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HK1038749A1 - 2-piperazino alkylamino benzoazole derivatives: dopamine receptor subtype specific ligands - Google Patents

2-piperazino alkylamino benzoazole derivatives: dopamine receptor subtype specific ligands Download PDF

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HK1038749A1
HK1038749A1 HK02100301.2A HK02100301A HK1038749A1 HK 1038749 A1 HK1038749 A1 HK 1038749A1 HK 02100301 A HK02100301 A HK 02100301A HK 1038749 A1 HK1038749 A1 HK 1038749A1
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piperazine
aminoethyl
hydrogen
methoxyphenyl
benzothiazol
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HK02100301.2A
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Chinese (zh)
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何晓舒
何曉舒
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纽罗根公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein: A is (un)substituted alkylene; R1 and R2 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, alkylthio, hydroxy, (un)substituted amino, cyano, nitro, sulfonamide, trifluoromethyl or trifluoromethoxy; R3, R4, R5, R6 and R8 are independently hydrogen or alkyl; and X is sulfur, oxygen or NR7 where R8 is defined herein; m is an integer chosen from 0, 1 or 2; and Ar is an aryl or heteroaryl group as further defined herein, which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

Description

2-piperazinoalkylaminobenzopyrrole derivatives: dopamine receptor subtype specific ligands
Background
Field of the invention
The present invention relates to 2-piperazinylalkylaminobenzopyrrole derivatives and to pharmaceutical compositions containing the same. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system disorders.
Description of the related Art
It is generally accepted that the common antipsychotic drugs, known as neuroleptics, act therapeutically by blocking dopamine receptors. However, antipsychotics often produce undesirable extrapyramidal side Effects (EPS) and delayed dyskinesia due to blockade of D in the striatal region of the brain2Caused by the receptor. The dopamine D receptor subtype has recently been identified (Nature, 350:610(Van Tol et al, 1991); Nature, 347:146(Sokoloff et al, 1990)). Its specific location in the limbic area and its differential recognition of various neuroleptic agents suggests that D4Receptors play a major role in the etiology of schizophrenia. D is considered to be selective4Antagonists are potent antipsychotics without the neurological side effects that are seen with conventional antipsychotics.
US5,632,898 discloses N-benzothiazol-2-yl-2- (4-phenylpiperazinyl) acetamide. US5,229,398 discloses aminomethyl piperidine derivatives.
Summary of The Invention
The invention provides a novel compound which reacts with dopamine subtype and has a general formula I. Accordingly, in a broad sense, the present invention is directed to compounds of the general formula:wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl1-C6A hydrocarbylene group;
R1and R2Are identical or different and are hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, C1-C6Alkylsulfonyl, sulfonamide, or C1-C6Alkylsulfonamides, perfluoro (C)1-C6) Alkyl or perfluoro (C)1-C6) An alkoxy group;
R3、R4、R5and R6Are identical or different and are hydrogen or C1-C6An alkyl group; and is
X is sulfur, oxygen or NR7Wherein R is7Is hydrogen or C1-C6An alkyl group;
R8is hydrogen or C1-C6An alkyl group;
m is 0 or an integer selected from 1 and 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
Dopamine D4Receptors focus on the limbic system of the brain (science, 265:1034(Taubes,1994)) to control cognition and emotion. Therefore, compounds that interact with these receptors may be useful in the treatment of perceptual disorders. Such diseases include cognitive deficits, which are a major component of the negative symptoms of mental disorders (social withdrawal)And no response). Other perceptual disorders include memory loss or attention deficit disorders.
The compounds of the invention have the formula4High affinity and selectivity for receptor subtype binding. These compounds are therefore useful in the treatment of various neuropsychological disorders such as psychotic disorders, psychotic depression and mania. Other dopamine mediated diseases such as Parkinson's disease and delayed dyskinesia can also be modulated by D4The receptor is treated directly or indirectly.
The compounds of the present invention may also be prepared by modulating D4The receptors are useful in the treatment of depression, memory loss or alzheimer's disease because they are selectively present in regions where control of emotion and recognition function is known.
Thus, in a further aspect, the invention provides a method of treatment and/or prophylaxis of neuropsychological or affective disorders, including, for example, schizophrenia, mania, dementia, depression, anxiety, obsessive-compulsive behaviour, substance abuse, memory loss, perceptual deficit, parkinsonian-like movement disorders such as Parkinson's disease and dystonia and movement disorders associated with the use of neuroleptic agents. In addition, the compounds of the present invention are also useful for the treatment of depression, memory loss or alzheimer's disease. Furthermore, the compounds of the invention are also useful in the treatment of other disorders associated with dopamine blockade, such as substance abuse and obsessive-compulsive disorders. These compounds may also be used to treat extrapyramidal side effects associated with the use of conventional antipsychotics.
In another aspect, the invention provides pharmaceutical compositions comprising compounds of formula I.
In a further aspect, the present invention provides intermediates useful in the preparation of compounds of formula I.
Detailed description of the invention
As mentioned above, the present invention relates to compounds of formula I. Preferred compounds of formula I include those wherein R is3、R4、R5And R6Each is hydrogen or methyl; and R8Is hydrogen. More preferred compounds of formula I are those wherein m is 0 or 1; and A is unsubstituted C1-C4More preferably unsubstituted C2、C3Or C4Alkylene groups. In preferred compounds of formula I, when X is S, Ar is other than unsubstituted phenyl and R is1And R2Are all hydrogen, R2-R6Are both hydrogen, and m is 0.
Preferred Ar groups in formula I are those having up to 3 non-hydrogen substituents selected from the above groups. More preferred Ar groups in formula I are those having no more than 2 substituents. Particularly preferred compounds of formula I include those wherein Ar is selected fromWherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In another particularly preferred compound of the formula I, R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl. In still other preferred compounds of formula I, Ar isWherein R is9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10One of which is hydrogen. Even more preferred are compounds wherein R is9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro.
