WO1992004356A1 - Phenanthridine compounds - Google Patents

Phenanthridine compounds Download PDF

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Publication number
WO1992004356A1
WO1992004356A1 PCT/US1991/006440 US9106440W WO9204356A1 WO 1992004356 A1 WO1992004356 A1 WO 1992004356A1 US 9106440 W US9106440 W US 9106440W WO 9204356 A1 WO9204356 A1 WO 9204356A1
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Prior art keywords
hydroxy
phenanthridine
compounds
hydrogen
dopamine
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PCT/US1991/006440
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French (fr)
Inventor
John W. Kebabian
Michael R. Michaelides
Robert W. Schoenleber
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Abbott Laboratories
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Publication of WO1992004356A1 publication Critical patent/WO1992004356A1/en

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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

Definitions

  • This invention relates to novel organic compounds which have biological activity, compositions containing these compounds and a method of treatment.
  • the invention concerns benzophenanthridine dopamine D-1 receptor antagonists, pharmaceutical compositions containing these compounds and a method for treating dopamine-related neurological, psychological and behavioral disorders with such compounds.
  • Dopamine is an important neurotransmitter in the central nervous system (CNS), and also has several important roles in the peripheral nervous system such as in the control of supply of blood to the kidneys and in autonomic ganglion transmission.
  • dopamine receptors in the CNS can be divided into two general categories, designated D-1 and D-2 receptors.
  • the division was originally based on biochemical and pharmacological differences between the two receptor types. Recently, further evidence which supports this division has come from study of the molecular biology of dopamine receptors in the CNS.
  • the dopamine D-1 receptor is linked to the enzyme adenylate cyclase through a stimulatory G protein such that stimulation of this receptor by dopamine or a dopamine D-1 receptor agonist causes an increase in the production of 3',5'-cyclic adenosine monophosphate (cAMP).
  • cAMP 3',5'-cyclic adenosine monophosphate
  • the D-2 receptor also regulates important functional activity within the CNS, although the biochemical events which follow stimulation of this receptor by dopamine or a D-2 receptor agonist are not as well understood.
  • Autoreceptors on dopaminergic neurons which have the pharmacological properties of D-2 receptors appear to control the firing rate of these ceils as well as the release of dopamine from the nerve terminals. It is also known that stimulation of the D-2 receptors in the intermediate lobe of the pituitary gland causes a decrease in cAMP production and that stimulation of the D- 2 receptors on the mammotrophs of the anterior pituitary gland suppresses prolactin secretion.
  • Dopaminergic neurons are also affected by and interact with other neurotransmitter systems in the CNS. For example, D-2 receptors on the cholinergic interneurons in the striatum (one of the components of the basal ganglia) regulate the release of acetylcholine from these cells.
  • Dopamine involvement has been proposed for several diverse neurological disorders such as Parkinson's disease and schizophrenia.
  • the putative roles of the two types of dopamine receptors differ in these disorders.
  • Schizophrenia is the most common psychosis and involves disturbance of thought processes, hallucinations and loss of touch with reality.
  • the theory of schizophrenia as a disease of the CNS was first formalized by Kraepelin and Bleuler in the early 1900's. It was not until chlorpromazine was discovered by Delay and Daniker in the early 1950's, however, that effective drug management of this disease was possible.
  • antipsychotic agents are widespread and hundreds of millions of patients have been treated with them in the past forty years.
  • the currently available antipsychotic agents frequently produce undesirable side-effects, the most common of which are the so-called extrapyramidal neurological effects that include unusual involuntary movements and Parkinson-like effects. Sedation and hypotension are also common side effects. Because of these often severe side-effects and the high incidence of patients unresponsive to currently available drugs, more potent and selective agents are needed.
  • dopamine also has a central role in the brain's reward system.
  • animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist.
  • the animals would increase the amount of cocaine administered in order to maintain the elevated dopamine levels responsible for the drugs euphorigenic and reinforcing properties. Because of this interrelationship, dopamine antagonists are potentially useful for the treatment of drug abuse and other addictive behavior disorders.
  • the present invention provides compounds represented by the following structural formula (I):
  • R 1 is selected from hydrogen, methyl, ethyl and prodrug amide group.
  • R 2 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, acetamino and -SO2R 7 wherein R 7 is lower alkyl.
  • R3 is selected from hydrogen and prodrug ester group.
  • R4, R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, amino, acetamino, aminomethyl and -SO2R8 wherein R ⁇ is lower alkyl.
  • R 4 , R 5 and R 6 are hydrogen, R 2 is not methoxy and
  • R 4 , R 5 and R 6 is nitro or -SO2R 8 .
  • compositions comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of treating dopamine-related neurological and psychological disorders, cognitive impairment, attention deficit disorder and addictive behavior disorders in humans or other mammals with the compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED
  • This invention relates to novel compounds which are dopamine D-1 receptor antagonists. It has been found that the compounds of formula (I) have the ability to antagonize the action of dopamine at dopamine D-1 receptors in the central and peripheral nervous systems.
  • the compounds of the present invention are, therefore, useful in the treatment of dopamine- related neurological and psychological disorders, as well as in the treatment of cognitive impairment, attention deficit disorders and addictive behavior disorders.
  • the compounds which are contemplated to be within the scope of the present invention include: frans-11-Hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phenanthridine; fra ⁇ s-N-Methyl-11 -hydroxy-5,6,6a,7a,8,12b- hexahydrobenzo[a]phenanthridine; fra ⁇ s-10-Bromo-11 -hydroxy-5,6,6a,7.8,12b- hexahydrobenzo[a ⁇ phenanthridine; and ra/7s-N-Methyl-10-bromo-11 -hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine; fra/.s-1 1 -Hydroxy-10-nitro-5,6,6a,7a,8,12bhexahydrobenzo[a]phen- anthridine; frans-N-Methyl-1 1 -hydroxy-10
  • the compounds of formula (I) contain two or more asymmetric carbon atoms and thus exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.
  • the present invention includes within its scope all of the isomeric forms.
  • the terms "R” and “S” configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45: 13-30.
  • alkanoyl refers to the following structures: o
  • R9 is selected from hydrogen and a lower alkyl group as defined below.
  • amino acid and dipeptide refer to a single ⁇ -amino acid or two amino acids joined by amide (peptide) bonds.
  • the amino acids are naturally occurring amino acids such as valine, glycine, norvaline, alanine, glutamic acid, glutamine, aspartic acid, leucine, isoleucine, proline, methionine, or phenylalanine or they may be synthetic amino acids such as cyclohexylalanine or cyclohexylglycine.
  • the amino acids can either be in the L or D configuration or a mixture of the two isomers. If not specified, amino acid substituents are optically active and have the L configuration.
  • halogen refers to bromo (Br), chloro (Cl), fluoro (F) and iodo (I).
  • halo-substituted lower alkyl refers to a lower alkyl group, as defined below, bearing at least one halogen substituent, for example chloromethyl, fluoromethyl, chloroethyl, trifl ⁇ oromethyl and the like.
  • lower alkoxy refers to a lower alkyl group, as defined below, which is bonded through an oxygen atom.
  • lower alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
  • lower alkyl refers to branched or straight chain alkyl groups comprising one to six carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
  • lower alkylamino refers to amino groups substituted with one or two lower alkyl groups, as defined above, including methylamino, ethylamino, dimethylamino, diethylamino, propylamino and . ethylmethylamino.
  • phenol-protecting group is used herein to mean substituents on the phenolic oxygen which prevent undesired reactions and degradations during a synthesis.
  • phenol-protecting groups include ethers, for example alkyl, alkenyl and cycloalkyl ethers (such as methyl, isopropyl, t-butyl, cyclopropylmethyl, cyclohexyl, allyl ethers and the like); alkoxyalkyl ethers such as methoxymethyl or methoxyethoxymethyl ethers and the like; alkylthioalkyl ethers such as methylthiomethyl ethers; tetrahydropyranyl ethers; arylalkyl ethers (such as benzyl, o-nitrobenzyl, p- " methoxybenzyl, 9-anthrylmethyl, 4-picolyl ethers and the like); trialkylsilyl ethers such as trimethylsilyl
  • protecting group is well known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
  • prodrug ester group and “prodrug amide group” are used herein to mean substituents which are rapidly cleaved in vivo, for example by hydrolysis in blood, to yield the parent compounds of the formula (I).
