EP0883609A1 - Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1 - Google Patents

Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1

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Publication number
EP0883609A1
EP0883609A1 EP97906688A EP97906688A EP0883609A1 EP 0883609 A1 EP0883609 A1 EP 0883609A1 EP 97906688 A EP97906688 A EP 97906688A EP 97906688 A EP97906688 A EP 97906688A EP 0883609 A1 EP0883609 A1 EP 0883609A1
Authority
EP
European Patent Office
Prior art keywords
group
lower alkyl
alkyl group
individual
alkylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97906688A
Other languages
German (de)
English (en)
Inventor
Mark Froimowitz
Emile Melvin Bellott
Robert Stevenson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmeco Laboratories Inc
Original Assignee
Pharmeco Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmeco Laboratories Inc filed Critical Pharmeco Laboratories Inc
Publication of EP0883609A1 publication Critical patent/EP0883609A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • Parkinson's disease is characterized by the progressive death of presynaptic dopamine neurons in the substantia ni ⁇ ra that innervate postsynaptic striatal neurons and a resultant loss of striatal dopamine (Cedarbaum and Schleifer, "Drugs for Parkinson's disease, spasticity and acute muscle spasms", in Goodman and
  • Parkinson's disease The primary therapy for Parkinson's disease involves compensating for the loss of dopamine in the striatum.
  • the most commonly administered drug for the treatment of Parkinson's disease is levodopa, which is converted into dopamine in the central nervous system.
  • levodopa can cause severe side effects such as nausea, vomiting, cardiac arrhythmias and hypotension. Long-term use of levodopa can result in abnormal involuntary movements and psychosis. Consequently, there is a need for new treatments for Parkinson's disease.
  • Dopaminergic receptors have also been implicated in cocaine abuse. Specifically, cocaine is thought to block the reuptake of dopamine into dopamine-releasing neurons; as a consequence, dopamine levels can return to normal in the chronic presence of cocaine and be depleted in its absence. Subsequent reduced levels of synaptic dopamine are thought to cause the craving for cocaine that is associated with its abuse (Dackis and Gold, J. Substance
  • Drug Al cohol Abuse 12 235 (1986))
  • Agonists for the Dl dopamine receptor subtype have been shown to be effective in treating Parkinson's disease induced in laboratory animals (Kebabian et al . , Eur. J.
  • the present invention is a compound represented by Structural Formula I :
  • R 1 is selected from the group consisting of -OH and -OR', wherein R 4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group.
  • R 3 is selected from the group consisting of -H, an amine protecting group, a lower alkyl group and a lower alkyl group substituted with an aryl group. In one aspect, R 3 is selected from the group consisting -H and a lower alkyl group.
  • the compound of the present invention is represented by Structural Formula II:
  • the compound of the present invention is represented by Structural Formula IV:
  • R'-R 3 are as defined above for Structural Formula I.
  • Yet another embodiment of the present invention is a method of stimulating a Dl dopamine receptor in an individual .
  • the method comprises administering to the individual a stimulatory amount of a compound represented by Structural Formulas I, II, III or IV.
  • Compounds 1 and 2 can be used to treat individuals with Parkinson's disease.
  • the monohydroxy analogs of 1 and 2 can be used to treat individuals with Parkinson's disease.
  • these compounds can be used to treat individuals who abuse cocaine.
  • these compounds are useful for molecular modeling in order to further define the required spatial orientation of the amine and hydroxy-substituted phenyl ring for binding to the Dl receptor. They can also be used as standards in in vi tro binding assays for screening compounds for their ability to bind to the Dl receptor and for characterizing the effect of these kinds of compounds in the body. Descrip ion of the Ficnirpg
  • Figures IA and IB represent the stereoscopic images of the superposition of the hydroxylated phenyl rings of the energy minimized compounds 1 and 2 (light lines) onto the energy minimized structure of the Dl-selective full agonist dihydrexidine (dark lines) .
  • Dl receptor Dl dopamine receptor
  • Dl agonists and antagonists stimulate and inhibit the enzyme adenylate cyclase, which produces the cellular messenger cyclic adenosine monophosphate (AMP) (Clement-Cormrer et al . , Proc . Na tl . Acad . Sci . USA 71:1113 (1974) and Stoof and Kebabian, Nature 294:366 (1981)) .
  • AMP messenger cyclic adenosine monophosphate
  • a compound which stimulates a Dl receptor can be an agonist, (i.e., a compound which causes the cellular activity affected or controlled by the Dl receptor to increase) or an antagonist (i.e., a compound which causes the cellular activity affected or controlled by the Dl receptor to decrease) .