In another preferred group of compounds of the formula I, R1And R2Each is hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkylsulfonyl, alkylsulfonamide, or sulfonamide. This classA very preferred group of compounds comprises those in which R is1And R2At least one of which is hydrogen and the others are methoxy, methyl, chloro, fluoro, methoxy, ethoxy or methylsulfonyl. Particularly preferred compounds of this group include those wherein R is1Is hydrogen and R2Is in the 4 or 6 position of the nitrogen containing ring.
In another group of preferred compounds of formula I, Ar is naphthyl of the formulaWherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl. A preferred group of compounds are those having the above-mentioned naphthyl group, wherein X is NH.
A preferred group of compounds of the present invention is represented by the following formula II:wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl2-C6A hydrocarbylene group;
R1and R2As defined in formula I;
R3、R4、R5and R6Each being hydrogen or C1-C3An alkyl group; preferably methyl;
R8is hydrogen or C1-C2An alkyl group;
m is an integer selected from 0, 1 or 2; and is
Ar is as defined in formula I.
In more preferred compounds of formula II, m is 0 or 1; a is unsubstituted C1-C4More preferably unsubstituted C2、C3Or C4Alkylene groups.
In particularPreferred compounds of formula II include those wherein Ar is selected fromWherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl. In a highly preferred class of compounds, when Ar is phenyl, R9And R10Not all being hydrogen, R1-R6Is hydrogen, m is 0 and A is ethylene. In another highly preferred compound of formula II, Ar is selected from pyridinyl and pyrimidinyl of the following formulae:wherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In other particularly preferred compounds of the formula II, R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl with the proviso that when Ar is phenyl, R9And R10Not all being hydrogen, R1-R6Is hydrogen, A is ethylene and m is 0. In a further highly preferred compound of the formula II, Ar isWherein each R9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10Only one is hydrogen. Even more preferred are compounds wherein R is9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro, with the proviso that when R is1-R6When is hydrogen, A is ethylene, m is 0, Ar is phenyl, R9And R10Not all are hydrogen.
In another group of preferred compounds of the formula II, R1And R2Each is hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkylsulfonyl, alkylsulfonamide, or sulfonamide. A very preferred group of such compounds comprises those in which R is1And R2At least one is hydrogen and the others are methoxy, methyl, chloro, fluoro, methoxy, ethoxy or methylsulfonyl. The most preferred compounds of this group include those wherein R is1Is hydrogen and R2Is in the 4 or 6 position of the nitrogen containing ring.
In another group of preferred compounds of formula II, Ar is a naphthyl group of the formula:wherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl. A preferred group of compounds are those having the above-mentioned naphthyl group, wherein X is NH.
Another preferred group of compounds of the present invention can be represented by formula III:
wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl2-C6A hydrocarbylene group;
R1and R2As defined in formula I;
R3、R4、R5and R6Each being hydrogen or C1-C3An alkyl group; preferably methyl;
R8is hydrogen or C1-C2An alkyl group;
m is an integer selected from 0, 1 or 2; and is
Ar is as defined in formula I.
In a more preferred wayIn the compounds of formula III, m is 0 or 1; a is unsubstituted C1-C4More preferably unsubstituted C2、C3Or C4Alkylene groups.
Particularly preferred compounds of formula III include those wherein Ar is selected fromWherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In a further particularly preferred compound of the formula III, R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl.
In highly preferred compounds of formula III, Ar is selected from pyridinyl and pyrimidinyl of the following formulae:wherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In other particularly preferred compounds of the formula III, Ar isWherein each R9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10One of which is hydrogen. Even more preferred are compounds wherein R is9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro.
In another preferred group of compounds of the formula III, R1And R2Each is hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide. A very preferred group of such compounds comprises those in which R1And R2At least one is hydrogen and the others are methoxy, methyl, chloro, fluoro, methoxy, ethoxy or methylsulfonyl. The most preferred compounds of this group include those wherein R is1Is hydrogen and R2Is in the 4 or 6 position of the nitrogen containing ring.
In another preferred group of compounds of formula III, Ar is a naphthyl group of the formula:wherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl. A preferred group of compounds are those having the above-mentioned naphthyl group, wherein X is NH.
Yet another preferred group of compounds of the present invention may be represented by formula IV:wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl2-C6A hydrocarbylene group;
R1and R2As defined in formula I;
R3、R4、R5and R6Each being hydrogen or C1-C3An alkyl group; preferably methyl;
R7is hydrogen or C1-C3An alkyl group;
R8is hydrogen or C1-C2An alkyl group;
m is an integer selected from 0, 1 or 2; and is
Ar is as defined in formula I.
In more preferred compounds of formula III, m is 0 or 1; a isUnsubstituted C1-C4More preferably unsubstituted C2、C3Or C4Alkylene groups.
Particularly preferred compounds of formula III include those wherein Ar is selected fromWherein each R9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In a further particularly preferred compound of the formula III, R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl. In a further very preferred compound of the formula III, Ar isWherein each R9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10One is not hydrogen. Even more preferred are compounds wherein R is9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro.
In another preferred group of compounds of the formula III, R1And R2Each is hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide. A very preferred group of such compounds comprises those in which R1And R2At least one is hydrogen and the others are methoxy, methyl, chloro, fluoro, methoxy, ethoxy or methylsulfonyl. The most preferred compounds of this group include those wherein R is1Is hydrogen and R2That is, a non-hydrogen group as specified immediately above and at the 4 or 6 position of the nitrogen-containing ring.
