GB2157950A - Selective D-2 dopamine receptor agonist - Google Patents

Abstract

Therapeutic compositions for treating parkinsonism by selectively stimulating D-2 dopamine receptors in humans comprise a therapeutically effective amount of 2 - (N - phenylethyl - N -propylamino) - 5 - hydroxytetralin (PPHT) or a pharmaceutically acceptable salt thereof. <IMAGE>

Description

SPECIFICATION Selector D-2 dopamine receptor agonist BACKGROUND OF THE INVENTION Field of the Invention The invention relates generally to the compound 2 (N - phenylethyl - N - propylamino) - 5 -hydroxytetralin (PPHT). More particularly the invention relates a method of selectively stimulating D-2 dopamine receptors.

Background of the PriorArt Dopamine (DA) receptors can be divided into two main classes, D-1 and D-2 (Kebabian et al., Nature 277,93,1979). In addition it is known that most of the behavioral and clinical effects of DA receptor agonists occurvia a stimulation ofthe D-2 receptor sites (Schachter et al., Nature 286,57,1980; Seeman, Pharmacol. Rev.,32,230, 1980; Seeman, Biochem.

Pharmacol. 31,2563,1982).

The compound 2 - (N - phenylethyl - N - propylamino)- 5- hydroxytetralin (PPHT)

has been found to be a DA agonist in animals (Hackselletal.,J. Med. Chem.22, 1469, 1979; Sumners ei al., Arch. Pharmacol. 316,304,1981).

SUMMARY OF THE INVENTION According to the present invention it has been found that the above mentioned compound, PPHT, is a potent and selective agonist of D-2 receptors. The compound is useful in the treatment of various human diseases of the central nervous system where a functional underactivity of the dopaminergic system plays a role such as in Parkinson's disease and related disorders and also disturbances of the endocrine system, e.g. hyperprolactinemia.

Prodrug esters ofthe phenolic group also lie within the scope of the present invention as well as pharmaceutically acceptable salts ofthis compound.

These havethe general formula:

where R is methyl, ethyl, isobutryl, pivaloyl and benzoyl. Ester prod rug of PPHT may be prepared by treating the compound with the corresponding acid chloride (Hornet al., J. Med. Chem. 25,993,1982).

The acid addition salts of PPHT are prepared in the conventional manner. As acid addition salts can be used the salts derived from a therapeutically acceptable acid such as hydrochoric acid, acetic acid, propionic acid and, more particularly, from a di- or polybasic acid such as phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, malic acid, and ascorbic acid.

All ofthe above compounds of the invention contain an asymmetric carbon atom at position 2. The therapeutic properties ofthe compounds may to a greater or lesser degree be ascribed to either or both ofthetwo enantiomers occurring.Thusthe pure enantiomers as well as mixtures thereof are within the scope ofthis invention.

Thus, the invention generally relates to a method of selectively stimulating D-2 dopamine receptors in humans comprising administering to a human requiring D-2 dopamine receptor stimulation, a therapeutically effective amount of 2 - (N - phenylethyl - N - propylamino) - 5 -hydroxytetralin or pharmaceutically acceptable salt thereof.

The invention further relates to a therapeutic compositionfortreating Parkinsonism comprising an effective, anti-Parkinsonism amount of the composition containing as the active ingredient 2 - (N phenylethyl - N - propylamino) - 5 - hydroxytetralin or a pharmaceutically acceptable saltoresterthereof.

The invention further relates to treatment of disturbances ofthe endocrine system such as, for example, dysfunction of prolactin synthesis (hyperprolactinemia) by inhibiting prolactin secretion.

The invention further relates to a method of treating Parkinsonism which comprises adminstering to a human having Parkinsonism an effective dosage of, as the active ingredient, 2 - (N -phenylethyl - N - propylamino) - 5 - hydroxytetralin or a pharmaceutically acceptable salt or ester thereof.

A preferred embodiment of this invention is a method of treatment which comprises the administration of a therapeutically effective amount ofthe foregoing compounds. In general the daily dose can be from 0.05 mg./kg. to 500 mg./kg. per day and preferably from 1 mg./kg.to 250 mg.tkg. 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 otherfactors which influence response to the drug.

Anotherembodimentofthis invention is the provision of pharmaceutical compositions in dosage unitform which comprise from about 1 mg. to 1 g. of a compound of the above formula.

