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WO2008093919A1 - Utilisation des dérivés de n-benzyl-n-(2-diméthylamino-éthyl) benzènesulfonamide pour traiter des troubles du système nerveux central - Google Patents

Utilisation des dérivés de n-benzyl-n-(2-diméthylamino-éthyl) benzènesulfonamide pour traiter des troubles du système nerveux central Download PDF

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Publication number
WO2008093919A1
WO2008093919A1 PCT/KR2007/003197 KR2007003197W WO2008093919A1 WO 2008093919 A1 WO2008093919 A1 WO 2008093919A1 KR 2007003197 W KR2007003197 W KR 2007003197W WO 2008093919 A1 WO2008093919 A1 WO 2008093919A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
ethyl
dimethylamino
benzenesulfonamide
nervous system
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2007/003197
Other languages
English (en)
Inventor
Ae Nim Pae
Yong Seo Cho
Hyunah Choo
Hye-Jung Kim
Hun Yeong Koh
Woo-Kyu Park
Jae Yang Kong
Myeong Yun Chae
Insun Cho
Bong Woon Hwang
Dong Ha Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Institute of Science and Technology KIST
DB HiTek Co Ltd
Original Assignee
Korea Institute of Science and Technology KIST
Dongbu HitekCo Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Institute of Science and Technology KIST, Dongbu HitekCo Ltd filed Critical Korea Institute of Science and Technology KIST
Publication of WO2008093919A1 publication Critical patent/WO2008093919A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to
  • N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide compounds useful for the treatment of central nervous system (CNS) disorders.
  • N r -benzyl-N-(2-dimethylamino-ethyl)-benzenesulf onamide compounds are useful for the treatment and prevention of central nervous system disorders, for example, anxiety, depression, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency, Alzheimer's disease, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders, drug abuse withdrawal symptoms, migraine, etc.
  • Serotonin is believed to be closely associated with mental disorders (e.g., depression, aggressiveness, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, Huntington' s chorea), sitophobia, bulimia, alcoholism-related disorders, cerebral vascular accidents and migraine [Meltzer, Neuropsychopharmacology, 21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neuros ⁇ . Biobehavioral Rev., 14:35 (1990)].
  • mental disorders e.g., depression, aggressiveness, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency
  • neurodegenerative disorders e.g., Alzheimer's disease, Parkinson's disease, Huntington' s chorea
  • sitophobia e.g., bulimia
  • bulimia e
  • Serotonin (5-hydroxytryptamine, or 5-HT) receptors are present in human and animal cells and play important roles in mediating physiological and behavioral functions. At present, about 15 genetically-different 5-HT receptor subtypes have been cloned. Each subtype is associated with specific preference and correlation with a specific ligand. Recently, the 5-HT2 receptor subtype has been known to be related with such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders. Several compounds having activity on serotonin 5-HT2a and 5-HT 2 C receptors have been disclosed in WO 95/21844, WO 01/068585, WO 03/057220, Med. Chem., 2002, 45, 54-71, Eur, ]. Pharm., 2000, 406, 163-169 and Bioorg. Med. Chem. Lett, 2005, 15, 4989-4993.
  • New drugs have been developed to improve the side effect problems of classical tricyclic antidepressants and offer better therapeutic effects. These drugs are also used in compulsions, panic disorders and other anxiety disorders. Typical of them are the selective serotonin reuptake inhibitors (SSRI) including fluoxetine (brand name: ProzacTM), paroxetine (brand name: SeroxatTM) and sertraline (brand name: ZoloftTM). These SSRI drugs have long half lives and thus can offer sufficient pharmaceutical effects with one administration a day. But, there is required a relatively long period of time of 2 to 4 weeks for the improvement of such symptoms and only 60 to 70 % of depression patients benefit from the drugs. Further, an overuse of the drugs may induce the impetus for suicide, the interaction with the CYP450 liver enzyme and such side effects as insomnia.
  • SSRI selective serotonin reuptake inhibitors
  • fluoxetine brand name: ProzacTM
  • paroxetine brand name: SeroxatTM
  • sertraline brand name: ZoloftTM
  • SARI serotonin antagonist/ reuptake inhibitor
