WO2007041936A1 - Isomeres optiques de derives de piperazine d'alcool d'alkyle et leurs sels ainsi que leurs applications - Google Patents

Isomeres optiques de derives de piperazine d'alcool d'alkyle et leurs sels ainsi que leurs applications Download PDF

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Publication number
WO2007041936A1
WO2007041936A1 PCT/CN2006/002571 CN2006002571W WO2007041936A1 WO 2007041936 A1 WO2007041936 A1 WO 2007041936A1 CN 2006002571 W CN2006002571 W CN 2006002571W WO 2007041936 A1 WO2007041936 A1 WO 2007041936A1
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WIPO (PCT)
Prior art keywords
isomer
salt
piperazine
optical isomer
piperazine derivative
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PCT/CN2006/002571
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English (en)
Chinese (zh)
Inventor
Jianqi Li
Zhijie Weng
Wenxin Dong
Liying Huang
Hua Jin
Shaojing Zhang
Fenghua Gu
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Shanghai Institute Of Pharmaceutical Industry
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Publication of WO2007041936A1 publication Critical patent/WO2007041936A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a sterol piperazine derivative optical isomer or a salt thereof, in particular, to N 1 -benzyl-N 4 -[l-methyl-2-(5,-chloro-6,-methoxy Synthesis of optical isomers of -2,-naphthyl)hydroxyethyl]piperazine or a salt thereof (hereinafter referred to as SIPIyy24, the same hereinafter) and its use in the preparation of an antidepressant drug.
  • SIPIyy24 N 1 -benzyl-N 4 -[l-methyl-2-(5,-chloro-6,-methoxy Synthesis of optical isomers of -2,-naphthyl)hydroxyethyl]piperazine or a salt thereof
  • Depression is a common disease in humans and is the most common mental illness that currently jeopardizes human health.
  • the main symptoms of depression are: low mood, reduced activity, altered appetite or weight, changes in sleep (insomnia or lethargy), fatigue, difficulty concentrating, hesitancy, and even suicide.
  • the incidence of depression worldwide is about 3.1%.
  • the disease ranks fourth in the world's most common diseases and will rise to the second most common disease in the world in the next 20 years.
  • antidepressants mainly act on neurotransmitters such as 5-hydroxytryptamine (5-HT) and norepinephrine (NE).
  • MAOI monoamine oxidase inhibitor
  • TCA tricyclic antidepressant
  • SSRI selective serotonin reuptake inhibitor
  • NRI norepinephrine reuptake inhibitor
  • 5-HT 5-HT
  • NE dual reuptake inhibitor SNRI
  • a 5-HT, NE dual reuptake inhibitor appeared, representing the drug venlafaxine.
  • Venlafaxine is superior to TCA and SSRI in the treatment of depression. It has obvious curative effect on severe depression and refractory depression, and it has a faster onset, about 1 week.
  • new antidepressants with fast acting effects and small side effects on the 5-HT and NA dual action pathways have become important development directions for research and development.
  • Mildoxetine hydrochloride was marketed in 2004 and is a dual inhibitor of serotonin and norepinephrine reuptake.
  • duloxetine is effective in treating the emotional and physical symptoms of depression, allowing it to gain a foothold in the antidepressant market.
  • the structure of the SIPIyy24 compound contains two chiral carbon atoms and has four optical isomers, of which two are erythro isomers and two are threo optical isomers, which may be biologically active, pharmacologically active. There are large differences and exploreability in activity and toxicity.
  • erythrosome of SIPIyy24 differs greatly from SIPIyy24 and threo racemate in terms of target and toxicity: erythrosome It has a high inhibitory activity on the reuptake of 5-HT, NA and DA, and is a compound acting on a triple-targeted target; the racemic racem only has a strong inhibitory effect on the reuptake of 5-HT and NA. It has no inhibitory effect on DA reuptake and is a compound that acts on two targets.
  • the results of acute toxicity test showed that the LD 5Q of the erythrosome was 1.5 g/kg, while the LD 5Q of the racemic form was about 220 mg kg. The toxicity of the erythro race was much less than that of the Soviet racemate. Most antidepressants are currently on the market.
  • the SIPIyy24 erythrosome has significant antidepressant activity and safety, and has the development and research value as a novel multi-effect antidepressant.
  • the two vertices still contain two optical isomers (1S, 2R) and (1R, 2S), and the two isomers may also have large differences in activity and safety; Although the overall toxicity is large, it is also possible that one of the optical isomers is more toxic and affects the overall toxicity. Therefore, it is necessary to conduct a comparative study on the biological activity and safety of the four optical isomers of SIPIyy24 to determine the low toxicity and high efficiency of candidate new drug structures for further preclinical development studies.
