CA1315689C - Quarternary derivatives of noroxymorphone which relieve nausea and emesis - Google Patents
Quarternary derivatives of noroxymorphone which relieve nausea and emesisInfo
- Publication number
- CA1315689C CA1315689C CA000548964A CA548964A CA1315689C CA 1315689 C CA1315689 C CA 1315689C CA 000548964 A CA000548964 A CA 000548964A CA 548964 A CA548964 A CA 548964A CA 1315689 C CA1315689 C CA 1315689C
- Authority
- CA
- Canada
- Prior art keywords
- administration
- noroxymorphone
- narcotic analgesic
- morphine
- emesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
Abstract
QUATERNARY DERIVATIVES OF NOROXYMORPHONE
WHICH RELIEVE NAUSEA AND EMESIS
ABSTRACT OF THE DISCLOSURE
Quaternary derivatives of noroxymorphone are used to prevent or relieve nausea and emesis associated with the use of narcotic analgesics without interfering with the analgesic activity of the drugs. A particularly preferred compound is methylnaltrexone. The compound is administered in a concentration between 0.05 mg/kg and 1.0 mg/kg prior to or concurrently with the administration of the narcotic analgesic.
WHICH RELIEVE NAUSEA AND EMESIS
ABSTRACT OF THE DISCLOSURE
Quaternary derivatives of noroxymorphone are used to prevent or relieve nausea and emesis associated with the use of narcotic analgesics without interfering with the analgesic activity of the drugs. A particularly preferred compound is methylnaltrexone. The compound is administered in a concentration between 0.05 mg/kg and 1.0 mg/kg prior to or concurrently with the administration of the narcotic analgesic.
Description
~3~ 3 ~0355--99 OUATERNARY DERIVATIVES OF NOROXYMORPHO
~HICH RELIEVE NAUSEA AND EMESIS
The administration of therapeutic doses of morphine and other clinically useful narcotie analgesies is often aecompanied by unpleasant side effects on the gas-tro-intestinal system. For instance, morphine and related opiates such as meperidine and methadone may reta~d intestinal mobility by causing con-traetions of -the small bowel eireular smooth musele.
Morphine and related narcoties may also induce nausea and increased mobility of the gastro-intes-tinal tract resulting in emesis or vomiting~ These side effects are eaused by direet stimulation of the chemoreeeptor trigger zone for emesis in the area postrema of the medulla. (Goodman and Bilman, The Pharmaeologieal Basis of Theraneu~ics, p. 502 [6`th ed. 1980]). Studies have shown that morphine and other nareoties eause emesis in dogs. For example, Wang and Glaviano, JPET 111:329-334 ~9143~, reported that administration of 0.5 mg/kg of morphine intravenously to 12 dogs resulted in emesis in 9 dogs within an average of 2.
minutes. (Mg/kg refers to milligrams of morphine per kilograms of body weight.) When 1.0 mg/kg of ~ ~.
, . . '. ' :
.
.
. .
.
1 morphine was administered intramuscularly to 13 dogs, 12 of them vomited within an average time of 3.5 minutes.
U. S. Patent No. 4,176,186 to myself and others disclosed treatment of intestinal immobility associated with the use of narcotic analgesics through the administration of guaternary derivatives of noroxymorphone.'' It has now been discovered that the same compounds are also useful fox the treatment, ~oth prophylactic.and therapeutic,'of the nausea and vomiting associated with the administration of these drugs.
'~'According to the invention, therefore, nausea and vomiting by warm-blooded animals receiving morphine and lS related opiates~ meperidine,-methadone or the like, may be prevented ~r relieved by the administration of methylnaltrexone or other quaternary derivatives of noroxymorphone represented by the formula:
rA/~ C~13 X
` ~`b wherein ~/0 R is allyl or a related radical such as chloroallyl, cyclopropyl-methyl Gr propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
These compounds are administered to the animal either prior to or . simultaneously with the administration of the narcotic analgesic. They may be ~3~
-- 3 ~
admini~-tered either enterally or paren-terally. There has no-t been observed any interference with the analgesic activi-ty of the opi~tes.
As used herein, unless the sense of the usage indicates otherwise, the term l'morphine" refers to any narcotic analgesic.