In another group of channelsIn preferred compounds of formula III, Ar is a naphthyl group of the formula:wherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl. A preferred group of compounds are those having the above-mentioned naphthyl group, wherein X is NH.
The invention also provides intermediates useful in the preparation of the compounds of formula I. These intermediates have the following general formula viii:
in the formula VIII, R3、R4、R5、R6A, m and Ar are as defined above for formula I.
In preferred compounds of formula VIII, m is 0 or 1; and A is unsubstituted C1-C4More preferably unsubstituted C2、C3Or C4Alkylene groups.
Particularly preferred compounds of formula VIII include those wherein Ar is selected fromWherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In a further particularly preferred compound of the formula VIII, R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl. In a further very preferred compound of the formula VIII, Ar isWherein each R9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10One is not hydrogen. Even more excellentSelected are compounds wherein R9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro.
In another group of preferred compounds of formula VIII, Ar is a naphthyl group of the formula:wherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
In some cases, the compounds of formula I may contain one or more asymmetric carbon atoms, and thus the compounds may exist in different stereoisomeric forms. For example, these compounds can be in racemic or optically active form. In these cases, the single enantiomer, i.e. the optically active form, can be obtained by asymmetric synthesis or resolution of the racemate. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example, an HPLC chiral column.
Representative compounds of the invention encompassed by formula I include, but are not limited to, the compounds of Table 1 and pharmaceutically acceptable addition salts thereof. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be formed by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutically acceptable salts include the salts of these acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids such as acetic acid, HOOC- (CH)2)n-COOH, wherein n is 0-4, etc. One of ordinary skill in the art will recognize that there are a wide variety of non-toxic pharmaceutically acceptable addition salts.
The invention also includes acylated prodrugs of the compounds of formula I. One of ordinary skill in the art will recognize a variety of synthetic methods for preparing non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by formula I.
When the compounds exist in various tautomeric forms, the invention is not limited to any particular tautomer. The present invention includes all tautomers of the compounds.
The term "C" in the present invention1-C6Alkyl "or" lower alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferably C1-C6Alkyl is methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.
The term "C" in the present invention1-C6Alkoxy "or" lower alkoxy "refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentyloxy. Preferred alkoxy groups of the invention are C1-C4An alkoxy group.
The term "halogen" in the present invention refers to fluorine, bromine, chlorine and iodine.
When the substituent is di (C)1-C6) In the case of alkylamino, the two alkyl groups are the same or different. Representative bis (C)1-C6) Alkylamino groups include dimethylamino, methylpropylamino, diisopropylamino, and ethylpentylamino.
Aryl refers to an aromatic carbocyclic ring containing one ring (e.g., phenyl) or two rings (e.g., biphenyl). Such groups may be substituted with up to 5 groups selected from the group consisting ofNot substituted: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, alkylsulfonamide, or sulfonamide.
Heteroaryl (heteroaromatic) as used in the present invention means one or more 5-, 6-or 7-membered aromatic ring(s), preferably 5-or 6-membered ring(s), containing at least 1 and up to 4, preferably 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur. The heteroaryl group Ar is attached to the alkylpiperazine core moiety through a carbon atom in the heteroaryl group, preferably a carbon atom immediately adjacent to a heteroatom such as nitrogen. Such heteroaryl groups include, for example, thienyl, furyl, thiazolyl, imidazolyl, (iso) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl, 1, 5-naphthyridinyl, benzimidazolyl and benzoxazolyl.
“C1-C6Alkylsulfonyl "refers to a group of the formula:the term "C1-C6Alkylsulfonamides "and" alkylsulfonamides "refer to groups of the general formulae:wherein R isaAnd RbEach is C1-C6An alkyl group.
Preferred is C1-C6The alkylsulfonamides are methylsulfonamide, dimethylsulfonamide and diethylsulfonamide.
The term "sulfonamide" refers to a group of the general formula:
the rules for labeling substituents on the nitrogen-containing ring are as follows:
typical compounds of the invention are shown in table 1.
TABLE 1Compound 1Compound 2Compound 3Compound 4Compound 5Compound 6Compound 9Compound 20Compound 37
The invention also relates to the use of compounds of general formula (I) for the treatment of neuropsychological disorders. The interaction of the compounds of the present invention with dopamine receptors is shown in the examples. This interaction results in the pharmacological activity of these compounds.
The compounds of formula I may be administered orally, topically, parenterally, by inhalation or spray, and rectally in unit dose formulations containing conventional non-toxic carriers, adjuvants and vehicles which are pharmaceutically acceptable. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of formula i may be combined with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if necessary, other active agents. The pharmaceutical compositions containing the compounds of formula I may be in a form suitable for oral administration, for example, as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents, thereby providing pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents, such as starch, gelatin or gum arabic, and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption of the tablet in the gastrointestinal tract and thereby provide a long-lasting effect. For example, a retarder such as glyceryl monostearate or glyceryl distearate may be employed.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid petrolatum or olive oil.
Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitol monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or cocoa butter, or in a mineral oil such as liquid paraffin. Oily suspensions contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Water is added to dispersible powders and granules suitable for preparation of aqueous suspensions to yield the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical composition of the present invention may also be an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Syrups and elixirs may also be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives and flavoring and coloring agents. The pharmaceutical composition may be a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile solid oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed such as synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions are prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of formula I may be administered parenterally in a sterile medium. The drug may be suspended or dissolved in the vehicle depending on the vehicle and concentration used. Advantageously, the vehicle has dissolved therein adjuvants such as a local anaesthetic, a preservative and a buffering agent.