  • Typical examples are Bristol-Myers' nefazodone (Biol. Psychiatry., 1998, 44, 341) and Yamanouchi's YM-35992 (WO 94/18182) and Lilly's LY367265 (WO 98/31686), which are currently under clinical development.
  • N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide compounds as new serotonin antagonist/ reuptake inhibitor (SARI) drugs with selective antagonistic activities on the serotonin 5-HT2a or 5-HT2c receptors and selective serotonin reuptake inhibitor (SSRI) activities.
  • SARI serotonin antagonist/ reuptake inhibitor
  • an objective of the present invention is to provide a pharmaceutical composition for the treatment and prevention of central nervous system disorders comprising N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, halogen, hydroxy, C 1 -Oo alkyl, C 1 -Qo alkoxy, C 1 -C 1 O haloalkyl, C 1 -C 1 O haloalkoxy, C 1 -C 1 O acyl, phenyl or phenyloxy and the benzene ring of the phenyl or phenyloxy may have a substituent selected from hydrogen, halogen, cyano, Ci-C 1 O alkyl and C 1 -CiO alkoxy.
  • N-benzyl-N-(2-dimethylairrino-ethyl)-benzenesulfonamide compound represented by the formula (1) or a pharmaceutically acceptable salt thereof has physical activity for both the serotonin receptors and serotonin reuptake channels and is thus useful as an SARI drug.
  • R is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, Ci-Ce haloalkoxy, Ci-C 6 acyl, phenyl or phenyloxy and the benzene ring of the phenyl or phenyloxy may have a substituent selected from hydrogen, halogen, cyano, Ci-C 6 alkyl and Ci-C 6 alkoxy.
  • N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide compound represented by the formula (1) are as follows:
  • the N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide compound represented by the formula (1) is a known compound having superior activities for both serotonin receptors and serotonin reuptake transporter. Accordingly, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is useful as an SARI- drug for treating central nervous system disorders, for example, anxiety, depression, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency, Alzheimer's disease, Parkinson's disease,
  • the pharmaceutical composition of the present invention is useful for the treatment and prevention of central nervous system disorders.
  • the pharmaceutically acceptable salt is one that can be prepared by a method commonly used by those skilled in the art.
  • it may be a salt with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sodium bisulfate, phosphoric acid, nitric acid, carbonic acid, etc.
  • a salt with an organic acid such as such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid, acetylsalicylic acid (aspirin), etc.
  • a salt with an amino acid such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, t
  • the pharmaceutical composition of the present invention may comprise a commonly used nontoxic pharmaceutically acceptable carrier, strengthener, excipient, etc. to be prepared into oral or non-oral preparation forms commonly used in pharmaceutical fields, for example, tablet, capsule, troche, liquid, suspension, etc., for the prevention and treatment of tumors.
  • the excipient that may be used in the pharmaceutical composition the present invention includes sweetener, binder, dissolver, dissolution aid, wetting agent, emulsifier, isotonizer, adsorbent, disintegrator, antioxidant, antiseptic, lubricant, filler, aromatic, etc.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc. may be used.
  • the administration dose of the compound represented by the formula (1) may vary depending on the patient's age, body weight, sex, physical conditions and severity of disease and administration type. In general, a daily dosage for an adult patient weighing 70 kg is 0.01 mg to 5,000 mg. The administration may be given once a day or several times a day at predetermined intervals as instructed by a doctor or pharmacist.
  • IC50 value of the test drug was calculated from a nonlinear regression (GraphPad Prism Program, San Diego, USA) of the isotherm curves obtained from 3 repeated tests for the two test tubes with concentrations of 7th and 8th steps test. The result is given in Table 1 below.
  • Test drug 1 nM [ 3 H]-mesulergine, 5-HT 2 c receptor membrane (4 ⁇ g/well), 0.1 % ascorbic acid and 50 mM Tris-HCl buffer (pH 7.7) containing 10 ⁇ M pargyline were added to obtain a reaction mixture with a final volume of 0.25 mL. After culturing for 30 minutes at 37 0 C, the mixture was quickly passed through a
