EP0550444A1 - Substituted naphthoxazines useful as dopaminergics - Google Patents

Substituted naphthoxazines useful as dopaminergics

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Publication number
EP0550444A1
EP0550444A1 EP91913320A EP91913320A EP0550444A1 EP 0550444 A1 EP0550444 A1 EP 0550444A1 EP 91913320 A EP91913320 A EP 91913320A EP 91913320 A EP91913320 A EP 91913320A EP 0550444 A1 EP0550444 A1 EP 0550444A1
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EP
European Patent Office
Prior art keywords
group
radicals
oxygen
carbon atoms
sulfur
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP91913320A
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German (de)
French (fr)
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EP0550444A4 (en
Inventor
Gevork Minaskanian
James V. Peck
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Whitby Research Inc
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Whitby Research Inc
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Publication of EP0550444A4 publication Critical patent/EP0550444A4/en
Publication of EP0550444A1 publication Critical patent/EP0550444A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings

Definitions

  • the invention relates generally to substituted naphthoxazines, processes for preparing such compounds, and their therapeutic use in treating disorders of the central nervous, cardiovascular and endocrine systems.
  • the compounds of the invention are also useful for alleviating glaucoma, par insonism, and schizophrenia, and for inducing weight loss in mammals.
  • 9-ol which is a potent dopamine D-2 agonist (however non-specific), showing high affinity at alpha-2 receptors.
  • R x and R 2 are selected from the group consisting of H and OA, wherein A is H, or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, for example lower alkyl radicals such as methyl, ethyl, propyl, etc.
  • R 5 is selected from the group consisting o hydrocarbyl radicals having between 1 and about 12, preferably between 1 and about 9, carbon atoms (and furthe provided that R l r R 2 and R 5 may be optionally substitute with one or more, e.g., two halogen atoms);
  • X is selecte from the group consisting of CH 2 , oxygen, sulfur, NH or NR 3 , wherein R 3 is a lower alkyl radical having from 1 to about carbon atoms;
  • R 4 is selected from the group consisting o
  • R 7 is selected from the group consisting of R 3 , OR 3 , 0C0R and H
  • Ar is selected from the group consisting o radicals represented by the following general formulae: wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acyla ino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl arid heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorous, and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from 1 to 2 and W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the provis
  • R*- ⁇ is H
  • R 2 is -OH
  • R 3 is propyl
  • R 4 is -(CH 2 ) n CH(R 7 )Ar.
  • the most preferred ring fusion is trans and R 4 is benzyl; i.e., n is O, R 7 is H, and Ar is phenyl. It has been found that trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro- 3-(phenylmethyl)-4-propyl-2H-naphth[l,2-b]-l, 4-oxazin-9-ol is especially preferred for its high affinity and selectivity for binding to dopamine D 2 receptors.
  • the compounds used in the present invention are selected from the group of stereoisomers or mixtures thereof of compounds having dopaminergic activity represented by th formula:
  • ⁇ and R 2 are selected from the group consisting o H and OA, wherein A is H, or is selected from the grou consisting of hydrocarbyl radicals having from 1 to about 1 carbon atoms for example, lower alkyl radicals such a methyl, ethyl, propyl, etc. or aromatic radicals such a benzyl, phenyl, etc., or A is -COR 5 , -CONHR 5 , or -COOR wherein R 5 is selected from the group consisting o hydrocarbyl radicals having between 1 and 12, preferabl between 1 and 9, carbon atoms (and further provided that R-_ R 2 and R 5 may be optionally substituted with one or more e.g.
  • X is selected from the grou consisting of CH 2 , oxygen, sulfur, NH or NR 3 , wherein R 3 i a lower alkyl radical having from 1 to about 4 carbon atoms
  • R 4 is selected from the group consisting of H, R 3 , COOR (wherein R 6 is H or R 3 ) , and -(CH 2 ) n -CH(R 7 )-Ar, wherei n is 0 or an integer of from 1 to about 4, R 7 is selecte from the group consisting of R 3 , OR 3 , OCOR 3 , and H, and Ar i selected from the group consisting of radicals represented b the following general formulae:
  • Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido,
  • tr ifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroato -substitutedhydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorous, and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, a is
  • R 4 0 or an integer of from 1 to 2 and W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z is two hydrogen radicals, then R 4 cannot be H.
  • R ⁇ is H and R 2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to about 12 carbon atoms, or A is -COR 5 , -CONHR 5 , or -COOR 5 , wherein R 5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body; for example methyl, t-butyl, phenyl, o-methylphenyl, o-chlorobenzyl, p-isopropylphenyl or o,p-dichlorophenyl.
  • R 3 is selected from the group consisting of methyl, ethyl and propyl.
  • X is O or S and most preferably X is 0.
  • Z is 0 or two hydroge radicals.
  • R is benzyl, phenethyl naphthylmethyl, naphthylethyl, 2-thienylmethyl
  • R 4 is benzyl, phenethyl or 2, dimethylpyrrolylethyl.
  • the preferred stereochemistry for ring fusion is trans
  • the most preferred substituten for R x is H
  • for R 2 is -OH
  • for R 3 is propyl
  • for R 4 i one of the aryl radicals set forth in the paragrap immediately above.
  • the alkaryl radicals are even mor preferred.
  • the most preferred substituent for R 4 is benzyl
  • tha trans-3, ,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl 2H-naphth[l,2-b]-l,4-oxazin-9-ol is especially preferred fo its high affinity and selectivity for binding to dopamine D receptors.
  • the compounds of the invention may exist as stereoisomer or mixtures thereof, having positive, negative or zer optical activity, and exhibit potent and selective dopamin receptor agonist activity when administered to mammals
  • these compounds are useful, as demonstrated by standar animal tests, for the treatment of disorders of the centra nervous system, especially those related to the dopaminergi systems.
  • the compounds of the invention may contain up to asymmetric carbon atoms. Three of these asymmetric carbo atoms are marked with asterisks (*) in the followin structural formula:
  • the remaining asymmetric carbon may be in the R radical.
  • the therapeutic properties of the compounds may to a greater or lesser degree be ascribed to any of the stereoisomers.
  • the pure enantiomers of the cis and trans forms, as well as mixtures thereof, are within the scope of the invention.
  • the invention also encompasses a method of preparation of the subject compounds and a method for inducing a dopaminergic response by administering the subject compounds to a patient.
  • the invention also provides pharmaceutical compositions comprising the foregoing compounds in combination with an inert pharmaceutical carrier.
  • compositions in dosage forms containing a clinically effective amount of one of the foregoing dopaminergic compounds are provided.
  • (Th R 8 H or represents an appropriate leaving group for th reaction, e.g., a hydrocarbyl radical having up to about 1 carbon atoms, such as a lower alkyl of up to about 5 carbo atoms or an aralkyl having up to about 10 carbon atoms, e.g., benzyl, and X' represents halogen, e.g., Cl, Br or I.)
  • the above reaction may be effected in a polar solvent e.g., acetone, in the presence of a suitable base, e.g. potassium carbonate. Conveniently, the reaction may tak place at reflux.
