CA2247468A1 - Selective d1 dopamine receptor agonists and partial agonists/antagonists - Google Patents
Selective d1 dopamine receptor agonists and partial agonists/antagonists Download PDFInfo
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- CA2247468A1 CA2247468A1 CA002247468A CA2247468A CA2247468A1 CA 2247468 A1 CA2247468 A1 CA 2247468A1 CA 002247468 A CA002247468 A CA 002247468A CA 2247468 A CA2247468 A CA 2247468A CA 2247468 A1 CA2247468 A1 CA 2247468A1
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- 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
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- 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
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- 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
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- 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
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- 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
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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
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- 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
Abstract
Disclosed are compounds (1) and (2), and derivatives and analogs thereof, which are agonists for the D1 dopamine receptor. These compounds can be used to treat an individual with Parkinson's disease. Also disclosed are monohydroxy analogs of compounds (1) and (2), and derivatives and analogs thereof, which are partial D1 agonists or antagonists. These compounds can be used to treat an individual who abuses cocaine.
Description
W O 97130977 PCTrUS97/02620 SFT~CTIVE D1 D~PAMIN~ ~PTOR AGONISTS AND
P~TIAT. AGONISTS/~TAGONISTS
,.
Rackgrol1nd Parkinson's disease is characterized by the progressive death of presynaptic dopamine neurons in the sl~hstantia n;gra 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 Gilman's The Pharmacological Basis of Therapeutics, A.G.
Goodman, T.W. Rall, A.S. Nies and P. Taylor, eds. Eighth Edition, McGraw Hill, pp. 463-484 (1992)). 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 ls levodopa, which is converted into dopamine in the central nervous system. However, 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, ~. Substance Abuse Treatment 2:139 (1985) and Kleber and Gawin, Am. J.
Drug Alcohol A~use 12:235 (1986)).
CA 02247468 l998-08-2l W 097130977 PCTrUS97/02620 Agonists ~or the D1 dopamine receptor subtype have been shown to be effective in treating Parkinson's disease r' induced in laboratory animals (Kebabian et al., Eur. ~.
Pharm. 229:203 ~1992), Taylor et al., Eur. ~. Pha~7n. ., 199:389 (1991) and Michaelides et al., J. Med. Chem.
38:3445 (1995)). Similarly, recent studies have shown that antagonists and partial agonists for the D1 dopamine receptor subtype may be effective in treating cocaine abuse (Caine and Koob, .J. Pharm Exp. Ther. 270:209 (1994~ and Bergman and Rosenzweig-Lipson, Problems of Drug Depende~ce, 1991 NIDA Research Monograph 119, page 185 (1992)).
Therefore, there is a need for new compounds in new structural classes having selective activities for the D1 dopamine receptor.
Sl~mrnary of the Invention It has now been found that Compounds 1 and 2 have the necessary pharmacophores in the regions of three dimensional space required ~or selective binding to the D1 dopamine receptor (Example 1). Thus, it is expected that these compounds will be selective D1 receptor agonists and their monohydroxy analogs will be partial D1 receptor agonist.
W 097/30977 PCTrUS97/02620 HO HO
HO ~ HO , NH2 H~
~ 2~
In one embodiment, the present invention is a compound represented by Structural Formula I:
Rl NH~3 (I) Rl is selected from the group consisting of -OH and -OR7, whereln R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group.
R~ is selected from the group consisting of -H, -OH, -oR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R~, when R4 is an alkylene group.
WO 97/30977 PCTrUS97/02620 R3 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, R3 is selected from the group consisting -H and a lower alkyl group.
In another embodiment, the compound of the present invention is represented by Structural Formula II:
R
~2~
R (II) wherein R -Rs are as defined above for Structural Formula I. In another embodiment, the compound of the present invention is represented by Structural Formula III:
J 1: J
NH
' (III) W O 97130977 ~CTnUS97/02620 wherein Ri-R5 are as de~ined above by Structural Formula I.
In another embodiment, the compound of the present invention is represented by Structural Formula IV:
Rl ~,J
~ (IV) 5 wherein R'-R~ are as defined above ~or Structural Formula I
Yet another embodiment o~ the present invention is a method o~ stimulating a D1 dopamine receptor in an individual. The method comprises administering to the 10 individual a stimulatory amount o~ a compound represented by Structural Formulas I, II, III or IV.
Compounds 1 and 2 can be used to treat individuals with ~arkinson's disease. The monohydroxy analogs o~ 1 and 2 can be used to treat individuals who abuse cocaine. In 15 addition, these compounds are use~ul for molecular modeling in order to ~urther de~ine the re~uired spatial orientation o~ the amine and hydroxy-substituted phenyl ring ~or binding to the D1 receptor. They can also be used as standards in ln vitro binding assays for screening 20 compounds ~or their ability to bind to the D1 receptor and ~ ~or characterizing the e~ect o~ these kinds o~ compounds in the body.
W 097/30977 PCT~US97/0~62 Descr;~tion of the Flgllres Figures lA and lB represent the stereoscopic images of the superposition of the hydroxylated phenyl rings of the energy ~in;~; zed compounds 1 and 2 (light lines) onto the energy m; n; m; zed structure o~ the D1-selective ~ull agonist dihydrexidine (dark lines).
