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WO1996002513A1 - Isomeres optiquement actifs de la dihydrexidine et de ses analogues substitues - Google Patents

Isomeres optiquement actifs de la dihydrexidine et de ses analogues substitues Download PDF

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Publication number
WO1996002513A1
WO1996002513A1 PCT/US1995/008598 US9508598W WO9602513A1 WO 1996002513 A1 WO1996002513 A1 WO 1996002513A1 US 9508598 W US9508598 W US 9508598W WO 9602513 A1 WO9602513 A1 WO 9602513A1
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WO
WIPO (PCT)
Prior art keywords
phenanthridine
hexahydrobenzo
compound
dihydroxy
arh
Prior art date
Application number
PCT/US1995/008598
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English (en)
Inventor
David E. Nichols
Richard B. Mailman
Original Assignee
Purdue Research Foundation
University Of North Carolina At Chapel Hill
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Publication date
Application filed by Purdue Research Foundation, University Of North Carolina At Chapel Hill filed Critical Purdue Research Foundation
Priority to AU29667/95A priority Critical patent/AU2966795A/en
Priority to EP95925584A priority patent/EP0773933A1/fr
Priority to JP8505085A priority patent/JPH10502923A/ja
Publication of WO1996002513A1 publication Critical patent/WO1996002513A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to optically active s t e r e o i s o m e r s o f t r a n s - dihydroxyhexahydrobenzo[a]phenanthridine (dihydrexidine) , their resolution, compositions, and methods of use.
  • the (+)- and (-)-isomers of dihydrexidine were resolved from the racemate using a non-classical technique after initial attempts using classical techniques failed.
  • Dopamine functions as a neurotransmitter in both the central and peripheral nervous systems.
  • Dopamine receptors have been implicated in several neurological disorders, such as schizophrenia and Parkinson's disease, as well as in vascular regulation. Additionally, dopamine receptors are the accepted loci of action of many psychotropic drugs, including amphetamine, cocaine, and the neuroleptics. Thus, ligands selective for dopamine receptors are important as basic research tools and potential therapeutic agents.
  • D 2 and D 2 dopamine receptors into two general classes called D 2 and D 2 (Kebabian, J. and Calne, D.B., in Nature 1979, 277, 93-
  • the "Di-like" receptors include at least two gene products (the D la and the D lb or D 5 ) , which are linked functionally to stimulation of cAMP synthesis, and which preferentially recognize 1-phenyl-tetrahydrobenzazepines
  • the "D 2 -like" receptors come from at least three genes, and include multiple splice variants.
  • the "D 2 -like" receptors (D 2l0ng , D 2short , D 3 , and D 4 ) sometimes are linked to inhibition of cAMP synthesis, and have the opposite pharmacological specificity from the D ⁇ like receptors (i.e., having much higher affini ty for spiperone or sulpiride vs. SCH23390) .
  • SKF38393 and related partial agonists have been used in many studies of D x receptor function because they were relatively selective, and because no alternatives were available.
  • Nichols, D. E. disclosed, in U.S. Patent No. 5,047,536, novel ligands for dopamine receptors which comprised generically certain t ra n s - hexahydrobenzophenanthridines of the formula (1)
  • H a and H b are trans across ring fusion bond c, R is hydrogen or - ⁇ - ⁇ alkyl; R x is hydrogen, benzoyl or pivaloyl; and X is hydrogen, chloro, bromo, iodo or a group of the formula 0R 2 wherein R 2 is hydrogen, benzoyl or pivaloyl.
  • the present invention provides the resolution of the enantiomers of 2 and its substituted hexahydrobenzo [a] phenanthridine analogs and discloses pharmacologic evidence that suggests that, quite unexpectedly, -both ⁇ ⁇ and D 2 receptor affinities, as well as functional effects, including the unprecedented D 2 postsynaptic selectivity, reside in the (6ai?, 12bS) - (+) - enantiomer of 2 and the corresponding enantiomers of its substituted analogs.
  • H a and H b are trans across ring fusion bond c
  • R is hydrogen or C - C 4 alkyl
  • R is hydrogen or a phenol protecting group
  • X is fluoro, chloro, bromo, iodo, or a group of the formula -OR ⁇ wherein is hydrogen or a phenol protecting group, provided that when X is a group of the formula -OR 5 , the groups R x and R 5 can be taken together to form a group of the formula -CH 2 -;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group -OR x wherein R is as defined above, provided said compound is optically active.
  • the compound is the (+) -isomer, although in other embodiments, the compound is the (-)- isomer.
  • the groups R 2 , R 3 , and R 4 are all hydrogen. In another, at least one of the groups R 2 , R 3 , and R 4 .is methyl.
  • compositions comprising the disclosed optically acitve compounds and methods of their use will be apparent to one of ordinary skill considering the detailed descriptions provided herein.
  • FIG. 1 Competition of enantiomers of 2 for D x receptors labeled by 3 H-SCH23390.
  • A Competition in rat striatal membranes.
  • B Competition in membranes prepared from Ltk-cells transfected with human D ⁇ receptor. (+) -2 had ca. twice the affinity of racemic 2 in both preparations. In the striatal membranes, (-)-2 had significantly less affinity than the racemate or (+) enantiomer.
