medical costs would
be significantly decreased in addition to the benefit of minimizing
patient discomfort. Thus, drugs which selectively act on opioid
receptors in the gut would be ideal candidates for preventing
and/or treating post-surgical and post-partum ileus. Of those,
drugs that do not interfere with the effects of opioid analgesics
in the CNS would be of special benefit in that they may be
administered simultaneously for pain management with limited side
effects.
[0008] Peripheral opioid antagonists that do not cross the
blood-brain barrier into the CNS are known in the literature and
have been tested in relation to their activity on the GI tract. In
U.S. Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No.
5,159,081, and U.S. Pat. No. 5,270,328, peripherally selective
piperidine-N-alkylcarboxylate opioid antagonists are described as
being useful in the treatment of idiopathic constipation, irritable
bowel syndrome and opioid-induced constipation. Also, U.S. Pat. No.
4,176,186 describes quaternary derivatives of noroxymorphone (i.e.,
methylnaltrexone) that are said to prevent or relieve the
intestinal immobility side-effect of narcotic analgesics without
reducing analgesic effectiveness. U.S. Pat. No. 5,972,954 describes
the use of methylnaltrexone, enteric-coated methylnaltrexone, or
other quaternary derivatives of noroxymorphone for preventing
and/or treating opioid- and/or non-opioid-induced side effects
associated with opioid administration.
[0009] General opioid antagonists, such as naloxone and naltrexone
have also been implicated as being useful in the treatment of GI
tract dysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek,
M. J. Schaefer, R. A., Hahn, E. F., Fishman, J., Lancet, 1983,
1(8319), 261 disclose naloxone and other morphinan-based opioid
antagonists (i.e., naloxone, naltrexone) for the treatment of
idiopathic gastrointestinal dysmotility. In addition, naloxone has
been shown to effectively treat non-opioid induced bowel
obstruction, implying that the drug may act directly on the GI
tract or in the brain (Schang, J. C., Devroede, G., Am. J.
Gastroenerol., 1985, 80(6), 407). Furthermore, it has been
implicated that naloxone may provide therapy for paralytic ileus
(Mack, D. J. Fulton, J. D., Br. J. Surg., 1989, 76(10), 1101).
However, it is well known that activity of naloxone and related
drugs is not limited to peripheral systems and may interfere with
the analgesic effects of opioid narcotics.
[0010] Inasmuch as post-surgical and post-partum ileus, for
example, are common illnesses that add to the cost of health care
and as yet have no specific treatments, there is a need for a
specific and effective remedy. The majority of currently known
opioid antagonist therapies are not peripherally selective and have
the potential for undesirable side effects resulting from
penetration into the CNS. Given the estimated 21 million inpatient
surgeries and 26 outpatient surgeries each year, and an estimate of
4.7 million patients experiencing post-surgical ileus, methods
involving opioid antagonists that are not only specific for
peripheral systems, but specific for the gut, are desirable for
treating post-surgical and post-partum ileus.
[0011] Alvimopan is an orally active, gastrointestinal (GI)
restricted .mu. opioid antagonist being developed to alleviate the
GI side effects associated with narcotic therapy. This compound
differs from previously characterized peripherally selective opioid
antagonists by its potency and degree of peripheral receptor
selectivity [Zimmerman et al., J. Med. Chem., 1994, 37,
2262-2265].
[0012] In clinical trials, alvimopan had heretofore been
administered at least two hours prior to a surgical procedure to
block the undesirable effects of opioid analgesics on the GI tract.
Oftentimes, however, there may be insufficient time to administer
the alvimopan at least two hours prior to surgery, especially prior
to emergency surgery.
[0013] Therefore, it would be desirable to provide methods for
preventing and/or treating gastrointestinal dysfunction,
particularly postoperative ileus, in a patient undergoing surgery.
The methods of the present invention are directed toward these, as
well as other, important ends.
SUMMARY OF THE INVENTION
[0014] The methods of the present invention are directed to
treating and preventing gastrointestinal dysfunction, particularly
postoperative ileus and postpartum ileus, in a patient undergoing
surgery or other biological stress.
[0015] In a first aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0016] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0017] in a manner so as to obtain a pharmacokinetic profile
wherein the free concentration in the plasma of said patient of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof is sufficient to substantially saturate the .mu. opioid
receptors in the gastrointestinal tract of said patient;
in a manner so as to obtain a pharmacokinetic profile wherein the
plasma or whole blood concentration of 4-aryl-piperidine derivative
or stereoisomer, prodrug, pharmaceutically acceptable salt,
hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is sufficient to achieve substantially
complete saturation of .mu. opioid receptors in the
gastrointestinal tract of said patient;
[0018] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0019] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0020] In a second aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0021] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0022] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes prior to said surgery;
[0023] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0024] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0025] In a third aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0026] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0027] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes after said administration;
[0028] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0029] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0030] In a fourth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0031] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0032] in a manner so as to obtain a pharmacokinetic profile
wherein the free concentration in the plasma of said patient of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof is sufficient to substantially saturate the vi opioid
receptors in the gastrointestinal tract of said patient;
[0033] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
sufficient to achieve substantially complete saturation of .mu.
opioid receptors in the gastrointestinal tract of said patient;
[0034] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0035] wherein said 4-aryl-piperidine derivative is a compound of
formula (IA):
##STR00001##
[0036] wherein:
[0037] R.sup.1 is hydrogen or alkyl;
[0038] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0039] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0040] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0041] A is OR.sup.5 or NR.sup.6R.sup.7;
[0042] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0043] R.sup.6 is hydrogen or alkyl;
[0044] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0045] B is
##STR00002##
[0046] C(.dbd.O)W or NR.sup.8R.sup.9;
[0047] R.sup.8 is hydrogen or alkyl;
[0048] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and R.sup.9 form
a heterocyclic ring;
[0049] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0050] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0051] R.sup.11 is hydrogen or alkyl;
[0052] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0053] E is
##STR00003##
[0054] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0055] R.sup.13 is alkyl substituted alkylene;
[0056] R.sup.14 is alkyl;
[0057] D is OR.sup.15 or NR.sup.16R.sup.17;
[0058] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0059] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0060] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached,
[0061] R.sup.16 and R.sup.17 form a heterocyclic ring;
[0062] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0063] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0064] R.sup.19 is hydrogen or alkyl;
[0065] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl or, together with the nitrogen atom to which they
are attached, R.sup.19 and R.sup.20 form a heterocyclic ring;
[0066] R.sup.21 is hydrogen or alkyl;
[0067] n is 0 to 4; and
[0068] p is 0 or 1.
[0069] In a fifth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0070] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0071] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes prior to said surgery;
[0072] wherein said gastrointestinal dysfunction is postoperative
ileus; and [0073] wherein said 4-aryl-piperidine derivative is a
compound of formula (IA):
##STR00004##
[0074] wherein:
[0075] R.sup.1 is hydrogen or alkyl;
[0076] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0077] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0078] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0079] A is OR.sup.5 or NR.sup.6R.sup.7;
[0080] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0081] R.sup.6 is hydrogen or alkyl;
[0082] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0083] B is
##STR00005##
[0084] C(.dbd.O)W or NR.sup.8R.sup.9;
[0085] R.sup.8 is hydrogen or alkyl;
[0086] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and R.sup.9 form
a heterocyclic ring;
[0087] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0088] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0089] R.sup.11 is hydrogen or alkyl;
[0090] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0091] E is
##STR00006##
[0092] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0093] R.sup.13 is alkyl substituted alkylene;
[0094] R.sup.14 is alkyl;
[0095] D is OR.sup.15 or NR.sup.16R.sup.17;
[0096] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0097] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0098] 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;
[0099] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0100] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0101] R.sup.19 is hydrogen or alkyl; [0102] R.sup.20 is hydrogen,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl,
aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.19 and R.sup.20
form a heterocyclic ring;
[0103] R.sup.21 is hydrogen or alkyl;
[0104] n is 0 to 4; and
[0105] p is 0 or 1.
