CN1099752A - Novel amidoalkyl- and imidoalkyl-piperazines - Google Patents

Novel amidoalkyl- and imidoalkyl-piperazines Download PDF

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CN1099752A
CN1099752A CN93118820A CN93118820A CN1099752A CN 1099752 A CN1099752 A CN 1099752A CN 93118820 A CN93118820 A CN 93118820A CN 93118820 A CN93118820 A CN 93118820A CN 1099752 A CN1099752 A CN 1099752A
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hydrogen atom
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S·本特森
L·弗罗瓦尔
D·杰克森
B·R·托尔夫
C·阿克森
G·哈尔内莫
S·罗斯
B·乌尔夫
L·张
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AstraZeneca AB
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Astra AB
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Priority to SE9201138A priority Critical patent/SE9201138D0/en
Priority to SK1389-93A priority patent/SK138993A3/en
Priority to HU9303520A priority patent/HUT68891A/en
Priority to PCT/SE1993/000295 priority patent/WO1993021179A1/en
Priority to EP93909109A priority patent/EP0594813A1/en
Priority to AU39643/93A priority patent/AU665825B2/en
Priority to CA002109816A priority patent/CA2109816A1/en
Priority to JP5518225A priority patent/JPH06508378A/en
Priority to CZ932701A priority patent/CZ270193A3/en
Priority to SI9300191A priority patent/SI9300191A/en
Priority to CN93118820A priority patent/CN1099752A/en
Application filed by Astra AB filed Critical Astra AB
Priority to NO934426A priority patent/NO180794C/en
Priority to NO934426D priority patent/NO934426D0/en
Priority to BG98281A priority patent/BG98281A/en
Priority to FI935494A priority patent/FI935494A0/en
Publication of CN1099752A publication Critical patent/CN1099752A/en
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Abstract

The general formula of the compound is:*** The method and intermediate product for preparing the compounds, contain medicinal preparation of these compounds and its usage for curing abalienation.

Description

Novel amidoalkyl- and imidoalkyl-piperazines
The present invention relates to novel 1-aryl-4(ω-amide group-1-alkyl and ω-imino--1-alkyl) piperazine, prepare their intermediate product and method, contain the pharmaceutical composition of this type of piperazine and relate to the purposes of described compound aspect therapeutics.
The object of the present invention is to provide novel being effective to treat compound such as the mental disorder disease of schizophrenia and other psychosis, anxiety, depression and manic-depressive psychopathia.
Buspirone is a known substance, is recently comprising that always the various central nervous system disorders of dysthymia disorders are detected.It all has affinity to 5HT1A acceptor and D2 acceptor.
Glennon and co-worker thereof (Glennon RA, Naiman NA, Lyon RA, Titeler M:Journal of Medicinal Chemistry, 1988,31,1968-1971) recorded and narrated some aryl piperazine derivative, this comprises the NAN190[=1-(2-methoxyphenyl that is attached to the 5HTlA acceptor of (3H)-8-hydroxyl DPAT mark)-the 4-(4-(2-phthalimido) butyl) piperazine.In another report, same lineup (Raghuparthi RK, RydelekFitzgerald L, Teitler M, Glennon RA:Journal of Medicical Chemistry 1991,34,2633-2638) also recorded and narrated some affinities, and some analogue in conjunction with the 5HTlA stimulant NAN190 of affinity has been arranged at α 1 acceptor at the 5HTlA acceptor.Further study on the synthesis in association area also on the books (Glennon RA, Naiman NA, Pierson ME, Smith JD, Ismaiel AM, Titeler M, Lyon RA:Journal of Medicinal 1989,32,1921-1926).
The present invention has found the new compound that general formula is following
Figure 931188202_IMG19
Or its pharmaceutically useful salt.
Wherein R is a hydrogen atom or phenyl,
M is the integer of 3-8,
R 4Be positioned at this ring between position or contraposition, and represent NO 2Group or group NR 7R 8, R wherein 7And R 8Can be identical or different, and respectively represent a hydrogen atom or to contain the alkyl of 1-3 carbon atom,
R 5Be positioned at ortho position, a position or contraposition, and represent hydrogen atom, halogen atom or CF 3,
R 6Be positioned at ortho position, a position or contraposition, and represent halogen atom or CF 3,
W is aromatic ring, heterocycle or carbocyclic ring or a methylene radical that replaces arbitrarily that is optionally substituted,
A is hydrogen atom, hydroxyl, halogen atom, CF 3, the alkyl of a 1-3 carbon atom, alkoxyl group, phenyl or the phenoxy group of a 1-3 carbon atom,
B is a hydrogen atom, or
A and B together constitute carbonyl,
n 1Be 0 or 1, and
n 2Be 0 or 1,
They exist with the form of racemic or optically active form, or the mixture of diastereomer, and condition is
1) when W is the aromatic ring that is optionally substituted, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A is hydrogen atom, halogen atom, CF 3, hydroxyl, the alkyl of a 1-3 carbon atom, alkoxyl group, the phenyl of a 1-3 carbon atom, or phenoxy group, and
B be hydrogen atom or
A and B together constitute carbonyl,
2) when W is carbocyclic ring or heterocycle, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A and B be hydrogen atom or
A and B together constitute carbonyl,
3) when W be one be optionally substituted methylene radical the time, then
R, m, R 4, R 5And R 6Define as above,
n 1And n 2Be 1 or
n 1Be 1 and n 2Be 0 or
n 1Be 0 and n 2Be 1,
A and B together constitute carbonyl.
This compound and salt thereof demonstrate D 2Affinity with the 5HTlA acceptor.The compound that this effect can will be defined in is used for the treatment of post traumatic stress disorder, as schizophrenia and dysthymia disorders.
Aromatic ring defined above is preferably phenyl or naphthyl, and coverlet replacement or disubstituted, and substituting group wherein is preferably and is selected from following substances: hydrogen atom, halogen atom, hydroxyl, CF 3, the alkyl of a 1-3 carbon atom or the alkoxyl group of 1-3 carbon atom.
Heterocycle defined above is preferably furyl, thienyl, pyrryl, pyridyl or indyl.
Carbocyclic ring defined above is preferably monocycle, dicyclo or many rings of 3-12 carbon atom.
Substituting group on Ding Yi the carbocyclic ring is preferably the alkyl of hydrogen atom or 1-3 carbon atom in the above.
Substituting group on Ding Yi the methylene radical is preferably the alkyl of hydrogen atom or 1-4 carbon atom in the above.
Halogen atom defined above is preferably chlorine, bromine or fluorine atom.
Preferred one group of compound or pharmaceutically acceptable salt thereof that compound is formula I a:
Figure 931188202_IMG20
R wherein 1Be arranged in 3-4-position, and represent hydrogen atom, halogen atom, CF 3, the alkyl of a 1-3 carbon atom, alkoxyl group, the NO of a 1-3 carbon atom 2, COCH 3, or NR 2R 3, R wherein 2And R 3Can be identical or different, and respectively represent the alkyl of hydrogen atom or 1-6 carbon atom,
M is the integer of 3-8,
R 4Be positioned at this ring between position or contraposition and represent NO 2Group or group NR 7R 8R wherein 7And R 8Can be identical or different, and respectively represent the alkyl of hydrogen atom or 1-3 carbon atom,
R 5Be positioned at ortho position, a position or the contraposition of this ring, and represent hydrogen atom, halogen atom or CF 3,
R 6Be positioned at the ortho position of this ring, a position, or contraposition and represent halogen atom or CF 3, W preferably is selected from following group:
Figure 931188202_IMG21
Figure 931188202_IMG23
When W be selected from group ⅰ-one of the time, the preferred 4-6 of m then,
R 4Be preferably NH 2,
R 4The best be between the position or the NH of contraposition 2,
R 5Be preferably hydrogen or halogen atom,
The R of particularly preferred compound 5Be hydrogen, chlorine or bromine,
R 5The best be between the position or the hydrogen or the chlorine of contraposition,
R 5Preferred CF 3Or halogen atom,
The R of more preferred compound 6Be CF 3Or chlorine,
Best R 5CF for a position 3Or chlorine.
When W was ⅰ-ⅹ, then R was preferably H.
When W is ⅰ, then
n 1Be preferably 0 and n 2Be preferably 0 or 1,
n 2The best is 0,
A is preferably adjacent hydrogen, methoxyl group or hydroxyl.
When W is ⅱ, then
n 1Be preferably 0.
When W is ⅲ-ⅶ, then
n 1Be preferably 0,
A is preferably hydrogen atom or the alkyl of 1-3 carbon atom is arranged,
And B is preferably hydrogen atom.
When W is ⅷ, then
n 1And n 2Be preferably 0, and
A and B preferably constitute a carbonyl.
When W is ⅸ, then
n 1And n 2Be preferably 1, and
A and B preferably constitute a carbonyl.
When W is ⅹ, then
n 1And n 2Be preferably 0, and
A and B preferably constitute a carbonyl.Best compound is as follows:
Figure 931188202_IMG26
Figure 931188202_IMG27
Organic acid and mineral acid all can be used to form the additive salt of the non-toxicity pharmaceutically acceptable acid of The compounds of this invention.Illustrative acid is sulfuric acid, nitric acid, phosphoric acid, oxalic acid, hydrochloric acid, formic acid, Hydrogen bromide, citric acid, acetate, lactic acid, tartrate, Pamoic, ethane disulfonic acid, thionamic acid, succsinic acid, propionic acid, oxyacetic acid, oxysuccinic acid, amygdalic acid, glyconic acid, pyruvic acid, toluylic acid, the 4-benzaminic acid, anthranilic acid, Whitfield's ointment, the 4-aminosallcylic acid, the 4-hydroxy-benzoic acid, nicotinic acid, methanesulfonic, ethane sulfonic acid, the hydroxyl ethane sulfonic acid, Phenylsulfonic acid, to a toluenesulphonic acids, sulfanilic acid, naphthene sulfonic acid, xitix, the cyclohexyl thionamic acid, fumaric acid, toxilic acid and phenylformic acid.Adopt means known in the art can easily prepare these acid.
Preparation
The compound of formula I is:
Figure 931188202_IMG28
Wherein R is hydrogen atom or phenyl,
M is the integer of 3-8,
R 4Be positioned at this ring between position or contraposition, and represent NO 2Group or group NR 7R 8,
R wherein 7And R 8Can be identical can be different, and respectively represent hydrogen atom or the alkyl of 1-3 carbon atom arranged,
R 5Be positioned at ortho position, a position or contraposition and represent hydrogen atom, halogen atom or CF 3,
R 6Be positioned at ortho position, a position or contraposition and represent halogen atom or CF 3,
W is aromatic ring, heterocycle or carbocyclic ring or a methylene radical that replaces arbitrarily that is optionally substituted,
A is hydrogen atom, hydroxyl, halogen atom, CF 3, the alkyl of 1-3 carbon atom, the alkoxyl group that 1-3 carbon atom arranged, phenyl or phenoxy group arranged,
B is a hydrogen atom, or
A and B together constitute a carbonyl,
n 1Be 0 or 1, and
n 2Be 0 or 1,
This compound is racemic modification or optically active form, or is a kind of mixture of non-corresponding body, and condition is:
1) when W is substituted aromatic ring, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A is hydrogen atom, halogen atom, CF 3, hydroxyl, the alkyl that 1-3 carbon atom arranged, the alkoxyl group that 1-3 carbon atom arranged, phenyl or phenoxy group, and
B is a hydrogen atom, or
A and B constitute a carbonyl,
2) when W is carbocyclic ring or heterocycle, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A and B are hydrogen atom, or
A and B constitute a carbonyl,
3) when W be one be optionally substituted methylene radical the time, then
R, m, R 4, R 5And R 6Define as above,
n 1And n 2Be 1 or,
n 1Be 1 and n 2Be 0 or,
n 1Be 0 and n 2Be 1,
A and B together constitute a carbonyl,
This compound can be by following method preparation at choice.
A) under room temperature or higher temperature, and in the presence of sodium halide that alkali (such as triethylamine, sodium hydroxide or salt of wormwood) and catalytic amount are arranged or potassium halide (as KI), the compound of general formula II and the compound of general formula III are reacted for a long time:
The compound of general formula II is:
Figure 931188202_IMG29
Wherein R, m, W, A, B, n 1And n 2Define as above, and X is for suitable leavings group, such as halogen atom, aryl sulfonic acid root or alkyl azochlorosulfonate; The compound of formula III is:
R wherein 4, R 5And R 6Definition as above.
B) adopt suitable hydrolysis method, reduction method, electrochemical process or other known method to transform the compound of general formula IV:
Wherein R, m, R 5, R 6, W, A, B, n 1And n 2The definition as above, and Y be positioned between the position or contraposition and the representative can change radicals R into 1 4A group, the R here 1 4Be positioned at this ring between position or contraposition and represent group NR 7R 8, R wherein 7And R 8Definition as above.The compound that can prepare the general formula IV by method A.Such group Y can be selected from acid amides, carbamate, imines, benzylamine or other the suitable protected amino group that is easy to rupture.This class group can be trifluoroacetamido, formamido group, tert-butoxycarbonyl amino; Or N-benzyloxy.
In addition, Y can be such as nitro, azido-, hydroxyl amino, hydrazono-, amido or imido grpup, and it is that available known reduction method changes it into R 1 4.
C) have in the presence of the suitable reductive agent (such as sodium cyanoborohydride or lithium aluminum hydride) with directly or mode progressively make the compound of general formula V and the compound reaction of general formula III.The compound of formula V is:
Wherein R, m, W, A, B, n 1And n 2Define as above, and Z is hydrogen, hydroxyl, halogen atom or alkoxyl group; The compound of formula III is:
Figure 931188202_IMG33
R wherein 4, R 5And R 6Definition as above.
D) in such as suitable solvent such as methylene dichloride, chloroform, toluene, acetate or tetrahydrofuran (THF) or net phase, the compound of general formula VI and the compound of general formula VII are reacted for a long time under room temperature or the high temperature; The compound of formula VI is: (VII and original text VI are not inconsistent herein)
Wherein W, n 1, n 2With A definition as above, T together represents an aliphatic series, ring grease, aromatics or heterocyclic acid derivative independently or with A, or such as acid derivative or other acid activation group of halogenide, ester, imide, acid anhydride; The compound of formula VII is:
Figure 931188202_IMG35
Wherein m, R 4, R 5And R 6Definition as above.
E) in The suitable solvent such as chloroform Huo diox, make the compound and suitable halide reagent such as a SULPHURYL CHLORIDE or a bromine reaction of general formula VIII; The compound of formula VIII is:
Figure 931188202_IMG36
Wherein R, m, R 4, W, A, B, n 1And n 2Define as above, and R 5Be H, halogen atom or CF 3
F), in a appropriate solvent such as DMF, acetonitrile or DMSO, the compound of general formula IX and the compound of general formula X are reacted for a long time at room temperature or higher temperature with have in the presence of the alkali such as triethylamine, sodium hydroxide or salt of wormwood.The compound of formula IX is
Figure 931188202_IMG37
Wherein W, n 1And n 2Define as above, A and B together represent carbonyl, and a kind of suitable basic metal of M representative such as sodium or potassium; The compound of formula X is:
Wherein X, R 4, R 5And R 6Definition as above.
Intermediate product
The compound of general formula II is:
Figure 931188202_IMG39
Wherein R, m, W, A, B, n 1, n 2With X definition as above, this compound can under room temperature or the high temperature in one such as the appropriate solvent of methylene dichloride, chloroform, toluene, acetate or tetrahydrofuran (THF) in or net phase the compound of general formula VI and the compound of general formula XI are reacted for a long time.The compound of formula VI is:
Figure 931188202_IMG40
Wherein W, n 1, n 2With A definition as above, and T together represents suitable aliphatic series, cyclic aliphatic, aromatics an or heterocyclic acid derivative independently or with A or such as the acid derivative of halogenide, ester, imide, acid anhydride, or other activating group; The compound of formula XI is:
Wherein the m definition as above; Make the intermediate product of general formula XII subsequently
(wherein R, m, W, A, B, n 1And n 2Definition is as above) with a suitable halogenating agent such as thionyl chloride, carbonyl chloride, oxalyl chloride or phosphorus tribromide, or with a suitable sulphonating agent reaction such as toluene sulfonyl chloride or other aryl sulfonyl chloride or alkyl sulfonyl chloride.
The general formula III 1Compound be:
Figure 931188202_IMG42
R wherein 1 4, R 5And R 6Define as above, it can be by being similar to the compound of method B by general formula *.The compound of formula * is:
Figure 931188202_IMG43
Wherein Y, R 5And R 6As defined above.
The compound of general formula X III (R wherein 5And R 6Definition as above and Y is NO 2)
Figure 931188202_IMG44
Preparation can be: the compound (R wherein that makes the formula IV 5And R 6Define as above, Y is
Figure 931188202_IMG45
NO 2And U is a halogen) be the suitably mono-substituted piperazine reaction that is easy to remove group with a piperazine or a substituting group such as benzyl or ethoxycarbonyl; Or make the compound of general formula X V
Figure 931188202_IMG46
(R wherein 5And R 6The definition as above and Y be NO 2) with the reaction of the compound of general formula X VI.The compound of formula X VI is:
Wherein X definition as above, and V is a hydrogen or such as the group that is easy to remove of benzyl or ethoxycarbonyl.
The compound of general formula X:
(wherein X, m, R 4, R 5And R 6Definition is as above) can be similar under the suitable reaction conditions of method A, by making the compound of general formula X V II
The compound of (wherein X and m definition as above) and general formula III
Figure 931188202_IMG49
(R wherein 4, R 5And R 6The definition as above) reaction prepare.
Pharmaceutical preparation
According to the present invention, the compound of formula I can be given by oral, rectum with the form of pharmaceutical preparation usually and use or use by injecting to give, this pharmaceutical preparation contains or is free alkali or is the activeconstituents of pharmaceutically acceptable non-toxicity acid salt, and described acid salt for example is hydrochloride, hydrobromide, lactic acid salt, acetate, phosphoric acid salt, vitriol, sulfamate, Citrate trianion, tartrate, oxalate reaches and the similar substance of pharmaceutically useful medicament pass.Medicine type can be solid, semisolid or flowing product.Usually, the 0.1-99% that active substance accounts for the weight of pharmaceutical preparation more specifically says, the preparation of desiring to be used to inject is then accounted for 0.5-20%, and the preparation that is suitable for oral medication is then accounted for 0.2-50%.
The pharmaceutical preparation that contains the generalformula of oral medication dosage unit form for production, can be with selected compound and solid excipient, as lactose, sucrose, sorbyl alcohol, mannitol, the starch such as potato starch, W-Gum or amylopectin, derivatived cellulose; Binding agent such as gelatin or Polyvinylpyrolidone (PVP) and lubricant, mixes such as Magnesium Stearate, calcium stearate, polyoxyethylene glycol, wax, paraffin or the like, is pressed into tablet then.If tablet needs coating, the medicine core for preparing as mentioned above can be coated with can contain priming just like things such as gum arabic, gelatin, talcum, titanium dioxide.Randomly, this tablet can be coated with well known in the art being dissolved in and be easy to evaporable organic solvent or ORGANIC SOLVENT MIXTURES or polymkeric substance soluble in water.Can in these coating, add tinting material so that difference contains the different activities material or contains the different tablets of measuring active compounds.
Preparation is during soft capsule, these active substances can with as vegetables oil or polyoxyethylene glycol blending.Hard capsule can contain has used above mentioned tablet excipient, as sucrose, sorbose, mannitol, starch, as the active material particle of potato starch, W-Gum or amylopectin, derivatived cellulose or gelatin.Also liquid or semi-solid medicament can be charged into hard capsule.
The dosage device of rectal application can be solution or suspension agent, or can be made into the suppository form of active substance of neutral fat alkali that contained fusion, or the rectal capsule of the active substance of the vegetables oil that contained fusion or paraffin oil.
The liquid preparation of oral medication can be syrup or suspension agent form, for example contains the about 20%(weight percent of about 0.2%-) active substance described herein, surplus is the solution of the mixture of sugar and ethanol, water, glycerine and propylene glycol.This class I liquid I preparation can randomly contain tinting material, flavouring agent, asccharin and as carboxymethyl cellulose or other vehicle well known in the art of thickening material.
The parenteral medical solution can be made into concentration and is preferably the about 10%(weight percent of about 0.5%-) the aqueous solution of water-soluble pharmacologically acceptable salt of active substance, these solution also can contain stablizer and/or buffer reagent and can supply with the injection of various medicament units easily.
The suitable per daily dose that is used for the The compounds of this invention of human body therapy is: oral medication 50-500mg, and through the maximum 100mg of parenteral medication.
Especially preferred is to using the following compound of chemical formula:
Figure 931188202_IMG50
Embodiment
Embodiment 1(method A)
1-(4-amino-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) the piperazine dihydrochloride
With 3.18g(0.01mol) KI, the 4.1g(0.03mol of 4-amino-3-trifluoromethyl piperazine, catalytic amount) salt of wormwood and 3.0g(0.01mol) the N-(4-brombutyl) mixture of the solution of phthalimide in 25ml DMF stirred liquid at 100 ℃.After adding 500ml water, with this mixture of extracted with diethyl ether.Washing extract with water extracts with dilute hydrochloric acid again.Water layer is separated, make it alkalize and use extracted with diethyl ether again with NaOH.With extract drying (Na 2SO 4) and in ether, use the hydrogenchloride acidifying.The throw out of output is leached and recrystallize in ethanol one ether.
Output: 3.0g(58%).
Fusing point: 226-227 ℃.
Compound (2-12) below preparing in a similar fashion:
Embodiment 2
1-(4-amino-3-trifluoromethyl)-and 4-(3-phthalimido-1-propyl group) the piperazine dihydrochloride
Fusing point: 167-169 ℃.
Embodiment 3
1-(4-amino-3-trifluoromethyl)-and 4-[5-(3-methoxyl group phthalimido-1-amyl group) the piperazine barkite
Fusing point: 114-118 ℃.
Embodiment 4
1-(4-amino-3-trifluoromethyl)-and 4-[4-(4-chloro phthalimido-1-butyl) the piperazine dihydrochloride
Fusing point: 203-204 ℃.
Embodiment 5
1-(4-amino-3-trifluoromethyl)-and 4-(5-phthalimido-1-amyl group) the piperazine dihydrochloride
Fusing point: 109-113 ℃.
Embodiment 6
1-(4-amino-3, the 5-difluorophenyl)-4-(4-phthalimido-1-butyl) piperazine
Fusing point: 116-119 ℃.
Embodiment 7
1-(4-amino-3-trifluoromethyl)-and 4-[3-(1, the 8-naphthalimido)-the 1-propyl group] piperazine
Fusing point: 156-158 ℃.
Embodiment 8
1-(4-amino-3-trifluoromethyl)-and 4-[4-(3,3-dimethyl-penten two acyliminos)-the 1-butyl] the piperazine dihydrochloride
Fusing point: 235-236 ℃.
Embodiment 9
1-(4-amino-3-trifluoromethyl)-and 4-[4-(3,3-tetramethylene glutaryl imino-)-the 1-butyl] the piperazine dihydrochloride
Fusing point: 243-245 ℃.
Embodiment 10
1-(4-amino-3-trifluoromethyl)-4-[5-(3-phenyl glutaryl imino-)-the 1-amyl group] the piperazine salt acidulants
Fusing point: 136-140 ℃.
Embodiment 11
1-(3-amino-4-chloro-phenyl-)-4-[5-(2-furans carboxamido)-the 1-amyl group] the piperazine barkite
Fusing point: 165-170 ℃.
Embodiment 12
1-(4-amino-3-trifluoromethyl)-and 4-(4-hexanaphthene carboxamido-1-butyl) piperazine
Fusing point: 127-128 ℃.
Embodiment 13(method B)
1-(4-amino-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) the piperazine acetate
The product (9.53g, 20mmol pd/c(1.0g) that will be dissolved in the embodiment 38 of 100ml ethanol and 50ml acetate was done catalyzer hydrogenation 5 hours.Filter this mixture, evaporating solvent and with residue crystallization in diisopropyl ether and ethanol produces the 10.0g title product.
Fusing point: 101-103 ℃
Prepare following compound (embodiment 14-24) in a similar fashion:
Embodiment 14
1-(4-amino-3-trifluoromethyl)-and 4-(6-phthalimido-1-hexyl) the piperazine acetate
Fusing point: 125-127 ℃
Embodiment 15
1-(4-amino-3-trifluoromethyl)-and 4-(8-phthalimido-1-octyl group) the piperazine acetate
Fusing point: 94-96 ℃
Embodiment 16
1-(3-amino-4-chloro-phenyl-)-and 4-(4-phthalimido-1-butyl) the piperazine acetate
Fusing point: 159-162 ℃
Embodiment 17
1-(3-amino-4-chloro-phenyl-)-and 4-(5-phthalimido-1-amyl group) the piperazine acetate
Fusing point: 149-150 ℃
Embodiment 18
1-(4-amino-3-aminomethyl phenyl)-and 4-(4-phthalimido-1-butyl) the piperazine acetate
Fusing point: 123-126 ℃
Embodiment 19
1-(3-amino-4-chloro-phenyl-)-and 4-[4-(3,3-tetramethylene glutaryl imino-)-the 1-butyl) piperazine
Fusing point: 133-136 ℃
Embodiment 20
1-(4-amino-3-trifluoromethyl)-4-[6-(3-phenoxy group benzamido)-the 1-hexyl) the piperazine acetate
Fusing point: 128-131 ℃
Embodiment 21
1-(4-amino-3-trifluoromethyl)-and 4-(6-hexanaphthene carboxamido-1-hexyl) the piperazine dihydrochloride
Fusing point: 112-115 ℃
Embodiment 22
1-(4-amino-3-trifluoromethyl)-and 4-(4-diamantane carboxamido-1-butyl) the piperazine dihydrochloride
Fusing point: 123-125 ℃
Embodiment 23
1-(4-amino-3-trifluoromethyl)-and 4-(4-diamantane acetylaminohydroxyphenylarsonic acid 1-butyl) piperazine
Fusing point: 115-116 ℃
Embodiment 24
1-(4-amino-3-trifluoromethyl)-and 4-(6-diamantane carboxamido-1-hexyl) piperazine
1H NMR（CDCl 3）d 7.00（s，1H），6.96（dd，1H），6.70（d，1H），5.57（bs，1H），3.26（bs，2H），3.24（m，2H），3.08（m，4H），2.61（m，4H），2.39（m，2H），2.04（bs，3H），1.84（bs，6H），1.71（bs，6H），1.52（m，4H），1.34（m，4H）.
Embodiment 25(method B)
1-(4-amino-2-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) the piperazine dihydrochloride
Follow stirring to 1-(4-nitro-2-trifluoromethyl)-4-(4-phthalimido-1-butyl) (7.8g, 0.01mol) mixed solution in 200ml ethanol and 60ml water adds the 11.2g V-Brite B and 100 ℃ of heating to piperazine in batches.This mixture of reflux 1 hour and ethanol evaporation.Make residuary water solution be alkalescence and use extracted with diethyl ether with NaOH.Wash extract, drying with water and ether is evaporated.The oil that generates is dissolved in the 100ml anhydrous diethyl ether and hydrogenchloride makes this dihydrochloride precipitation in the ether by being added in.This salt recrystallize in ethanol/ether gets 2.3g(44%) the purpose compound.
Fusing point: 243-244 ℃.
Embodiment 26(method B)
1-(4-diethylamino-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) piperazine
To be dissolved in the product that derives from embodiment 13 in the 5ml acetate (1.0g, 2mmol) be added to sodium borohydride (304mg, 8mmol) with the mixture of 20ml toluene in.This mixture 80 ℃ of heating 6 hours, is cooled off and is added in 50ml water and the 50ml ether and make it to be alkaline with 2M NaOH.Dry and the evaporation with organic phase.Make residue recrystallize in hexane, output 440mg purpose product.
Fusing point: 70-71 ℃.
Embodiment 27(method B)
1-(4-amino-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) piperazine
To be dissolved in the 4-(4-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl of 2ml ethanol and 0.2ml2M hydrochloric acid)-1-(4-phthalimido-1-butyl) piperazine (4.9mg, 0.01mmol) 80 ℃ of heating 5 hours, after removing solvent, gas chromatography shows that this residue is identical with the product of embodiment 1.
Embodiment 28(method C)
4-(4-amino-3-trifluoromethyl)-and 1-(4-phthalimido-1-butyl) piperazine
(0.804g is 3.25mmol) in CHCl for piperazine to 4-phthalimido-1-butyraldehyde (0.713g is 3.25mmol) with N-(4-amino-3-trifluoromethyl) in 20 minutes 3Reflux solution (10ml) adds 10ml formic acid dropwise in CHCl 3In 98% solution.This solution of reflux 2 hours.Remove solvent and with the residue chromatographic purification, tlc shows that with gas chromatography this residue is identical with the product of embodiment 1.
Embodiment 29(method D)
1-(4-amino-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) piperazine
With 4-(4-amino-3-trifluoromethyl)-the amino butyl of 1-(4-) piperazine (32mg, 0.1mmol) and Tetra hydro Phthalic anhydride (30mg 0.2mmol) is dissolved in the solution of 1ml acetate in 75 ℃ of stirrings 3 hours.Remove solvent, and gas chromatography and tlc show that this residue is identical with product among the embodiment 1.
Embodiment 30(method D)
1-(4-amino-3-trifluoromethyl)-and 4-[4-(5-bromo-2,3-dimethoxy benzamido)-the 1-butyl] piperazine dioxalic acid salt
(3.3g 6.4mmol) is dissolved in 60ml ethanol, makes it to be alkalescence and this alkali and hydrazine hydrate (2.0ml) were heated 3.5 hours at 75 ℃ with 2MNaOH with the product of embodiment 1.After the cooling, solution with 27ml 2M HCl acidifying, is evaporated then.Residue is dissolved in 75ml H 2In O and the 75ml ether.Make water be alkalescence and use chloroform extraction.Evaporating solvent produces the amino butyl of thick level 1-(4-)-4-(4-amino-3-trifluoromethyl) piperazine.With 5-bromo-2, (0.52g, 2.0mmol) (2ml 23mmol) heated 3 hours at 60 ℃ with several DMF the 3-dimethoxybenzoic acid for the solution in 10ml toluene, thionyl chloride.Evaporating solvent also is dissolved in 15ml methylene dichloride and revaporization with residue.The residue chloride of acid is dissolved in the 15ml methylene dichloride and follows cooling to add derive from aforesaid thick level amine (0.51g, 1.6mmol) and triethylamine (0.45g, 3.2mmol) solution in the 10ml methylene dichloride.The stirring back evaporating solns and residue is distributed in rare HCl and ether that spends the night.The water extracted organic phase also makes the water of merging be alkalescence to use the chloroform re-extract again.Dry (Na 2SO 4) and evaporation obtain 0.57g and be the oily product.This alkali is dissolved in acetone and gets the 0.95g title product with oxalic acid treatment.
Fusing point: 174-175 ℃.
Prepare following compounds (embodiment 31-34) in a similar fashion:
Embodiment 31
1-(4-amino-3-trifluoromethyl)-the 4-(4-benzamido)-the 1-butyl) piperazine
Fusing point: 117-120 ℃.
Embodiment 32
1-(4-amino-3-trifluoromethyl)-and 4-[5-(5-bromo-2,3-dimethoxy benzamido)-the 1-amyl group] piperazine dioxalic acid salt
Fusing point: 151-154 ℃.
Embodiment 33
1-(4-amino-3-trifluoromethyl)-4-[4-(2-norbornane carboxamido)-the 1-butyl] the piperazine salt acidulants
Fusing point: 77-80 ℃.
Embodiment 34
(R, introversion)-1-(4-amino-3-trifluoromethyl)-4-[4-(2-norbornane carboxamido)-the 1-butyl] the piperazine salt acidulants
Fusing point: 142-146 ℃.
