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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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group
compound
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hydrogen atom
halogen atom
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Inventor
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 FI935494A priority patent/FI935494A7/en
Priority to CA002109816A priority patent/CA2109816A1/en
Priority to AU39643/93A priority patent/AU665825B2/en
Priority to SK1389-93A priority patent/SK138993A3/en
Priority to EP93909109A priority patent/EP0594813A1/en
Priority to JP5518225A priority patent/JPH06508378A/en
Priority to CZ932701A priority patent/CZ270193A3/en
Priority to HU9303520A priority patent/HUT68891A/en
Priority to PCT/SE1993/000295 priority patent/WO1993021179A1/en
Priority to SI9300191A priority patent/SI9300191A/en
Application filed by Astra AB filed Critical Astra AB
Priority to CN93118820A priority patent/CN1099752A/en
Priority to NO934426A priority patent/NO180794C/en
Priority to NO934426D priority patent/NO934426D0/en
Priority to BG98281A priority patent/BG98281A/en
Publication of CN1099752A publication Critical patent/CN1099752A/en
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Abstract

通式I的化合物：

制备这些化合物的方法和中间产物，含有这些化 合物的药物制剂及其在治疗精神紊乱方面的用途。

Figure 93118820

Compounds of general formula I:

Processes and intermediates for the preparation of these compounds, pharmaceutical formulations containing these compounds and their use in the treatment of psychiatric disorders.

Figure 93118820

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、一种通式Ⅰ的化合物，1. A compound of general formula I,
Figure 931188202_IMG2
Figure 931188202_IMG2
 或其可药用的盐，or a pharmaceutically acceptable salt thereof, 其中R为氢原子或苯基，Wherein R is a hydrogen atom or a phenyl group, m为3-8的整数，m is an integer of 3-8, R4位于该环的间位或对位，且代表NO2基团或基团NR7R8，其中R7和R8可相同或不同，且各代表氢原子或有1-3个碳原子的烷基，R 4 is located at the meta or para position of the ring, and represents a NO 2 group or a group NR 7 R 8 , wherein R 7 and R 8 can be the same or different, and each represents a hydrogen atom or has 1-3 carbon atoms the alkyl, R5位于邻位、间位或对位，且代表氢原子，卤原子或CF3，R 5 is located at the ortho, meta or para position, and represents a hydrogen atom, a halogen atom or CF 3 , R6位于邻位、间位或对位，且代表卤原子或CF3，R 6 is located at the ortho, meta or para position, and represents a halogen atom or CF 3 , W为被任意取代的芳环、杂环、碳环或一被任意取代的亚甲基，W is an optionally substituted aromatic ring, heterocyclic ring, carbocyclic ring or an optionally substituted methylene group, A为氢原子、羟基、卤原子、CF3、1-3个碳原子的烷基、1-3个碳原子的烷氧基、苯基、或苯氧基，A is a hydrogen atom, a hydroxyl group, a halogen atom, CF 3 , an alkyl group with 1-3 carbon atoms, an alkoxy group with 1-3 carbon atoms, a phenyl group, or a phenoxy group, B为氢原子，或B is a hydrogen atom, or A与B一同构成羰基，A and B together form a carbonyl group, n1为0或1，且n 1 is 0 or 1, and n2为0或1， n2 is 0 or 1, 该物质呈外消旋体或旋光体形式，或为非对映体的混合物，条件是：The substance is in racemic or optical form, or as a mixture of diastereomers, provided that: 1)当W为被任意取代的芳环时，则1) When W is an aromatic ring optionally substituted, then R、m、R4、R5和R6定义如上，R, m, R 4 , R 5 and R 6 are as defined above, n1为0或1，n 1 is 0 or 1, n2为0或1， n2 is 0 or 1, A为氢原子、卤原子、CF3、羟基、1-3个碳原子的烷基、1-3个碳原子的烷氧基、苯基，或苯氧基，且A is a hydrogen atom, a halogen atom, CF 3 , a hydroxyl group, an alkyl group of 1-3 carbon atoms, an alkoxy group of 1-3 carbon atoms, a phenyl group, or a phenoxy group, and B为氢原子或B is a hydrogen atom or A与B一同构成羰基，A and B together form a carbonyl group, 2)当W为碳环或杂环时，则2) When W is a carbocyclic or heterocyclic ring, then R、m、R4、R5和R6定义如上，R, m, R 4 , R 5 and R 6 are as defined above, n1为0或1，n 1 is 0 or 1, n2为0或1， n2 is 0 or 1, A和B为氢原子或A and B are hydrogen atoms or A与B一同构成羰基，A and B together form a carbonyl group, 3)当W为一被任意取代的亚甲基时，则3) When W is an optionally substituted methylene group, then R、m、R4、R5和R6定义如上，R, m, R 4 , R 5 and R 6 are as defined above, n1和n2为1或n 1 and n 2 are 1 or n1为1而n2为0或1n 1 is 1 and n 2 is 0 or 1 n1为0而n2为1，n 1 is 0 and n 2 is 1, A与B一同构成羰基。A and B together form a carbonyl group. 2、根据权利要求1的化合物，其化学式为：2. A compound according to claim 1, having the formula:
Figure 931188202_IMG3
Figure 931188202_IMG3
Figure 931188202_IMG4
Figure 931188202_IMG4
 3、一种制备按权利要求1中的通式Ⅰ定义的化合物的方法，其特征在于：3. A process for the preparation of compounds defined by general formula I in claim 1, characterized in that: A）使通式Ⅱ的化合物与通式Ⅲ的化合物反应，通式Ⅱ的化合物为：A) make the compound of general formula II react with the compound of general formula III, the compound of general formula II is:
Figure 931188202_IMG7
Figure 931188202_IMG7
 其中R、m、W、A、B、n1和n2按权利要求1中的定义，且X为一离去基团;通式Ⅲ的化合物为：Wherein R, m, W, A, B, n 1 and n 2 are as defined in claim 1, and X is a leaving group; the compound of general formula III is:
Figure 931188202_IMG8
Figure 931188202_IMG8
 其中R4、R5和R6按权利要求1中的定义，或wherein R 4 , R 5 and R 6 are as defined in claim 1, or B）转化通式Ⅳ的化合物：B) conversion of compounds of general formula IV:
Figure 931188202_IMG9
Figure 931188202_IMG9
 其中R、m、R5、R6、W、A、B、n1和n2是按权利要求1中的定义，且Y位于间位或对位，并代表一可转变为基团R 14的基团，此处R 14位于该环的间位或对位且代表按权利要求1中定义的基团NR7R8，或where R, m, R5, R6, W, A, B, n1and n2According to the definition in claim 1, and Y is located in the meta or para position, and represents a group that can be converted into a group R 14group, where R 14Located at the meta or para position of the ring and representing the group NR as defined in claim 17R8,or C）使通式Ⅴ的化合物与通式Ⅲ的化合物反应，通式Ⅴ的化合物为：C) make the compound of general formula V react with the compound of general formula III, the compound of general formula V is:
Figure 931188202_IMG10
Figure 931188202_IMG10
 其中R、m、W、A、B、n1和n2按权利要求1中的定义，且Z为氢、羟基、卤原子、或烷氧基：通式Ⅲ的为：Wherein R, m, W, A, B, n1 and n2 are as defined in claim 1, and Z is hydrogen, hydroxyl, halogen atom, or alkoxyl group: the general formula III is:
Figure 931188202_IMG11
Figure 931188202_IMG11
 其中R4、R5和R6如权利要求1中的定义，或wherein R 4 , R 5 and R 6 are as defined in claim 1, or D）使通式Ⅵ的化合物与通式Ⅶ的化合物反应，式Ⅶ的化合物为：D) react the compound of general formula VI with the compound of general formula VII, the compound of formula VII is:
Figure 931188202_IMG12
Figure 931188202_IMG12
 其中W、n1、n2和A如权利要求1中的定义，且T独自地或与A一同地代表一适宜的脂族的、环脂族的、芳族的或杂环的酸的衍生物或酸衍生物;式Ⅶ的化合物为：wherein W, n 1 , n 2 and A are as defined in claim 1, and T alone or together with A represents a derivative of a suitable aliphatic, cycloaliphatic, aromatic or heterocyclic acid Compound or acid derivative; The compound of formula VII is: 其中m、R4、R5和R6如权利要求1中的定义，或wherein m, R 4 , R 5 and R 6 are as defined in claim 1, or E）使通式Ⅷ的化合物与一适当的卤化试剂反应，式Ⅷ的化合物为：E) reacting a compound of general formula VIII, which is:
