WO1990012574A1

WO1990012574A1 - Dopamine agonist compounds

Info

Publication number: WO1990012574A1
Application number: PCT/US1989/001747
Authority: WO
Inventors: John L. Neumeyer; Sten Ramsby
Original assignee: Northeastern University
Priority date: 1989-04-25
Filing date: 1989-04-25
Publication date: 1990-11-01

Abstract

Orally effective dopamine agonist compounds are described including in particular novel aporphine compounds. The compounds have a dioxy group on an aromatic nucleus which is cleaved in vivo to release compounds with two adjacent hydroxy groups on the aromatic nucleus. Also described are novel dopamine agonist aporphine compounds wherein the phenolic hydroxyl group is replaced by amino, bromo or fluoro groups.

Description

DOPAMINE AGONIST COMPOUNDS

The invention described herein was made in the course of work under a grant or award from the Department of Health and Human Services

BACKGROUND OF THE INVENTION

This present application is a continuation-in-part of my copending United States patent application Serial No. 735,519 filed January 31, 1985 which is a division of Serial No. 379,557 filed May 18, 1982, now United States Patent 4,543,256 which is a continuation-in-part of Serial No. 358,918, now abandoned, and Serial No. 358,917, now abandoned, both filed March 17, 1982, which in turn are continuations-in-part of application 346,841, filed February 8, 1982, now abandoned, and is also a continuation-in-part of my copending application Serial No. 651,091, filed August 13, 1984, which in turn is a continuation of Serial No. 274,772 filed June 18, 1981, now abandoned, which in turn is a continuation-in-part of my application, Serial No. 148,179, filed May B, 1980 and now abandoned, all said applications being incorporated herein by reference.

Many aporphine compounds have therapeutic activity. Thus, apomorphine (APO) and N-n-propylnorapormorphine (NPA) have potent and selective actions at central and other dopamine receptor sites. Such aporphine compounds have been used clinically, especially in neurological and psychiatric disorders, but their clinical use has been limited by their poor oral bio-availability and short duration of action.

SUMMARY OF INVENTION

In accordance with this invention, a dopamine agonist compound which has two adjacent hydroxy groups on an aromatic nucleus and which has a therapeutic effect when administered subcutaneously or intraperitoneally can be converted into an orally effective therapeutic compound by bridging the hydroxy groups to form a dioxy group as for example, methylenedioxy. The dioxy group is cleaved in vivo to provide the compound with two adjacent hydroxy groups. Such compounds include novel aporphine compounds.

Therapeutic aporphine compounds having the following structure are particularly useful in this invention and are convertible to an orally effective therapeutic composition which is cleaved in vivo to release the compound with the two adjacent hydroxy groups

wherein R₁ is lower alkyl, substituted lower alkyl, cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lover alkyl, phenyl lower alkenyl and phenyl lower alkynyl. R₂ is hydrogen, hydroxy. methoxy, bromo, fluoro, or amino: R₃ and R₄ are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl, phenyl lower alkynyl, or COR₅ , where R₅ is methyl or lower alkyl; and pharmaceutically acceptable addition salts thereof .

This invention is generally applicable to dopamine agonist compounds which have two hydroxy groups on adjacent positions on an aromatic nucleus and which have dopamine agonist activity when administered subcutaneously or interperitoneally. Such compounds include not only aporphine compounds but also non-aporphine compounds , as for example , compounds of the following structures :

wherein R₁ and R₂ are hydrogen, methyl and lower alkyl

wherein R₁ and R₂ are hydrogen, methyl and lower alkyl

wherein R₁ and R₂ are hydrogen, methyl and lower alkyl. Also, in accordance with the present invention aporphine compounds are described which are orally effective in treating neurological and psychiatric disorders. In addition aporphine compounds are described which are effective in the prevention and treatment of duodenal ulcers and can be administered orally, subcutaneously or peritoneally. Preferred examples of these novel compounds with dioxy groups have the following structures:

wherein R₁ is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, and R₂ and R₃ are hydrogen, methyl, lover alkyl, substituted lover alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lover alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lover alkenyl and phenyl lover alkynyl and pharmaceutically acceptable acid additional salts thereof.

In particular 1 have found that (-) 10, 11-methylenedioxy-N- n-propylnoraporphine (as described in U.S. patent 4,543,246) is especially effective when administered orally in the prevention and treatment of duodenal ulcers and in the treatment of psychiatric and neurological disorders. I have also found that the methylene dioxy group is an especially effective dioxy group. It is believed that the compounds of this invention are converted in vivo to the dihydroxy compound and are orally effective and long acting.

As used herein, the term "lower-alkyl" means saturated monovalent aliphatic radicals, including straight and branched- chain radicals, of from two to six carbon atoms, as illustrated by, but not limited to ethyl, propyl, isopropyl, butyl, sec- butyl, amyl, or hexyl.

