WO1991019719A1

WO1991019719A1 - Substituted naphthoxazines useful as dopaminergics

Info

Publication number: WO1991019719A1
Application number: PCT/US1991/004112
Authority: WO
Inventors: Gevork Minaskanian; James V. Peck
Original assignee: Whitby Research, Inc.
Priority date: 1990-06-15
Filing date: 1991-06-11
Publication date: 1991-12-26
Also published as: CA2083146A1; AU8224991A; AU651608B2; EP0550444A1; EP0550444A4; JPH05508408A

Abstract

The present invention comprises the 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 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 R1, 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 general formulae: (a), (b), (c), (d), (e), (f), (g), 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, and pharmaceutical compositions comprising said compounds and a pharmaceutically-acceptable vehicle. Said compounds and compositions are effective for inducing a dopaminergic response in a subject, e.g., a mammal, and are useful for alleviating glaucoma, parkinsonism, etc., and inducing weight loss.

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 R_x 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 -C00R_5^ 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 R_{l 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, R_χ 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 R_x 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 R_1# 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 R_x 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 0^βC 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- 220^βC 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 37^βC 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 -70^βC 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 -70^βC 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 37^βC 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 R_λ 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 R_{l 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 -COR_5f -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 R_{l 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 R_λ 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 R_χ, 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 R_λ 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.