The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, aqueous or oilysuspensions, dispersible powdersorgranules emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the artforthe 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 orderto provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients Formulae in the printed specification were reproduced from drawings submitted after the date of filing, in accordance with Rule 20(14) of the Patents Rules 1982.

may be, forexample, inert diluents, for example calcium carbonate, sodium carbonate, lactos, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents,forexamplestarch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated orthey 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 gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active compound in admixture with excipients suitableforthe manufacture ofaqueous suspensions. Such excipients are suspending agents, for examplesodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyviny Ipyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents may be a naturallyoccurring phosphatide,for example lecithin, or condensation products of an alkylene oxide with fatty acids,forexample polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylenesorbitan monooleate.The said aqueous suspensions may also contain one or more preservatives,for example ethyl, or n-propyl, phydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin, 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 admix ture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified bythose 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 be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension.

This suspension may be formulated according to the known art 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 orsuspen- sion in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol.

The pharmaceutical compositions may betableted or otherwiseformulated so thatfor every 100 parts by weight ofthe composition there are present between Sand 95 parts by weight ofthe active ingredient and preferably between 25 and 85 parts by weight ofthe active ingredient. The dosage unitform will generally contain between about 100 mg. and about 500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparentthatthe compositions ofthis invention can be administered orally or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection our fusion techniques.

The following examples illustrate the present invention.

EXAMPLE I Synthesis of2 - (N - phenylethylamino} -5- h ydroxytetralin (PPHT) To a solution of 20.3 g (149 mMol) of phenylacetic acid in 100 ml of dry benzenewas added 1.71 g (45 mMol) of sodium borohydride. Under an atmosphere of nitrogen the temperature was held at about 20"C for1 hour. To this solution wasthen added 1.71 g (7.8) mMol) of 2 -(propylamino) - 5 - methoxytetralin and the mixture was refluxed for 5 hr. After cooling the benzene layerwaswashed with 2N NaOH (3 x 60 ml).

The benzenelayerwasthen extractedwith 1N HCI (5 x 15 ml). The acid extracts were washed with ether (2 x 10 ml) made alkaline to litmus and then extracted with ether (4 x 40 ml). The ether extacts were washed with a saturated NaCL solution (2 x 20 ml) and after drying over MgSo4 evaporated to yield an oil and refluxed for 3 hr. with 15 ml of 48% HBr solution to yield afterworkup 540 mg of a white HCI salt.

Recrystallizationfrom ethanoletheryielded an analytical sample m.p. 205-206"C. The structure was confirmed by IR, NMR, MS and elemental analyses.

EXAMPLEII Three in vitro test systems were used to evaluate the potency and selectivity of PPHT, i.e. the D-1 receptor in carp retina,the D-2 receptor in the intermediate lobe ofthe rat pituitary gland and the binding of3H-spiperone to dopamine receptor con- taining fractions of the rat corpus striatum.

The results ofthethree in vitro tests are shown below in terms of 'ICSo'' which is the concentration of agonist required to inhibit the biochemical response by 50%.

Intermediate lobe Fish Retina Inhibition of 311 O2 receptor Di receptor spiperone binding md 350 (un) S5o (urn) m50 (nun) PPST 0.04 3.7 3 Dagavine 10.0 10.0 300 Apanorphine 1.5 1.5 57 The results ofthe study show that PPHT is a very potent, selective D-2 receptor agonist. That is, the foregoing studies show that PPHT is approximately 40 times more potentthan the dopamine agonist apomorphine and 250 times more potentthan dopamine at the D-2 receptor. Regarding selectivity, the foregoing studies show that PPHT is approximately 100 times more active atthe D-2 receptorthan at the D-1 receptor in contrast to dopamine and apomorphinewhich havethe same activity at both the D-1 and D-2 receptors.

Claims (5)

1. Atherapeutic composition fortreating Parkinsonism comprising an effective, anti-Parkinsonism amount of a composition containing as the active ingredient 2 - (N - phenylethyl -N - propylamino) - 5 hydroxytetralin ora pharmaceutically acceptable salt or ester thereof.

2. A method of selectively stimulating D-2 dopamine receptors in humans comprising administering to a human requiring D-2 dopamine receptor stimulation, a therapeutically effective amount of 2 - (N phenylethyl - N - propylamino) - 5 - hydroxytetralin or a pharmaceutically acceptable salt or ester thereof.

3. A method for making a pharmaceutical composition useful for treating Parkinsonism comprising combining an effective, anti-Parkinsonism amount of a composition containing asthe active ingredient 2 (N - phenylethyl - N - propylamino) - 5 - hydroxytetralin or a pharmaceutically acceptable salt or ester thereofwith a pharmaceutically acceptable carrier.

4. Atherapeutic composition substantially as hereinbefore described with reference to Examples 7 and 2.

5. A method of making a pharmaceutical composition substantially as hereinbefore described with reference to Examples 1 and 2.