  • prodrug is well known in the art and T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975).
  • esters useful as prodrugs for compounds containing phenol groups include alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates; carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, vinyl, benzyl and carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl.
  • alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates
  • carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, vinyl, benzyl and carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl.
  • addictive behavior is used herein to mean symptoms and maladaptive behavioral changes associated with periodic or continued use of psychoactive substances. These behavioral changes, for example, continued compulsive use of the psychoactive substance despite the presence of persistent or recurrent social, occupational, psychological or physical problems that the person knows are caused by or may be exacerbated by continued use of the substance, would be viewed as extremely undesirable in almost all cultures.
  • cognate disorder refers to disorders that are characterized by changes in mood as the primary clinical manifestation, for example, depression.
  • antipsychotic agent refers to drugs used extensively in the symptomatic management of all forms of schizophrenia, organic psychosis, the manic phase of manic depressive illness and other acute idiopathic illnesses and occasionally used in depression or in severe anxiety.
  • the term "attention deficit disorder” refers to a recently classified pediatric neuropsychiatric disorder characterized by inattention, impulsivity. di'.tr&ctibility and sometirres hyp ⁇ ctivity which replaces the less formal diagnoses of hyperactivity syndrome, hyperkinetic syndrome, minimal brain dysfunction and specific learning disability.
  • the disorder is prevalent among pre-adolescent children and is reflected in poor school performance and social behavior arid has been described in experimental reports of impaired perceptual, cognitive and motor function.
  • cognitive impairment refers to a deficiency in any of the aspects of the cognitive (information processing) functions of perceiving, thinking and remembering.
  • dopamine-related neurological disorders refers to behavioral disorders, such as psychoses and addictive behavior disorders; affective disorders, such as major depression; and movement disorders such as Parkinson's Disease, Huntington's Disease and Gilles de la Tourette's syndrome; which have been linked, pharmacologically and/or clinically, to either insufficient or excessive functional dopaminergic activity in the CNS.
  • pharmaceutically acceptable it is meant those salts, amides and esters which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically salts in detail in J. Pharmaceutical Sciences, 66: 1 - 19, 1977.
  • the amine salts can be prepared according to conventional methods in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the free base with a suitable organic acid.
  • Representative acid addition salts of the amine include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oleate, oxalate, palmitate, pamoate, pectinate, persul
  • Representative alkali or alkaline earth metal salts of the phenolic hydroxyl group include sodium, - calcium, potassium, magnesium salts and the like.
  • Examples of pharmaceutically acceptable, non-toxic esters of the compounds of formula (I) include esters derived from C1 to C6 alkyl carboxylic acids wherein the alkyl group is straight or branched chain. Acceptable esters also include esters derived from C5 to C7 carbocyclic carboxylic acids and aromatic carboxylic esters such as benzoates and phenyl acetic acid esters. Also contemplated are carbonate esters and carbamates. Esters of the compounds of formula (I) may be prepared by conventional methods.
  • amides of the compounds of formula (I) include amides derived from C1 to C6 alkyl acids wherein the alkyl groups are straight or branched chain. Amides of the compounds of formula (I) may be prepared from the amines of Formula (I) according to conventional methods. It is understood that amides of the compounds of the present invention include amino acid and polypeptide derivatives.
  • the term "pharmaceutically acceptable carriers” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • Some examples of the 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 cccoa 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 ethy
  • wetting agents 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 ascorbyi palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-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 ascorbyi palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propy
  • a “therapeutically effective amount” of the dopaminergic agent is meant a sufficient amount of the compound to treat neurological or behavior disorders at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • 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 compounds of this invention administered to a host 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 10 mg to about 1000 mg of the compound(s) of this invention per day in multiple doses or in a single dose of from 10 mg to 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.
  • the compounds of the present invention may also be co-administered with agents, for example enzyme inhibitors, which block their metabolic transformation outside the CNS.
  • 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 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 drug is 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-polygiycoiide.
  • 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 liposomes 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 exipients 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. Examples of 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 lactose, 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.
  • R 7 and R 8 correspond to the R groups identified by formula (I), P is a phenol-protecting group and Bn is a benzyl group.
  • a tetralone of Formula 1 is condensed with benzylamine and the resultant enamine is acylated with an aromatic acid chloride, for example benzoyl chloride to afford a compound of Formula 2.
  • Compounds of Formula 2 are cyclized photolytically to afford the compounds of Formula 3.
  • the compounds of Formula 3 are, in turn, treated with a suitable reducing agent for reducing the amide, for example lithium aluminum hydride to afford the compounds of Formula 4.
  • the benzyl protecting group is then removed using standard methods, preferably catalytic hydrogenatio ⁇ to afford compounds of Formula 5.
  • a suitable catalyst is palladium hydroxide.
  • Compounds of Formula 5 are treated with an appropriate reagent for removing the phenol protecting group to afford compounds of the Formula (I A).
  • an appropriate reagent for removing the phenol protecting group for example, when the protecting group is methyl, boron tribromide is preferably used.
  • Compounds of Formula (I A), in which R 2 is hydrogen and none of R 4 , R5 and R6 are hydroxy or amino, can further be treated with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid, to afford compounds of Formula (I B).
  • the compounds of Formula 5 are alkylated using standard reductive- amination techniques to give the compounds of Formula 6.
  • N-methyl derivative (compound 6 wherein R 1 is methyl) is prepared when a compound of Formula 5 is treated with formaldehyde and sodium cyanoborohydride. The phenol protecting group is then removed as described above to afford compounds of Formula (I C).
  • Compounds of Formula 6, in which R 2 is hydrogen and none of R 4 , R5 and R 6 are hydroxy or amino can further be treated with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid, and the phenol protecting group is then removed as described above to afford compounds of Formula (I D).
  • compounds of Formula I C wherein R 2 is hydrogen are converted to compounds of Formula I D by treatment with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid.
  • the ⁇ -tetralones of Formula . are prepared by literature methods (see for example, D.E Nichols, et al, Organic Preparations and Procedures Intl., 1977, 9, 277-80) from the corresponding ⁇ -tetralones.
  • the ⁇ -tetralones are prepared from substituted benzaldehyde compounds according to the procedures illustrated in Schemes lA and IB and described in detail in Example 1 of U.S. Patent Number -.—,— (Serial Number 07/359448, filed May 31 , 1989 by R. Schoenleber, et al.) incorporated herein by reference.
  • the appropriate benzaldehyde starting materials are either commercially available or readily prepared by literature methods.
  • compounds of Formula (I) are nitrated using standard nitrating agents such as nitric acid/sulfuric acid to afford compounds of Formula (1 E).
  • the compounds of Formula (IE) are reduced by catalytic hydrogenation or by treatment with a suitable reducing agent, for example using a metal and an acid such as tin and hydrochloric acid or zinc and hydrochloric acid, to afford the compounds of Formula (IF).
  • a suitable acetylating agent such as acetic anhydride in the presence of a suitable base such as triethylamine to afford the compounds of Formula (I G).
  • compounds of Formula (I) (wherein R 1 is hydrogen, methyl or ethyl and R 2 is hydrogen) are treated with chlorosulfonic acid to afford the compounds of Formula (I H).
  • the compounds of Formula (I H) are reduced, for example using a metal and an acid such as zinc and sulfuric acid, to afford the compounds of Formula (I J).
  • the compounds of Formula (I J) are alkylated by treatment of a suitable alkyl halide, for example methyl iodide, and a base such as potassium carbonate, preferably in a polar solvent such as acetone to afford the compounds of Formula (I K).
  • Step 1 N-Benzoyl-N-benzyl-7-methoxy-3.4-dihvdro-2-naphthylamine
  • a three-neck flask equipped with a Dean-Stark trap was charged with a solution of 10.0 g (56.8 mmol) of 7-methoxy-2-tetralone (commercially available from Aldrich Chemical Company) and 6.20 mL (56.8 mmol) of benzylamine in 90 mL of toluene.
  • the reaction mixture was refluxed for 5 h and then concentrated in vacuo.
  • the residue was dissolved in 120 mL of methylene chloride.
  • the methylene chloride solution was cooled to 0°C and 8.6 mL (74.1 mmol) of benzoyl chloride and 11.1 mL (76.6 mmol) of triethylamine were added.
