[go: up one dir, main page]

WO1994009005A1 - 4-7 isoindoles pontes utilises comme agents antipsychotiques et antidyskinetiques - Google Patents

4-7 isoindoles pontes utilises comme agents antipsychotiques et antidyskinetiques Download PDF

Info

Publication number
WO1994009005A1
WO1994009005A1 PCT/US1993/009161 US9309161W WO9409005A1 WO 1994009005 A1 WO1994009005 A1 WO 1994009005A1 US 9309161 W US9309161 W US 9309161W WO 9409005 A1 WO9409005 A1 WO 9409005A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
agents
minutes
antipsycchotic
isoindoles
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.)
Ceased
Application number
PCT/US1993/009161
Other languages
English (en)
Inventor
Engelbert Ciganek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Publication of WO1994009005A1 publication Critical patent/WO1994009005A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/72—4,7-Endo-alkylene-iso-indoles

Definitions

  • This invention relates to novel nitrogen-containing tricyclic compounds , to pharmaceutical compositions containing them, to methods of using them in mammals to treat physiological or drug induced psychosis and to methods of using them in mammals as antidyskinetic agents .
  • R 2 is H or Ph, a is a single or double bond, and
  • Y is OCH 3 or O 2 CCH 3 .
  • 5-HT 1a agonists having utility as anxiolytics/antipsychotics
  • antipsychotic agents have been potent dopamine receptor antagonists.
  • phenothiazines such as chlorpromazine and most
  • butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists.
  • EPS extra-pyramidal side-effects
  • dyskinesias including tarcive dyskinesias at high doses.
  • EPS extra-pyramidal side-effects
  • the object of the present invention is to provide compounds, compositions and methods useful for the treatment of physiological and/or drug-induced psychosis and dyskinesia.
  • the present invention provides antipsychotic agents which are sigma receptor antagonists, not traditional dopamine receptor blockers known in the art; and therefore, the compounds of the present invention maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic- induced behavior while having low potential for the typical movement disorder side-effects associated with the traditional dopamine antagonist antipsychotic agents.
  • Compounds of the present invention demonstrate sigma receptor affinity. It is this sigma receptor affinity of the compounds of the present invention which makes them so advantageous over the compounds in the prior art.
  • the present invention provides the following compounds and their pharmaceutically acceptable salts:
  • the present invention also provides pharmaceutical compositions containing the compounds of this invention and it also provides methods for the treatment of physiological or drug-induced psychosis or dyskinesia by administering to a host suffering from such
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds that are modified by making acid or base salts.
  • compositions of the invention can be prepared by reacting the free acid or base forms of these compounds with a
  • the compounds of this invention may be prepared by methods disclosed in United States Patents 4,855,430, 4,927,934, and 4,937,347 which is incorporated by reference herein, or by methods disclosed below.
  • Scheme 1 shows a general method for the
  • Imides 6 may also be obtained by catalytic hydrogenation of imides 3
  • the compounds of this invention 7 may also be obtained by catalytic
  • Scheme 2 shows an alternate general method, which is particularly preferred for compounds of this
  • substituted maleimides 8 to a Diels-Alder reaction with appropriately substituted dienes 9 followed by reduction.
  • the fumarate had mp 192-193° (dec.) after
  • Table 1 shows data for other examples of this invention prepared by the disclosed methods.
  • compositions possess psychotropic properties, particularly antipsychotic activity of good duration with selective sigma receptor antagonist activities while lacking the typical movement disorder side-effects of standard dopamine receptor antagonist antipsychotic agents.
  • These compounds may also be useful as antidotes for certain psychotomimetic agents such as phencyclidine (PCP), and as antidyskinetic agents.
  • Brain membranes were prepared by the method of Tam (Proc. Natl. Acad. Sci. USA 80: 6703-6707, 1983).
