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WO1994024115A1 - Nouveau derive de piperazine - Google Patents

Nouveau derive de piperazine Download PDF

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Publication number
WO1994024115A1
WO1994024115A1 PCT/JP1994/000614 JP9400614W WO9424115A1 WO 1994024115 A1 WO1994024115 A1 WO 1994024115A1 JP 9400614 W JP9400614 W JP 9400614W WO 9424115 A1 WO9424115 A1 WO 9424115A1
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Prior art keywords
group
groups
compound
phenylethyl
lower alkyl
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PCT/JP1994/000614
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English (en)
Japanese (ja)
Inventor
Yoichi Kawashima
Junzo Matsumoto
Hirotaka Osaki
Kiyoshi Matsuno
Toshihiko Senda
Keiko Hirano
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Santen Pharmaceutical Co., Ltd.
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Publication of WO1994024115A1 publication Critical patent/WO1994024115A1/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
    • C07D295/092—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 with aromatic radicals attached to the chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention has an affinity for receptors and receptors, and is used to treat dementia, depression, schizophrenia, anxiety and other cranial nerve dysfunctions, diseases associated with immune and endocrine disorders, and digestive ulcers. It relates to a new compound that is useful as an agent.
  • 1,2-diphenylbiperazine derivatives have been studied as analgesics (Japanese Patent Publication No. 47-634, Japanese Patent Publication No. 49-188, J. Med. Chem., _0_1240 (1975)).
  • Etc. a substituent in which a substituent such as an alkyl group, an alkenyl group, a cycloalkyl group, or a phenylalkyl group is introduced at the 4-position of the piperazine ring.
  • a substituent such as a halogen atom, a hydroxy group, or a lower alkoxy group is added to the phenyl ring.
  • the compounds introduced have been reported.
  • 1,2-diphenylpyrazine derivatives in which the 4-position of the piperazine ring is substituted with a phenylalkyl group or a phenoxyalkyl group have a calcium antagonism and a cerebral nerve function improvement action ( JP-A-63-141 966, JP-A-3-72229).
  • the present inventors focused on the alkylene chain of the diphenylalkylpiperazine derivative, synthesized a novel piperazine derivative having an oxygen atom introduced into the alkylene chain, and examined its pharmacological action.o
  • the compound of the present invention is useful for the treatment of cranial nerve dysfunction such as dementia, depression, schizophrenia, and insecurity, diseases associated with immunoreceptor and endocrine disorders, and digestion, It was found to be useful as a therapeutic agent for organ ulcers and the like.
  • the present invention provides a novel pyrazine compound represented by the following general formula [I] and a salt thereof (hereinafter, referred to as the compound of the present invention).
  • R 1 represents a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyl lower alkyl group, and a phenyl ring of a phenyl group, a phenyl lower alkyl group or a phenyl lower alkyl group.
  • the cycloalkyl group may be substituted with one or more lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxy groups, lower alkoxy groups or lower alkylenedioxy groups.
  • R 2 and R 3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a cyano group.
  • a and B are the same or different and represent a lower alkylene group. You.
  • n 0 or 1. same as below. ]
  • lower alkyl is a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, and teft.-butyl.
  • a branched alkyl, and a lower alkenyl is a straight-chain or branched alkenyl having 2 to 6 carbon atoms containing a double bond such as vinyl, aryl, and hexenyl
  • a lower alkynyl is Represents a straight-chain or branched alkynyl having 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, hexynyl and the like.
  • Lower alkoxy is methoxy, ethoxy, propoxy, hexyloxy, Is a straight-chain or branched alkoxy having 1 to 6 carbon atoms such as isopropoxy, tert.-butoxy, etc.
  • cycloalkyl is cyclopropyl, cyclolob.
  • Cycloalkyl having 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
  • lower alkylene means methylene, ethylene, (dimethyl) It represents a straight-chain or branched alkylene having 1 to 6 carbon atoms such as methylene, (methyl) methylene and the like.
  • the lower alkylenedioxy is methylenedioxy, ethylenedioxy, (dimethyl) methylenedioxy, (getyl).
  • the salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, maleate and fumarate.
  • R 1 is a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyloxy lower alkyl group, and Is different and includes a compound of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a cyano group. More preferred examples include R 1 is a cyclohexyl group or a phenylethyl group, R 2 is a hydrogen atom or a halogen atom,
  • R 3 is a compound represented by a hydrogen atom, a halogen atom or a lower alkoxy group.
  • R 2 is a hydrogen atom or a fluorine atom