  • Step 2 ra ⁇ s-N-Benzyl-1 1 -methoxy-5.6.6a.7.8.12b- hexahydrobenzo[a]phen-anthridine-5-one
  • Step 3 fra ⁇ s-N-Benzyl-11 -methoxy-5.6.6a.7.8.12b- hexahvdrobenzo[a]phenanthridine
  • Step 4 trans- 1 -Methoxy-5.6.6a.7.8.12b- hexahydrobenzo[a]phenanthridine formate
  • Step 1 fra ⁇ s-N-Methyl-11 -methoxy-5.6.6a.7a.8.12b- hexahvdrobenzo[a]phen-anthridine hydrochloride
  • Step 2 fra ⁇ s-1 1 -Hvdroxv-5.6.6a.7a.8 12b- hexahydrobenzo[a]phenanthridine hydrobromide
  • Bromine (68 ⁇ L, 1.31 mmol) was added to a solution of 330 mg (1.31 mmol) of fra ⁇ s-1 1 -hydroxy-5, 6, 6a.7a, 8, 12b- hexahydrobenzo[a]phenanthridi ⁇ e, the product of Example 1 , in 7 mL of formic acid at 0°C.
  • the resultant solution was stirred for 15 minutes at 0°C and 15 minutes at ambient temperature and then poured into a 50% aqueous solution of ammonium hydroxide.
  • the aqueous mixture was extracted with 100 mL of methylene chloride and 150 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo.
  • Step 1 fra ⁇ s-N-Methyl-10-bromo-1 1 -methoxy-5.6.6a.7.8.12b-hexahvdro- benzofalphenanthridine
  • Examples 5 - 60 are synthesized.
  • the substituted- benzoyl chlorides are either commercially available or they are readily prepared from the corresponding commercially available benzoic acid derivatives according to standard methods.
  • the phenolic hydroxyl group of the b-tetralone starting material is protected as a methoxy derivative and the methoxy derivative of the hydroxy-benzoyl chloride starting material is used affording as an intermediate a dimethoxy derivative of the desired product.
  • the methoxy groups are simultaneously converted to the hydroxy products to afford Example 39, 40 and 41.
  • Dopamine produces biological responses through stimulation of its receptors on cell membranes.
  • a ligand-receptor binding assay was carried out as an initial screen.
  • the affinity of the antagonist for the receptor is expressed as an inhibitory affinity constant (Ki) obtained by plotting the inhibitor concentration versus the reciprocal concentration of the isotopically labeled ligand that is displaced by the antagonist.
  • Homogenized rat caudate was incubated in the presence of [ 1 25 l]SCH-23982 (a selective antagonist of the dopamine D-1 receptor) and the compounds of this invention, according to procedures described by A. Sidhu, et al. in European J Pharmacology, 1 13: 437. 1985 and in European J Pharmacology, 128: 213, 1986.
  • the compounds compete with the radiolabeled ligand for occupancy of the receptors and the molar potency of each compound was quantified.
  • the affinity of the compound for the receptor (Ki) was calculated as described by Y.C. Cheng and W.H.
  • Ki IC50(1 +[L]/KD) where IC50 is the concentration of test compound which produces a 50% inhibition in the specific binding of the radioligand, L; [L] is the concentration of radioligand; and KD is the affinity of the radioligand for the receptor.
  • the procedure for the dopamine D-2 receptor binding assay was similar to that used for the D-1. receptor assay.
  • Homogenized rat caudate was the source of the D-2 receptors.
  • the tissue homogenate was incubated in the presence of [ 1 5 l]-p-aminopheny!ethyl spiroperidol (a selective antagonist of the dopamine D-2 receptor) and the compounds being evaluated, according to the protocol described by T. Agui, N. Amiaiky, M.G. Caron and J.W. Kebabian in Molecular Pharmacology, 33: 163, 1988.
  • the molar affinity of the compound for the receptor binding site was calculated by the same method used for the D-1 receptor assay, assuming a competitive interaction between the compound and the radiolabeled ligand.
  • Ki values The competitive binding data (Ki values) from the D-1 and D-2 receptor binding assays are shown in Table 2.
  • the Ki values are inversely proportional to the affinity of the compound for the receptor, therefore it is apparent that the compounds of the invention have high affinity for dopamine receptors.
  • the interaction of dopamine or a dopamine D-1 receptor agonist with the D-1 receptor causes a dose-dependent increase in the ade ⁇ ylate cyclase-catalyzed conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).
  • ATP adenosine triphosphate
  • cAMP cyclic adenosine monophosphate
  • the functional activity of the compounds of the invention was determined by assaying, in vitro, its ability to antagonize a dopamine-induced increase in cAMP levels.
  • the protocol for the adenylate cyclase assays was described by K.J. Watling and J.E.Dowling in J Neurochemistry, 36: 559, 1981 and by J.W. Kebabian, et al. in Proc Natl Acad Sci, USA, 69: 2145, 1972.
  • the tissue was obtained from either goldfish retina or rat striatum
  • IC50 is defined as the concentration of test compound which produces a 50% reduction in the response to an agonist, S; [S] is the concentration of agonist in the assay; and KD is the affinity of the agonist for the receptor.
  • the compounds of the invention are potent antagonists of the dopamine receptor-mediated adenylate cyclase-catalyzed conversion of adenosine triphosphate (ATP) to cAMP and, therefore, prevent the physiological effects of excessive stimulation of dopamine receptors.
  • ATP adenosine triphosphate

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Abstract

Novel compounds are provided of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof, wherein R1 is selected from hydrogen, methyl, ethyl and prodrug amide group. R2 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, acetamino and -SO¿2R?7 wherein R7 is lower alkyl. R3 is selected from hydrogen and prodrug ester group. R?4, R5 and R6¿ are independently selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, nitro, amino, acetamino, aminomethyl and -SO¿2R?7 wherein R7 is lower alkyl. The compounds of formula (I) are subject to the proviso that: 1) when R?4, R5 and R6¿ are hydrogen, R2 is not methoxy and 2) not more than one of R?4, R5 and R6¿ is nitro or -SO¿2R?7. The compounds of the present invention are useful in the treatment of dopamine-related neurological and psychological disorders, as well as in the treatment of cognitive impairment, attention deficit disorders and addictive behavior disorders.

Description

PHENANTHRIDINE COMPOUNDS
TECHNICAL FIELD
This invention relates to novel organic compounds which have biological activity, compositions containing these compounds and a method of treatment. In particular, the invention concerns benzophenanthridine dopamine D-1 receptor antagonists, pharmaceutical compositions containing these compounds and a method for treating dopamine-related neurological, psychological and behavioral disorders with such compounds.
BACKGROUND OF THE INVENTION
Dopamine is an important neurotransmitter in the central nervous system (CNS), and also has several important roles in the peripheral nervous system such as in the control of supply of blood to the kidneys and in autonomic ganglion transmission.
It is now widely accepted that dopamine receptors in the CNS can be divided into two general categories, designated D-1 and D-2 receptors. The division was originally based on biochemical and pharmacological differences between the two receptor types. Recently, further evidence which supports this division has come from study of the molecular biology of dopamine receptors in the CNS. The dopamine D-1 receptor is linked to the enzyme adenylate cyclase through a stimulatory G protein such that stimulation of this receptor by dopamine or a dopamine D-1 receptor agonist causes an increase in the production of 3',5'-cyclic adenosine monophosphate (cAMP). The D-2 receptor, on the other hand, also regulates important functional activity within the CNS, although the biochemical events which follow stimulation of this receptor by dopamine or a D-2 receptor agonist are not as well understood. Autoreceptors on dopaminergic neurons which have the pharmacological properties of D-2 receptors appear to control the firing rate of these ceils as well as the release of dopamine from the nerve terminals. It is also known that stimulation of the D-2 receptors in the intermediate lobe of the pituitary gland causes a decrease in cAMP production and that stimulation of the D- 2 receptors on the mammotrophs of the anterior pituitary gland suppresses prolactin secretion. Dopaminergic neurons are also affected by and interact with other neurotransmitter systems in the CNS. For example, D-2 receptors on the cholinergic interneurons in the striatum (one of the components of the basal ganglia) regulate the release of acetylcholine from these cells.
Dopamine involvement has been proposed for several diverse neurological disorders such as Parkinson's disease and schizophrenia. The putative roles of the two types of dopamine receptors differ in these disorders.