  • a compound which stimulates a Dl receptor can also be a partial agonist (a mixed agonist/antagonist, i.e., a compound which can act as either an agonist or an antagonist, depending on the tissue type) .
  • a "stimulatory amount" of a compound is the quantity of a compound which, when administered to an individual, results in a discernable increase or decrease of cellular activity affected or controlled by the Dl receptor.
  • Administration of a stimulatory amount of a compound typically causes an observable physiological response resulting from the increase or decrease in a cellular activity under the control of a Dl receptor (see, for example, Taylor et al . , Eur. J. Pharm . 199 : 389 (1991) and Kebabian et al . , Eur. J. Pharm . 229 : 203 (1995)) .
  • Dl agonists can stimulate a bovine parathyroid gland to produce an increase in the release of parathyroid hormone (Brown et al . , Proc . Na tl . Acad . Sci . USA 74:4210
  • “stimulatory amount” can also refer to the amount of compound which decreases or alleviates the symptoms of a disease involving the Dl receptor or a disease involving molecules, such as dopamine, which stimulate the Dl receptor, e.g. Parkinson's disease or cocaine abuse.
  • a “stimulatory amount” of the compound ranges from about 1 mg/day to about 1000 mg/day.
  • Compounds of the invention which act as Dl receptor agonists can be used in a method of treating an individual afflicted with Parkinson's disease.
  • the method comprises administering a therapeutically effective amount of the Dl receptor agonist to the individual afflicted with Parkinson's disease.
  • Compounds of the invention which are Dl receptor agonists are compounds represented by Structural Formulas I-IV, wherein R : is selected from the group consisting of -OH and -OR " , and wherein R : is as defined above.
  • Examples of compounds which can be used for the treatment of Parkinson's disease include compounds represented by Structural Formulas II and IV, wherein R 1 and R 2 are each -OH and R 3 is -H.
  • Other examples include compounds represented by Structural Formulas I and III, where R " and R : are each -OH and R 3 is -H or -CH 3 .
  • Compounds of the invention which act as Dl receptor partial agonist can be used in a method for treating an individual who abuses cocaine.
  • the method of the invention comprises administering a therapeutically effective amount of the Dl receptor partial agonist to an individual who abuses cocaine.
  • Compounds of the invention which act as a Dl receptor partial agonist are compounds represented by Structural Formulas I-IV, wherein R ⁇ is -H or a halogen.
  • Examples of compounds which can be used for the treatment of cocaine abuse include compounds represented by Structural Formulas II and IV, wherein R 1 is -OH and R and R" are each -H.
  • Other examples include compounds represented by Structural Formulas I and III, wherein R 1 is -OH, R : is -H and R- ' is -H or -CH 3 .
  • a “therapeutically effective” amount of a compound is the amount of compound which decreases or alleviates the severity of the symptoms associated with a disease, e.g., Parkinson's disease or cocaine abuse, in an individual being treated with the compound.
  • a “therapeutically effective” amount of a compound can be the amount of compound which decreases an addicted individual's craving for cocaine.
  • a “therapeutically effective amount” of the compound ranges from about 1 mg/day to about 1000 mg/day.
  • a "lower alkyl” group is a substituted or unsubstituted C1-C12 alkyl group, and can be straight- chained, branched or cyclic. A lower alkyl group can also include one or more units of unsaturation.
  • an "aryl group” includes, for example, phenyl, substituted phenyl, heteroaryl (e.g. thienyl, furanyl, pyridinyl and benzothienyl) or substituted heteroaryl groups.
  • Suitable substituents on an aryl or heteroaryl group include -CN, -N0 : , halogen, lower alkyl, -OR, -NHR, and -SR, wherein R is a C1-C6 alkyl group or a protecting group for an alcohol, amine or thiol group.
  • suitable halogens include chlorine, bromine and fluorine.
  • Alkylene groups can be used to form a bridge between two ort o phenolic oxygens, e.g., R' and R 3 in Structures
  • a preferred alkylene group is methylene.
  • Protecting group has the definition commonly afforded to the term, namely a chemical moiety bonded to a functional group in a molecule, which is removable when exposed to suitable chemical reagent (s) or enzyme (s) to regenerate a free functional group.
  • Suitable phenol and alcohol protecting groups include t-butyl, methoxymethyl, 2-tetrahydropyranyl, O O
  • silyl esters e.g. triisopropylsilyl and t-butyldimethyl silyl
  • trifluoracetate 2-methoxyethoxy-methyl, siloxymethyl, benzyloxycarbonyl (BOC) and carboxycarbonyl (CBZ) .
