WO1998025914A1 - N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate - Google Patents

N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate Download PDF

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Publication number
WO1998025914A1
WO1998025914A1 PCT/JP1997/004451 JP9704451W WO9825914A1 WO 1998025914 A1 WO1998025914 A1 WO 1998025914A1 JP 9704451 W JP9704451 W JP 9704451W WO 9825914 A1 WO9825914 A1 WO 9825914A1
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Prior art keywords
acetyl
piperazinyl
fluorobenzamide
hydrate
compound
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Ceased
Application number
PCT/JP1997/004451
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French (fr)
Inventor
Satoshi Kitamura
Hisashi Mimura
Hiroshi Yamasaki
Yukihisa Baba
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority to EP97946110A priority Critical patent/EP0944612B1/en
Priority to JP50681698A priority patent/JP3254683B2/en
Priority to IL13027397A priority patent/IL130273A/en
Priority to US09/319,271 priority patent/US6147079A/en
Priority to CA002274682A priority patent/CA2274682A1/en
Priority to DK97946110T priority patent/DK0944612T3/en
Priority to AT97946110T priority patent/ATE205198T1/en
Priority to HK00103880.7A priority patent/HK1024482B/en
Priority to HU0002975A priority patent/HUP0002975A3/en
Priority to AU51368/98A priority patent/AU722095B2/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to EA199900530A priority patent/EA001715B1/en
Priority to DE69706562T priority patent/DE69706562T2/en
Publication of WO1998025914A1 publication Critical patent/WO1998025914A1/en
Anticipated expiration legal-status Critical
Priority to GR20010401324T priority patent/GR3036542T3/en
Ceased legal-status Critical Current

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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
    • C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to N- ( 4-acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate which is useful as a medicament.
  • This invention relates to N- ( -acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate.
  • One object of this invention is to provide N-(4-acetyl-
  • 1-piperazinyl) -4-fluorobenzamide in a form easy to handle under ordinary interior humidity conditions and resistant to stress testings i.e. N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide hydrate.
  • Another object of this invention is to provide an agent and a pharmaceutical composition comprising, as an active ingredient, said hydrate.
  • a further object of this invention is to provide a therapeutical method for the treatment and/or prevention of disorders m the central nervous system for human beings, and more particularly m the treatment and/or prevention of amnesia, dementia, senile dementia ana the like.
  • N- (4-acetyl-l-p ⁇ perazmyl) -4-fluorobenzamide free of water of crystallization undergoes change in water content by absorbing moisture under ordinary interior nu idity conditions and the rate of its moisture absorption also varies with the ambient relative humidity, thus offering the disadvantage that it cannot be easily handled m the laboratory room and the pharmaceutical manufacturing room.
  • N-(4- acetyl-1-p ⁇ perazmyl ) -4-fluorobenzamide wnich would show little change m water content under ordinary interior humidity conditions ana could, therefore, oe easily nandled m both the laboratory room and the pharmaceutical manufacturing room and discovered that the hydrate, preferably the monohydrate (theoretical water content 6.36%), of the above compound shows substantially no change m water content m addition to the advantage that it can be easily handled.
  • this N- ( 4-acetyl-l-p ⁇ perazmyl ) -4- fluorobenzamide hydrate, preferably monohydrate thereof, is chemically stable even under accelerated heat, humidity, and light exposure test conditions.
  • N- ⁇ 4-acetyl-l-p ⁇ perazmyl) -4-fluorobenzamide hydrate preferably monohydrate thereof, remains chemically stable without undergoing crystallographic change in the accelerated heat, humidity, and light exposure tests.
  • N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide hydrate may include all hydrate containing one or more water molecule (s) such as monohydrate, dihydrate, trihydrate, etc., in which preferable one is monohydrate.
  • N- (4-Acetyl-l-piperazinyl) -4-fluorobenzamide monohydrate 0.2 g was weighed into an amber-colored No. 1 bottle which was then placed in a desiccator controlled at 75% R.H. with a saturated aqueous solution of sodium chloride and stirred in a minijet oven at 70°C for 9 days.
  • 0.2 g of N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide monohydrate was accurately weighed, spread thinly in a dish about 4 cm in diameter, covered with polyvinylidene chloride film, and exposed to a chemical lamp for 24 hours.
  • the quality parameters of description water content (K.F.
  • N- ( 4-acetyl-l-piperazinyl) - 4-fluorobenzamide monohydrate is chemically stable against accelerated 70°C, 75% R.H. heat and humidity test and accelerated chemical lamp exposure test conditions, undergoing no change in crystal morphology.
  • N- (4-acetyl-l-piperazmyl) -4-fluorobenzamide (192.0 g) is added to 50% aqueous ethanol (960 mi) and dissolved therein by heating. The solution is filtered when hot and washed with prewarmed 25% aqueous ethanol (384 ml) . Then, water (1540 ml) is added under warming and the mixture is cooled gradually under constant stirring. The resulting crystals are collected by filtration and dried in vacuo .
  • the anhydrous N- (4-acetyl-l-piperazinyl) -4-fluorobenzamide thus obtained is allowed to stand for equilibration under a water- filled tray disposed in the bottom stage of a dryer at a shelf temperature of 25°C and a vacuum of 25-30 m Hg to provide N- (4-acetyl-l-piperazinyl) -4-fluorobenzamide monohydrate (183.5 g) .
  • N- (4-Acetyl-l-piperazinyl) -4-fluorobenzamide hydrate as provided by this invention undergoes little change in water content under ordinary interior humidity conditions and can, therefore, be easily handled. It has also been established that the hydrate is chemically stable against accelerated heat, humidity and light exposure test conditions, showing no alteration in crystal morphology, either.
  • N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide hydrate of the present invention can be used in a form of pharmaceutical preparation containing said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension of emulsion. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • N- ( 4-acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of N- ( 4-acetyl-l-piperazinyl) -4-fluorobenzamide hydrate may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • Fig. 2 A powder X-ray diffraction pattern of N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
  • Fig. 3 A thermal analysis (TG/DTA) diagram of N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
  • Fig. 4 The three-dimensional structure of N- ( 4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
  • Fig. 5 The X-ray diffraction pattern calculated from the 3- dimensional structure of N- (4-acetyl-l-piperazinyl) - 4-fluorobenzamide monohydrate.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention has for its object to provide N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide in a form easy to handle and stable against stress testings. N-(4-Acetyl-1-piperazinyl)-4-fluorobenzamide hydrate is easy to handle under ordinary interior humidity conditions and stable against accelerated heat, humidity, and light exposure test conditions.

