TWI225487B - New phenylpiperazines - Google Patents

Abstract

The invention relates to novel phenylpiperazine derivatives of the formula (1) wherein: R represents the group (a) or (b) as indicated in the description. These compounds are (partial) D2 receptor agonists and are usefull for treating CNS disorders, in particular Parkinson's disease.

Description

1225487 A7 B7 V. Description of the invention The activity of the reuptake inhibitors can enhance the behavioral response of 5-HTP in mice. This compound is used for clinically used antipsychotic drugs (such as: conditioned avoidance response; Van der Heyden & Bradford, Behav · Brain Res ·, 1988, 31: 6I-67) and antidepressant or anxiolytic drugs (such as : Suppression of vocal behaviors caused by stress; vanderPoel et al., Psychopharmacology, 1 898, 9 7: 14 7 -14 8) Sensitive treatment paradigms have significant effects. This compound has significant utility in clinically relevant paradigms of Parkinson's disease (eg, · altering the behavior of rats; U. Ungerstedt, Acta Physiol. Scand., 1971, 82 (suppl. 367): 69-93). Unlike clinically used dopamine Da receptor antagonists, this compound is less likely to cause ankylosing syncope in dentition animals, and therefore may cause fewer side effects of extrapyramidal nervous systems than currently available antipsychotic drugs. The therapeutic effects observed on behavioral paradigms that are sensitive to antidepressants or anxiolytics may be due to the serotonin reuptake-inhibiting activity of this compound. μ This compound can be used to treat central nervous system abnormalities or diseases caused by disorders of the dopamine activation system or serotonin activation system, {listed as ... attack, anxiety, orphan, dizziness, depression, recognition or memory Disorders, Parkinson's disease and schizophrenia and other mental illnesses. A pharmacologically usable acid includes hydrochloric acid (hydrochloric acid), sulfuric acid, phosphoric acid, organic and organic acids like citric acid, fugulic acid (tetrasuccinic acid), :: arsinoic acid, benzene Formic acid, p-toluenesulfonic acid, methanesulfonic acid, and sulfonic acid compounds can form suitable acid-containing salts with these acids. 6 1225487 A7 B7 V. Description of the invention (3 This compound and its acid salts can pass through some auxiliary substances like liquid and solid media materials through appropriate procedures to be made into a form suitable for administration. It has the structural formula (1) The compound can be a compound of the formula HN.

NH is also (2) prepared by reacting with a compound of the formula L — (a) or L — (b) under basic conditions; wherein the formula (“and (b) are as defined above” and L is the so-called The leaving group is, for example, a self-prime atom or a mesylate group. The hexahydropyridine compound having the structural formula (2) can be prepared according to the method described in European Patent 0189612. The structural formula L in the starting material — (A) can be prepared according to the following reaction scheme:

0H

1,) 2

Ml l2 .HCI 1p1 H2〇

Process A

This paper ruler M Α4 ^ (21〇 × 297 ^ ¥) 1225487 A7 B7 5 Description of the invention (

Compound 1ρ2 can be generated from lpl, so compound 2p4 (including compound L- (b),

The same is true for the method in which L is a formazanium group) derived from compound 2p3 (see the following equation B). ‘丨 U

The invention is illustrated by the following examples.