[0106] In a sixth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0107] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0108] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes after said administration;
[0109] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0110] wherein said 4-aryl-piperidine derivative is a compound of
formula (IA):
##STR00007##
[0111] wherein:
[0112] R.sup.1 is hydrogen or alkyl;
[0113] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0114] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0115] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0116] A is OR.sup.5 or NR.sup.6R.sup.7;
[0117] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0118] R.sup.6 is hydrogen or alkyl;
[0119] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0120] B is
##STR00008##
[0121] C(.dbd.O)W or NR.sup.8R.sup.9;
[0122] R.sup.8 is hydrogen or alkyl;
[0123] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and form R.sup.9
a heterocyclic ring;
[0124] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0125] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0126] R.sup.11 is hydrogen or alkyl;
[0127] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0128] E is
##STR00009##
[0129] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0130] R.sup.13 is alkyl substituted alkylene;
[0131] R.sup.14 is alkyl;
[0132] D is OR.sup.11 or NR.sup.16R.sup.17;
[0133] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0134] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0135] 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;
[0136] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0137] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0138] R.sup.19 is hydrogen or alkyl;
[0139] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl or, together with the nitrogen atom to which they
are attached, R.sup.19 and R.sup.20 form a heterocyclic ring;
[0140] R.sup.21 is hydrogen or alkyl;
[0141] n is 0 to 4; and
[0142] p is 0 or 1.
[0143] These and other aspects of the invention will become more
apparent from the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0144] FIG. 1 shows the free plasma concentration of alvimopan (12
mg dose) as a function of time.
[0145] FIG. 2 shows GI score as a function of log of plasma
concentrations measured as AUC (.tau.) (in ng-ml/hr) with a GI
score measured by radio-opaque markers in subjects given loperamide
with either placebo or one of three doses of I.V. alvimopan (0.1 mg
b.i.d, 0.45 mg b.i.d., and 1 mg b.i.d.) selected to target
different plasma concentrations (4.5, 20, and 45 ng/ml,
respectively).
DETAILED DESCRIPTION OF THE INVENTION
[0146] The methods of the present invention are directed to
treating and preventing gastrointestinal dysfunction, particularly
postoperative ileus and post-partum ileus, in a patient undergoing
surgery. Different types of ileus may be treated and/or prevented
using the methods of the present invention. The present methods are
particularly suitable for treating and/or preventing postoperative
ileus and post-partum ileus. "Postoperative ileus," which may
follow surgery such as laparotomy, may be characterized by such
symptoms as, for example, obstruction of the gut, particularly in
the colon, resulting in nausea, vomiting, lack of passage of flatus
and/or stools, abdominal distention and lack of bowel sounds. This
condition generally lasts from about 3 to about 5 days, but may
endure longer, including up to about one week. Longer durations are
generally characteristic of a more severe form of ileus, termed
post-surgical paralytic ileus, which may affect other portions of
the GI tract in addition to the colon. "Post-partum ileus"
generally refers to obstruction of the gut, particularly the colon,
following parturition. Both natural and surgically-assisted
procedures during parturition may lead to post-partum ileus treated
by the present invention. Symptoms of post-partum ileus and
postoperative ileus are similar.
Error! Bookmark not Defined.
[0147] As employed above and throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0148] As used herein, "alkyl" refers to an optionally substituted,
saturated straight, branched, or cyclic hydrocarbon having from
about 1 to about 20 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 1 to about 8 carbon atoms, herein
referred to as "lower alkyl", being preferred. "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. Alkyl groups include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl,
cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl,
2,2-dimethylbutyl, and 2,3-dimethylbutyl.
[0149] As used herein, "alkylene" refers to a bivalent alkyl
radical having the general formula --(CH.sub.2).sub.n--, where n is
1 to 10, and all combinations and subcombinations of ranges
therein. The alkylene group may be straight, branched or cyclic.
Non-limiting examples include methylene, methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), propylene (--(CH.sub.2).sub.3--),
trimethylene, pentamethylene, and hexamethylene. There may be
optionally inserted along the alkylene group one or more oxygen,
sulfur or optionally substituted nitrogen atoms, wherein the
nitrogen substituent is alkyl as described previously. Alkylene
groups can be optionally substituted. The term "lower alkylene"
herein refers to those alkylene groups having from about 1 to about
6 carbon atoms. Preferred alkylene groups have from about 1 to
about 4 carbons.
[0150] As used herein, "aralkylene" refers to a bivalent alkyl
radical having the general formula --(CH.sub.2).sub.n--, wherein
any one of the hydrogens on the alkylene radical is replaced by an
aryl group, and where n is 1 to 10. Aralkylene groups can be
optionally substituted. Non-limiting examples include
phenylmethylene, 2-phenyltrimethylene, 3-(p-anisyl)-pentamethylene,
and 2-(m-trifluromethylphenyl)-hexamethylene. Aralkylene groups can
be substituted or unsubstituted. The term "lower aralkylene" herein
refers to those aralkylene groups having from about 1 to about 6
carbon atoms in the alkylene portion of the aralkylene group.
[0151] As used herein, "alkenyl" refers to a monovalent alkyl
radical 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. Alkenyl groups
can be optionally substituted. 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.
[0152] As used herein, the term "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.
[0153] As used herein, "aryl" refers to an optionally substituted,
mono-, di-, tri-, or other multicyclic aromatic ring system having
from about 5 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbons being preferred.
Non-limiting examples include, for example, phenyl, naphthyl,
anthracenyl, and phenanthrenyl.
[0154] As used herein, "aralkyl" refers to alkyl radicals bearing
an aryl substituent and have from about 6 to about 50 carbon atoms
(and all combinations and subcombinations of ranges and specific
numbers of carbon atoms therein), with from about 6 to about 10
carbon atoms being preferred. Aralkyl groups can be optionally
substituted in either the aryl or alkyl portions. Non-limiting
examples include, for example, phenylmethyl(benzyl),
diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl and
3-(4-methylphenyl)propyl.
[0155] As used herein, "heteroaryl" refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aromatic ring
system that includes at least one, and preferably from 1 to about 4
sulfur, oxygen, or nitrogen heteroatom ring members. Heteroaryl
groups can have, for example, from about 3 to about 50 carbon atoms
(and all combinations and subcombinations of ranges and specific
numbers of carbon atoms therein), with from about 4 to about 10
carbons being preferred. Non-limiting examples of heteroaryl groups
include, for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl,
pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,
pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl,
benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,
carbazolyl, benzimidazolyl, and isoxazolyl.
[0156] As used herein, "cycloalkyl" refers to an optionally
substituted, alkyl group having one or more rings in their
structures having from about 3 to about 20 carbon atoms (and all
combinations and subcombinations of ranges and specific numbers of
carbon atoms therein), with from about 3 to about 10 carbon atoms
being preferred, with from about 3 to about 8 carbon atoms being
more preferred, with from about 3 to about 6 carbon atoms being
even more preferred. Multi-ring structures may be bridged or fused
ring structures. The cycloalkyl group may be optionally substituted
with, for example, alkyl, preferably C.sub.1-C.sub.3 alkyl, alkoxy,
preferably C.sub.1-C.sub.3 alkoxy, or halo. Non-limiting examples
include, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl cyclooctyl, and adamantyl.