As used herein, the term "lower-alkenyl" means monovalent, aliphatic radicals of from three to seven carbon atoms which contain at least one double bond, and are either straight or branched-chain, as illustrated by, but not limited to 1-(2- propenyl), 1-(3-methyl-2-propenyl), 1-(1,3-dimethyl-2-propenyl), or 1-(2-hexanyl).

As used herein, the tern "lower-alkynyl" means monovalent, alphatic radicals of from three to seven carbon atoms which contain at least one triple bond, and are either straight or branched, as illustrated by, but not limited to 1-(2-proρynyl), 1-(1-methyl-2-propynyl), or 1- (2-heptynl).

As used herein, the term "cycloalkyl" means cyclic, saturatd aliphatic radicals of from three to eight ring carbon atoms, as illustrated by, but not limited to cyclopropyl, cyclobutyl, 2- methylcyclobutyl, cyclohexyl, 4-methycyclohexyl, or cyclooctyl. As used herein, the terms "phenyl- lower-alkyl," "phenyl- lower-alkenyl," and "phenyl-lower-alkynyl" mean monovalent radicals consisting of a phenyl nucleus bonded to the rest of the molecule through, respectively, a divalent lower-alkylene radical of from one to four carbon atoms, as illustrated by, but not limited to methylene, 1, 1-ethylene, 1, 2-ethylene, 1,3- propylene, 1,2-propylene, or 1,3-butylene; or through a divalent lower-alkynylene radical of from two to four carbon atoas, as illustrated by, but not limited to 1,2-ethyny 1 ene, 1,3- propynylene, 1,3-(1-butynylene), and the like. Moreover the benzene ring of such phenyl- lower-alkyl, phenyl-lower-alkenyl, and phenyl-lower-alkynyl radicals can be substituted by one or more substituents selected from the group consisting of lower- alkyl, lower-alkoxy, halo (chloro, bromo, iodo, or fluoro), nitro, lower-alky Imercapto, methylenedioxy, and trifluoromethyl.

Apropriate acid addition salts are those derived froα such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphtha lenecarboxy 1 ic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonie acid, acetylene dicar boxy lie acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxyl ic acid, 2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, benzenesulf inic acid, butylarsonic acid, ptoluenesulfonic acid, benzenesulf inic acid, butylarsonic acid. diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like.

CHEMISTRY

The N-substituted noraporphines of this invention may be prepared from the readily available opium alkaloid thebaine by the synthesis scheme illustrated in Figure 1.

In this synthesis scheme, thebaine is N-demethy lated to northebaine υseing diethylazodicarboxylate according to the method disclosed in British Patent 1,124, -441 (August 21, 1968). The rearrangement of the northebaine to normorphothebaine is accomplished with concentrated HCI in a sealed pressure bottle on a steam bath for 2.5 hours according to a published procedure

(F.E. Granchelli, A. H. Soloway, J.L. Neumeyer and C. N. Filer, J. Org. chem:42, 2014 (1977).) Formation of the N-R₁- normorphothebaine. HCI is carried out in the presence of an acid acceptor (e.g., Na₂CO₃ or NaHCO₃) using the appropriate

R₁- iodide or R₁ bromide in a suitable solvent system at about

100ºC under nitrogen for 16 to 24 hours. After isolation and purification of the product N-R₁-normorphothebaine, it is heated with 481 HBr at 130-135ºC under nitrogen for three to four hours to form the HBr acid addition salt of the desired N-R₁-2,10, 11- trihydroxynoraporphine. Neutralization of the acid addition salt with NH₄OB forms the free base which then may, if required, be converted to the HCI salt by treatment with ethereal HCI.

The ester derivatives wherein R₂,R₃ or R₄ are -C-R₅ and R₅ is lower alkyl, are conveniently prepared by reacting the appropriate N-R₁-2,10,11-trihydroxynoraporphine HBr or free base with an appropriate acyl halide to give the substituted triacyl noraporphine. Using well-known techniques, the free base and acid addition salts may thus be converted from one form to the other and one acid addition salt may be converted to another by regenerating the free base and acidifying it.

The synthesis of MDO-NPA from codeine is described in U.S. patent 4,543,256 which has been incorporated herein by reference.

BIOLOGICAL ACTIVITY

With respect to dopamine agonist activity, the compounds of this invention were tested for stereotyped gnawing behaviour of rats in accordance with the techniques described in Baldessarini,

R.J., Walton, K.G., and Bergman. R.J. 1976, ("Prolonged apomorphine-like behavioural effects of apomorphine esters. "Neuropharmacology 15, 471.) In some rats fore-brain tissue was assayed after administration of (-)10,11-methylene-dioxy-N-n- propylnoraporphine (MDO-NPA) for the presence of free N-n- propylnorapomorphine (NPA) by a sensitive and specific high- performace liquid chromatographic method with electrochemical detection (HPLC/ec). (Westerink, B.H.C. and Horn, A.S. 1979. "Do neuroleptics prevent the penetration of dopamine agonists into the brain?" Eur. J. Pharmaco. 58,39.) The results are shown in Table 1. The dioxy compounds of this invention are very active in inducing stereotypy behaviour in vivo when administered orally. MEASUREMENT OF BIOLOGICAL ACTIVITY

Male Sprague-Dawley (Charles River Labs.) rats (initially

175-200 g) were housed four per cage, with free access to food and water, under controlled lighting (on 7:00 a.m. to 7:00 p.m.), constant temperature (21-23ºC.) and controlled humidity (40-501).

