NZ249346A - 2,6-methano-2h-quinolizine ester derivatives and medicaments thereof - Google Patents
2,6-methano-2h-quinolizine ester derivatives and medicaments thereofInfo
- Publication number
- NZ249346A NZ249346A NZ249346A NZ24934693A NZ249346A NZ 249346 A NZ249346 A NZ 249346A NZ 249346 A NZ249346 A NZ 249346A NZ 24934693 A NZ24934693 A NZ 24934693A NZ 249346 A NZ249346 A NZ 249346A
- Authority
- NZ
- New Zealand
- Prior art keywords
- treatment
- compound
- release
- matrix
- pharmaceutically acceptable
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £49346 <br><br>
9 3 4 6 <br><br>
New Zealand No. 24! <br><br>
International No. PCT/US93/00880 <br><br>
TO BE EhfTERED AFTER ACCEPTANCE AND PUBLICATION <br><br>
priority dates: gm_- z_ ^2. <br><br>
International fiiing date: 3 2.. <33, <br><br>
Classification: coi tx+rvAis; A<oH<£-"2>\\ <br><br>
Publication date: £ 6 0 CT 1995 Journal No.: <br><br>
jviO DRAWINGS <br><br>
NEW ZEALAND PATENTS ACT 1953 <br><br>
COMPLETE SPECIFICATION <br><br>
Title of invention: <br><br>
2,6-methano-2H-quinolizin derivative as 5-HT3-receptor antagonist <br><br>
Name, address and nationality of applicants) as in international a-DDlication form: <br><br>
MERRELL DOW PHARMACEUTICALS INC., 2110 East Galbraith <br><br>
Road, Cincinnati, Ohio 45215, United States of America 4 A-S. <br><br>
Ct>rf6y*h <br><br>
WO 93/17019 PCT/U! <br><br>
- 1 - <br><br>
2,6-Methano-2H-qu1noHz1n derivative as 5-HT3-receptor antagonist <br><br>
This invention relates to 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylie acid-octahydro-3-hydroxy-5 2,6-methano-2H-quinolizin-8-yl ester, a novel 5-HT3-receptor antagonist, its method of preparation, and to its end-use application in the treatment of conditions responsive to 5-HT3 receptor antagonism such as radio- and chemo-therapeu-tically-induced nausea and vomiting, in the treatment of 10 pain associated with migraine, in the treatment of cognitive disorders such as Alzheimer's Disease, the treatment of hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, the treatment of irritable or inflammatory bowel syndrome, or to 15 combat drug abuse. <br><br>
More specifically this invention relates to compounds of the formula <br><br>
20 <br><br>
H <br><br>
WO 93/17019 <br><br>
- 2 - <br><br>
2 43 3 4 6 <br><br>
PCT7US93/TO88':t its tautomers, stereo- and geometrical isomers, and mixtures thereof, and to the pharmaceutical^ acceptable salts thereof. <br><br>
5 As used herein, the wavy line bonding the oxygen atom of the ester moiety to the 8-position of the octahydro-2,6-methano-2H-quinolizin moiety (hereinafter sometimes referred to as the methano bridged quinolizinyl moiety) indicates that the bonding may be in the endo (trans) or the exo (cis) 10 configuration. The preferred configuration is endo. <br><br>
Preparation of such geometric isomers may be effected by the processes and techniques of U.S. Patent 4,906,755 which is incorporated herein by reference. A chirality exists at the 3-position of the methano-bridged quinolizinyl moiety 15 presenting d- or 1-isomers and racemate mixtures thereof. When desired resolution of said racemates may be effected by standard procedures and techniques well known in the art. The (+) enantiomer is preferred. <br><br>
20 The pharmaceutical^ acceptable acid addition salts referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic 25 acids, for example, acetic, propionic, glycolic, maleic, <br><br>
hydroxymaleic, malic, tartaric, citric, salicylic, 2-acetyl-oxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example, methanesulfonic* ethanesulfonic., 2-hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalene-30 sulfonic. <br><br>
The preparation of the compounds of the present invention may be illustrated by the following example. <br><br>
35 <br><br>