  • Whole brains were homogenized (20 seconds) in 10 vol (wt/vol) of ice-cold 0.34 M sucrose with a Brinkmann Polytron (setting 8). The homogenate was centrifuged at 920 ⁇ g for 10 minutes. The supernatant was centrifuged at 47,000 ⁇ g for 20 minutes.
  • the resulting membrane pellet was resuspended in 10 vol (original wt/vol) of 50 mM Tris HCl (pH 7.4) and incubated at 37°C for 45 minutes to degrade and dissociate bound endogenous ligands. The membranes were then centrifuged at 47,000 ⁇ g for 20 minutes and resuspended in 50 mM Tris HCl (50 mL per brain).
  • Membranes were prepared from guinea pig striatum by the method described for sigma receptor binding. The membranes were then resuspended in 50 mM Tris HCl (9 mL per brain).
  • Nonspecific binding was measured in the presence of 100 nM (+)-butaclamol. After 15 minutes of incubation at 100 nM (+)-butaclamol. After 15 minutes of incubation at 100 nM (+)-butaclamol. After 15 minutes of incubation at 100 nM (+)-butaclamol. After 15 minutes of incubation at 100 nM (+)-butaclamol. After 15 minutes of incubation at 100 nM (+)-butaclamol. After 15 minutes of incubation at
  • samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed three times with ice-cold binding buffer (5 mL).
  • IC 50 s were calculated from log-logit plots.
  • K i IC 50 [1+(L/K d )](4), where L is the concentration of radioligand and K d is its dissociation constant.
  • CF1 Mice (Charles River) were injected orally with test compound and placed singly into square (13 cm) Plexiglass observation chambers. Twenty minutes later mice were injected orally with mescaline (25 mg/kg). Beginning 25 minutes after treatment with mescaline (45 minutes after treatment with test compound), scratching episodes were counted during a 5 minute observation period. A scratching episode is defined as a brief (1-2 sec) burst of scratching either the head or the ear with the hind foot. For each dose of test compound, the mean number of scratching episodes is expressed as a
  • mice Male Balb/c mice (Charles River) were used. After 4-6 weeks of isolation in plastic cages (11.5 ⁇ 5.75 ⁇ 6 in) the mice were selected for aggression by placing a normal group-housed mouse in the cage with the isolate for a maximum of 3 minutes. Isolate mice failing to consistently attack an intruder were eliminated from the colony.
  • Drug testing was carried out by treating the isolate mice with test drugs or standards. Thirty minutes after dosing with test drugs by the oral route, one isolate mouse was removed from its home cage and placed in the home cage of another isolate. Scoring was a yes or no response for each pair. A maximum of 3 minutes was allowed for an attack and the pair was separated immediately upon an attack. Selection of home cage and intruder mice was randomized for each test.
  • mice were treated and tested once a week with at least a 5 day washout period between treatments.
  • the data are shown in Table 2 under the heading MUR MIIA.
  • Dosage forms (compositions) suitable for administration ranges from 1 mg to 2000 mg.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from. the atmosphere, or enteric-coated for selective disintegration in the
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • saline aqueous dextrose (glucose)
  • glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • suitable stabilizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain
  • preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à de nouveaux composés contenant de l'azote, tels que les composés de la formule (1-4), à des compositions pharmaceutiques contenant lesdits composés, ainsi qu'à des procédés d'utilisation de ces composés pour traiter les psychoses physiologiques et/ou induites par médicaments ainsi que comme agents antidyskinétiques.
PCT/US1993/009161 1992-10-09 1993-10-01 4-7 isoindoles pontes utilises comme agents antipsychotiques et antidyskinetiques Ceased WO1994009005A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95913792A 1992-10-09 1992-10-09
US07/959,137 1992-10-09

Publications (1)

Publication Number Publication Date
WO1994009005A1 true WO1994009005A1 (fr) 1994-04-28

Family

ID=25501713

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/009161 Ceased WO1994009005A1 (fr) 1992-10-09 1993-10-01 4-7 isoindoles pontes utilises comme agents antipsychotiques et antidyskinetiques

Country Status (1)

