Ergolinyl heterocycles for the treatment of Parkinson&#39;s disease and dyskinetic symptoms
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to ergoline derivatives which are effective in the central nervous system (CNS) and are useful as anti-Parkinson agents. 
     2. Brief Description of the Background: 
     The inventors are not aware of any prior disclosures of the ergoline derivatives disclosed herein. 
     SUMMARY OF THE INVENTION 
     The present invention provides compounds of formula I ##STR5## wherein R 1  represents a hydrogen atom or a methyl group; 
     R 2  represents a hydrogen atom or a methoxy group; 
     R 3  represents a hydrocarbon group having from 1 to 4 carbon atoms; and 
     X represents a nitrogen atom and Y represents an oxygen atom, a ##STR6## group wherein R 4  represents a hydrogen atom, a C 1  -C 4  alkyl or a phenyl group, R 5  represents a hydrogen atom, a C 1  -C 4  alkyl, a phenyl, an amino or a di(C 1  -C 4  alkyl) amino group and the nitrogen atom of the group ##STR7## is not joined to the nitrogen atom represented by X, or Y represents a nitrogen atom and X represents an oxygen atom or a ##STR8## group wherein R 4  is as above defined; and pharmaceutically acceptable salts of such ergoline derivatives. 
     The ergoline derivatives of the formula I and their pharmaceutically acceptable salts are useful in therapy, particularly in the therapy of extrapyramidal syndromes such as Parkinson&#39;s disease and dyskinetic symptoms. 
     Furthermore, in three other aspects, the invention concerns methods for treating extrapyramidal syndromes such as Parkinson&#39;s disease and dyskinetic symptoms in a subject, pharmaceutical compositions and methods for preparing medicaments useful for these purposes, which methods and compositions employ compounds of formula I or their pharmaceutically acceptable salts. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     In the definition of R 3 , a &#34;hydrocarbon group having from 1 to 4 carbon atoms&#34; is intended to include alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups. Representative groups include methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, methylcyclopropyl, allyl and propargyl. 
     In the definitions of R 4  and R 5 , a &#34;C 1  -C 4  alkyl group&#34; is intended to include methyl, ethyl, n-propyl, i-propyl, butyl, t-butyl and i-butyl groups. Preferably, R 4  denotes methyl. Preferably, R 5  denotes methyl. When R 5  is a di(C 1  -C 4  alkyl)amino group, preferably it is dimethylamino. 
     &#34;Pharmaceutically acceptable salts&#34; refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic or salicylic acid. 
     Preferred compounds of the invention are those in which R 1  and R 2  are hydrogen atoms, R 3  is a methyl group, X is a nitrogen atom and Y is an oxygen atom, a ##STR9## group wherein R 4  represents hydrogen atom, a C 1  -C 4  ;l alkyl or phenyl group and R 5  represents a C 1  -C 4  alkyl or amino group, or Y represents a nitrogen atom and X is an oxygen atom or a ##STR10## group wherein R 4  is as defined immediately above. 
     The invention further provides a process for preparing the compounds of the formula I as defined above, which process is characterized by reacting a compound of the formula II ##STR11## wherein R 1 , R 2  and R 3  are as above defined, with a compound of the formula A-NH 2  wherein A represents a group of the formula ##STR12## a hydroxy group or a group of the formula --NHR 4 , wherein R 4  and R 5  are as above defined. 
     The reaction is preferably carried out in a protic solvent such as an alcohol or an organic acid, most preferably in ethanol or acetic acid, at a temperature of from 0° to 100° C. for a period of from 5 minutes to 60 hours. The crude product may be purified by crystallization, salt formation, or by chromatography on a silica gel column. The ergoline derivative of formula (I) may therefore be converted into a pharmaceutically acceptable salt if desired. 
     The ergoline-8-propionaldehyde II may be prepared by established procedures starting from the corresponding 8β-acetyl ergolines (Bernardi et al, Gazz. Chim. It., p. 961, 94, 1964). 
     The ergoline derivatives according to the invention and their pharmaceutically acceptable salts are useful in the therapy of extrapyramidal syndromes such as Parkinson&#39;s disease and dyskinetic symptoms. By &#34;dyskinetic symptoms&#34; is meant disordered movements of voluntary or involuntary muscles, due to disorders of the extrapyramidal system (i.e. extrapyramidal syndromes), such as Parkinsonism, tardive diskinesia induced by long-term administration of neuroleptic agents, Huntington&#39;s chorea, etc. Thus, the inventive compounds may also be used for the making of medicaments effective against extrapyramidal syndromes. Accordingly, the invention also provides a pharmaceutical composition comprising an ergoline derivative having the general formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. The present invention also relates to methods of treating Morbus Parkinson and dyskinetic symptoms using said compounds, said compositions or medicaments. 