Aporphines were administered, as described below, freshly dissolved in ImM citric acid mixed with 0.9t (w/v) saline (1:4 vols) this solvent was also used as a vehicle ("placebo") control. Haloperidol was given in the same medium; 2-diethyl aminoethyl-2,2 diphenyl va lerate HCI (SKF-525A) was given in saline.

Locomotor activity was evaluated by use of a printing electronic activity monitor (EAM, Soelting Co., Chicago, IL) within a sound-attenuated chamber, typically for 60 min., as previously described (Stewart, Campbell, Sperk and Baldessarini, 1979,

Psychopharmacology 60 281-289; Campbell and Baldessarini, 1981a,

Psychopharmacology 73:219-222.)

Stereotyped behaviour was evaluated by a trained observer according to a rating scale method reported previously (Campbell -and Baldessarini, 1981a). Briefly, the ratings were as follows: 0, no stereotypy, normal locomotion; 1, discontinuous sniffing, reduced locomotion: 2, continuous sniffing, only periodic exploration; 3, continuous smiffing mouth movements, infrequent, exploratory activity. Ratings were made each 10 min. by observation for 30 sec, typically for 60 min. (maximum score=18.0/hour).

Catalepsy was assessed as described in detail elsewhere (Campbell and Baldessarini, 1981a; 1981b, Life Sciences 29 1341- 46). Briefly, rats were evaluated every 10 min. by timing (stopwatch) their maintenance of an abnormal posture with forelimbs on a 1 cm-diameter steel bar parallel to, and 8cm above the bench, so that the rate rested on its hindquarters only; 60 sec. was taken as a maximum and nearly all normal untreated rats remained on the bar for less than 5 sec. Ratings were made as follows: O, remaining on the bar 0-10 sec; 1, 10-29 sec; 2, 30-59 sec; 3, 60 sec. Thus, in a typical 60 min. session, the maximunm score was 18.0.

In all experiments except those which evaluated the time- course for drug effects, rats were given as injection of vehicle and then allowed to rest for 15 min. to adapt to non-specific arousal effects, prior to a second injection of test agent or

(placebo) and immediate behavioural testing. Behavioural data were evaluated by Student's t- test and are always expressed as ± SEM.

The halo and amino compounds were tested for their ability to displace ³H-spiperone in porcine anterior pituitary gland. [George, S.R., M. Watanabe, and P. Seeman. Dopamine D₂ receptors in pituitary: A single population without reciprocal agonist/antagonist states. J. Neurochem. 44:1168-1177 (1985)].

The results are summarized in Table 13 showing the affinities and proportions of high and low affinity states of the dopamine receptor of the porcine anterior pituitary. These results demonstrate for the first time that the substitution of a hydroxy group with a f lυoro or bromo group produces dopamine agonists with a high degree of potency. 2-Fluroaporaorphine is in fact slightly more potent than is (-)apomorphine itself.

EXAMPLES OF INVENTION

The following examples of the preparation and testing of exemplary compounds, which are meant to be illustrative and not limiting, are provided as a further description of the invention. Examples 1-10 and 15-22 describe preparation of compounds made in accordance with this invention. Examples 11-14 describe biological testing. Tables 1-12 describe biological activity.

Examples 1-4

Normorphothebaine hydrochloride was prepared from thebaine using the synthesis scheme outlined above and according to the teaching of British Patent 1,124,441 and Granchelli et al. Four

N-substituted normorphothebaines were then made using the halides and solvent systems detailed below in Table 8.

In these syntheses a mixture of 5.10 grams (0.016 mole) of the normorphothebaine hydrochloride, 5.0 grams (0.06 mole) of

NaHCO₃, 0.02 mole of the R₁ halide in 130 milliliters of acetonitrile was heated at 100ºC under nitrogen for 16 hours. In

Examples 3 and 4 where the R₁ halide was a bromide, 0.014 mole of potassium iodide was added to the mixture with the bromide. The resulting reaction mixture was cooled and filtered, and the filtrate was evaporated to a residue. The residue was then treated with 100 milliliters of chloroform and filtered. The filtrate, concentrated to about 5 milliliters solution, was then chromatographed on silica gel (1:30) packed and eluted with a mixed solvent (5t CH₃OH in CHCl₃) to give the desired compound in a yield and with a melting point given in Table 8. Examples 5-7

Separate mixtures of 1.8 mmoles of the N-ethyl-, N-n-propyl- and N-allylnormorphothebaines of Examples 1-3. respectively, with 18 milliϋters of 481 HBr were heated at 130 to 135ºC under nitrogen for three to four hours. The reaction mixtures were cooled and then evaporated to a dry residue in vacuo. The residues were recrystallized from methanol /ethyl esther to give off-white solids in the yields and with the melting point, given below in Table 9.