Embodiment 35(method E)
1-(4-amino-5-bromo-3-trifluoromethyl)-and 4-(4-phthalimido-1-butyl) the piperazine oxalate
(1.0g 2mmol) is dissolved in 20ml diox and 5ml methyl alcohol with the product of embodiment 13.Add the bromine be dissolved in the 3ml diox (350mg, 2.2mmol) and this mixture was stirred under room temperature 5 hours, evaporating solvent, with the 2M NaOH aqueous solution make residue be alkalescence also use dichloromethane extraction it.Remove solvent and make residue be dissolved in diisopropyl ether and also obtain sedimentary title compound with being dissolved in alcoholic acid oxalic acid.
Fusing point: 172-175 ℃.
Embodiment 36(intermediate product, compound ii)
N-(5-bromine amyl group)-3-methoxyl group phthalimide
With 3-methoxyl group Tetra hydro Phthalic anhydride (3.0g, 16.8mmol) and 5-amino-1-amylalcohol (1.7g, 16.8mmol) mix and be heated to 120 ℃ with 2 hours, the cooling back adds phosphorus tribromide (3.5g, 13mmol) and hot to 110 ℃ again poured ice in 2 hours this mixture, use ethyl acetate extraction, and with organic phase separation, dry revaporization solution.Residue is recrystallize in ethyl ester/hexane.
Fusing point: 65-67 ℃.
Embodiment 37(intermediate product, compound ii)
N-(5-tosyl group oxygen amyl group)-and 5-bromo-2,3-dimethoxy benzamide
With 5-bromo-2, (1.56g, 6.0mmol) (6ml 70mmol) heated 3 hours at 60 ℃ with several DMF the 3-dimethoxybenzoic acid for the solution in 25ml toluene, thionyl chloride.Evaporating solvent, and with residue be dissolved in the 20ml methylene dichloride and once more the evaporation.With residual chloride of acid be dissolved in the 20ml methylene dichloride and-35 ℃ be added to the amino amylalcohol of 5-(1.8g, 18mmol) and triethylamine (4ml 28mmol) in the solution of 30ml methylene dichloride, and made temperature rise to 0 ℃ in 4 hours.Wash this solution, separate organic phase and remove solvent with dilute hydrochloric acid, output 2.2g is oil slightly.This oil is dissolved in the 20ml methylene dichloride, add triethylamine (4ml, 28mmol) and toluene sulfonyl chloride (1.33g 7mmol), and stirs this mixture and to spend the night under room temperature.Add ether (100ml) and use sodium carbonate solution and this organic phase of water washing.After the drying, the evaporation organic solvent produces 2.7g(5.5mmol) the oily title compound.
1H NMR（CDCl 3）d 7.9（bs，1H），7.81（d，1H），7.77（d，2H），7.34（d，2H），7.13（d，1H），4.03（t，2H），3.89（s，3H），3.87（s，3H），3.42（q，2H），2.44（s，3H），1.73-1.40（m，6H）.
Embodiment 38(intermediate product, the compound IV)
1-(4-nitro-3-trifluoromethyl)-and 4-(phthalimido-1-butyl) piperazine
With derive from embodiment 39 compound (8.5g, 30mmol), 4-brombutyl phthalimide (11.1g, 40mmol), salt of wormwood (5.0g, 36mmol) and the potassiumiodide of catalytic amount in 80ml DMF, be warmed to 90 ℃ with 6 hours.Pour into this mixture in the 500ml water and use dichloromethane extraction.Dry organic phase, evaporating solvent and with residue with ethanol/yellow crystalline product of diisopropyl ether development output.
Fusing point: 152-154 ℃.
Embodiment 39(intermediate product, compound X III)
1-(4-nitro-3-trifluoromethyl) piperazine
With 22.4g(0.1mol) 4-nitro-3-Trifluoromethyl-1-chlorobenzene, 50.0g(0.58mol) mixture of KI in the 80ml1-propyl alcohol of Piperazine anhydrous and catalytic amount spend the night 100 ℃ of following stirring heating.After the cooling, follow to stir to add 11 frozen water.Leach the throw out of generation, wash with water and drying.
Output 26.6g(94%).Fusing point: 81-83 ℃.
Embodiment 40(intermediate product, compound X III)
4-amino-2,6-dichlorophenyl piperazine
Make catalyzer with carbon coating platinum and in 8 hours, will be dissolved in 2 of 100ml methyl alcohol and 10ml 2M HCl under normal temps and the pressure, 6-two chloro-4-N-methyl-p-nitroaniline (10.4g, 50mmol) hydrogenations.Leach catalyzer and remove solvent.Residue is dissolved in ether and makes it to be alkalescence with output 5.1g(29mmol) the crystalline powder of grey.This product along with being heated to 100 ℃, is made it in the n-butanols that 3 * 1g yellow soda ash (30mmol) is arranged that (5.4g, 30mmol) reaction is 26 hours with two-(2-chloroethyl) amine salt acidulants.Evaporating solvent is dissolved in residue in the ether and makes it to be alkalescence with output 3.4g(48%) be the buttery product.
1H NMR（CDCL 3）d 6.82（s，2H），4.10（s，2H），3.02（m，8H），1.82（s，1H）.
Pharmaceutical preparation
Following example illustrative desires to be used for the appropriate drug composition of the inventive method.Composition is to be used to prepare tablet below producing.
Composition 1
The compound 50g of embodiment 1
Lactose 85g
Potato starch 40g
Polyvinylpyrolidone (PVP) 5g
Microcrystalline Cellulose 18g
Magnesium Stearate 2g
Composition 2
The compound 100g of embodiment 1
Lactose 90g
Potato starch 50g
Polyvinylpyrolidone (PVP) 5g
Microcrystalline Cellulose 23g
Magnesium Stearate 2g
Can make 1000 tablets of tablets that contain 50mg and 100mg active substance respectively from top composition.If need, the tablet of gained can be used and film as the solution or the water of Vltra tears in an organic solvent.
Pharmacology
It has been generally acknowledged that, be incorporated into d2 dopamine receptor and in these acceptors the medicine for the anti-thing of knot be effective clinically as the medicine that suppresses psychosis (for example schizophrenia).It is also believed that owing to reduce the influence of the outer side effect of pyramidal tract and improve this material the avidity of serotonin (5HTlA) acceptor in the time of can making as stimulant to psychotic effect and become effective performance.Because these materials have the binding ratio of certain D2 and 5HTlA, these materials just can keep suppressing psychotic usefulness in side effects that reduces and improved effect.
Table 1 illustrative several compounds Dopamine HCL (D2) and serotonin (5HTlA) acceptor in conjunction with affinity (the Ki value, nM) and the D2/5HTlA ratio.
Recorded and narrated pharmacological method below.