  • a suitable solvent e.g., a mixture o ethyl acetate and petroleum ether.
  • the above reaction may be effected by contacting II with an appropriate base in a polar solvent, e.g., tetrahydrofuran.
  • a polar solvent e.g., tetrahydrofuran.
  • the base is added to a solution of II in such polar solvent with stirring at a temperature of less than 0*C, e.g., -78*C, and the resulting reaction product recovered by raising the temperature of the reaction mixture to room temperature, quenching and extracting a crude reaction product for subsequent separation by flash chromatography, utilizing a silica gel column and a mixture of ethyl acetate and petroleum ether.
  • Compound III can also be prepared directly by reaction of compound I with an appropriately R 4 -substituted (alpha)-halogenated acetic acid derivative (ii) .
  • Reduction of Compound III with an appropriate reducing agent such as boron trifluoride etherate/lithium aluminum hydride, provides another series of the compounds of this invention wherein Z is two hydrogen radicals (see General Formula IV) .
  • This reduction may also be effected in a polar solvent, e.g., tetrahydrofuran, at a temperature of about 0°C and the resulting product recovered as discussed above.
  • aryl ether cleavage (not shown) , wherein R ⁇ . and/or R 2 is OA and A is a suitable leaving group (e.g., a lower alkyl group) , provides another of the series of novel compounds herein claimed wherein R*- ⁇ and/or R 2 is -OH.
  • Prodrug esters, ethers and carbamates are prepared by derivatization of the resultant phenols, resorcinols, or catechols in the conventional manner [see, e.g., Horn, et al., J. Med. Chem., 25_, 993 (1982), Thorberg, et al., J. Med. Chem., ___, 2008 (1987)].
  • prodrug ethers will result from isolation of the above-described intermediate (wherein R 1 or R 2 is not H) before aryl ether cleavage.
  • esters and acid addition salts of the compounds o the general formula are prepared in the conventional manner.
  • acid addition salts the salts derived from therapeutically acceptable acid (such as hydrochloric acid, acetic acid, propionic acid) and, more particularly, from a di- or poly- basic acid (such as phosphoric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, malic acid, and ascorbic acid) are suitable.
  • a preferred embodiment of this invention is a method of treatment which comprises the administration of a therapeutically effective amount of the compounds of the above formula.
  • the daily dose can be from 0.01 mg/kg to 10 mg/kg per day and preferably from 0.2 mg/kg to 4 mg/kg per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, metabolism, age and other factors which influence response to the drug.
  • compositions in dosage unit form which comprise from about 1 mg to about 150 mg of a compound of the above formula, and preferably from about 5 mg to about
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients may be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calciu phosphate; granulating and disintegrating agents, such a corn starch, or alginic acid; binding agents, for exampl starch, gelatin or acacia; and lubricating agents, such a magnesium stearate, stearic acid or talc.
  • the tablets may b uncoated or they may be coated by known techniques to dela disintegration and absorption in the gastrointestinal trac and thereby provide a sustained action over a longer period.
  • Formulations for oral use may also be presented as har gelatin capsules wherein the active ingredient is mixed wit an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsule wherein the active ingredient is mixed with an oil medium, for example, arachis oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, arachis oil, liquid paraffin or olive oil.
  • the present invention also comprehends aqueou suspensions containing the active compound in admixture wit suitable pharmacologically-acceptable excipients.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose hydroxypropylmethyl-cellulose, sodium alginate polyvinylpyrrolidone, gum tragacanth and gum acacia dispersing or wetting agents such as a naturally-occurrin phosphatides, for example, lecithin, or condensation product of an alkylene oxide with fatty acids, for example polyoxythylene stearate, or condensation products of ethylen oxide with long chain aliphatic alcohols, for example heptadecaethyl-eneoxycetanol, or condensation products o ethylene oxide with partial esters derived from fatty acid and a hexitol, for example, polyoxyethylene sorbito monooleate, or condensation product of ethylene oxide wit partial esters derived from fatty acids and hexito anhydrides, for example, polyoxyethylene sorbitan monooleate
  • the said aqueous suspensions may also contain one or more pre
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • a dispersing or wetting agent, suspending agent, and one or more preservatives are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, may also be present.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent,a preservative, and flavoring and coloring agents.
  • compositions may also be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous suspension.
  • This suspension may be formulated as is conventional using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in an non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • compositions may be tabulated or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably between 25 and
  • the dosage unit form for humans will generally contain between about 1 mg and about 100 mg of the active ingredient of the formula stated above.
  • compositions may also be in the form of topical preparations formulated to allow transdermal delivery of the active agent.
  • topical preparations formulated to allow transdermal delivery of the active agent.
  • These can include conventional preparations optionally employing penetration enhancers such as n-dodecylazacycloheptan-2-one or conventional polymeric delivery devices (e.g., patch devices).
  • compositions of this invention can be administered orally, topically or parenterally.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.
  • Example 2 can also be obtained directly by replacing ethyl bromoacetate in Example 1 with ethyl 2-bromohydrocinnamate.
  • Example 3 To the product of Example 3 was added an excess of pyridine hydrochloride and the mixture was heated to 200- 220 ⁇ C and monitored by TLC. Upon completion it was worked up and the crude reaction mixture was subjected to flash chromatography (Silica, 95:5 petroleum ether/EtOAc) and the isolated product showed characteristic peaks at: NMR (300 MHZ, CDC1 3 ) ⁇ 7.3-6.6 (8H,m) , 4.3 (lH,d) , 3.75 (lH,dd) , 3.5 (lH,dd), 3.15 (lH,dd), 0.85 (3H,t) .
  • Anal. Calc. for C 22 H 27 N0 2 -HC1 C, 70.71; H, 7.49; N, 3.75. Observed: C, 70.60; H, 7.46; N, 3.76.
  • Example 5 To test the selectivity and specificity of the present compounds for binding to dopamine receptors, tests were conducted using the following standard procedures.
  • the bovine caudate nuclei assay was employed. Bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mM Tris; 1 m Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4) using Brink an Polytron. The homogenate was centrifuged at 40,000 x g for 20 minutes and washed once. The pellet was resus pended in Buffer A, incubated at 37 ⁇ C for 15 minutes, the centrifuged.
  • Buffer A 50 mM Tris; 1 m Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4
  • the pellet was washed once more, resuspended t a protein concentration of 5-10 mg/ml in Buffer A and froze at -70 ⁇ C until used.
  • the rat cerebral cortex assay was employed. Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM MgCl 2 (pH 7.4), and centrifuged at 40,000 x g for 10 minutes.
  • the pellet was washed once, resuspended in Tris/MgCl 2 and incubated with 8 units/ml adenosine deaminase at 37*C for 30 minutes.
  • the homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70 ⁇ C until use.
  • radioligands were used as radioligands for each of the receptors tested: [ 3 H]-Spiperone 21-24 Ci/mmol for dopamine D 2 receptors, [ 3 H]-SCH23390 75-85 Ci/mmol for dopamine D-L receptors, and [ 3 H]-Para amino- clonidine 48-52 Ci/mmol for ⁇ 2 -adrenergic receptors.
