Classifications

• • 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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• 1991
  • 1991-06-11 EP EP91913320A patent/EP0550444A1/de not_active Withdrawn
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  • 1991-06-11 CA CA002083146A patent/CA2083146A1/en not_active Abandoned
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