Dosage levels in the range of about 0.1mg to about 140mg per kilogram of body weight per day may be used to treat the above-mentioned conditions (about 0.5mg to about 7mg per patient per day). The amount of active ingredient mixed with the carrier material to produce a single dosage form will vary depending upon the patient being treated and the particular mode of administration. Unit dosage forms often contain between about 1mg to about 500mg of active ingredient.
It will be understood, however, that the specific dose level for any particular patient will vary with a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route and rate of administration, drug combination and the severity of the particular disease undergoing therapy.
A typical synthesis of the compounds of the present invention is shown in reaction scheme 1. One skilled in the art would recognize modifications to the starting materials and additions to the procedures used to produce the compounds of the present invention.
Reaction scheme IWherein R is1、R2、R3、R4、R5、R6、R8X, m and Ar are as defined above for formula I. L is1、L2And L3Represents a leaving group as discussed below.
As shown in scheme I, N-alkyl phthalimide VI substituted with a suitable leaving group L is reacted with a suitably substituted piperazine VII in the presence of a base to provide N- (piperazinylalkyl) phthalimide VIII. The leaving group on VI may be halogen, trialkylamino, sulfonyl ester, or the like. Any suitable base may be used; typical bases include inorganic bases such as sodium hydroxide, potassium carbonate, and the like, and organic bases such as triethylamine, pyridine, and the like.
Phthalimide VIII can be treated with hydrazine or the like to give amine IX. Then reacting the amine IX with an appropriately substituted leaving group L in the 2-position2To give compounds of the general formula I. Leaving group L on alkylated reagent X2May be a halide, sulfonate, or the like. With appropriate alkyl halides R8L3Process I may be carried out by subjecting R to8Is the conversion of I of hydrogen to R8A compound of formula I which is alkyl.
When the compounds of formulae VI, VII and X are not commercially available, they can be prepared by procedures analogous to those described in the literature. The compounds of the formulae VI, VII and X are either known or can be prepared by processes known from the prior art. One skilled in the art would recognize modifications to the starting materials and additions to the procedures used to produce the compounds of the present invention. The base used may be inorganic base such as potassium carbonate, sodium hydroxide, etc.; or an organic base such as triethylamine, pyridine, etc.
Or, in the presence of a base, wherein L2Is NH2Of the general formula (II)X can be reacted in turn with chloroacetyl chloride and a compound of the formula VII, which is reduced to give a compound of the formula I, wherein A is ethylene.
Example 1
1- (5-fluoropyrimidin-2-yl) -4- (4-aminobutyl) piperazine
A solution of 4-bromo-N-butylphthalimide (8.37g) and 1- (5-fluoropyrimidin-2-yl) piperazine (5.4g) in dimethylformamide (100mL) containing potassium carbonate (8.2g) was stirred at 80 ℃ for 12 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether layer was dried over sodium sulfate, filtered and concentrated to give a yellow solid intermediate. The resulting phthalimide was then dissolved in hydrazine monohydrate (100ml) and refluxed under nitrogen overnight. After cooling, the mixture was poured into 30% potassium carbonate (500ml) solution and extracted with dinitrogen methane, dried and concentrated to give an orange semi-solid (4.66 g). This material was dissolved in a 10% methanol/isopropanol mixture (50ml), treated with fumaric acid (4.27g,2 equivalents) and the solvent volume reduced to 20 ml. The resulting yellow crystals (6.5g) were collected by filtration.
Example 2
1- (5-Fluoropyrimidin-2-yl) -4- (2- [ 6-benzothiazol-2-ylamino)]Butyl) piperazine hydrogen fumarate
A solution of 2-chlorobenzothiazole (920mg) and 1- (5-fluoropyrimidin-2-yl) -4- (4-aminobutyl) piperazine (254mg) in acetonitrile (10mL) containing potassium carbonate (300mg) was refluxed under nitrogen for 10 hours. After cooling, the mixture was concentrated and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated and extracted with 10% citric acid. The acidic aqueous phase was basified with 10n naoh solution and extracted with chloroform. The chloroform layer was then dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (0.31 g). [ also known as benzothiazol-2-yl {4- [4- (5-fluoropyrimidin-2-yl) piperazinyl ] butyl } amine ]. The material was dissolved in 10% methanol/isopropanol and treated with fumaric acid (190 mg). The solvent volume was reduced in part and the resulting crystals were isolated by filtration (347mg, m.p.168-170 ℃ C.).
Example 3
1- (2-Methylphenyl) -4- (2- [ 6-fluorobenzothiazol-2-ylamino)]Ethyl) piperazine hydrogen fumarate
During the dropwise addition of a chloroform (10ml) solution of chloroacetyl chloride (5ml), a chloroform (100ml) solution of 6-fluoro-2-aminobenzothiazole (5g) and triethylamine (5ml) was vigorously stirred. The reaction mixture was stirred overnight, filtered and concentrated. Trituration of the residue with isopropanol gave a white solid (3.82 g).
A part of this solid (150mg,0.61mmol) was dissolved in acetonitrile (10ml) and the resulting solution was added with 1- (2-methoxyphenyl) piperazine (118mg) and potassium carbonate (150 mg). The mixture was refluxed overnight. After cooling, the solvent was removed and the resulting residue was partitioned between ethyl acetate and water. The organic phase was dried and evaporated to give a yellow oil which was purified by preparative thin layer chromatography eluting with 9% methanol in chloroform.