Example 8

(-)N-(2'-Bromoallyl)-2,10,11-trihydroxynoraporphine hydrochloride.

A mixture of 0.30 gram (0.93 mrnol.) of the N- Propargylnormorphothebaine of Example 4 in 10 milliliters of 48% HBr was heated and evaporated in the same manner as described for the preparation of Example, 5-7 to give a dry residue (0.35 9ram). Further purification of the product was carried out through the preparation of its triacetoxy derivative followed by subsequent hydrolysis. The residue wa, diluted with 10 millilitets of trifluoroacetic acid and added dropwise with 4.0 milliliters of acetyl bromide to form a complete solution. After the initial exothermic reaction subsided, the reaction mixture was heated at 90ºC under nitrogen for 2 hours and then evaporated to a residue. The residue was taken up with 50 milliliters of chloroform, washed with 30 milliliters of 3% NaHCO₃, brine, dried, and concentrated to approximately a 2 milliliter solution. This solution was then chromatographed on silica gel packed and eluted with chloroform/ethyl ether to give a pure product which showed R_f of 0.32 (in chloroform) on TLC. The triacetoxy derivative underwent alcoholysis after being treated with a mixture of 25 milliliters of absolute methanol and 12.5 milliliters of ethereal HCI for 16 hours. The reaction mixture was evaporated to a residue which was recrystal lized from methanol/ethyl ether to give an off-whit. solid (120 mg. 38%), mp 180-184ºC. TLC showed R_f of 0.40 in methanol/chloroform (1:6) -30.5º

In a manner similar to that detailed in Examples 1-4, the N- R₁-normorphothebaines wherein R₁ is phenyl lower alkyl, phenyllower alkenyl or phenyl lower alkynyl are advantageously prepared by reaction, in the presence of an acid acceptor, of the normorphothebaine CHCl₃ with an appropriate phenyl lower alkyl halide, phenyl lower alkenyl halide or phenyl lower alkyny halide.

Example 9

(-)N-n-Propyl-2,10,11-triacetoxynoraporphine

hydrochloride hydrate.

A mixture of N-n-propyl-2,10,11-trihydroxynoraρorphine hydrobromide (1.16 grams, 0.0029 mole) prepared as in Example 6 and trifluoroacetic acid (10 milliliters) was added with acetyl bromide (5.0 milliliters) to result complete solution. The reaction mixture was heated at 90ºC under nitrogen for four hours and evaporated to a viscous residue. The residue was taken up with 50 milliliters of chloroform and the resulting solution was washed with 3% NaHCO₃ (30 milliliters), brine, dried and evaporated to give an oily residue. This residue was chromatographed on a silica gel column packed and eluted with chloroform/ethyl ether (1:1) to give the pure desired product (R_f=0.25 in chloroform).

The hydrochloride salt was prepared by dissolving the free base in 200 milliliters of anhydrous ether and the solution was treated with an excess of ethereal HCI. Filtration of the mixture gave a white solid (1.09 grams, 80%) with m.p. 179-183ºC, and a structure confirmed by NMR and infrared spectra. Anal. Calcd. for C₂₅H₂₇NO₆.HCl.1.5H₂O (MW 500.97): C, 59.93; H, 6.23 N, 2.80. Found: C, 59.81; H. 6.34, N. 2.81.

Example 10

N-Propargyl-2,10,11-trihydroxynorapnrphine A mixture of normorphothebaine hydrochloride (1.5 g, 4.7 moles) in 481 HBr was heated at 130ºC under nitrogen for 3 hours and evaporated to a dry residue in vacoo. The residue was taken up with minimal amount of absolute methanol and the solution added dropwise to 200 mL of ethyl ether to give a precipitate. Filtration of the mixture yielded the intermediate 2,10,11- trihydroxynoraporphine (1.55 g). A mixture of 3a, propargyl bromide (0.54 g 4.5 moles), NaHCO₃ (0.92 g, 11 mole,) and 0.3g of potassium iodide in 75 mL of acetonitrile was heated at reflux under nitrogen for 18 hours, cooled, and filtered. The filtrate wa, evaporated to a residue which wa, taken up with 5 mL of chloroform and methanol mixture (1:1) and the .olution added dropwi,. to 100 mL of ethyl ether to result in precipitation. The supernatant wa, decanted and evaporated to give the crude desired product (0.45 g. 32%). Further purification of the product wa, carried out through the preparation of it. triacetoxy derivative followed by column chromatography and acid hydrolysis in the same manner as the preparation of 3f to give pure 3g a. hydrochloride salt. (275 mg. 17%); mp 178-181ºC; NMR (CDCl₃:CD₃OD) & 2.8-4.4 (broad signals, H at C-4. C-5, C-6a, C-7. N-CH₂ C=CH), 6.4-6.7 (m. 3 H at C-3, C-8. C-9), 7.8 (d, 1, H at C-1);

^UV max(EtOH) 238 nm (log e, 4.40), 259 (log e, 4.40), 280 (log e, 4.14), 306 (log e, 4.03), 358 (log e, 3.62), 376 (log e, 3.61); MS, M/e 307 (M+). Anal. (C₁₉H₁₇NO₃.HCl.H₂O) C, H, N.