  • Suitable amine protecting groups include t-butyloxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) , 9-fluorenylmethoxycarbonyl (f-MOC) , 2, 2, 2-trichloroethoxycarbonyl, 2-haloethoxy- carbonyl, benzoyl, phthalimidyl, diphenylphosphinyl and benzensulfonyl .
  • BOC t-butyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • f-MOC 9-fluorenylmethoxycarbonyl
  • f-MOC 9-fluorenylmethoxycarbonyl
  • 2-haloethoxy- carbonyl 2, 2, 2-trichloroethoxycarbonyl, 2-haloethoxy- carbonyl
  • benzoyl phthalimidyl
  • diphenylphosphinyl diphenylphosphinyl
  • the compounds of the present invention can be administered to an individual in the form of a pro-drug, i.e., the compound being administered is converted into the active agent in vivo .
  • a pro-drug is often used to enhance certain desirable properties of the compound.
  • the pro-drug can have greater lipophilicity than the parent drug and, therefore, greater ability to cross the blood brain barrier.
  • a pro-drug can also stabilize the pharmacologically active substance, e.g., by preventing metabolism of the pharmacologically active substance by, for example, oxidation.
  • the compounds of the present invention can be converted into pro-drugs by protecting the phenol (s) and/or amine functionalities with groups that are capable of being removed in vivo .
  • phenolic esters, carbonates and carbamates are degraded by cellular enzymes to yield phenols (Dittert et al . , J. Pharm. Sci . 57 : 783 (1968) , Dittert et al . , J. Pharm . Sci . 57:828 (1968) , Dittert et al . , J. Pharm . Sci . 58 : 551 (1969) and Ratie et al . , J.
  • Ii removable in vivo include phenyl-O-C- and (C1-C6
  • the compounds of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g. , intramuscular, intravenous, subcutaneous, nasal or topical) .
  • parenteral routes e.g. , intramuscular, intravenous, subcutaneous, nasal or topical
  • the form in which the compounds are administered will be determined by the route of administration.
  • Such forms include, but are not limited to capsular and tablet formulations (for oral and rectal administration) , liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration) .
  • the formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives.
  • Suitable physiologically acceptable vehicles may include saline, sterile water, Ringer's solution, and isotonic sodium chloride solutions.
  • the specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.
  • the compounds of the present invention used in the treatment of an individual with Parkinson's disease can be co-administered with other pharmaceutically active agents used in the treatment of Parkinson's disease.
  • the compounds of the present invention used in the treatment of an individual who abuses cocaine can be combined with other therapies used to treat individuals who abuse cocaine.
  • Such therapies can include the co-administration of other pharmaceutically active agents used to treat cocaine abuse or psychological therapies.
  • Dihydrexidine is a known Dl selective agonist.
  • the monohydroxy analog of the Dl receptor agonist dihydrexidine is a partial Dl agonist (Seiler et al . , J. Med . Chem. 36 : 911 (1993)) .
  • the same modification to the catechol-containing partial agonist apomorphine produces a Dl antagonist (Schaus et al J. Med.
  • the preparation of the dimethoxybenzalphthalide 8 is carried out by reaction of 2, 3-dimethoxyphenylacetic acid 4 with phthalic anhydride 6 in the presence of sodium acetate (Weiss, Organic synthesis, Collective Volume II, page 61) . Catalytic reduction (Raney nickel/hydrogen) of the dimethoxybenzalphthalide 8 yields the phenethylbenzoic acid
  • the aryl hydrogens of the activated benzo ring of the cycloheptadienone 12 are protected by electrophilic dibromination with Br to give the cycloheptadienone 18.
  • the carbonyl group of the cycloheptadienone 18 is converted to a methylamino group by successive reduction with NaBH, , alcohol tosylation, displacement with cyanide and reduction to produce compound 20.
  • the benzocyclo-heptatriene- isoquinoline ring system is then produced according to literature methods (Humber et al . , J. Heterocyclic Chem.
  • lactam 22 Reduction of lacta 22 with lithium aluminum hydride effects the reduction of the lactam functionality and the reductive debromination of the protecting halogens to produce compound 24.
  • Chiral resolution is carried out as described in Example 1. Demethylation is then accomplished with BBr, or HBr to give 2.
  • the binding assay for the Dl receptor utilizes homogenized rat striatal membrane preparations.
  • Binding is assessed by filtering incubates on polyethylenimine-presoaked Whatman GF/B filters and by scintillation counting (Billard et al . , Life
  • the radioactive ligand is " H SCH-
  • the buffer consists of 50 mM Tris-HCl (pH 7.4) , 120 mM KCl, 2 mM CaCl : and 1 mM MgCl; (Billard et al . , Life Sci . 35:1885 (1984)) . Incubation time is fifteen minutes at 37°C. Non-specific binding is defined with 1 ⁇ M (+) -butacla ol .