The product isolated after chromatography was dissolved in tetrahydrofuran (5ml) and the resulting solution was mixed with a 1M solution of alane in tetrahydrofuran. After 2 hours, the reaction mixture was treated with 20ml of 15% sodium hydroxide solution, stirred and extracted with chloroform. The organic phase was dried and concentrated. The resulting residue was purified by preparative thin layer chromatography eluting with 10% methanol/chloroform. The resulting oil was dissolved in isopropanol (5mL) and the solution was treated dropwise with a saturated solution of fumaric acid in methanol until the pH was 3. After 2 hours, the desired crystals were collected as 1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-ylamino)]Ethyl) piperazine hydrogen fumarate (180mg, m.p.169-170 ℃), a pale white solid. The compound 2, the base,1HNMR(CDCl3):7.45(m,1H),7.25(m,1H),6.8-7.05(m,5H),6.18(bs,1H),3.85(s,3H),3.55(m,2H),3.0-3.1(b,4H),2.7(b,6H)。
example 4
The following compounds were prepared essentially following the procedures described in examples 1-3.
(a) Hydrogen fumarate salt of 1- (pyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 7, m.p.161-163 ℃ C.)
(b) Hydrogen fumarate salt of 1- (pyrimidin-2-yl) -4- (4- [ benzothiazol-2-yl ] aminobutyl) piperazine (compound 8)
(c) Hydrogen fumarate salt of 1- (5-fluoropyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 9, m.p.174-175 ℃).
(d) The hydrogen fumarate salt of 1- (5-methylpyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.167-170 ℃) [ also known as benzothiazol-2-yl {2- [4- (5-methylpyrimidin-2-yl) piperazinyl ] ethyl } amine ] (Compound 10).
(e) The hydrogen fumarate salt of 1-phenyl-4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.131-132 deg.C) [ also known as benzothiazol-2-yl [2- (4-phenylpiperazinyl) ethyl ] amine (Compound 11).
(f) Hydrogen fumarate salt of 1- (pyridin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.159-160 ℃ C.) [ also known as benzothiazol-2-yl [2- (4- (2-pyridyl) piperazinyl) ethyl ] amine ] (Compound 12).
(g) Dihydrochloride salt of 1- (4-chlorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.230-232 ℃ C.) [ benzothiazol-2-yl {2- [4- (4-chlorophenyl) piperazinyl ] ethyl } amine ] (Compound 13).
(h) Dihydrochloride of 1- (4-fluorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.229-231 deg.C) [ benzothiazol-2-yl {2- [4- (4-fluorophenyl) piperazinyl ] ethyl } amine ] (Compound 14).
(i) The fumarate salt of 1- (2-methoxyphenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (m.p.101-103 ℃ C.) [ benzothiazol-2-yl {2- [4- (2-methoxyphenyl) piperazinyl ] ethyl } amine ] (Compound 15).
(j) A hydrobromide salt of 1- (2-methoxyphenyl) -4- (3- [ benzothiazol-2-yl ] aminopropyl) piperazine (m.p.195-197 ℃) [ benzothiazol-2-yl {3- [4- (2-methoxyphenyl) piperazinyl ] propyl } amine ] (compound 16).
(k) The hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 4-methoxybenzothiazol-2-yl ] aminoethyl) piperazine (compound 17, m.p.171-173 ℃ C.).
(l) The hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 4-methylbenzothiazol-2-yl ] aminoethyl) piperazine (compound 18, m.p.226 ℃ -227 ℃ C.).
(m) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 4-chlorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 19, m.p.194-195 deg.C), [ (4-chlorobenzothiazol-2-yl) {2- [4- (2-methoxyphenyl) piperazinyl ] ethyl } amine ].
(n) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 6-ethoxybenzothiazol-2-yl ] aminoethyl) piperazine (compound 20, m.p.227-228 ℃ C.).
(o) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 6-methylsulfonylbenzothiazol-2-yl ] aminoethyl) piperazine (Compound 21, m.p.190-196 ℃ C.) [2- ({2- [4- (2-methoxyphenyl) piperazinyl ] ethyl } amino) -6- (methylsulfonyl) benzothiazole ]
(p) fumarate salt of 1- (pyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 22, m.p.179-180 deg.C) [ (6-fluorobenzothiazol-2-yl) [2- (4-pyrimidin-2-ylpiperazinyl) ethyl ] amine ]
(q) the fumarate salt of 1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 23, m.p.169 ℃ -170 ℃).
(r) the fumarate salt of 1-benzyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 24, m.p.228-229 ℃).
(s) the hydrobromide salt of 1- (4-chlorobenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 25, m.p.238-240 ℃ C.).
(t) the hydrobromide salt of 1- (2-ethoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 26, m.p.235-237 ℃ C.).
(u) the hydrobromide salt of 1- (5-fluoropyrimidin-2-yl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 27, m.p.279-281 ℃ C.).
(v) A hydrobromide salt of 1- (5-methylpyrimidin-2-yl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 28, m.p.240-250 ℃ C.).
(w) a hydrobromide salt of 1- (pyridin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 29, m.p.259-260 ℃ C.).
(x) A hydrobromide salt of 1- (3-trifluoromethylphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 30, m.p.259-261 ℃ C.).
(y) a hydrobromide salt of 1-phenyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 31, m.p.268-270 ℃ C.).
(z) a hydrobromide salt of 1- (4-fluorophenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 32, m.p.270-271 ℃ C.).
(aa) the hydrobromide salt of 1- (2-isopropoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine (compound 33, m.p.216-217 ℃ C.) [ also known as (6-fluorophenothiazol-2-yl) [2- (4- { [2- (methylethoxy) phenyl ] methyl } piperazinyl) ethyl ] amine ]
(bb) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 34).
(cc) the hydrobromide salt of 1- (2-isopropoxybenzyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine [ (6-fluorophenothiazol-2-yl) [2- (4- { [2- (methylethoxy) phenyl ] methyl } piperazinyl) ethyl ] amine ] (compound 35).
(dd) hydrochloride salt of 1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenyloxazol-2-yl ] aminoethyl) piperazine; [ also referred to as (6-fluorobenzoxazol-2-yl) {2- [4- (2-methoxyphenyl) piperazinyl ] ethyl } amine ] (Compound 36).