Description

DESCRIPTION
N- (4-ACETYL-l-PIPERAZINYL) -4-FLU0R0BENZAMIDE HYDRATE
TECHNICAL FIELD
This invention relates to N- ( 4-acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate which is useful as a medicament.
BACKGROUND ART N- (4-Acetyl-l-piperazinyl) -4-fluorobenzamide having the following chemical formula:
Figure imgf000003_0001
was first described by the applicant of the instant application in WO 91/01979 and is a per se known compound. This compound has the potentiation of the cholinergic activity and is known to have excellent antidementia and antiamnesic actions.
DISCLOSURE OF INVENTION This invention relates to N- ( -acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate.
One object of this invention is to provide N-(4-acetyl-
1-piperazinyl) -4-fluorobenzamide in a form easy to handle under ordinary interior humidity conditions and resistant to stress testings, i.e. N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide hydrate.
Another object of this invention is to provide an agent and a pharmaceutical composition comprising, as an active ingredient, said hydrate. A further object of this invention is to provide a therapeutical method for the treatment and/or prevention of disorders m the central nervous system for human beings, and more particularly m the treatment and/or prevention of amnesia, dementia, senile dementia ana the like.
More particularly, the inventors of this invention endeavored m earnest to accomplish the above object and discovered the hydrate form of N- ( 4-acetyl-l-pιperazmyl) -4- fluorobenzamide which can oe handled with ease under ordinary interior humidity conditions and stable even under accelerated heat, humidity, and light exposure test conditions. This invention has been accomplished on the basis of the above finding.
Thus, N- (4-acetyl-l-pιperazmyl) -4-fluorobenzamide free of water of crystallization undergoes change in water content by absorbing moisture under ordinary interior nu idity conditions and the rate of its moisture absorption also varies with the ambient relative humidity, thus offering the disadvantage that it cannot be easily handled m the laboratory room and the pharmaceutical manufacturing room.
Therefore, the inventors explored for a stable form of N-(4- acetyl-1-pιperazmyl ) -4-fluorobenzamide wnich would show little change m water content under ordinary interior humidity conditions ana could, therefore, oe easily nandled m both the laboratory room and the pharmaceutical manufacturing room and discovered that the hydrate, preferably the monohydrate (theoretical water content 6.36%), of the above compound shows substantially no change m water content m addition to the advantage that it can be easily handled. Furthermore, this N- ( 4-acetyl-l-pιperazmyl ) -4- fluorobenzamide hydrate, preferably monohydrate thereof, is chemically stable even under accelerated heat, humidity, and light exposure test conditions. It was also confirmed that N- ^4-acetyl-l-pιperazmyl) -4-fluorobenzamide hydrate, preferably monohydrate thereof, remains chemically stable without undergoing crystallographic change in the accelerated heat, humidity, and light exposure tests. The following are experimental findings substantiating the above description.
In this invention, it is to be noted that N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide hydrate may include all hydrate containing one or more water molecule (s) such as monohydrate, dihydrate, trihydrate, etc., in which preferable one is monohydrate.
Experiment 1: Moisture absorption test
1) Method
About 0.2 g of N- (4-acetyl-l-piperazinyl) -4- fluorobenzamide monohydrate was accurately weighed into a weighing bottle about 3 cm in diameter and placed in a desiccator controlled at a relative humidity (R.H.) value of 43% with a saturated potassium carbonate solution. This test sample was stored in a constant-temperature room at 25°C for 24 hours and the change in water content was sequentially monitored.
2) Results Table 1 Time 0 1 2 3 4 5 6 24
( Hr )
Water content 6.23 6.23 6.23 6.27 6.23 6.27 6.23 6.18
(%)
The above results indicate that N- ( -acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate undergoes little change in water content in an environment of 43% R.H. even for as many as 24 hours.
Experiment 2: Stability in solid state 1 ) Method