     BIOLOGICAL TESTS AND DOSES 
     The profile of dopamine agonists of the compound of the formula I was preliminarily assessed in vitro by binding assays to receptors of rat cerebral tissue (e.g. SCHWARCZ, R. et al, Nature, 271: 766, 1978), where they showed affinity for the dopamine D-2 receptors, at a concentration of about 10 -8  M. 
     In vivo interaction studies with the specific D-1 antagonist SCH 23390 and with the specific D-2 antagonist 1-sulpiride in the Ungerstedt&#39;s rotational model in the rat (Ungerstedt, U., Acta Physiol. Scand., Suppl. 367: 69, 1971) unexpectedly proved that the title compounds are highly specific functional D-1 agonists at a dosage of from 0.5 to 1 mg/kg s.c. The orientative acute toxicity of the compounds I in rats is higher than 400 mg/kg p.o. 
     The compounds are therefore indicated for use as anti-parkinson agents and as therapeutic agents in dyskinetic symptoms. The amount of active compound for this indication will, of course, be dependent on the subject being treated, the severity of the application, the manner of administration and the judgment of the prescribing physician. 
     However, an effective dosage is in the range of about 0.2 to about 10 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.10 to about 5 mg of the compound or in sustained release form. 
     ADMINISTRATION AND COMPOSITIONS 
     Administration of the active compound and salts described herein can be via any of the accepted modes of administration for anti-parkinson agents. These methods include oral and parenteral modes, preferably oral administration. 
     Depending on the intended mode, such compositions may be formulated in conventional manner so as to be, for example, a solution or a tablet. 
     The composition will include a conventional pharmaceutical carrier or excipient and an active compound of formula I or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. 
     For solid composition, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like may be used. Liquid pharmaceuticlly administerable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as defined above and an optional pharmaceutical adjuvant in a carrier, such as, for example, water saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. 
     The compound of Example 2 hereinafter is the preferred compound, and the preferred activity is anti-parkinson activity. 
    
    
     The invention now being generally described, the same will be better understood by reference to certain specific examples which are included herein for purposes of illustration only and are not intended to be limiting of the invention or any embodiment thereof, unless specified. 
     EXAMPLE 1 (FCE 21642) 
     6-Methyl-8β-(1-methyl-pyrazol-5-yl)-ergoline (I, R 1  ═R 2  ═H, R 3  ═R 4  ═CH 3 , X=NR 4 , Y=N) 
     (a) 3-oxo-3-(6-Methyl ergolin-8β-yl)-propionaldehyde. 
     To a suspension of 10.8 g (0.2 mole) of sodium methoxide in 150 ml of toluene was added a solution of 26.8 g (0.1 mole) of 8β-acetyl ergoline in 200 ml of toluene while stirring and cooling (icy water). 
     After 30 minutes, 10 ml of ethyl formate was added dropwise and stirring was continued for 5 hours. 
     The resulting suspension of sodium enolate was filtered off, washed with toluene and dissolved in icy water. 
     The basic aqueous solution was extracted with ethyl acetate to remove the unreacted 8β-acetyl ergoline, then acidified with acetic acid and extracted several times with ethyl acetate. The organic solution was dried over Na 2  SO 4  and evaporated to dryness, affording 23 g of the title compound as clear yellow foam, yield 77%. 
     (b) 6-Methyl-8β-(1 methyl-pyrazol-5-yl)-ergoline. 
     A solution of 5 g (0.017 mole) of 3-oxo-3-6-methylergolin-8β-yl)-propionaldehyde and methylhydrazine in 100 ml of ethanol was refluxed for 2 hours. After cooling, the product was filtered off, washed with ethanol, and dried to give the title compound, 1.5 g, m.p. 218°-220° C. 
     EXAMPLE 2 (FCE 21641) 
     6-Methyl-8β-(1-methyl-pyrazol-3-yl)-ergoline (I, R 1  ═R 2  ═H, R 3  ═R 4  ═CH 3 , X=N, Y=NR 4 ) 
     The mother liquors obtained in Example 1 after separation of 6-Methyl-8β-(1-methyl-3-pyrazolyl)-ergoline, were chromatographed on silica gel using ethyl acetate/cyclohexane 2/1 as eluent to give the title compound, 1.7 g, m.p. 243°-246° C. 