WO 93/17019 <br><br>
249 3 46 <br><br>
PCT/US93/00880 <br><br>
- 3 -EXAMPLE <br><br>
5-CHLORO-2,3-DIHYDRO-2,2-DIMETHYLBENZOFURAN-7-CARBOXYLIC ACID ITRANS-OCTAHYDRO-3-HYDROXY-2 , 6-METHANO-2H-QUINOLIZIN-8-5 YL ESTER <br><br>
STEP A: Using triphosgene <br><br>
5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid frans-octahvdro-3-oxo-2,6-methano-2H-guinolizin-8-yl 10 ester <br><br>
A solution of triethylamine (1.79 g), 4-dimethylamino-pyridine {1.09 g) and 5-chloro-2,3-dihydro-2,2-dimethyl-benzofuran-7-carboxylic acid (3.8 g) in dichloromethane 15 (75 ml) was slowly added to a stirred solution of triphosgene (5.28 g) in dichloromethane (100 ml) at 0°C, <br><br>
nitrogen being continuously bubbled through the mixture. After the addition, the mixture was stirred at room temperature overnight under nitrogen, filtered and 20 evaporated. <br><br>
A suspension of the residue in anhydrous toluene was refluxed with a stirred suspension of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one (3.25 g) overnight. The 25 cooled solution was filtered, the toluene washed with aqueous potassium carbonate, dried over magnesium sulphate and evaporated to give a residue (4.8 g) containing the title compound. It was then purified by partitioning between ethyl acetate (200 ml) and IN methanesulphonic acid (40 ml). 30 Basification of the separated methanesulphonic acid solution with a saturated aqueous solution of potassium carbonate gave a crystalline solid which was further purified by crystallization, e.g., from aqueous methanol or by silica gel chromatography to give a pure sample of the title 35 compound. <br><br>
WO 93/17019 <br><br>
- 4 - <br><br>
MS.L 6 <br><br>
Step A' (Alternate to Step A): Using trichloromethyl chloroformate <br><br>
5 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester <br><br>
A solution of trichloromethyl chloroformate (1.76 g, 10 1.08 ml) in dichloromethane (10 ml) was added to a stirred solution of 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid (2 g) and triethylamine (1.4 ml) in dichloromethane (30 ml) at 0°C. The mixture was stirred overnight at room temperature, washed with an ice cold 15 saturated aqueous solution of ammonium chloride, dried over magnesium sulphate and evaporated to give an oil (2.2 g). A stirred mixture of the oil ((2.2 g), hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one (1.6 g) and toluene (30 ml) was refluxed overnight. The cooled mixture was 20 washed with a saturated aqueous solution of potassium carbonate and then four times with water to remove any unreacted hexahydroquinolizine one. Evaporation of the dried toluene solution (MgS04) gave a solid residue which was recrystallized from ethyl acetate/hexane to give the title 25 compound (0.35 g). <br><br>
STEP B: <br><br>
5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxvlic acid fra7is-octahydro-3-hydroxv-2,6-methano-2H-quinolizin-8-30 vl ester <br><br>
Sodium borohydride (1.52 g) was slowly added to a stirred solution of 5-chloro-2,3-dihydro-2,2-dimethylbenzo-furan-7-carboxylic acid £rans-octahydro-3-oxo-2,6-methano-2H-35 quinolizin-8-yl ester (3.9 g) in ethanol* (75 ml) at room <br><br>
2,A <br><br>
WO 93/17019 PCT/I5S93 <br><br>
- 5 - <br><br>
temperature and the mixture stirred at room temperature overnight. The ethanol was evaporated, the residue dissolved in a mixture of water (20 ml) and 2N hydrochloric acid (20 ml), and the acidic solution almost immediately basified 5 by the addition of an excess of a saturated solution of aqueous potassium carbonate. Extraction with a mixture of tetrahydrofuran-ethyl acetate (1.1) and evaporation of the dried extract gave the title compound, m.p.: 192-193°C. <br><br>
10 Conversion to the methane sulphonate salt was effected by the addition of one equivalent of an alcoholic solution of methanesulphonic acid and evaporation of the solvent. <br><br>
