WO1993024471A1 - Naphtoxazines substitues efficaces en tant que dopaminergiques - Google Patents

Naphtoxazines substitues efficaces en tant que dopaminergiques Download PDF

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Publication number
WO1993024471A1
WO1993024471A1 PCT/US1993/005305 US9305305W WO9324471A1 WO 1993024471 A1 WO1993024471 A1 WO 1993024471A1 US 9305305 W US9305305 W US 9305305W WO 9324471 A1 WO9324471 A1 WO 9324471A1
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WIPO (PCT)
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group
radicals
oxygen
lower alkyl
sulfur
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PCT/US1993/005305
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English (en)
Inventor
James Vanolden Peck
Gevork Minasakanian
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Whitby Research, Inc.
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Publication of WO1993024471A1 publication Critical patent/WO1993024471A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems

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 compound of the invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing weight loss in mammals.
  • dopaminergic activity having the following general structural formula:
  • R, 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 1-12 carbon atoms, for example, lower alkyl radicals such as methyl, ethyl, propyl, and butyl, or aromatic radicals such as benzyl or phenyl, or A is -COR 5 , -CONHR 5 , or - COOR 5 wherein R 5 is selected from the group consisting of hydrocarbyl radicals having 1-12, preferably 1-9 carbon atoms and further provided that R v R 2 and R 5 may be optionally substituted with one or more, e.g., two halogen atoms; R 3 is a lower alkyl radical such as methyl, ethyl, propyl or butyl; X is selected from the group consisting of CH 2 , oxygen, sulfur, NH and NR 3 , R 4 is selected from the group consisting of -(CH 2 ,
  • 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 1-12 carbon atoms, a is 0 or an integer of from 1 to 2 and W is selected from the group consisting of oxygen, sulfur, NH and NR 3 and Z represents two hydrogen radicals, oxygen or sulfur.
  • R. is H
  • R 2 is -OH
  • R 3 is propyl
  • R 4 is -(CH,) n CH(R 7 )Ar.
  • the most preferred ring fusion is trans and the most preferred substituent for R 4 is benzyl; i.e., n is 0, R 7 is H, and Ar is phenyl.
  • trans-3,4,4a,5,6,10b-hexahydro-2-(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, 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 the above formula.
  • 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 1-12 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 O.
  • Z is O or two hydrogen radicals.
  • the more preferred groups for R 4 are benzyl, phenethyl, naphthylmethyl, naphthylethyl, 2-thienylmethyl, 2-thienylethyl and 2,5- dimethylpyrrolylethyl, and even more preferably, R 4 is benzyl, phenethyl or 2,5- dimethylpyrrolylethyl.
  • the preferred stereochemistry for ring fusion is trans.
  • the most preferred substituent for R t is H
  • for R 2 is -OH
  • for R 3 is propyl
  • for R 4 is one of the aryl radicals set forth in the paragraph immediately above. (The alkaryl radicals are even more preferred.)
  • the most preferred substituent for R 4 is benzyl.
  • trans-3,4,4a,5,6,10b- hexahydro-2-(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 of the invention may exist as stereoisomers or mixtures thereof, having positive, negative or zero optical activity, and exhibit potent and selective dopamine receptor agonist activity when administered to mammals.
  • these compounds are useful, as demonstrated by standard animal tests, for the treatment of disorders of the central nervous system, especially those related to the dopaminergic systems.
  • Particularly preferred compounds are as follows: trans-3,4,4a,5,6,10b-hexahydro-2-(pheny]-methyl)-4-propyl-2H-naphth[l,2-b]-l,4-oxazin- 9-ol; trans-3,4,4a,5,6,10b-hexahydro-2-[(2,6-dimethylphenyl)methyl]-4- ⁇ ropyl-2H-naphth[l,2- b]-l,4-oxazin-9-ol; trans-3,4,4a,5,6,10b-hexahydro-2-[(3,5-dimethylphenyl)methyl]-4-propyl-2H-naphth[l,2- b] - 1 ,4-oxazin-9-ol ; trans-3,4,4a,5,6,10b-hexahydro-2-(phenylethyl) -propyl-2H-naphth [l,2-b]-l
  • the compounds of the invention may contain up to 4 asymmetric carbon atoms. Three of these asymmetric carbon atoms are marked with asterisks (*) in the following structural formula:
  • the remaining asymmetric carbon may be in the R 4 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) a method of preparation of the subject compounds and a method for inducing a dopaminergic response by administering the subject compounds to a patient, (B) pharmaceutical compositions comprising the foregoing compounds in combination with an inert pharmaceutical carrier, and (C) pharmaceutical compositions in dosage forms containing a clinically effective amount of one of the foregoing dopaminergic compounds.
  • reaction o compound I with an appropriate R 4 -substituted (alpha)-halogenated acetic aci derivative [i] results in intermediate which can be converted to naphthoxazine derivatives (II) using sodium hydride o sodium hydroxide.
  • alkylation of the naphthoxazine compound III [see Jones, et al J. Med. Chem.. 27, 1607 (1984)] using a strong base (e.g., lithium diisopropyl amide with an appropriate alkylating agent R 4 X", wherein R 4 is not hydrogen and X" is a suitable halogen leaving group (e.g., Cl, Br or I) results in a substituted naphthoxazine (Compound II).
  • a strong base e.g., lithium diisopropyl amide with an appropriate alkylating agent R 4 X", wherein R 4 is not hydrogen and X" is a suitable halogen leaving group (e.g., Cl, Br or I)
  • the above reaction may be effected by contacting III 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 III 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.
  • Reduction of Compound II with an appropriate reducing agent provides the compound series 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 or diethyl ether, 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 j 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..30, 2008 (1987)].
  • prodrug ethers will result from isolation of the above-described intermediate (wherein R j or R 2 is not H) before aryl ether cleavage.
  • esters and acid addition salts of the compounds of the general formula are prepared in the conventional manner.
  • acid additional salts the salts derived from a 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 mid, 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 100 mg.
  • 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, calcium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules 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 aqueous suspensions containing the active compound in admixture with suitable pharmacologically-acceptable excipients.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose,sodiumalginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides, for example, lecithin, or condensation products of an alkylen oxide with fatty acids, for example, polyoxythylene stearate, or condensation product of ethylene oxide with long chain aliphatic alcohols, for exampl heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partia esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbito monooleate, or condensation product of ethylene oxide with partial esters derive from fatty acids and hexitol anhydr
