USE OF COMPOUNDS HAVING COMBINED DOPAMINE D2,5-HT1A AND ALPHA ADRENORECEPTOR AGONISTIC ACTION FOR TREATING CNS DISORDERS The invention relates to the use of compounds having combined dopamine D2-agonistic activity, 5-HT1A agonistic and a adrenoceptor agonistic activity for the preparation of pharmaceutical compositions for the treatment of CNS disorders such as Parkinson's disease.

W099/62902 describes the use of compounds having affinity for the dopamine D2-receptor and/or the 5-HT1A receptor and/or the a,-adrenoceptor for the treatment of a large number of disorders, e. g. depression, anxiety, psychoses, obesity etc. The compounds described therein have significantly less affinity for the a,-adrenoceptor than compounds previously described.

This is said to be important as it is known in the art that (xl-receptor antagonism mediates serious side-effects such as hypertension, sedation and sexual dysfunction.

It has now been found that compounds having combined dopamine D2-agonistic activity, serotonin 5-HTlA-agonistic activity and noradrenergic a,-adrenoceptor agonistic activity are particularly useful for the treatment of CNS disorders. Such compounds allow for a more complete treatment of Parkinson's disease without mediating the serious side-effects of compounds having the oc1-adrenoceptor antagonistic activity component.

Parkinson's disease is characterized by a slow but progressive degeneration of primarily nigrostriatal dopamine neurons. Loss of dopamine eventually results in movement disorders that are characteristic for the disorder.

It has been established that compounds with agonistic activity at dopamine D receptors are beneficial in treating symptoms in Parkinson's disease. Drawback with this approach is that systems slowly desensitize and do not stop the so-called'wearing-off'of pharmacotherapy.

It is considered that using partial dopamine D2 receptor agonists are equally efficacious in models for Parkinson's disease but have no or greatly reduced down-regulation of D receptor sensitivity, thereby prolonging the period in which pharmacotherapy has efficacy.

Compounds that are partial dopamine D agonists, i. e. with intrinsic activity between 0.3 and 0.8 (a full agonist and a full antagonist having an intrinsic activity of 1.0 and 0.0 respectively) have full efficacy in animal models for Parkinson's disease, including the induction of contralateral rotation in unilateral 6-OHDA-lesioned rats, and the MPTP-lesioned Marmoset monkeys.

Interestingly, depending on intrinsic activity compounds may act as partial agonists in partially denervated systems such as reserpinized rats. Moreover, all compounds are active in classical dopamine agonist models such as climbing behavior and locomotion in rats and mice.

Intrinsic activity lower than 0.3 produces truly partial efficacy in animal models. This is parallelled by an increase in dosage necessary to achieve behavioral responses.

Interfering with central dopamine systems is also likely to interupt reward-seeking behavior which is associated with psychological and physical dependence (addiction) as well as withdrawal, and impulsive disorders like Gilles de la Tourette syndrome. Furthermore, there is evidence that dopaminergic agonists may be effective also in the treatment of anxiety symptoms.

Underneath the neurological symptoms related to Parkinson's disease, more than half of the patients also suffer from mood disorders, which affect the quality of life in many cases immensely. This may be attributed at least in part to the neurodegeneration of the serotonergic raphe nuclei and the noradrenalin-producing cells in the locus coeruleus, although this degeneration lags behind that of the dopaminergic substantia nigra.

Thus by combining partial D receptor agonism with 5-HT, A, and a-adrenoceptor agonism, treatment of the primary Parkinson's disease symtoms, like bradykynesia, resting tremor, stiffness and rigidity, and in addition secondary symptoms, like depression, panic, generalized anxiety and dementia, will be possible.

Compounds having this unique combination of pharmacological activities are indeed not only active in animal models for Parkinson's disease but are also active in animal models predictive for anxiolytic behavior, such as the adult ultrasonic vocalization and stress-induced hyperthermia, as well as in animal tests that are predictive for anti-depressant activity, such as the forced swim test.

In conclusion, such compounds are extremely potent, display partial agonism at dopamine D receptors for prime treatment of movement disorders such as Parkinson's disease, and include agonism at serotonin 5-HT, A and noradrenergic a-adrenoceptors to treat mood disorders and dementia, and may also be effective in treating dependence (addiction).