[0157] As used herein, "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. Non-limiting examples include,
for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylethyl,
cyclopentylpropyl, cyclopropylmethyl and the like.
[0158] As used herein, "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.
[0159] As used herein, "alkylcycloalkyl" refers to an optionally
substituted ring system comprising a cycloalkyl group having one or
more alkyl substituents. Non-limiting examples include, for
example, alkylcycloalkyl groups include 2-methylcyclohexyl,
3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and
4-methyldecahydronaphthalenyl.
[0160] As used herein, "heteroaralkyl" refers to an optionally
substituted, heteroaryl substituted alkyl radicals having from
about 2 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 25 carbon atoms being
preferred. Non-limiting examples include 2-(1H-pyrrol-3-yl)ethyl,
3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and
3-(pyrimidin-2-yl)-2-methylcyclopentanyl.
[0161] As used herein, "heterocycloalkyl" refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aliphatic ring
system that includes at least one, and preferably from 1 to about 4
sulfur, oxygen, or nitrogen heteroatom ring members.
Heterocycloalkyl groups can have from about 3 to about 20 carbon
atoms (and all combinations and subcombinations of ranges and
specific numbers of carbon atoms therein), with from about 4 to
about 10 carbons being preferred. The heterocycloalkyl group may be
unsaturated, and may also be fused to aromatic rings. Non-limiting
examples include, for example, tetrahydrofuranyl,
tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,
isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,
piperazinyl, morpholinyl, piperadinyl, decahydroquinolyl,
octahydrochromenyl, octahydro-cyclopenta[c]pyranyl,
1,2,3,4,-tetrahydroquinolyl, octahydro-[2]pyrindinyl,
decahydro-cycloocta[c]furanyl, and imidazolidinyl.
[0162] As used herein, the term "spiroalkyl" refers to an
optionally substituted, alkylene diradical, both ends of which are
bonded to the same carbon atom of the parent group to form a
spirocyclic group. The spiroalkyl group, taken together with its
parent group, as herein defined, has 3 to 20 ring atoms.
Preferably, it has 3 to 10 ring atoms. Non-limiting examples of a
spiroalkyl group taken together with its parent group include
1-(1-methyl-cyclopropyl)-propan-2-one,
2-(1-phenoxy-cyclopropyl)-ethylamine, and
1-methyl-spiro[4.7]dodecane.
[0163] As used herein, the term "alkoxy" refers to an optionally
substituted alkyl-O-- group wherein alkyl is as previously defined.
Non-limiting examples include, for example, include methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy.
[0164] As used herein, the term "aryloxy" refers to an optionally
substituted aryl-O-- group wherein aryl is as previously defined.
Non-limiting examples include, for example, phenoxy and
naphthoxy.
[0165] As used herein, the term "aralkoxy" refers to an optionally
substituted aralkyl-O-- group wherein aralkyl is as previously
defined. Non-limiting examples include, for example, benzyloxy,
1-phenylethoxy, 2-phenylethoxy, and 3-naphthylheptoxy.
[0166] As used herein, the term "aryloxyaryl" refers to an aryl
group with an aryloxy substituent wherein aryloxy and aryl are as
previously defined. Aryloxyaryl groups can be optionally
substituted. Non-limiting examples include, for example,
phenoxyphenyl, and naphthoxyphenyl.
[0167] As used herein, the term "heteroarylaryl" refers to an aryl
group with a heteroaryl substituent wherein heteroaryl and aryl are
as previously defined. Heteroarylaryl groups can be optionally
substituted. Non-limiting examples include, for example,
3-pyridylphenyl, 2-quinolylnaphthalenyl, and 2-pyrrolylphenyl.
[0168] As used herein, the term "alkoxyaryl" refers to an aryl
group bearing an alkoxy substituent wherein alkoxy and aryl are as
previously defined. Alkoxyaryl groups can be optionally
substituted. Non-limiting examples include, for example,
para-anisyl, meta-t-butoxyphenyl, and methylendioxyphenyl.
[0169] As used herein, the term "carbon chain of said alkoxy
interrupted by a nitrogen atom" refers to a carbon chain of an
alkoxy group, wherein a nitrogen atom has been inserted between two
adjacent carbon atoms of the carbon chain and wherein alkoxy is as
previously defined. Both the alkoxy group and the nitrogen atom can
be optionally substituted. Exemplary groups include
--OCH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.3 and
--OCH.sub.2CH.sub.2NHCH.sub.3.
[0170] As used herein, the term "heterocycloalkylheteroaryl" refers
to an heteroaryl group with a heterocycloalkyl substituent wherein
heterocycloalkyl and heteroaryl are as previously defined.
Heterocycloalkylheteroaryl groups can be optionally substituted.
Exemplary heterocycloalkylheteroaryl groups include
3-[N-morpholinyl]pyridine and 3-[2-piperidinyl]pyridine.
[0171] As used herein, the term "heteroarylheteroaryl" refers to a
heteroaryl group with a heteroaryl substituent wherein heteroaryl
is as previously defined. Heteroarylherteroaryl groups can be
optionally substituted. Exemplary heteroarylheteroaryl groups
include 4-[3-pyridyl]pyridine and 2-[2-quinolyl]quinuclidine.
[0172] As used herein, the term "aralkoxyaryl" refers to an aryl
group with an aralkoxy substituent wherein aralkoxy and aryl are as
previously defined. Aralkoxyaryl groups can be optionally
substituted. Exemplary aralkoxyaryl groups include benzyloxyphenyl
and meta-toluenyloxyphenyl.
[0173] As used herein, the term "arylheteroaryl" refers to a
heteroaryl group with an aryl substituent wherein aryl and
heteroaryl are as previously defined. Arylheteroaryl groups can be
optionally substituted. Exemplary arylheteroaryl groups include
3-phenylpyridyl and 2-naphthalenylquinolinyl.
[0174] As used herein, the term "alkoxyheteroaryl" refers to an
heteroaryl group with an alkoxy substituent wherein alkoxy and
heteroaryl are as previously defined. Alkoxyheteroaryl groups can
be optionally substituted. Exemplary alkoxyheteroaryl groups
include 2-methoxypyridine and 6-n-propoxyquinoline.
[0175] As used herein, "bicycloalkyl" refers to an optionally
substituted, alkyl group having two bridged rings in its structure
and having from about 7 to about 20 carbon atoms (and all
combinations and subcombinations of ranges and specific numbers of
carbon atoms therein), with from about 7 to about 15 carbon atoms
being preferred. Exemplary bicycloalkyl-ring structures include,
but are not limited to, norbornyl, bornyl, [2.2.2]-bicyclooctyl,
cis-pinanyl, trans-pinanyl, camphanyl, iso-bornyl, and fenchyl.
[0176] As used herein, "bicycloalkenyl" refers to an optionally
substituted, alkenyl group having two bridged rings in its
structure and having from about 7 to about 20 carbon atoms (and all
combinations and subcombinations of ranges and specific numbers of
carbon atoms therein), with from about 7 to about 15 carbon atoms
being preferred. Exemplary bicycloalkenyl-ring structures include,
but are not limited to, bicyclo[2.2.1]hept-5-en-2-yl, bornenyl,
[2.2.2]-bicyclooct-5-en-2-yl, .alpha.-pinenyl, .beta.-pinenyl,
camphenyl, and fenchyl.