  • the radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of time as follows: 75 minutes at room temperature for D 2 receptors, 15 minutes at 37 ⁇ C for D__ receptors, or 30 minutes at room temperature for ⁇ 2 receptors.
  • D 2 assays contained 30 nM ketaserin in order to block the binding of 3 H-spiperone to 5-HT 2 receptors.
  • the assays were terminated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1% polyethyleneimine, and the filters were washed three times by filtration of cold buffer. The filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a Beckman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980) . The results are presented as Ki values if the data were best fitted to a one-site model, or as KH and KL values if a two-site model produced the better fit.
  • This table shows the high dopamine D 2 receptor affinity of the compound of example 4 chosen from the examples above, with unexpectedly high degrees of selectivity and specifi ⁇ city.
  • the compound 2-(N-n-propyl-N-thienylethyl-amino)-5- hydroxytetralin, a potent dopamine D 2 agonist (U.S. Patent No. 4,564,628), is included as a reference compound for comparative purposes.

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Abstract

L'invention comprend les composés sélectionnés dans le groupe de composés représentés par la formule (1), dans laquelle R1 et R2 sont choisis dans le groupe composé de H et OA, dans lequel A représente H ou est choisi dans le groupe composé de radicaux hydrocarbyle contenant 1 à environ 12 atomes de carbone, ou A représente -COR5, -CONHR5, ou -COOR5, où R5 est choisi dans le groupe composé de radicaux hydrocarbyle contenant entre 1 et environ 12 atomes de carbone, R1, R2 et R5 étant facultativement remplacés par 1 ou plusieurs atomes d'halogène; X est choisi dans le groupe composé de CH2, oxygène, soufre, NH ou NR3, dans lequel R3 représente un radical alkyle inférieur contenant 1 à environ 4 atomes de carbone; R4 est choisi dans le groupe composé de H, R3, COOR6, et -(CH2)n2-CH(R7)-Ar, dans lequel R6 repréente H ou R3, n représente 0 ou un nombre entier compris entre 1 et environ 4, R7 est choisi dans le groupe composé de R3, OR3, OCOR3 et H, et Ar est choisi dans le groupe composé de radicaux représentés par les formules: (a), (b), (c), (d), (e), (f), (g), dans lesquelles Y est choisi dans le groupe composé de hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluorométhyle, sulfate, sulfonamido, halogène, hydrocarbyle et des radicaux hydrocarbyle à substitution d'hétéroatomes, lesdits hétéroatomes étant choisis dans le groupe composé d'halogène, azote, oxygène, soufre et phosphore, et lesdits radicaux hydrocarbyle comprennent de 1 à environ 12 atomes de carbone, a représente 0 ou un nombre entier choisi entre 1 et 2, W représente de l'oxygène, du soufre ou de l'azote et Z représente deux radicaux hydrogène, oxygène ou soufre, à condition que lorsque Z représente deux radicaux d'hydrogène alors R4 ne peut pas représenter H. Sont également décrites des compositions pharmaceutiques comprenant lesdits composés ainsi qu'un véhicule pharmaceutiquement acceptable. Lesdits composés et lesdites compositions présentent une efficacité afin de provoquer une réponse dopaminergique chez un sujet, par exemple,The invention includes compounds selected from the group of compounds represented by formula (1), wherein R1 and R2 are selected from the group consisting of H and OA, wherein A represents H or is selected from the group consisting of radicals hydrocarbyl containing 1 to about 12 carbon atoms, or A represents -COR5, -CONHR5, or -COOR5, where R5 is selected from the group consisting of hydrocarbyl radicals containing between 1 and about 12 carbon atoms, R1, R2 and R5 being optionally replaced by 1 or more halogen atoms; X is selected from the group consisting of CH2, oxygen, sulfur, NH or NR3, in which R3 represents a lower alkyl radical containing 1 to about 4 carbon atoms; R4 is chosen from the group consisting of H, R3, COOR6, and - (CH2) n2-CH (R7) -Ar, in which R6 represents H or R3, n represents 0 or an integer between 1 and approximately 4, R7 is selected from the group consisting of R3, OR3, OCOR3 and H, and Ar is selected from the group consisting of radicals represented by the formulas: (a), (b), (c), (d), (e) , (f), (g), in which Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hydrocarbyl substituted radicals heteroatoms, said heteroatoms being selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus, and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a represents 0 or an integer chosen from 1 and 2, W represents oxygen, sulfur or nitrogen and Z represents two hydrogen, oxygen or sulfur radicals, provided that when Z represents two radicals hydrogen then R4 cannot represent H. Also described are pharmaceutical compositions comprising said compounds as well as a pharmaceutically acceptable vehicle. Said compounds and said compositions are effective in causing a dopaminergic response in a subject, for example,

Description

SϋBSTITϋTED NAPHTHOXAZINES USEFUL AS DOPAMINBRGICS
BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates generally to substituted naphthoxazines, processes for preparing such compounds, and their therapeutic use in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of the invention are also useful for alleviating glaucoma, par insonism, and schizophrenia, and for inducing weight loss in mammals.
Background of the Art
Different approaches have been used in the discovery of dopamine agonists. Many compounds have been identified through chemical modification of naturally-occurring substances. One class of compounds that has resulted from this approach is the 9-oxaergolines. [See Anderson, et al., J. Med. Chem. ___, 363 (1983), Nedelec, et al., J. Med. Chem. ___, 522 (1983), Boissier, et al., Eur. J. Pharmacol., 82, 183 (1983).] Further chemical modification of this class resulted in the non-indolic hexahydronaphthoxazines. [See Jones, U.S.P. 4,420,480, Jones, et al., J. Med. Chem. 27, 1607 (1984), Horn, U.S.P. 4,540,691, Muenter, et al. Neurology .38., 1541 (1988), and Coleman, et al.. Movement Disorders 4. (2), 129 (1989).] One compound resulting from this work was trans-hexahydro-4-propyl-2H-naphth-l,4-oxazin-
9-ol, which is a potent dopamine D-2 agonist (however non-specific), showing high affinity at alpha-2 receptors.
There is continued interest in identifying compounds that are highly potent at the dopamine D-2 receptor, while displaying relatively low affinity at other receptors. The resultant pharmacologic specificity will improve therapy by minimizing side .effects.