Example 11

Compounds of this invention have been found to be very effective emetics. Emetic efficency was measured in alert dogs with three particulate (15 um spheres) and three soluble markers (phenol red theophylline and tobramycin) instilled 5, 25, and 55 minutes before rapid intraveneous injection of the emetic. Apomorphine was used as a control emetic. Measurements included time interval to first emesis and recovery in the vomitus of the particulate and soluble markers.

The (-)N-n-propyl-2,10,11-trihydroxynoraporphine.HBr of

Example 6, made up in a solution of physiological saline or other suitable vehicle and administered in doses ranging between 0.005 and 1mg/kg body weight, produced emesis in conscious dogs within two minutes of an intraveneous injection. Even at the high dosage level of 1 mg/kg there was no evidence of cardiovascular, central nervous system or respiratory toxcity. At a dosage level of 0.1 mg/kg the ( - ) N - n - propyl -2, 10, 11- trihydroxynorapomorphine.HBr was found to be 50 times more potent that apomorphine. The (-) N- n -propy 1-2, 10,11- triacetoxynoraporphine.HCl of Example 9 was determined by the above-described test, to be 43 time, more potent a, an esetic than apomorphine.

It wa, also found that these two noraporphines of this invention were effective emetics when inhaled in solutions in an appropriate solvent system or in powder form. Example 12

DBA/2 mice 18.28, show a fixed sequence of seizure phenomena in response to a loud sound. Dopamine agonists prevent the later stages of this response (Tabl e 10 ) When administered ip in the mouse, (-)-2, 10, 11-trihydroxy-N-propylnorapomorphine (TNPA) has a prolonged sedative action. In terms of ED₅₀ for the clonic phase of the seizure response, TNPA is equipotent with apomorphine (tested 30 minutes after drug administration).

Example 13

Dopamine agoni s ts protect agins t pa roxysma l EEG and myoc Ionic responses to photic stimulation in Papio Papio (Table

11 ) . In this model of epilepsy, seizure responses are potential ly modified by drugs acting on serotoninergic transmission, Meldrum et a l Epi lepsy: Post Traumatic Epi lepsy, Pharmacological Prophylaxis of Epilepsy, J. Majkowski ed, Polish Chapter of ILEA,

Warsaw pp 139-153 (1977 ). TNPA, 0.02 mg/kg, iv produced a mi ld sedative effect but did not modify tuyoclonic responses to photic stimulation. However, complete protection was seen for 3-7 hours after TNPA, 0.5 and 2.5 mg/kg, given intravenously. These doses are a l so fol lowed by pupi l di lation, yawning, s lowing of EEG background rhythms, and at the highest dose, by excess salivation and piloerection.

Example 14

The presence of substantia l amounts of a highly specific dopamine-sensitive adenylate cyclase in carp (Cyprinus carpio) retina l hoaogenates which possesses a pharmacologica l profile simi lar to the dopamine-sensitive adenylate cyclase found in other areas of the brain make this a useful model in which to evaluate the activity of dopamine agonists. When tested in this system using methods previously described [Watling, et al. j. Keurochem. 36 559 (1981)] TNPA produces a significant stimulation of adenylate cyclase activity in comparison with (-)-

NPA and DA (Table 12).

My previous studies indicated that substitution of the hydrogen atom on apomorphine and N-n-propylnorapomorphine with such functional groups as OH or OCH₃ modified the receptor binding properties of such ligands. I thus investigated replacing the phenolic hydroxyl group with such groups as an amino or halogen (Br or F) substituents.

The synthetic route employed for the synthesis of 2-amino- 10, 11-methylenedioxyaporphine 8 is in Scheme 1. The crucial step in this scheme is the substitution of the 2-hydroxy group with an amino group, accomplished using a Smiles rearrangement reaction on the amide 6 to give 7 which was hydrolyzed to the amino derivative 8. The 2-amino derivative 8 could then be converted to the 2-bromo or 2-fluoro substituted aporphines (10 and 12) and further converted to the 2-Br or 2-F apomorphine analog, 11 and 13. (Scheme 2)

Melting points were determined on a Thomas-Hoover apparatus and are υncorrected. TLC was performed with precoated silica gel 13181 foils (Eastman-Kodak, Rochester NY) to follow reactions and check the purity of the products. The spots were visualized with

iodine vapors. NMR (Varian T-60) and mas, spectra (12-90-G Nuclide) were consistent with the assigned structures. Optical rotations were obtained on a Perkin-Elmer 141 polarimeter. Elemental analyses were performed by Atlantic Microlaboratories. Analytical results indicated by elemental symbols were within ±

0.41 of the theoretical values.