One neurological disorder in which dopamine has been implicated is the psychosis schizophrenia. The psychoses are serious psychiatric illnesses characterized by abnormal behavior which may include delusions, hallucinations, violence, mania and serious long-lasting depression. Schizophrenia is the most common psychosis and involves disturbance of thought processes, hallucinations and loss of touch with reality. The theory of schizophrenia as a disease of the CNS was first formalized by Kraepelin and Bleuler in the early 1900's. It was not until chlorpromazine was discovered by Delay and Daniker in the early 1950's, however, that effective drug management of this disease was possible.
The pioneering work of Carlsson and others led to the now widely-held dopamine theory of schizophrenia. According to this theory, schizophrenia is caused by a functional overactivity of dopamine in the brain. Several lines of evidence support this hypothesis. For example, chronic abuse of stimulants such as amphetamines, known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is almost indistinguishable from classic paranoid schizophrenia. The mechanism-of- action proposed for drugs with anti-schizophrenic activity is the blockade by these compounds of the dopamine receptors, and consequently, the prevention of excess dopamine receptor stimulation. In the mid 1970's it was observed that virtually all of the currently used antipsychotic agents could displace radiolabeled haloperidol (a dopamine antagonist) from striatal dopamine receptors with a good correlation between average effective clinical dose and drug binding affinity.
The use of antipsychotic agents is widespread and hundreds of millions of patients have been treated with them in the past forty years. Unfortunately, the currently available antipsychotic agents frequently produce undesirable side-effects, the most common of which are the so- called extrapyramidal neurological effects that include bizarre involuntary movements and Parkinson-like effects. Sedation and hypotension are also common side effects. Because of these often severe side-effects and the high incidence of patients unresponsive to currently available drugs, more potent and selective agents are needed.
Published evidence suggests that dopamine also has a central role in the brain's reward system. In particular, it has been reported that animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist. It was proposed that the animals would increase the amount of cocaine administered in order to maintain the elevated dopamine levels responsible for the drugs euphorigenic and reinforcing properties. Because of this interrelationship, dopamine antagonists are potentially useful for the treatment of drug abuse and other addictive behavior disorders.
C.-C. Wei and S. Teitel reported in Heterocycles, 8: 97-102, 1977 the synthesis of 9,10-dihydroxyhexahydrobenzo[a]phenanthridine. According to the authors the compound was devoid of any noteworthy dopamimetic activity. D.E. Nichols, et al. in European J. Pharmacology, 166: 111-113, 1989 and J. Medicinal Chemistry, 33: 1756-1764, 1990 report the synthesis of transΛ 0,11 -dihydroxy-5,6,6a,7,8, 12b- hexahydrobenzo[a]phenanthridine (dihydrexidine), a dopamine receptor agonist.
SUMMARY OF THE INVENTION
In one aspect the present invention provides compounds represented by the following structural formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, amide or ester thereof, wherein R1 is selected from hydrogen, methyl, ethyl and prodrug amide group.
R2 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, acetamino and -SO2R7 wherein R7 is lower alkyl. R3 is selected from hydrogen and prodrug ester group.
R4, R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, amino, acetamino, aminomethyl and -SO2R8 wherein Rδ is lower alkyl.
The compounds of formula (I) are subject to the proviso that:
1 ) when R4, R5 and R6 are hydrogen, R2 is not methoxy and
2) not more than one of R4, R5 and R6 is nitro or -SO2R8.
In another aspect the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
In another aspect the present invention provides a method of treating dopamine-related neurological and psychological disorders, cognitive impairment, attention deficit disorder and addictive behavior disorders in humans or other mammals with the compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED
EMBODIMENTS
This invention relates to novel compounds which are dopamine D-1 receptor antagonists. It has been found that the compounds of formula (I) have the ability to antagonize the action of dopamine at dopamine D-1 receptors in the central and peripheral nervous systems. The compounds of the present invention are, therefore, useful in the treatment of dopamine- related neurological and psychological disorders, as well as in the treatment of cognitive impairment, attention deficit disorders and addictive behavior disorders.
The compounds which are contemplated to be within the scope of the present invention include: frans-11-Hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phenanthridine; fraπs-N-Methyl-11 -hydroxy-5,6,6a,7a,8,12b- hexahydrobenzo[a]phenanthridine; fraπs-10-Bromo-11 -hydroxy-5,6,6a,7.8,12b- hexahydrobenzo[a}phenanthridine; and ra/7s-N-Methyl-10-bromo-11 -hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine; fra/.s-1 1 -Hydroxy-10-nitro-5,6,6a,7a,8,12bhexahydrobenzo[a]phen- anthridine; frans-N-Methyl-1 1 -hydroxy-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Amino-11-hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phen- anthridine; trans-10-Amino-11 -hydroxy-6-methyl-5,6,6a,7a.8,12b-hexahydro- benzo[a]phenanthridine ; trans-10-Acetamino-11 -hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phen- anthridine; fra 7S-10-Acetamino-11 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans 1 -Hydroxy-10-methylthio-5,6,6a,7a,8,12b-hexahydrobenzo[a]phen- anthridine; frans-11-Hydroxy-6-methyl-10-methylthio-5,6,6a,7a,8, .2b-hexahydro- benzo[a]phenanthridine; frans-11-Hydroxy-4-methyl-5,6,6a,7a,8,12b-hexahydrobenzo[a]phen- anthridine; fraπs-10-Bromo-11 -hydroxy-4-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; frans-4,6-Dimethyl-11 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-4,6-dimethyl-11 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; frans-11 -Hydroxy-4-methyl-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fra/7S-2-t-Butyl-11 -hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phen- anthridine; fraπs-10-Bromo-2-t-butyl-1 1 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-2-t-Butyl-11 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-2-t-butyl-1 1 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]pheπanthridiπe; aπs-2-t-Butyl-l 1 -hydroxy-1 O-nitr o-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine ; fraπs-4-Chloro-1 1 -hydroxy-5,6,6a,7a,8,12b-hexahydroben?o[alphen- anthridine; trans- 0-Bromo-4-chloro-1 1 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-4-Chloro-11-hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans 0-Bromo-4-chloro-11 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-4-Chloro-11 -hydroxy-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-2-Fluoro-11-hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; aπs-10-Bromo-2-fluoro-11-hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; frans-2-Fiuoro-11-hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-2-fluoro-11-hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; ?raπs-2-Fluoro-11 -hydroxy-10-nitro-5, 6, 6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-2-Chloromethy.-11-hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-2-chloromethyl-11-hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-2-Chloromethyl-1 1-hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine ; frans-10-Bromo-2-chloromethyl-11 -hydroxy-6-methyl-5,6,6a,7a,8.12b- hexahydrobenzo[a]pheπanthridine; ?raπs-2-Chloromethyl-11 -hydrσxy-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-11-Hydroxy-2-trifluoromethyl-5, 6, 6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans 0-Bromo-11-hydroxy-2-trifluoromethyl-5,6,6a)7a,8I12b-hexahydro- benzo[a]phenanthridine; trans 1 -Hydroxy-6-methyl-2-trifluoromethyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans 0-Bromo-11 -hydroxy-6-methyl-2-trifluoromethyl-5)6,6a,7a,8,12b- hex*ahydro-benzo[a]phenanthridine; fraπs-11 -Hydroxy-10-nitro-2-trifluoromethyl-5,6,6a,7a,8, 12b-hexahydro- benzo[a]phenanthridine; fraπs-2-Ethoxy-11 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-2-ethoxy-1 1 -hydroxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; _rans-2-Ethoxy-11 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-2-ethoxy-11 -hydroxy-6-methyl-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-2-Ethoxy-1 1 -hydroxy-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]pheπanthridine; fraπs-4-Chloro-11 -hydroxy-3-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-4-chloro-1 1 -hydr oxy-3-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-4-Chloro-11 -hydroxy-6-methy!-3-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans-A 0-Bromo-4-chloro-11-hydroxy-6-methyI-3-nitro-5,6,6a,7a,8,12b- hexahydrobenzo[a]phenanthridine; frans-4-Chloro-1 1-hydroxy-3,10-dinitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-11 -Hydroxy-3-methoxy-2-methyl-5,6,6a,7a.8, 12b- hexahydrobenzo[a]phenanthridine; trans- 0-Bromo-11 -hydroxy-3-methoxy-2-methyl-5,6,6a,7a,8,12b- hexahydrobenzo[a]pheπanthridine; fraπs-2,6-Dimethyl-11 -hydroxy-3-methoxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans-10-Bromo-2,6-dimethyl-1 1 -hydroxy-3-methoxy-5,6,6a,7a,8,12b- hexahydrobenzo[a]phenanthridine; fraπs-11-Hydroxy-3-methoxy-2-methyl-10-nitro-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine ; fraπs-11 -Hydroxy-2,3,4-trimethoxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; fraπs-10-Bromo-11-hydroxy-2, 3, 4-trimethoxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans-11 -Hydroxy-6-methyl-2,3,4-trimethoxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine; trans-10-Bromo-1 1 -hydroxy-6-methyl-2,3,4-trimethoxy-5,6,6a)7a,8,12b- hexahydro-benzo[a]phenanthridine; trans- 1 -Hydroxy-10-nitro-2,3,4-trimethoxy-5,6,6a,7a,8,12b-hexahydro- benzo[a]phenanthridine, and pharmaceutically acceptable salts, amides or esters thereof.
