DE3417859A1 - Therapeutic composition for the treatment of parkinsonism - Google Patents

Abstract

Composition and method for the selective stimulation of the D-2 dopamine receptors in humans by administration of a therapeutically effective amount of 2-(N-phenylethyl-N-propylamino)-5-hydroxytetralin or a pharmaceutically compatible salt or ester thereof to a person requiring D-2 dopamine receptor stimulation.

Description

³ 34 Ί 7859

description

The invention relates generally to the new compound 2- (N -phenylethyl-N-propylamino) -5-hydroxytetralin (PPHT), it relates in particular to one of these compounds or a pharmaceutically acceptable salt or pharmaceutical Therapeutic preparation containing compatible esters thereof as active ingredient (pharmaceutical Means) as well as the use thereof for the treatment of parkinsonism, in particular for selective stimulation of D-2 dopamine receptors.

Dopamine (DA) receptors can be divided into the 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 occur as a result of stimulation of the D-2 receptor centers (Schachter et al., "Nature" 286 , 57, 1980; Seeman, " Pharmacol. Rev. ", 3_2_, 230, 1980; Seeman," Biochem. Pharmacol. "3J_, 2563, 1982).

It was found that the compound 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin (PPHT) of the formula

it

is a DA agonist in animals (Hackseil et al., "J. Med. Chem. 22, 1469, 1979; Sumners et al.," Arch. Pharmacol. ", 316 , 304, j 1981). 'I.

It has now been found that the above-mentioned compound PPHT is a potent and selective agonist for D-2 receptors. This compound is useful for treating various Human central nervous system diseases in which functional underactivity of the dopaminergic system plays a role, such as in Parkinson's disease and related disorders, as well as disorders of the endocrine system, such as hyperprolactinemia.

Phenolic group prodrug esters are also within the scope of the present invention as well also the pharmaceutically acceptable salts of this compound. These have the general formula:

Ph

Pr

O-C-R

wherein R is methyl, ethyl, isobutyl, pivaloyl and benzoyl.

PPHT's prodrug esters * can be manufactured by treating the connection with the appropriate

Acid chloride (Horn et al., "J. Med. Chem. ¹¹ , 2 ^, 993, 1982). Mprodrug esters)

The acid addition salts of PPHT are made in a conventional manner. As acid addition salts, the salts used that are derived from a therapeutically acceptable acid such as hydrochloric acid, acetic acid, propionic acid, and in particular of 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, are derived.

Contain all of the above-mentioned compounds according to the invention in position 2 an asymmetric carbon atom. The therapeutic properties of the compounds can be found in to a greater or lesser extent can be attributed to one or both of the two enantiomers occurring. Therefore Both the pure enantiomers and mixtures thereof are within the scope of the present invention.

The invention relates generally to the selective stimulation of D-2 dopamine receptors in humans by administration a therapeutically effective amount of 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or a pharmaceutically acceptable salt or a pharmaceutically acceptable one Esters of it to a person in need of D-2 dopamine receptor stimulation.

The invention also relates to a therapeutic preparation or a pharmaceutical agent for the treatment of Parkinsonism, the one effective amount against Parkinsonism

2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or one pharmaceutically acceptable salt or ester thereof as an active ingredient (as a component) and optionally a pharmaceutical Compatible carrier and / or excipient contains.

The invention also relates to the treatment of disorders of the endocrine system, such as dysfunction of the pro | lactin synthesis (hyperprolactinemia) by inhibiting prolactin secretion.

The invention also relates to the treatment of parkihsonism by administering an effective dose of 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or one pharmaceutically acceptable salt or ester thereof as an active ingredient (active ingredient) to one suffering from Parkinsonism suffering people.

In a preferred embodiment, the invention relates to the treatment of parkinsonism by administration a therapeutically effective amount of the above compounds. In general, the daily dose can be 0.05 to 500 mg per kg and preferably 1 to 250 mg / kg per day, of course, it must be taken into account that in the Selection of the appropriate dose in each specific case

the weight, the general state of health, the substance |

change, age and other factors of the patient j

j affect the response to the drug, take into account |

must be viewed. !

According to a further embodiment, the invention relates to

pharmaceutical preparations in one dosage form -!

i form containing about 1 mg to about 1 g of a compound of the above!

contains the specified formula. ι

The pharmaceutical preparation (agent) can be in a for

oral use suitable form, for example in the form ■

of tablets, aqueous or oily suspensions, dispersible powders or granulate emulsions, hard or
soft capsules or syrups or elixirs are present. Preparations intended for oral use,

can by any method known per se for;

Manufacture of pharmaceutical products and ' the preparations can contain one or more agents,

which are selected from the group of sweeteners,;

i of the flavorings, the coloring agents and the preservatives, in order to produce a pharmaceutically elegant and tasty preparation. Tablets contain the active ingredient (active ingredient) mixed with non-toxic, pharmaceutical
compatible auxiliaries (excipients) that are suitable for the production of tablets. These auxiliaries
can for example be inert diluents such as ^; Calcium carbonate, sodium carbonate, lactose, calcium phosphate, ■ or sodium phosphate; Granulating and disintegrating agents, such as _: for example corn starch or alginic acid; Binders such as starch,
Gelatin or acacia gum, and lubricants such as magnesium stearate, stearic acid or talc. The tablets can

be uncoated or they can be | be coated in order to delay the disintegration and the absorption in the gastrointestinal tract and thereby an over

i to give lasting effects for a longer period of time. j

j Preparations for oral use can also be in the form i

of hard gelatin capsules in which the active ingredient (active ingredient) is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or they can be in the form of soft gelatin capsules in which the active ingredient (active ingredient) is mixed with an oil medium, such as peanut oil, liquid Paraffin or olive oil.

Aqueous suspensions contain the active compound in a mixture with auxiliary substances (excipients), which are necessary for the production

; of aqueous suspensions are suitable. Such Hilfει
ί Substances (excipients) are suspending agents, such as sodium

carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, Sodium alginate, polyvinylpyrrolidone, tragacanth

j rubber and acacia; Dispersants or wetting agents can! its a naturally occurring phosphatide, e.g.

Lecithin, or condensation products of an alkylene oxide with

: Fatty acids, such as polyoxyethylene stearate, or condensate

tion products of ethylene oxide with long-chain aliphatic

! Alcohols, such as heptadecaethyleneoxycetanol, or condensate

sation products of ethylene oxide with partial esters that of

; Fatty acids and a hexitol are derived, such as poly-

oxyethylene sorbitol monooleate, or condensation products of

j Ethylene oxide with partial esters, those of fatty acids and

; Hexitanhydrides are derived, e.g. polyoxyethylene sorbitan

j monooleat. These aqueous suspensions can also be a

j or more preservatives, such as ethyl or n-propyl

! p-hydroxybenzoate or one or more colorants, one or more

j more flavorings and one or more sweeteners, such as

! Sucrose, saccharin or sodium or calcium cyclamate,

contain.

Dispersible powder and granules which, by adding water, are suitable for the preparation of an aqueous suspension contain the active ingredient (active ingredient) mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are, for example those as mentioned above. Additional aids (excipients), such as sweeteners, Flavors and colorants can also be present.

Syrups and elixirs can be mixed with sweeteners such as e.g. Glycerin, sorbitol or sucrose. These formulations can also be a demulgent, a preservative and contain flavoring and coloring agents. The pharmaceutical preparations (agents) can be in the form a sterile injectable preparation, for example in the form of a sterile injectable aqueous suspension.

This suspension can be prepared in a known manner using suitable dispersing or wetting agents and Suspending agents as already mentioned above. The sterile injectable preparation can also be a sterile injectable Solution or suspension in a non-toxic / parenterally acceptable diluent or solvent be, for example in the form of a solution in 1,3-butanediol are present.

The pharmaceutical preparations (agents) can be tabletted or otherwise formulated so that on each 100 parts by weight of the preparation (agent) 5 to 95 parts by weight of the active ingredient (active ingredient), preferably 25 to 85 parts by weight of the active ingredient (active ingredient) are present. The dosage unit form contains generally about 100 to about 500 mg of the active ingredient (active ingredient) of the formula given above.