18.1 g (0.1 mol) of 2P1 was dissolved in 250 ml of CH2C12 and placed in (TC), and a solution prepared by pouring 50 ml of concentrated sulfuric acid into 200 g of ice was added to this chal solution. The mixed solution was borrowed Cool the bath with ice / acetone to maintain it at 0 ° C. Then, a solution prepared by dissolving 83 g (0.12 mol) of NaNO 2 in 50 ml of water was added dropwise to the previous mixed solution, and the process was The intermediate temperature is kept below 2.0, and the holding ## is stirred for 1 hour. After the organic layer is separated, the aqueous layer is re-extracted (CHAL) once, and the combined organic layer portion is dried with MgS04. The desiccant is filtered After removing and concentrating the filtrate in vacuo, a crude product of 17.8 g (99%) of dark yellow 2p2 was produced. A solution of 17.8 g (0.099 mol) of 2p2 in 100 ml of anhydrous THF was prepared under a nitrogen pressure environment, Carefully drip the flowing LiAlH4 (9.75 g, 244 mol) suspension into anhydrous THF. After the addition is complete, let the final mixture continue to react for 40 minutes. The reaction is then placed at room temperature and further cooled with ice / acetone The bath is cooled. Then add 9.75 ml of water and THF (1/1), 18.5 -8- Paper size applies to China National Standards (CNS) A4 (210X 297 mm) 1225487 A7 B7 V. Description of the invention 2NNaOH (aqueous solution) in ml and 18.5 ml of water, and keep the mixture to reflux for 20 minutes. Allow to cool down After that, the reaction mixture was filtered (using Hyflo), and the obtained filtrate was concentrated under vacuum to obtain a residue of 15.9 g. This residue was dissolved in 98 ml of a solution of IN HC1 in EtO Ac. The precipitate was filtered to form 17.5 g (87%) of the 2p3.HCl compound. 17.5 g (86 mmol) of 2p3.HCl was dissolved in a mixture of 190 ml of ethylene glycol and 90 ml of water, and heated to At 95 °, 7.96 g (94.6 mmol) of (3,4) -bisdihydro-p-pyran was carefully added dropwise. After the addition was complete, stirring was continued at 95 ° C for 3 hours. When the reaction After the temperature was reduced to room temperature, water and some brine were added and extracted with EtOAc (3 times). Part of the combined organic layer was sequentially with water, NaHS03 (aqueous solution), water, NaHC03 (aqueous solution), and NaCl (aqueous solution). ) Rinse, then dry this organic layer part with Na2S04. Drier After the solvent was removed, the residue was purified by column chromatography (Si02, eluent: MeOH / CH2Cl2 (3/97)) to obtain 12 g (63%) of a dark red oil, which contained The corresponding alcohol of 2p4 is solidified in the process. Then the standard alcohol (MsCl, diisopropylethylamine in CH2C12, 0 ° C) is used to convert this corresponding alcohol into its methanesulfonate to produce 2p4 (98% yield) ). The phenyl hexahydro p ratio spray having the structural formula (2) is reacted with 2p4 according to the procedure described in European Patent 0900792, to generate a compound (1) in which R is a group of the structural formula (b); (melting point: 182 -5 ° C). Example 2 Similar to 2p4 preparation (in Example 1), ipi was converted to lp2. Following the procedure described by RajanBabu et al. (RajanBabu et.al., j .. C / zem. 51, (1986), 1704), 1ρ2 was converted to lp3 (98%). -9- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Hold

k 1225487 A7 _ B7_ V. Description of the invention (6) Under a nitrogen pressure environment, 31.9 g (103 mmol) of ιρ3 was dissolved in 49 ml of DMF, and this solution was slowly added to another containing 5.88 Grams (134 millimoles, 1.3 equivalents) of an oily suspension (the suspension is 148 ml of DMF containing 55% NaH), and then stirred at room temperature for 1 hour, then the reaction mixture was cooled down (to Ice / water). Next, a solution prepared by diluting 8.34 ml (19.02 g, 134 mmol, 1.3 equivalents) of Mel in 49 ml of DMF was added dropwise to the previous solution. The reaction mixture was stirred for a further 16 hours at room temperature. Then, water was added and extraction was performed. After extracting Et20 (twice), the organic layer portion was washed with water (twice) and brine (once), and finally dried over MgS04. After the desiccant and solvent were removed in vacuo, the remaining residue was analyzed by column chromatography (Si02, eluent: CH2C12 / hexane (3/1)) to obtain 26.2 g (79%) of a yellow oil. State 44. Under a nitrogen pressure environment, 25.03 g (78 mmol) of 1ρ4 was dissolved in 110 ml of THF, followed by lN (wBut) 4N + F in THF, 93 ml (0.93 mmol, 1 · 2 equivalents). After stirring for 1 hour, Et20 was added, and the resulting mixture was washed with water (3 times) and brine (1 time). This organic layer was dried over Na2S04. After the desiccant and solvent are removed, the remaining residue is dissolved in toluene and then concentrated in vacuo to remove residual (tert.) Butyltrimethylsilyfluoride. After layer analysis (SiO2, eluent: Et20), 14.8 g (92%) of 1ρ5 was finally produced. 1.69 g (6.45 mmol) of PPh3 and 0.44 g (6.44 mmol) of micon were dissolved in 20 ml of CH2C12, and then 1.64 g (6.45 mmol) of iodine was added in portions. The reaction mixture was stirred for another 30 minutes at room temperature. Next, 1.07 g (5.1 6 mmol) of 1ρ5 was dissolved in 10 ml of CH2C12, and the previous mixture was slowly added. After 30 minutes, rinse the reaction mixture with NaHC03 (aqueous solution), NaHS03 (aqueous solution) and brine. -10- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Binding