SUMMARY OF THE INVENTION
There have now been discovered certain novel compounds displaying dopaminergic activity having the following general structural formula:
wherein Rx and R2 are selected from the group consisting of H and OA, wherein A is H, or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, for example lower alkyl radicals such as methyl, ethyl, propyl, etc. or aromatic radicals such a benzyl, phenyl, etc., or A is -COR5, -CONHR5, or -C00R5^ wherein R5 is selected from the group consisting o hydrocarbyl radicals having between 1 and about 12, preferably between 1 and about 9, carbon atoms (and furthe provided that Rl r R2 and R5 may be optionally substitute with one or more, e.g., two halogen atoms); X is selecte from the group consisting of CH2, oxygen, sulfur, NH or NR3, wherein R3 is a lower alkyl radical having from 1 to about carbon atoms; R4 is selected from the group consisting o
H, R 3/ COOR* (wherein R6 is H or R3) , an
-(CH2)n-CH(R7)-Ar, wherein n is 0 or an integer of from 1 t 4, R7 is selected from the group consisting of R3, OR3, 0C0R and H, and Ar is selected from the group consisting o radicals represented by the following general formulae: wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acyla ino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl arid heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorous, and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from 1 to 2 and W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z is two hydrogen radicals, then R4 cannot be H.
One of the more preferred substitutents for R*-^ is H, for R2 is -OH, for R3 is propyl, and for R4 is -(CH2)nCH(R7)Ar. The most preferred ring fusion is trans and R4 is benzyl; i.e., n is O, R7 is H, and Ar is phenyl. It has been found that trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro- 3-(phenylmethyl)-4-propyl-2H-naphth[l,2-b]-l, 4-oxazin-9-ol is especially preferred for its high affinity and selectivity for binding to dopamine D2 receptors.
DETAILED DESCRIPTION OF THE INVENTION
The compounds used in the present invention are selected from the group of stereoisomers or mixtures thereof of compounds having dopaminergic activity represented by th formula:
wherein ^ and R2 are selected from the group consisting o H and OA, wherein A is H, or is selected from the grou consisting of hydrocarbyl radicals having from 1 to about 1 carbon atoms for example, lower alkyl radicals such a methyl, ethyl, propyl, etc. or aromatic radicals such a benzyl, phenyl, etc., or A is -COR5, -CONHR5, or -COOR wherein R5 is selected from the group consisting o hydrocarbyl radicals having between 1 and 12, preferabl between 1 and 9, carbon atoms (and further provided that R-_ R2 and R5 may be optionally substituted with one or more e.g. , two halogen atoms) ; X is selected from the grou consisting of CH2, oxygen, sulfur, NH or NR3, wherein R3 i a lower alkyl radical having from 1 to about 4 carbon atoms R4 is selected from the group consisting of H, R3, COOR (wherein R6 is H or R3) , and -(CH2)n-CH(R7)-Ar, wherei n is 0 or an integer of from 1 to about 4, R7 is selecte from the group consisting of R3, OR3, OCOR3, and H, and Ar i selected from the group consisting of radicals represented b the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido,
'tr'ifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroato -substitutedhydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorous, and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, a is
0 or an integer of from 1 to 2 and W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z is two hydrogen radicals, then R4 cannot be H.
Preferably, Rχ is H and R2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to about 12 carbon atoms, or A is -COR5, -CONHR5, or -COOR5, wherein R5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body; for example methyl, t-butyl, phenyl, o-methylphenyl, o-chlorobenzyl, p-isopropylphenyl or o,p-dichlorophenyl.
Preferably R3 is selected from the group consisting of methyl, ethyl and propyl. Preferably X is O or S and most preferably X is 0. Preferably Z is 0 or two hydroge radicals.
The more preferred groups for R are benzyl, phenethyl naphthylmethyl, naphthylethyl, 2-thienylmethyl
2-thienylethyl and 2,5-dimethylpyrrolylethyl, and even mor preferably, R4 is benzyl, phenethyl or 2, dimethylpyrrolylethyl.
The preferred stereochemistry for ring fusion is trans In the trans conformation, the most preferred substituten for Rx is H, for R2 is -OH, for R3 is propyl, and for R4 i one of the aryl radicals set forth in the paragrap immediately above. (The alkaryl radicals are even mor preferred.) The most preferred substituent for R4 is benzyl In particular, it has been found tha trans-3, ,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl 2H-naphth[l,2-b]-l,4-oxazin-9-ol is especially preferred fo its high affinity and selectivity for binding to dopamine D receptors.
The compounds of the invention may exist as stereoisomer or mixtures thereof, having positive, negative or zer optical activity, and exhibit potent and selective dopamin receptor agonist activity when administered to mammals Thus, these compounds are useful, as demonstrated by standar animal tests, for the treatment of disorders of the centra nervous system, especially those related to the dopaminergi systems.
Particularly preferred compounds are as follows:
trans-3,4,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl 2H-naphth [l,2-b]-l,4-oxazin-9-ol trans-3 , 4 , 4a , 5 , 6 , 10b-hexahydro-3- [ ( 2 , 6-dimethylphenyl ) methy 1 ] -4-propyl-2H-naphth[ 1 , 2-b] -1 , 4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- [ (3 , 5-dimethylphenyl) methy l]-4-propyl-2H-naphth[l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- (phenylethyl ) -4-propyl- 2H-naphth [ 1 , 2-b] -1, 4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- (2 , 5-dimethylpyrrolylraethy l)-4-propyl-2H-naphth[l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 , 4a , 5 , 6 , 10b-hexahydro-3 - (2 , 5-dimethylpyrrolylethyl ) - 4-propyl-2H-naphth[l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-9-methoxy-4-propyl-2H-naphth [ 1 , 2-b] -1 , 4-oxazin-2-one
trans-3 , 4 , 4a , 5 , 6 , 10b-hexahydro-4-propyl-2H-naphth [ 1 , 2-b] -l , 4- oxazin-9-ol-2-one
trans-3 , 4 , 4a , 5 , 6 , 10b-hexahydro-9-methoxy-3- (phenylmethyl ) - 4-propyl-2H-naphth [ 1 , 2-b] -1 , 4-oxazin-2-one
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- (phenylmethyl) -4 -propyl - 2H-naphth [l,2-b]-l,4-oxazin-9-ol-2-one
trans-3 , 4 , 4a, 5, 6 , 10b-hexahydro-3- (methyl) -4 -propyl-2H-naphth [l,2-b]-l,4-oxazin-9-ol-2-one
trans-3 , 4 , 4a , 5 , 6 , 10b-hexahydro-3- (ethyl ) -4-propyl-2H-naphth [ 1 , 2-b] -1 , 4-oxazin-9-ol-2-one
trans-3,4,4a,5, 6, 10b-hexahydro-3- (phenylethyl) -4 -propyl - 2H-naphth [l,2-b]-l,4-oxazin-9-ol-2-one trans-3 , 4 , 4a, 5, 6, lOb-hexahydro-3- (methyl) -4-propyl-2H-napht [l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- (ethyl) -4-propyl-2H-napht [l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , lOb-hexahydro-3- (2-thienylmethyl) -4 -propyl 2H-naphth [ 1 , 2-b] -1 , 4-oxazin-9-ol
trans-3 , 4 , 4a, 5, 6 , 10b-hexahydro-3- (2-thienylethyl) -4-propyl 2H-naphth[l,2-b]-l,4-oxazin-9-ol
trans-3 , 4 ,4a, 5,6, 10b-hexahydro-3 (2-methoxyphenylethyl) 4-propyl-2H-naphth [ 1 , 2-b] -1 , 4-oxazin-9-ol
trans-3 , 4 , 4a, 5 , 6 , 10b-hexahydro-3- (carboxy) -4-propyl-2H-napht [ 1 , 2-b] -1 , 4-oxazin-9-ol
trans-3,4, 4a, 5,6,10b-hexahydro-3-(carbethoxy) -4-propyl 2H-naphth [l,2-b]-l,4-oxazin-9-ol
trans-3,4,4a,5,6,10b-hexahydro-3-(carbobenzyloxy)-4-propyl 2H-naphth[1,2-b]-1,4-oxazin-9-ol
trans-3,4,4a,5,6,10b-hexahydro-3-(naphthylmethyl)-4-propyl 2H-naphth[1,2-b]-1,4-oxazin-9-ol
The compounds of the invention may contain up to asymmetric carbon atoms. Three of these asymmetric carbo atoms are marked with asterisks (*) in the followin structural formula:
The remaining asymmetric carbon may be in the R radical. The therapeutic properties of the compounds may to a greater or lesser degree be ascribed to any of the stereoisomers. Thus, the pure enantiomers of the cis and trans forms, as well as mixtures thereof, are within the scope of the invention.