Det~;led De.~cr;pt;on of the Invent;on The ~eatures and other details o~ the invention will now be more particularly described with re~erence to the accompanying examples and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way o~ illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention.
"Stimulating" a D1 dopamine receptor (referred to herein as a "D1 receptor") refers to causing a molecule to bind, complex or interact with the D1 receptor so that the cellular activity which is affected or controlled by the D1 receptor either increases or decreases. For example, D1 agonists and antagonists, respectively, stimulate and inhibit the enzyme adenylate cyclase, which produces the cellular messenger cyclic adenosine monophosphate (AMP) ~Clement-Cormrer et al ., Proc. Natl . Acad. Sci . USA 71:1113 (1974) and Stoo~ and Kebabian, Nature 294:366 (1981)). A
compound which stimulates a D1 receptor can be an agonist, ~i.e., a compound which causes the cellular activity a~ected or controlled by the D1 receptor to increase) or an antagonist (i.e., a compound which causes the cellular activity a~ected or controlled by the D1 receptor to decrease). A compound which stimulates a D1 receptor can also be a partial agonist (a mixed agonist/antagonist, W O 97/30977 PCT~US97102620 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, as used herein, 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 D1 receptor. A~lm;n~ stration of~ a stimulatory amount o:E a compound typically causes an observable physiological response resulting from the increase or decrease in a cellular activity under the control o~ a D1 receptor (see, for example, Taylor et al., Eur. J. Pharm. 199:389 (1991) and Kebabian et al., Eur. ~. Pharm. 229:203 (1995)). For example, Dl agonists can stimulate a bovine parathyroid gland to produce an increase in the release of parathyroid hormone (Brown et al ., Proc. Natl . Acad. Sci . USA 74 :4210 (1977) and Brown et al., Mol. Pharm. 18:335 (1980~). A
"stimulatory amount" can also refer to the amount of compound which decreases or alleviates the symptoms of a disease involving the D1 receptor or a disease involving molecules, such as dopamine, which stimulate the D1 receptor, e.g. Parkinson's disease or cocaine abuse.
Typically, a "stimulatory amount~ of the compound ranges from about l mg/day to about 1000 mg/day.
Compounds of the invention which act as D1 receptor 25 agonists can be used in a method o~ treating an individual af~licted with Parkinson's disease. The method comprises administering a therapeutically effective amount o~ the Dl receptor agonist to the individual afflicted with Parkinson '8 disease.
Compounds of the invention which are Dl receptor agonists are compounds represented by Structural Formulas I-IV, wherein R- is selected ~rom the group consisting of -OH and -ORs, and wherein R is as de~ined above. Examples of compounds which can be used for the treatment of W097~0977 PCT~US97/02620 Parkinson' 5 disease include compounds represented by Structural ~ormulas II and IV, wherein R- and R- are each -O~ and R3 is -H. Other examples include compounds represented by Structural Formulas I and III, where R and R- are each -OH and R3 is -H or -CH,.
Compounds of the invention which act as D1 receptor partial agonist can be used in a method ~or treating an individual who abuses cocaine. In this embodiment, the method of the invention comprises administering a therapeutically effective amount of the D1 receptor partial agonist to an individual who abuses cocaine.
Compounds of the invention which act as a D1 receptor partial agonist are compounds represented by Structural Formulas I-IV, wherein R- is -H or a halogen. Examples bf compounds which can be used for the treatment of cocaine abuse include compounds represented by Structural Formulas II and IV, wherein Rl is -OH and R- and R are each -H.
Other examples include compounds represented by Structural Formulas I and III, wherein Rl is -OH, R- is -H and R- is -H
or -CH3.
A 'Itherapeutically 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. In the case of treatment of cocaine abuse, a "therapeutically effective" amount of a compound can be the amount of compound which decreases an addicted individual's craving for cocaine. Typically, a "therapeutically effective amount" of the compound ranges from about l mg/day to about 1000 mg/day.
As used herein, 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.
W O 97J30977 PCTrUS97/02620 As used herein, an "aryl group 1l includes, for example, phenyl, substituted phenyl, heteroaryl (e.g. thienyl, furanyl, pyridinyl and benzothienyl) or substituted heteroaryl groups. Examples o~ suitable substituents on an aryl or heteroaryl group include -CN, -NO~, 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.
E~amples o~ suitable halogens include chlorine, bromine and fluorine.
Alkylene groups can be used to form a bridge between two ortho phenolic oxygens, e.g., R~ and R~ in Structures I-IV, taken together, can form an alkylene group.
Examples of suitable l'alkylene groups" include -~CH~ (CH--CH~)-, -(CHX)-, -(CXY)-, -(CHX-CH.)- and -(CHX-CHY)-, wherein X and Y are C1-C4 alkyl groups and are independently chosen. A preferred alkylene group is methylene.
'IProtecting 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 ~unctional group.
Examples of suitable phenol and alcohol protecting groups include t-butyl, methoxymethyl, 2-tetrahydropyranyl, 2~ O O
Il 11 2-tetrahydrofuranyl, -CO(lower alkyl), (lower alkyl)-O-C-, O O
Il 11 3G (lower alkyl) -NH-C-, -~O(aryl), silyl esters, (e.g.
triisopropylsilyl and t-butyldimethyl silyl), tri~luoracetate, 2-methoxyethoxy-methyl, siloxymethyl, benzyloxycarbonyl (BOC) and carboxycarbonyl (CBZ).