Country Link
WO (1) WO1994009005A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013637A3 (fr) * 1998-12-23 2001-03-14 Bayer Aktiengesellschaft Procédé de préparation de phénéthylamines contenant du fluor et des composés bèta-iminovinyl- et bèta-iminoéthylphényl contenant du fluor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL73028B1 (fr) * 1970-06-24 1974-08-31
US4855430A (en) * 1987-11-12 1989-08-08 American Home Products Corporation Polycyclicamine with psychotropic activity
US5216018A (en) * 1992-02-14 1993-06-01 Du Pont Merck Pharmaceutical Company Hydroisoindolines and hydroisoquinolines as psychotropic

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL73028B1 (fr) * 1970-06-24 1974-08-31
US4855430A (en) * 1987-11-12 1989-08-08 American Home Products Corporation Polycyclicamine with psychotropic activity
US5216018A (en) * 1992-02-14 1993-06-01 Du Pont Merck Pharmaceutical Company Hydroisoindolines and hydroisoquinolines as psychotropic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 84, no. 11, 15 March 1976, Columbus, Ohio, US; abstract no. 74103s, E. W. HAHN ET AL: "N-Substituted derivatives of 4,7-endomethylene-4,7,8,9-tetrahydroisoindoline" *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013637A3 (fr) * 1998-12-23 2001-03-14 Bayer Aktiengesellschaft Procédé de préparation de phénéthylamines contenant du fluor et des composés bèta-iminovinyl- et bèta-iminoéthylphényl contenant du fluor

Similar Documents

Publication Publication Date Title
BE1005921A4 (fr) Utilisation en therapeutique des antagonistes des recepteurs serotoninergiques 5ht3.
US5229516A (en) Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
US6043239A (en) Heterocyclic compounds
AU762958B2 (en) New beta-carboline compounds a process for their preparation and pharmaceutical compositions containing them
US20040259903A1 (en) Pyrido [2,1-a] isoquinoline derivatives
CS244148B2 (en) Method of aminomethylpyrrolidine production
JPH08508738A (ja) ５−ｈｔ１ａ及び／又は５−ｈｔ２リガンドとしてのインドール誘導体
WO1997036905A1 (fr) Diazepino-indoles inhibiteurs de phosphodiesterases 4
JPH03504010A (ja) ジベンゾフランカルボキサミド
EP0623621A1 (fr) Dérivés oxazabicycliques et leur utilisation comme agonsistes de récepteurs 5-HT4
US5216018A (en) Hydroisoindolines and hydroisoquinolines as psychotropic
FR2674849A1 (fr) Nouveaux derives de n-cyclohexyl benzamides ou thiobenzamides, leurs preparations et leurs applications en therapeutique.
EP0785789B1 (fr) Diazepino-indoles inhibiteurs de phosphodiesterases iv
WO1993022310A1 (fr) (n-phthalimidoalkyl)piperidines pour le traitement des psychoses
US5698551A (en) Heterocyclic compounds
PL142583B1 (en) Method of obtaining 1-position-substituted 4-hydroxymethylpyrolidinones
JPH09506083A (ja) フエニルインドール化合物
CA2089349C (fr) Nouveaux derives de pyrrolidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
JP4467648B2 (ja) 新規インドールカルボキサミド、医薬組成物およびカルパインの阻害方法
WO1994009005A1 (fr) 4-7 isoindoles pontes utilises comme agents antipsychotiques et antidyskinetiques
EP0004342B1 (fr) Carbazoles, procédé pour leur préparation, compositions pharmaceutiques les contenant et leurs intermédiaires
DE10318609A1 (de) 5-Hydroxyindole mit N-Oxidgruppen und deren Verwendung als Therapeutika
EP2917204A1 (fr) Derives de 1 h-indole-3-carboxamide et leurs utilisation comme antagonistes du p2y12
US5962449A (en) Tricyclic compounds in treating hyperalgesic conditions and NIDDM
US4343812A (en) Antidepressant 2-amino-and-2-(substituted amino)-cis-hexahydro-carbazoles, compositions and use

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase