MEDICINAL PRODUCT AND METHOD FOR TREATMENT AND PREVENTION OF DYSKINESIA

Abstract: The invention relates to use of compounds according to formula (I), wherein n preferably is 2; R1 preferably is SO2CH3, R2 preferably is H, and R3 preferably is a C1-C8 alkyl, or pharmaceutically acceptable salts thereof for the production of a medicinal product for treatment and/or prevention of dyskinesia such as dystonia, tremor or chorea. The invention also relates to methods for treatment and prevention of dyskinesia such as dystonia, tremor or chorea, said method comprising administration of a compound according to formula (I).

Description: MEDICINAL PRODUCT AND METHOD FOR TREATMENT AND PREVENTION OF DYSKINESIA Field of the Invention The present invention relates to the use of specific substituted 3-phenylpiperidines and 3-penylpyrrolidine analogs, for the production of a medicinal product for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea. Background art Dyskinesia is characterised by involuntary movements affecting all parts of the body. Depending on the type of involuntary movement, dyskinesia can be divided into several different categories. Involuntary movements characterised by muscle activity leading to a state of irregular contractions of various parts of the body is gener- ally referred to as chorea, whereas dystonia is a condition characterised by sustained involuntary muscle contractions. Tremor is characterised by fine oscillating movements of higher frequency. Dyskinesia may be the result of functional, struc- tural or pharmacologically-induced changes within certain areas of the brain. Dopamine is an abundant neurotrans- mitter closely linked to the control of movements. It is therefore plausible that drugs affecting the dopaminergic system have effects in these conditions. Dyskinesia is e.g. common in patients suffering of Huntington's disease. Huntington's disease is a hereditary neurodegenerative disorder affecting fronto-striatal neuronal systems. The clinical manifestations of the disorder include a wide variety of movement disorders in- eluding symptoms such as tremor, dystonia and chorea. Compound similar to the ones used according to the present invention have been described earlier, e.g. in the International Patent Application No. WO 92/18475, which discloses various phenylazacycloalkanes , in the German Patent publication No. DE 4425143, which discloses 2- (piperazinoalkylthio) pyrmidines and analogs as dopamine D3 receptor ligands, and in the American Patent No. US 4,259,337, which discloses 3- (3-trifluoromethylphenyl) - piperidines such as 3- (3-trifluoromethylphenyl) -N-n- propyl-piperidine with effects upon DA receptors. US Patents Nos. 4,426,386, 4,719,219 and 4,937,346 (Arvidsson et al . ) relate to structural analogs to the compounds used according to the present invention, where the previous are described to be agonists of DA receptors. The compounds used according to the present invention are thought to have DA receptor inhibitory properties. These two categories of pharmacological agents have opposite effects in physiological systems and can therefore not be expected to be useful in the treatment of the same disorders. In addition, a number of papers dealing with 3- substituted 3-phenylpiperidines/pyrrolidines have been published in the literature. However, none of the above mentioned patent publications or articles discuss motor disturbances such as dystonia, tremors or chorea. Summary of the Invention The substituted 3-phenylpiperidine or 3-penyl- pyrrolidine analogs used according to the invention have the ability to modulate dopaminergic transmission by both direct and indirect interactions with dopamine receptors and will thus be useful in the treatment of dyskinesia. Thus, the present invention relates to use of a com- pound according to formula I wherein n = 1-2; Ri is S0 2 R 4 , OS0 2 R 4 , S0 2 NR 4 R 5 , COR 4 , CN, CF 3 , halogen, or H; R 2 in position 2, 4, 5 or 6 is H, F, Cl , Br, or I ; R 3 is H, CF 3 , CH 2 CF 3 , a C^C g alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl , a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3, 3 , 3-trif luoropropyl, 4 , 4 , 4-trif luorobutyl , -(CH 2 ) m -R 6 (wherein m is 1-8) , or CH 2 SCH 3 ; R 4 and R 5 , respectively, are independently H, CF 3 , CH 2 CF 3 , a C 1 -C 8 alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3 , 3 , 3-trif luoropropyl , 4,4, 4-trif luorobutyl, -(CH 2 ) m -R 6 (where m is 1-8), or pheny 1 ; R 6 is phenyl, phenyl substituted with a CN, CF 3 , S0 2 CH 3 , halogen, CH 2 CF 3 , alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkenyl, 2-thiophenyl , 3-thiophenyl, NR 7 C0NR 8 R 9 , or -C0NR 7 R 8 ; R 7 , R 8 and R 9 , respectively, are independently H, C^C,, alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, or a pharmaceutically acceptable salt thereof, for the production of a medicinal product for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea . The present invention also relates to a method for treatment and/or prevention of dyskinesia, such as tremor, dystonia or chorea, said method comprising ad- ministration