This invention relates to the use of quaternary derivatives of noroxymorphone to prev~nt or relieve nausea and vomiting associated with the administration of morphine to warm-blooded animals. The useful compounds are represented by the formula:
R X
I ~ CH3 r- N
wherein R is allyl or a related radical such as chloroallyl, cyclopropyl-methyl or propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
!
The compounds are synthesized as described in United 5tates Patent No. 4,176,I86. A particularly preferred noroxymorphone derivative is methylnaltrexone, but other compounds represented by the above formula are also suitable.
Methylnaltrexone or other noroxymorphone deriva-tives may be administered to the patient either -? ~: 1 '`' ~
' ., ~ . .. .
. . .
,: ~ , . ' "; ' ' , ~ ' ' ' ' " ', ' ' ' ' ' ':
'" ' : : ' ~ :- ~' . ' :
~3~LS~
1 enterally or parenterally. However, a preferred method of administration is by injection. Nausea and emesis may follow after even a single does sf morphine, unlikP
intestinal immobility which is usually the effect of chronic repeated usage of the drug. Consequently, it is contemplated that-the patient will be given an injection of methylnaltrexone prior to surgery or other occasion when morphine is used to treat acute pain.
As illustrated :-by :~he ~ifollowing Controls and Examples, our studies show that methylnaltrexone inhibits emesis when administered either together with the morphine or before the morphine is administered. It is thought that methylnaltrexone- or other quaternary noroxymorphone derivatives may be administered up to two hours before the administration of morphine, but that period may be variable. In our studies, methylnaltrexone was administered intramuscularly by means of a syringé. Methylnaltrexone may also be administered enteraIly or parenterally by other means.
It has been found to be effective in dosages in the range of about 0.05 mg/kg to about 1.0 mg~kg for each 1 mg/kg of administered morphine. It was found effective when administered in the same syringe as morphine and also when administered up to about one hour before the administration of morphine.
The effect of methylnaltrexone in reversing the emetic effects of morphine is illustrated herein. The unit of mg/kg refers to milligrams of substance administered per kilograms of body weight.
. ~ CONTROL 1 AND EXAMPLE_1 one mg/kg of morphine was administered intramuscularly to five dogs. Four dogs vomited. In each instance, vomiting occurred within four minutes.
On a different day the same dose of morphine was ~3~5~
1 administered intramuscularly to the same five dogs in the same syringe with 1 mg/kg of methylnaltrexone. None of the dogs vomited.
Six dogs were given intramuscular doses of 1 mg/kg of morphine. All six dogs vomited. On an ~dditional day the same dose of morphine was combined with 0.5 mg/kg of methylnaltraxone and administered in the same syringe to the same dogs. None of the dogs vomited.
one mg/kg of morphine was administered intramuscularly to three dogs. All three dogs vomited.
On an additional day the morphine was combined with 0.25 mg/kg of methylnaltrexone and administered in the same syringe. None of the dogs vomited.
Methylnaltrexone was administered to two dogs prior to the administration of 1 mg/kg morphine. In one dog, 0.5 mg/kg of methylnaltrexone was administered intramuscularly 15 minutes before the morphine. No vomiting occurred. In the second dog, the same dose o~
methylnal~rexone was administered 30 minutes before the administration of morphine. No vomiting occurred.
O. 05 mg/kg methylnaltrexone was administered intravenously to four dogs one minute prior to the administration of 1.0 mg/kg morphine. No vomiting occurred in any of the dogs. On a different day, the same animals were given 1.0 mg/kg morphine without the administration of methylnaltrexone. All four dogs 3 5 vomited .
~3~6t~
The administration of methylnaltrexone alone was found to produce no noticeable effec-ts in the animals. Previous studies with larger doses of methylnaltrexone have demonstrated that unlike the non-quaternary naltrexone, methylnaltrexone does no-t precipitate withdrawal systems in morphine-tolerant dogs. Russell et al., Eur~ J. Pharmacol.
78:255-261 ~19823. Methylnaltrexone has not been found -to interfere with the analgesic activity of morphine or narcotics.
, . :
~HICH RELIEVE NAUSEA AND EMESIS
The administration of therapeutic doses of morphine and other clinically useful narcotie analgesies is often aecompanied by unpleasant side effects on the gas-tro-intestinal system. For instance, morphine and related opiates such as meperidine and methadone may reta~d intestinal mobility by causing con-traetions of -the small bowel eireular smooth musele.