(ee) hydrochloride of 1- (pyrimidin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine (compound 37, m.p.197-202 ℃) [ also known as benzooxazol-2-yl [2- (4-pyrimidin-2-ylpiperazinyl) ethyl ] amine ].
(ff) hydrochloride salt of 1- (pyridin-2-yl) -4- (2- [ benzoxazol-2-yl ] aminoethyl) piperazine (m.p.255-265 ℃ C.) [ also known as benzoxazol-2-yl [2- (4- (2-pyridin-2-yl) piperazinyl) ethyl ] amine ] (Compound 3).
(gg) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ benzimidazol-2-yl ] aminoethyl) piperazine (compound 38, m.p.215-216 ℃ C.) [ benzimidazol-2-yl {2- [4- (2-methoxyphenyl) piperazinyl ] ethyl } amine ].
(hh) hydrobromide salt of 1-phenyl-4- (2- [ benzimidazol-2-yl ] aminoethyl) piperazine (Compound 39, m.p.241-247 deg.C)
(ii) A hydrobromide salt of 1- (pyridin-2-yl) -4- (2- [ benzimidazol-2-yl ] aminoethyl) piperazine (compound 42, m.p.290-291 ℃).
(jj) the hydrobromide salt of 1- (pyridin-2-yl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine; [ 1-ethylbenzimidazol-2-yl [2- (4- (2-pyridyl) piperazinyl) ethyl } amine ] (Compound 41).
(kk) the hydrobromide salt of 1- (pyridin-2-yl) -4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 42).
(ll) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 43, m.p.273-274 ℃ C.).
(mm) the hydrobromide salt of 1- (2-isopropoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 44, m.p.285 ℃, reduced).
The hydrobromide salt of (nn)1- (3-trifluoromethylphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 1, m.p.283 ℃, reduced) [ otherwise known as (1-methylbenzimidazol-2-yl) (2- {4- [3- (trifluoromethyl) phenyl ] piperazinyl } ethyl) amine ].
(oo) the hydrobromide salt of 1- (2-methoxyphenyl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 45, m.p.109-110 ℃ C.).
(pp) the hydrobromide salt of 1-phenyl-4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 46, m.p.270 ℃, reduced).
(qq) the hydrobromide salt of 1-phenyl-4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 47).
(rr) benzothiazol-2-yl [2- (4- (2-naphthyl) piperazinyl) ethyl ] amine (Compound 4).
Example 5
The following salts are prepared essentially following the procedures described in examples 1-6, and, if desired, the references to methods for preparing pharmaceutically acceptable salts.
1- (5-Fluoropyrimidin-2-yl) -4- (2- [ 6-benzothiazol-2-ylamino ] butyl) piperazine (compound 48).
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenylthiazol-2-ylamino ] ethyl) piperazine (compound 49).
(a)1- (pyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 50).
(b)1- (pyrimidin-2-yl) -4- (4- [ benzothiazol-2-yl ] aminobutyl) piperazine (compound 51).
(c)1- (5-Fluoropyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 52).
(d)1- (5-methylpyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (Compound 53).
(e) 1-phenyl-4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 54).
(f)1- (pyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 55).
(g)1- (4-chlorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 56).
(h)1- (4-fluorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 57).
(i)1- (2-methoxyphenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine (compound 58).
(j)1- (2-methoxyphenyl) -4- (3- [ benzothiazol-2-yl ] aminopropyl) piperazine (compound 59).
(k)1- (2-methoxyphenyl) -4- (2- [ 4-methoxybenzothiazol-2-yl ] aminoethyl) piperazine (compound 60).
(l)1- (2-methoxyphenyl) -4- (2- [ 4-methylbenzothiazol-2-yl ] aminoethyl) piperazine (compound 61).
(m)1- (2-methoxyphenyl) -4- (2- [ 4-chlorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 62).
(n)1- (2-methoxyphenyl) -4- (2- [ 6-ethoxybenzothiazol-2-yl ] aminoethyl) piperazine (compound 63).
(o)1- (2-methoxyphenyl) -4- (2- [ 6-methylsulfonylbenzothiazol-2-yl ] aminoethyl) piperazine (compound 64).
(p)1- (pyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 65).
(q)1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 66).
(r) 1-benzyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 67).
(s)1- (4-fluorobenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 68).
(t)1- (2-ethoxyphenyl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 69).
(u)1- (5-Fluoropyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 70).
(v)1- (5-methylpyrimidin-2-yl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine (compound 71).
(w)1- (pyridin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 72).
(x)1- (3-trifluoromethylphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 73).
(y) 1-phenyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 74).
(z)1- (4-fluorophenyl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine (compound 75).
(aa)1- (2-isopropoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (compound 76).
(bb)1- (2-methoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (Compound 77).
(cc)1- (2-Isopropoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine (Compound 78).
(dd)1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenyloxazol-2-yl ] aminoethyl) piperazine (compound 79).
(ee)1- (pyrimidin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine (compound 80).
(ff)1- (pyridin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine (Compound 81).
(gg)1- (2-methoxyphenyl) -4- (2- [ benzimidazol-2-yl ] aminoethyl) piperazine (compound 82).
(hh) 1-phenyl-4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine (compound 83).
(ii)1- (pyridin-2-yl) -4- (2- [ benzimidazol-2-yl ] aminoethyl) piperazine (compound 84).
(jj)1- (pyridin-2-yl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine (Compound 85).
(kk)1- (pyridin-2-yl) -4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 86).
(ll)1- (2-methoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 87).
(mm)1- (2-Isopropoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (Compound 88).
(nn)1- (3-trifluoromethylphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 89).
(oo)1- (2-methoxyphenyl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 90).