  • Test drug 1 nM [ 3 H]- imipramine, serotonin transporter membrane (9 ⁇ g/well), 120 mM NaCl and 50 mM Tris-HCl buffer (pH 7.4) containing 5 mM KCl were added to obtain a reaction mixture with a final volume of 0.25 mL. After culturing for 30 minutes at 25 0 C, the mixture was quickly passed through a Whatman GF/ C glass fiber filter soaked with 0.5 % PEI using Inotech Harvester (Inotech) to terminate the reaction. After washing with cold 0.9 % NaCl solution, the following procedure was performed identically as in the above 5-HT 2 A receptor binding test, except that nonspecific binding was measured in the presence of 200 ⁇ M imipramine. The result is given in Table 1 below.
  • Table 1 shows the physical activity of the compounds represented by the formula (1) as SARIs. [Table 1]
  • the compounds of the present invention represented by the formula (1) can be prepared into various preparation forms depending on purposes. Hereunder are given a non-limiting few examples of the preparation forms comprising the compounds represented by the formula (1) as active ingredients.
  • 100 mg of the compound of the present invention or a pharmaceutically acceptable salt thereof, 100 mg of cornstarch, 100 mg of lactose and 2 mg of magnesium stearate were mixed and prepared into a tablet in accordance with the conventional tablet making method.
  • Capsule 100 mg of the compound of the present invention or a pharmaceutically acceptable salt thereof, 100 mg of cornstarch, 100 mg of lactose and 2 mg of magnesium stearate were mixed and filled in a gelatin capsule in accordance with the conventional capsule making method.
  • Powder 2 g of the compound of the present invention or a pharmaceutically acceptable salt thereof and 1 g of lactose were mixed and filled in an airtight container to obtain a powder.
  • N-benzyl-N-(2-dimethylamino-ethyl)-benzenesulfonamide compound represented by the formula (1) is useful as SARI with superior binding affinity to serotonin 5-HT2a and 5-HT 2 C receptors and serotonin transporter (SERT), it can be used for the prevention or treatment of central nervous system disorders such as anxiety, depression, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency, Alzheimer's disease, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders, drug abuse withdrawal symptoms related with cocaine, ethanol, nicotine, benzodiazepine, etc. and migraine.
  • central nervous system disorders such as anxiety, depression, seizure, compulsive neurosis, psychosis, schizophrenia, suicidal tendency, Alzheimer's disease, Parkinson's disease, Huntington's chorea, sleep disorders, appetite disorders, drug abuse withdrawal symptoms related with cocaine, ethanol, nicotine, benzodiazepine, etc. and migraine.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des composés de N-benzyl-N-(2-diméthylamino-éthyl)-benzènesulfonamide utiles pour le traitement des troubles du système nerveux central (CNS).
PCT/KR2007/003197 2007-01-30 2007-07-02 Utilisation des dérivés de n-benzyl-n-(2-diméthylamino-éthyl) benzènesulfonamide pour traiter des troubles du système nerveux central Ceased WO2008093919A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070009626A KR100843351B1 (ko) 2007-01-30 2007-01-30 중추신경계 질환 치료제로 유효한ｎ-벤질-ｎ-(2-디메틸아미노-에틸)-벤젠술폰아미드 화합물
KR10-2007-0009626 2007-01-30

Publications (1)

Publication Number Publication Date
WO2008093919A1 true WO2008093919A1 (fr) 2008-08-07

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Country Status (2)

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WO (1) WO2008093919A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501992B2 (en) 2008-06-09 2013-08-06 Bristol-Myers Squibb Company Hydroxyphenyl sulfonamides as antiapoptotic bcl inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038986A1 (fr) * 1996-04-12 1997-10-23 G.D. Searle & Co. Derives benzenesulfonamide substitue utilisables comme precurseurs des inhibiteurs du cox-2
WO2005090296A2 (fr) * 2004-03-11 2005-09-29 Elan Pharmaceuticals, Inc. Benzene sulfonamides n-substitues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038986A1 (fr) * 1996-04-12 1997-10-23 G.D. Searle & Co. Derives benzenesulfonamide substitue utilisables comme precurseurs des inhibiteurs du cox-2
WO2005090296A2 (fr) * 2004-03-11 2005-09-29 Elan Pharmaceuticals, Inc. Benzene sulfonamides n-substitues

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501992B2 (en) 2008-06-09 2013-08-06 Bristol-Myers Squibb Company Hydroxyphenyl sulfonamides as antiapoptotic bcl inhibitors

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KR100843351B1 (ko) 2008-07-03

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