  • FIG. 4 A schematic illustration is provided for the isolation of the enantiomers of dihydrexidine.
  • the lower case letters for each step denote the following reaction conditions: (a) i. (J?) - Methoxyphenyl acetyl chloride, 20% NaOH (aq) , CH 2 C1 2 ; ii. chromatography; (b) LiEt 3 BH, THF; (c) BBr 3 , CH 2 C1 2 .
  • the diastereomeric (J?) -O- ethyl mandelic acid amides of racemic trans-10, 11- dimethoxy-5, 6,6a, 7, 8,12b-hexahydrobenzo[a]phenanthridine 4 were prepared by an adaptation of the procedure of Johansson, A.M. et al. , described in J. Med. Chem. 1987, 30, 602-611. In this procedure, the ether-protected amine 3 was coupled with (J?) -O-methyl mandeloyl chloride to yield the two diastereomeric amides.
  • the resulting amides were separated by centrifugal chromatography (chromatotron) using 40% ethyl acetate/hexane eluent and a 2 mm silica gel rotor. While the chromatron was used to effect this separation on a small scale, any of a variety of chromatographic techniques would apply on larger scales, such as column chromatography. Crystallization of the individual amides provided the diastereomers in greater than 99% purity, as judged by HPLC analysis. An X-ray quality crystal was obtained for the diastereomer with lower R f on TLC and the analysis demonstrated that it corresponded to (6aS, 12bi?) -4.
  • the enantiomericallypure catecholamines (6aJ?,12bS) - (+)-2 and (6aS, 12bJ?) - (-) -2 were prepared from the corresponding methoxy precursors by treatment with BBr 3 and crystallized as their hydrochloride salts.
  • (+) -2 had about twice the affinity of ( ⁇ ) -2 for the D x receptor in both rat striatal membranes, and in transfected Ltk " cells.
  • the (-) -enantiomer shows significantly less affinity than either the racemate or (+) -enantiomer.
  • (+) -2 causes a doubling of cAMP synthesis in striatal membranes, indicating that
  • (+) -2 is a full agonist. Conversely, (-)-2 is nearly 100-fold less potent than (+)-2, and does not cause a fully maximal response (relative to dopamine) at the highest concentration tested (5 ⁇ M) . In competition for D 2 receptors, (+) -2 exhibits about twice the affinity of
  • the (6aS, 12bJ?;- (-) enantiomer had significantly lower affinity than either (6ai?, 12bS) - (+) -2 or ( ⁇ ) -2 at the D-_ receptor.
  • NA not applicable (these compounds are antagonists) .
  • compositions comprising the optically active compounds disclosed herein.
  • these compositions include pharmaceutical compositions comprising a therapeutically effective amounr of an optically active compound along with a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable" carrier means a non-toxic, inert solid, semi- solid liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; .
  • esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, , Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations.
  • Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.
  • antioxidants examples include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, aloha-tocopherol and the like: and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (B
  • a “therapeutically effective amount” of an optically active compound such as a dopaminergic agent
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidently with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the optically active compounds of the present invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 25 mg/kg body weight or more usually from 0.1 to 15 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a human or other mammal in need of such treatment from about 1 mg to about 1000 mg of the compound(s) of this invention per day in multiple doses or in a single dose of from 1 mg, 5 mg, 10 mg, 100 mg, 500 mg or 1000 mg.
  • the compounds of the present invention may be administered alone or in combination or in concurrent therapy with other agents which affect the central or peripheral nervous system.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; sweetening, flavoring and perfuming agents.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water,
  • Ringer's solution U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility.
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying absorption of a is drug to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycoside.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly- orthoesters and polyanhydrides.
  • the depot injectables can also be made by entrapping the drug in iiposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release- controlling coatings.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro- encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as iactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the. body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the present invention is useful in the treatment or alleviation of disease, especially those disorders related to a central nervous system dysfunction.
  • Such dysfunctions of the central nervous system may be characterized by an apparent neurological, physiological, psychological, or behavioral disorder, the symptoms of which can be reduced by the administration of an effective amount of the optically active compounds of the present invention.
  • the present invention is used in a method of alleviating the effects of Parkinson's disease.