The mensuration of D2 receptors bind
Tissue preparation: be partitioned into striatum with rat broken end and on ice, this be organized under 0 ℃ homogenizing in the tris-HCl of 20ml0.05M pH7.7 buffer reagent with Branson B30 acoustic wave device.With homogenate under 4 ℃ in Sorvall RC-5B refrigeration ultracentrifugation device (Refrigerated Superspeed Centrifuge) with 48000g centrifugation 10 minutes.To deposit sheet resuspending and centrifugation again.Final deposition sheet (is contained 0.1% xitix, 120mMNaCl, 5mM KCl, 2mM, CaCl in cultivating buffer reagent 2, 1mM MgCl 20.05Mtris-HCl with the pH7.6 of 10 μ M pargylines) resuspending in, to ultimate density be 2.5mg weight in wet base/0.5ml.Homogenate was cultivated 10 minutes in advance at 37 ℃.
Receptors bind is measured: at room temperature with test compound, the radioligand (1nM of different concns 3H-Raclopride) and homogenate cultivated 60 minutes.By adding 1 μ M(+)-Butaclamol measures non-specific binding.Use cell collection device, by cultivation here in the quick filtration of glass fiber paper (Whatman GF/B) also comes with cold cultivation damping fluid washing subsequently.In Packard 2200CA liquid scintillation counter, measure the radioactivity of this filter.Be expressed as the Ki value with the LIGAND program with the non-linear regression method analytical data and with it.
The 5-HTlA receptors bind is measured
Tissue preparation: dissect pallium+hippocampus of every mouse and use Ultra-Turrax(Janke ﹠amp; Kunkel, Staufen is FRG) with its 4.0mMCaCl that contains in 15ml pH7.5 2With homogenizing in the ice-cold tris-HCl damping fluid of 50mM of 5.7mM xitix 10 seconds.With 12.5 minutes (39800xg of 17000rpm centrifugation, (Beckman Palo Alto CA in the Beckman whizzer of the JA-17 rotor that has chilling, USA)) after, with deposition sheet resuspending in identical damping fluid and repeat homogenizing and centrifugation is handled.Added the ice-cold 0.32M sucrose of 5ml and homogenizing 5 seconds to each deposition sheet.Make these samples keep freezing down in-70 ℃.With this buffer reagent it was diluted to 8mg tissue/ml and homogenizing 10 seconds during use.This homogenate was cultivated 10 minutes down at 37 ℃, and cultivated 10 minutes subsequently 10 μ M pargylines in addition again then.According to Peroutka, J.Neurochem.47,529-540(1986) the described combination mensuration of carrying out.The 4.0mMCaCl that contains at 50mM 2Contain with this culturing mixt (2ml) in the tris-HCl damping fluid of the pH7.5 of 5.7mM xitix 3H-8-OH-DPAT(0.25-8nM), 5mg/ml homogenate.Six kinds of different concns of analysis 3H-8-OH-DPAT.Add homogenate and begin and cultivated 10 minutes at 37 ℃ subsequently in conjunction with testing.With Brandel Cell Harvester(Gaithersburgh, MD, USA) filter this culturing mixt through Whatman GF/B glass filter.50mMtris-HCl damping fluid with the ice-cold pH7.5 of 5ml washs this filter twice, and uses 5ml Ultima Gold in Beckman LS3801 scintillation counter TM(Packard) numeration.Add 10 μ M 5-HT to this reaction mixture and measure non-specific binding.Handle this binding data (Munson and Rodbard, Anal, Biochem.107,220-239,1980) with the nonlinear least square method Computer Analysis.Data are expressed with Ki value (nM).

Claims (13)

1, a kind of compound of formula I,
Figure 931188202_IMG2
Or its pharmaceutically useful salt,
Wherein R is hydrogen atom or phenyl,
M is the integer of 3-8,
R 4Be positioned at this ring between position or contraposition, and represent NO 2Group or group NR 7R 8, R wherein 7And R 8Can be identical or different, and respectively represent hydrogen atom or the alkyl of 1-3 carbon atom is arranged,
R 5Be positioned at ortho position, a position or contraposition, and represent hydrogen atom, halogen atom or CF 3,
R 6Be positioned at ortho position, a position or contraposition, and represent halogen atom or CF 3,
W is the methylene radical that the aromatic ring, heterocycle, the carbocyclic ring or that are optionally substituted are optionally substituted,
A is hydrogen atom, hydroxyl, halogen atom, CF 3, the alkyl of a 1-3 carbon atom, alkoxyl group, phenyl or the phenoxy group of a 1-3 carbon atom,
B is a hydrogen atom, or
A and B together constitute carbonyl,
n 1Be 0 or 1, and
n 2Be 0 or 1,
This material is racemic modification or optically active form form, or is the mixture of diastereomer, and condition is:
1) when W is the aromatic ring that is optionally substituted, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A is hydrogen atom, halogen atom, CF 3, hydroxyl, the alkyl of a 1-3 carbon atom, alkoxyl group, the phenyl of a 1-3 carbon atom, or phenoxy group, and
B be hydrogen atom or
A and B together constitute carbonyl,
2) when W is carbocyclic ring or heterocycle, then
R, m, R 4, R 5And R 6Define as above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A and B be hydrogen atom or
A and B together constitute carbonyl,
3) when W be one be optionally substituted methylene radical the time, then
R, m, R 4, R 5And R 6Define as above,
n 1And n 2Be 1 or
n 1Be 1 and n 2Be 0 or 1
n 1Be 0 and n 2Be 1,
A and B together constitute carbonyl.
