WO1997030977A1 - 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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- WO1997030977A1 WO1997030977A1 PCT/US1997/002620 US9702620W WO9730977A1 WO 1997030977 A1 WO1997030977 A1 WO 1997030977A1 US 9702620 W US9702620 W US 9702620W WO 9730977 A1 WO9730977 A1 WO 9730977A1
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- Prior art keywords
- group
- lower alkyl
- alkyl group
- individual
- alkylene
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- 0 C*(CC(c1ccccc1CC1)c(cc2)c1c(*)c2P)N Chemical compound C*(CC(c1ccccc1CC1)c(cc2)c1c(*)c2P)N 0.000 description 3
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
- 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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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97906688A EP0883609A1 (en) | 1996-02-23 | 1997-02-19 | Selective d1 dopamine receptor agonists and partial agonists/antagonists |
AU21316/97A AU2131697A (en) | 1996-02-23 | 1997-02-19 | Selective D1 dopamine receptor agonists and partial agonists/antagonist |
JP9530301A JP2000506832A (en) | 1996-02-23 | 1997-02-19 | Selective D1 dopamine receptor agonists and partial agonists / antagonists |
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 |
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WO1997030977A1 true WO1997030977A1 (en) | 1997-08-28 |
Family
ID=24427785
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/002620 WO1997030977A1 (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) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1320367A1 (en) * | 2000-08-11 | 2003-06-25 | Purdue Research Foundation | Process for the preparation of dinapsoline |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2491067C2 (en) * | 2007-08-06 | 2013-08-27 | Байотай Терапис, Инк | Method of treating addiction |
Citations (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 WO PCT/US1997/002620 patent/WO1997030977A1/en not_active Application Discontinuation
- 1997-02-19 EP EP97906688A patent/EP0883609A1/en not_active Withdrawn
- 1997-02-19 CA CA002247468A patent/CA2247468A1/en not_active Abandoned
- 1997-02-19 AU AU21316/97A patent/AU2131697A/en not_active Abandoned
- 1997-02-19 JP JP9530301A patent/JP2000506832A/en active Pending
Patent Citations (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 |
Non-Patent Citations (2)
Title |
---|
DAVID L.LADD ET AL: "Synthesis and dopaminergic binding of 2-Aryldopamine analogues:Phenethylamines,3-Benzazepines,and 9-(aminomethyl)fluorenes", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 10, October 1986 (1986-10-01), WASHINGTON US, pages 1904 - 1912, XP002031848 * |
SCOTT E.SNYDER ET AL: "Synthesis and evaluation of 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine,6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4cd]azepine,and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene as conformationally restricted analogs of beta-phenyldopamine", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 13, June 1995 (1995-06-01), WASHINGTON US, pages 2395 - 2408, XP002031849 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1320367A1 (en) * | 2000-08-11 | 2003-06-25 | Purdue Research Foundation | Process for the preparation of dinapsoline |
EP1320367A4 (en) * | 2000-08-11 | 2007-01-17 | Purdue Research Foundation | Process for the preparation of dinapsoline |
Also Published As
Publication number | Publication date |
---|---|
CA2247468A1 (en) | 1997-08-28 |
EP0883609A1 (en) | 1998-12-16 |
JP2000506832A (en) | 2000-06-06 |
AU2131697A (en) | 1997-09-10 |
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