Suitable amine protecting groups include t-butyloxycarbonyl ~BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethoxycarbonyl (~-MOC), 2,2,2-trichloroethoxycarbonyl, 2-haloethoxy-W O 97/30977 PCT~US97/02620 carbonyl, benzoyl, phthalimidyl, diphenylphosphinyl and benzensulfonyl. Other suitable phenol, alcohol, amine and thiol protecting groups are given in Greene, "Protecting Groups in Organic Synthesis," John Wiley and Sons, Second 5~ Edition, (1991), and are within the scope of the present invention.
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 certaln desirable properties of the compound. For example, 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 15 : 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. For example, 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., ~. Pharm. Sci. 57 828 (1968), Dittert et 25 al., J. Pharm. Sci. 58:557 (1969) and Ratie et al., J.
Pharm. Sci . 59:1739 (1970) ) . Suitable, phenol protecting groups which can be removed in vivo to regenerate the o ~0 free phenol, include (cl-c8 alkyl)-CO-, (Cl-C8 alkyl)-O O
!l 11 O-C- and (Cl-C8 alkyl)-NH-C-. Also included is when the phenols are protected in the form a methylene dioxy group.
In addition, a variety of carbamate groups used to protect WO 97/30977 PCTrUS97/02620 amines are known to undergo spontaneous cleavage in solution at kinetically favorable rates (Saari, et al. J.
Med. Chem., 33:97 (1990)) and would thus be expected to degrade in vivo. Carbamates are also degraded enzymatically, (King, et al., Biochemistry, 26:2294 (1987)), particularly in blood (Tunek, et al., Biochemical Pharmacology, 37:3867 (1988)) to a~ford an unprotected amine. Suitable amine protecting groups which are ll removable in vivo include phenyl-O-C- and (C1-C6 alkyl substituted phenyl)-O-C- and (C1-C3 alkoxy substituted phenyl)-O-C-.
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). The form in which the compounds are administered will be determined by the route o~ 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, W 097/30977 PCT~US97/02620 for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual belng treated.
The compounds of the present invention used in the 5~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.
When the compounds of the present invention are used in combination with other pharmaceutically active agents, the specific combination will vary, depending on a number of factors, including, for example, activity of the agents, their side-effects, and the weight, age, sex and general health of the individual being treated.
The preparation of compounds of the present invention are shown in Schemes 1 and 2 and described more fully in Examples 2 and 3.
The invention is further illustrated by the following examples, which are not intended to be limiting in any way.
.xample 1 - ~.nergy Minimization Studies on Compounds 1 and 2 Energy minimization studies were performed on Compounds 1 and 2.
The energy minimized structures of 1 and 2 have been superimposed onto the energy minimized conformation of the W O 97/30977 PCTrUS97/02620 active enan~iomer of dihydrexidine (Knoerzer et al., J.
Med. Chem. 37:2453 (199~) ), as shown in Figures 1~ and lB.
Dihydrexidine is a known D1 selective agonist.
Compounds 1 and 2 present similar nonplanar pharmacophores with the amine group and phenyl rings placed in similar regions of three dimensional space, as in dihydrexidine and other D1 selective compounds (Froimowitz and Bellott, J. Mol . Model . 1:36 (1995)).
Calculations of the conformational flexibilities of 1 and 2 were performed and compared with that o~
dihydrexidine. These studies show that in dihydrexidine, one phenyl ring can be either above or below the plane of the other, due to close contacts between the phenyl rings (Fromowitz and Bellott, J. Mol. Model. 1:36 (1995)). Both conformers were energy minimized with the result that the con~ormer shown in Figures lA and lB is preferred by 1.5 kcal/mole. This is also the conformer observed in the crystal state of a dihydrexidine analog (Knoerzer et al.
1994).
These results also indicate that Compounds 1 and 2 have two possible con~ormations o~ the two-carbon link between the phenyl ~ings and that there is a substantial energy di~ference (3.4 kcal/mole for 2) between these two conformers. Compound 1, as with other nonplanar tricyclic structures, has additional flexibility in that the tricyclic structure can invert (Froimowitz and Ramsby, J.
Med. Chem. 34:1707 (1991)) and the preferred folding will be the one in which the side chain is pseudoequatorial. In addition, the amine-containing side chain can be conformationally trans to either phenyl ring and there is little energy dif~erence between these possibilitles due to the near symmetry o~ the molecule. Compound 2 is a less CA 02247468 l998-08-2l W O 97/30977 PCT~US97/02620 flexible analog o~ l and the ammonium hydrogens are similarly placed to those in dihydrexidine.
The monohydroxy analog of the D1 receptor agonist dihydrexidine is a partial D1 agonist (Seiler et al., J.
5 Med. Chem. 36:977 (1993)). In addition, the same modification to the catechol-containing partial agonist apomorphine produces a Dl antagonist (Schaus e t al J. Med .
C~em. 33:600 (1990). Thus, it is expected that the monohydroxy analog of 1 and 2 will result in a D1 partial agonist or antagonist.
Energy minimization of the compounds in this study were performed with respect to all internal coordinates using the MM2-87 program and parameter set of Allinger and Yuh, Quantum Chem. Program Exch. 12:program 395 (1980).