  • a patient can also be treated for a CNS movement-related disorder, including, but not limited to, Huntington's disease, Pick's disease or Creutzfeldt-Jakob disease.
  • Dihydrexidine has also been shown to be a specific renal vasodilator. See, e.g., Kohli, J., in Europ. J. Pharmacol . 1993, 235, 31-35.
  • the optically active compounds of the present invention can be used in a method of treating or alleviating the effects of a cardiovascular disorder, such as congestive heart failure.
  • a method of enhancing endocrine function comprises administering to a patient in need of such enhancement an effective amount of the optically active compounds of the present invention, especially (6aJ2, 12bS) - (+) -10, 11- dihydroxy-5,6, 6a,7, 8,12b-hexahydrobenzo[a]phenanthridine, an O-alkylated or N-alkylated analog thereof, or its pharmaceutically acceptable acid addition salt, such as the hydrochloride.
  • such enhancement leads to an increase in endocrine function or secretion.
  • a pharmaceutically acceptable antipyschotic composition which comprises an effective amount of the compound (6ai?, 12bS) - ⁇ +) -10, ll-dihydroxy-5, 6, 6a, 7, 8, 12b- hexahydrobenzo[a]phenanthri-dine, an O-alkylated or N- alkylated analog thereof, or its pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable carrier.
  • Racemic 10,11- dimethoxy-5, 6,6a, 7, 8,12b-hexahydrobenzo[a]phenan-thridine hydrochloride 50 mg, 0.15 mmol was dissolved in water (1 mL) and dichloromethane (1 mL) . After the salt had dissolved, 1 N NaOH (0.5 mL) was added, followed by addition of the dichloromethane solution of the mandeloyl chloride.
  • the residual oil was then separated into its components using a Chromatotron (Harrison Research, Palo Alto, CA) by elution on a 1 mm silica gel rotor with 40% ethyl acetate/hexane. The two major fractions were collected and concentrated by rotary evaporation. The faster moving component was crystallized from hexane to provide 16 mg (24%), mp 147-149 °C; [ ⁇ ] D -97.45 degrees
  • the scan rate varied from 1 to 20 degrees/min (in omega) .
  • the variable scan rate allows rapid data collection for intense reflections where a fast scan rate is used and assures good counting statistics for weak reflections where a slow scan rate is used.
  • Data were collected to a maximum 2 (theta) of 55.0 degrees.
  • the scan range (in deg) was determined as a function of theta to correct for the separation of the Ka doublet (see, CAD4 Operations Manual, Enraf-Nonius,
  • Moving-crystal moving-counter background counts were made by scanning an additional 25% above and below this range. Thus, the ratio of peak counting time to background counting time was 2:1.
  • the counter aperture was also adjusted as a function of theta.
  • the horizontal aperture width ranged from 1.9 to 2.4 mm; the vertical aperture was set at 4.0 mm.
  • the diameter of the incident beam collimator was 0.7 mm and the crystal to detector distance was 21 cm. For intense reflections an attenuator was automatically inserted in front of the detector; the attenuator factor was 12.9.
  • H a and H b are trans across ring fusion bond c;
  • R is hydrogen or alkyl;
  • Ri is hydrogen or a phenol protecting group;
  • X is fluoro, chloro, bromo, or iodo, or a group of the formula -OR 5 , wherein R 5 is hydrogen or a phenol protecting group, provided that when X is a group of the formula -OR 5 , the groups R ⁇ and R 5 can be taken together to form a -CH 2 - group, thus representing a methylenedioxy functional group bridging the C-10 and C-ll positions on the hexahydrobenzo- [a]phenanthridine ring system (as labeled in the formula above) ; and R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, Ci-C 4 alkyl, phenyl, fluoro, chloro,
  • C 1 -C 4 alkyl refers to branched or straight chain alkyl groups comprising one to four carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t- butyl and cyclopropylmethyl.
  • C 1 -C 4 alkoxy refers to branched or straight chain alkyl groups comprising one to four carbon atoms bonded through an oxygen atom, including, but not limited to, methoxy, ethoxy and t- butoxy.
  • the 4-methylbenzoyl chloride acylating agent was prepared by suspending 3.314 g (24.3 mmol) of p-toluic acid in 200 mL benzene. To this solution was added 2.0 equiv. (4.25 mL) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0 °C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
  • reaction mixture was washed successively with 2 x 30 mL of 5% aqueous HCl, 2 x 30 mL of saturated sodium bicarbonate solution, saturated NaCl solution, and was dried over MgS0 4 . After filtration, the filtrate was concentrated under vacuum. Crystallization from diethyl ether gave 5.575 g (69.3%) of the enamide mp 96-98 °C.
  • the 3-methylbenzoyl chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of jn-toluic acid in 100 mL benzene. To this solution was added 2.0 equiv. (3.84 mL) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0 °C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
  • the 2-methylbenzoyl chloride acylating agent was prepared by suspending 4.750 g (42.2 mmol) of o-toluic acid in 100 mL benzene. To this solution was added 2.0 equiv. (7.37 mL) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0 °C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