  • R 3 is a hydrogen atom, a fluorine atom or a methoxy group.
  • the lower alkylene group of A and B is preferably a methylene group.
  • Examples of the compounds of the present invention which have particularly excellent effects include 1- (2-benzyloxy-1-1-phenylethyl) -4-cyclohexylbiperazine, 1- (1-benzyloxymethyltinole-2—phenylethyl 1) 4—cyclohexylolepiperazine, 4—cyclohexyl 1 1— [2— (4—fluorobenziloxoxy) 1—1-phenylenyl) piperazine, 4—cyclohexyl 1—1—2— (4— —Methoxybenzyloxy) 1- 1-phenylethyl) piperazine and 1- (2—benzyloxy 1- 1-phenylethyl) 1-4- (2—phenylethyl) piperazine, and the respective salts And stereoisomers and optically active isomers.
  • Representative methods for synthesizing the compounds of the present invention include the following a) and b) ⁇ )
  • R 4 represents a protecting group for an amino group such as a lower alkanoyl group or a lower alkoxycarbonyl group
  • X represents a leaving group such as a halogen atom or a lower alkane sulfonyloxy group.
  • the amino group of the compound represented by the formula [11] is protected to give a compound of the formula [111], and the compound of the formula [IV] is reacted with the compound of the formula [IV] to obtain a compound of the formula [11]
  • the compound of formula [V] is converted to the compound of formula [V], and then the protecting group for the amino group is removed to obtain a compound of formula [VI].
  • the compound of formula [VII] is reacted with a compound of formula [VII] to form a piperazine ring. To obtain the compound [I] of the present invention.
  • the method of b) comprises reacting the compound of formula [VI] obtained by the method of a) with a halogenated alcohol such as 2-bromoethanol to give the compound of formula [VI] with the compound of formula [V111]. After that, thionyl chloride or methanesulfonyl chloride or the like is reacted therewith, the compound of the formula [V111] is led to the compound of the formula [], and then R 1 NH 2 is reacted to form a piperazine ring. To obtain the compound [I] of the present invention.
  • a halogenated alcohol such as 2-bromoethanol
  • the compound obtained by the above method can be converted into a salt as described above by a conventional method.
  • the compound represented by the general formula [I] has optical isomers, all of which are included in the present invention.
  • an optically active material When an optically active material is used, an optically active substance can be obtained.However, when a racemic substance is used as a raw material, a racemic product can be optically separated using an optical resolving agent or the like. it can.
  • Et al is, [3 ⁇ ] (+) - ⁇ where the T Zeta was as a labeled ligand consider the affinity, the compounds of the present invention [3 ⁇ ] (+) - SKF - 1 0 0 4 7 of As in the case, it showed strong affinity for the ⁇ receptor.
  • an experiment was performed to determine whether the compound of the present invention exhibits a morphine-like effect. It is known that a compound having a morphine-like action has a strong affinity for a ⁇ receptor, and if the affinity for a receptor is weak, it can be determined that the compound has a weak morphine-like action.
  • the affinity of the compound of the present invention for the ⁇ receptor was examined using [ 3 H] DAMG0 as a labeled ligand. As a result, it was found that the compound of the present invention has a weak affinity for the // receptor, and the compound of the present invention does not substantially exhibit a morphine-like effect.
  • the difference between the effect expression amount and the side effect expression amount is large. That is, in the present invention, it is preferable that the affinity for the ⁇ receptor is strong and the affinity for the ⁇ receptor is weak, and the experimental results described below show that the compound of the present invention is excellent as a pharmaceutical. It proves.
  • a learning disorder model due to ischemia which is known as a disease model of dementia due to cerebrovascular disorders, that is, four arteries are obtained by the method of Pulsinel li (Stroke, H, 267-272 (1979)).
  • Pulsinel li Pulsinel li
  • the compound of the present invention had an improving effect on learning disability.
  • a compound that increases the amount of acetylcholine in the brain was dementia. J. Med, 315, 1241-1245 (1986)), it was reported by Matsuno et al. (Brain Res., 575, 315-). 319 (1992))
  • the compound of the present invention showed an effect of increasing acetylcholine.
  • the compound of the present invention shows that the compound of the present invention is a disease involving dementia, depression, schizophrenia, anxiety, etc. It has a wide range of pharmaceutical uses as a therapeutic agent for organ ulcers and the like, and is particularly useful as a therapeutic agent for cranial nerve dysfunction.
  • the method of administration of the compound of the present invention may be oral or parenteral.
  • the dosage form include tablets, capsules, soft capsules, granules, and injections.
  • the compound of the present invention can be formulated using a technique that is widely used.
  • oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystal cell mouth, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, etc.
  • Binders such as hydroxypropylcellulose and polyvinylidene, disintegrants such as low-substituted hydroxypropylcellulose mouth, calcium carboxymethylcellulose, hydroxypropylmethylcellulose, macrogol, silicone It can be formulated using a coating agent such as a resin or a film agent such as a gelatin film.
  • the dosage is appropriately selected depending on the symptoms, dosage form, etc., but usually 1 mg to 100 mg, preferably 1 mg to 200 mg per day may be administered once or in several divided doses.o
  • N, N-bis (2-chloroethyl) cyclohexylamine hydrochloride (0.75 g) dimethyl formamide (0.71 g) of nilethylamine (Reference compound 41, 0.65 g) (40 ml), add sodium iodide (0.886 g) and potassium carbonate (1.19 g) to the solution, and stir at 60 ° C for 5 hours.
  • the organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained oil is purified by silica gel column chromatography, ethanol ethanolic hydrochloride solution is added, and the mixture is concentrated under reduced pressure to obtain 0.69 g (53%) of the title compound (compound 3-1).
  • Example 3 The same operation as in Example 3 is performed to obtain the following compound.
  • the membrane preparation was prepared by the following method according to the paper by Tam et al. (Proc. Natl. Acad. Sci. USA, Jl ⁇ 703-670? (1983)).
  • the specific binding amount of [ ⁇ ⁇ ] (+) — SKF— 10047 was determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, bets squirrel - was dissolved in hydrochloric acid buffer solution [3 ⁇ ] (+) - SKF - 1 0 0 4 7 (5 ⁇ ⁇ ) was added (test compound The reaction was carried out at 25 ° C. for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount.
  • (+) — SKF— 100 4 7 A mixture of (5 nM) and (+)-SKF-10047 (100 M) without radioactivity was added (without adding the test compound), and the membrane was labeled using the same method as above. The amount of binding to the product was determined, and the result was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.
  • Table 1 shows the results of Compound 1-1, Compound 2-1, Compound 3-1, and Compound 3-5 as examples of the experimental results.
  • the compound of the present invention was found to significantly inhibit the specific binding amount of [ 3 H] (+)-SKF-107 at a low concentration. It was found to have strong affinity for the sigma receptor.
  • the membrane preparation was prepared according to the following method according to a paper by Tam et al. (Proc. Natl., Acad. Sci. USA, 80, 6703-6707 (1983)).
  • the brain is removed from a Hartley guinea pig (body weight: 300-400 g), and a tris-hydrochloric acid buffer (5 OmM, pH 7.7, 0. After homogenization in 32 M sucrose), the mixture was centrifuged to obtain a supernatant. The pellet obtained by ultracentrifuging the supernatant for 20 minutes is suspended in Tris-monohydrochloride buffer (50 mM, pH 7.7, the same applies hereinafter), and centrifuged again to obtain a membrane. A sample was obtained.
  • Table 2 shows the results of compound 3-1, compound 3-5, compound 5-1, and compound 5-2 as an example of the experimental results.
  • the membrane preparation was prepared by the following method according to the paper by Kosterli et al. (Br. J. Pharmac., 68, 333-342 (1980)).
  • Brain is removed from a Wistar male rat (body weight: about 300 g), and is dissolved in Tris-HCl buffer (50 mM, pH 7.7, the same applies hereinafter) 20 times the brain weight. After homogenizing with, ultracentrifugation was performed for 15 minutes to obtain pellets. This pellet was suspended in a Tris-HCl buffer, incubated at 37 ° C for 30 minutes, and ultracentrifuged for 15 minutes to obtain a pellet, which was used as a membrane sample.
  • Tris-HCl buffer 50 mM, pH 7.7, the same applies hereinafter
  • the specific binding amount of [ 3 H] DAMG0 was determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, Application Benefits scan - dissolved in hydrochloric acid buffer solution [3 H] D AM GO to (1 n M) was added (test compound without added), 2 5 The reaction was carried out at 30 ° C for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount.
  • Table 3 shows the results of Compound 11-1, Compound 2-1, Compound 3-1, and Compound 3-5 as examples of the experimental results.
  • the compound of the present invention has a strong affinity for the bireceptor, shows almost no morphine-like action, and is a disease involving the receptor such as dementia, depression, and schizophrenia. It has a wide range of medical uses as a therapeutic agent for cranial nerve dysfunction such as anxiety disorders, diseases associated with immune abnormalities and endocrine abnormalities, and gastrointestinal ulcers. It proved to be useful.
  • the present invention has an affinity for the receptor, dementia, It is intended to provide a novel compound useful as a therapeutic agent for cranial nerve dysfunction such as depression, schizophrenia and anxiety disorder, a disease associated with immune abnormality and endocrine abnormality, and gastrointestinal ulcer.