All calculations were performed for the protonated molecule. Initial Cartesian coordinates of the molecules were generated with PCMODEL pro~ram (Serena So~tware, Box 3076, Bloomington, IN 47402-3076) or the DRIVER option of the MM2-87 program. The dielectric constant was set to 80 and the hydrogen bonding terms involving the ammonium group were set to zero to approximate a water solution and to prevent intramolecular electrostatic ~orces from dominating the calculations in the absence o~ explicit water molecules ~Froimowitz, J. Comput . Chem. 14: 934 (1993) and Froimowitz 25 et al., J. Med. Chem. 36:2219 (1993)). To ensure complete convergence of the calculations, the convergence criteria was set to 1/8 o~ its default.
Fxam~le 2 - Synthesis of Compound 1 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 =
W 097/30977 PCT~US97/02620 (Weiss, Organic synthesis, Collective Volume II, page 61).
Catalytic reduction (Raney nickel/hydrogen) o~ the dimethoxybenzalphthalide 8 yields the phenethylbenzoic acid - 10. Cyclization o~ the phenethylbenzoic acid 10 with polyphosphoric acid yields the cycloheptadienone 12 (Winthrop et al., J. Org. Chem. 27:230 (1962)).
Condensation o~ the cycloheptadienone 12 with nitromethane yields the nitroalkane 14, which is catalytically hydrogenated to produce compound 16. Chiral resolution o~ the racemate is carried out by HP~C with a chiral column such as CHIRACEL OD (J.T. Baker) (Froimowitz et al ., Drug Design and Discovery 13 :73 (1g95) ) .
Demethylation o~ each enantiomer with BBr~ or HBr provides the ~inal optically pure product 1.
Alkyl groups are introduced onto the amine by reductive alkylation (Gribble et al., J. Am. Chem. Soc., 9 6 : 7 8 12 ( 1 9 74 ) ) .
mple ~- Synthesis of Compound 2 To prevent cyclization to the activated benzo ring, the aryl hydrogens o~ the activated benzo ring of the cycloheptadienone 12 are protected by electrophilic dibromination with Br. to give the cycloheptadienone 18.
The carbonyl group o~ 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 toliterature methods (~umber et al., J. ~eterocyclic Chem.
P~TIAT. AGONISTS/~TAGONISTS
,.
Rackgrol1nd Parkinson's disease is characterized by the progressive death of presynaptic dopamine neurons in the sl~hstantia n;gra 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 Gilman's The Pharmacological Basis of Therapeutics, A.G.
Goodman, T.W. Rall, A.S. Nies and P. Taylor, eds. Eighth Edition, McGraw Hill, pp. 463-484 (1992)). 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 ls levodopa, which is converted into dopamine in the central nervous system. However, 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, ~. Substance Abuse Treatment 2:139 (1985) and Kleber and Gawin, Am. J.
Drug Alcohol A~use 12:235 (1986)).
CA 02247468 l998-08-2l W 097130977 PCTrUS97/02620 Agonists ~or the D1 dopamine receptor subtype have been shown to be effective in treating Parkinson's disease r' induced in laboratory animals (Kebabian et al., Eur. ~.
Pharm. 229:203 ~1992), Taylor et al., Eur. ~. Pha~7n. ., 199:389 (1991) and Michaelides et al., J. Med. Chem.
38:3445 (1995)). Similarly, recent studies have shown that antagonists and partial agonists for the D1 dopamine receptor subtype may be effective in treating cocaine abuse (Caine and Koob, .J. Pharm Exp. Ther. 270:209 (1994~ and Bergman and Rosenzweig-Lipson, Problems of Drug Depende~ce, 1991 NIDA Research Monograph 119, page 185 (1992)).
Therefore, there is a need for new compounds in new structural classes having selective activities for the D1 dopamine receptor.
Sl~mrnary of the Invention It has now been found that Compounds 1 and 2 have the necessary pharmacophores in the regions of three dimensional space required ~or selective binding to the D1 dopamine receptor (Example 1). Thus, it is expected that these compounds will be selective D1 receptor agonists and their monohydroxy analogs will be partial D1 receptor agonist.
W 097/30977 PCTrUS97/02620 HO HO
HO ~ HO , NH2 H~
~ 2~
In one embodiment, the present invention is a compound represented by Structural Formula I:
Rl NH~3 (I) Rl is selected from the group consisting of -OH and -OR7, whereln R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group.
R~ is selected from the group consisting of -H, -OH, -oR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R~, when R4 is an alkylene group.
WO 97/30977 PCTrUS97/02620 R3 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, R3 is selected from the group consisting -H and a lower alkyl group.
In another embodiment, the compound of the present invention is represented by Structural Formula II:
R
~2~
R (II) wherein R -Rs are as defined above for Structural Formula I. In another embodiment, the compound of the present invention is represented by Structural Formula III:
J 1: J
NH
' (III) W O 97130977 ~CTnUS97/02620 wherein Ri-R5 are as de~ined above by Structural Formula I.
In another embodiment, the compound of the present invention is represented by Structural Formula IV:
Rl ~,J
~ (IV) 5 wherein R'-R~ are as defined above ~or Structural Formula I
Yet another embodiment o~ the present invention is a method o~ stimulating a D1 dopamine receptor in an individual. The method comprises administering to the 10 individual a stimulatory amount o~ a compound represented by Structural Formulas I, II, III or IV.