The racemic mixture can be separated into its separate 15 enantiomers by standard techniques. <br><br>
20 <br><br>
25 <br><br>
30 <br><br>
35 <br><br>
WO 93/17019 <br><br>
2 4 9 3 4 <br><br>
PCT/US93/0088" <br><br>
- 6 - <br><br>
The compounds of the present invention block the M receptors for 5-hydroxytryptamine (5HT) on afferent sensory neurons otherwise known as 5HT3-receptors. The activity of the compounds of this invention against the 5HT3-receptor 5 can be assessed by determining their pA2 values in the isolated rabbit heart as described by J. R. Pozard et al., Eur. J. Pharmacol. 59., 195-210 (1979). The in vivo 5HT3-receptor antagonist activity can be assessed by measurement of the effect of the compound on the Von Bezold-10 Jarisch reflex induced by 5HT injected intravenously into the rat (see Paintal A. S., Physiol. Rev. 53, 159-227 (1973); J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol. 326, 36-44 (1984). <br><br>
15 Using the foregoing standard procedures, as well as other standard procedures recognized to illustrate 5HT3-receptor antagonist activity for the above-stated end-use applications, as well as by comparison with other 5HT3-receptor antagonists known to be useful for such 20 purposes, the compounds of this invention may be utilized in a variety of treatments. <br><br>
Generally, the compounds of the present invention are useful :.n treating conditions responsive to 5-HT3 receptor 25 antagonism. Examples of conditions responsive to 5-HT3 <br><br>
receptor antagonism are well known to those skilled in the art. Some examples of these conditions are treating anxiety, psychosis, glaucoma and for stimulating gastric motility (U.S. Patent No. 5,011,846), treatment of panic disorders 30 and/or agoraphobia or obsessive compulsive disorders (Patent No. EP 422,154); treatment of autism or other disorder originating in childhood in which there is mental retardation (Patent No. EP 450,757); treatment of cognitive disorders such as Alzheimer's Disease (U.S. Patent 35 Application Serial No. 806,987); production of orexiogenic <br><br>
WO 93/17019 <br><br>
- 7 - <br><br>
effect (U.S. Patent Application Serial No. 742,951); serotonin-induced nasal disorders, rhinitis or impaired approach-oriented behavior in stressful situations or for increasing vigilance ( Patent No. GB 2,193,633); relief or 5 prevention of withdrawal syndrome resulting from addiction to and/or for the suppression of dependence on a drug or substance (Patent No. EP 279,114 and GB 2,206,788); <br><br>
treatment of lung embolism (Patent No. GB 2,231,265); treatment of cough and/or bronchoconstriction (Patent No. EP 10 340,270); treatment of nausea, bradycardia, and/or hypotension associated with myocardial instability (Patent No. W091/09593); treatment of urinary incontinence (Patent No. EP 467,365); and combination therapy with ACE inhibitors (Patent No. EP 477,625 and EP 477,624), with 3—[2— 15 (dimethylamino)ethyl]-N-methyl-lH-indole-5- <br><br>
methanesulphonamide (Patent No. EP 433,043); and histamine H2~receptor antagonist (Patent No. EP 275,669). All of the foregoing are incorporated herein by reference. <br><br>
20 Preferred uses for the compounds of the present invention include the treatment of nausea® and vomiting, particularly radio- and chemo-therapeutically induced in those patients being treated for cancer, in the treatment of pain associated with migraine and neuralgia, in the 25 treatment of cognitive dysfunctions such as memory and learning disorders as well as dysfunctions in selective attention, in the treatment of hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, for the treatment of irritable or 30 inflammatory bowel syndrome, as well as to be useful in combating drug abuse. <br><br>