The invention also encompasses a method of preparation of the subject compounds and a method for inducing a dopaminergic response by administering the subject compounds to a patient.
The invention also provides pharmaceutical compositions comprising the foregoing compounds in combination with an inert pharmaceutical carrier.
In still another embodiment of the present invention, there are provided pharmaceutical compositions in dosage forms containing a clinically effective amount of one of the foregoing dopaminergic compounds.
The process for preparing the novel compounds of the present invention may be represented by the general method outlined below: GENERAL SYNTHETIC METHOD
The 1,2,3,4-tetrahydro-2-alkylamino-l-naphthalenol (Compound I) are known [see Jones, et al., J. Med. Chem., 27. 1607 (1984)]. The preparation of the novel compounds of thi invention is shown in the general reaction scheme shown belo wherein R1# R2, R3 and R are as defined above, X i illustrated by O and Z is illustrated by O (II and III) o two hydrogen radicals (IV) . The reaction of Compound I wit an appropriate (alpha)-halogenated acetic acid derivativ (i) provides a substituted naphthoxazine (Compound II) in on step, without isolation of the intermediate compound. (Th R8 = H or represents an appropriate leaving group for th reaction, e.g., a hydrocarbyl radical having up to about 1 carbon atoms, such as a lower alkyl of up to about 5 carbo atoms or an aralkyl having up to about 10 carbon atoms, e.g., benzyl, and X' represents halogen, e.g., Cl, Br or I.)
The above reaction may be effected in a polar solvent e.g., acetone, in the presence of a suitable base, e.g. potassium carbonate. Conveniently, the reaction may tak place at reflux. The resulting reaction product (II) may b recovered by filtering, concentrating the filtrate an recrystallization from a suitable solvent, e.g., a mixture o ethyl acetate and petroleum ether.
Alkylation of the resultant novel naphthoxazine Compoun II using a strong base (e.g., lithium diisopropyl amide) wit an appropriate alkylating agent R4X* ' , wherein R4 is no hydrogen and X1 * is a suitable halogen leaving group, e.g. Cl, Br or I) results in a substituted naphthoxazine (Compound III) .
The above reaction may be effected by contacting II with an appropriate base in a polar solvent, e.g., tetrahydrofuran. Conveniently, the base is added to a solution of II in such polar solvent with stirring at a temperature of less than 0*C, e.g., -78*C, and the resulting reaction product recovered by raising the temperature of the reaction mixture to room temperature, quenching and extracting a crude reaction product for subsequent separation by flash chromatography, utilizing a silica gel column and a mixture of ethyl acetate and petroleum ether.
Compound III can also be prepared directly by reaction of compound I with an appropriately R4-substituted (alpha)-halogenated acetic acid derivative (ii) .
Reduction of Compound III with an appropriate reducing agent, such as boron trifluoride etherate/lithium aluminum hydride, provides another series of the compounds of this invention wherein Z is two hydrogen radicals (see General Formula IV) . This reduction may also be effected in a polar solvent, e.g., tetrahydrofuran, at a temperature of about 0°C and the resulting product recovered as discussed above. Furthermore, aryl ether cleavage (not shown) , wherein R^. and/or R2 is OA and A is a suitable leaving group (e.g., a lower alkyl group) , provides another of the series of novel compounds herein claimed wherein R*-^ and/or R2 is -OH.
Prodrug esters, ethers and carbamates (wherein Rx and/or R2 is OA and A is -COR5, a hydrocarbyl radical or C0NHR5, respectively) are prepared by derivatization of the resultant phenols, resorcinols, or catechols in the conventional manner [see, e.g., Horn, et al., J. Med. Chem., 25_, 993 (1982), Thorberg, et al., J. Med. Chem., ___, 2008 (1987)]. Alternatively, prodrug ethers will result from isolation of the above-described intermediate (wherein R1 or R2 is not H) before aryl ether cleavage. Furthermore, by starting with the thiols corresponding to the above-mentioned l,2,3,4-tetrahydro-2-alkylamino-l-naphthalenols, the compounds of this invention (wherein X is sulfur) ar prepared by the above synthetic method.
PHARMACEUTICAL FORMULATION
The esters and acid addition salts of the compounds o the general formula are prepared in the conventional manner. As acid addition salts, the salts derived from therapeutically acceptable acid (such as hydrochloric acid, acetic acid, propionic acid) and, more particularly, from a di- or poly- basic acid (such as phosphoric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, malic acid, and ascorbic acid) are suitable.
A preferred embodiment of this invention is a method of treatment which comprises the administration of a therapeutically effective amount of the compounds of the above formula. In general the daily dose can be from 0.01 mg/kg to 10 mg/kg per day and preferably from 0.2 mg/kg to 4 mg/kg per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, metabolism, age and other factors which influence response to the drug.
In another embodiment of this invention there are provided pharmaceutical compositions in dosage unit form which comprise from about 1 mg to about 150 mg of a compound of the above formula, and preferably from about 5 mg to about
100 mg.
The pharmaceutical composition may be in any form suitable for oral use, such as tablets, aqueous or oily suspensions, dispersible powders or granules emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calciu phosphate; granulating and disintegrating agents, such a corn starch, or alginic acid; binding agents, for exampl starch, gelatin or acacia; and lubricating agents, such a magnesium stearate, stearic acid or talc. The tablets may b uncoated or they may be coated by known techniques to dela disintegration and absorption in the gastrointestinal trac and thereby provide a sustained action over a longer period.
Formulations for oral use may also be presented as har gelatin capsules wherein the active ingredient is mixed wit an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsule wherein the active ingredient is mixed with an oil medium, for example, arachis oil, liquid paraffin or olive oil.
The present invention also comprehends aqueou suspensions containing the active compound in admixture wit suitable pharmacologically-acceptable excipients.
Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose hydroxypropylmethyl-cellulose, sodium alginate polyvinylpyrrolidone, gum tragacanth and gum acacia dispersing or wetting agents such as a naturally-occurrin phosphatides, for example, lecithin, or condensation product of an alkylene oxide with fatty acids, for example polyoxythylene stearate, or condensation products of ethylen oxide with long chain aliphatic alcohols, for example heptadecaethyl-eneoxycetanol, or condensation products o ethylene oxide with partial esters derived from fatty acid and a hexitol, for example, polyoxyethylene sorbito monooleate, or condensation product of ethylene oxide wit partial esters derived from fatty acids and hexito anhydrides, for example, polyoxyethylene sorbitan monooleate The said aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one and more sweetening agents, such as sucrose, saccharin, aspartame, mannitol, sorbitol, or sodium or calcium cyclamate.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, may also be present.
Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent,a preservative, and flavoring and coloring agents.
The pharmaceutical compositions may also be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous suspension. This suspension may be formulated as is conventional using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in an non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
The pharmaceutical compositions may be tabulated or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably between 25 and
85 parts by weight of the active ingredient. The dosage unit form for humans will generally contain between about 1 mg and about 100 mg of the active ingredient of the formula stated above.
The pharmaceutical compositions may also be in the form of topical preparations formulated to allow transdermal delivery of the active agent. These can include conventional preparations optionally employing penetration enhancers such as n-dodecylazacycloheptan-2-one or conventional polymeric delivery devices (e.g., patch devices).
From the foregoing formulation discussion it is apparent that the compositions of this invention can be administered orally, topically or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.
Details of the synthesis, together with modifications and variations specifically tailored for particular compounds, are set out more fully in the specific examples which follow.
Example l Preparation of (±)-trans-3,4,4a,5,6-10b-hexahydro-9- methoxy-4-propyl-2H-napth [1,2-b]-1,4-oxazin-2-one.
To a solution of 5.0 g of l,2,3,4-tetrahydro-7-methoxy 2-(propylamino)-l-naphthalenol [prepared according to J. Med. Chem., 2 , 1607, (1984)] and 2.4 mL ethyl bromoacetate i acetone was added an excess of potassium carbonate. Th reaction mixture was refluxed and monitored by thin laye chromatography (TLC) . After completion, it was filtered, concentrated, and the product was isolated by crystallizatio from a solution of ethylacetate and petroleum ethe (EtOAc/ether) as a white solid: characteristic peaks at: NMR (300 MHZ, CDC13) δ 7.1-6.8 (3H,m) , 5.25 (lH,d) , 3.9 (lH,d), 3.8 (3H,s), 3.2 (lH,d) , 0.9 (3H,t) . Anal. Calc. for C16H21N03: C, 69.79; H, 7.69; N, 5.09. Observed: C, 69.87; H, 7.71; N, 5.07.
Example 2 Preparation of (±)-trans-3,4,4a,5,6,10b-hexahydo- 9-methoxy-3-(phenylmethyl)-4-propyl-2H-naphth[l,2-b]-1,4- oxazin-2-one.
To a stirred solution of 1.1 mL lithium diisopropylamide
(1.5 M in cyclohexane) at -78*C was added a tetrahydrofuran
(THF) solution of 0.5 g of the product of Example 1. After stirring for 30 minutes at that temperature, 0.24 L of benzyl bromide was added followed by additional stirring for one hour. It was brought to room temperature, quenched, and after extraction, the crude mixture was subjected to flash chromatography (Silica, 9:1 petroleum ether/EtOAc) . The isolated product showed characteristic peaks at: NMR (300 MHZ, CDC13) δ 7.3 (5H,m) , 7.0-6.7 (3H,m) , 4.35 (lH,d) , 3.9
(lH,dd), 3.8 (3H,s), 3.1 (2H,m) , 0.9 (3H,t) . Anal. Calc. for
C23H27N03: C, 75.63; H, 7.39; N, 3.84. Observed: C, 75.43;
H, 7.51; N, 3.85. The product of Example 2 can also be obtained directly by replacing ethyl bromoacetate in Example 1 with ethyl 2-bromohydrocinnamate.
Example 3 Preparation of (±)-trans-3,4,4a,5,6,10b-hexahydro- 9-methoxy-3 - ( phenylmethyl ) -4 -propyl - 2H-naphth[l,2-b]-l,4-oxazine.
To a stirring suspension of 180 mg lithium aluminum hydride in 50 mL ether at 0βC was added a mixture of 200 mg of the product of Example 2 and 2.2 mL boron trifluoride etherate in THF. After 45 minutes at 0°C, the above was refluxed for 4 hours. After workup and purification (Silica, 9:1 petroleum ether/EtOAc) the desired product was isolated and showed characteristic peaks at: NMR (300MHz, CDC13) δ 7.3-6.7 (8H,m), 4.3 (lH,d) , 3.8 (lH,dd) , 3.75 (3H,s), 3.5 (lH,dd), 3.15 (lH,dd), 0.85 (3H,t) .
Example 4 Preparation of (±)-trans-3,4,4a,5,6,10b-hexahydro- 3-(phenylmethyl)-4-propyl-2H-naphth[1,2-b]-1,4-oxazin-9-ol.
To the product of Example 3 was added an excess of pyridine hydrochloride and the mixture was heated to 200- 220βC and monitored by TLC. Upon completion it was worked up and the crude reaction mixture was subjected to flash chromatography (Silica, 95:5 petroleum ether/EtOAc) and the isolated product showed characteristic peaks at: NMR (300 MHZ, CDC13) δ 7.3-6.6 (8H,m) , 4.3 (lH,d) , 3.75 (lH,dd) , 3.5 (lH,dd), 3.15 (lH,dd), 0.85 (3H,t) . Anal. Calc. for C22H27N02-HC1: C, 70.71; H, 7.49; N, 3.75. Observed: C, 70.60; H, 7.46; N, 3.76.
Example 5 To test the selectivity and specificity of the present compounds for binding to dopamine receptors, tests were conducted using the following standard procedures.
To test binding to dopamine receptors, the bovine caudate nuclei assay was employed. Bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mM Tris; 1 m Na2-EDTA; 5 mM KCl; 1 mM MgCl2; 2 mM CaCl2; pH 7.4) using Brink an Polytron. The homogenate was centrifuged at 40,000 x g for 20 minutes and washed once. The pellet was resus pended in Buffer A, incubated at 37βC for 15 minutes, the centrifuged. The pellet was washed once more, resuspended t a protein concentration of 5-10 mg/ml in Buffer A and froze at -70βC until used. To test binding of the compounds to c_2-adrenergic receptors, the rat cerebral cortex assay was employed. Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM MgCl2 (pH 7.4), and centrifuged at 40,000 x g for 10 minutes. The pellet was washed once, resuspended in Tris/MgCl2 and incubated with 8 units/ml adenosine deaminase at 37*C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70βC until use.