1225487 A7 B7 5. Description of the invention (7), the remaining organic layer part was dried with Na2S04. After the desiccant and solvent are removed under vacuum, the remaining residue is dissolved in Et20, and the precipitate formed (Ph3PO) is removed by filtration. After the filtrate was concentrated in vacuo, the residue was purified by scintillation chromatography (Si02, eluent: CH2C12 / hexane (1/1)) to produce 1.45 g (88%) of the desired 1ρ6 iodide. Phenylhexahydropyridine having the structural formula (2) is reacted with 1P6 according to the steps described in European Patent 0900792 to produce a compound (1) in which R is a structural formula ⑻ group; (melting point: 202-4 ° C).

Hold

Line -11-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

1225487 A8 B8 C8 The compounds within the scope of the patent application are reacted, wherein formula L is a leaving group, and (a) and (b) are the same as those described in the first patent scope. 3. A pharmaceutical composition for treating central nervous system diseases, which contains at least one compound as claimed in item i of the patent application as an active ingredient. 4. Use of a compound such as the one described in the patent application for the preparation of a medicament for treating Parkinson's disease. 5. —Use of a compound such as item 1 of the patent application for the preparation of a drug for treating central nervous system dysfunction. 6 'The use as claimed in item 5 of the patent application, wherein the central nervous system disorders include schizophrenia, anxiety and anxiety. -2-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Announcement of this I application date V ', W case number category (the above columns are filled out by the Office) A4 Chinese specification for β ^ (Sept. 1993) Patent specification 1225487 Chinese novel phenylhexahydropyramine invention Shi Ying English NEW PHENYLPIPERAZINES Name Nationality Inventor Residence and Residence 1. ROLOF W. FEENSTRA 2. ROELOF W. FEENSTRA 2. ERIC RONKEN 3. Cornelius G. Koruse 1.-3. THE NETHERLANDS 1. The Netherlands CJ VAN HOUTENLAAN 36, WEESP, THE NETHERLANDS 2. The Netherlands CJ VAN HOUTENLAAN 36, Vespo City, The Netherlands , WEESP, THE NETHERLANDS 3. CJ VAN HOUTENLAAN 36, WEESP, THE NETHERLANDS s Table name CJ VAN HOUTENLAAN 36, WEESP, THE NETHERLANDS M. VERHAGE National Standard (CNS) A4 (2l0 × 297 male I) 1225487 The present invention relates to a novel phenylhexahydropyridine derivative with the structural formula (1) ⑴ R is a group of the formula (a) or (b) (PH2); (CH2): (a) (b) * and their salts. It has been found that the compounds of the present invention have high affinity with the dopamine A receptor (opannne D2 receptor) and the serotonin reabsorption sites (such as reupt, Slte). This combination can be used to treat schizophrenia (including positive and negative symptoms) and other mental illnesses. Kingson's disease. 〇, so it is also used in the treatment of barben compounds have dopamine D2 receptor activity and morphine-induced scratching behavior in mice. This straw anti-amidine compound also has similar serum -5- 1225487 Scope of patent application 1. A phenyl hexahydropyrine derivative with structural formula (1) Where R is a group of formula (a) or (b) F CH, ⑻ And its salts. 2., which is characterized in that a method for preparing the compound of the scope of patent application No. 1 lies in the compound of formula (2) under basic conditions With structural formula L — (a) or L — (b) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)