[0177] As used herein, "carboxy" refers to a --C(.dbd.O)OH
group.
[0178] As used herein, "alkanoyl" refers to a --C(.dbd.O)-alkyl
group, wherein alkyl is as previously defined. Exemplary alkanoyl
groups include acetyl(ethanoyl), n-propanoyl, n-butanoyl,
2-methylpropanoyl, n-pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl,
2,2-dimethylpropanoyl, heptanoyl, decanoyl, and palmitoyl.
[0179] As used herein, "alkoxy-alkyl" refers to an alkyl-O-alkyl
group where alkyl is as previously described.
[0180] As used herein, "heterocyclic" refers to a monocyclic or
multicyclic 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. Non-limiting
examples include, for example, pyrrole and piperidine groups.
[0181] As used herein, "halo" refers to fluoro, chloro or
bromo.
[0182] Typically, substituted chemical moieties include one or more
substituents that replace hydrogen. Exemplary substituents include,
for example, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl,
alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl,
heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (--OH), nitro
(--NO.sub.2), cyano (--CN), amino (--NH.sub.2), --N-substituted
amino (--NHR''), --N,N-disubstituted amino (--N(R'')R''), carboxyl
(--COOH), --C(.dbd.O)R'', --OR'', --C(.dbd.O)OR'',
--NHC(.dbd.O)R'', aminocarbonyl (--C(.dbd.O)NH.sub.2),
--N-substituted aminocarbonyl (--C(.dbd.O)NHR''),
--N,N-disubstituted aminocarbonyl (--C(.dbd.O)N(R'')R''), thiol,
thiolato (SR''), sulfonic acid (SO.sub.3H), phosphoric acid
(PO.sub.3H), S(.dbd.O).sub.2R.sup.11, S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NHR'', S(.dbd.O).sub.2NR''R'', NHS(.dbd.O).sub.2R'',
NR''S(.dbd.O).sub.2R'', CF.sub.3, CF.sub.2CF.sub.3,
NHC(.dbd.O)NHR'', NHC(.dbd.O)NR''R'', NR''C(.dbd.O)NHR'',
NR''C(.dbd.O)NR''R'', NR''C(.dbd.O)R'' and the like. In relation to
the aforementioned substituents, each moiety R'' can be,
independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl,
heteroaryl, or heterocycloalkyl, for example.
[0183] As used herein, the phrase "to substantially saturate"
refers to the providing sufficient compound to the patient to
achieve a maximum free (unbound) concentrations greater than or
equal to 10-fold above the Ki to produce greater than 91% receptor
occupancy, as defined in Copeland, R. E., Enzymes. A Practical
Introduction to Structure, Mechanism, and Data Analysis, 2.sup.nd
Edition, (New York: Wiley-VCH, 2000), page 88, the disclosure of
which is incorporated herein by reference.
[0184] As used herein, the term "surgery" refers to any methodical
action of the hand, or of the hand with instruments, on a patient,
to produce a curative or remedial effect, and specifically includes
Caesarian births and sterilizations.
[0185] As used herein, the term "side effect" refers to a
consequence other than the one(s) for which an agent or measure is
used, as the adverse effects produced by a drug, especially on a
tissue or organ system other then the one sought to be benefited by
its administration. In the case, for example, of the treatment of
gastrointestinal dysfunction, such as the treatment of
postoperative ileus, the term "side effect" may refer to such
conditions as, for example, nausea, vomiting, diarrhea, and
combinations thereof.
[0186] As used herein, "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).
[0187] As used herein, "pharmaceutically acceptable" refers to
those compounds, materials, compositions, and/or dosage forms that
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.
[0188] As used herein, "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. These physiologically
acceptable salts are prepared by methods known in the art, e.g., by
dissolving the free amine bases with an excess of the acid in
aqueous alcohol, or neutralizing a free carboxylic acid with an
alkali metal base such as a hydroxide, or with an amine.
[0189] Compounds described herein throughout, can be used or
prepared in alternate forms. For example, many amino-containing
compounds can be used or prepared as an acid addition salt. Often
such salts improve isolation and handling properties of the
compound. For example, depending on the reagents, reaction
conditions and the like, compounds as described herein can be used
or prepared, for example, as their hydrochloride or tosylate salts.
Isomorphic crystalline forms, all chiral and racemic forms,
N-oxide, hydrates, solvates, and acid salt hydrates, are also
contemplated to be within the scope of the present invention.
[0190] 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. It is well known in the art
that compounds containing both amino and carboxyl groups often
exist in equilibrium with their zwitterionic forms. Thus, any of
the compounds described herein throughout that contain, for
example, both amino and carboxyl groups, also include reference to
their corresponding zwitterions.
[0191] As used herein, "patient" refers to animals, including
mammals, preferably humans.
[0192] As used herein, "prodrug" refers to compounds specifically
designed to maximize the amount of active species that reaches the
desired site of reaction that are of themselves typically inactive
or minimally active for the activity desired, but through
biotransformation are converted into biologically active
metabolites.
[0193] As used herein, "stereoisomers" refers to compounds that
have identical chemical constitution, but differ as regards the
arrangement of the atoms or groups in space.
[0194] As used herein, "N-oxide" refers to compounds wherein the
basic nitrogen atom of either a heteroaromatic ring or tertiary
amine is oxidized to give a quaternary nitrogen bearing a positive
formal charge and an attached oxygen atom bearing a negative formal
charge.
[0195] As used herein, "hydrate" refers to a compound of the
present invention which is associated with water in the molecular
form, i.e., in which the H--OH bond is not split, and may be
represented, for example, by the formula R.H.sub.2O, where R is a
compound of the invention. A given compound may form more than one
hydrate including, for example, monohydrates (R.H.sub.2O) or
polyhydrates (R.nH.sub.2O wherein n is an integer >1) including,
for example, dihydrates (R.2H.sub.2O), trihydrates (R.3H.sub.2O),
and the like, or hemihydrates, such as, for example, R.n/2H.sub.2O,
R.n/3H.sub.2O, R.n/4H.sub.2O and the like wherein n is an
integer.
[0196] As used herein, "solvate" refers to a compound of the
present invention which is associated with solvent in the molecular
form, i.e., in which the solvent is coordinatively bound, and may
be represented, for example, by the formula R.(solvent), where R is
a compound of the invention. A given compound may form more than
one solvate including, for example, monosolvates (R.(solvent)) or
polysolvates (R.n(solvent)) wherein n is an integer >1)
including, for example, disolvates (R.2(solvent)), trisolvates
(R.3(solvent)), and the like, or hemisolvates, such as, for
example, R.n/2(solvent), R.n/3(solvent), R.n/4(solvent) and the
like wherein n is an integer. Solvents herein include mixed
solvents, for example, methanol/water, and as such, the solvates
may incorporate one or more solvents within the solvate.
[0197] As used herein, "acid salt hydrate" refers to a complex that
may be formed through association of a compound having one or more
base moieties with at least one compound having one or more acid
moieties or through association of a compound having one or more
acid moieties with at least one compound having one or more base
moieties, said complex being further associated with water
molecules so as to form a hydrate, wherein said hydrate is as
previously defined and R represents the complex herein described
above.