In one preferred embodiment of the present invention are provided compounds of formula (I) in which R4, R5 and R^ are hydrogen.
The following compounds are representative of the preferred compounds of formula (I): trans- 1 -Hydroxy-5,6,6a,7a,8,12b-hexahydrobenzo[a]phenanthridine; fraπs-N-Methyl-11 -hydroxy-5,6,6a,7a,8,12b- hexahydrobenzo[a]phenanthridiπe; fraπs-10-Bromo-11 -hydroxy-5,6,6a,7,8, 12b- hexahydrobenzo[a}phenaπthridine; and fraπs-N-Methyl-10-bromo-11 -hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine, and pharmaceutically acceptable salts, amides or esters thereof. The compounds of formula (I) contain two or more asymmetric carbon atoms and thus exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention includes within its scope all of the isomeric forms. The terms "R" and "S" configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45: 13-30.
The following terms are used as defined below throughout this dsiclosure and in the appended claims.
The term "alkanoyl" refers to the following structures: o
- 'R9 in which R9 is selected from hydrogen and a lower alkyl group as defined below.
The terms "amino acid" and "dipeptide" refer to a single α-amino acid or two amino acids joined by amide (peptide) bonds. The amino acids are naturally occurring amino acids such as valine, glycine, norvaline, alanine, glutamic acid, glutamine, aspartic acid, leucine, isoleucine, proline, methionine, or phenylalanine or they may be synthetic amino acids such as cyclohexylalanine or cyclohexylglycine. The amino acids can either be in the L or D configuration or a mixture of the two isomers. If not specified, amino acid substituents are optically active and have the L configuration.
The term "halogen" refers to bromo (Br), chloro (Cl), fluoro (F) and iodo (I).
The term "halo-substituted lower alkyl" refers to a lower alkyl group, as defined below, bearing at least one halogen substituent, for example chloromethyl, fluoromethyl, chloroethyl, triflπoromethyl and the like.
The term "lower alkoxy" refers to a lower alkyl group, as defined below, which is bonded through an oxygen atom. Examples of lower alkoxy groups include methoxy, ethoxy, t-butoxy and the like. The term "lower alkyl" refers to branched or straight chain alkyl groups comprising one to six carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
The term "lower alkylamino" refers to amino groups substituted with one or two lower alkyl groups, as defined above, including methylamino, ethylamino, dimethylamino, diethylamino, propylamino and . ethylmethylamino.
The term "phenol-protecting group" is used herein to mean substituents on the phenolic oxygen which prevent undesired reactions and degradations during a synthesis. Commonly used phenol-protecting groups include ethers, for example alkyl, alkenyl and cycloalkyl ethers (such as methyl, isopropyl, t-butyl, cyclopropylmethyl, cyclohexyl, allyl ethers and the like); alkoxyalkyl ethers such as methoxymethyl or methoxyethoxymethyl ethers and the like; alkylthioalkyl ethers such as methylthiomethyl ethers; tetrahydropyranyl ethers; arylalkyl ethers (such as benzyl, o-nitrobenzyl, p- " methoxybenzyl, 9-anthrylmethyl, 4-picolyl ethers and the like); trialkylsilyl ethers such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl ethers and the like; alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, beπzoates and the like; carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, vinyl, benzyl and the like; carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl and the like.
The term "protecting group" is well known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
The terms "prodrug ester group" and "prodrug amide group" are used herein to mean substituents which are rapidly cleaved in vivo, for example by hydrolysis in blood, to yield the parent compounds of the formula (I). The term "prodrug" is well known in the art and T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing phenol groups include alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates; carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, vinyl, benzyl and carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl.
The term "addictive behavior" is used herein to mean symptoms and maladaptive behavioral changes associated with periodic or continued use of psychoactive substances. These behavioral changes, for example, continued compulsive use of the psychoactive substance despite the presence of persistent or recurrent social, occupational, psychological or physical problems that the person knows are caused by or may be exacerbated by continued use of the substance, would be viewed as extremely undesirable in almost all cultures.
The term "affective disorder" as used herein refers to disorders that are characterized by changes in mood as the primary clinical manifestation, for example, depression.
The term "antipsychotic agent" as used herein refers to drugs used extensively in the symptomatic management of all forms of schizophrenia, organic psychosis, the manic phase of manic depressive illness and other acute idiopathic illnesses and occasionally used in depression or in severe anxiety.
The term "attention deficit disorder" refers to a recently classified pediatric neuropsychiatric disorder characterized by inattention, impulsivity. di'.tr&ctibility and sometirres hyp^ ctivity which replaces the less formal diagnoses of hyperactivity syndrome, hyperkinetic syndrome, minimal brain dysfunction and specific learning disability. The disorder is prevalent among pre-adolescent children and is reflected in poor school performance and social behavior arid has been described in experimental reports of impaired perceptual, cognitive and motor function.
The term "cognitive impairment" refers to a deficiency in any of the aspects of the cognitive (information processing) functions of perceiving, thinking and remembering.
The term "dopamine-related neurological disorders" as used herein refers to behavioral disorders, such as psychoses and addictive behavior disorders; affective disorders, such as major depression; and movement disorders such as Parkinson's Disease, Huntington's Disease and Gilles de la Tourette's syndrome; which have been linked, pharmacologically and/or clinically, to either insufficient or excessive functional dopaminergic activity in the CNS.
By "pharmaceutically acceptable" it is meant those salts, amides and esters which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically salts in detail in J. Pharmaceutical Sciences, 66: 1 - 19, 1977. The amine salts can be prepared according to conventional methods in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the free base with a suitable organic acid. Representative acid addition salts of the amine include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivafate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts of the phenolic hydroxyl group include sodium, - calcium, potassium, magnesium salts and the like. Examples of pharmaceutically acceptable, non-toxic esters of the compounds of formula (I) include esters derived from C1 to C6 alkyl carboxylic acids wherein the alkyl group is straight or branched chain. Acceptable esters also include esters derived from C5 to C7 carbocyclic carboxylic acids and aromatic carboxylic esters such as benzoates and phenyl acetic acid esters. Also contemplated are carbonate esters and carbamates. Esters of the compounds of formula (I) may be prepared by conventional methods. Examples of pharmaceutically acceptable, amides of the compounds of formula (I) include amides derived from C1 to C6 alkyl acids wherein the alkyl groups are straight or branched chain. Amides of the compounds of formula (I) may be prepared from the amines of Formula (I) according to conventional methods. It is understood that amides of the compounds of the present invention include amino acid and polypeptide derivatives.
As used herein, the term "pharmaceutically acceptable carriers" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of the 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 cccoa 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. Examples of pharmaceutically acceptable, antioxidants include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyi palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-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.
By a "therapeutically effective amount" of the dopaminergic agent is meant a sufficient amount of the compound to treat neurological or behavior disorders at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. 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 compounds of this invention administered to a host 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. In general, treatment regimens according to the present invention comprise administration to a human or other mammal in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in multiple doses or in a single dose of from 10 mg to 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. The compounds of the present invention may also be co-administered with agents, for example enzyme inhibitors, which block their metabolic transformation outside the CNS.
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.
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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, 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.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of a drug from subcutaneous or intramuscular injection. 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 drug is 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-polygiycoiide. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly-orthoesters and polyanhydrides. The depot injectables can also be made by entrapping the drug in liposomes 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.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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 exipients 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. Examples of 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.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, 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 compounds of the present invention are synthesized by the reaction schemes I and II presented below, in which R , R2, R3, R4, R5,R6. R7 and R8 correspond to the R groups identified by formula (I), P is a phenol-protecting group and Bn is a benzyl group.