an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof . Preferably, in formula I, n is 2; Rj is S0 2 CH 3 , R 2 is H, and R 3 is a alkyl. The compounds used according to the present invention possess pharmacological effects, direct or indirect, on dopamine receptors. Among the different dyskinesias, e.g. idiopatic torsion dystonia including the focal seg- mental and generalised dystonias, cerebral paresis, he- reditary dystonias, dystonia caused by hereditary metabolic diseases such as Wilson's disease, neuroleptic induced movement disorders, dyskinesias in schizophrenia, stuttering, movement disorders due to stroke, only L-DOPA induced dyskinesias show a direct relation to dopamin overactivity. In dyskinesias with other underlying patho- pysiology, dopamine receptor overactivity has not been shown. Therefore the effect of the compounds used according to the invention of dystonias, tremor and chorea in e.g. Huntington's disease is surprising. Furthermore, pa- tients with Huntington's disease show no evidence of a dysfunctional dopamine system. The compounds used according to the invention may be both racemic mixtures and the pure enantiomers. However, preferred compounds have the S absolute configuration, according to the Cahn-Ingold- Prelog priority rules. Depending on the N-substituent , some of these S-enantiomers are dextrorotatory while others are levorotatory. Detailed Description of the Invention The term "patient" used herein refers to an individual in need of the treatment and/or prevention according to the invention. As used herein the term C m -C n relates to compounds consisting of m-n carbon atoms, for example a C^C g alkyl refers to an alkyl containing 1-8 carbon atoms in any isomeric form. The various carbon moieties are defined as follows. Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, i-hexyl, n-heptyl, i-heptyl and n-octyl . Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbon having a double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-1-ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl -4 -pentenyl, 3 -methyl -1-pentenyl, 3 -methyl-2- pentenyl , 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1- methyl-4-hexenyl, 3 -methyl-1-hexenyl, 3 -methyl -2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl- 4-heptenyl, 3 -methyl-1-heptenyl, 3 -methyl-2-heptenyl, 1- octenyl, 2-octenyl or 3-octenyl. Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl . It will be apparent to persons skilled in the art that the compounds used according to the invention contain one chiral centre. The compounds according to formula I contain an asymmetric carbon atom in the aliphatic ring moiety (carbon 3 in the heterocyclic ring relative to phenyl ring junction) . Some of these compounds have DA receptor modulating properties. Some of the therapeutic effects lies in the modulation of dopamine receptor properties. The scope of this invention includes both the S and the R enantiomers of the compounds of formula I in their pure form, as well as mixtures thereof .. Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisul- fonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are readily prepared by methods known in the art . The compounds used according to the invention may e.g. be obtained by one of the methods in the Interna- tional Patent Publication WO 92/18475. The medicinal product containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations. Such sub- stances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives. In clinical practice the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The use and administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art . In therapeutical treatment an effective amount or a therapeutic amount of the compounds of the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily. The compounds may be administered in any suitable way, such as orally or parentarally. The daily dose will preferably be admin- istered in individual dosages 1 to 4 times daily. The compounds used according the invention wherein R x is H and R 2 C1-C8 alkyl are DA receptor ligands. These compounds have central stabilising properties without self-administration liability. Uses for these compounds include preventing and treating dyskinesia. The utilisation of the compounds of this invention in treatment of dyskinesia is shown by their ability to reduce symptoms, such as specially tremor, dystonia and chorea in patients suffering of Huntington's disease. They can also be used for the treatment of movement disturbances in patients suffering from idiopatic torsion dystonia including the focal segmental and generalised dystonias, cerebral paresis, hereditary dystonias, dystonia caused by hereditary metabolic diseases such as Wilson's disease, neuroleptic induced movement disorders, dyskinesias in schizophrenia, stuttering, and movement disorders due to stroke. Since the motor symptoms in these disorders are not dependent on over-stimulation of central dopamine receptors, as is the case with L-DOPA induced dyskinesias, the symptom reduction obtained by the compounds used according to the invention in the disorders listed above, e.g. Huntington's disease, must be achieved by different mechanisms than in L-DOPA induced dyskinesia. The compounds used according to the invention have high oral availability and sufficient duration of action. Both these features are beneficial for effective clinical treatment. It is also possible to use the compounds according to formula I for treatment and prevention of dyskinesia in combination with other psychological or alternative pharmacological treatments. The invention is further illustrated in the example below, which in no way is intended to limit the scope of the invention. Brief description of the drawings In the example below reference is made to the appended drawings on which: Fig. 1 illustrates the effects of a substance according to the invention on postural tremor in patients with Huntington's disease. The ratings for tremor was done upon clinical examination according to the scale of Jankovic et al . before administration (baseline) and 5 hours after administration. Fig. 2 illustrates the effects of a substance according to the invention on dystonia in patients with Huntington's disease. Dystonia was rated according to the UHDRS before administration (baseline) and one day after administration. Fig. 3 illustrates the effects of a substance according to the invention on chorea in patients with Huntington's disease. The average number of the patents' involuntary movement events for two peri- ods of two minutes each was determined before administration (baseline) and 1, 3 and 5 hours, respectively after administration. Example This example describe how to prepare the various compounds and/or perform the various processes of the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to re- actants and as to reaction conditions and techniques. In the example Huntington's disease is used as a model disorder in order to establish a potential clinical efficacy on dyskinesia such as tremors, dystonia and chorea, but the application can be used for all types of dyskinesia. The substance according to the invention used in the example was S- (-) -3- [3- (methylsulfonyl) phenyl] -1- propylpiperidine [below called (-) -OSU6162] . The substance was administered intravenously in an amount of 0.5 g/kg to patients with Huntington's disease and the ef- feet on tremor, dystonia and chorea was studied. In a clinical open-label study the effects of single doses (-)-OSU6162 given intravenously to HD patients was investigated. The motor status of the patients was scored from video recordings made before and after drug admini- stration under standardised conditions as well as by a regular clinical examination. First the score of postural tremor in two patients with Huntington's disease was determined. The ratings for tremor was done upon clinical examination according to the scale of Jankovic et al . (see Jankovic J. et al . , J. Mov. Disord. 1996; 11:250-256) graded from 0 (absent) to 4 (severe, coarse, disabling) . The ratings were performed before administration of the substance according to the invention (baseline) and 5 hours following administration of (-)-OSU6162. The result is illustrated in figure 1. The values shown are means ± S.D. Then the score of dystonia in 7 patients with Huntington's disease were determined before administration (baseline) and after administration of (-)-OSU6162. Dystonia was rated according to the UHDRS (Unified Huntington's Disease Rating Scale, Mov. Disord. 1996, 11:136-142) with a scale for maximal dystonia graded from 0 (absent) to 4 (marked/prolonged) in trunk, right and left upper extremities and right and left lower extremities. Dystonia was rated before administration (baseline) and one day after (-)-OSU6162 administration. The result is illustrated in figure 2. The values shown are means ± S.D. The reduction in dystonia is significant at the P=0.043 level (Wilcoxon signed rank Test). Finally, chorea in six patients with Huntington's disease was studied. The patients were instructed to sit still in a chair for 10 minutes. Choreatic events were counted during two two-minute periods (2-4 minutes and 6- 8 minutes in the 10 minute time span) . These 10 minute recordings were done on the same day at least three times before drug administration. Following drug administration the patients underwent the same procedure at one, three and five hours. Patients also underwent clinical examinations by a specialist in neurology when rating for dystonia and tremor was performed before and after drug ad- ministration. The results are illustrated in figure 3. The values shown are means ± S.D. The reduction in chore- atic events is significant at the P=0.028 level 5 hours after treatment (Wilcoxon signed rank Test) .

Claims: CLAIMS 1. Use of a compound according to formula I wherein n = 1-2; Ri is S0 2 R 4 , OS0 2 R 4 , S0 2 NR 4 R 5 , C0R 4 , CN, CF 3 , halogen, or H; R 2 in position 2, 4, 5 or 6 is H, F, Cl , Br, or I; R 3 is H, CF 3 , CH 2 CF 3 , a alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3, 3 , 3-trif luoropropyl, 4 , 4 , 4-trif luorobutyl , -(CH 2 ) m -R 6 (wherein m is 1-8) , or CH 2 SCH 3 ; R 4 and R 5 , respectively, are independently H, CF 3 , CH 2 CF 3 , a C 1 -C 8 alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3 , 3 , 3-trif luoropropyl , 4, 4, 4-trif luorobutyl, -(CH 2 ) ra -R 6 (where m is 1-8) , or phenyl ; R 5 is phenyl, phenyl substituted with a CN, CF 3 , S0 2 CH 3 , halogen, CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkenyl, 2-thiophenyl, 3-thiophenyl, NR 7 CONR 8 R 9 , or -CONR 7 R 8 ; R 7 , R 8 and R 9 , respectively, are independently H, C 1 -C 8 al- kyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, or a pharmaceutically acceptable salt thereof, for the production of a medicinal product for treatment and/or prevention of dyskinesia. 2. Use according to claim 1, wherein the compound according to formula I is a pure R enantiomer. 3. Use according to claim 1, wherein the compound according to formula I is a pure S enantiomer. 4. Use according to any one of the claims 1-3, wherein n = 2, R 1 is S0 2 CH 3 , R 2 is H, and R 3 is a C 1 -C 8 alkyl. 5. Use according to claim 4, wherein R 3 is n-propyl . 6. Use according to any one of the claims 1-5, wherein the medicinal product is formulated for oral administration. 7. Use according to any one of the claims 1-5, wherein the medicinal product is formulated for parental administration . 8. Use according to any one of the claims 1-7, wherein the medicinal product is intended for treatment and/or prevention of dyskinesia in the form of tremor, dystonia or chorea. 9. Use according to any one of the claims 1-8, wherein the medicinal product is intended for treatment and/or prevention of Huntington's disease. 10. Use according to any one of the claims 1-8, wherein the medicinal product is intended for treatment and/or prevention of movement disturbances in patients suffering from idiopatic torsion dystonia, cerebral paresis, hereditary dystonias, dystonia caused by hereditary metabolic diseases, dyskinesias in schizophrenia, stuttering, and/or movement disorders due to stroke. 11. Use according to any one of the claims 1-8, wherein the medicinal product is intended for treatment and/or prevention of neuroleptic induced movement disorders. 12. A method for treatment and prevention of dyskinesia, which comprises administration to a patient of an effective amount of a phenyl -piperidine/pyrrolidine according to formula I : wherein n =1-2; R τ is S0 2 R 4 , OS0 2 R 4 , S0 2 NR 4 R 4 , COR 4 , CN, CF 3 , halogen, or H; R 2 in position 2, 4, 5 or 6 is H, F, Cl , Br, or I; R 3 is H, CF 3 , CH 2 CF 3 , a C^-C 8 alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3, 3 , 3-trif luoropropyl, 4 , 4 , 4-trif luorobutyl , -(CH 2 ) ra -R s (wherein m is 1-8) , or CH 2 SCH 3 ; R 4 is CF 3 , CH 2 CF 3 , a C^C g alkyl, a C 3 -C 8 cycloalkyl, a C 4 -C 9 cycloalkylmethyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, 3,3,3- trif luoropropyl, 4 , 4 , 4-trif luorobutyl , -(CH 2 ) m -R 5 (where m is 1-8) , or phenyl, R 5 is phenyl, phenyl substituted with a CN, CF 3 , S0 2 CH 3 , halogen, CH 2 CF 3 , C^C g alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkenyl, 2-thiophenyl , 3-thiophenyl, NR 6 CONR 6 R 7 , OR -CONR s R 7 R 6 and R 7 , respectively, are independently H, alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkylmethyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, or a pharmaceutically acceptable salt thereof. 13. A method according to claim 12, wherein the compound according to formula I is a pure R enantiomer. 14. A method according to claim 12, wherein the compound according to formula I is a pure S enantiomer. 15. A method according to any one of the claims 12- 14, wherein n = 2, R x is S0 2 CH 3 , R 2 is H, and R 3 is a Ci-C 8 alkyl . 16. A method according to claim 15, wherein R 3 is n- propyl . 17. A method according to any one of the claim 12- 16, wherein the compound according to formula I or its pharmaceutically acceptable salt is administered to a patient in a daily dose of 0.01-500 mg/kg body weight. 18. A method according to any one of the claims 12- 17, wherein the dyskinesia to be treated and/or prevented is tremor, dystonia or chorea. 19. A method according to any one of the claims 12- 18, wherein the dyskinesia to be treated and/or prevented is Huntington's disease. 20. A method according to any one of the claims 12- 18, wherein the dyskinesia to be treated and/or prevented is a movement disturbance in a patient suffering from a condition selected from the group consisting of idiopatic torsion dystonia, cerebral paresis, hereditary dystonias, dystonia caused by hereditary metabolic diseases, dyskinesias in schizophrenia, stuttering, and movement disor- ders due to stroke. 21. A method according to any one of the claims 12- 18, wherein the dyskinesia to be treated and/or prevented is a neuroleptic induced movement disorder.

Inventors: CARLSSON ARVID, SONESSON CLAS AAKE, WATERS ROSS NICHOLAS, CARLSSON, ARVID, SONESSON, CLAS, AAKE, WATERS, ROSS, NICHOLAS
Applicants: CARLSSON ARVID, SONESSON CLAS AAKE, WATERS ROSS NICHOLAS, CARLSSON, ARVID, SONESSON, CLAS, AAKE, WATERS, ROSS, NICHOLAS
Application year: 1999
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D211