The following tritiated drugs were used as radioligands for each of the receptors tested: [3H]-Spiperone 21-24 Ci/mmol for dopamine D2 receptors, [3H]-SCH23390 75-85 Ci/mmol for dopamine D-L receptors, and [3H]-Para amino- clonidine 48-52 Ci/mmol for α2-adrenergic receptors. The radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of time as follows: 75 minutes at room temperature for D2 receptors, 15 minutes at 37βC for D__ receptors, or 30 minutes at room temperature for α2 receptors. Specific binding was defined using lμM butaclamol (D2) , 1 μM SCH23390 (D ) , or 1 μM yohimbine (α2) . In addition the D2 assays contained 30 nM ketaserin in order to block the binding of 3H-spiperone to 5-HT2 receptors.
The assays were terminated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1% polyethyleneimine, and the filters were washed three times by filtration of cold buffer. The filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a Beckman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980) . The results are presented as Ki values if the data were best fitted to a one-site model, or as KH and KL values if a two-site model produced the better fit.
Results of the binding tests are summarized in Table 1 below:
Table 1 RECEPTOR AFFINITIES (Ki, nM)
This table shows the high dopamine D2 receptor affinity of the compound of example 4 chosen from the examples above, with unexpectedly high degrees of selectivity and specifi¬ city. The compound 2-(N-n-propyl-N-thienylethyl-amino)-5- hydroxytetralin, a potent dopamine D2 agonist (U.S. Patent No. 4,564,628), is included as a reference compound for comparative purposes.
There is currently much interest in the utility of dopaminergic agonists selective for the D2 receptor, as abnormalities with this receptor function are thought to be involved in disease states. It is desirable to minimize the effects of these compounds on O and α2 receptors in order to lessen side effects (e.g., cardiovascular) seen with these drugs.
While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto since many obvious modifications can be made, and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims.

Claims

Having now described the invention, we claim:
1. The compounds selected from the group o stereoisomers or mixtures thereof of compounds represented b the formula:
wherein Rr_ and R2 are selected from the group consisting of H and OA, wherein A is H or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, or A is -COR5, -CONHR5, or -COOR5, wherein R5 is selected from the group consisting of hydrocarbyl radicals having between 1 and about 12 carbon atoms and wherein R , R2 and R5 are optionally substituted with one or more halogen atoms; X is selected from the group consisting of CH2, oxygen, sulfur, NH or NR3, wherein R3 is a lower alkyl radical having from 1 to about 4 carbon atoms; R4 is selected from the group consisting of H, R3, COOR6, and -(CH2)n2- CH(R7)-Ar, wherein R6 is H or R3, n is 0 or an integer of from 1 to about 4, R7 is selected from the group consisting of R3, OR3, OCOR3 and H, and Ar is selected from the group consisting of radicals represented by the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, tri luoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur, and phosphorous and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from l to 2, W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z represents 2 hydrogen radicals, then R4 cannot be H.
2. The compound of claim 1, wherein R_^ is H; R2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals, or A is -C0R5 -CONHR5 or -COOR5, wherein R5 is selected from the group consisting of methyl, t-butyl, phenyl, o-methylphenyl , o-chlorobenzyl, p-isopropyl- phenyl and o,p-dichlorophenyl; R3 is methyl, ethyl, or propyl; X is O or S; Z is oxygen or two hydrogen radicals and R4 is selected from the group consisting of benzyl, phen¬ ethyl, naphthylmethyl, naphthylethyl, 2-thienylmethyl, 2-thienylethyl, and 2,5 dimethylpyrrolylethyl.
3. The compound of claim 2 wherein X is oxygen.
4. The compound of claim 3, wherein R4 is selected fro the group consisting of benzyl, phenethyl, an 2,5 dimethylpyrrolylethyl.
5. The compound of claim 4, wherein R3 is propyl.
6. The compound of claim 5, wherein χ is H and R2 i OH.
7. The compound of claim 6, wherein R2 is situated o the C9 position of the ring system.
8. The compound of claim 5, wherein the ring fusion is trans.
9. The compound of claim 8, wherein R4 is benzyl.
10. trans-3,4,4a,5,6,10b-hexahydro-3-(phenylmethyl)- 4-propyl-2H-naphth[l,2-b]-l,4-oxazin-9-ol, or a pharmaceu¬ tically acceptable salt thereof.
11. A pharmaceutical composition, comprising, as an active ingredient, one or more of the compounds selected from the group of stereoisomers of mixtures thereof of compounds having dopaminergic activity represented by the formula:
with positive, negative, or zero optical activity, wherein R2 and R2 are independently selected from H and OA, wherein A is H or is selected from the group consisting of hydrocarbyl radicals having from about 1 to 12 carbon atoms, or A is -COR5, -CONHR5, and -COOR5, wherein R5 is selected from the group consisting of hydrocarbyl radicals having between 1 and about 12 carbon atoms and wherein R , R2 , and R5 are option¬ ally substituted with one or more halogen atoms; X is selected from the group consisting of CH2, oxygen, sulfur, NH or NR3; R3 is lower alkyl radical having from 1 to about 4 carbon atoms; R4 is selected from the group consisting of H, R3, COOR6, wherein R6 is H or R3, and -(CH2)n-CH(R7)-Ar, wherein n is 0 or an integer of from 1 to about 4, R7 is selected from the group consisting of R3, 0R3, 0C0R3, and H; Ar is selected from the group consisting of radicals repre¬ sented by the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substitutedhydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur, and phosphorous and said hydrocarbyl radicals comprise from 1 to about .12 carbon atoms, a is 0 or an integer of from 1 to 2, W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the provision that when Z represents 2 hydrogen radicals, then R4 cannot be H, and a suitable inert pharmaceutically acceptable vehicle.
12. The composition of claim 11, wherein R is H; R2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals, or A is -COR5 -CONHR5 or -COOR5, wherein R5 is selected from the group consisting of methyl, t-butyl, phenyl, o-methylphenyl, o-chlorobenzyl, p-isopropylphenyl and o,p-dichlorophenyl; R3 is methyl, ethyl, or propyl; X is O or S; Z is oxygen or two hydrogen radicals and R4 is selected from the group consisting of benzyl, phenethyl, naphthylmethyl, naphthylethyl, 2-thienyl- methyl, 2-thienylethyl, and 2,5 dimethylpyrrolylethyl.
13. The composition of claim 12 wherein X is oxygen.
14. The composition of claim 13, wherein R4 is selected from the group consisting of benzyl, phenethyl, and 2,5 dimethylpyrrolylethyl.
15. The composition of claim 14, wherein R3 is propyl.
16. The composition of claim 15, wherein Rλ is H and R2 is OH.
17. The composition of claim 16, wherein R2 is situated on the C9 position of the ring system.
18. The composition of claim 15, wherein the ring fusion is trans.
19. The compound of claim 18, wherein R4 is benzyl.
20. The composition of claim 11 wherein said compound istrans-3,4,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl- 2H-naphth[l,2-b]-l,4-oxazin-9-ol, or a pharmaceutically acceptable salt thereof.