Scheme I
According to reaction scheme I, a tetralone of Formula 1 is condensed with benzylamine and the resultant enamine is acylated with an aromatic acid chloride, for example benzoyl chloride to afford a compound of Formula 2. Compounds of Formula 2 are cyclized photolytically to afford the compounds of Formula 3. The compounds of Formula 3 are, in turn, treated with a suitable reducing agent for reducing the amide, for example lithium aluminum hydride to afford the compounds of Formula 4. The benzyl protecting group is then removed using standard methods, preferably catalytic hydrogenatioπ to afford compounds of Formula 5. A suitable catalyst is palladium hydroxide. Compounds of Formula 5 are treated with an appropriate reagent for removing the phenol protecting group to afford compounds of the Formula (I A). For example, when the protecting group is methyl, boron tribromide is preferably used. Compounds of Formula (I A), in which R2 is hydrogen and none of R4, R5 and R6 are hydroxy or amino, can further be treated with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid, to afford compounds of Formula (I B).
Alternately, the compounds of Formula 5 are alkylated using standard reductive- amination techniques to give the compounds of Formula 6. For example the N-methyl derivative (compound 6 wherein R1 is methyl) is prepared when a compound of Formula 5 is treated with formaldehyde and sodium cyanoborohydride. The phenol protecting group is then removed as described above to afford compounds of Formula (I C). Compounds of Formula 6, in which R2 is hydrogen and none of R4, R5 and R6 are hydroxy or amino, can further be treated with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid, and the phenol protecting group is then removed as described above to afford compounds of Formula (I D). Alternately, compounds of Formula I C wherein R2 is hydrogen are converted to compounds of Formula I D by treatment with a suitable halogenating agent such as bromine, preferably in the presence of an acid, for example formic acid.
The β-tetralones of Formula . are prepared by literature methods (see for example, D.E Nichols, et al, Organic Preparations and Procedures Intl., 1977, 9, 277-80) from the corresponding α-tetralones. The α-tetralones, in turn, are prepared from substituted benzaldehyde compounds according to the procedures illustrated in Schemes lA and IB and described in detail in Example 1 of U.S. Patent Number -.—,— (Serial Number 07/359448, filed May 31 , 1989 by R. Schoenleber, et al.) incorporated herein by reference. The appropriate benzaldehyde starting materials are either commercially available or readily prepared by literature methods. For example, the preparation of 4-methoxy-3-trifluoromethylbenzaldehyde is described by E.L Stogryn in J. Med. Chem, 1973, 16, 1399-1401. The preparation of 4- methoxy-3-methylbenzaldehyde is described by S. Torii, et ai m J. Organic Chem. 1982, 47, 1647-1652. The preparation of 3-isopropyl-4- methoxybenzaldehyde is described in Example 1 of U.S. Patent Number 3,544,623, issued December 1 , 1970 to H.V. Hansen and R.I. Meltzer. The preparation of 3-t-butyl-4-methoxybenzaldehyde is described by A. McKillop, et al. in Tetrahedron Letters, 1983, 24, 1933-6 and the preparation of 3-chloromethyl-4-methoxybenzaldehyde is described by M.S. Carpenter and W.M. Easter, Jr. in U.S. Patent Numbers 2,450,877 and 2,450,878, issued May 24, 1947. Examples of commercially available benzaldehyde starting materials are vanillin, (4-hydroxy-3- methoxybenzaldehyde), ethyl vanillin (3-ethoxy-4-hydroxybenzaldehyde and 4-benzyloxybenzaldehyde.
Scheme II
According to reaction scheme II, compounds of Formula (I) (wherein R"1 is hydrogen, methyl or ethyl and R2 is hydrogen) are nitrated using standard nitrating agents such as nitric acid/sulfuric acid to afford compounds of Formula (1 E). The compounds of Formula (IE) are reduced by catalytic hydrogenation or by treatment with a suitable reducing agent, for example using a metal and an acid such as tin and hydrochloric acid or zinc and hydrochloric acid, to afford the compounds of Formula (IF). The compounds of Formula (IF) are treated with a suitable acetylating agent such as acetic anhydride in the presence of a suitable base such as triethylamine to afford the compounds of Formula (I G).
Alternately, compounds of Formula (I) (wherein R1 is hydrogen, methyl or ethyl and R2 is hydrogen) are treated with chlorosulfonic acid to afford the compounds of Formula (I H). The compounds of Formula (I H) are reduced, for example using a metal and an acid such as zinc and sulfuric acid, to afford the compounds of Formula (I J). The compounds of Formula (I J) are alkylated by treatment of a suitable alkyl halide, for example methyl iodide, and a base such as potassium carbonate, preferably in a polar solvent such as acetone to afford the compounds of Formula (I K). Scheme I
Figure imgf000025_0001
Scheme II
th
Figure imgf000026_0004
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0006
.
Figure imgf000026_0005
Figure imgf000026_0003
The foregoing may be better understood by reference to the following examples which are provided for the illustration and not the limitation of the invention.
Example 1
fraπs-1 1 -Hvdroxv-5.6.6a.7a.8.12b-hexahvdrobenzo[ henanthridine
Step 1 : N-Benzoyl-N-benzyl-7-methoxy-3.4-dihvdro-2-naphthylamine
A three-neck flask equipped with a Dean-Stark trap was charged with a solution of 10.0 g (56.8 mmol) of 7-methoxy-2-tetralone (commercially available from Aldrich Chemical Company) and 6.20 mL (56.8 mmol) of benzylamine in 90 mL of toluene. The reaction mixture was refluxed for 5 h and then concentrated in vacuo. The residue was dissolved in 120 mL of methylene chloride. The methylene chloride solution was cooled to 0°C and 8.6 mL (74.1 mmol) of benzoyl chloride and 11.1 mL (76.6 mmol) of triethylamine were added. After being stirred overnight at ambient temperature, the reaction mixture was partitioned between diethyl ether (300 mL) and water (200 mL). The ethereal extract was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15% ethyl acetate in hexane to afford 18.15 g (87% yield) of the title compound.
Step 2: raπs-N-Benzyl-1 1 -methoxy-5.6.6a.7.8.12b- hexahydrobenzo[a]phen-anthridine-5-one
A solution of 10.0 g (27.09 mmol) of N-benzoyl-N-benzyl-7-methoxy- 3,4-dihydro-2-naphthylamine, from Step 1 , in 1 L of diethyl ether was placed in a photolysis cell and then irradiated with a 200 Watt Hanovia mercury vapor lamp for 4.5 h. The resulting mixture was concentrated in vacuo to give 10.8 g of the title compound as a foamy yellow solid. This product was taken on to the next step without purification.
Step 3: fraπs-N-Benzyl-11 -methoxy-5.6.6a.7.8.12b- hexahvdrobenzo[a]phenanthridine
A solution of 2.77 g (7.5 mmol) of raπs-N-benzyl-11-methoxy- 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-5-one, from Step 2, in 12 mL of dry diethyl ether, at 0°C, was treated with 10 mL of a 1.0 M solution of lithium aluminum hydride in diethyl ether (10.0 mL, 10 mmol) The resulting suspension was allowed to warm to ambient temperature, stirred at ambient temperature for 1.75 h, and then quenched by the sequential addition of 0.38 mL of water, 0.38 mL of 15% aqueous sodium hydroxide solution and 1.2 mL of water. The reaction mixture was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.41 g (91% yield) of the title compound.