[0198] When any variable occurs more than one time in any
constituent or in any formula, its definition in each occurrence is
independent of its definition at every other occurrence.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0199] The piperidines derivatives useful in the methods of the
invention as illustrated in formula (IA) can occur as the trans and
cis stereochemical isomers at the 3- and 4-positions of the
piperidine ring. The term "trans" as used herein refers, for
example, in formula (IA) to the R.sup.2 substituent being on the
opposite side of the R.sup.4 substituent, whereas in the "cis"
isomer, the R.sup.2 substituent and the R.sup.4 substituent are on
the same side of the ring. The present invention contemplates the
individual stereoisomers, as well as racemic mixtures. In the most
preferred compounds of formula (IA), the R.sup.2 substituent and
the R.sup.4 substituent are in the "trans" orientation on the
piperidine.
[0200] In addition to the "cis" and "trans" orientation of the
R.sup.2 substituent and the R.sup.4 substituent of formula (IA),
the absolute stereochemistry of the carbon atoms bearing R.sup.2
substituent and the R.sup.4 substituent of formula (IA) is also
defined as using the commonly employed "R" and "S" definitions
(Orchin et al., The Vocabulary of Organic Chemistry, John Wiley and
Sons, Inc., 1981, page 126, which is incorporated herein by
reference). The preferred compounds of the present invention are in
which the configuration of both the R.sup.2 substituent and the
R.sup.4 substituents of formula (IA) on the piperidine ring are
"R."
[0201] Furthermore, asymmetric carbon atoms may be introduced into
the molecule depending on the structure of R.sup.4. As such, these
classes of compounds can exist as the individual "R" or "S"
stereoisomers at these chiral centers, or the racemic mixture of
the isomers, and all are contemplated as 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 is "R" or "S", i.e., those
compounds in which the configuration at the three chiral centers
are preferably 3R, 4R, S or 3R, 4R, R.
[0202] As used herein, "peripheral" or "peripherally-acting" refers
to an agent that acts outside of the central nervous system.
[0203] As used herein, "centrally-acting" refers to an agent that
acts within the central nervous system (CNS).
[0204] In certain preferred embodiments, the methods may involve a
peripheral opioid antagonist compound. The term "peripheral"
designates that the compound acts primarily on physiological
systems and components external to the central nervous system. In
preferred form, the peripheral opioid antagonist compounds employed
in the methods of the present invention exhibit high levels of
activity with respect to peripheral tissue, such as,
gastrointestinal tissue, while exhibiting reduced, and preferably
substantially no, CNS activity. The phrase "substantially no CNS
activity," as used herein, means that less than about 20% of the
pharmacological activity of the compounds employed in the present
methods is exhibited in the CNS, preferably less than about 15%,
more preferably less than about 10%, even more preferably less than
about 5% and most preferably 0% of the pharmacological activity of
the compounds employed in the present methods is exhibited in the
CNS.
[0205] Furthermore, it is preferred in certain embodiments of the
invention that the compound of formula (IA) does not substantially
cross the blood-brain barrier and thereby interfere with the
receptors in the CNS. The phrase "does not substantially cross," as
used herein, means that less than about 20% by weight of the
compound employed in the present methods crosses the blood-brain
barrier, preferably less than about 15% by weight, more preferably
less than about 10% by weight, even more preferably less than about
5% by weight and most preferably 0% by weight of the compound
crosses the blood-brain barrier.
[0206] The methods of the present invention are directed to
treating and preventing gastrointestinal dysfunction in a patient
undergoing surgery or other biological stress, including the birth
process. Such gastrointestinal dysfunction includes postoperative
ileus and post-partum ileus.
[0207] The methods of the present invention may further employ one
or more other active ingredients that may be conventionally
employed in preventing or treating gastrointestinal dysfunction.
Such conventional ingredients include, for example, laxatives,
fiber, stool softeners, or bowel stimulants. Typical or
conventional ingredients that may be included are described, for
example, in the Physicians' Desk Reference, 2003, the disclosure of
which is hereby incorporated herein by reference, in its entirety.
Other optional components 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.
[0208] Suitable 4-aryl-piperidine derivatives and a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide and an isomorphic crystalline form
thereof. Preferred 4-aryl-piperidine derivatives include, for
example, the compounds disclosed in U.S. Pat. No. 5,250,542; U.S.
Pat. No. 5,159,081; U.S. Pat. No. 5,270,328; and U.S. Pat. No.
5,434,171, U.S. Pat. No. 6,451,806 and U.S. Pat. No. 6,469,030, the
disclosures of which are hereby incorporated herein by reference,
in their entireties.
[0209] In a first aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0210] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0211] in a manner so as to obtain a pharmacokinetic profile
wherein the free concentration in the plasma of said patient of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof is sufficient to substantially saturate the .mu. opioid
receptors in the gastrointestinal tract of said patient;
[0212] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
sufficient to achieve substantially complete saturation of .mu.
opioid receptors in the gastrointestinal tract of said patient;
[0213] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0214] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0215] In a second aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0216] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0217] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes prior to said surgery;
[0218] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0219] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0220] In a third aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0221] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0222] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes after said administration;
[0223] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0224] wherein said 4-aryl-piperidine derivative is
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid.
[0225] In preferred embodiments, the
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid is in hydrate form, more preferably,
[[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpro-
panoyl]amino]acetic acid dihydrate, even more preferably in
substantially pure isomeric form, most especially
[[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-
-3-phenylpropanoyl]amino]acetic acid dihydrate (alvimopan).
[0226] In a fourth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0227] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0228] in a manner so as to obtain a pharmacokinetic profile
wherein the free concentration in the plasma of said patient of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof is sufficient to substantially saturate the .mu. opioid
receptors in the gastrointestinal tract of said patient;
[0229] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
sufficient to achieve substantially complete saturation of .mu.
opioid receptors in the gastrointestinal tract of said patient;
[0230] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0231] wherein said 4-aryl-piperidine derivative is a compound of
formula (IA):
##STR00010## [0232] wherein:
[0233] R.sup.1 is hydrogen or alkyl;
[0234] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0235] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0236] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0237] A is OR.sup.5 or NR.sup.6R.sup.7;
[0238] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0239] R.sup.6 is hydrogen or alkyl;
[0240] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0241] B is
##STR00011##
[0242] C(.dbd.O)W or NR.sup.8R.sup.9;
[0243] R.sup.8 is hydrogen or alkyl;
[0244] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and R.sup.9 form
a heterocyclic ring;
[0245] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0246] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0247] R.sup.11 is hydrogen or alkyl;
[0248] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0249] E is
##STR00012##
[0250] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0251] R.sup.13 is alkyl substituted alkylene;
[0252] R.sup.14 is alkyl;
[0253] D is OR.sup.15 or NR.sup.16R.sup.17;
[0254] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0255] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0256] 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;
[0257] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0258] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0259] R.sup.19 is hydrogen or alkyl;
[0260] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl or, together with the nitrogen atom to which they
are attached, R.sup.19 and R.sup.20 form a heterocyclic ring;
[0261] R.sup.21 is hydrogen or alkyl;
[0262] n is 0 to 4; and
[0263] p is 0 or 1.