2, according to the compound of claim 1, its chemical formula is:
Figure 931188202_IMG3
Figure 931188202_IMG4
3, a kind of preparation is characterized in that by the method for the compound of the definition of the formula I in the claim 1:
A) make the compound of general formula II and the compound reaction of general formula III, the compound of general formula II is:
Figure 931188202_IMG7
Wherein R, m, W, A, B, n 1And n 2By the definition in the claim 1, and X is a leavings group; The compound of general formula III is:
Figure 931188202_IMG8
R wherein 4, R 5And R 6By the definition in the claim 1, or
B) compound of conversion general formula IV:
Figure 931188202_IMG9
Wherein R, m, R 5, R 6, W, A, B, n 1And n 2Be by the definition in the claim 1, and Y be positioned between position or contraposition, and represent one can change radicals R into 1 4Group, R herein 1 4Be arranged in this ring between position or contraposition and representative by the group NR of claim 1 definition 7R 8, or
C) make the compound of general formula V and the compound reaction of general formula III, the compound of general formula V is:
Figure 931188202_IMG10
Wherein R, m, W, A, B, n 1And n 2By the definition in the claim 1, and Z is hydrogen, hydroxyl, halogen atom or alkoxyl group: the general formula III be:
Figure 931188202_IMG11
R wherein 4, R 5And R 6As the definition in the claim 1, or
D) make the compound of general formula VI and the compound reaction of general formula VII, the compound of formula VII is:
Figure 931188202_IMG12
Wherein W, n 1, n 2With the definition in A such as the claim 1, and T together represents the derivative or the acid derivative of suitable aliphatic series, cyclic aliphatic, aromatics an or heterocyclic acid by oneself or with A; The compound of formula VII is:
Wherein m, R 4, R 5And R 6As the definition in the claim 1, or
E) make the compound and the suitable halide reagent reaction of general formula VIII, the compound of formula VIII is:
Figure 931188202_IMG14
Wherein R, m, R 4, W, A, B, n 1And n 2As the definition in the claim 1, and R 5Be H, halogen atom or CF 3, or
F) compound of general formula IX compound and general formula X is reacted, the compound of formula IX is:
Wherein W, n 1And n 2As the definition in the claim 1, A and B together represent a carbonyl, and M represents basic metal; The compound of formula X is:
Figure 931188202_IMG16
Wherein X, R 4, R 5And R 6As the definition in the claim 1, in addition,, will use A if need)-the compound that any means obtained among F) is converted into its pharmaceutically useful salt.
4, a kind of method as claimed in claim 3 is characterized in that preparing the compound of claim 2.
5, a kind of compound of general formula II,
Figure 931188202_IMG17
R is hydrogen atom or phenyl,
M is the integer of 3-8,
W is the methylene radical that the aromatic ring, heterocycle, the carbocyclic ring or that are optionally substituted are optionally substituted,
A is hydrogen atom, hydroxyl, halogen atom, CF 3, the alkyl of 1-3 carbon atom, the alkoxyl group that 1-3 carbon atom arranged, phenyl or phenoxy group arranged,
B is a hydrogen atom, or
A and B together constitute carbonyl,
n 1Be 0 or 1, and
n 2Be 0 or 1, this compound is racemize or optically active form form, or is a kind of mixture of diastereomer, and condition is:
1) when W is the aromatic ring that is optionally substituted, then
R and m as defined above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A is hydrogen atom, halogen atom, CF 3, hydroxyl, the alkyl that 1-3 carbon atom arranged, the alkoxyl group that 1-3 carbon atom arranged, phenyl or phenoxy group and
B be hydrogen atom or
A and B together constitute carbonyl,
2) when W is a carbocyclic ring or a heterocycle, then
R and m as defined above,
n 1Be 0 or 1,
n 2Be 0 or 1,
A and B be hydrogen atom or
A and B together constitute carbonyl,
3) when W be one be optionally substituted methylene radical the time, then
R and m define as above,
n 1And n 2Be 1 or
n 1Be 1 and n 2Be 0 or
n 1Be 0 and n 2Be 1,
A and B together constitute carbonyl.
6, the compound of chemical formula III 1,
R wherein 1 4Be positioned at this ring between position or contraposition, and represent group NR 7R 8, R wherein 7And R 8Can be identical or different, and respectively represent hydrogen atom or the alkyl of 1-3 carbon atom is arranged,
R 5Be positioned at ortho position, a position or contraposition, and represent hydrogen atom, halogen atom or CF 3,
R 6Be positioned at ortho position, a position or contraposition, and represent halogen atom or CF 3
7, a kind ofly contain arbitrary compound among the claim 1-2 as the pharmaceutical preparation of activeconstituents.
8, a kind of claim 7 is pharmaceutical preparations in dosage units.
9, the pharmaceutical preparation that contains the activeconstituents that combines pharmaceutically acceptable carrier of a kind of claim 8-9.
10, each of a kind of claim 1-2 is as the compound of the active substance in the treatment.
11, the compound of each of claim 1-2 has the purposes of the medicine of anti-abalienation effect to preparation.
12, a kind of treatment comprises the method for people's mammiferous abalienation, it is characterized in that giving with any compound among the claim 1-2 of significant quantity to the main body of this treatment of needs.
13, be included in the claimed compounds among the claim 1-12 and be used for preparing their method and intermediate product, the medicinal compositions that contains described compound and said composition in the purposes of treatment aspect the abalienation.
CN93118820A 1992-04-09 1993-08-31 Novel amidoalkyl- and imidoalkyl-piperazines Pending CN1099752A (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
SE9201138A SE9201138D0 (en) 1992-04-09 1992-04-09 NOVEL PHTHALIMIDOALKYL PIPERAZINES
AU39643/93A AU665825B2 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
CZ932701A CZ270193A3 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl piperazines
EP93909109A EP0594813A1 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
HU9303520A HUT68891A (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
CA002109816A CA2109816A1 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
JP5518225A JPH06508378A (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
SK1389-93A SK138993A3 (en) 1992-04-09 1993-04-06 Amidoalkyl - and imidoalkylpiperazines
PCT/SE1993/000295 WO1993021179A1 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
SI9300191A SI9300191A (en) 1992-04-09 1993-04-09 New aminoalkyl- and iminoalkyl-piperazine derivatives
CN93118820A CN1099752A (en) 1992-04-09 1993-08-31 Novel amidoalkyl- and imidoalkyl-piperazines
NO934426A NO180794C (en) 1992-04-09 1993-12-06 Novel amidoalkyl and imidoalkylpiperazines and pharmaceutical preparations containing such compounds
NO934426D NO934426D0 (en) 1992-04-09 1993-12-06 New amidoalkyl and imidoalkylpiperines
BG98281A BG98281A (en) 1992-04-09 1993-12-08 Amidoalkyl- and imidoalkylpiperazines
FI935494A FI935494A0 (en) 1992-04-09 1993-12-08 Nya amidolacyl and imidoalkyl piperazine

Applications Claiming Priority (2)

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SE9201138A SE9201138D0 (en) 1992-04-09 1992-04-09 NOVEL PHTHALIMIDOALKYL PIPERAZINES
CN93118820A CN1099752A (en) 1992-04-09 1993-08-31 Novel amidoalkyl- and imidoalkyl-piperazines

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CZ270193A3 (en) 1994-08-17
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NO180794C (en) 1997-06-25
SE9201138D0 (en) 1992-04-09
HUT68891A (en) 1995-08-28
EP0594813A1 (en) 1994-05-04
AU3964393A (en) 1993-11-18
SK138993A3 (en) 1994-11-09
BG98281A (en) 1994-09-30

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