Step 4: trans- 1 -Methoxy-5.6.6a.7.8.12b- hexahydrobenzo[a]phenanthridine formate
A solution of 5.18 g (14.6 mmol) of fraπs-N-beπzyl-11 -methoxy- 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine, from Step 3, in 100 mL of ethyl alcohol and 11.5 mL of formic acid was treated with 700 mg of palladium hydroxide and the mixture was shaken under 4 atmospheres of hydrogen for 1 day. The reaction mixture was diluted with ethyl alcohol and filtered through Celite® filter aid. The filtrate was concentrated in vacuo Xo afford 6.86 g of the title compound. This product was taken on to the next step without purification. Step 5: fraπs-t 1 -Hvdroxv-5.6.6a.7a.8.12b- hexahvdrobenzofajphenanthridine
Boron tribromide (33 mL of a 1.0 M solution in methylene chloride, 3 mmol) was added dropwise to a -78°C solution of 3.43 g of fraπs-11- methoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine formate, from Step 4, in 15 mL of methylene chloride. The resulting mixture was stirred at -78°C for 1 h and then at ambient temperature for 1.5 h. After being cooled to -78°C, the reaction was quenched by the careful addition of 25 mL of methanol. The mixture was allowed to warm to ambient temperature, stirred overnight and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (400 mL) and ethyl acetate (2 X 400 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with chloroform/methylene chloride to give 1.51 g (82% yield from trans- - benzyl-11 -methoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine) of the title compound as a tan solid, m.p. 221 -222°C; MS DCI-NH3 M/Z: 252 (M+H)+. 1 H NMR (CDCl3) δ 9.02 (s, 1 H, OH), 7.1 -7.4 (m, 4H), 6.97 (d, J=9 Hz), 6.63 (d, J=3 Hz), 6.52 (dd, J=3, 9 Hz), 4.11 (br s, 1 H, NH), 3.88 (s, 2H), 3.71 (d, J=10.5 Hz), 2.80 (m, 1 H), 2.66 (ddd, J= 3, 9, 10.5 Hz), 2.40 (m, 1 H), 2.0 (m, 1 H), 1.62 (m, 1 H). Analysis calculated for Ci7Hi7NO)+0.5CH2Cl2: C, 71.54; H, 6.18; N, 4.77. Found: C, 71.93; H, 5.99; N, 4.55.
Example 2
_raπs-N-Methyl-11 -hvdroxy-5.6.6a.7a.8.12b- hexahvdrobenzo[a]phenanthridine
Step 1 : fraπs-N-Methyl-11 -methoxy-5.6.6a.7a.8.12b- hexahvdrobenzo[a]phen-anthridine hydrochloride
A suspension of 3.12 g (10.0 mmol) of fraπs-1 1-methoxy- 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine formate, the product of • Step 4 of Example 1 , in 20 mL of methanol was treated with 4.5 mL of a 37% aqueous formaldehyde solution (60 mmol), followed by 1.57 (25 mmol) of sodium cyanoborohydride. The resultant mixture was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between aqueous sodium bicarbonate solution (250 mL)and ethyl acetate (2 X 250 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with diethyl ether saturated with anhydrous hydrogen chloride and the resultant suspension was concentrated. The crude product was chromatographed on silica gel eluting with 5% methanol in methylene chloride to afford 1.34 g (48% yield) of fraπs-N-methyl-1 1- methoxy-5,6,6a,7α,8,12b-hexahydrobenzo[a]phenanthridine, which after treatment with ethereal hydrogen chloride and removal of solvent, gave 1.33 g of the title compound as a white solid, m.p. 119-121 °C; MS DCI-NH3 M/Z: 280 (M+H)+. Analysis calculated for C19H22CINO+O.I H2O: C, 71.84; H, 7.04; N, 4.41. Found: C, 71.52; H, 7..14; N, 4.40.
Step 2: fraπs-1 1 -Hvdroxv-5.6.6a.7a.8 12b- hexahydrobenzo[a]phenanthridine hydrobromide
Boron tribromide (7.5 mL of a 1.0 M solution in methylene chloride, 7.5 mmol) was added dropwise to a solution, at -78°C of 450 mg (1.42 mmol) of fraπs-N-methyl-11 -methoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine in 4 mL of methylene chloride. The reaction mixture was allowed to warm to ambient temperature over a period of 1 h and then stirred at ambient temperature for 2 h. After being cooled again to -78°C, the reaction was quenched by the addition of methanol. The resultant solution was stirred overnight at ambient temperature and then concentrated from methanol several times. The residue was crystallized from methanol-methylene chloride-diethyl ether to afford 402 mg (81 % yield) of the title compound, m.p. 266-267°C; MS DCI-NH3 M/Z: 266 (M+H)+. Analysis calculated for C18H2θBrNO+0.1 H2O: C, 61.79; H, 5.87; N, 4.00. Found: C, 61.87; H, 5.86; N, 4.03.
Example 3
fraπs-10-Bromo-1 1 -hvdroxy-5.6.6a.7.8.12b- hexahvdrobenzo[a. phenanthridine
Bromine (68 μL, 1.31 mmol) was added to a solution of 330 mg (1.31 mmol) of fraπs-1 1 -hydroxy-5, 6, 6a.7a, 8, 12b- hexahydrobenzo[a]phenanthridiπe, the product of Example 1 , in 7 mL of formic acid at 0°C. The resultant solution was stirred for 15 minutes at 0°C and 15 minutes at ambient temperature and then poured into a 50% aqueous solution of ammonium hydroxide. The aqueous mixture was extracted with 100 mL of methylene chloride and 150 mL of ethyl acetate. The combined organic extracts were concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to give 30 mg (7% yield) of fraπs-12-bromo-11 -hydroxy- 5,6,6a,7,8,12b-hexahydrobeπzo[ajphenanthridine and 83 mg (19% yield) of the title compound, m.p. 243-245°C; MS DCI-NH3 M/Z: 330 (M+H)+. Analysis calculated for C-|7Hi6BrNO+0.3H2θ: C, 60.83; H, 4.98; N, 4.17. Found: C, 60.64; H, 5.11 ; N, 3.79.
Example 4
fraπs-N-Methyl-10-bromo-11 -hvdroxy-5.6.6a.7.8.12b- hexahvdrobenzofa]phen-anthridine hvdrobromide
Step 1 : fraπs-N-Methyl-10-bromo-1 1 -methoxy-5.6.6a.7.8.12b-hexahvdro- benzofalphenanthridine
Bromine (38 μL, 0.74 mmol) was added dropwise to a 0°C solution of 234 mg (0.74 mmol) of fraπs-N-methyl-1 l -methoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phen-anthridine, the product of Step 1 of Example 2, in 4 mL of formic acid. The reaction mixture was stirred at 0°C for 20 minutes and then for 45 minutes at ambient temperature. The reaction mixture was diluted with water and neutralized with a 50% aqueous solution of ammonium hydroxide. The aqueous suspension was extracted with 2 X 100 mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give 259 mg (87% yield) of the title compound. This product was carried on to the next step without purification.
Figure imgf000033_0001
hexahydrobenzofajphen-anthridine hydrobromide
Following the procedure described in Step 2 of Example 2, trans-N- methyl-10-bromo-11-methoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine, from Step 1 , was converted to the title compound, m.p. 277-278°C (dec); MS DCI-NH3 M/Z: 344 (M+H)+. Analysis calculated for Ci8HιgBr2NO+0.5H2θ: C, 49.80; H, 4.64; N, 3.22. Found: C, 49.98; H, 4.37; N, 3.22.
Examples 5 - 60
Following the procedures described in Examples 1 and 2, replacing benzoyl chloride with the appropriate substituted-benzoyl chloride, Examples 5 - 60, as disclosed in Table 1 , are synthesized. The substituted- benzoyl chlorides are either commercially available or they are readily prepared from the corresponding commercially available benzoic acid derivatives according to standard methods. For Examples 39, 40 and 41 the phenolic hydroxyl group of the b-tetralone starting material is protected as a methoxy derivative and the methoxy derivative of the hydroxy-benzoyl chloride starting material is used affording as an intermediate a dimethoxy derivative of the desired product. The methoxy groups are simultaneously converted to the hydroxy products to afford Example 39, 40 and 41.
Table 1 : Examples 5 - 60
Figure imgf000034_0001
R6
H H
CH3 H H H H H H Cl H H Br H H
F ". H I
H H
Figure imgf000034_0002
H
Figure imgf000035_0001
Figure imgf000036_0001
The N-methylation of the compounds listed in Table 1 (Examples 5 - 63), with the phenolic hydroxyl group protected, for example as the methoxy or benzyloxy derivative, is carried out according to the procedures given in Example 2 and the phenol protecting groups are removed to give the desired N-methyl compounds.
Halogenation of the compounds listed in Table 1 (Examples 5 - 63), with the exception of those compounds in which any of R4, R5 or R^ is hydroxy or amino (Examples 35, 36, 37, 39, 40, 41 , 50, 51 and 52), can be carried out to afford the corresponding 10-halo compounds. Following the procedures described in Example 4 for the bromination of the 10-position of the benzo[a]phenanthridine ring system, the 10-bromo-derivatives of the compounds listed in Table 1 are made.