  • the dual inhibitors that inhibit both 5-HT and NA reuptake have the advantages of good antidepressant effect, small side effects and fast onset, but at the same time, triple acting compounds with inhibitory activity against DA reuptake are more effective. It still shows the anti-depressant effect and reflects the side effects. It is still a hot spot in the research of new monoamine antidepressants.
  • the SIPIyy24 erythrosome has triple inhibitory activity on 5-HT, NA and DA reuptake, and the inhibition of DA by the two optical isomers may be significantly different from that of the erythrosome. Therefore, SIPIyy24
  • the results of the erythro isomers have theoretical value for understanding the relationship between multiple inhibition of monoamine transmitter reuptake and ideal antidepressant therapeutics.
  • One of the technical problems to be solved by the present invention is to disclose an optical isomer of a sterol piperazine derivative or a salt thereof and use thereof to overcome the above-mentioned drawbacks of the prior art to meet the needs of people for treating depression.
  • the second technical problem to be solved by the present invention is to disclose the use of the above optical isomers for the preparation of a medicament for treating an antidepressant.
  • optical isomer of an alkyl alcohol piperazine derivative or a salt thereof according to the present invention and the optical isomer of the sterol piperazine derivative has the following structural formula:
  • C ⁇ n C 2 two chiral carbon atoms have the following configurations: (1S, 2R), (1S, 2S), (1R, 2S), (1R, 2R);
  • Said salt is a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or a methanesulfonate;
  • a preferred salt is a hydrochloride or a hydrobromide salt, the salt of which may contain 0.5 to 4 molecules of water of crystallization.
  • the present invention synthesizes the compound N 1 -benzyl-N 4 -[l-methyl-2-(5,-chloro-6,-methoxy-2'-naphthyl) by a prochiral method.
  • the four optical isomers of hydroxyethyl]piperazine are (1S, 2R), (IS, 2S), (1R, 2S) and (1R, 2R) optical isomers, respectively.
  • a mixture of (1S, 2R) isomer and (1S, 2S) isomer is synthesized from L-alanine;
  • (1R, 2S) isomer is synthesized from D-alanine and
  • a mixture of 1R, 2R) isomers was separated by column chromatography to give four single isomers.
  • the purity of the four optical isomers was determined by capillary electrophoresis; the configuration was estimated by correlating with the configuration of the prochiral starting material and the coupling constant value of the nuclear magnetic resonance of the target product.
  • the present invention carries out five monoamine transmitters of 5-HT, NA, and DA for four optical isomers by the method recommended in the literature (Br J Pharmacol, 1997, 122: 302-306, 1992, 105: 147-151).
  • the reuptake inhibition assay showed that the (IS, 2R) isomer and the (1R, 2S) isomer have a triple action of inhibiting 5-HT, NA and DA reuptake, while the (1S, 2S) isomer and The (1R, 2R) isomer only inhibited the reuptake of 5-HT and NA, and did not inhibit the reuptake of DA.
  • the present invention measures the ED 5 o values of four optical isomers by a method recommended by the "Modern Pharmacological Experimental Method" (edited by Zhang Juntian), a single oral administration of a mouse tail suspension test, and a mouse swimming test.
  • the ED 5 o value of the mouse tail suspension test was determined as follows: (1S, 2R) isomer 12.6 mg/kg; (1R, 2S) isomer 16.5 mg kg; (1S, 2S) isomer 27.9 mg kg; (1R, 2R) isomer 24.5 mg / kg; ED 5Q value of mouse swimming test: (1S, 2R) isomer 28.9 mg kg; (1R, 2S) isomer 49.2 mg / kg; No statistically significant difference was observed after administration of the 1S, 2S) isomer and the (1R, 2R) isomer.
  • the invention adopts the method recommended by the "Modern Pharmacological Experimental Method” (edited by Zhang Juntian), and the minimum effective dose of four optical isomers is determined by tail suspension test, mouse swimming test and rat swimming test of oral administration for one week. .
  • the results showed that the minimum effective doses of the four isomers were: (1S, 2R) isomer 15-20 mg kg; (1R, 2S) isomer 30-40 mg kg; (1S, 2S) isomer 30-40 mg/kg; (1R, 2R) isomer 30-40 mg/kg.
  • the invention adopts the method recommended by the "Modern Pharmacological Experimental Method” (edited by Zhang Juntian), and the LD 5Q value of four optical isomers is determined by oral administration of mice, and the results show that the LD 5 o values of the four isomers are respectively For: ( IS, 2 ) isomer 1030-1202 mg/kg; (1R, 2S) isomer 1171-1259 mg kg; (1S, 2S) isomer 300-400 mg/kg; (1R, 2R ) Isomer 200-250 mg / kg. The toxicity is significantly lower than that of the racemate.
  • optical isomer of the present invention can be administered to a patient in need of such treatment by oral administration, injection or the like in the form of a composition.
  • composition comprises a therapeutically effective amount of an alkanolpiperazine derivative optical isomer of the invention or a salt thereof and a pharmaceutically acceptable carrier;
  • the carrier is a conventional carrier in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like; a filler such as starch, etc.; a cracking agent such as carbonic acid Calcium, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
  • a diluent an excipient such as water, etc.
  • a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like
  • a filler such as starch, etc.
  • a cracking agent such as carbonic acid Calcium, sodium bicarbonate
  • other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
  • a conventional solid preparation such as a tablet, a powder or a capsule
  • for injection it can be prepared as an injection.
  • compositions of the present invention can be prepared by conventional methods in the medical field, wherein the active ingredient is present in an amount of from 0.1% to 99.5 °/. (weight ratio).
  • the administration amount of the present invention may vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the like, and the daily dose is 5-30 mg/kg body weight (oral) or 1-10 mg/kg. Weight (injection).
  • the optical isomer compounds of the present invention show an antagonistic effect on depression in animal tests.
  • the anti-depressant effect of the optical isomer of the present invention is lower than that of the currently used single-targeted antidepressant, such as diazepam, fluoxetine, and a dual-targeted antidepressant.
  • the currently used single-targeted antidepressant such as diazepam, fluoxetine, and a dual-targeted antidepressant.
  • venlafaxine, duloxetine may have a wider indication and less neurotoxic side effects.
  • EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the research method of re-uptake of monoamine neurotransmitters by brain synaptosome is one of the most important methods for the study of central nervous system in the world. This method can be used not only to study the mechanism of action of drugs, but also to screen New drugs in this session.
  • the present invention employs a method for reuptake of monoamine neurotransmitters 5-HT, NA and DA by brain synaptosomes, with an effective 5-HT reuptake inhibitor fluoxetine, a NA reuptake inhibitor, dipamamine. And the dual reuptake inhibitor venlafaxine as a positive control drug, the effects of the four optical isomers inhibited by brain inducing the reuptake of 5-HT, NA and DA by brain synaptosomes were investigated. Methods as below:
  • Venlafaxine 0.35 ⁇
  • Venlafaxine 1.4 ⁇
  • the ED 5 o values of the four optical isomers were determined by mouse tail suspension and swimming test. Table 1 (1S, 2R), effects of oral administration of (1R, 2S) isomers on tail suspension and swimming tests in mice (single dose)
  • ED 5Q for tail suspension test (IS, 2R) isomer: 12.6 mg/kg; (1R, 2S) isomer: 16.5 mg/kg.
  • ED 50 for swimming test (IS, 2R) isomer: 28.9 mg/kg; (1R, 2S) isomer: 49.2 mg/kgo Table 2 (1S, 2S), (1R, 2R) isomer orally Effect of administration on tail suspension and swimming test in mice (single dose)
  • the minimum effective doses of the four isomers obtained from the above results are: (1S, 2R) isomer 15-20 mg/kg; (1R, 2S) isomer 30-40 mg/kg; (1S, 2S ) Isomer 30-40 mg kg; (1R, 2R) isomer 30-40 mg / kg.
  • the (1S, 2R) isomer has the lowest minimum effective dose value and is more active than the other three isomers.
  • the LD 5 o values of the four optical isomers in a single administration were: (1S, 2R) isomer 1030-1202 mg/kg; (1R, 2S) isomer 1171- 1259 mg/kg; (1S, 2S) isomer 300-400 mg/kg; (1R, 2R) isomer 200-250 mg/kg.
  • the (IS, 2R) isomer and the (1R, 2S) isomer are significantly safer than the other two isomers.
  • Calcium stearate 2 mg Preparation method: The active ingredient is mixed with sucrose and corn starch, moistened with water, stirred evenly, dried, pulverized and sieved, added with calcium stearate, mixed and hooked, and compressed. Each tablet weighs 200 mg and has an active ingredient content of 10 mg.
  • Preparation method The active ingredient is dissolved in water for injection, uniformly mixed, filtered, and the obtained solution is dispensed in an ampoule under sterile conditions, 10 mg per bottle, and the active ingredient content is 2 mg/bottle.