Example 15

2-Hydroxy-10,11-methylenedioxyapomorphine (4) Finely ground NaOH (4.8 g, 0.12 mol) was added to a solution of 2,10,11-trihydroxyapomorphine hydrobromide (3) (14.5 g, 0.04 mol) prepared form morphothebaine (2) in 500 ml of dry DMSO at ambient temperature under N₂. Stirring was continued for 1 h. CH₂Br₂ (9.1 g, 0.052 mol) was added and the mixture was heated at 80ºC for 4 hrs. After cooling the solution was poured on ice- water and extracted with AcOEt. Drying (MgSO₄) and evaporation of the organic solvent under reduced pressure gave 9.6g of an oil. The title compound was isolated by f lash-chromatography (SiO₂, 0.04-0.06 am, 600 9) and 5% MeOH in CH₂Cl₂ as elυent. Recrystallization of the product from AcOEt afforded 7.2 g (61%) of the desired compound 4, mp 193-195 C (dec.)

Anal. (C₁₈H₁₇NO₃) C, H, N.

Example 16

2-(α,α-dimethylacetoxyamide) 10, 11-methylenedioxyaporphine (6) The M DO -phenol 4 (2.95 g, 10 mmol) was suspended in 50raL of dry acetone at room temperature under nitrogen. Pulverized NaOH

(2.04 g, 66 mmol) was added in 2 portions and the reaction mixture was heated to reflux. Chloroform (1.78 g, 15 mmol) was added dropwise and reluxing was continued for 4 hrs.

After cooling 5 mL of water wa, added and the solution was concentrated in vacuo and the aqueous solution was cooled and acidified with concentrated HCI. The solvent was evaporated and the residue dried azeotropical ly by evaporation of EtOH and then

CHCl₃. Yield 4.9 g of the crude acid hydrochloride that was used directly in the next step.

The crude propionic acid derivative 5 (4.0 g) was dissolved in 50 mL of SO₂Cl₂ and stirred at room temperature overnight.

The excess of thionyl chloride was removed under reduced pressure. The crude acid chloride was dissolved in 20 mL of dry THF and added dropwise with stirring to an ice cooled concentrated ammonia solution. After the addition, the solution was allowed to reach room temperature and stirring was continued for an additional 2 hrs. The solution was concentrated in vacuo and aqueous solution was extracted with ethyl acetate. The combined extract was dried (MgSO₄) and evaporated yielding 4.2 g of a dark brown oil. The amide 6 va, isolated by flash chromatography on a silica column (150 g, 0.040-0.063 mm) and 5%

MeOH in CH₂Cl₂ as elυent to yield 2.3 9 (60%) of a light brown oil that crystallized on standing. Recrystal lization from of 6.

benzene gave 1.9g m.p.195-197ºC.

Anal (C₂₂H₄N₂O₄) C, H, H. Example 17

2-Amino-10,11-methylendioxyaporphine hydrochloride (8)

The amide 6 (3.0 g, 7.8mmol) was dissolved in 50 mL of dry HMPT and NaH (50% in oil. 0.42 g) was added under N₂ at room temperature. The solution was heated at 100ºC for 1 h with stirring. The reaction mixture was cooled and poured into ice- water and extracted with AcOEt. The combined extracts were washed with water and dried (MgSO₄). Removal of the solvent gave 3.6 g of crude hydroxy amide, 7.

This crude amide (3.0g) was dissolved in 50 mL of 5 M HCI solution and heated at 100ºC for 1 h. After evaporation of the solvent the residue (2.9 g) was teated with 5 mL of EtOH with stirring for 1 h at room temperature. AcOEt (5ml) was added to the suspension and the precipitate wa, collected by filtration. Recry.tal lization from 95% EtOH gave 1.7 g of the amine mono hydrochloride. 8, mp 252-253ºC (dec). .53.2ºC. (c=0.44, MeOH). Anal. (C₁₈H₁₉ClN₂O₂) C, H. Cl. N.