Morphine and related narcoties may also induce nausea and increased mobility of the gastro-intes-tinal tract resulting in emesis or vomiting~ These side effects are eaused by direet stimulation of the chemoreeeptor trigger zone for emesis in the area postrema of the medulla. (Goodman and Bilman, The Pharmaeologieal Basis of Theraneu~ics, p. 502 [6`th ed. 1980]). Studies have shown that morphine and other nareoties eause emesis in dogs. For example, Wang and Glaviano, JPET 111:329-334 ~9143~, reported that administration of 0.5 mg/kg of morphine intravenously to 12 dogs resulted in emesis in 9 dogs within an average of 2.
minutes. (Mg/kg refers to milligrams of morphine per kilograms of body weight.) When 1.0 mg/kg of ~ ~.
, . . '. ' :
.
.
. .
.
1 morphine was administered intramuscularly to 13 dogs, 12 of them vomited within an average time of 3.5 minutes.
U. S. Patent No. 4,176,186 to myself and others disclosed treatment of intestinal immobility associated with the use of narcotic analgesics through the administration of guaternary derivatives of noroxymorphone.'' It has now been discovered that the same compounds are also useful fox the treatment, ~oth prophylactic.and therapeutic,'of the nausea and vomiting associated with the administration of these drugs.
'~'According to the invention, therefore, nausea and vomiting by warm-blooded animals receiving morphine and lS related opiates~ meperidine,-methadone or the like, may be prevented ~r relieved by the administration of methylnaltrexone or other quaternary derivatives of noroxymorphone represented by the formula:
rA/~ C~13 X
` ~`b wherein ~/0 R is allyl or a related radical such as chloroallyl, cyclopropyl-methyl Gr propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
These compounds are administered to the animal either prior to or . simultaneously with the administration of the narcotic analgesic. They may be ~3~
-- 3 ~
admini~-tered either enterally or paren-terally. There has no-t been observed any interference with the analgesic activi-ty of the opi~tes.
As used herein, unless the sense of the usage indicates otherwise, the term l'morphine" refers to any narcotic analgesic.
This invention relates to the use of quaternary derivatives of noroxymorphone to prev~nt or relieve nausea and vomiting associated with the administration of morphine to warm-blooded animals. The useful compounds are represented by the formula:
R X
I ~ CH3 r- N
wherein R is allyl or a related radical such as chloroallyl, cyclopropyl-methyl or propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
!
The compounds are synthesized as described in United 5tates Patent No. 4,176,I86. A particularly preferred noroxymorphone derivative is methylnaltrexone, but other compounds represented by the above formula are also suitable.
Methylnaltrexone or other noroxymorphone deriva-tives may be administered to the patient either -? ~: 1 '`' ~
' ., ~ . .. .
. . .
,: ~ , . ' "; ' ' , ~ ' ' ' ' " ', ' ' ' ' ' ':
'" ' : : ' ~ :- ~' . ' :
~3~LS~
1 enterally or parenterally. However, a preferred method of administration is by injection. Nausea and emesis may follow after even a single does sf morphine, unlikP
intestinal immobility which is usually the effect of chronic repeated usage of the drug. Consequently, it is contemplated that-the patient will be given an injection of methylnaltrexone prior to surgery or other occasion when morphine is used to treat acute pain.
As illustrated :-by :~he ~ifollowing Controls and Examples, our studies show that methylnaltrexone inhibits emesis when administered either together with the morphine or before the morphine is administered. It is thought that methylnaltrexone- or other quaternary noroxymorphone derivatives may be administered up to two hours before the administration of morphine, but that period may be variable. In our studies, methylnaltrexone was administered intramuscularly by means of a syringé. Methylnaltrexone may also be administered enteraIly or parenterally by other means.
It has been found to be effective in dosages in the range of about 0.05 mg/kg to about 1.0 mg~kg for each 1 mg/kg of administered morphine. It was found effective when administered in the same syringe as morphine and also when administered up to about one hour before the administration of morphine.
The effect of methylnaltrexone in reversing the emetic effects of morphine is illustrated herein. The unit of mg/kg refers to milligrams of substance administered per kilograms of body weight.