  • the reaction mixture was washed successively with 2 x 30 mL of 5% aqueous HCl, 2 x 30 mL of saturated sodium bicarbonate solution, saturated NaCl solution, and was dried over MgS0 4 . After filtration, the filtrate was concentrated under vacuum. The resulting oil was purified via the chro atotron utilizing a 5% ether/dichloromethane eluent mobile phase to yield 3.950 g (38.5%) of the pure oil.
  • dihydrexidine and its substituted analogs are resolved into their respective enantiomers, i.e., their (6aR, 12bS) - ( + ) - and (6aS, 12biR) -(-) -optical isomers. Accordingly, the following compounds, including their salts (especially their acetic and hydrochloride acid addition salts) , O-alkylated, and N-alkylated analogs, are provided by the methods of the present invention:
  • [ 3 H] -SCH23390 was synthesized as described by Wyrick, S. et al. , in J " . Label . Comp. Radiopharm. 1986, 23 , 685-692. ( ⁇ ) -2 was synthesized as previously described.
  • [ 3 H] -Spiperone was purchased from A ersham Corp (Arlington Heights, IL) . Na 125 I was supplied by New England Nuclear (Boston, MA) , and HEPES buffer was purchased from Research Organics, Inc. (Cleveland, OH) .
  • SCH23390 was a gift from Schering Corp. (Bloomfield, NJ) or was purchased from Research Biochemicals Inc. (Natick, MA) .
  • Domperidone and ketanserin were gifts of Janssen Pharmaceutica (New Brunswick, NJ) .
  • Dopamine, cAMP, isobutyl methylxanthine (IBMX) , and chlorpromazine were obtained from Sigma Chemical Co (St. Louis, MO) .
  • cAMP primary antibody was obtained from Dr. Gary Brooker
  • rat striata were homogenized by seven manual strokes in a Wheaton Teflon-glass homogenizer with ice cold 50 mM HEPES buffer with 4.0 mM MgCl 2 , pH 7.4 (25 °C) . Tissue was centrifuged at 27,000 x g (Sorvall RC-5B/SS-34 rotor, DuPont, Wilmington DE) for 10 min, and the supernatant was discarded.
  • the pellet was homogenized (five strokes) and resuspended in ice cold buffer and centrifuged again. The final pellet was suspended at a concentration of approximately 2.0 mg wet weight/mL. Assay tubes (1 mL final volume) were incubated at 37 °C for 15 minutes. Nonspecific binding of [ 3 H] -SCH23390 (ca. 0.25 nM) was defined by adding unlabeled SCH23390 (1 ⁇ M) . Binding was terminated by filtering with 15 mL ice cold buffer on a Skatron or Brandel cell harvester (Skatron Inc., Sterling, VA; Brandel Inc., Gaithersburg, MD) using glass fiber filter mats (Skatron no. 7034; Brandel GF/B) .
  • Skatron or Brandel cell harvester Skatron Inc., Sterling, VA; Brandel Inc., Gaithersburg, MD
  • D 2 -like receptors the procedure was as described for D ⁇ like receptors with the following changes.
  • [ 3 H] -Spiperone was used as the radioligand, and non-specific binding of [ 3 H] -spiperone was defined by adding unlabeled 1 ⁇ M chlorpromazine.
  • Ketanserin 50 nM was added to mask binding of [ 3 H] -spiperone to serotonin receptors.
  • tissue homogenate was added to a prepared reaction mixture, yielding a final volume of 100 ⁇ L containing 0.5 mM ATP, 0.5 mM IBMX, [ ⁇ 32 P] -ATP (0.5 ⁇ Ci) , 1 mM cAMP, 2 mM MgCl 2 , 100 mM HEPES buffer, 2 ⁇ M GTP, 0 or 100 ⁇ M dopamine and/or drug, 10 mM phosphocreatine and 5U creatine phosphokinase.
  • the reaction was initiated by transferring the samples from an ice bath to a water bath at 30 °C and terminated 16 minutes later by the addition of 100 ⁇ L of 3% sodium dodecyl sulfate. Proteins and much of the non-cyclic nucleotides were precipitated by the addition of 300 ⁇ L each of 4.5% ZnS0 4 and 10% Ba(0H) 2 to each incubation tube. The samples were centrifuged at 10,000 g for 8 minutes, and the supernatants removed and loaded onto an ISIS Autoinjector.
  • the HPLC separations were carried out using a Waters RCM 8 x 10 module equipped with a C18, 10 ⁇ m cartridge, using a mobile phase of 150 mM sodium acetate, 24% methanol, pH 5.0. A flow rate of 1.3 mL/min was used for separation. A UV detector set at 254 nm was used to measure the unlabeled cAMP, which was added to the sample tubes to serve as an internal standard and as a marker for the labeled cAMP. Sample recovery was based on UV measurement of total unlabeled cAMP peak areas. The radioactivity in each fraction was determined by an on ⁇ line HPLC radiation detector (Inus Systems, Tampa FL) .
  • the cells were grown in DMEM-H medium containing 4,500 mg/L glucose, L-glutamine, 10% fetal bovine serum and 700 ng/mL G418. In these studies, D x receptor levels were ca. 5,000 fmol/mg protein. All cells were maintained in a humidified incubator at 37 °C with 5% C0 2 . Cells were grown in 75 cm 2 flasks until confluent. The cells were rinsed and lysed with 10 mL of ice cold hypoosmotic buffer (HOB) (5 mM HEPES, 2.5 mM MgCl 2 , 1 mM EDTA; pH 7.4) for 10 minutes at 4 °C.
  • HOB ice cold hypoosmotic buffer
  • the supernatant was removed, and the pellet was resuspended (10 strokes) in 1 mL of ice cold HOB for each original flask of cells homogenized. This homogenate was then spun again at 43,000 x g at 4 °C for 20 minutes. The supernatant was removed and the final pellet was resuspended (10 strokes) in ice cold storage buffer (50 mM HEPES, 6 mM MgCl 2 , 1 mM EDTA; pH 7.4) to yield a final concentration of ca. 2.0 mg of protein/mL. Aliquots of the final homogenate were stored in microcentrifuge tubes at -80 °C.
  • protein levels for each membrane preparation were quantified using the BCA protein assay reagent (Pierce, Rockford, IL) adapted for use with a microplate reader (Molecular Devices; Menlo . Park, CA) .