Example 18

2-Bromo -10,11,methylenedioxyaporphine (10) To a solution of the amine hydrochloride (750 mg. 2.3 mmol) in 3 mL of 48% hydrogen bromide solution at 0ºC was added dropwise with stirring a solution of NaNO₂ (157 mg , 2.3 mmol) in 0.1 mL of

H₂O. The reaction mixture wa. stirred for 1 h at 0ºC. Cuprous bromide dissolved in 0.5 mL of 48% aqueous HBr wa. added and the solution was heated at 80ºC for 1/2 h. After cooling 3 mL of water was added and the raction mixture wa. mad. alkalin. with concentrated ammonia vith cooling. The precipitate was filtered off and washed with water and dried. The product was triturated with AcOEt and the insoluble material was filtered off. The solvent was removed under reduced pressure to give 580 mg of product. TLC (CH₂Cl₂ : MeOH, 9: 1 as eluent) of the product indicated two major components that were separated by chromatography on a SiO₂ column (30 g, 0.040-060 mm) and eluted with AcOEt. The component with Rf value 0.74 is probably a dibrominated compound as indicated by mass spectroscopy. The compound with Rf value 0.63 is the desired monobromo derivative. Yield 295 mg (361). mp 163-164ºC

Example 19

2-Fluoro-10,11-methelenedioxyaporphine

To a solution of the 2-aminoaporphine HCI 8 (130 mg, 0.4 mmol) in 2 mL of water was added dropwise with stirring a solution of NaNO₂ (35 mg, 0.5 mmol) in0.1mL of water at 0ºC. After 1/2 h 75% HPF₆ (130mg, 0.62 mmol) was added. The suspension was diluted with 1 mL of water and stirring was continued for 1 h at 0ºC. The reaction mixture was filtered and the precipitate was washed with MeOH: ether (1:10) and dried over

P₂O₅ in vacuo. The diazonium salt was decomposed portionwise by heating at 170ºC for 10 min. After cooling a saturated Na₂CO₃ solution was added, extracted with AcOEt and dried (MgSO₄).

Evaporation of the solvent afforded 95 mg of crude material. The fluoro compound was isolated by chromatography on a SiO₂ column

(10 g) using ethyl acetate as eluent. Yield 65 mg (55%).

Example 20

General Method for the Demethylenation Reaction

2-A_mino-apomorphine.HBr (9).

To a solution of the MDO-amine 8(15.0 mg, 0.5 mmol) in 5 mL of CH₂Cl₂ was added dropwise with stirring 1 mL of 1 M BBr₃ in

CH₂Cl₂ (1 mmol) at ambient temperature. Stirring was continued overnight. Methanol (1 mmol) was added and the solvent evaporated in vacuo. The resulting product was recrystallized from methanol-ether affording 110 mg (63%) of the 2- aminoapomorphine.HBr, mp 216-218ºC.

This compound and also the following catechols were characterized by TLC and MS.

Example 21

2 -Bromoapomorphine.HBr (11)

This compound vas prepared from the corresponding MDO- derivative (10) (70 mg, 0.2 mmol) as described for the amino- compound above. Yield 45 mg (54%).

Example 22

2-Fluoroapomorphine.HBr(13)

The title compound was synthesized from the MDO-derivative

(12) (60 mg, 0.2 mmol)) as described for the amino- compound above. Yield 42 mg (57%).

Haloperidol or its vehicle was given 30 min before MDO-NPA (both dissolved in the same citric acid-saline vehicle). Stereotypy was rated for 60 min as described in Methods. Data are πeans SEM (stereotypy scores, when 18 = maximum in 1 hour) for N = 6 rats per group; (*) indicates p < 0.0001 by t test.

TABLE 1

Charac teristics of NPA and MDO-NPA. Data are for stimulation of cAMP in rat striatal honogenates ; inhibition of binding of [ ³H]APO to beef caudate synaptosomal membranes ; stereotypy scores (αaxiauα possible " 18.0) ; and cerebral levels of NPA by HPLC/ec; (*) p < 0.01.

Th e grours consisted of 3-4 Spragu e-Dewley female rats (160-180g) . Each experiment was repeated at least twice and the results of those gropes were pooled. The dopemine agonists were injected s. c. once daily for seven days prior to the administration of cysteamine HCl (Aldrieh) 26mg/100g . p.o. three times with 3 hr intervals. The animals were killed 46 hr after the duodenal ulcer- ogen. The intensity of duodenal υlecr was evaluated on a scale of 0-3 , where 0 = no ulcer, 1 = superficial mucosal erosion, 2 = transmural necrosis, deep ulcer, 3 = perforated or penetrated duodenal ulcer. In the above table , MDO-NPA is converted in vivo to NPA eg N-n-propylnorapomorphine .

tt of

Additional biological data for compounds of this invention, with particular reference to anti-convulsant activity may be found in my following publications:

Advances in the Biosciences, vol. 37, pages 291-296(1982) Pyschopharmacology, vol. 81, pages 135-139 (1983)

Also, my review article entitled "Synthesis and Structure- Activity Relationships of Aporphines as Dopamine Receptor

Agonists and Antagonists", pages 146-170in the book entitled "The Chemistry and Biology of Isoquinoline Alkaloids," ed. by Phillipson et al, published by Springer-Ver lag, Berlin Heidelberg, 1985 provides an accumulation of biological data for the compounds of this invention.