Figure 931188202_IMG14
Figure 931188202_IMG14
 其中R、m、R4、W、A、B、n1和n2如权利要求1中的定义，且R5为H、卤原子、或CF3，或wherein R, m, R 4 , W, A, B, n 1 and n 2 are as defined in claim 1, and R 5 is H, a halogen atom, or CF 3 , or F）使通式Ⅸ化合物与通式Ⅹ的化合物反应，式Ⅸ的化合物为：F) reacting the compound of general formula IX with the compound of general formula X, the compound of formula IX is: 其中W、n1和n2如权利要求1中的定义，A和B一同代表一羰基，且M代表碱金属;式Ⅹ的化合物为：Wherein W, n and n are as defined in claim 1 , A and B together represent a carbonyl group, and M represents an alkali metal; the compound of formula X is:
Figure 931188202_IMG16
Figure 931188202_IMG16
 其中X、R4、R5和R6如权利要求1中的定义，此外，若需要，将用A）-F）之中的任意方法所获得的化合物转化为其可药用的盐。wherein X, R 4 , R 5 and R 6 are as defined in claim 1, and if necessary, the compound obtained by any method in A)-F) is converted into its pharmaceutically acceptable salt. 4、一种如权利要求3的方法，其特征在于制备权利要求2的化合物。4. A process as claimed in claim 3, characterized in that the compound of claim 2 is prepared. 5、一种通式Ⅱ的化合物，5. A compound of general formula II,
Figure 931188202_IMG17
Figure 931188202_IMG17
 R为氢原子或苯基，R is a hydrogen atom or a phenyl group, m为3-8的整数，m is an integer of 3-8, W为被任意取代的芳环、杂环、碳环、或一被任意取代的亚甲基，W is an optionally substituted aromatic ring, heterocyclic ring, carbocyclic ring, or an optionally substituted methylene group, A为氢原子、羟基、卤原子、CF3、有1-3个碳原子的烷基、有1-3个碳原子的烷氧基、苯基、或苯氧基，A is a hydrogen atom, a hydroxyl group, a halogen atom, CF 3 , an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B为氢原子，或B is a hydrogen atom, or A与B一同构成羰基，A and B together form a carbonyl group, n1为0或1，且n 1 is 0 or 1, and n2为0或1，该化合物为外消旋或旋光体形式，或为一种非对映体的混合物，条件是： n2 is 0 or 1, the compound is in racemic or optically active form, or is a mixture of diastereomers, provided that: 1）当W为被任意取代的芳环时，则1) When W is an aromatic ring that is optionally substituted, then R和m如前所定义，R and m are as defined before, n1为0或1，n 1 is 0 or 1, n2为0或1， n2 is 0 or 1, A为氢原子、卤原子、CF3、羟基、有1-3个碳原子的烷基、有1-3个碳原子的烷氧基、苯基、或苯氧基、且A is a hydrogen atom, a halogen atom, CF 3 , a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group, or a phenoxy group, and B为氢原子或B is a hydrogen atom or A与B一同构成羰基，A and B together form a carbonyl group, 2）当W为碳环或一杂环时，则2) When W is a carbocycle or a heterocycle, then R和m定义如前，R and m are defined as before, n1为0或1，n 1 is 0 or 1, n2为0或1， n2 is 0 or 1, A和B为氢原子或A and B are hydrogen atoms or A与B一同构成羰基，A and B together form a carbonyl group, 3）当W为一被任意取代的亚甲基时，则3) When W is an optionally substituted methylene group, then R和m定义如上，R and m are defined as above, n1和n2为1或n 1 and n 2 are 1 or n1为1且n2为0或n 1 is 1 and n 2 is 0 or n1为0且n2为1，n 1 is 0 and n 2 is 1, A和B一同构成羰基。A and B together form a carbonyl group. 6、化学式Ⅲ1的化合物，6. A compound of formula III1, 其中R1 4位于该环的间位或对位，且代表基团NR7R8，其中R7和R8可相同或不同，且各代表氢原子或有1-3个碳原子的烷基，Wherein R 1 4 is located at the meta or para position of the ring, and represents the group NR 7 R 8 , wherein R 7 and R 8 may be the same or different, and each represents a hydrogen atom or an alkyl group with 1-3 carbon atoms , R5位于邻位、间位或对位，且代表氢原子、卤原子、或CF3，R 5 is located at the ortho, meta or para position, and represents a hydrogen atom, a halogen atom, or CF 3 , R6位于邻位、间位或对位，且代表卤原子或CF3。R 6 is located at the ortho, meta or para position, and represents a halogen atom or CF 3 . 7、一种含有权利要求1-2中之任一化合物作为活性成分的药物制剂。7. A pharmaceutical preparation comprising a compound according to any one of claims 1-2 as an active ingredient. 8、一种权利要求7的呈剂量单位形式的药物制剂。8. A pharmaceutical formulation according to claim 7 in dosage unit form. 9、一种权利要求8-9的含有结合了可药用载体的活性成分的药物制剂。9. A pharmaceutical formulation according to claims 8-9 comprising the active ingredient in combination with a pharmaceutically acceptable carrier. 10、一种权利要求1-2之任一项的，用作治疗上的活性物质的化合物。10. A compound according to any one of claims 1-2 for use as a therapeutically active substance. 11、权利要求1-2之任一项的化合物对制备有抗精神紊乱效果的药物的用途。11. Use of a compound according to any one of claims 1-2 for the preparation of a medicament having an antipsychotic effect. 12、一种治疗包括人的哺乳动物的精神紊乱的方法，其特征在于向需要这种治疗的主体给用有效量的权利要求1-2之中的任一种化合物。12. A method of treating psychiatric disorders in mammals, including humans, characterized by administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-2. 13、包括在权利要求1-12中的所要求保护的化合物及用来制备它们的方法和中间产物、含所述化合物的药用组合物以及该组合物在治疗精神紊乱方面的用途。13. Compounds as claimed in claims 1-12, processes and intermediates for their preparation, pharmaceutical compositions containing said compounds and the use of such compositions in the treatment of psychiatric disorders.
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AU39643/93A AU665825B2 (en) 1992-04-09 1993-04-06 Novel amidoalkyl- and imidoalkyl-piperazines
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1948298B (en) * 2006-11-09 2010-09-01 东南大学 Dopamine D3 acceptor portion agonist and its application