N- (4-Acetyl-l-piperazinyl) -4-fluorobenzamide monohydrate, 0.2 g, was weighed into an amber-colored No. 1 bottle which was then placed in a desiccator controlled at 75% R.H. with a saturated aqueous solution of sodium chloride and stirred in a minijet oven at 70°C for 9 days. Separately, 0.2 g of N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide monohydrate was accurately weighed, spread thinly in a dish about 4 cm in diameter, covered with polyvinylidene chloride film, and exposed to a chemical lamp for 24 hours. Using the above 2 samples, the quality parameters of description, water content (K.F. method), infrared spectrum, and liquid chromatographic assay [detector: ultraviolet spectrophotometer (exciting wavelength 254 nm) , column: TSK gel ODS-80TM (5 μm) (4.6 mm in. dia. x 15 cm long), column temperature: room temperature; mobile phase: water-acetonitrile (4:1), sample concentration: 0.5 mg/ml (solvent: acetonitrile) , flow rate: the retention time of N- (4-acetyl-l-piperazinyl) -4-fluorobenzamide adjusted to ca 7 min.) (ca 1.0 ml/min.), infection size: 5 μl] were determined.
2) Results
Table 1
Storage 70°C Chemical lamp conditions Initial 75% R.H., exposure test, Test parameters 9 days 24 hrs
White White White
Description powders powders powders
Water content (%; ) 6.23 6.40 6.10
IR spectrum - No change No change
Residue (%) 100.0 100.5 99.9
Those results indicate that N- ( 4-acetyl-l-piperazinyl) - 4-fluorobenzamide monohydrate is chemically stable against accelerated 70°C, 75% R.H. heat and humidity test and accelerated chemical lamp exposure test conditions, undergoing no change in crystal morphology.
Example 1
N- (4-acetyl-l-piperazmyl) -4-fluorobenzamide (192.0 g) is added to 50% aqueous ethanol (960 mi) and dissolved therein by heating. The solution is filtered when hot and washed with prewarmed 25% aqueous ethanol (384 ml) . Then, water (1540 ml) is added under warming and the mixture is cooled gradually under constant stirring. The resulting crystals are collected by filtration and dried in vacuo . The anhydrous N- (4-acetyl-l-piperazinyl) -4-fluorobenzamide thus obtained is allowed to stand for equilibration under a water- filled tray disposed in the bottom stage of a dryer at a shelf temperature of 25°C and a vacuum of 25-30 m Hg to provide N- (4-acetyl-l-piperazinyl) -4-fluorobenzamide monohydrate (183.5 g) .
Water content (K.F. method):
6.23% (theoretical value for the monohydrate: 6.36%) Infrared (IR) spectrum (Nujol) As shown in Fig. 1. Powder X-ray diffraction pattern As shown in Fig. 2. Thermal analysis (TG/DTA data) As shown in Fig. 3
By subjecting the compound obtained by the above procedure to recrystallization from a saturated chloroform solution, colorless clear platelets can be obtained. X-ray crystallographic analysis of the above crystal crop yielded the crystal structure containing one molecule of water as shown in Fig. 4 and the X-ray diffraction pattern (Fig. 5) calculated from this crystal structure was found to agree well with the powder X-ray diffraction pattern shown in Fig. 2.
Effects of the Invention
N- (4-Acetyl-l-piperazinyl) -4-fluorobenzamide hydrate as provided by this invention undergoes little change in water content under ordinary interior humidity conditions and can, therefore, be easily handled. It has also been established that the hydrate is chemically stable against accelerated heat, humidity and light exposure test conditions, showing no alteration in crystal morphology, either.
For therapeutic purpose, N- ( 4-acetyl-l-piperazinyl) -4- fluorobenzamide hydrate of the present invention can be used in a form of pharmaceutical preparation containing said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension of emulsion. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of N- ( 4-acetyl-l-piperazinyl ) -4- fluorobenzamide hydrate will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of N- ( 4-acetyl-l-piperazinyl) -4-fluorobenzamide hydrate may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1: An infrared absorption spectrum of N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
Fig. 2: A powder X-ray diffraction pattern of N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
Fig. 3: A thermal analysis (TG/DTA) diagram of N- (4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
Fig. 4: The three-dimensional structure of N- ( 4-acetyl-l- piperazinyl) -4-fluorobenzamide monohydrate.
Fig. 5: The X-ray diffraction pattern calculated from the 3- dimensional structure of N- (4-acetyl-l-piperazinyl) - 4-fluorobenzamide monohydrate.