Claims

I CLAIM:

1. A compound of the formula

wherein R₁ is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl or phenyl lower alkynyl; R₂ is hydrogen, hydroxy, methoxy, bromo, fluoro, or amino; R₃ and R₄ are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl, phenyl lower alkynyl, or COR₅, where R₅ is methyl or lower alkyl; and pharmaceutically acceptable acid addition salts thereof.

2. A compound in accordance with Claim 1 wherein R₂ is hydrogen.

3. A compound in accordance with Claim 1 wherein R₂ is hydroxy.

4. A compound in accordance with Claim 1 wherein R₃ and R₄ are linked, and bridge the oxygen atoms to which they are

attached, to form a dioxy group.

5. A compound in accordance with Claim 4 wherein the dioxy group is methylenedioxy.

6. A method for inhibiting the effects of an epileptic seirure by administering orally a therapeutically effective amount of a compound of Claim 4.

7. A method for prevention and treatment of a duodenal ulcer comprising administering a therapeutically effective amount of a compound of Claim 1 .

8. A method in accordance with Claim 7 wherein the compound is administered orally.

9. A method for preparing an orally effective therapeutic form of a dopamine agonist compound which has two hydroxy groups on adjacent positions on an aromatic nucleus and which has dopamine agonist activity when administered subcutaneously or intraperitoneally, said method comprising providing the compound in a form wherein a dioxy group bridges said positions, said dioxy group being characterized as being cleaved in vivo to provide the dopamine agonist compound with the two adjacent hydroxy groups.

10. A method for preparing an orally effective therapeutic form of an aporphine compound which has two hydroxy groups on adjacent positions on an aromatic nucleus and which has a therapeutic effect when administered subcutaneously or intraperitoneally, said method comprising providing the compound in a form wherein a dioxy group bridges said positions, said dioxy group being characterized as being cleaved in vivo to provide the aporphine compound with the two adjacent hydroxy groups.

11. The method of Claim 10 wherein the aporphine compound has the structure of Claim 1.

12. The method of Claim 9, 10, or 11 wherein the dioxy group has the following structure

wherein R₂ and R₃ are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cyclo alkyl. lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkenyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkenyl.

13. An orally effective dopamine agonist made by the method of Claim 9.

14. A compound having orally effective dopamine agonist activity and characterised as having an aromatic nucleus with a dioxy group bridging two adjacent positions on the nucleus and being further characterised in that said dioxy group is cleaved in vivo to provide two adjacent hydroxy groups.

15. A compound having the structure (-) 2-R_a - R_b wherein R_a is bromo, fluoro or amino and R_b is apomorphine or 10, 11- methyl enedioxyaporphine and pharmaceutically acceptable addition salts thereof.

16. The compound of Ciaim 15 wherein R_b is apomorphine.

17. The compound of Claim 15 wherein R_b is 10, 11, methylenedioxyaporphine.

18. The compound of Claim 15 wherein R_a is bromo.

19. The compound of Claim 15 wherein R_a is fluoro.

20. The compound of Claim 15 wherein R_a is amino.

21. A compound having the structure (-) NR₁- 2, 10, 11 trihydroxynoraporphine, wherein R₁ is ethyl, n-propyl,eyelopropyl methyl, allyl or propargyl and pharmaceutically acceptable addition salts thereof.

22. The compound of Claim 21 wherein R₁ is ethyl.

23. The compound of Claim 21 wherein R₁ is n-propyl.

24. The compound of Claim 21 wherein R ₁ is cyclopropylmethyl..

25. The compound of Claim 21 wherein R₁ is allyl.

26. The compound of Claim 21 wherein R₁ is propargyl.

27. The compound of Claim 1 wherein R₂, R₃ and R₄ are all hydrogen.

28. The compound of Claim 27 wherein R₁ is ethyl, n-propyl, cyclopropylmethyl, allyl or propargyl.

29. A compound in accordance with Claim 1 wherein R₁ is n- propyl, ethyl, allyl, 2' bromoallyl or propargyl, R₂ is hydroxy,

R₃ is hydrogen, and R₄ is hydrogen.

30. A compound in accordance with Claim 29, namely (-) N-n- propyl-2,10,11 trihydroxynoraporphine.

31. A compound in accordance with Claim 29, namely (-) N- ethyl-2,10,11 trihydroxynoraporphine.

32. A compound in accordance with Claim 29, namely (-) N- allyl-2,10,11 trihydroxynoraporphine.

33. A compound in accordance with Claim 29, namely (-) N-

2' bromoallyl-2, 10, 11 trihydroxynoraporphine.

34. A compound in accordance with Claim 29, namely (-) N- propargyl-2,10,11 trihydroxynoraporphine.

35. A compound in accordance with Claim 29, namely (-) N- n-propyl-2,10,11 triacetoxynoraporphine.

36. A method for inhibiting the effects of an epileptic seizure by administering a therapeutically effective amount of a compound of Claim 29, 30, 31, 32, 33, 34 or 35 or the pharmaceutically acceptable addition salt thereof.