. ~ CONTROL 1 AND EXAMPLE_1 one mg/kg of morphine was administered intramuscularly to five dogs. Four dogs vomited. In each instance, vomiting occurred within four minutes.
On a different day the same dose of morphine was ~3~5~
1 administered intramuscularly to the same five dogs in the same syringe with 1 mg/kg of methylnaltrexone. None of the dogs vomited.
Six dogs were given intramuscular doses of 1 mg/kg of morphine. All six dogs vomited. On an ~dditional day the same dose of morphine was combined with 0.5 mg/kg of methylnaltraxone and administered in the same syringe to the same dogs. None of the dogs vomited.
one mg/kg of morphine was administered intramuscularly to three dogs. All three dogs vomited.
On an additional day the morphine was combined with 0.25 mg/kg of methylnaltrexone and administered in the same syringe. None of the dogs vomited.
Methylnaltrexone was administered to two dogs prior to the administration of 1 mg/kg morphine. In one dog, 0.5 mg/kg of methylnaltrexone was administered intramuscularly 15 minutes before the morphine. No vomiting occurred. In the second dog, the same dose o~
methylnal~rexone was administered 30 minutes before the administration of morphine. No vomiting occurred.
O. 05 mg/kg methylnaltrexone was administered intravenously to four dogs one minute prior to the administration of 1.0 mg/kg morphine. No vomiting occurred in any of the dogs. On a different day, the same animals were given 1.0 mg/kg morphine without the administration of methylnaltrexone. All four dogs 3 5 vomited .
~3~6t~
The administration of methylnaltrexone alone was found to produce no noticeable effec-ts in the animals. Previous studies with larger doses of methylnaltrexone have demonstrated that unlike the non-quaternary naltrexone, methylnaltrexone does no-t precipitate withdrawal systems in morphine-tolerant dogs. Russell et al., Eur~ J. Pharmacol.
78:255-261 ~19823. Methylnaltrexone has not been found -to interfere with the analgesic activity of morphine or narcotics.
, . :
Claims (19)
1. Use of a compound of the formula:
wherein R is allyl or a related radical; and X is the anion of an acid;
prior to or simultaneously with administration of a narcotic analgesic to prevent or relieve nausea and emesis associated with the use of the narcotic analgesics in warm-blooded animals.
wherein R is allyl or a related radical; and X is the anion of an acid;
prior to or simultaneously with administration of a narcotic analgesic to prevent or relieve nausea and emesis associated with the use of the narcotic analgesics in warm-blooded animals.
2. Use as claimed in claim 1 in which R is chloroallyl, cyclopropyl-methyl or propargyl.
3. Use as claimed in claim 1 in which X is a choride, bromide, iodide or methylsulfate anion.
4. Use as claimed in claim 1, where the compound is is in an amount between 0.05 mg/kg and about 1.0mg/kg of animal body weight.
5. Use as claimed in claim 1, as an enterally administered compound.
6. Use as claimed in claim 1, as parenterally administered compound.
7. Use as claimed in claim 6, as an injectably administered compound.
8. Use as claimed in claim 1, prior to the administration of the narcotic analgesic.
9. Use as claimed in claim 1, up to about two hours prior to the administration of the narcotic analgesic.
10. Use as claimed in claim 1, concurrently with the administration of the narcotic analgesic.
11. Use of methylnaltrexone to prevent or relieve nausea and emesis associated with the use of a narcotic analgesic in war-blooded animals.
12. Use as claimed in claim 11 in an amount of between 0.05 mg/kg of animal body weight and about 1.0 mg/kg of animal body weight simultaneously with or up to about two hours prior to the time of administration of the narcotic analgesic.
13. Use as claimed in claim 12, as a parenterally administered compound.
-8a-
-8a-
14. A pharmaceutical composition for preventing or relieving nausea and emesis comprising a narcotic analgesic in combination with at least one quaternary derivative of noroxymorphone:
wherein R is allyl or a related radical; and X is the anion of an acid;
and wherein the quaternary derivative of noroxymorphone is present in an amount effective to prevent or relieve nausea induced by the narcotic analgesic.
wherein R is allyl or a related radical; and X is the anion of an acid;
and wherein the quaternary derivative of noroxymorphone is present in an amount effective to prevent or relieve nausea induced by the narcotic analgesic.