[0264] In a fifth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0265] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0266] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes prior to said surgery;
[0267] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0268] wherein said 4-aryl-piperidine derivative is a compound of
formula (IA):
##STR00013##
[0269] wherein:
[0270] R.sup.1 is hydrogen or alkyl;
[0271] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0272] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0273] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0274] A is OR.sup.5 or NR.sup.6R.sup.7;
[0275] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0276] R.sup.6 is hydrogen or alkyl;
[0277] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0278] B is
##STR00014##
[0279] C(.dbd.O)W or NR.sup.8R.sup.9;
[0280] R.sup.8 is hydrogen or alkyl;
[0281] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and R.sup.9 form
a heterocyclic ring;
[0282] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0283] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0284] R.sup.11 is hydrogen or alkyl;
[0285] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0286] E is
##STR00015##
[0287] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0288] R.sup.13 is alkyl substituted alkylene;
[0289] R.sup.14 is alkyl;
[0290] D is OR.sup.15 or NR.sup.16R.sup.17;
[0291] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0292] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0293] 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;
[0294] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0295] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0296] R.sup.19 is hydrogen or alkyl;
[0297] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl or, together with the nitrogen atom to which they
are attached, R.sup.19 and R.sup.20 form a heterocyclic ring;
[0298] R.sup.21 is hydrogen or alkyl;
[0299] n is 0 to 4; and
[0300] p is 0 or 1.
[0301] In a sixth aspect, the present invention is directed, in
part, to methods of treating or preventing gastrointestinal
dysfunction in a patient undergoing surgery, comprising the step
of:
[0302] administering to said patient an effective amount of at
least one 4-aryl-piperidine derivative or a stereoisomer, a
prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate,
an acid salt hydrate, an N-oxide or an isomorphic crystalline form
thereof;
[0303] in a manner so as to obtain a pharmacokinetic profile
wherein the plasma or whole blood concentration of
4-aryl-piperidine of said 4-aryl-piperidine derivative or
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, N-oxide or isomorphic crystalline form
thereof reaches a maximum concentration from about 30 minutes to
about 120 minutes after said administration;
[0304] wherein said gastrointestinal dysfunction is postoperative
ileus; and
[0305] wherein said 4-aryl-piperidine derivative is a compound of
formula (IA):
##STR00016##
[0306] wherein:
[0307] R.sup.1 is hydrogen or alkyl;
[0308] R.sup.2 is hydrogen, alkyl, or alkenyl;
[0309] R.sup.3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0310] R.sup.4 is hydrogen, alkyl, or alkenyl;
[0311] A is OR.sup.5 or NR.sup.6R.sup.7;
[0312] R.sup.5 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0313] R.sup.6 is hydrogen or alkyl;
[0314] R.sup.7 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
cycloalkyl-substituted alkyl, cycloalkenyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, B, or alkylene substituted B or, together with the
nitrogen atom to which they are attached, R.sup.6 and R.sup.7 form
a heterocyclic ring;
[0315] B is
##STR00017##
[0316] C(.dbd.O)W or NR.sup.8R.sup.9;
[0317] R.sup.8 is hydrogen or alkyl;
[0318] R.sup.9 is hydrogen, alkyl, alkenyl, cycloalkyl-substituted
alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl,
aryl, aralkyl; heteroaryl, or heteroarylalkyl or, together with the
nitrogen atom to which they are attached, R.sup.8 and R.sup.9 form
a heterocyclic ring;
[0319] W is OR.sup.10, NR.sup.11R.sup.12, or OE;
[0320] R.sup.10 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, or aralkyl;
[0321] R.sup.11 is hydrogen or alkyl;
[0322] R.sup.12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl,
heteroarylalkyl, 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;
[0323] E is
##STR00018##
[0324] alkylene substituted (C.dbd.O)D, or
--R.sup.13OC(.dbd.O)R.sup.14;
[0325] R.sup.13 is alkyl substituted alkylene;
[0326] R.sup.14 is alkyl;
[0327] D is OR.sup.15 or NR.sup.16R.sup.17;
[0328] R.sup.15 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0329] R.sup.16 is hydrogen, alkyl, alkenyl, aryl, aralkyl,
heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl,
cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
[0330] R.sup.17 is hydrogen or alkyl or, together with the nitrogen
atom to which they are attached,
[0331] R.sup.16 and R.sup.17 form a heterocyclic ring;
[0332] Y is OR.sup.18 or NR.sup.19R.sup.20;
[0333] R.sup.18 is hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl;
[0334] R.sup.19 is hydrogen or alkyl;
[0335] R.sup.20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl,
cycloalkenyl, cycloalkyl-substituted alkyl,
cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or
heteroarylalkyl or, together with the nitrogen atom to which they
are attached, R.sup.19 and R.sup.20 form a heterocyclic ring;
[0336] R.sup.21 is hydrogen or alkyl;
[0337] n is 0 to 4; and
[0338] p is 0 or 1.
[0339] In preferred embodiments, the compound of formula (IA) is a
trans 3,4-isomer.
[0340] In certain embodiments employing compounds of formula (IA),
it is preferred that [0341] R.sup.1 is hydrogen; [0342] R.sup.2 is
alkyl; [0343] n is 1 or 2; [0344] R.sup.3 is benzyl, phenyl,
cyclohexyl, or cyclohexylmethyl; and [0345] R.sup.4 is alkyl.
[0346] In certain embodiments employing compounds of formula (IA),
it is preferred that [0347] A is OR.sup.5; and [0348] R.sup.5 is
hydrogen or alkyl.
[0349] In certain embodiments employing compounds of formula (IA),
it is preferred that [0350] A is NR.sup.6R.sup.7; [0351] R.sup.6 is
hydrogen; [0352] R.sup.7 is alkylene substituted B; and [0353] B is
C(O)W.
[0354] In certain embodiments employing compounds of formula (IA),
it is preferred that [0355] R.sup.7 is (CH.sub.2).sub.q--B; [0356]
q is about 1 to about 3; [0357] W is OR.sup.10; and [0358] R.sup.10
is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl or
cycloalkyl-substituted alkyl.
[0359] In certain embodiments including compounds of formula (IA),
it is preferred that [0360] W is NR.sup.11R.sup.12 [0361] R.sup.11
is hydrogen or alkyl; and [0362] R.sup.12 is hydrogen, alkyl or
alkylene substituted C(.dbd.O)Y.
[0363] In certain embodiments employing compounds of formula (IA),
it is preferred that [0364] R.sup.12 is (CH.sub.2).sub.mC(O)Y;
[0365] m is 1 to 3; [0366] Y is OR.sup.18 or NR.sup.19R.sup.20; and
[0367] R.sup.18, R.sup.19 and R.sup.20 are independently hydrogen
or alkyl.
[0368] In certain embodiments employing compounds of formula (IA),
it is preferred that [0369] W is OE; [0370] E is
CH.sub.2C(.dbd.O)D; [0371] D is OR.sup.15 or NR.sup.16R.sup.17;
[0372] R.sup.15 is hydrogen or alkyl; [0373] R.sup.16 is methyl or
benzyl; and [0374] R.sup.17 is hydrogen.
[0375] In certain embodiments employing compounds of formula (IA),
it is preferred that [0376] W is OE; [0377] E is
R.sup.13OC(.dbd.O)R.sup.14; [0378] R.sup.13 is --CH(CH.sub.3)-- or
--CH(CH.sub.2CH.sub.3)--; and [0379] R.sup.14 is alkyl.
[0380] In certain embodiments including compounds of formula (IA),
it is preferred that p is 1.
[0381] In certain embodiments employing compounds of formula (IA),
it is preferred that the configuration at positions 3 and 4 of the
piperidine ring is each R.