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Abstract

L'invention concerne des hexahydrobenzo[a]phénanthridines optiquement actives de la formule (I). Dans cette formule, R est un hydrogène ou un C1-C4 alkyle; R1 est un hydrogène ou un groupe protecteur du phénol, X est un fluoro, un chloro, un bromo, un iodo ou un groupe de la formule OR5; R2, R3 et R4 sont choisis d'une manière indépendante dans le groupe constitué par l'hydrogène, C1-C4 alkyle, phényle, fluoro, chloro, bromo, iodo ou un groupe -OR1. On décrit également un procédé pour fractionner le mélange racémique de trans-hexahydrobenzo[a]phénanthridines en composants énantiomères. Les études pharmacologiques montrent qu'un seul des enantiomères d'une phénanthridine préférée, la dihydrexidine, en l'occurrence l'isomère (6aR, 12bS)-(+) se fixe activement simultanément aux récepteurs de la dopamine du type D1 et du type D2. On décrit également différents autres composés, ainsi que des compositions et des procédés d'utilisation des stéréoisomères optiquement actifs.
PCT/US1995/008598 1994-07-15 1995-07-10 Isomeres optiquement actifs de la dihydrexidine et de ses analogues substitues WO1996002513A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU29667/95A AU2966795A (en) 1994-07-15 1995-07-10 Optically active isomers of dihydrexidine and its substituted analogs
EP95925584A EP0773933A1 (fr) 1994-07-15 1995-07-10 Isomeres optiquement actifs de la dihydrexidine et de ses analogues substitues
JP8505085A JPH10502923A (ja) 1994-07-15 1995-07-10 ジヒドレキシジンおよびその置換類似体の光学活性異性体