Compounds 1 and 2 can be used to treat individuals with ~arkinson's disease. The monohydroxy analogs o~ 1 and 2 can be used to treat individuals who abuse cocaine. In 15 addition, these compounds are use~ul for molecular modeling in order to ~urther de~ine the re~uired spatial orientation o~ the amine and hydroxy-substituted phenyl ring ~or binding to the D1 receptor. They can also be used as standards in ln vitro binding assays for screening 20 compounds ~or their ability to bind to the D1 receptor and ~ ~or characterizing the e~ect o~ these kinds o~ compounds in the body.
W 097/30977 PCT~US97/0~62 Descr;~tion of the Flgllres Figures lA and lB represent the stereoscopic images of the superposition of the hydroxylated phenyl rings of the energy ~in;~; zed compounds 1 and 2 (light lines) onto the energy m; n; m; zed structure o~ the D1-selective ~ull agonist dihydrexidine (dark lines).
Det~;led De.~cr;pt;on of the Invent;on The ~eatures and other details o~ the invention will now be more particularly described with re~erence to the accompanying examples and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way o~ illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention.
"Stimulating" a D1 dopamine receptor (referred to herein as a "D1 receptor") refers to causing a molecule to bind, complex or interact with the D1 receptor so that the cellular activity which is affected or controlled by the D1 receptor either increases or decreases. For example, D1 agonists and antagonists, respectively, stimulate and inhibit the enzyme adenylate cyclase, which produces the cellular messenger cyclic adenosine monophosphate (AMP) ~Clement-Cormrer et al ., Proc. Natl . Acad. Sci . USA 71:1113 (1974) and Stoo~ and Kebabian, Nature 294:366 (1981)). A
compound which stimulates a D1 receptor can be an agonist, ~i.e., a compound which causes the cellular activity a~ected or controlled by the D1 receptor to increase) or an antagonist (i.e., a compound which causes the cellular activity a~ected or controlled by the D1 receptor to decrease). A compound which stimulates a D1 receptor can also be a partial agonist (a mixed agonist/antagonist, W O 97/30977 PCT~US97102620 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, as used herein, 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 D1 receptor. A~lm;n~ stration of~ a stimulatory amount o:E a compound typically causes an observable physiological response resulting from the increase or decrease in a cellular activity under the control o~ a D1 receptor (see, for example, Taylor et al., Eur. J. Pharm. 199:389 (1991) and Kebabian et al., Eur. ~. Pharm. 229:203 (1995)). For example, Dl agonists can stimulate a bovine parathyroid gland to produce an increase in the release of parathyroid hormone (Brown et al ., Proc. Natl . Acad. Sci . USA 74 :4210 (1977) and Brown et al., Mol. Pharm. 18:335 (1980~). A
"stimulatory amount" can also refer to the amount of compound which decreases or alleviates the symptoms of a disease involving the D1 receptor or a disease involving molecules, such as dopamine, which stimulate the D1 receptor, e.g. Parkinson's disease or cocaine abuse.
Typically, a "stimulatory amount~ of the compound ranges from about l mg/day to about 1000 mg/day.
Compounds of the invention which act as D1 receptor 25 agonists can be used in a method o~ treating an individual af~licted with Parkinson's disease. The method comprises administering a therapeutically effective amount o~ the Dl receptor agonist to the individual afflicted with Parkinson '8 disease.
Compounds of the invention which are Dl receptor agonists are compounds represented by Structural Formulas I-IV, wherein R- is selected ~rom the group consisting of -OH and -ORs, and wherein R is as de~ined above. Examples of compounds which can be used for the treatment of W097~0977 PCT~US97/02620 Parkinson' 5 disease include compounds represented by Structural ~ormulas II and IV, wherein R- and R- are each -O~ and R3 is -H. Other examples include compounds represented by Structural Formulas I and III, where R and R- are each -OH and R3 is -H or -CH,.
Compounds of the invention which act as D1 receptor partial agonist can be used in a method ~or treating an individual who abuses cocaine. In this embodiment, the method of the invention comprises administering a therapeutically effective amount of the D1 receptor partial agonist to an individual who abuses cocaine.
Compounds of the invention which act as a D1 receptor partial agonist are compounds represented by Structural Formulas I-IV, wherein R- is -H or a halogen. Examples bf compounds which can be used for the treatment of cocaine abuse include compounds represented by Structural Formulas II and IV, wherein Rl is -OH and R- and R are each -H.
Other examples include compounds represented by Structural Formulas I and III, wherein Rl is -OH, R- is -H and R- is -H
or -CH3.
A 'Itherapeutically 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. In the case of treatment of cocaine abuse, a "therapeutically effective" amount of a compound can be the amount of compound which decreases an addicted individual's craving for cocaine. Typically, a "therapeutically effective amount" of the compound ranges from about l mg/day to about 1000 mg/day.
As used herein, 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.
W O 97J30977 PCTrUS97/02620 As used herein, an "aryl group 1l includes, for example, phenyl, substituted phenyl, heteroaryl (e.g. thienyl, furanyl, pyridinyl and benzothienyl) or substituted heteroaryl groups. Examples o~ suitable substituents on an aryl or heteroaryl group include -CN, -NO~, 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.
E~amples o~ suitable halogens include chlorine, bromine and fluorine.