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1266582B1 (en) * 1993-07-30 1997-01-09 Recordati Chem Pharm (DI) AZACYLO-HEXANIC AND DIAZACYLO-HEPTANIC DERIVATIVES
US5395835A (en) * 1994-03-24 1995-03-07 Warner-Lambert Company Naphthalamides as central nervous system agents
GB9411099D0 (en) * 1994-06-03 1994-07-27 Wyeth John & Brother Ltd Piperazine derivatives
FR2742149B1 (en) * 1995-12-11 1998-02-13 Inst Nat Sante Rech Med NOVEL 2-NAPHTAMIDE DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS
US5763609A (en) 1996-03-21 1998-06-09 Neurogen Corporation Certain pyrrolo pyridine-3-carboxamides; a new class of gaba brain receptor ligands
US5703235A (en) * 1996-03-21 1997-12-30 Neurogen Corporation N-Aminoalkyl-2-anthracenecarboxamides; new dopamine receptor subtype specific ligands
PL329190A1 (en) * 1996-04-05 1999-03-15 Sod Conseils Rech Applic Antagonists of alpha -adrenergic receptor
HU227543B1 (en) * 2001-09-28 2011-08-29 Richter Gedeon Nyrt N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them
HUP0103987A3 (en) * 2001-09-28 2004-11-29 Richter Gedeon Vegyeszet Phenylpiperazinylalkyl carboxylic acid amid derivatives, process for their preparation, pharmaceutical compositions containing them and their intermediates
RU2320656C2 (en) * 2002-07-04 2008-03-27 Шварц Фарма Аг Derivatives of heteroarene carboxamide, method for their preparing, pharmaceutical composition based on thereof and using