  • the said aqueous suspensions may also contain one or mor preservatives, for example, ethyl, n-propyl-p-hydroxy benzoate, one or more colorin agents, one or more flavoring agents, and one or more sweetening agents, such a sucrose, saccharin, aspartame, mannitol, sorbitol, or sodium or calcium cyclamate.
  • mor preservatives for example, ethyl, n-propyl-p-hydroxy benzoate
  • colorin agents for example, ethyl, n-propyl-p-hydroxy benzoate
  • one or more flavoring agents such aspartame, mannitol, sorbitol, or sodium or calcium cyclamate.
  • sweetening agents such as a sucrose, saccharin, aspartame, mannitol, sorbitol, or sodium or calcium cyclamate.
  • Dispersible powders and granules suitable for preparation of an aqueou suspension by the addition of water provide the active ingredient in admixture wit a dispersing or wetting agent, suspending agent, and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified by thos 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, preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may also be in the form of a steril injectable preparation, for example, as a sterile injectable aqueous suspension.
  • Thi suspension may be formulated as is conventional using those suitable dispersing o wetting agents and suspending agents which have been mentioned above.
  • the steril injectable preparation may also be a sterile injectable solution or suspension in non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 butanediol.
  • the pharmaceutical compositions may be tabulated or otherwise formulate so that for every 100 parts by weight of the composition there are present betwee 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.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.
  • Example 2 The product of Example 2 and an excess of pyridine hydrochloride was heated to 200-220 ° C under nitrogen for 30 minutes. After workup the reaction mixture was purified by flash chromatograph (Silica, 95:5 petroleum ether/EtOAc) to obtain the product. NMR (300 MHz, CDC1 3 ) showed characteristic peaks at ⁇ 7.3 (m, 5H), 6.9 (m, 2H), 6.6 (m, 1H), 4.3 (d, 1H), 4.1 (m, 1H), 0.9 (t, 3H). The product was dissolved in ether and converted to its hydrochloride salt by the addition of dry ether- HC1.
  • Example 4 The product of Example 4 was reduced with lithium aluminum hydride as in Example 2 to provide the desired compound.
  • Example 5 The product of Example 5 was treated with pyridine hydrochloride as in Example 3 and the final product was isolated.
  • 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 mM Na 2 -EDTA; 5 mM KC1; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4) using a Brinkman Polytron. The homogenate was centrifuged at 40,000 x g for 20 minutes and washed once.
  • Buffer A 50 mM Tris; 1 mM Na 2 -EDTA; 5 mM KC1; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4
  • the pellet was resuspended in Buffer A, incubated at 37 ° C for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70 ° C until used.
  • the rat cerebr cortex assay was employed. Male Sprague Dawley rats were killed by decapitatio and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; mM MgCl 2 (pH 7.4), and centrifuged at 40,000 x g for 10 minutes. The pellet wa washed once, resuspended in Tris/MgCl 2 and incubated with 8 units/ml adenosin 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
  • the following tritiated drugs were used as radioligands for each of th receptors tested: [ 3 H]-Spiperone 21-24 Ci/mmol for dopamine D 2 receptors, [ 3 H] SCH2339075-85 Ci/mmol for dopamine D ⁇ receptors, and [ 3 H]-Para aminoclonidin 48-52 Ci/mmol for ⁇ 2 -adrenergic receptors.
  • the radioligands were incubated wit various concentrations of competing drug and the appropriate membrane source fo periods of time as follows: 75 minutes at room temperature for D 2 receptors, 1 minutes at 37 ° C for D j receptors, or 30 minutes at room temperature for ⁇ receptors.
  • D 2 1 ⁇ M butaclamol
  • D j 1 ⁇ SCH23390
  • ⁇ 2 1 ⁇ M yohimbine
  • the D 2 assays contained 30 n 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 harveste over filters that had been previously soaked in 0.1% polyethyleneimine, and the filter were washed three times by filtration of cold buffer. The filters were then placed i 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, an each vial was counted for 2 minutes in a Beckman 3801 scintillation counte calibrated for conversion of cpm to dpm. Binding data were analyzed using th Ligand program of Munson and Rodbard (1980). The results are presented as values if the data were best fitted to a one-site model, or as KH and KL values if two-site model produced the better fit.
  • Comparative 1 is described in Jones U.S. 4,420,480 and Comparative 2, 2-(N-n-propyl-N-thienylethyl-amino)-5-hydroxytetralin, is described in U.S. Patent No. 4,564,628; they are included as reference compounds for comparative purposes.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention comprend les composés sélectionnés à partir du groupe de stéréoisomères, ou de leurs mélanges de composés représentés par la formule (a) dans laquelle R1 et R2 sont sélectionnés à partir du groupe constitué par H et OA, où A est H ou est sélectionné à partir du groupe constitué par des radicaux d'alkyle inférieur et des radicaux aromatiques ou A représente -COR5, -CONHR5 ou -COOR5, où R5 est sélectionné à partir du groupe constitué par des radicaux d'alkyle inférieur et des radicaux aromatiques et où R1, R2 et R5 sont éventuellement substitués par un ou plusieurs atomes d'halogène; R3 représente un radical d'alkyle inférieur; X est sélectionné à partir du groupe constitué par CH2, oxygène, soufre, NH ou NR3, où R3 représente un radical d'alkyle inférieur; R4 est sélectionné à partir du groupe constitué par -(CH2)n-COOR6 et -(CH2)n-CH(R7)-Ar, où R6 représente H ou R3, n est 0 ou un entier situé entre 1 et 4, R7 est sélectionné à partir du groupe constitué par R3, ouR3, OCOR3 et H et Ar est sélectionné à partir du groupe constitué par des radicaux représentés par les formules générales (b), (c), (d), (e), (f), (g), (h) où Y est sélectionné à partir du groupe constitué par hydroxy, nitro, cyano, azido, amino, trifluorométhyle, halogène et hydrocarbyle, où lesdits radicaux hydrocarbyles comprennent entre 1 et 12 atomes de carbone, a est 0 ou un entier de 1-12 atomes de carbone, a est 0 ou un entier situé entre 1 et 2, W est sélectionné à partir du groupe constitué par oxygène, soufre, NH et NR3 et Z représente deux radicaux d'hydrogène, oxygène ou soufre, ainsi que des compositions pharmaceutiques comprenant lesdits composés et un véhicule acceptable pharmaceutiquement. Lesdits composés et lesdites compositions sont efficaces pour provoquer une réaction dopaminérgique chez un sujet, par exemple un mammifère, ainsi que pour soulager le glaucome et la maladie de Parkinson.
PCT/US1993/005305 1992-06-02 1993-06-02 Naphtoxazines substitues efficaces en tant que dopaminergiques WO1993024471A1 (fr)