Claims

1. N- (4-Acetyl-l-piperazinyl-4-fluorobenzamide hydrate
2. The monohydrate according to claim 1.
3. The monohydrate according to claim 2 which has the following physical constants:
(i) a powder X-ray diffraction pattern with characteristic peaks around 7.0°, 13.8°, 17.7°, 22.0°, 24.4° and 26.1°
(ii) an infrared spectrum (Nujol) with absorption bands near
3196, 1641, 1618, 1240 and 849 cm -1-
4. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.
5. A compound of claim 1 for use as a medicament.
6. A method of therapeutic treatment and/or prevention of amnesia, dementia or senile dementia which comprising an effective amount of a compound of calim 1 to human beings .
7. Use of a compound of claim 1 for the manufacture of a medicament for treating and/or preventing amnesia, dementia or senile dementia in human beings.
PCT/JP1997/004451 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate Ceased WO1998025914A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
HU0002975A HUP0002975A3 (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate and pharmaceutical composition containing it
IL13027397A IL130273A (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate, pharmaceutical compositions containing the same and the use thereof for the manufacture of medicaments
US09/319,271 US6147079A (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate
CA002274682A CA2274682A1 (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate
DK97946110T DK0944612T3 (en) 1996-12-12 1997-12-05 N- (4-acetyl-1-piperazinyl) -4-fluorbenzamidhydrat
AT97946110T ATE205198T1 (en) 1996-12-12 1997-12-05 N-(4-ACETYL-1-PIPERAZINYL)-4-FLUOROBENSAMIDEHYDR T
HK00103880.7A HK1024482B (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate
EP97946110A EP0944612B1 (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate
JP50681698A JP3254683B2 (en) 1996-12-12 1997-12-05 N- (4-acetyl-1-piperazinyl) -4-fluorobenzamide hydrate
AU51368/98A AU722095B2 (en) 1996-12-12 1997-12-05 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate
EA199900530A EA001715B1 (en) 1996-12-12 1997-12-05 N-(acetyl-1piperazynil)-4-fluorobenzamide hydrate
DE69706562T DE69706562T2 (en) 1996-12-12 1997-12-05 N- (4-acetyl-1-piperazinyl) -4-FLUOROBENZAMIDHYDRAT
GR20010401324T GR3036542T3 (en) 1996-12-12 2001-09-06 N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP33178496 1996-12-12
JP8/331784 1996-12-12

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WO1998025914A1 true WO1998025914A1 (en) 1998-06-18