The combination of three desired types of activity into one molecule has a number of advantages in view of combining three different active components in a composition: 1. constant ratio of all activities due to one kinetic behaviour 2. less burden for the body of the patient with chemical compounds 3. less possibilities for undesired side-effects 4. no interaction between active components. The invention is illustrated by but is not restricted to the use of the group of compounds having formula(I)

0 wherein -Y is hydrogen, halogen, alkyl (1-3C), or CN, CF3, OCF3, SCF3, alkoxy (1-3C), amino or mono- or dialkyl (1-3C) substituted amino or hydroxy, -X is O, S, SO or SO2, ----Z represents-C, =C or-N, -R, and R2 independently represent hydrogen or alkyl (1-3C), -Q is benzyl or 2-, 3-or 4-pyridylmethyl, wich groups may be substited with one or more substituents from the group halogen, nitro, cyano, amino, mono-or di (1-3C) alkylamino, (1-3C) alkoxy, CF3, OCF3, SCF3, (1-4C)-alkyl, (1-3C) alkylsulfonyl or hydroxy, and salts and prodrugs thereof.

The compounds are their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials.

Preferrably the compounds of the invention have a high oral bioavailibility (F) which is at least higher than 30% and even more preferred higher than 50%.

The compounds having formula (I) can be obtained as follows : Method A Compounds having formula (I) wherein---Z represents-N or-C can be obtained by reacting the corresponding compound wherein Q is hydrogen with a compound Q-Hal, wherein Q has the

above meanings and Hal is halogen, preferably bromine. This reaction can be carried out in a solvent such as acetonitrile in the presence of a base, for example ethyl-diisopropylamine or triethylamine.

The starting compounds wherein Q is hydrogen and---Z is-N are known or can be obtained as described in EP 0189612. Starting compounds wherein Q is hydrogen and---Z is-C can be obtained as described below in schema A. i (compound III-H).

Method B The compounds B1, i. e compounds having formula (I) wherein---Z represents =C can be obtained according to the method indicated in the following scheme A. i: B1 scheme A. i The starting compound for step (ii) can be obtained according to the procedure described in J.

Org. Chem. 45, (1980), 4789, and step (ii) itself can be carried out as described in J. Org.

Chem., 47, (1982), 2804.

Step (iii) is carried out in a manner known for this type of chemical reactions.

The preparation of the compounds having formula (I) will be illustrated in the following Examples: Example 1: General Procedure for method A : a) To 1 mmol of halide Q-Hal, 0.8 mmol of l-H (---Z =-N) dissolved in 7.5 mi of CH3CN was

added. Subsequently 0.43 ml (2.5 mmol) of (i-Pr) 2NEt was added and the resulting mixture was stirred for 3 hrs at 85 °C. After the reaction mixture had reached roomtemperature, 7.5 ml of dichloromethane were added, the resulting solution was put on top of a solid phase extraction column (Varian 5g type Si) and the fraction containing the desired product was subsequently put on top of a solid phase extraction column (Varian 5g 0.8 meq./g type Strong Cationic Exchange (SCX), conditioned on MeOH, then CH2CI2)) after which the column was washed 2 times with MeOH. Then, the latter column, was washed with 0.1 M NH3/MeOH and elution was performed with 1.0 M NHJMEOH. The eluate was concentrated in vacuo removing solvent and the rest of (i-Pr) 2NEt, yielding the expected product.

It is also possible to perform the purification with standard chromatographic procedures. In a single case (i. e. A1), the solvent used was dimethylformamide (DMF), see below. b) 10.2 g (40 mmol) of l-H. HCI were suspended in 150 ml of DMF, to the stirred resulting mixture 21 ml (120 mmol) of (i-Pr) 2NEt were added. During a period of 10 minutes a solution of 7.0 g (41 mmol) of benzylbromide in 25 mi of DMF was added at room temperature, the process is slightly exothermic (5-10 °C). Stirring was continued 3 hrs at room temperature after which the reaction mixture was poured on to 700 ml of water. Subsequently extraction was performed with 3x 250 ml of ethylacetate, the combined organic fractions washed with 2x 150 ml of water and dried with MgSO4. Removal of the drying agent by filtration and of the solvent in vacuo yielded 10. 5 g of raw product. The latter was purified by flash column chromatography (SiO2, eluent CH2CI2/MeOH 98/2), yielding 8.5 g (69%) of pure product A1 as a free base, m. p.: 189-190 °C.

The compounds A2 to A46 as indicated in table A have been prepared analogously to procedure a) of method A.

TABLE A d = decomposition fb = free base 3 4 HNO 2 5 S c position(s) substitution(s) melting compound Hai salt 2 3 4 5 6 point °C A1 Br fb 189-90 A2 Br fb 220-22 d Br A3 Br fb 170-2 d F F F F F A4 Br fb 220-2 d CN A5 Br fb 130-2 d OMe A6 Br fb 223-5 d SO2Me A7 Br fb 235-7 d Cl Cl A8 Br fb 190-2 d F Me A9 Br fb 200-2 d F F A10 Br fb 122-4 d SCF3 A11 Br fb >250 d Cl Cl A12 Br fb 160-70 d Me A13 Cl fb 165-7 d OMe A14 Br fb 177-9 F F A15 Br fb 150-2 OCF3 A16 Br fb 146-8 Br A17 Br fb 193-5 Br OMe A18 Br fb 170-1 F F F A19 Br fb 195-7 F F A20 Br fb 171-3 OCF3 A21 Br fb 191-6 d Cl ci A22 Br fb 183-6 Me A23 Br fb 132-4 CF3 A24 Br fb 194-206 d F F A25 Br fb 124-7 CF3 A26 Br fb 184-6 tBut A27 Br fb 216-8 d Cl A28 Br fb 115-20 CF3 F A29 Br fb 175-8 CF3 A30 Br fb 186-8 Cl CF3 A31 Br fb 197-200 F F F A32 Br fb 159-63 Br A33 Cl fb 152-8 d Me Me A34 Br fb 178-83 F A35 Br fb 215-9 CN A36 Br fb 198-200 Me Me A37 Br fb 190-5 Me A38 Br fb 166-76 CN A39 Br fb 188-90 CF3 F A40 Br fb 210-4 Cl A41 Br fb 180-6 F A42 Br fb 159-63 F A43 Br fb 178-80 F Cl

TABLE A (continued) 0 HN) 0 NN N/Ng compound Hal salt menti ou point C tb-pyri y me A45 Cl fb 175-9 3-pyridlmethyl A46 Cl fb 230-5 d 4-pyridlmethyl Example 2: Step ii and iii (scheme A. i) : Under an inert atmosphere, 16.5 g (78. 2 mmol) of N- (teft. butyloxycarbonyl)-meta-fluoroaniline were dissolved in 230 ml of dry tetrahydrofuran (THF) after which the solution was cooled to-75 °C (dry ice, acetone). While stirring, a solution of tert. butyl-lithium in heptane (ca. 156 mmol, 2 molequivalents) was added slowly after which the reaction mixture was stirred for 0.5 hrs at-70 °C, and subsequently for an additional 2 hrs at-25 °C. Again the reaction mixture was brought to -75 °C and a solution of 14.4 ml N-benzylpiperidone (78 mmol, 1 molequivalent) in 25 mi of dry THF. The reaction mixture was allowed to reach room temperature and stirred for an additional 16 hrs. Subsequently, 250 ml of 2M HCI was carefully added, the resulting mixture was extracted with EtOAc (3x). The water layer was, while stirring, poured on to 84 g of NaHCO3 after which the waterlayer was again extracted with EtOAc. The resulting organic layer was dried on Na2SO4. After removal of the drying agent by filtration and of the solvent by evaporation in vacuo, 15 g of a dark yellow oil was isolated. Column chromatography (SiO2, eluent : CH2CI2/MeOH 9I1) yielded 7.5 g (ca. 30%) of a light yellow foam. While stirring, 1 g of the foam was triturated with di-ethyl ether and a small volume of EtOAc. After 50 hrs the solid material was filtered and washed with with di-ethyl ether/hexane to yield 0.5 g of a nearly white solid x1, mp 125-8 °C.

Step iv (scheme A. i) : While stirring, 6.3 g (19.4 mmol) of x1 (scheme A. i.) was dissolved in 250 ml of dioxane after which 150 ml of concentrated HCI was added, the resulting mixture was refluxed for 1. 5 hrs.

The reaction mixture was allowed to reach room temperature after which it was poured on to 140 g of NaHCO3, subsequently about 250 ml of EtOAc were added and an amount of water enough to solve all of the solid material, the pH was >7. The layers were separated and the waterlayer was extracted with EtOAc (2x). The combined organic fractions (3), were dried on Na2SO4. After

removal of the drying agent by filtration and of the solvent by concentration in vacuo, 8 g of a dark yellow oil was isolated which solidified on standing. Column chromatography (SiO2, eluent : EtOAc) yielded 4.56 g (ca. 30%) of a nearly white product. The latter was suspended in hexane and stirred for 20 hrs. Filtration and drying of the residue yielded 3.5 g (59%) of a white solid B1 as a free base, mp ca. 153 °C.

Example 3: Preparation of intermediate III-H of scheme A. i.

Step v (scheme A « n 2.71 g (8.9 mmol) of B1 of scheme A. i. were dissolved in 250 ml of absolute EtOH. To the latter solution 0.6 g of 20% Pd (OH) Z on carbon was added after which the reaction mixture was subjected to hydrogenation for 18 hrs at roomtemperature. Subsequently the reaction mixture was filtered (hyflo supercel) and the residu (hyflo) washed with methanol/triethylamine 97/3. The filtrate was concentrated in vacuo yielding 1.87 g of a nearly white solid which was suspended in EtOAc and stirred for 20 hrs. Filtration of the solid and subsequently drying afforded 1.56 g (81 %) of the intermediate III-H (scheme A. i.).