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US27534294A 1994-07-15 1994-07-15
US08/275,342 1994-07-15

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WO1996002513A1 true WO1996002513A1 (fr) 1996-02-01

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JP (1) JPH10502923A (fr)
AU (1) AU2966795A (fr)
CA (1) CA2195239A1 (fr)
IL (1) IL114608A0 (fr)
WO (1) WO1996002513A1 (fr)
ZA (1) ZA955931B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10111486A1 (de) * 2001-03-09 2002-10-02 Ralph R Dawirs Verwendung einer oder mehrerer neuroaktiver Substanzen zur Behandlung der Parkinsonschen Krankheit
EP1414457A4 (fr) * 2001-08-10 2004-12-29 Purdue Research Foundation Dinapsoline chirale
EP1480647A4 (fr) * 2002-02-15 2005-07-13 Darpharma Inc Promedicaments a base de monoester et de diester a substitution asymetrique des agonistes des recepteurs d1 de la dopamine
WO2010017093A2 (fr) 2008-08-05 2010-02-11 Effipharma, Inc. Ligands de récepteur de dopamine à durée d'action prolongée
WO2021021953A2 (fr) 2019-07-30 2021-02-04 Sanford Burnham Prebys Medical Discovery Institute Agonistes du récepteur d1 de la dopamine et leurs méthodes d'utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047536A (en) * 1989-03-17 1991-09-10 Purdue Research Foundation Hexahydrobenzo(A)phenanthridine compounds
WO1992004356A1 (fr) * 1990-09-07 1992-03-19 Abbott Laboratories Composes de phenanthridine
WO1993024462A1 (fr) * 1992-05-26 1993-12-09 Purdue Research Foundation Hexahydrobenzo[a]phenanthridines substituees

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047536A (en) * 1989-03-17 1991-09-10 Purdue Research Foundation Hexahydrobenzo(A)phenanthridine compounds
WO1992004356A1 (fr) * 1990-09-07 1992-03-19 Abbott Laboratories Composes de phenanthridine
WO1993024462A1 (fr) * 1992-05-26 1993-12-09 Purdue Research Foundation Hexahydrobenzo[a]phenanthridines substituees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Vol. 33, issued 1990, BREWSTER et al., "Trans 10, 11 D Hydroxy-5, 6, 6a, 7, 8, 12b Hexahydro Benzo(a) Phenanthridine: A Highly Potent Selective Dopamine D Full Agonist", pages 1756-1764. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10111486A1 (de) * 2001-03-09 2002-10-02 Ralph R Dawirs Verwendung einer oder mehrerer neuroaktiver Substanzen zur Behandlung der Parkinsonschen Krankheit
EP1414457A4 (fr) * 2001-08-10 2004-12-29 Purdue Research Foundation Dinapsoline chirale
EP1480647A4 (fr) * 2002-02-15 2005-07-13 Darpharma Inc Promedicaments a base de monoester et de diester a substitution asymetrique des agonistes des recepteurs d1 de la dopamine
US7220754B2 (en) 2002-02-15 2007-05-22 Darpharma, Inc. Mono-ester and asymmetrically substatuted di-ester pro-drugs of dopamide D1 receptor agonists
WO2010017093A2 (fr) 2008-08-05 2010-02-11 Effipharma, Inc. Ligands de récepteur de dopamine à durée d'action prolongée
EP2364317B1 (fr) * 2008-08-05 2015-07-29 Effipharma, Inc. Ligands de récepteur de dopamine à durée d'action prolongée
WO2021021953A2 (fr) 2019-07-30 2021-02-04 Sanford Burnham Prebys Medical Discovery Institute Agonistes du récepteur d1 de la dopamine et leurs méthodes d'utilisation
EP4003339A4 (fr) * 2019-07-30 2023-02-22 Sanford Burnham Prebys Medical Discovery Institute Agonistes du récepteur d1 de la dopamine et leurs méthodes d'utilisation

Also Published As

Publication number Publication date
IL114608A0 (en) 1995-11-27
EP0773933A1 (fr) 1997-05-21
JPH10502923A (ja) 1998-03-17
CA2195239A1 (fr) 1996-02-01
AU2966795A (en) 1996-02-16
ZA955931B (en) 1996-01-26

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