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention a trait à des composés (1) et (2), à leurs dérivés et à leurs analogues, agonistes du récepteur de la dopamine D1. On peut utiliser ces composés pour traiter des sujets atteints de la maladie de Parkinson. Cette invention porte également sur des analogues mono-hydroxy des composés (1) et (2) ainsi que sur leurs dérivés et analogues, agonistes ou antagonistes partiels de D1. On peut utiliser ces composés pour traiter des personnes abusant de la cocaïne.
EP97906688A 1996-02-23 1997-02-19 Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1 Withdrawn EP0883609A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60639396A 1996-02-23 1996-02-23
US606393 1996-02-23
PCT/US1997/002620 WO1997030977A1 (fr) 1996-02-23 1997-02-19 Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1

Publications (1)

Publication Number Publication Date
EP0883609A1 true EP0883609A1 (fr) 1998-12-16

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP97906688A Withdrawn EP0883609A1 (fr) 1996-02-23 1997-02-19 Agonistes selectifs et agonistes/antagonistes partiels du recepteur de la dopamine d1

Country Status (5)

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EP (1) EP0883609A1 (fr)
JP (1) JP2000506832A (fr)
AU (1) AU2131697A (fr)
CA (1) CA2247468A1 (fr)
WO (1) WO1997030977A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA03001272A (es) * 2000-08-11 2004-04-02 Purdue Research Foundation Procedimiento para la preparacion de dinapsolina.
SG183696A1 (en) 2007-08-06 2012-09-27 Biotie Therapies Inc Medicaments comprising nepicastat for use in treating dependence on a substance

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992445A (en) * 1972-08-25 1976-11-16 Merck & Co., Inc. 5-Formamidomethyl-5H-dibenzo[a,d]cycloheptene derivatives
WO1990012574A1 (fr) * 1989-04-25 1990-11-01 Northeastern University Composes agonistes de la dopamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9730977A1 *

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Publication number Publication date
WO1997030977A1 (fr) 1997-08-28
JP2000506832A (ja) 2000-06-06
CA2247468A1 (fr) 1997-08-28
AU2131697A (en) 1997-09-10

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