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  • Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention a trait à des procédés de préparation d'isomères optiques de dérivés de pipérazine d'alcool d'aralkyle de formule générale (I) et leurs sels ainsi que leurs applications. L'activité antidépressive des isomères optiques de la présente invention est supérieure à celle des agents anti-dépressifs de l'état de la technique d'effet d'inhibition simple tels que la désipramine, la fluoxétine ou des agents anti-dépressifs d'effet d'inhibition double tels que la venlaflaxine, la dutoxétine étant donné qu'ils peuvent avoir des indications plus larges et un moindre effet secondaire du système nerveux.
PCT/CN2006/002571 2005-10-10 2006-09-29 Isomeres optiques de derives de piperazine d'alcool d'alkyle et leurs sels ainsi que leurs applications WO2007041936A1 (fr)

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CN200510030354.1 2005-10-10
CNB2005100303541A CN100415728C (zh) 2005-10-10 2005-10-10 烷醇哌嗪衍生物光学异构体或其盐及其制备药物的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012505166A (ja) * 2008-10-07 2012-03-01 石薬集団中奇制薬技術（石家庄）有限公司 １‐ブチル‐２‐ヒドロキシアラルキルピペラジン誘導体およびその抗鬱剤としての使用

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101302214B (zh) * 2007-05-11 2012-06-20 江苏国华投资有限公司 芳烷基哌啶(嗪)衍生物及在治疗精神神经疾病中的应用
CN101602708B (zh) * 2008-06-10 2012-11-21 江苏国华投资有限公司 芳烷醇哌啶衍生物及其在制备抗抑郁症药物中的应用
CN101619056B (zh) 2008-07-02 2013-07-17 石药集团中奇制药技术（石家庄）有限公司 苯并噻吩烷醇哌嗪衍生物及其作为抗抑郁症药物的应用
CN102050801B (zh) * 2009-11-03 2013-05-29 石药集团中奇制药技术（石家庄）有限公司 一种芳烷哌嗪衍生物光学异构体的制备方法
CN102050800B (zh) * 2009-11-03 2013-05-29 石药集团中奇制药技术（石家庄）有限公司 一种1-丁基-2-羟基芳烷醇哌嗪衍生物光学异构体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1172919C (zh) * 2002-06-03 2004-10-27 上海医药工业研究院 芳烷醇哌嗪衍生物及其在制备抗抑郁症药物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1172919C (zh) * 2002-06-03 2004-10-27 上海医药工业研究院 芳烷醇哌嗪衍生物及其在制备抗抑郁症药物中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012505166A (ja) * 2008-10-07 2012-03-01 石薬集団中奇制薬技術（石家庄）有限公司 １‐ブチル‐２‐ヒドロキシアラルキルピペラジン誘導体およびその抗鬱剤としての使用

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CN100415728C (zh) 2008-09-03

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