[0382] Preferred compounds of formula (IA) include: [0383]
Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH, [0384]
Q-CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OCH.sub.2CH.sub.3,
[0385] Q-CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)OH,
[0386]
Q-CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.3,
[0387]
Q-CH.sub.2CH.sub.2CH(C.sub.6H.sub.5)C(O)NHCH.sub.2C(O)NHCH.sub.2CH.sub.3,
[0388] G-NH(CH.sub.2).sub.2C(O)NH.sub.2, [0389]
G-NH(CH.sub.2).sub.2C(O)NHCH.sub.3, [0390]
G-NHCH.sub.2C(O)NH.sub.2, [0391] G-NHCH.sub.2C(O)NHCH.sub.3, [0392]
G-NHCH.sub.2C(O)NHCH.sub.2CH.sub.3, [0393]
G-NH(CH.sub.2).sub.3C(O)OCH.sub.2CH.sub.3, [0394]
G-NH(CH.sub.2).sub.3C(O)NHCH.sub.3, [0395]
G-NH(CH.sub.2).sub.2C(O)OH, [0396] G-NH(CH.sub.2).sub.3C(O)OH,
[0397] Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NHCH.sub.2C(O)OH,
[0398]
Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub.2C(O)OH,
[0399]
Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.11))C(O)NH(CH.sub.2).sub.2C(O)N-
H.sub.2, [0400] Z--NHCH.sub.2C(O)OCH.sub.2CH.sub.3, [0401]
Z--NHCH.sub.2C(O)OH, [0402] Z--NHCH.sub.2C(O)NH.sub.2, [0403]
Z--NHCH.sub.2C(O)N(CH.sub.3).sub.2, [0404]
Z--NHCH.sub.2C(O)NHCH(CH.sub.3).sub.2, [0405]
Z--NHCH.sub.2C(O)OCH.sub.2CH(CH.sub.3).sub.2, [0406]
Z--NH(CH.sub.2).sub.2C(O)OCH.sub.2(C.sub.6H.sub.5), [0407]
Z--NH(CH.sub.2)C(O)OH, [0408]
Z--NH(CH.sub.2).sub.2C(O)NHCH.sub.2CH.sub.3, [0409]
Z--NH(CH.sub.2).sub.3C(O)NHCH.sub.3, [0410]
Z--NHCH.sub.2C(O)NHCH.sub.2C(O)OH, [0411]
Z--NHCH.sub.2C(O)OCH.sub.2C(O)OCH.sub.3, [0412]
Z--NHCH.sub.2C(O)O(CH.sub.2).sub.4CH.sub.3, [0413]
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.3, [0414]
Z--NHCH.sub.2C(O)O-(4-methoxycyclohexyl), [0415]
Z--NHCH.sub.2C(O)OCH.sub.2C(O)NHCH.sub.2(C.sub.6H.sub.5) and [0416]
Z--NHCH.sub.2C(O)OCH(CH.sub.3)OC(O)CH.sub.3; [0417] wherein:
[0418] Q represents
##STR00019##
[0419] G represents
##STR00020##
and
[0420] Z represents
##STR00021##
[0421] More preferred compounds of formula (IA) include: [0422]
(+)-Z--NHCH.sub.2C(O)OH, [0423] (-)-Z--NHCH.sub.2C(O)OH, [0424]
(3R,4R)--Z--NHCH.sub.2C(O)NHCH.sub.2(C.sub.6H.sub.5) and [0425]
(3R,4R)-G-NH(CH.sub.2).sub.3C(O)OH,
[0426] wherein Q, Z and G are as defined above.
[0427] Even more preferred compounds of formula (IA) include
(+)-Z--NHCH.sub.2C(O)OH and (-)-Z--NHCH.sub.2C(O)OH, most
especially (+)-Z--NHCH.sub.2C(O)OH, where Z is as defined
above.
[0428] Even more preferred compounds of formula (IA) include
Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH, wherein Q is as
defined above. It is especially preferred when said compound is
(3R,4R, S)-Q-CH.sub.2CH(CH.sub.2(C.sub.6H.sub.5))C(O)OH.
[0429] 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):
##STR00022##
[0430] The compound of formula (II) has low solubility in water
except at low or high pH conditions.
[0431] In especially preferred embodiments, the compound of a
formula (IA) is a substantially pure stereoisomer.
[0432] In preferred embodiments, the methods may further comprise
the step of administering at least one opioid to the patient. The
opioid may be administered to the patient before, during, or after
surgery or another biological stress. Suitable opioids include
alfentanil, buprenorphine, butorphanol, codeine, dezocine,
dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,
meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone,
oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, and
tramadol. Preferred opioids include morphine, codeine, oxycodone,
hydrocodone, dihydrocodeine, propoxyphene, fentanyl, and
tramadol.
[0433] The opioid component 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 disclosure of which is hereby incorporated
herein by reference, in its entirety.
[0434] 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.
Phannacol., 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.
[0435] 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.
[0436] In certain preferred embodiments, the 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered to the patient from about
30 minutes to less than about 120 minutes prior to the
administration of the opioid (and all combinations and
subcombinations of ranges and specific administration times
therein), preferably from about 30 minutes to less than about 90
minutes prior to the administration of the opioid, more preferably
from about 30 minutes to less than about 60 minutes prior to the
administration of the opioid, and even more preferably from about
30 minutes to less than about 45 minutes prior to the
administration of the opioid.
[0437] In certain preferred embodiments, the 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered to the patient from about
30 minutes to less than about 120 minutes prior to surgery (and all
combinations and subcombinations of rangers and specific
administration times therein), preferably from about 30 minutes
prior to surgery to less than about 90 minutes prior to surgery,
more preferably from about 30 minutes prior to surgery to less than
about 60 minutes prior to surgery, and even more preferably from
about 30 minutes prior to surgery to less than about 45 minutes
prior to surgery.
[0438] In certain preferred embodiments, the 4-aryl-piperidine
derivative or stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof is administered to the patient orally.
[0439] In certain other preferred embodiments, the
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered to the patient parenterally, more preferably
intravenously.
[0440] 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 that release the
active parent drug, for example, as according to formulas (IA) 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 (IA), 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.
[0441] 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.
[0442] 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,
using the methods described in U.S. Pat. No. 5,250,542, U.S. Pat.
No. 6,469,030, and U.S. Pat. No. 6,451,806, the disclosures of
which are hereby incorporated by reference, in their entireties.
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.
[0443] 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.
[0444] 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.
[0445] 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-alkoxyphenyl)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.
[0446] 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.
[0447] Although the (+)trans-3,4 stereoisomer is preferred, all of
the possible stereoisomers 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.
[0448] The compounds employed in the methods of the present
invention 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.
[0449] 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 Publishing Co., Easton,
Pa., 1980), the disclosures of which is hereby incorporated herein
by reference, in its entirety.
[0450] 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, and
intraperitoneal. Other acceptable routes of administration are
transepithelial including transdermal, transnasal, ophthalmic,
sublingual and buccal; topically including ophthalmic, dermal,
ocular, and rectal; nasal or pulmonary inhalation via insufflation
or aerosol; and rectal systemic.
[0451] The active compound may be orally administered, for example,
with an inert diluent or with an assimilable edible carrier, it may
be enclosed in hard or soft shell gelatin capsules, 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
from about 0.1 mg/day to about 500 mg/day of active compound,
including all combinations, and subcombinations thereof.
[0452] In certain preferred embodiments of the invention, said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered at a level of at least about 0.75 mg/day, more
preferably at a level of at least about 1 mg/day, even more
preferably at a level of at least about 2 mg/day, and yet even more
preferably at a level of at least about 3 mg/day.