From the above formulation discussion it can be seen that the preparation or agent according to the invention orally or can be administered parenterally. The term "parenteral" as used herein includes subcutaneous injection, intravenous, intramuscular or intrasternal injection or fusion procedures.

The invention is illustrated in more detail by the following examples purifies, but is not limited to it.

- - " 3A17859

EXAMPLE 1

j

Synthesis of 2- (N-phenylethylamino) -5-hydroxytetralin (PPHT )

,

To a solution of 20.3 g (149 mmol) of phenylacetic acid in

100 ml of dry benzene was 1.71 g (45 mmol) of sodium boron
hydride was added. Under a nitrogen atmosphere, the

Temperature maintained for one hour at about 2O ⁰ C. To the-

This solution was then 1.71 g (7.8 mmol) 2- (propylamino) -

] 5-methoxytetralin was added and the mixture was refluxed for five hours. After cooling, the benzene layer with 3 times 60ml2N. NaOH washed. The benzene layer was then extracted with 5 times 15 ml of 1N HCl. The acid extracts were washed twice with 10 ml of ether which had been made alkaline with respect to lakmus, and then extracted with 4 intramuscular 40 ml of ether. The ether extracts were washed twice with 20 ml of a saturated NaCl solution and, after drying, over MgSO. evaporated to give an oil, and refluxed for three hours with 15 ml of a 48% HBr solution, 540 ml of a white HCl salt being obtained after work-up. After recrystallization from Äthanoläther to give an analytical sample, mp 205-206 ⁰ C. The structure was confirmed by IR, NMR, MS and elemental analyzes.

EXAMPLE 2

To assess the effectiveness (strength) and selectivity of PPHT, three in vitro test systems were used, viz the D-1 receptor in the carp retina, the D-2 Re-

ceptor in the middle lobe of the pituitary gland of a rat and the binding of H-spiperone to the dopamine receptor, the Contains fractions of the rat corpus striatum.

The results of the three in vitro tests are presented below using the "IC ₅₀ " values, which are the concentrations of the agonist required to inhibit the biochemical response by 50%.

Compound D-2 receptor in the D-1 receptor in inhibition of the 'H-

middle hypo- the fish retina spiperone bond

physical flap IC- _n (um) ICr _n (nM)

IC ₅₀ M ^{bU bü}

PPHT 0.04 3.7 3

Dopamine 10.0 10.0 300

Apomorphine 1.5 1.5 57

The results of the investigation show that PPHT is a very potent (strong), selective D-2 receptor agonist. That is, the above studies show that PPHT is about 40 times more effective (stronger) than the dopamine agonist Apomorphine and that it is 250 times more effective (stronger) than dopamine at the D-2 receptor. Regarding the selectivity the above studies show that PPHT is about times more active on the D-2 receptor than on the D-1 receptor in contrast to dopamine and apomorphine, which have the same activity on both the D-1 receptor and the D-2 receptor exhibit.

Claims (3)

19732 MacArthur Boulevard, Irvine, California 92715, V.St.A. Therapeutic preparation for the treatment of Parkinsonism P_a_t_e_n_t_a_n_s_ £ _r_ü_c_h_e 1. Therapeutic preparation for the treatment of Parkinsonism, geke "nn is characterized by a content of a therapeutically effective amount of 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or a pharmaceutically acceptable salt or ester thereof as an active ingredient (active Component), optionally in combination with a pharmaceutically acceptable carrier and / or excipient. 2. Use of the therapeutic preparation according to claim for the selective stimulation of D-2 dopamine receptors Humans by administering a therapeutically effective amount of 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or a pharmaceutically acceptable salt or ester thereof to a human undergoing D-2 dopamine receptor stimulation requirement. 3. Process for the preparation of the therapeutic preparation for the treatment of parkinsonism according to claim 1, characterized in that an amount effective against parkinsonism of 2- (N-phenylethyl-N-propylamino) -5-hydroxytetralin or a pharmaceutically acceptable salt or ester thereof as an active ingredient with a pharmaceutically acceptable carrier and / or adjuvant is combined.