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US07/889,940 1992-06-02

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0686637A1 (fr) 1994-06-08 1995-12-13 Adir Et Compagnie Nouveaux dérivés tétracycliques de la 1,4-oxazine, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0773223A1 (fr) 1995-11-09 1997-05-14 Adir Et Compagnie Nouveaux composés tétracycliques de la 1,4-oxazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2010059905A2 (fr) * 2008-11-24 2010-05-27 General Electric Company Ligands d'imagerie

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4540691A (en) * 1984-04-13 1985-09-10 Nelson Research & Development Co. Dopamine agonists and use thereof
WO1991019719A1 (fr) * 1990-06-15 1991-12-26 Whitby Research, Inc. Naphtoxazines substituees utiles comme dopaminergiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4540691A (en) * 1984-04-13 1985-09-10 Nelson Research & Development Co. Dopamine agonists and use thereof
WO1991019719A1 (fr) * 1990-06-15 1991-12-26 Whitby Research, Inc. Naphtoxazines substituees utiles comme dopaminergiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0686637A1 (fr) 1994-06-08 1995-12-13 Adir Et Compagnie Nouveaux dérivés tétracycliques de la 1,4-oxazine, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0773223A1 (fr) 1995-11-09 1997-05-14 Adir Et Compagnie Nouveaux composés tétracycliques de la 1,4-oxazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2010059905A2 (fr) * 2008-11-24 2010-05-27 General Electric Company Ligands d'imagerie
WO2010059905A3 (fr) * 2008-11-24 2010-08-26 General Electric Company Ligands d'imagerie
JP2012509887A (ja) * 2008-11-24 2012-04-26 ゼネラル・エレクトリック・カンパニイ イメージングリガンド

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