15. A pharmaceutical composition as claimed in claim 12 in which R is chloroallyl, cyclopropyl-methyl or propargyl.
16. A composition as claimed in claim 12 in which X is a chloride, bromide, iodide or methylsulfate anion.
17. A composition according to claim 14, wherein the quaternary derivative of noroxymorphone is present in a unit dose of between about 0.05 mg and about 1.0 mg for each 1 mg of morphine.
18. A composition as claimed in claim 14, wherein the narcotic analgesic is morphine.
-8b-
-8b-
19. A composition as claimed in claim 14, wherein the quaternary derivative of noroxymorphone is methylnaltrexone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/092,470 US4861781A (en) | 1986-03-07 | 1987-09-03 | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
| US092,470 | 1987-09-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1315689C true CA1315689C (en) | 1993-04-06 |
Family
ID=22233375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000548964A Expired - Lifetime CA1315689C (en) | 1987-09-03 | 1987-10-09 | Quarternary derivatives of noroxymorphone which relieve nausea and emesis |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2625457B2 (en) |
| KR (1) | KR890004704A (en) |
| CA (1) | CA1315689C (en) |
| DK (1) | DK167340B1 (en) |
| NZ (1) | NZ222911A (en) |
| PH (1) | PH22582A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7563899B2 (en) | 2005-05-25 | 2009-07-21 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
| US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
| US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
| US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
| US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
| US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
| US6451806B2 (en) | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
| US6469030B2 (en) | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| CN101171010B (en) | 2005-03-07 | 2014-09-17 | 芝加哥大学 | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| EP1946759A4 (en) * | 2005-10-11 | 2009-12-23 | Toray Industries | Therapeutic agent for nausea and/or vomiting |
| US8263807B2 (en) * | 2007-08-09 | 2012-09-11 | Rensselaer Polytechnic Institute | Quaternary opioid carboxamides |
-
1987
- 1987-10-09 CA CA000548964A patent/CA1315689C/en not_active Expired - Lifetime
- 1987-12-07 PH PH36178A patent/PH22582A/en unknown
- 1987-12-14 NZ NZ222911A patent/NZ222911A/en unknown
- 1987-12-28 JP JP62330356A patent/JP2625457B2/en not_active Expired - Lifetime
- 1987-12-29 KR KR1019870015208A patent/KR890004704A/en not_active Application Discontinuation
- 1987-12-30 DK DK693387A patent/DK167340B1/en not_active IP Right Cessation
Cited By (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10376584B2 (en) | 2003-04-08 | 2019-08-13 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
| US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
| US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| US8343992B2 (en) | 2005-05-25 | 2013-01-01 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
| US8003794B2 (en) | 2005-05-25 | 2011-08-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
| US7563899B2 (en) | 2005-05-25 | 2009-07-21 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
| US9597327B2 (en) | 2005-05-25 | 2017-03-21 | Progenics Pharmaceuticals, Inc. | Synthesis of (R)-N-methylnaltrexone |
| US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
| US8916581B2 (en) | 2005-05-25 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
| US8772310B2 (en) | 2007-03-29 | 2014-07-08 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
| US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
| US9879024B2 (en) | 2007-03-29 | 2018-01-30 | Progenics Pharmaceuticals., Inc. | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
| US8853232B2 (en) | 2007-03-29 | 2014-10-07 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
| US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
| US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
| US8916706B2 (en) | 2008-02-06 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
| US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
| US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US10383869B2 (en) | 2008-03-21 | 2019-08-20 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US8455644B2 (en) | 2008-09-30 | 2013-06-04 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| US9492445B2 (en) | 2008-09-30 | 2016-11-15 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
| US9180125B2 (en) | 2008-09-30 | 2015-11-10 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
| US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
| US8822490B2 (en) | 2008-09-30 | 2014-09-02 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
| US8420663B2 (en) | 2008-09-30 | 2013-04-16 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DK693387D0 (en) | 1987-12-30 |
| JPS6468376A (en) | 1989-03-14 |
| DK693387A (en) | 1989-03-04 |
| PH22582A (en) | 1988-10-17 |
| JP2625457B2 (en) | 1997-07-02 |
| KR890004704A (en) | 1989-05-09 |
| NZ222911A (en) | 1990-11-27 |
| DK167340B1 (en) | 1993-10-18 |
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