[0453] In certain preferred embodiments of the invention, said
4-aryl-piperidine derivative or stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, N-oxide or isomorphic crystalline form thereof is
administered at a level of less than about 300 mg/day, more
preferably at a level of less than about 120 mg/day, even more
preferably at a level of less than about 60 mg/day, and yet even
more preferably at a level of less than about 30 mg/day.
[0454] 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.
[0455] The active compound may also be administered parenterally.
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.
[0456] 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 antifungal 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.
[0457] 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 that yield a powder of the active ingredient, plus any
additional desired ingredient from the previously sterile-filtered
solution thereof.
[0458] 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.
[0459] 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.
[0460] The combination products useful in the methods of this
invention, such as pharmaceutical compositions comprising
4-aryl-piperidine derivatives with additional active ingredients,
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 4-aryl-piperidine derivative and additional active
ingredient may be administered at the same time or simultaneously
(that is, together), or in any order. When not administered at the
same time or simultaneously, that is, when administered
sequentially, preferably the administration of a 4-aryl-piperidine
derivative and additional active ingredient 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.
[0461] Preferably, administration of the combination products of
the invention is oral or intravenously, 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 4-aryl-piperidine derivative and the additional active
ingredients are all 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.
[0462] Particularly when provided as a single dosage form, the
potential exists for a chemical interaction between the combined
active ingredients. 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).
[0463] 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 product wherein one of the active
ingredients is coated with a sustained-release material that
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.
[0464] 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-pareils, which are then
enteric coated. These enteric coated microtablets, particles,
granules or non-pareils are then placed into a capsule or
compressed into a capsule along with a granulation of the other
active ingredient.
[0465] 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.
[0466] Pharmaceutical kits useful in the methods of the invention
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 4-aryl-piperidine derivative and
the optional additional active ingredient 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.
EXAMPLES
[0467] The present invention will now be illustrated by reference
to the following specific, non-limiting examples. The examples are
not intended to limit the scope of the present invention.
Example 1
[0468] Twelve milligrams of alvimopan (two 6 mg capsules) was
administered orally to patients about 120 minutes prior to surgery.
The free alvimopan plasma concentration was measured for about 24
hours. The results are shown in FIG. 1.
[0469] FIG. 1 shows the free plasma concentration of alvimopan (12
mg dose) (in nM) as a function of time (in hours). This figure
shows that a single 12 mg oral dose of alvimopan produced free
plasma concentrations sufficient to substantially saturate .mu.
opioid receptors in the GI tract. Maximum concentrations achieved
were 11-fold greater than the Ki. Moreover, the profile
demonstrates that the Ki is exceeded at various times by a factor
ranging from approximately 6 to twice the Ki; concentrations that
would be estimated to produce receptor occupancy of greater than
68%, still within a reasonable interpretation of "substantial
saturation."
Example 2
[0470] A randomized, double-blind, placebo-controlled study of
different doses of alvimopan (opioid antagonist) I.V. for 4 days in
the presence and absence of loperamide (opioid) 2 mg p.o. q.i.d. in
60 healthy subjects (n=12 in each of five treatment groups) was
carried out. Subjects were randomly assigned to receive one of the
following five treatments:
Group 1: Placebo for alvimopan I.V. b.i.d.+placebo for loperamide
p.o. q.i.d. (n=12) Group 2: Placebo for alvimopan I.V.
b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12) Group 3: Alvimopan 1 mg
I.V. b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12) Group 4: Alvimopan
0.45 mg I.V. b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12) Group 5:
Alvimopan 0.1 mg I.V. b.i.d.+loperamide 2 mg p.o. q.i.d. (n=12)
Oral SITZMARKS capsules containing radio-opaque markers were be
administered on Days 1, 2, and 3. Alvimopan and loperamide was
administered at the same time, when applicable.
Study Assessments
[0471] Serial blood samples were collected for the determination of
concentrations of alvimopan and its amide hydrolysis metabolite in
plasma.
[0472] Subjects were assessed for their pain at the I.V. infusion
site using a categorical four-point verbal scale (i.e., no
discomfort/pain, mild discomfort/pain, moderate pain, or severe
pain). The Investigator also assessed certain characteristics
(e.g., erythema) of the I.V. site (i.e., none, mild, moderate, or
severe). Abdominal x-rays and x-rays of stool samples were
performed to determine the location of the SITZMARKS markers.
[0473] The appropriate dose was drawn into the delivery system,
normal saline was added to bring the total volume to 6 mL, and the
contents will be mixed thoroughly. Placebo for alvimopan I.V. was 6
mL of normal saline.
[0474] Alvimopan or matching placebo and loperamide or matching
placebo were administered on Days 1 through 4. Note that only the
morning doses of alvimopan and loperamide were administered on Day
4.
[0475] Oral SITZMARKS capsules were administered on Days 1, 2, and
3 at the same time that study medication is administered each
day.
Pharmacokinetic Sampling
[0476] The first eight subjects in each treatment group followed a
full sampling schedule and the last four subjects followed a sparse
sampling schedule. For the first eight subjects (full sampling
schedule), blood samples was collected just prior to administration
of alvimopan I.V. on Days 1 through 4 (four samples); and at 0.5,
1, 1.5, 2, 5, 10, 20, 30, and 60 minutes and at 2, 4, 6, 8, 10, 12,
16, 24, 48, 72, 96, 120, 144, and 168 hours after the end of the
infusion of alvimopan I.V. on Day 4. This is a total of 27 samples
per subject (135 mL per subject). For the last four subjects in
each treatment group (sparse sampling schedule), blood was
collected prior to administration of alvimopan I.V. on Days 1
through 4 (four samples), and immediately following the last
infusion on Day 4. Subjects were randomized to have one sample
collected during each of the following intervals, relative to the
end of the infusion on Day 4:
[0477] Interval 1: 3, 5, 10, or 15 minutes
[0478] Interval 2: 1, 2, 2.5, or 3 hours
[0479] Interval 3: 4, 5, 6, or 8 hours
[0480] Interval 4: 10, 12, 14, or 16 hours
[0481] Interval 5: 24, 48, 72, or 96 hours
[0482] Interval 6: 120 or 144 hours
[0483] GI transit score (GITS) was measured by the transit of
radio-opaque markers administered on Days 1, 2 and 3 with an
abdominal x-ray on Day 4.
[0484] FIG. 2 shows GI score as a function of log of plasma
concentrations measured as AUC (.tau.) (in ng-ml/hr) with a GI
score measured by radio-opaque markers in subjects given loperamide
with either placebo or one of three doses of I.V. alvimopan (0.1 mg
b.i.d, 0.45 mg b.i.d., and 1 mg b.i.d.) selected to target
different plasma concentrations (4.5, 20, and 45 ng/ml,
respectively).
[0485] The means for the groups are:
TABLE-US-00001 AUC (.tau.) of log AUC (.tau.) of Alvimopan
Alvimopan Group (ng-ml/hr) (ng-ml/hr) GI Score 1 0 -- 255.56 2 0 --
208.67 3 4.36 0.639486 231 4 22.06 1.343606 274.62 5 49.79 1.697142
278.5
[0486] The R.sup.2 value for the means is 0.76. The normal GI score
(no loperamide, no alvimopan) was 255.56. Groups 4 and 5 are
statistically different from Group 2 and not different from normal
(Group 1). This data suggests that that plasma concentrations are
important in antagonizing the effect of opioids on GI transit.
Further, the figures show that increasing exposure, as measured by
AUC, which takes into account both concentration and time, produces
an improved effect (antagonizing the effect of opioids on GI
transit).
[0487] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[0488] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0489] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *