TWI292314B - - Google Patents

Description

1292314 V. INSTRUCTIONS (1) t-producing the treatment of extrapyramids with respect to α)-(-)-2-[5_(4-fluorophenyl)_3f-ylaminomethyl]-purine or its physiologically acceptable salt The drug for action lesions and/or the use of it for the adverse effects of in vitro action lesions < M times ^ manufacturing treatment of anti-Bakinson drugs, relaxant-induced extrapyramidal syndrome (Eps and / or manufacturing treatment) By nerve pine (R)-(-)-2-[5-(4-fluoro stupid drug. 々a its physiologically acceptable salt (American dipyridylmethylamine methyl) a spray?# or, Lines 6 to 32) and it/they, No. 5,767,132, col. 9, No. 5,767,132, Example 19), U.S. Patent No. 5, the compound referred to herein is the fifth in the national patent case. 767, 1 32 Dopamine D2 Receptor Antagonists and 5~HT 'patent are described as a selective which reveals the use of a combination of (R)-(-)-2~ agonists. Therefore, Kib sputum and It is physiologically acceptable for the sequelae of cerebral infarction caused by bismuth fluorophenyl guanidinium amide (addition of salt to the brain to prevent and control and control brain diseases (such as head, such as stroke and brain) Partial deficiency Blood; pre-existing with some ergot alkaloids), especially in geriatrics, its dysfunction and depression, by the central gods; treatment of anxiety, mental tightness and food absorption disorders; or treatment of sputum = sexual dysfunction caused by the system; sleep, in addition, it is suitable to eliminate the recognition;; disease (schizophrenia). Treatment of Alzheimer's disease. It can also be used to improve the learning and memory, and treatment, endocrine In the study of gynecology and gynecology, in the treatment of sputum blood pressure treatment, the side effects can be insufficient, continuous menopause, such as treatment of acromegaly, gonads, the purpose of the invention is to provide (R f f group or undesired childbirth . Alkylmethyl]-biting > rabbit and its physiological ^ 2 - [5 - (tetrafluoro-phenyl) - 3 -pyridinium ^ ^ acceptable salt of the novel use.

1292314 V. INSTRUCTIONS (2) (R)-(-)-2 - [5-(4-Fluorophenyl)-3-pyridinemethylaminemethyl]-bit disclosed herein and its physiologically acceptable Salts have significantly better pharmacological properties than the compounds of the prior art. It has been found that (R)-(-)-2- [5-(4-fluorophenyl)-3 - π-pyridylmethylaminomethyl]-spray % or its physiologically acceptable salts are also Action lesions such as idiopathic Parkinson's disease, Parkinson's syndrome, dyskinesia, chorea, or dystonia syndrome, Yan dynasty, Drett syndrome, Fu Jie, myoclonus, restless legs syndrome Or Wilson's disease and extrapyramidal motion disorder caused by nerve relaxants [synonymous with extrapyramidal symptoms (EPS)] with >rapeutic activity. In addition, it has been found that (R)-2-(5-(4-fluorophenyl)-3-pyridylmethylamine methyl bromide or a physiologically acceptable salt thereof has antibacterial action against the Parkinson's disease. Adverse effects (especially anti-Parkinson's agents on the adverse effects of dopamine in spontaneous S. Parkinson's disease or Parkinson's syndrome). It has also been found that (R) -(-)- 2 - [5 -(4-fluorophenyl)-3 - π than methylamine methyl]-penetration or its physiologically acceptable salt exhibits extremely low performance The tendency to induce extrapyramidal side effects. Extrapyramidal side effects, such as in rodents, can be measured by the ability of the drug to cause tonic fainting. Tonic fainting is defined as the state in which an animal continues to maintain an abnormal (non-physiological "uncomforty π) posture for a prolonged period of time (eg, Μ·Ε. Stanley (Μ·Ε·Stanley) and S· Neuropharmacology of SD Glick, 1996; 15: 393-394; CJE Niemegeers and S·Jensen (Ρ· Janssen) Life Sci·, 1979, 20b 2216) . For example, if one

1292314 V. INSTRUCTIONS (3) ~—The rear paw of a rat is placed in an elevated horizontal plane (for example, a height of 3 cm above the ground: a V. 隹 正 正 常 常 常 会 会 会 会 会 会 会The claws are retracted to = 丄 and a f-toothed faint squirrel will even keep this - unnatural for a few minutes. , 2(10 -(-)-2-(4-Better phenyl)- 3 - decylamine oxime Base

% fΪ Ί 文 salt has a dopamine antagonism mechanism known to induce extrapyramidal side effects (C.J E. Nimes (c; E

Niemegeers) and Ρ·Jensen (Ρ· Janssen) LifeSci·, 1 9 7 9, 2 0 1 -2 2 1 6 ) ' However, unexpectedly, (R)-(>) —2_[5_(4 Fluorophenyl)-3-pyridylmethylamine:yl]-biting did not cause any tonic fainting in the animal model (which showed the aforementioned indication for treatment) when the effective agent s reached a 500-fold dose. Even more extravagant 6^疋'(R)-(a)-1-2-[5-(4-fluorophenyl)-3-pyridylmethyl^methyl]-spray v/〇 or its physiologically acceptable salt It can prevent the tonic fainting caused by traditional anti-dopamine agents, and even reduce the tonic fainting caused by traditional anti-dopamine agents such as haloperidol; the dose of this anti-straight fainting effect is the same as the aforementioned animal model (which shows the foregoing The effective dosage indication for indication of treatment is within the same dosage range. Other agents having a 5 - HT1A agonistic effect on the extra-pyramidal motion system have been previously described. For example, Buspirone, a sexually remedy agent, exhibits mild anti-motor difficulties in patients with late-stage Parkinson's disease (B. Kleedorfer et al., J Neurol Neurosurg Psychiatry, 1991, 54: 3 76-3 77; V. Bonifati et al., Clin Neuropharmacol, 1994,

Page 6 1292314 V. Description of invention (4) 1 7 : 7 3 - 8 2 ). The main mechanism of this effect is apparently the 5-HT1A receptor e(R)-(~)-2-[5_(4-fluorophenyl)-3-D-pyridylmethyl via the stimulation of the substantia nigra and the fringe path. Amidoxime]-sneezing and its physiologically acceptable salts are very different from those of spirulina, which is an IC5 at the 5-HT1A receptor. For 1 nmole/Ι (buspirone IC5G: 30 nmol/1), it is apparent (30-fold) a more potent agonist. In addition, (R)-(-)- 2 -[5-(4-fluorophenyl)-3-pyridylmethylaminemethyl]-propion 03⁄4 and its physiologically acceptable salts show d2 antagonisticity at doses This property is an additional advantage compared to the traditional 5 - Η T1A agonist (such as 巴斯皮隆). On the one hand, D2 antagonism reduces the risk of psychosis due to stimulation of serotonin receptors, and on the other hand indirectly enhances the non-selective Di/Dg agonist levodopa#iDi characteristics. More selective stimulators are known to be beneficial for the treatment of Parkinson's disease (PJ Blanchet et al., J Neural Transm, 1 9 9 5, 45 (Suppl): 103-112). Therefore, (R)-(-)-2-[5-(4-fluorophenyl 3-pyridinylaminomethyl)-spray & or its physiologically acceptable salt 5 - HT1A agonism and 〇 Both antagonistic effects provide beneficial effects on the extrapyramidal system. (R)-(-)-2-[5-U-fluorophenyl)-3-pyridinemethylaminemethyl]one bite or Another pharmacologically characteristic salt of a physiologically acceptable salt is the high affinity for the dopamine])3 receptor. D3 receptors are clearly associated with the onset of dyskinesia. Therefore, the relationship between the genetic polymorphism of the dopamine D3 receptor and the tendency to develop delayed onset dyskinesia has recently been published (Segma η η et al. 1999, Mol - Psychiatry 4: 247) ). In addition, cited by levodopa

1292314 V. INSTRUCTIONS (5) The density of dopamine receptors in patients with exercise difficulties in Parkinson's disease is significantly increased. Therefore, '(R)-(-)- 2-[5-(4-d-phenyl)- 3 - π is a bite-methylamine methyl bromide or one of its physiologically acceptable salts and dopamine D3 receptor The interaction is another important mechanism that has a beneficial effect on extrapyramidal systems, especially in the treatment of motor difficulties. The atypical mental relaxant clozapine is associated with extrapyramidal effects, but not related to structure or side effects, this is related to (R)-(-)-2-[5-(4-phenylphenyl)-3-pyridine Mercaptoamine methyl] a bite or a physiologically acceptable salt thereof (especially in the range of properties against tonic fainting). Recent studies have provided evidence that Qi Pingping improves exercise difficulties in Parkinson's disease (F·Pirelli).

Acti Neurol Scan of Perelli et al., 1 9 9 8, 9 7: 2 9 5- 2 9 9 ; Ρ· Poliak et al. 1^11.61;, 1999, 353:2041- 2 0 4 1). In addition, it is known that gas flattening has many other beneficial effects on extrapyramidal lesions, such as delayed onset dyskinesia, tremor, hallidonic disease, drett syndrome, sedative (akathisia) and pseudo-dopamine psychosis ( C. non-fog (pfeiffer) and ml · Wagner's Am J Hosp

Pharm, 1 9 94, 51·· 3 047-3 0 5 3 ). (1〇-(-)-2_[5-(4-fluorobenzene)

A 3-pyridylmethylamine methyl]-snack or a physiologically acceptable salt thereof to improve the risk of such actional lesions and even no fatal side effects (such as granulocytic leukemia and acute nephritis) (J · Ai V (J · A 1 vir ) et al.

Engl J Med, 1 9 9 3, 3 2 9: 1 6 2 - 1 6 7 ; T\J. T.J. Elias et al. Lancet, 1999, 3 54: 1180 - 1181). Thus, the present invention relates to the use of (R)-(i)-2-[5-(4-fluorophenyl)-3-pyridinylaminomethyl]-injection or a physiologically acceptable salt thereof, Used for

1292314 V. INSTRUCTIONS (6) Manufacture of agents for treating extrapyramidal lesions. A preferred (R)-(-)-2 - [5-(4-carbophenyl)-3-batch methylamine thiol]-penetrating salt is (R)-(-)-2 - [ 5-(4-IPhenyl)-3-batch guanidinoamine thiol]-penetration hydrochloride. Accordingly, the present invention relates to the manufacture of a medicament for the treatment of extrapyramidal lesions, wherein the pharmacologically acceptable salt is (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinemethylamine Methyl]-bite: bite hydrochloride. Furthermore, the present invention relates to the use of a pharmaceutical composition for treating extrapyramidal motion lesions, wherein the pharmaceutical composition comprises at least one (R)-(-)-2_[ 5-(4-fluorophenyl 3-pyridinemethylamine oxime) One of the base compounds or a biocompatible salt thereof and at least one solid, liquid or semi-fluid excipient or additive. (R) -(-)- 2 - [5 -(4 - ILphenyl) -3-[1 than 唆methylaminoindenyl]-spray or physiologically acceptable salts can be used to treat extrapyramidal lesions, especially in the treatment of spontaneous Parkinson's disease, Parkinson's syndrome, dyskinesia, chorea Or dystonia syndrome, extrapyramidal dysfunction of mental relaxants, tremors, Drett syndrome, snoring, myoclonus, leg restless syndrome or Wilson's disease and/or for the treatment of spontaneous Bajinsen An adverse effect of the disease or Parkinson's syndrome, which comprises a pharmaceutical composition as defined below, preferably in an amount of from 0.1 to 100 mg, preferably from about 1 to 20 mg. The composition can be administered one or more times a day, such as daily. 2, 3, or 4 times. The specific dose of each patient depends on a variety of Depending on factors, such as, depending on the particular active compound used according to the age, body weight, general health, the number and manner by sex, diet, administration, rate of excretion by, and associated pharmaceutical compositions of matter by treating

1292314 V. Inventive Note (7) The severity of the specific lesion. Oral administration is preferred, but parenteral administration (e.g., intravenous or transdermal) can also be used. Anti-Bakinson's agents are traditional agents such as levodopa and a combination of levodopa and benserazide or carbidopa; dopamine agonists such as bromocriptine, morphine, kay Caberoline, pramipexol, ropinirol, perg〇iide, dihydro-α-ergoline or ergoside plus all An agent that stimulates the action of dopamine receptors; a catechin--0-methyltransferase (C0MT) inhibitor, such as an entacapone or tolcapone; a monoamine oxidized plum (MAO) inhibitor, Such as selegiline; and N-methyl-D-aspartate (NMDA) agonists, such as amantadine or budipine ° The adverse effects of this anti-Bakinson drug are various Difficulties in exercise, such as chorea, dystonia, dysfunction or difficulty in movement of myoclonus, and movement (reaction) changes or mental illness. Accordingly, the present invention relates to the use of (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamino)- thiophene- or a physiologically acceptable salt thereof, It is used in the manufacture of drugs to treat the adverse effects of anti-Parkinson's drugs in spontaneous Parkinson's disease. The adverse treatment of the traditional anti-Parkinson's agent as defined above is based on the P. J. Blanchet special Exp. Neurology 1998; 153: 2 1 4-222. Model improvement method. Repeated injection of diterpene-4-phenyl-1,2,3,6-tetrahydro[1 than the lake (|^7?) to make the wolf

Page 10 1292314 V. Description of invention (8) One---. Get Bajinsen's disease. This Bajinsen monkey such as BUnchet) and others Mov. Disord., l 9 9 8; 7 9 8_ I], ^ The condition is treated with standard levodopa. In the long-term of levodopa: 斤 Ϊ Ϊ t ί in vitro adverse effects and mental state can be based on abnormal state;; autonomous, momentum meter (P. J. Blanchet et al.

Disced· 1 9 9 8; 1 3: 7 9 8 - 8〇 2) Determine the quality and quantity of different body parts (face: i trunk, limbs), and observe the monkey's note, Responsiveness and activity to assess mental status. (R) — (-)— 2—[5-, (4-Fluorophenyl)-1,3-pyridinylaminomethyl]-spray strips reduce the exercise difficulty of the dance and the difficulty of dystonia and mental illness. A typical study investigating the efficacy of a compound according to the invention against adverse effects of Parkinson's disease is described below. There are 4 cases of spontaneous gender-specific Parkinson's disease in patients with "severe dose" (peak dose) who have difficulty in exercise. The main criteria for inclusion are Hoen && Yahr) Stage-2· 5 (Document: Hoen η. M· (Hoehn Η·Μ·) and others Neurology 1 9 6 7; 1 7: 42 7-442 ), age 4:1 7 5 During the years, the symptoms persist for at least 5 years, and at least 3 years of levodopa treatment. (R) - (- Bu 2 - [5 - (4-fluorophenyl) - 3 -pyridinyl fluorenyl] Spray this with hydrochloride or placebo in the form of "addition" in traditional Parkinson's therapy, which remained unchanged throughout the study period. The dose of blind drug was between 2 and 5 -1 mg per 3 stars. Titrate within the second day of the day. Then maintain this fixed treatment for 1 week. Before starting the titration and at the end of the treatment period, according to P. Damier et al. (Movement Disord, 1999, 14 (Suppl. 1) , 5 4 - 5 9 ) Apply levodopa and record it with a video recorder. In the process of the main

1292314 V. INSTRUCTIONS (9) The results of the measurement are the average scores of exercise difficulty during the first hour of π-starting π state after administration of levodopa. Therefore, the investigator assessed the severity of exercise difficulties per minute in the seven parts of the body (upper and lower limbs, face, torso, neck) from 0 to 4 (0 = no, 4 = severe disability, non-autonomous movement). After the two-week clearance period, cross the two study groups and repeat the process. Statistical analysis of the mean motor difficulty scores showed that under (R)_(-)-2-[5-(4-fluorophenyl)-3-indolyl]-deuterated hydrazinyl]-spray hydrochloride treatment Significant clinical improvement. A preferred (R)-(-)-2 - [5-(4-phenylphenyl)-3-pyrene-pyridylpyridylamine fluorenyl]-spray salt-free R-(-)-2- [5-(4-Fluorophenyl)-3-pyridinemethylamine fluorenyl]-bite; HCl salt. Accordingly, the present invention relates to the manufacture of a medicament for treating an adverse effect of an anti-Parkinson's drug in spontaneous Parkinson's disease, wherein the pharmacologically acceptable salt is (R)-(-)-2-[5-(4- Fluorophenyl)-3-pyridinylamine fluorenyl]-spray 13⁄4 hydrochloride. Further, the present invention relates to the use of a pharmaceutical composition for treating an adverse effect of an anti-Parkinson's drug in spontaneous Parkinson's disease, the pharmaceutical composition comprising at least one (r)-(a)-one-one [5-( 4-fluorophenyl)-3-pyrene ratio 曱 曱 曱 ] ] ] ] : : : : : : : 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 。 。 。 。 。 。 。 。 。 。 。 Further, the present invention relates to the use of (R)-(-)-2-[5-(4-fluorophenyl)_3-D[ta-decylaminomethyl]-bit; 03⁄4 or a physiologically acceptable salt thereof It is used to manufacture drugs for the treatment of spontaneous Parkinson's disease. A typical animal model of spontaneous Parkinson's disease is based on P. J. B. anchet's Exp. Neurology 1 9 9 8; 1 5 3: 2 1 4- 2 2 2

Page 12 1292314 V. Description of the invention (10) The recorded Bajinsen monkey. Repeated injections of 1-indolyl-4-phenyl-indole and 2,3 6-tetrahydropyridine (MPTP) gave monkeys Parkinson's disease. The following symptoms of Parkinson's disease were qualitatively measured using the Laval University Disability Scale (B High Metz-Mancilla et al 1993; Mov· Disord. 8: 144-150): posture, live Power, climbing, pace, grasping food, vocalization, dressing, social interaction. (R) — ( — ) — 2 — [ 5 - ( 4 -Gasphenyl)-3-pyridinylamine thiol]-spray 13⁄4 reduces all Parkinson's symptoms and increases overall activity. A typical study investigating the efficacy of a compound according to the invention in the treatment of spontaneous Parkinson's disease is as follows. There are 180 spontaneous sex rats of any gender. Patients with Jinsen's disease participate in this double-blind study. The main criteria are Jue & Yahr stage S2.0 (Horn Η·Μ · (Hoehn H· Μ·), Neurology 1967; 17: 427-442), age 50-80 years, symptoms lasting at least 5 years. (1〇-(-)_2-[5-(4-fluorobenzene) ))-3-pyridine 曱 曱 曱 ] ] ] ] ] 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬 咬The dose of the drug is titrated for a period of 4 weeks in the range of 2.5 to 10 mg twice a day. This fixed treatment is then maintained for one week. Before the start of the titration, at the end of the treatment period, and 2 weeks after the end of the titration period, in each The patient was assigned the Unified Parkinson's disease rating scale (UPDRS Part I to V, according to S. Fahn et al., 1987 by Macmillan Health Information. Published recently, Developments in Parkinson's Disease, Volume 2, pp. 153-163 (S. Fahn et al., in: Recent developments in Park) Inson’s disease,

Page 13 1292314 V. Description of invention (11) vo1· 2, MacMillan health information 1 9 8 7 Ί c0 16 3)) Analyze. At the same time ('~ two rur human based on its physiologically acceptable salt yf ^z (4- disordered phenyl) - 3 pyridylamine Yi Zhu (7) 疋 机 function 'tension disorder, motion disturbance, Chu salt) The statistical analysis of the number shows that it is clinically treated under the treatment of (1〇_(_)_2_[5_(4__„°71)^分基胺曱基]-Spray hydrochloride; If]盖3一吼甲甲A preferred (r)-(_)_2_[5_(4_ phenylene). The base (iv) salt is (1)-(+2-[5_Ji-; dimethylaminomethyl]- squid hydrochloride. (4 chaotic base)-3-3⁄4 bite methylamine A. The present invention relates to the manufacture of a medicament for the treatment of spontaneity, wherein the physiologically acceptable salt is (R)_(_)_2_[5_(4_l-based octadecylamine) In addition, the present invention relates to the use of a pharmaceutical composition for treating spontaneous Parkinson's disease, the pharmaceutical composition comprising at least one (r) - (")_2-[5 a (4-phenylphenyl)-3-pyridinylaminomethyl]- sneezing compound or a bismuth biocompatible salt and at least one solid, liquid or semi-fluid excipient or additive. And/or dopamine agonists for the treatment of Parkinson's disease The system is usually caused by mental illness or exercise difficulties or other movement changes. It has been found that (R)-(-)-2-[5-(4-fluorophenyl)-3 - mouth ratio bite methylamine thiol] spray The physiologically acceptable salt thereof or the physiologically acceptable salt thereof enhances the anti-Parkinson's anti-Parkinson's efficacy without causing extrapyramidal side effects.

Page 14 1292314 V. INSTRUCTIONS (12) Therefore, (R)-[5-(4-fluorophenyl)-3-pyridinylamine sulfhydryl]-penetration or its physiologically acceptable salt (special Is an additional therapy with (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminoindolyl]-spray hydrochloride, which now opens with the addition of levodopa and / or dopamine agonist and / or all other doses of anti-Parkinson's agent as defined above, to offset the period of insufficient motor function (π closed π phase), and does not cause the side effects mentioned above. This represents a completely novel treatment for Parkinson's disease that is significantly beneficial to the patient.

Accordingly, the present invention relates to a pharmaceutical composition comprising (i) (R) -(-)-2 - [5-(4-phenyl)_3 - D as a living group as an active ingredient - a bite or a physiologically acceptable salt thereof and (ii) at least one anti-Parkinson's drug, in combination with one or more pharmaceutically acceptable excipients. In particular, the present invention relates to a pharmaceutical composition comprising (i) (R)-(-)-2-[ [4-(4-fluorophenyl)-3-吼π曱 as an active ingredient. Amidoxime]-bite; hydrochloride and (ii) levodopa or levodopa in combination with silkworm or carbidopa, in combination with one or more pharmaceutically acceptable excipients. , (R) -- 2-[5 -(4-fluorophenyl)-3-port ratio sigma-decylamine sulfhydryl]-spray or one of its physiologically acceptable salts and various doses of traditional anti-bakinson agents The ratio therefore varies depending on the outcome.

(R)-(-)-2_[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]-spray? ^ The weight ratio of one of its physiologically acceptable salts to the conventional anti-Parkinson's agent is preferably from 1:1 to 1:100, preferably from 1:10 to 1:90, and is 1: 4 0 to 1: 6 0 is better.

Page 15 1292314 V. INSTRUCTIONS (13) Another subject of the present invention is (R)-(-) 2 - [5-(4-fluoromethane, decylamine sulfhydryl)-spray or its physiology Another use of one of the above acceptable salts and two: 3, a combination of pyridinium and phenoxygen, which is used in a pharmaceutical composition for anti-Bakinson's anti-Bakinson efficacy. According to the present invention, the term "pharmaceutical composition" means the above-mentioned medical compound 戍) (wherein two active ingredients or compounds are the same composition of the same composition, ', or both) The set of the composition, the first one contains when the group is to be sturdy, smashed, and divided into (f〇-(-)-2[5-(4-fluorophenyl]-Ipyridinium 1 ^ single bracelet 涪a sputum or a physiologically acceptable salt thereof, and a second one comprising at least one thiol group. The anti-Bakinson medicinal agent. For the cleansing when the pharmaceutical composition is in the form of a kit, the drug is administered separately. Two compositions, but they are a combination therapy. Preferably, the set of (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinemethylaminemethyl]-spray Use the acid salt form. The adverse effects of defining anti-Bakinson's agents are known in the Parkinson's syndrome. ... ^Kinsen syndrome is, for example, multiple systemic atrophy (MS A ), Stie-Richardlin's syndrome (Steele-Richardson-Olszewski) Synjr^ome) (== progressive nucleus itching), cortical basal degeneration, olive pons

Cerebellar atrophy or shy Drager syndrome. (R)-( Ib 2~[5-(4-fluorophenyl)-3-pyridinylamino)]-salt or its physiologically acceptable salt is effective in the treatment of Parkinson's syndrome, especially multiple The system shrinks. The present invention therefore relates to (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinium

Page 16 1292314 V. INSTRUCTIONS (14) The use of a ketamine methyl]-spray or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of adverse effects of Parkinson's syndrome. The invention further relates to the use of (R)-(-)-2-[5-(4-fluorophenyl)-3-D-nonylaminoindenyl]- sneezing or a physiologically acceptable salt thereof, It is used to make medicines for the treatment of Parkinson's syndrome. A typical animal model is the blood-thinning rat or mouse (such as MS·Starr and BS Starr). J· Neural Transm· - Park. Dis· Dement. Sect . , 1 9 9 4; 7: 1 3 3- 1 42 ; J. Neural' by Μ·Gorse (Μ·Gossel) et al.

Transm. - Park. Dis. Dement. Sect., 1995; 10: 27-39; N.R. Hughes et al., Mov. Disord, 1998; 13: 228-233). Reserpine is an effective monoamine depleting agent and causes almost complete exercise in both species. The important 24 hours after application is measured by the traditional activity meter and the moving distance and activity time are almost zero. (R)-(-) - 2 - [5 -(4-fluorophenyl)-1,3-pyridinylamine hydrazino]-spray or its pharmaceutically acceptable salt can not reduce the movement in a dose-dependent manner, ie Restore the distance of movement and the time of activity to the level of about normal animals. Another recent animal model is described in J. Neural Transm. Suppl., 9 9 9; 5 5: 1 0 3 - 1 1 3 by G. κ· Wenning et al. The striatum denaturation method. In the left middle forebrain nerve bundle of mice, a one-sided injection of dopamine was performed, followed by injection of quinic acid in the ipsilateral striatum to induce striatum degeneration. This degeneration has a turning behavior after taking a dopamine (such as morphine and amphetamine). Disturbance behavior is measured by an automated delta recorder. Caused by Yan Yizhen and amphetamine m ill

I ii illli

Page 17 1292314 V. INSTRUCTIONS (15) The behavior is (R)-(-)-2-[5-(4- Iphenyl)-3-pyridinylamine thiol]-biting > Chr 〇mane ) or a pharmaceutically acceptable salt thereof is antagonized in a dose-dependent manner. Multiple system atrophy (MS A) is a neurodegeneration that spreads out of the extrapyramidal and autonomic nervous systems, which can lead to a Parkinson's syndrome in which unmotivated dysfunction is not possible. Very different from spontaneous Parkinson's disease, the density of the central dopamine receptor is significantly reduced, so MSA patients hardly respond to dopaminergic agents. Because (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamino)- sneezing or its pharmaceutically acceptable salt acts primarily through the extrapyramidal system Serotonin receptors, therefore, can enhance the athletic performance of patients who are unable to treat most of these other methods.

A typical study investigating the efficacy of compounds according to the invention in MSA patients included 30 patients of any gender with symptoms lasting at least five years and positive electron emission tomography (PET) scans showing a significant reduction in central dopamine receptors. The design of this study is similar to the above-mentioned Parkinson's disease. (R ) - ( - ) - 2 -[5 -( 4 -fluorophenyl)- 3 -pyridinylamine fluorenyl]-penetrating hydrochloride or placebo is titrated by means of "additional π-shaped traditional treatment" (Dose range 2.5 to 20 mg twice daily). Complete UPDRS measurements (primary outcome measures) were performed for each patient before titration and at the end of the treatment period. After a two-week washout period, exchange Study Group 2, and repeat this process. Statistical analysis of UPDRS showed that (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine sulfhydryl]-spray hydrochloric acid A significant improvement in clinical improvement under salt treatment. A preferred (R)-(-)-2-[5-(4-fluorophenyl)-3-indole ratio is determined by the sulfhydryl group. (R) - 2 - [5-(4-Fluorophenyl)-3 - 比 σ 曱 曱 曱 曱 曱 ] ] ]]]]

Page 18 1292314 V. INSTRUCTION DESCRIPTION (16) Accordingly, the present invention relates to the manufacture of a medicament for treating an adverse effect of an anti-Parkinson's agent in Parkinson's syndrome, wherein the pharmacologically acceptable salt is (R)-(-)- 2-[5-(4-Fluorophenyl)-3-pyridinemethylamine fluorenyl]-spray@hydrochloride. Further, the present invention relates to the use of a pharmaceutical composition for treating an anti-Parkinson's agent in Parkinson's disease, the pharmaceutical composition comprising at least one (R)-(-)-2-[5-(4-fluorobenzene) One of the phenylpyridinylamine hydrazino]-bite compounds or a biocompatible salt thereof and at least one solid, liquid, or semi-fluid excipient or additive. Accordingly, the present invention relates to the manufacture of a medicament for the treatment of Parkinson's syndrome, wherein the pharmacologically acceptable salt is (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine A Base]-spray '^ hydrochloride. Further, the present invention relates to the use of a pharmaceutical composition for treating Parkinson's syndrome, the pharmaceutical composition comprising at least one (R)-(-)-2-[5-(4-fluorophenyl 3-pyridylmethylamine fluorenyl group) a bite; one of a compound or a biocompatible salt thereof and at least one solid, liquid, or semi-fluid excipient or additive. The present invention relates to the use of (R) -(-)- 2 -[5 -(4-Fluorophenyl)-3-ene oxime hydrazinyl--spray or its physiologically acceptable salt to produce a medicament for the treatment of dyskinesia and/or dance syndrome. / or dance syndrome is, for example, Huntington's disease, small chorea or surname genus chorea. (R)-(-)-2 - [5-(4-fluorophenyl)-3-pyridinylamine曱基]-Bite biting or its physiologically acceptable salt is particularly useful for the treatment of Huntington's disease. A typical animal model is according to CV Borlongan (CV Borlongan)

Page 19 1292314 V. INSTRUCTIONS (17) Brain Res·, 1995; 697: 254-257 The systemic 3-nitropropyl acid (3-NP) model of rats. Mice were treated with selective stripe neurotoxin 3 _ N p (intraperitoneal) every four days (C.V. Borlongan et al.

Brain Res· Protocols, 1997; 1: 253-257). After two injections of 3 - NP, the mice showed signs of nocturnal hyperreflexia in early Handyton's disease. However, after 4 injections of 3 - NP, the mice showed that nighttime exercise of late Handyton was not possible (low exercise) ) Reflex symptoms. Night activities are automatically measured by infrared rays in normal activity cages. (R) — ( - ) - 2 - [ 5 _( 4 -Fluorophenyl)_ 3 -pyridinyl hydrazino]--Bite or a physiologically acceptable salt thereof reduces nighttime hyperactivity and exercise inability. A typical test demonstrating the efficacy of a compound according to the invention in patients with schizophrenia, autonomous motor performance, and functional disability in Handington's disease includes 32 genetically diagnosed patients. (R)-(a)-2-[5-(4-fluorophenyl)-3-pyridinylaminemethyl]-biting hydrochloride or placebo is administered "additional" to traditional treatments, It remained unchanged throughout the study. The dose of the blind drug was titrated over a period of 3 weeks from 2 to 5 to 20 mg twice daily. The fixed drug was then maintained for 1 week. Measurements were taken within 1 week and the last day before the test. The chorea is based on the Abnormal Involuntary Movement Scale (AI MS, W. Gabriel, 1967, published by the US Department of Health, Education, and Welfare in the ECDEU Measurement Manual, Rockwell, MD, pp. 534-537 (AIMS, W. Guy in: ECDEU assessment manual. Rockville MD: US dept, of health, education and welfare, 1976: 534-537)), United Handyton Rating Scale (UHDRS, Huntington Research Group, 1 9 9 6,

Page 20 1292314 V. Description of invention (18)

Movement Disord, 11: 136 - 42) and judged by videotape recording. Autonomic performance was measured on a UHDRS exercise scale. Patients and their partners completed a questionnaire on functional disability. Statistical analysis shows that under the treatment of (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]-bito; guanidine or a physiologically acceptable salt thereof, Significant improvement in autonomous and involuntary exercise performance in patients with Huntington's disease. A preferred (R)-(-)- 2-[5-(4-fluorophenyl)-3-indole-decylamine methyl]-bit: the absorption-salt is (R)-(-)- 2-[5-(4-Fluorophenyl)-3-pyridylmethylamine sulfhydryl]-spray-hydrochloride.

Accordingly, the present invention relates to the manufacture of a medicament for the treatment of exercise difficulties and/or dance syndrome (especially Handington's disease), wherein the pharmacologically acceptable salt is (1〇-(-)-2-[5-(4) Further, the present invention relates to the use of a pharmaceutical composition for the treatment of dyskinesia and/or dance syndromes. The pharmaceutical composition comprises at least one of them (the pharmaceutical composition comprises at least one of (the fluorophenyl)-3 pyridine hydrazinyl hydrazino group) R ) _ ( - ) _ 2 -[5 -(4-fluorophenyl)-3-pyridylmethylamine fluorenyl]-bite; one of the compounds or a biocompatible salt thereof with at least one solid, liquid or Semi-liquid excipient or additive.

The present invention relates to the use of (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]-spray or a physiologically acceptable salt thereof, which is used for Manufacture of drugs for the treatment of dystonia syndrome. The dystonia syndrome is, for example, spastic torticollis, writing sputum, facial paralysis, Meige syndrome, or dopa-sensitive dystonia. (R) -(-)-2-[5-(4-Fluorophenyl)-3-pyridinylamine thiol]-spray or

Page 21 1292314 V. INSTRUCTIONS (19) Physiologically acceptable salts are particularly effective against spastic tortillas and/or tendons. A typical animal model is A. Richter and? • Mutant dystocia hamster as described in Prog. Neurobiol. 1998; 54: 633-6 7 7 by W. Ltischer. In this hereditary dystonia hamster, the animal is removed from the living cage and placed on a balance to trigger an onset of dystonia. This dystonia syndrome contains continuous anomalous actions, while the severity of a single syndrome is assessed by a scoring system. (r) — ( — ) _ 2 — [5-(4-Fluorophenyl 3 -pyridinyl fluorenyl)-spray 173⁄4 or a pharmaceutically acceptable salt thereof reduces the severity of dystonia symptoms in a dose-dependent manner. To demonstrate the efficacy of the compounds according to the invention for dystonia syndrome, a double-blind, placebo-controlled study of patients with cervical dystonia (sacral torticollis) who cannot tolerate botulinum toxin injection. (R) _ ( _ ) — 2 — [ 5 — ( 4 —Fluorophenyl)-3-pyridinylaminomethyl]- sneeze hydrochloride as described above, titrated within $ 2 of 2 to 2 〇 m days, 1 Toronto. Western Skewed Neck Scale (TWSTRS, CL Kemela (CL·c〇melu) et al. 1997,

Movement Disord, ι ο . c 7 η r7rNffl.. ' twqtpq φ 57〇 a 575) for the main result measurement. In the TWSRS score, the phonetic stone | ^, 0 is called > Tian Qi face, its 1 to (R) one (one) - 2 one [5-(4-fluorophenyl)-3-pyridinium Aminyl]-nozzles or their pharmaceuticals can be significantly improved. The text is covered, the heart of the oral therapy is beautiful, and the sputum is cm). )-2-[5_(4-Denyl)-biting> sulphate hydrochloride. Soil" 30 疋 暴 fe fe 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此 因此

Page 22 1292314 V. Description of the invention (20) The salt is (R)-(-)_2 - [5-(4-fluorophenyl)-3_〇 ratio 17 decylamine fluorenyl]-injection Hydrochloride. Further, the present publication relates to the use of a pharmaceutical composition for treating a dystonia syndrome comprising at least one (R)-(-)-2-[5-(4-fluorophenyl:-yl)- 3 - one of at least one solid, liquid or semi-fluid excipient or additive, with a hydrazine sulfonate conjugate or a biocompatible salt thereof. The present invention relates to the use of (R)-(-)_ 2 -[ 5 - ( 4 _ II phenyl)-3 -pyridylmethylamine fluorenyl]-spray or a physiologically acceptable salt thereof, which is used In the manufacture and treatment of drugs for the treatment of extrapyramidal symptoms caused by nerve relaxants. Extrapyramidal movement disorders caused by neuroleptic agents are, for example, early exercise difficulties, dystonia, exercise inability, Parkinson's disease, especially bradykinesia or delayed onset dyskinesia. (R)-(-) - 2-[5 -(4 - disordered phenyl)-3 - ratio. The hydrazino group]-spray < or its physiologically acceptable salt is particularly useful for the treatment of motor inability, and/or late onset dyskinesia and/or Parkinson's disease. A typical animal model is described in S. Wol farth et al., Arch. Pharmacol. 1992; 345: 209-212, which describes the muscle stiffness of mice induced by a neuroleptic. Rats take the traditional nerve relaxant Haber to increase muscle tone. Muscle tone is the electrical resistance of the hind limb to passive buckling and elongation. (R)-(-)-2-[5-(4-Fluorophenyl)-3-acridinylamine hydrazino]-spray & or its pharmaceutically acceptable salt is reduced by Hapod Muscle tension. Another typical animal model is the nerve pine according to D. E. Casey, Psychopharmacology, 1996; 124: 134-140.

Page 23 1292314 V. Description of invention (21), allergic monkeys. - Repeatedly administered by traditional nerves, the neurotropin is very sensitive. ', the monkeys who deal with the evaluation of the scoring system, such as Zhang Liubian and Tian Tian medicine, the monkey immediately showed the tension as assessed by the scoring system... a "just,,, extra-cone motion side effects. Traditional dilemma And the exercise is slow. When the aforementioned extrapyramidal motion < Haberian system is used as a kind of stimulating (4-disorganized) 1,3-pyridylmethyl 2, the administration (R) one (one) one = 孓Salt; (R)~2-[5-(4-Fluoro-Met)-spray % or its pharmaceutically acceptable bite-dependent reduction cone ~3~pyridine methylamine:. Research according to this;::: The type study was as follows. There were 32 cases of therapy for the age of 25# late I-sports difficulty (at least 5% of the age of 5 years, receiving long-term stable anti-adaptation studies. (RH 〇 schizophrenia (DSM-UI- R) Inpatients' base] A sneeze 趟 Sa赜 10)—[5-(4-fluorophenyl)-3-pyridylmethylamine A is administered, potted ^ 'female consolation with "attached, for antipsychotic treatment The way of 2·5 to 2 〇 吞 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广 广Titration. This treatment is followed by a double-blind movement. After the 2-week washout period, the test drug is crossed. Delayed operation I, difficult to measure 1 with abnormal non-autonomous exercise scale (aims, see above) and Ba Jin In vitro side effects (UPDRS, see above) before treatment and treatment of ramie) 1 2 [5 "" (4 a gas phenyl) a 3 ci ratio ° 曱 曱 曱 曱 基 基 基^ The A IMS score for salt treatment was significantly lower than that during the comfort period. ^ ΰ 车 I I I (R)-(-)-2-[5-(4-I-phenyl)-3-吼 曱 曱 曱 曱The salt of the soil spray is (R) -(-)-2-[5-(4-phenylphenyl)-3~π-specific decylamine sulfhydryl]-sneeze hydrochloride.

Page 24 1292314

V. INSTRUCTIONS (22) Therefore, the extrapyramidal pharmacologically amidomethyl]-in addition, the agent-initiated (-)-2 - [5 (chroman body, liquid inventive sulfhydryl)-spray to treat the tremor package Trembling, small (1) - its physiological tremor is particularly invented in the manufacture of medicinal agents to treat the symptoms caused by nerve relaxants, which are exercise-incapable or delayed-moving/difficult), where (1)_(_)-2_ [5-(4~Fluoryl)di-3-d is more than a bit of methyl spray 03⁄4 hydrochloride. The pharmaceutical composition comprises at least one (R)-(4-fluorophenyl-3-pyridinylaminomethyl)-penetrating e-compound for the use of a pharmaceutical composition for treating extrapyramidal symptoms by nerve relaxation. Or one of its biocompatible salts and at least one solid or semi-fluid excipient or additive. The use of (R)-(-)- 2 - U -(4-I-phenyl)-1,3-pyridylf-amine or a physiologically acceptable salt thereof for the manufacture of trembling. Contains all types of tremors, such as idiopathic tremors, active cerebral tremors, erect tremors, or drug-induced tremors. } - - U-Fluorophenyl 3 pyridine pyridylamine sulfhydryl squirting or X-salt treatment for idiopathic tremor and/or drug-induced tremors 0 A typical animal model utilizes genetically modified animals or Using a model of tremor caused by a drug (review: H. Wilms and others)

Disord·, 1999; 14: 557-571).

The genetic model of a typical mutant animal is a pietrain pig kanji as described in A. Richter et al. (Exp. Neuroiogy, 1 9 9 5; 134: 2〇 5 213). CampUS Syndrome, or according to JR Simon (JR·Simon) and 盖·Ghetti

Page 25 1292314 V. Description of invention (23)

Mol. Neurobiol·, 1994: 9: 183-189 The Weaver (W e a v e r ) mutant mouse. In the Campes syndrome model, these mutant pigs showed high frequency of tremor when standing or moving, but not when lying still. The trembling measurement is done with an accelerometer. On the Weaver mutant mice, degenerative cerebellar atrophy was found to be trembling, the pace was unstable, and a few steps fell to the sides. The unstable pace and the fall result in a drastic reduction in mobility, which is measured by the distance measured by the pedometer and the time spent in the traditional activity cage.

(1〇-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]- saponin or one of its pharmaceutically acceptable salts improves the skin pig Syndrome, which reduces the disability tremor during standing and moving, and increases the mobility of the Weaver mutant mouse. The typical animal model of drug-induced tremor is trembling caused by oxotremorine (such as H. H. Hallberg and 0. Agrand (Acta Physiol· Scand., 1 9 8 7; 129: 4 0 7- 1 3; JG Clement and WR · WR Dyck J. Pharmacol. Meth., 1989; 22: 25-36). The trembling of the oxytropin is measured by a measurement scale. (R ) - (-)- 2 - [5-(-Fluorophenyl)-3-pyridinylguanidino)-bite; or one of its pharmaceutically acceptable salts inhibits the tremor induced by oxymotolin.

A preferred (R)-(-)-2-[5-(4-phosphophenyl)-3-pyrene-pyridylhydrazinyl]-sneezing salt is (R)-(-)-2 -[5-(4-Fluorophenyl)-3-pyridinylamine fluorenyl]-propane hydrochloride. The invention therefore relates to the manufacture of medicaments for the treatment of tremors (especially idiopathic tremors and/or drug-induced tremors), wherein the pharmacologically acceptable salt is

Page 26 1292314 V. INSTRUCTIONS (24) (R)-(-)-2 - [5 -(4-Fluorophenyl)-3- 吼 ° 曱 曱 胺 甲基 甲基 甲基 甲基 甲基 ▽尧 ▽尧. Furthermore, the present invention relates to the use of a pharmaceutical composition comprising at least one (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine oxime for treating tremor One of the biocompatible salts and at least one solid, liquid or semi-fluid excipient or additive. The present invention relates to the use of (R) - ( - ) - 2 - [ 5 - ( 4 - fluorophenyl) - 3 - pyridyl hydrazino - hydrazinyl]-propion 17 or its physiologically acceptable salt, It is used to manufacture a medicament for treating a group selected from the group consisting of: Drett syndrome, chorea, myoclonus, leg restlessness syndrome, and extrapyramidal lesions of Wilson's disease. A typical myoclonus animal model is caused by an acute hypoxic event as described by D. D. Truong et al., Mov Dsord, 1994; 9: 201-206). Myoclonus. In this hypoxic myofibrillar model, the mice recovered after 8 minutes of cardiac arrest. Myoclonus convulsions occur spontaneously (but can also be triggered by auditory stimuli), which are progressively worsened after cardiac arrest. (R)-(-)-2-[5-(4-Fluorophenyl)-3-pyridinylamine fluorenyl]-spraying rabbit or one of its physiologically acceptable salts reduces the spontaneity by a dose-dependent manner And the myoclonus caused by hearing. A preferred (R)-(-)-2-[5-(4-fluorophenyl)-3-indolizidine methylamine thiol]-bite; the salt is (R)-(-)_2- [5-(4-Fluorophenyl)-3-pyridinylamine fluorenyl]-spray 4 hydrochloride. The present invention therefore relates to the manufacture of a medicament for the treatment of a group selected from the group consisting of: Drett syndrome, chorea, myoclonus, leg restless syndrome, and Wilson's extrapyramidal lesions, wherein the pharmacologically acceptable Salt is (R) -

Page 27 1292314 V. INSTRUCTIONS (25) (-)-2-[5-(4-Fluorophenyl)-3-pyridinylamine fluorenyl]-biting> Further, the present invention relates to the use of a pharmaceutical composition for treating a group selected from the group consisting of: Drett syndrome, snoring, myoclonus, leg restlessness syndrome, and extrapyramidal lesions of Wilson's disease, the medicine The composition comprises at least one (R)-(-)-2-[5-(4-phenylphenyl)-3-pyridinylaminoindenyl]-injection compound or one of its biocompatible salts and At least one solid, liquid or semi-fluid excipient or additive. Such as Stie-Richardson-Oschi syndrome, progressive nucleus pruritus, cortical basal degeneration, olivine bridge cerebellar atrophy, shy tow syndrome, small chorea, chorea chorea, writing sputum, face痉挛, Mickey syndrome, dopa-sensitive dystonia, Drett syndrome, snoring, myoclonus, leg restlessness, and extrapyramidal lesions of Wilson's disease are not often sufficient for a general double-blind trial . However, because there are currently not enough effective therapies, the medical needs in this area are very urgent. Therefore, the open label (〇pe η - 1 abe 1 ) observation method in several selected patients is sufficient to verify (R) 2-[5-(4-fluorophenyl)-3-pyridinylaminomethyl - biting; % or the potency of its physiologically acceptable salt. All pharmaceutical preparations (including pharmaceutical combinations) which are used for the treatment of extrapyramidal lesions and/or for the treatment of adverse effects of anti-bajinsen agents in extrapyramidal action lesions can be used in human or veterinary medicine. Although other routes of administration (e.g., rectal administration) are not excluded, the compositions of the present invention are preferably administered parenterally, or by oral means. Suitable excipients are organic or inorganic substances which are suitable for enteral (eg, oral), parenteral, or topical administration and are not associated with (R)-(-)·*2_[5-(4-fluoro 1292314 V. Description of invention (26)

Phenyl)-3-pyridinylamine fluorenyl]- spray is one of / and / or a biocompatible salt thereof, for example, water, vegetable oil, benzyl alcohol, alkanediol, polyethylene Alcohol, triacetin, gel, carbohydrate (such as lactose or starch), magnesium stearate, talc, petrolatum. For oral administration, in particular, tablets, pills, dragees, capsules, powders, granules, syrups, liquids or drops; rectal administration forms (especially) suppositories; parenteral administration forms ( In particular, the solvent is preferably an oily or aqueous solution, in addition to a suspension, solution or implant; and the topical administration is in the form of a skin plaster, ointment, cream or powder. 1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-aminoindenyl-benzopyran-5-yl)-hexahydroindole and/or One of its physiologically acceptable salts is lyophilized, and the resulting lyophilizate can be used, for example, to prepare an injectable product. The above preparations may be in a sterile form and/or contain adjuvants such as slips, preservatives, stabilizers, and/or moisturizers, emulsifiers, salts which modify the osmotic pressure, buffer substances, pigments, flavoring agents, and / or other active ingredients, such as one or more vitamins. If desired, the formulation can be designed to slowly release (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]- sneeze or its biocompatibility salt. The following examples are related to pharmaceutical products: Example A: Small vial

100 g of (R)-2-(5-(4-fluorophenyl)-3-pyridinylaminomethyl]-spray or its physiologically acceptable salt and 5 g in 3 liters of double distilled water The disodium hydrogen phosphate solution was adjusted to pH 6.5 with 2N hydrochloric acid, filtered and sterilized, filled into a vial, lyophilized under sterile conditions and sealed in sterile form. Each vial contains 5 mg of active ingredient.