(pp) 1-phenyl-4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 91).
(qq) 1-phenyl-4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine (compound 92).
Example 6
And D2、D3And D4Determination of receptor binding Activity
The assay uses a recombinant-containing human D2And D4COS cell granules of the receptor. The samples were homogenized in 100 volumes (w/vol) of 0.05M Tris HCl buffer at 4 ℃ and pH 7.4. The samples were then centrifuged at 30,000 Xg and resuspended and recentrifuged. The final tissue samples were then centrifuged at 30,000 Xg and frozen until use. The tissue was resuspended in 1: 20(wt/vol) 0.05M Tris HCl buffer containing 100mM NaCl.
Incubations were carried out at 48 ℃ and contained in 1.0ml of total incubationWith 0.4ml of tissue sample, 0.5nM3H-YM 09151-2 (nimorapril, cis-5-chloro-2-methoxy-4- (methylamino) -N- (2-methyl-2- (phenylmethyl) -3-pyrrolidinyl) benzamide) and the compounds of the invention. Non-specific binding is defined as that found in the presence of 1mM spiperone; without further mention, nonspecific binding was less than 20% of total binding. Table 2 shows examples of the invention and D in murine striatal homogenates2And D4Binding characteristics of receptor subtypes.
TABLE 2
Compound No. D4K(nM) D2K(nM)
1 3 ＞10,000
2 1 175
3 11 ＞10,000
6 6 1637
The binding coefficient of compounds of formula I in nM to the D receptor is generally in the range of about 0.1 nanomolar (nM) to about 75 nanomolar (nM). Preferably, such compounds have a binding coefficient of about 0.1 to 20 nM. These compounds generally have a D of at least about 100nM2The receptor binding coefficient. Accordingly, the compounds of the invention and D4Ratio of acceptors to D2Receptor binding is generally at least about 10-fold more selective. Preference is given to these compounds with D4Ratio of acceptors to D2Receptor binding is at least 20, more preferably at least 25-50 fold more selective. Most preferably compounds of formula I and D4Ratio of acceptors to D2At least 500-fold more selective for receptor binding.
The manner and method of making and using the present invention have now been described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It should be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made thereto without departing from the spirit and scope of the invention as set forth in the claims. The specification of the present application, both as to its summary and as to its generality, particularly points out and distinctly claims the subject matter that is claimed.

Claims (30)

1. A compound having the general formula:wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl1-C6A hydrocarbylene group;
R1and R2Are identical or different and are hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkyl sulfurHydroxy, amino, mono-or bis (C)1-C6) Alkylamino, cyano, nitro, C1-C6Alkylsulfonyl, sulfamide, perfluoro C1-C6Alkyl or perfluoro C1-C6An alkoxy group;
R3、R4、R5and R6Are identical or different and are hydrogen or C1-C6An alkyl group; and is
X is sulfur, oxygen or NR7Wherein R is7Is hydrogen or C1-C6An alkyl group;
R8is hydrogen or C1-C6An alkyl group;
m is 0, 1 or 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
2. The compound according to claim 1, wherein a is unsubstituted C1-C6Alkylene groups.
3. The compound according to claim 1, wherein A is C2、C3Or C4Alkylene groups.
4. A compound according to claim 3, wherein Ar is selected from:wherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
5. A compound according to claim 4, wherein R9And R10Each is selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy, chloro or fluoro or trifluoromethyl.
6. The compound according to claim 3, wherein Ar is selected fromWherein R is9And R10Each is selected from hydrogen, 4-C1-C3Alkyl, 2-C1-C3Alkoxy, 4-halogen or 3-trifluoromethyl, with the proviso that R9And R10One of which is hydrogen.
7. A compound according to claim 6, wherein R9And R10Each selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, chloro or fluoro.
8. A compound according to claim 3, wherein R1And R2Each selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
9. The compound according to claim 8, wherein R1And R2At least one is hydrogen and the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy or methylsulfonyl.
10. The compound according to claim 9, wherein R1Is hydrogen, R2Is in the 4 or 6 position of the nitrogen containing ring.
11. A compound according to claim 1 having the formula:wherein:
a is a group which may be substituted by one or two C1-C6C substituted or not by alkyl1-C6A hydrocarbylene group;
R1and R2Are identical or different and are hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, C1-C6Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoromethoxy;
R3、R4、R5and R6Are identical or different and are hydrogen or methyl; and is
R8Is hydrogen or C1-C6An alkyl group;
m is 0, 1 or 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
12. The compound according to claim 11, wherein when R is1-R6When is hydrogen, Ar is not unsubstituted phenyl, A is ethylene, R8Is hydrogen and m is 0.
13. The compound according to claim 3, wherein Ar isWherein R is9And R10Each is selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy, halogen or trifluoromethyl.
14. The compound according to claim 13, wherein X is NH.
15. A compound according to claim 1 having the formula:wherein:
a is a group which may be substituted by one or two C1-C6Alkyl-substituted or unsubstituted alkylene;
R1and R2Are identical or different and are hydrogen, halogen, C1-C6Alkyl radical, C1-C4Alkoxy radical, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, C1-C6Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoromethoxy;
R3、R4、R5and R6Are identical or different and are hydrogen or methyl; and is
R8Is hydrogen or C1-C6An alkyl group;
m is 0, 1 or 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
16. A compound according to claim 1 having the formula:wherein:
a is a group which may be substituted by one or two C1-C6Alkyl-substituted or unsubstituted alkylene;
R1and R2Are identical or different and are hydrogen, halogen, C1-C6Alkyl radical, C1-C4Alkoxy radical, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, C1-C6Alkylsulfonyl, sulfonamide, trifluoromethyl or trifluoromethoxy;
R3、R4、R5and R6Are identical or different and are hydrogen or methyl; and is
R7Is hydrogen or C1-C6An alkyl group; and is
R8Is hydrogen or C1-C6An alkyl group;
m is 0, 1 or 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
17. A compound according to claim 1 which is
1- (pyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (pyrimidin-2-yl) -4- (4- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (5-fluoropyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (5-fluoropyrimidin-2-yl) -4- (4- [ benzothiazol-2-yl ] aminobutyl) piperazine;
1- (5-methylpyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1-phenyl-4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine; or
1- (pyridin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine.