Alkylene groups can be used to form a bridge between two ortho phenolic oxygens, e.g., R~ and R~ in Structures I-IV, taken together, can form an alkylene group.
Examples of suitable l'alkylene groups" include -~CH~ (CH--CH~)-, -(CHX)-, -(CXY)-, -(CHX-CH.)- and -(CHX-CHY)-, wherein X and Y are C1-C4 alkyl groups and are independently chosen. A preferred alkylene group is methylene.
'IProtecting 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 ~unctional group.
Examples of suitable phenol and alcohol protecting groups include t-butyl, methoxymethyl, 2-tetrahydropyranyl, 2~ O O
Il 11 2-tetrahydrofuranyl, -CO(lower alkyl), (lower alkyl)-O-C-, O O
Il 11 3G (lower alkyl) -NH-C-, -~O(aryl), silyl esters, (e.g.
triisopropylsilyl and t-butyldimethyl silyl), tri~luoracetate, 2-methoxyethoxy-methyl, siloxymethyl, benzyloxycarbonyl (BOC) and carboxycarbonyl (CBZ).
Suitable amine protecting groups include t-butyloxycarbonyl ~BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethoxycarbonyl (~-MOC), 2,2,2-trichloroethoxycarbonyl, 2-haloethoxy-W O 97/30977 PCT~US97/02620 carbonyl, benzoyl, phthalimidyl, diphenylphosphinyl and benzensulfonyl. Other suitable phenol, alcohol, amine and thiol protecting groups are given in Greene, "Protecting Groups in Organic Synthesis," John Wiley and Sons, Second 5~ Edition, (1991), and are within the scope of the present invention.
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 certaln desirable properties of the compound. For example, 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 15 : 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. For example, 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., ~. Pharm. Sci. 57 828 (1968), Dittert et 25 al., J. Pharm. Sci. 58:557 (1969) and Ratie et al., J.
Pharm. Sci . 59:1739 (1970) ) . Suitable, phenol protecting groups which can be removed in vivo to regenerate the o ~0 free phenol, include (cl-c8 alkyl)-CO-, (Cl-C8 alkyl)-O O
!l 11 O-C- and (Cl-C8 alkyl)-NH-C-. Also included is when the phenols are protected in the form a methylene dioxy group.
In addition, a variety of carbamate groups used to protect WO 97/30977 PCTrUS97/02620 amines are known to undergo spontaneous cleavage in solution at kinetically favorable rates (Saari, et al. J.
Med. Chem., 33:97 (1990)) and would thus be expected to degrade in vivo. Carbamates are also degraded enzymatically, (King, et al., Biochemistry, 26:2294 (1987)), particularly in blood (Tunek, et al., Biochemical Pharmacology, 37:3867 (1988)) to a~ford an unprotected amine. Suitable amine protecting groups which are ll removable in vivo include phenyl-O-C- and (C1-C6 alkyl substituted phenyl)-O-C- and (C1-C3 alkoxy substituted phenyl)-O-C-.
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). The form in which the compounds are administered will be determined by the route o~ 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, W 097/30977 PCT~US97/02620 for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual belng treated.
The compounds of the present invention used in the 5~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.
When the compounds of the present invention are used in combination with other pharmaceutically active agents, the specific combination will vary, depending on a number of factors, including, for example, activity of the agents, their side-effects, and the weight, age, sex and general health of the individual being treated.
The preparation of compounds of the present invention are shown in Schemes 1 and 2 and described more fully in Examples 2 and 3.
The invention is further illustrated by the following examples, which are not intended to be limiting in any way.
.xample 1 - ~.nergy Minimization Studies on Compounds 1 and 2 Energy minimization studies were performed on Compounds 1 and 2.
The energy minimized structures of 1 and 2 have been superimposed onto the energy minimized conformation of the W O 97/30977 PCTrUS97/02620 active enan~iomer of dihydrexidine (Knoerzer et al., J.
Med. Chem. 37:2453 (199~) ), as shown in Figures 1~ and lB.
Dihydrexidine is a known D1 selective agonist.
Compounds 1 and 2 present similar nonplanar pharmacophores with the amine group and phenyl rings placed in similar regions of three dimensional space, as in dihydrexidine and other D1 selective compounds (Froimowitz and Bellott, J. Mol . Model . 1:36 (1995)).
Calculations of the conformational flexibilities of 1 and 2 were performed and compared with that o~
dihydrexidine. These studies show that in dihydrexidine, one phenyl ring can be either above or below the plane of the other, due to close contacts between the phenyl rings (Fromowitz and Bellott, J. Mol. Model. 1:36 (1995)). Both conformers were energy minimized with the result that the con~ormer shown in Figures lA and lB is preferred by 1.5 kcal/mole. This is also the conformer observed in the crystal state of a dihydrexidine analog (Knoerzer et al.
1994).
These results also indicate that Compounds 1 and 2 have two possible con~ormations o~ the two-carbon link between the phenyl ~ings and that there is a substantial energy di~ference (3.4 kcal/mole for 2) between these two conformers. Compound 1, as with other nonplanar tricyclic structures, has additional flexibility in that the tricyclic structure can invert (Froimowitz and Ramsby, J.