Page 29 1292314 V. INSTRUCTIONS (27) Example B: suppository, 20 g of (R)-(-)-2 - [>5-(4-fluorophenyl)-3-pyridylmethylaminomethyl] A spout or a mixture of physiologically acceptable salts was melted with gram of soy lecithin and 14,000 g of cocoa butter, and the mixture was poured into a mold and allowed to stand for cooling. Each suppository contains 20 mg of active ingredient. Example C: A solution consisting of 1 gram of (R)-(a)- 2-[5-(4-fluorophenyl)-3-anthracenemethylaminemethyl]-nozzle contained in 94 ml of double distilled water t Or a physiologically acceptable salt thereof, 9.38 g of NaH2P〇4 · 2H20, 28·48 g of Na2HP04 · 1 2H20 and 0.1 g of benzyl chloride. Adjust the pH to 6.8, then make up the solution to 1 liter and illuminate the halogen. This solution can be used in the form of eye drops. Example D: Ointment - 2_[5_(4-fluorophenyl)_3 - mouth ratio. The decylamine-spray/especially or a physiologically acceptable salt thereof is mixed with 99.5 g of Vase Aseptic A. 1 thousand examples Ε - 1 : 旋剂1广斤』R) 一(一)一二一[5一(4-fluorophenyl)-3-pyridinylamine 曱其/犬^9八/\ Acceptable salt, 4 kg of lactose, 丨·2 kg of horse It ΐ 洛 〜 八 八 八 八 八 八 八 八 八 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Example of use Ε-2: tablets ~ acid salt, 1 kg of levodopa magnesium

.6kg horse yam potato starch, 〇 9 八匕w \匕 υ υ · z kg talcum powder and 0 · 1 kg hard moon |

Page 30 1292314 V. Description of the invention (28) A tablet is prepared in a conventional manner such that each tablet contains 0.2 mg of (R)-(-) -2-[5-(4-fluorophenyl) -3-pyridinylamine hydrazino]-spray 1?|1 hydrochloride, 10 mg levodopa and 2.5 mg benserazide.

Example F: Sugar-coated tablet mixture A tablet was prepared in a manner similar to that of Example E, and the tablet was then coated with sucrose, potato starch, talc, tragacanth, and a pigment layer in a conventional manner. Example G: Capsule

2 kg of (R)-(-)-2-[5-(4-fluorophenyl-3-pyridinylamine fluorenyl)-bit: 17 rabbits or physiologically acceptable salts thereof are filled into hard capsules by conventional methods In each capsule, each capsule contains 20 mg of the active ingredient. Example Η : An ampoule will contain 1 kg of (R)-(-)-2 - [5-(4-fluorophenyl)- in 60 liters of twice distilled water 3-pyridylhydrazinyl]-sprayed or its physiologically acceptable salt solution is filter sterilized, filled into ampoule, lyophilized under sterile conditions and sealed in sterile form. Each ampule contains 10 mg of active ingredient. Example I: Inhalation Spray

14 g of (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridinylamine fluorenyl]-spray or a physiologically acceptable salt thereof is dissolved in 1 liter of NaCl, etc. The solution is then filled into a commercially available pump spray container. This solution can be sprayed into the mouth or nose. Each press (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Page 31 1292314 7ττ~~η— --------------.....--..............—, φΛΛφ»·' r__wi 1 Check Miscellaneous: Qfhn 月曰修- >849 < L· H: Category·· ~~ΓΥΤ7-^以匕J hb \ t ^ /〇<> K above the long shed tb 士 &丄古二士, "一"" -- for the supplement of 曰 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom chrom OF 一死[5-(4-FLU0R0PHENYL)-3_PYRIDYLMETHYLAMIN0METHYL]-CHR0MANE AND ITS PHYSIOLOGICALLY ACCEPTABLE SALTS Name (Chinese) 1·Jid Batuhi* ................. .__ 2. Herman Ross Nine from the name of the inventor of the company (English) 1. GERD BARTOSZYK 2. HERMANN RUSS 3. CHRISTOPH SEYFRIED 4. FRANK WEBER Nationality 1 · Germany 2 · Germany 3. Germany 4. Germany , Residence & f J Frankfurt Road 25 § § f f Frankfurt Road 250 5 · Frankfurt Road 250 4. No. 250 Frankfurt Road, Dasdart, Germany Name 1. Dema Mae Patent Company -- Name ( Name) (English) l.MMU LATENT GMBH---- Second Applicant Residence, Residence (Company) I·Desta Dasdakfu Road 250 - Representative Name (Chinese) Xia 4 Temple Le---- Representative Name (English) I . SCHUTTLER~~~---- Page 1

O:\69\69101-93052l.ptc 1292314 Fix _ Case No. 90102849 Simple description of the schema

Correction Supplement 卬" Calling Circle ill O:\69\69101-920124.ptc Page 32

Claims (1)

June 1292 Station 4 告木I Case No. 90102849 VI. Scope of Application Patent Supplement 1. A pharmaceutical composition for treating extrapyramidal motion lesions comprising (R) -(-)- 2-[5-(4-fluorobenzene A pyridylmethylamine methyl]-chroman or a physiologically acceptable salt thereof. 2. A pharmaceutical composition for treating an adverse effect of an anti-bajinson agent in spontaneous Parkinson's disease or Parkinson's syndrome, comprising (R) -- 2-[5-(4-fluorophenyl)- 3-pyridylhydrazinyl]-bite; A or a physiologically acceptable salt thereof. 3. A pharmaceutical composition for treating spontaneous Parkinson's disease or Parkinson's syndrome comprising (R)-(-)-2-[5-(4fluorophenyl)-3-pyridinylamine Methyl]-spray or physiologically acceptable. 4. A treatment for exercise difficulties or salt. Medical Composition of Dance Syndrome It contains (R) -(-)-2-[54-fluorophenyl 3-pyridinylaminomethyl]-bit: Eat or its physiologically acceptable salt. a product comprising: - bite; bite 3 or a combination thereof (R)-(-)-2-[5-(4 - Ιιphenyl)-3-pyridinylaminomethyl 5. It is used to treat dystonia physiologically. A pharmaceutical composition for treating extrapyramidal syndrome caused by a neuroleptic comprising (R)-(-)-2 - [5-(4-ILphenyl)-3-indole ratio. Methylamine thiol]-spray i or its physiologically acceptable species for the treatment of tremors. A composition comprising (R) -(-)-2 - [5-(4-fluorophenyl)-3-pyridylmethylaminemethyl]-spray or a physiologically acceptable salt thereof. 8. A pharmaceutical composition for treating a group selected from the group consisting of myoclonus, extrapyramidal motion lesions, comprising (R)-(-)-2-[5-(4-fluorobenzene 7· O:\69\69101-960613.ptc Page 33 1292314 _ Case No. 90102849_Yearly Month Day Correction _ 6. Patent Application Base) - 3 - Pyridylmethylamine thiol]-spray or its physiologically acceptable salt . A pharmaceutical composition for treating extrapyramidal side effects of an anti-bajinson agent comprising (i) (R)-(-)-2-[5-(4-fluorophenyl)- as an active ingredient 3-Pyridylmethylaminemethyl]-injection 13⁄4 or a physiologically acceptable salt thereof and (ii) at least one anti-Bakinson agent in combination with one or more pharmaceutically acceptable excipients. A pharmaceutical composition according to claim 9 of the patent application, which is for increasing the anti-Parkinson efficacy of an anti-Bakinson agent. A pharmaceutical composition according to claim 9 wherein (i) the active ingredient is in the form of its hydrochloride salt, and (i i) the conventional anti-Parkinson's agent is levodopa. 1 2. The pharmaceutical composition according to claim 9 wherein (i) the active ingredient is in the form of its hydrochloride salt, and (i i) the conventional anti-Parkinson's agent is a combination of levodopa and T-wire. 1 3. The pharmaceutical composition according to claim 9 wherein (i) the active ingredient is in the form of its hydrochloride and (ii) the traditional anti-Bakinson agent is levodopa and carbidopa. combination. O:\69\69101-960613.ptc第34页