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3398151A (en) * 1966-02-01 1968-08-20 Mead Johnson & Co Azaspirodecanediones and azaspiroundecanediones
US3488352A (en) * 1966-10-11 1970-01-06 Shulton Inc Basically substituted alkoxy anthranilamides,their corresponding 2-nitro compounds and derivatives thereof
US3505338A (en) * 1966-11-25 1970-04-07 American Cyanamid Co Thiophenecarbonylalkylene-diamines
FR1537901A (en) * 1967-07-19 1968-08-30 Bruneau & Cie Lab Amide derivatives of halogeno and nitro benzoic acids and their preparation
US3558777A (en) * 1968-06-21 1971-01-26 Mead Johnson & Co Pharmacologic processes and compositions containing azaspirodecanediones and azaspiroundecanediones
US3465080A (en) * 1968-10-07 1969-09-02 American Cyanamid Co Therapeutic compositions containing morpholinoalkylene - indoles and methods of administering such in the treatment of depression
JPS504650B2 (en) * 1971-09-03 1975-02-22
US3940397A (en) * 1974-11-13 1976-02-24 E. R. Squibb & Sons, Inc. 2-[(Substituted-piperazinyl)alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones
NL8005133A (en) * 1980-09-12 1982-04-01 Duphar Int Res PHENYLPIPERAZINE DERIVATIVES WITH ANTIAGRESSIVE ACTION.
US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
DE3529872A1 (en) * 1985-08-21 1987-02-26 Kali Chemie Pharma Gmbh NEW TETRAOXY CONNECTIONS
US4892943A (en) * 1985-10-16 1990-01-09 American Home Products Corporation Fused bicyclic imides with psychotropic activity
CA1340113C (en) * 1988-05-24 1998-11-03 Magid A. Abou-Gharbia Aryl-and heteroaryl piperazinyl carboxamides having central nervous system activity
US5071845A (en) * 1988-12-28 1991-12-10 Suntory Limited Benzoxazepine derivative
US4939137A (en) * 1989-06-28 1990-07-03 Ortho Pharmaceutical Corporation Ring-fused thienopyrimidinedione derivatives
EP0507863A4 (en) * 1989-12-28 1993-07-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
US5143923B1 (en) * 1991-04-29 1993-11-02 Hoechst-Roussel Pharmaceuticals Incorporated Benzoisothiazole-and benzisoxazole-3-carboxamides
IT1251144B (en) * 1991-07-30 1995-05-04 Boehringer Ingelheim Italia BENZIMIDAZOLONE DERIVATIVES

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1948298B (en) * 2006-11-09 2010-09-01 东南大学 Dopamine D3 acceptor portion agonist and its application

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