Med. Chem. 34:1707 (1991)) and the preferred folding will be the one in which the side chain is pseudoequatorial. In addition, the amine-containing side chain can be conformationally trans to either phenyl ring and there is little energy dif~erence between these possibilitles due to the near symmetry o~ the molecule. Compound 2 is a less CA 02247468 l998-08-2l W O 97/30977 PCT~US97/02620 flexible analog o~ l and the ammonium hydrogens are similarly placed to those in dihydrexidine.
The monohydroxy analog of the D1 receptor agonist dihydrexidine is a partial D1 agonist (Seiler et al., J.
5 Med. Chem. 36:977 (1993)). In addition, the same modification to the catechol-containing partial agonist apomorphine produces a Dl antagonist (Schaus e t al J. Med .
C~em. 33:600 (1990). Thus, it is expected that the monohydroxy analog of 1 and 2 will result in a D1 partial agonist or antagonist.
Energy minimization of the compounds in this study were performed with respect to all internal coordinates using the MM2-87 program and parameter set of Allinger and Yuh, Quantum Chem. Program Exch. 12:program 395 (1980).
All calculations were performed for the protonated molecule. Initial Cartesian coordinates of the molecules were generated with PCMODEL pro~ram (Serena So~tware, Box 3076, Bloomington, IN 47402-3076) or the DRIVER option of the MM2-87 program. The dielectric constant was set to 80 and the hydrogen bonding terms involving the ammonium group were set to zero to approximate a water solution and to prevent intramolecular electrostatic ~orces from dominating the calculations in the absence o~ explicit water molecules ~Froimowitz, J. Comput . Chem. 14: 934 (1993) and Froimowitz 25 et al., J. Med. Chem. 36:2219 (1993)). To ensure complete convergence of the calculations, the convergence criteria was set to 1/8 o~ its default.
Fxam~le 2 - Synthesis of Compound 1 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 =
W 097/30977 PCT~US97/02620 (Weiss, Organic synthesis, Collective Volume II, page 61).
Catalytic reduction (Raney nickel/hydrogen) o~ the dimethoxybenzalphthalide 8 yields the phenethylbenzoic acid - 10. Cyclization o~ the phenethylbenzoic acid 10 with polyphosphoric acid yields the cycloheptadienone 12 (Winthrop et al., J. Org. Chem. 27:230 (1962)).
Condensation o~ the cycloheptadienone 12 with nitromethane yields the nitroalkane 14, which is catalytically hydrogenated to produce compound 16. Chiral resolution o~ the racemate is carried out by HP~C with a chiral column such as CHIRACEL OD (J.T. Baker) (Froimowitz et al ., Drug Design and Discovery 13 :73 (1g95) ) .
Demethylation o~ each enantiomer with BBr~ or HBr provides the ~inal optically pure product 1.
Alkyl groups are introduced onto the amine by reductive alkylation (Gribble et al., J. Am. Chem. Soc., 9 6 : 7 8 12 ( 1 9 74 ) ) .
mple ~- Synthesis of Compound 2 To prevent cyclization to the activated benzo ring, the aryl hydrogens o~ the activated benzo ring of the cycloheptadienone 12 are protected by electrophilic dibromination with Br. to give the cycloheptadienone 18.
The carbonyl group o~ 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 toliterature methods (~umber et al., J. ~eterocyclic Chem.
3:247 (1966)) to af~ord lactam 22. Reduction o~ lactam 22 with lithium aluminum hydride e~ects the reduction o~ the _ CA 02247468 l998-08-2l W 097/30977 PCTrUS97/02620 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 BBr7 or HBr to give 2.
~xample 4 - B;n~ing ~say for the D1 Receptor The binding assay for the D1 receptor utilizes homogenized rat striatal membrane preparations. An IC3~
curve is generated from 10 concentrations o~ the test compound (10-~ to 10-5 M) peri~ormed in duplicate using the LIGAND program for data analysis (Munson and Rodbard, Anal.
Biochem. 107:220 (1980)). Binding is assessed by filtering incubates on polyethylenimine-presoaked Whatman GF/B
~ilters and by scintillation counting (Billard et al., Life Sci. 3~:1885 (1984)). The radioactive ligand is H SCH-23390 at a concentration of O .3 nM and the bufi~er consists of 50 mM Tris-HCl (pH 7.4), 120 mM KCl, 2 mM CaCl- and 1 mM
MgCl7 (Billard et al., Life Sci. 35:1885 (1984)).
Incubation time is fifteen minutes at 37~C Non-speci~ic binding is de~ined with 1 ~M (+)-butaclamol.
~quivalents Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed by the ~ollowing claims.
Demethylation is then accomplished with BBr7 or HBr to give 2.
~xample 4 - B;n~ing ~say for the D1 Receptor The binding assay for the D1 receptor utilizes homogenized rat striatal membrane preparations. An IC3~
curve is generated from 10 concentrations o~ the test compound (10-~ to 10-5 M) peri~ormed in duplicate using the LIGAND program for data analysis (Munson and Rodbard, Anal.
Biochem. 107:220 (1980)). Binding is assessed by filtering incubates on polyethylenimine-presoaked Whatman GF/B
~ilters and by scintillation counting (Billard et al., Life Sci. 3~:1885 (1984)). The radioactive ligand is H SCH-23390 at a concentration of O .3 nM and the bufi~er consists of 50 mM Tris-HCl (pH 7.4), 120 mM KCl, 2 mM CaCl- and 1 mM
MgCl7 (Billard et al., Life Sci. 35:1885 (1984)).