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US (1) US6147079A (en)
EP (1) EP0944612B1 (en)
JP (1) JP3254683B2 (en)
KR (1) KR20000057342A (en)
CN (1) CN1073104C (en)
AT (1) ATE205198T1 (en)
AU (1) AU722095B2 (en)
CA (1) CA2274682A1 (en)
DE (1) DE69706562T2 (en)
DK (1) DK0944612T3 (en)
EA (1) EA001715B1 (en)
ES (1) ES2160371T3 (en)
GR (1) GR3036542T3 (en)
HU (1) HUP0002975A3 (en)
IL (1) IL130273A (en)
PT (1) PT944612E (en)
TW (1) TW422844B (en)
WO (1) WO1998025914A1 (en)
ZA (1) ZA9710872B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042011A1 (en) * 1999-01-14 2000-07-20 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
US6344358B1 (en) 1999-05-28 2002-02-05 Fujisawa Pharmaceutical Co., Ltd. Agent for expression of long-term potentiation of synaptic transmission comprising compound having brain somatostatin activation property
WO2002020016A1 (en) * 2000-09-06 2002-03-14 Fujisawa Pharmaceutical Co, Ltd AGENT FOR MODULATING EXCITATORY SYNAPTIC TRANSMISSION COMPRISING A COMPOUND HAVING ALPHA α7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATION PROPERTY
WO2002034735A1 (en) * 2000-10-23 2002-05-02 Fujisawa Pharmaceutical Co., Ltd. Method of obtaining solvate and solvate
WO2003084542A1 (en) * 2002-04-10 2003-10-16 Fujisawa Pharmaceutical Co., Ltd. Neurotrophic factor production accelerator

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010030637A (en) * 1997-10-09 2001-04-16 후지야마 아키라 New process for producing aminopiperazine derivatives
CA2431181A1 (en) * 2000-12-07 2002-06-13 Nobuya Matsuoka Nootropic effect enhancer

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1991001979A1 (en) * 1989-08-02 1991-02-21 Fujisawa Pharmaceutical Co., Ltd. New aminopiperazine derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5250528A (en) * 1989-08-02 1993-10-05 Fujisawa Pharmaceutical Co., Ltd. New aminopiperazine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001979A1 (en) * 1989-08-02 1991-02-21 Fujisawa Pharmaceutical Co., Ltd. New aminopiperazine derivatives
EP0436734A1 (en) * 1989-08-02 1991-07-17 Fujisawa Pharmaceutical Co., Ltd. New aminopiperazine derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042011A1 (en) * 1999-01-14 2000-07-20 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
US6710043B1 (en) 1999-01-14 2004-03-23 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
US6344358B1 (en) 1999-05-28 2002-02-05 Fujisawa Pharmaceutical Co., Ltd. Agent for expression of long-term potentiation of synaptic transmission comprising compound having brain somatostatin activation property
WO2000072834A3 (en) * 1999-05-28 2002-07-11 Fujisawa Pharmaceutical Co Agent for expression of long-term potentiation of synaptic transmission comprising compound having brain somatostatin activation property
US6613572B2 (en) 1999-05-28 2003-09-02 Fujisawa Pharmaceutical Co., Ltd. Agent for expression of long-term potentiation of synaptic transmission comprising compound having brain somatostatin activation property
WO2002020016A1 (en) * 2000-09-06 2002-03-14 Fujisawa Pharmaceutical Co, Ltd AGENT FOR MODULATING EXCITATORY SYNAPTIC TRANSMISSION COMPRISING A COMPOUND HAVING ALPHA α7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATION PROPERTY
WO2002034735A1 (en) * 2000-10-23 2002-05-02 Fujisawa Pharmaceutical Co., Ltd. Method of obtaining solvate and solvate
WO2003084542A1 (en) * 2002-04-10 2003-10-16 Fujisawa Pharmaceutical Co., Ltd. Neurotrophic factor production accelerator

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KR20000057342A (en) 2000-09-15
AU5136898A (en) 1998-07-03
EP0944612B1 (en) 2001-09-05
EA001715B1 (en) 2001-08-27
IL130273A (en) 2003-05-29
HUP0002975A2 (en) 2001-12-28
CA2274682A1 (en) 1998-06-18
DK0944612T3 (en) 2001-11-19
CN1073104C (en) 2001-10-17
GR3036542T3 (en) 2001-12-31
ES2160371T3 (en) 2001-11-01
PT944612E (en) 2002-01-30
DE69706562T2 (en) 2002-05-29
ATE205198T1 (en) 2001-09-15
EP0944612A1 (en) 1999-09-29
DE69706562D1 (en) 2001-10-11
US6147079A (en) 2000-11-14
HUP0002975A3 (en) 2002-01-28
HK1024482A1 (en) 2000-10-13
JP2000514460A (en) 2000-10-31
AU722095B2 (en) 2000-07-20
ZA9710872B (en) 1998-06-15
EA199900530A1 (en) 1999-12-29
TW422844B (en) 2001-02-21
JP3254683B2 (en) 2002-02-12
IL130273A0 (en) 2000-06-01

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