18. A compound according to claim 1 which is
1- (4-chlorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (4-fluorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (3- [ benzothiazol-2-yl ] aminopropyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 4-methoxybenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 4-methylbenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 4-chlorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 6-ethoxybenzothiazol-2-yl ] aminoethyl) piperazine; or
1- (2-methoxyphenyl) -4- (2- [ 6-methylsulfonylbenzothiazol-2-yl ] aminoethyl) piperazine.
19. A compound according to claim 1 which is
1- (pyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine;
1-benzyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (4-oxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-ethoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (5-fluoropyrimidin-2-yl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine;
1- (5-methylpyrimidin-2-yl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine; or
1- (pyridin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine.
20. A compound according to claim 1 which is
1- (3-trifluoromethylphenyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine;
1-phenyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (4-fluorophenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-isopropoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-isopropoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine;
1- (pyridin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine; or
1- (pyrimidin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine.
21. A compound according to claim 1 which is
1- (2-methoxyphenyl) -4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine;
1-phenyl-4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine;
1- (pyridin-2-yl) -4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine;
1- (pyridin-2-yl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine;
1- (pyridin-2-yl) -4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine;
1- (2-isopropoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine;
1- (3-trifluoromethylphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine;
1- (2-methoxyphenyl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine;
1-phenyl-4- (2- [ 1-ethylbenzoimidazol-2-yl ] aminoethyl) piperazine; or
1-phenyl-4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine.
22. A compound having the general formula:wherein:
a is a group which may be substituted by one or two C1-C6Alkyl-substituted or unsubstituted alkylene;
R3、R4、R5and R6Are identical or different and are hydrogen or C1-C6An alkyl group; and is
m is 0, 1 or 2; and is
Ar is a mono-or bicyclic aryl or heteroaryl group, each of which may be independently substituted or unsubstituted with up to 5 groups selected from: c1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Alkylthio, hydroxy, amino, mono-or di (C)1-C6) Alkylamino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6An alkylsulfonyl, sulfonamide or alkylsulfonamide.
23. A method for the treatment and/or prophylaxis of neuropsychological disorders, which comprises administering to a host in need of such treatment an effective amount of a compound according to claim 1.
24. The method of claim 23, wherein the neuropsychological disorder is selected from the group consisting of schizophrenia, mania, dementia, depression, anxiety, obsessive-compulsive behavior, memory loss, perceptual disorders, substance abuse, parkinson-like movement disorders, and movement disorders associated with the use of neuroleptic agents.
25. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a neuropsychological disorder.
26. A salt according to claim 1 which is
1- (5-fluoropyrimidin-2-yl) -4- (2- [ 6-benzothiazol-2-ylamino ] butyl) piperazine hydrogen fumarate;
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-ylamino ] butyl) piperazine hydrogen fumarate;
1- (pyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (pyrimidin-2-yl) -4- (4- [ benzothiazol-2-yl ] aminobutyl) piperazine hydrogen fumarate;
1- (5-fluoropyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (5-methylpyrimidin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1-phenyl-4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (pyridin-2-yl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (4-chlorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine dihydrochloride; or
1- (4-fluorophenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine dihydrochloride.
27. A salt according to claim 1 which is
1- (2-methoxyphenyl) -4- (2- [ benzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (2-methoxyphenyl) -4- (3- [ benzothiazol-2-yl ] aminopropyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 4-methoxybenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 4-methylbenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 4-chlorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 6-ethoxybenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 6-methylsulfonylbenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (pyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate;
1-benzyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrogen fumarate; or
1- (4-chlorobenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide.
28. A salt according to claim 1 which is
1- (2-ethoxyphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (5-fluoropyrimidin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (5-methylpyrimidin-2-yl) -4- (2- [ 6-fluorophenothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (pyridin-2-yl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (3-trifluoromethylphenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1-phenyl-4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (4-fluorophenyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-isopropoxyphenyl) -4- (2- [ 6-fluorophenylthiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-Isopropoxybenzyl) -4- (2- [ 6-fluorobenzothiazol-2-yl ] aminoethyl) piperazine hydrobromide.
29. A salt according to claim 1 which is
1- (2-methoxyphenyl) -4- (2- [ 6-fluorophenyloxazol-2-yl ] aminoethyl) piperazine hydrochloride;
1- (pyrimidin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine hydrochloride;
1- (pyridin-2-yl) -4- (2- [ benzooxazol-2-yl ] aminoethyl) piperazine hydrochloride;
1- (2-methoxyphenyl) -4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1-phenyl-4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (pyridin-2-yl) -4- (2- [ benzoimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (pyridin-2-yl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (pyridin-2-yl) -4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide; or
1- (2-Isopropoxyphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide.
30. A salt according to claim 1 which is
1- (3-trifluoromethylphenyl) -4- (2- [ 1-methylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1- (2-methoxyphenyl) -4- (2- [ 1-ethylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1-phenyl-4- (2- [ 1-ethylbenzoimidazol-2-yl ] aminoethyl) piperazine hydrobromide;
1-phenyl-4- (2- [ 1-isopropylbenzimidazol-2-yl ] aminoethyl) piperazine hydrobromide.
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