Doses administered to patients are within the range of about 0.01 to about 10 mg per kilogram of body weight, with 35 0.01 to 1 mg per kilogram of body weight being preferred for <br><br>
249346 <br><br>
PCT/DS93/00880 <br><br>
WO 93/17019 <br><br>
2 4 0 3 4 6 <br><br>
PCI7US93/008P <br><br>
- 8 - <br><br>
parenteral administration and 0.25 to 1 mg per kilogram of body weight upon enteral administration. Of course, the dosage required for the treatment of the foregoing disease states will depend upon such factors as the severity and 5 stage of the particular disease, the age and condition of the patients as such other normal factors taken into consideration by the attending diagnostician. <br><br>
The term "patient" means warm-blooded animals such as 10 rats, mice, dogs, cats, guinea pigs, primates and humans. The term "treat" means to prevent or alleviate the patient's disease or condition. <br><br>
The compounds of Formula (I) can be administered in 15 various manners to achieve the desired effect. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin 20 type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula (I) can be tableted with conventional tablet bases such as lactose, sucrose, and 25 cornstarch in combination with binders, such as acacia, <br><br>
cornstarch, or gelatin, disintegrating agents such as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-30 aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art. <br><br>
For parenteral administration, the compounds may be 35 dissolved in a physiologically acceptable pharmaceutical <br><br>
WO 93/17019 <br><br>
- 9 - <br><br>
£cM3/L£ <br><br>
carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. <br><br>
5 The pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art. <br><br>
The compounds of this invention can also be administered topically. This can be accomplished by simply preparing a 10 solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and 15 porous membrane type or of a solid matrix variety. <br><br>
Some suitable transdermal devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894 incorporated herein. These devices generally contain a 20 backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces. Alternatively, the active agent may be contained in a 25 plurality of microcapsules distributed throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or 30 mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. <br><br>
35 <br><br></p>
</div>
Claims (7)
1. The compound of the formula H<br><br> HO<br><br> its tautomers, stereo- and geometrical isomers, and mixtures 15 thereof, and the pharmaceutically acceptable salts thereof.<br><br>
2. The compound according to Claim 1 suitable for use aa a pharmaceutically active compound.<br><br> 20<br><br> 25<br><br>
3. The compound according to Claim 1 suitable for use in the treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment of schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abuse.<br><br>
4. A pharmaceutical composition comprising the compound according to Claim 1, optionally in combination with a pharmaceutically acceptable carrier.<br><br> 30
5. A pharmaceutical composition according to Claim 4 suitable for use in the treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment of schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abus<br><br> 35<br><br> WO 93/17019<br><br> PCT/US93/00880<br><br> 12<br><br> 24834<br><br>
6. Use of a compound according to Claim 1,<br><br> in combination with a pharmaceutically acceptable carrier,<br><br> for the preparation of a pharmaceutical composition suitable for use in the 5 treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment of schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abuse.<br><br>