21. A method for inducing a dopaminergic response comprising the step of administering to a patient an effective amount of one or more of the compounds selected from the group of stereoisomers or mixtures thereof of compounds having dopaminergic activity represented by the formula:
with positive,negative, or zero optical activity, wherein R2 and R2 are selected from the group consisting of H and OA, wherein A is H or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, or A is -C0R5, -CONHR5, or -C00R5, wherein R5 is selected from the group consisting of hydrocarbyl radicals having between 1 and about 12 carbon atoms and wherein Rl r R2 and R5 are optionally substituted with one or more halogen atoms; X is selected from the group consisting of CH2, oxygen, sulfur, NH or NR3, wherein R3 is a lower alkyl radical having from 1 to about 4 carbon atoms; R4 is selected from the group consisting of H, R3, C00R6, and -(CH2)n2-CH(R7)-Ar, wherein R6 is H or R3, n is 0 or an integer of from 1 to about 4, R7 is selected from the group consisting of R3, OR3, 0C0R3 and H, and Ar is selected from the group consisting of radicals represented by the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoro ethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur, and phosphorous and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from 1 to 2, W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z represents 2 hydrogen radicals, then R cannot be H.
22. The method of claim 21, wherein R2 is H; R2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals, or A is -COR5f -CONHR5 or -COOR5, wherein R5 is selected from the group consisting of methyl, t-butyl, phenyl, o-methylphenyl, o-chlorobenzyl, p-isopropylphenyl and o,p-dichlorophenyl; R3 is methyl, ethyl, or propyl; X is O or S; Z is oxygen or two hydrogen radicals and R4 is selected from the group consisting of benzyl, phenethyl, naphthylmethyl, naphthylethyl, 2-thienyl- methyl, 2-thienylethyl, and 2,5 dimethylpyrrolylethyl.
23. The method of claim 22 wherein X is oxygen.
24. The method of claim 23, wherein R4 is selected from the group consisting of benzyl, phenethyl, and 2,5 dimethyl¬ pyrrolylethyl.
25. The method of claim 24, wherein R3 is propyl.
26. The method of claim 25, wherein is H and R2 is OH.
27. The method of claim 26, wherein R2 is situated on the C9 position of the ring system.
28. The method of claim 25, wherein the ring fusion is trans.
29. The method of claim 28, wherein R4 is benzyl.
30. The method of claim 21 wherein said compound is trans-3,4,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl-2H- naphth [l,2-b]-l,4-oxazin-9-ol, or a pharmaceutically acceptable salt thereof.
31. A method for alleviating glaucoma, parkinsonism, schizophrenia, or inducing weight loss in mammals, including humans which comprises the step of administering to said mammals an effective amount of one or more of the compounds selected from the group of stereoisomers or mixtures thereof of compounds represented by the formula:
wherein R__ and R2 are selected from the group consisting of H and OA, wherein A is H or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, or A is -C0R5, -C0NHR5, or -C00R5, wherein R5 is selected from the group consisting of hydrocarbyl radicals having between 1 and about 12 carbon atoms and wherein Rl t R2 and R5 are optionally substituted with one or more halogen atoms; X is selected from the group consisting of CH2, oxygen, sulfur, NH or NR3, wherein R3 is a lower alkyl radical having from 1 to about 4 carbon atoms; R4 is selected from the group consisting of H, R3, C00R6, and -(CH2)n2-CH(R7)-Ar, wherein R6 is H or R3, n is 0 or an integer of from 1 to about 4, R7 is selected from the group consisting of R3, OR3, 0C0R3 and H, and Ar is selected from the group consisting of radicals represented by the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur, and phosphorous and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from 1 to 2, W is oxygen, sulfur or nitrogen and Z represents two hydrogen radicals, oxygen or sulfur; with the proviso that when Z represents 2 hydrogen radicals, then R4 cannot be H.
32. The method of claim 31, wherein Rλ is H; R2 is OA, wherein A is H or is selected from the group consisting of phenyl and alkyl radicals, or A is -C0R5 -CONHR5 or -CO0R5, wherein R5 is selected from the group consisting of methyl, t-butyl, phenyl, o-methylphenyl, o-chlorobenzyl, p-isopropylphenyl and o,p-dichlorophenyl; R3 is methyl, ethyl, or propyl; X is 0 or S; Z is oxygen or two hydrogen radicals and R4 is selected from the group consisting of benzyl, phenethyl, naphthylmethyl, naphthylethyl, 2-thienyl- methyl, 2-thienylethyl, and 2,5 dimethylpyrrolylethyl.
33. The method of claim 32 wherein X is oxygen.
34. The method of claim 33, wherein R3 is propyl, R2 is situaatteeid on the C9 position of the ring system and R4 is benzyl.
35. The method of claim 34 wherein said compound is trans-3,4,4a,5,6,10b-hexahydro-3-(phenylmethyl)-4-propyl-2H- naphth[l,2-b]-l,4-oxazin-9-ol, or a pharmaceutically acceptable salt thereof.
36. A method of making a compound selected from the group of compounds represented by the formula:
wherein R*-^ and R2 are selected from the group consisting of H and OA, wherein A is H or is selected from the group consisting of hydrocarbyl radicals having from 1 to about 12 carbon atoms, or A is -COR5, -CONHR5, or -COOR5, wherein R5 is selected from the group consisting of hydrocarbyl radicals having between 1 and about 12 carbon atoms and wherein Rχ, R2 and R5 are optionally substituted with one or mope halogen atoms; M is selected from the group consisting of oxygen arid sulfur, R3 is a lower alkyl radical, having from 1 to about 4 carbon atoms; R4 is selected from the group consisting of H, R3, COOR6, and -(CH2)n2-CH(R7)-Ar, wherein R6 is H or R3, n is 0 or an integer of from 1 to about 4, R7 is selected from the group consisting of R3, OR3, OCOR3 and H, and Ar is selected from the group consisting of radicals represented by the following general formulae:
wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, a ino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substitutedhydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur, and phosphorous and said hydrocarbyl radicals comprise from 1 to about 12 carbon atoms, a is 0 or an integer of from 1 to 2, W is oxygen, sulfur or nitrogen which comprises reacting a compound of the general formula:
with an (alpha)-halogenated acetic acid derivative represented by the general formula:
-,-CH-COO*. X" wherein R8 represents H or a hydrocarbyl radical having up to about 10 carbon atoms.
37. The method of claim 36 further comprising reducing the reaction product of claim 36 to provide a compound represented by the general formula:
38. The method of claim 36 wherein R4 is H and the reaction product is alkylated with an alkylating agent represented by the general formula RX* ' wherein R4 is not H and X11 is selected from the group consisting of Cl, Br and I.
39. The method of claim 36 wherein at least one of Rλ and R is OA, wherein A is a hydrocarbyl radical, and the reaction product of claim 36 is reacted to provide a compound wherein A is H.
40. The method of claim 36 wherein M is oxygen.
EP91913320A 1990-06-15 1991-06-11 Substituted naphthoxazines useful as dopaminergics Withdrawn EP0550444A1 (en)

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