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  • Pain & Pain Management (AREA)
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Abstract

Composé représenté par la formule générale (I), ainsi que ses sels. Dans ladite formule, R1 représente alkyle inférieur, cycloalkyle, phényle, alkyle inférieur à substitution phénylique ou bien alkyle inférieur à substitution phénoxique, où le cycloalkyle, phényle et les groupes phényle de l'alkyle inférieur à substitution phénylique et de l'alkyle inférieur à substitution phénoxique peuvent être substitués par un ou plusieurs groupes alkyle inférieur, alcényle inférieur, alcynyle inférieur, hydroxy, alcoxy inférieur ou alkylènedioxy inférieur; R2 et R3 représentent chacun indépendamment hydrogène, halogène, alkyle inférieur, hydroxy, alcoxy inférieur ou cyano; A et B représentent chacun indépendamment alkylène inférieur; et n représente 0 ou 1. Ce composé est utile comme remède contre les troubles fonctionnels des nerfs craniens, tels que la démence, la dépression, la schizophrénie et l'anxiété, les affections associées à l'immunopathologie et à l'anomalie endocrinienne, ainsi que les ulcères à l'estomac.
PCT/JP1994/000614 1993-04-16 1994-04-12 Nouveau derive de piperazine WO1994024115A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2883970B2 (ja) 1993-07-28 1999-04-19 参天製薬株式会社 新規１，４−（ジフェニルアルキル）ピペラジン誘導体
US6713626B2 (en) 2002-03-12 2004-03-30 Wyeth Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution
US6784294B2 (en) 2002-03-12 2004-08-31 Wyeth Preparation of N1-(2′-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines
US6916797B2 (en) * 1999-12-20 2005-07-12 Ucb, S.A. α-arylethylpiperazine derivatives as neurokinin antagonists
US7019137B2 (en) 2002-03-12 2006-03-28 Wyeth Process for making chiral 1,4-disubstituted piperazines
US7091349B2 (en) 2002-03-12 2006-08-15 Wyeth Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution
US7361773B2 (en) 2002-03-12 2008-04-22 Wyeth Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines
CN103420865A (zh) * 2013-08-27 2013-12-04 罗梅 一种手性酰胺晶体化合物的制备及合成方法
CN103570578A (zh) * 2013-11-17 2014-02-12 罗梅 一种手性酰胺晶体化合物的合成方法

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Publication number Priority date Publication date Assignee Title
JPH037229A (ja) * 1989-03-15 1991-01-14 Santen Pharmaceut Co Ltd 脳神経機能改善剤
WO1991009594A1 (fr) * 1989-12-28 1991-07-11 Virginia Commonwealth University Ligands de recepteur sigma et leur emploi
EP0566189A1 (fr) * 1992-04-13 1993-10-20 Akzo N.V. Dérivé de pipérazine psychotropique

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
JPH037229A (ja) * 1989-03-15 1991-01-14 Santen Pharmaceut Co Ltd 脳神経機能改善剤
WO1991009594A1 (fr) * 1989-12-28 1991-07-11 Virginia Commonwealth University Ligands de recepteur sigma et leur emploi
EP0566189A1 (fr) * 1992-04-13 1993-10-20 Akzo N.V. Dérivé de pipérazine psychotropique

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Title
CHEMICAL ABSTRACTS, Vol. 88 (21), 145965v, (1978). *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2883970B2 (ja) 1993-07-28 1999-04-19 参天製薬株式会社 新規１，４−（ジフェニルアルキル）ピペラジン誘導体
US6916797B2 (en) * 1999-12-20 2005-07-12 Ucb, S.A. α-arylethylpiperazine derivatives as neurokinin antagonists
CN1304388C (zh) * 2002-03-12 2007-03-14 惠氏公司 合成手性n－芳基哌嗪的方法
US6784294B2 (en) 2002-03-12 2004-08-31 Wyeth Preparation of N1-(2′-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines
US7019137B2 (en) 2002-03-12 2006-03-28 Wyeth Process for making chiral 1,4-disubstituted piperazines
US7091349B2 (en) 2002-03-12 2006-08-15 Wyeth Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution
US6713626B2 (en) 2002-03-12 2004-03-30 Wyeth Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution
US7256289B2 (en) 2002-03-12 2007-08-14 Wyeth Process for making chiral 1,4-disubstituted piperazines
US7361773B2 (en) 2002-03-12 2008-04-22 Wyeth Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines
CN103420865A (zh) * 2013-08-27 2013-12-04 罗梅 一种手性酰胺晶体化合物的制备及合成方法
CN103420865B (zh) * 2013-08-27 2015-08-26 罗梅 一种手性酰胺晶体化合物的制备及合成方法
CN103570578A (zh) * 2013-11-17 2014-02-12 罗梅 一种手性酰胺晶体化合物的合成方法
CN103570578B (zh) * 2013-11-17 2015-01-14 罗梅 一种手性酰胺晶体化合物的合成方法

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