7. a method of making a compound having the formula:<br><br> H<br><br> 20<br><br> HO<br><br> O-C<br><br> O<br><br> II<br><br> H,C<br><br> 25<br><br> CI<br><br> by reacting the oxoderivative<br><br> WO 93/17019<br><br> 249 346<br><br> PCT / US93/00880<br><br> - 13 -<br><br> with an appropriate reducing agent at about room temperature until the alcohol<br><br> H<br><br> is produced; and optionally producing a pharmaceutically acceptable salt thereof.<br><br> 20<br><br> 25<br><br> 30<br><br> 35<br><br> </p> </div>
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92400474 | 1992-02-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ249346A true NZ249346A (en) | 1995-10-26 |
Family
ID=8211614
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ249346A NZ249346A (en) | 1992-02-24 | 1993-02-03 | 2,6-methano-2h-quinolizine ester derivatives and medicaments thereof |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0628043A1 (en) |
JP (1) | JPH07504192A (en) |
KR (1) | KR100287933B1 (en) |
AU (1) | AU675060B2 (en) |
CA (1) | CA2130563C (en) |
FI (1) | FI105917B (en) |
HU (1) | HU216831B (en) |
IL (1) | IL104821A (en) |
MX (1) | MX9300948A (en) |
NO (1) | NO943101D0 (en) |
NZ (1) | NZ249346A (en) |
TW (1) | TW226374B (en) |
WO (1) | WO1993017019A1 (en) |
ZA (1) | ZA931146B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000048597A1 (en) | 1999-02-18 | 2000-08-24 | Novartis Ag | Systemic use of 5-ht3 receptor antagonists against rheumatic inflammatory processes |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | 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 |
JP5241484B2 (en) | 2005-03-07 | 2013-07-17 | ザ ユニヴァーシティー オヴ シカゴ | Use of opioid antagonists to attenuate endothelial cell proliferation and endothelial cell migration |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2080727T3 (en) * | 1988-02-23 | 1996-02-16 | Merrell Pharma Inc | USE OF QUINOLIZIN AND QUINOLIZINONE DERIVATIVES IN THE MANUFACTURE OF MEDICINES. |
EP0517984A1 (en) * | 1991-06-11 | 1992-12-16 | Merrell Dow Pharmaceuticals Inc. | Derivatives of amide analogs of certain methano bridged quinolizines |
-
1993
- 1993-02-03 HU HU9402436A patent/HU216831B/en unknown
- 1993-02-03 AU AU36034/93A patent/AU675060B2/en not_active Expired
- 1993-02-03 NZ NZ249346A patent/NZ249346A/en not_active IP Right Cessation
- 1993-02-03 EP EP93904797A patent/EP0628043A1/en not_active Withdrawn
- 1993-02-03 JP JP5514868A patent/JPH07504192A/en active Pending
- 1993-02-03 KR KR1019940702945A patent/KR100287933B1/en not_active IP Right Cessation
- 1993-02-03 CA CA002130563A patent/CA2130563C/en not_active Expired - Lifetime
- 1993-02-03 WO PCT/US1993/000880 patent/WO1993017019A1/en active IP Right Grant
- 1993-02-18 ZA ZA931146A patent/ZA931146B/en unknown
- 1993-02-19 TW TW082101189A patent/TW226374B/zh not_active IP Right Cessation
- 1993-02-22 IL IL10482193A patent/IL104821A/en not_active IP Right Cessation
- 1993-02-22 MX MX9300948A patent/MX9300948A/en unknown
-
1994
- 1994-08-23 NO NO943101A patent/NO943101D0/en unknown
- 1994-08-23 FI FI943872A patent/FI105917B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CA2130563C (en) | 1997-11-11 |
FI105917B (en) | 2000-10-31 |
TW226374B (en) | 1994-07-11 |
CA2130563A1 (en) | 1993-09-02 |
MX9300948A (en) | 1993-08-01 |
NO943101L (en) | 1994-08-23 |
NO943101D0 (en) | 1994-08-23 |
FI943872A0 (en) | 1994-08-23 |
KR100287933B1 (en) | 2001-05-02 |
IL104821A (en) | 1997-01-10 |
ZA931146B (en) | 1993-09-14 |
HUT68249A (en) | 1995-06-28 |
IL104821A0 (en) | 1993-06-10 |
AU3603493A (en) | 1993-09-13 |
JPH07504192A (en) | 1995-05-11 |
KR950700297A (en) | 1995-01-16 |
AU675060B2 (en) | 1997-01-23 |
EP0628043A1 (en) | 1994-12-14 |
WO1993017019A1 (en) | 1993-09-02 |
HU216831B (en) | 1999-09-28 |
FI943872A (en) | 1994-08-23 |
HU9402436D0 (en) | 1994-10-28 |
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