     EXAMPLE 3 
     6-Methyl-8β-(isoxazol-5-yl)-ergoline (I, R 1  ═R 2  ═H, R 3  ═CH 3 , X=O, Y=N) 
     A mixture of 5 g (0.017 mole) of 3-oxo-3-(6-methylergolin-8β-yl)-propionaldehyde in 100 ml of glacial acetic acid and 5 g of hydroxylamine hydrochloride was stirred for 20 hours at room temperature and then poured in ice-cold water. After basification with ammonium hydroxide, the solid which separated was filtered and dissolved in ethyl acetate. The organic solution was washed with brine, dried and the solvent was removed, and the residue was crystallized twice from acetone affording the title compound, 1.8 g; m.p. 132°-134° C. 
     EXAMPLE 4 
     6-Methyl-8β-(isoxazol-3-yl)-ergoline (R 1  ═R 2  ═H, R 3  ═CH 3 , X=N, Y=O) 
     The mother liquors obtained in Example 3 were chromatographed on silica gel using acetone/cyclohexane 1/5 as eluent giving the title compound, 0.3 g, m.p. 182°-185° C. 
     EXAMPLE 5 (FCE 21643) 
     6-Methyl-8β-(pyrazol-3-yl)-ergoline (R 1  ═R 2  ═R 4  ═H, R 3  ═CH 3 , X=NR 4 , Y=N) 
     Operating as in Example 1, but employing hydrazine instead of methyl hydrazine, the title compound was obtained in 75% yield, m.p. 160°-162° C. 
     EXAMPLE 6 (FCE 21639) 
     6-Methyl-8β-(1-phenyl-pyrazol-5-yl)-ergoline (R 1  ═R 2  ═H, R 3  ═CH 3 , X=NR 4 , R 4  =Ph, Y=N) 
     Operating as in Example 1, but employing phenylhydrazine of methylhydrazine the title compound was obtained, m.p. 256°-158° C. 
     EXAMPLE 7 (FCE 21640) 
     6-Methyl-8β-(1-phenyl-pyrazol-3-yl)-ergoline (R 1  ═R 2  ═H, R 3  ═CH 3 , X=N, Y=NR 4 , R 4  =Ph) 
     The mother liquors obtained in Example 6 were chromatographed on silica gel using ethyl acetate/cyclohexane 1/4 as eluent to give the title compound, m.p. 234°-236° C. 
     EXAMPLE 8 
     6-Methyl-8β-(2-amino-pyrimidin-4-yl)-ergoline (R 1  ═R 2  ═H, R 3  ═CH 3 , X=N, ##STR13## 
     R 5  ═NH 2 ) 
     Operating as in Example 1, but employing guanidine instead of methyl hydrazine the title compound was obtained in 42% yield. 
     EXAMPLE 9 
     6-Methyl-8β-(2-methyl-pyridimidin-4-yl)-ergoline (R 1  ═R 2  ═H, R 3  ═R 5  ═CH 3 , X=N, ##STR14## 
     Operating as in Example 1, but employing acetamidine instead of methyl hydrazine the title compound was obtained in 60% yield. 
     The compounds of the invention can be prepared in typical formulations, and for example the following are representative, the active ingredient being one of the pharmacologically active compounds. 
     
                       EXAMPLE 10                                                  
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Tablet  Active ingredient    5       mg                                   
        Dried starch         300     mg                                   
        Polivinylpyrrolidone 50      mg                                   
        Sodium carboxymethyl starch                                       
                             50      mg                                   
        Stearic acid         20      mg.                                  
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     The active ingredient and starch are mixed together and mixed with a solution of polivinylpyrrolidone in alcohol. The mixture is extruded through a screen, dried, sized and mixed with sodium carboxymethyl starch and stearic acid prior to compression on a tablet machine. Tablets weighing 425 mg are obtained. 
     
                       EXAMPLE 11                                                  
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Capsules     Active ingredient                                            
                             0.10   mg                                    
             Starch (flowable)                                            
                             50     mg                                    
             Silicone fluid  0.5    mg.                                   
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     A portion of the starch is mixed with the silicone fluid. To the power is added the active ingredient and the remainder of the starch. The blended mixture is filled into hard gelatin capsules. 
     The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.