Incubation time is fifteen minutes at 37~C Non-speci~ic binding is de~ined with 1 ~M (+)-butaclamol.
~quivalents Those skilled in the art will know, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed by the ~ollowing claims.
Claims (32)
1. A compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
2. The compound of Claim 1 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
3. The compound of Claim 1 wherein:
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
4. A compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
5. The compound of Claim 4 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H.
a) R1 and R2 are each -OH; and b) R3 is -H.
6. The compound of Claim 4 wherein:
a) R1 is -OH; and b) R2 and R3 are each -H.
a) R1 is -OH; and b) R2 and R3 are each -H.
7. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
8. The method of Claim 7 wherein:
a) R1 is -OH; and b) R2 and R3 are each -H.
a) R1 is -OH; and b) R2 and R3 are each -H.
9. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
10. The method of Claim 9 wherein:
a) R1 is -OH; and b) R2 and R3 are each -H.
a) R1 is -OH; and b) R2 and R3 are each -H.
11. A method of treating an individual with Parkinson's disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
12. The method of Claim 11 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H.
a) R1 and R2 are each -OH; and b) R3 is -H.
13. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
R3 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.
14. The method of Claim 13 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
15. A method of stimulating a D1 dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
16. A method of stimulating a D1 dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
17. A compound represented by the following structural formula:
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
18. The compound of Claim 17 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
19. The compound of Claim 17 wherein:
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
20. A compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R~, when R4 is an alkylene group;
and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R~, when R4 is an alkylene group;
and R3 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.
21. The compound of Claim 20 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H.
a) R1 and R2 are each -OH; and b) R3 is -H.
22. The compound of Claim 20 wherein:
a) R1 is -OH; and b) R2 and R3 are each -H.
a) R1 is -OH; and b) R2 and R3 are each -H.
23. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
24. The method of Claim 23 wherein:
a) R1 is -OH; and b) R2 and R3 are each -H.
a) R1 is -OH; and b) R2 and R3 are each -H.
25. A method of treating an individual who abuses cocaine, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group and a phenol protecting group;
R2 is selected from the group consisting of -H
and a halogen; and R3 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.
26. The method of Claim 25 wherein:
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
a) R1 is -OH;
b) R2 is -H; and c) R3 is -H or -CH3.
27. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group; and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group; and R3 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.
28. The method of Claim 27 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H.
a) R1 and R2 are each -OH; and b) R3 is -H.
29. A method of treating an individual with Parkinson's Disease comprising administering to the individual a therapeutically effective amount of a compound represented by the following structural formula:
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group; and R3 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.
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -OH
and -OR5, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group; and R3 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.
30. The method of Claim 29 wherein:
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
a) R1 and R2 are each -OH; and b) R3 is -H or -CH3.
31. A method of stimulating a D1 dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
wherein:
R1 is selected from the group consisting of -OH
and -OR4, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
32. A method of stimulating a D1 dopamine receptor in an individual, comprising administering to the individual a stimulatory amount of a compound represented by the following structural formula:
;
wherein:
R1 is selected from the group consisting of -OH
and -OR, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
;
wherein:
R1 is selected from the group consisting of -OH
and -OR, wherein R4 is selected from the group consisting of a lower alkyl group, an alkylene group and a phenol protecting group;
R2 is selected from the group consisting of -H, -OH, -OR5 and a halogen, wherein R5 is selected from the group consisting of a lower alkyl group, a phenol protecting group and R4, when R4 is an alkylene group;
and R3 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60639396A | 1996-02-23 | 1996-02-23 | |
| US08/606,393 | 1996-02-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2247468A1 true CA2247468A1 (en) | 1997-08-28 |
Family
ID=24427785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002247468A Abandoned CA2247468A1 (en) | 1996-02-23 | 1997-02-19 | Selective d1 dopamine receptor agonists and partial agonists/antagonists |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0883609A1 (en) |
| JP (1) | JP2000506832A (en) |
| AU (1) | AU2131697A (en) |
| CA (1) | CA2247468A1 (en) |
| WO (1) | WO1997030977A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03001272A (en) * | 2000-08-11 | 2004-04-02 | Purdue Research Foundation | Process for the preparation of dinapsoline. |
| RU2491067C2 (en) | 2007-08-06 | 2013-08-27 | Байотай Терапис, Инк | Method of treating addiction |
Family Cites Families (2)
| 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 (en) * | 1989-04-25 | 1990-11-01 | Northeastern University | Dopamine agonist compounds |
-
1997
- 1997-02-19 CA CA002247468A patent/CA2247468A1/en not_active Abandoned
- 1997-02-19 WO PCT/US1997/002620 patent/WO1997030977A1/en not_active Application Discontinuation
- 1997-02-19 AU AU21316/97A patent/AU2131697A/en not_active Abandoned
- 1997-02-19 JP JP9530301A patent/JP2000506832A/en active Pending
- 1997-02-19 EP EP97906688A patent/EP0883609A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997030977A1 (en) | 1997-08-28 |
| JP2000506832A (en) | 2000-06-06 |
| EP0883609A1 (en) | 1998-12-16 |
| AU2131697A (en) | 1997-09-10 |
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