Competitive Binding to Dopamine Receptors
Dopamine produces biological responses through stimulation of its receptors on cell membranes. For the purpose of identifying compounds as dopamine antagonists which are capable of interacting with the dopamine receptor, a ligand-receptor binding assay was carried out as an initial screen. The affinity of the antagonist for the receptor is expressed as an inhibitory affinity constant (Ki) obtained by plotting the inhibitor concentration versus the reciprocal concentration of the isotopically labeled ligand that is displaced by the antagonist.
D- 1 and D-2 Receptor Binding Assays
Homogenized rat caudate was incubated in the presence of [1 25l]SCH-23982 (a selective antagonist of the dopamine D-1 receptor) and the compounds of this invention, according to procedures described by A. Sidhu, et al. in European J Pharmacology, 1 13: 437. 1985 and in European J Pharmacology, 128: 213, 1986. The compounds compete with the radiolabeled ligand for occupancy of the receptors and the molar potency of each compound was quantified. The affinity of the compound for the receptor (Ki) was calculated as described by Y.C. Cheng and W.H. Prusoff in Biochemical Pharmacology, 22: 3099, 1973 from the relationship Ki = IC50(1 +[L]/KD) where IC50 is the concentration of test compound which produces a 50% inhibition in the specific binding of the radioligand, L; [L] is the concentration of radioligand; and KD is the affinity of the radioligand for the receptor.
The procedure for the dopamine D-2 receptor binding assay was similar to that used for the D-1. receptor assay. Homogenized rat caudate was the source of the D-2 receptors. The tissue homogenate was incubated in the presence of [1 5l]-p-aminopheny!ethyl spiroperidol (a selective antagonist of the dopamine D-2 receptor) and the compounds being evaluated, according to the protocol described by T. Agui, N. Amiaiky, M.G. Caron and J.W. Kebabian in Molecular Pharmacology, 33: 163, 1988. The molar affinity of the compound for the receptor binding site was calculated by the same method used for the D-1 receptor assay, assuming a competitive interaction between the compound and the radiolabeled ligand.
The competitive binding data (Ki values) from the D-1 and D-2 receptor binding assays are shown in Table 2. The Ki values are inversely proportional to the affinity of the compound for the receptor, therefore it is apparent that the compounds of the invention have high affinity for dopamine receptors.
Table 2 m itiv Bin in f r D-1 n -
Figure imgf000038_0001
The interaction of dopamine or a dopamine D-1 receptor agonist with the D-1 receptor causes a dose-dependent increase in the adeπylate cyclase-catalyzed conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The functional activity of the compounds of the invention was determined by assaying, in vitro, its ability to antagonize a dopamine-induced increase in cAMP levels. The protocol for the adenylate cyclase assays was described by K.J. Watling and J.E.Dowling in J Neurochemistry, 36: 559, 1981 and by J.W. Kebabian, et al. in Proc Natl Acad Sci, USA, 69: 2145, 1972. The tissue was obtained from either goldfish retina or rat striatum.
In order to determine functional antagonist activity, cell-free tissue homogenates are incubated in an ionic buffer solution containing ATP, 10 μM dopamine and increasing concentrations of the compound being evaluated. The results of the assays for antagonist activity are shown in Table 3. The Ki values were calculated as described by Y.C. Cheng and W.H. Prusoff in Biochemical Pharmacology, 22: 3099, 1973 from the relationship Ki = ICSO([S]/KD). The applicability of this relationship is based on the assumption that tissues used in the assay do not have large receptor reserves for the D-1 and D-2 receptors. In this expression IC50 is defined as the concentration of test compound which produces a 50% reduction in the response to an agonist, S; [S] is the concentration of agonist in the assay; and KD is the affinity of the agonist for the receptor.
The compounds of the invention are potent antagonists of the dopamine receptor-mediated adenylate cyclase-catalyzed conversion of adenosine triphosphate (ATP) to cAMP and, therefore, prevent the physiological effects of excessive stimulation of dopamine receptors.
Tab'e 3 Antagonist Activity in Adenylate Cvclase Assay
Example # Ki (μM)
1 0.376
2 0.058
3 0.095
4 0.063 The foregoing examples are merely illustrative of the invention and are not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

What is claimed is:
1. A compound having the formula:
Figure imgf000041_0001
or a pharmaceutically acceptable salt, amide or ester thereof, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl and prodrug amide group; R2 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, lower alkylthio, nitro, acetamino and
-SO2R7 wherein R7 is lo ver alky!; R3 is selected from hydrogen and prodrug ester group; R4, R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, halo-substituted lower alkyl, nitro, amino, acetamino, lower alkylamino and -SO2F.8 wherein R8 is lower alkyl, subject to the proviso that:
1) when R4, R5 and R6 are hydrogen, R2 is not methoxy and
2) not more than one of R4, R5 and R6 is nitro or -SO2R8.
2. A compound of claim 1 wherein R4, R5 and R^ are hydrogen.
3. A compound selected from the group consisting of: fraπs-11 -Hydroxy-5, 6, 6a, 7a, 8,12b-hexahydro- benzo{a}phenanthridine; fraπs-N-Methyl-1 1 -hydroxy-5,6,6a.7a,8,12b-hexahydro- benzo{a}phenanthridine; fraπs-10-Brom 0-1 1 -hydroxy-5.6,6a,7,8,12b-hexahydro- benzo{a}phenanthridine; and fraπs-N-Methyl-10-bromo-1 1 -hydroxy-5,6,6a,7,8,12b-hexahydro- benzo{a}phenanthridine, or a pharmaceutically acceptable salt, amide or ester thereof.
4. A pharmaceutical composition for blocking dopamine receptors comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.
5. A pharmaceutical composition for treating dopamine-related neurological disorders comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.
6. A pharmaceutical composition for treating' dopamine-related psychological disorders comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.
7. A pharmaceutical composition for treating dopamine-related behavioral disorders comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.
8. A method for blocking dopaminergic receptors comprising administering to a human or other mammal in need a therapeutically effective amount of a compound according to claim 1.
9. A method for treating dopamine-related neurological disorders comprising administering to a human or other mammal in need a therapeutically effective amount of a compound according to claim 1.
10. A method for treating dopamine-related psychological disorders comprising administering to a human or other mammal in need a therapeutically effective amount of a compound according to claim 1.
11. A method for treating dopamine-related behavioral disorders comprising administering to a human or other mammal in need a therapeutically effective amount of a compound according to claim 1.
PCT/US1991/006440 1990-09-07 1991-09-06 Phenanthridine compounds WO1992004356A1 (en)

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
WO1993024462A1 (en) * 1992-05-26 1993-12-09 Purdue Research Foundation Substituted-hexahydrobenzo[a]phenanthridines
US5420134A (en) * 1992-05-26 1995-05-30 Purdue Research Foundation Substituted hexahydrobenzo[A]phenanthridines
WO1996002513A1 (en) * 1994-07-15 1996-02-01 Purdue Research Foundation Optically active isomers of dihydrexidine and its substituted analogs
US5659037A (en) * 1994-08-18 1997-08-19 Abbott Laboratories Process for preparing chiral tetracyclic dopaminergic compounds
US5959110A (en) * 1995-08-18 1999-09-28 Purdue Research Foundation Fused isoquinolines as dopamine receptor ligands
US6194423B1 (en) * 1995-08-18 2001-02-27 Purdue Research Foundation Fused isoquinolines as dopamine receptor ligands
EP1480647A1 (en) * 2002-02-15 2004-12-01 Darpharma, INC. Mono-ester and asymmetrically substituted di-ester pro-drugs of the dopamine d1 receptor agonists
EP1480647A4 (en) * 2002-02-15 2005-07-13 Darpharma Inc Mono-ester and asymmetrically substituted di-ester pro-drugs of the dopamine d1 receptor agonists
JP2005526728A (en) * 2002-02-15 2005-09-08 ダーファーマ，インコーポレイテッド Monoester and asymmetrically substituted diester prodrugs of dopamine D1 receptor agonists
US7220754B2 (en) 2002-02-15 2007-05-22 Darpharma, Inc. Mono-ester and asymmetrically substatuted di-ester pro-drugs of dopamide D1 receptor agonists
US9359303B2 (en) 2009-04-21 2016-06-07 Purdue Research Foundation Octahydrobenzoisoquinoline modulators of dopamine receptors and uses therefor
US9463161B2 (en) 2009-05-29 2016-10-11 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems

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