CN1154693A - Benzimidazole derivative having dopaminergic activity - Google Patents
Benzimidazole derivative having dopaminergic activity Download PDFInfo
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- CN1154693A CN1154693A CN 95194447 CN95194447A CN1154693A CN 1154693 A CN1154693 A CN 1154693A CN 95194447 CN95194447 CN 95194447 CN 95194447 A CN95194447 A CN 95194447A CN 1154693 A CN1154693 A CN 1154693A
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Abstract
This invention relates to novel, pharmaceutically active benzimidazole derivatives of formula (I), wherein the dotted line, X and R<1> through R<7>, R<11> and R<15> through R<17> are defined as in the specification. These compounds exhibit central dopaminergic activity and are useful in the treatment of CNS disorders.
Description
The present invention relates to new benzimidizole derivatives and their acid salt with pharmacologically active.The disease that compound of the present invention has the active of central dopamine energy and can be used for treating central nervous system (CNS).Compound of the present invention preferably acts on the D4 Dopamine Receptors.
What people generally admitted in the prior art is that Dopamine Receptors all has important effect for the intravital multiple function of animal.For example, the various variation functions of these acceptors have participated in the generation of psychosis, habit-forming, sleep, feed, study, memory, sexual behaviour, and have participated in the adjusting of immunne response and the adjusting of blood pressure.Because Dopamine Receptors has been controlled multiple pharmacological effect, and on the other hand, do not understand the whole pharmacological actions that are subjected to Dopamine HCL control at present as yet.Therefore, have such possibility, the compound that promptly preferably acts on the D4 Dopamine Receptors may have multiple therapeutic action for human body.
On February 3rd, 1993, disclosed European patent application EP 0526434 was that a class contains the substituent benzimidazolyl-2 radicals-ketone compounds of 1-(aryl and heteroaryl) 4-propyl group-piperidines, and pointed out that this compounds has been found to be the thrombotonin activator of central action.On June 30th, 1993, disclosed European patent application EP 0548813 was that a class contains 1-[3-(4-aryl and heteroaryl) piperazine-1-yl] indole derivatives of the substituent replacement of propyl group, and point out that this compounds has been found to be the thrombotonin activator of central action.On October 15th, 1970, disclosed German patent application DE2017265 disclosed 1-[3-(4-aryl and heteroaryl) piperazine-1-yl that a class replaces] propyl group-2-methyl isophthalic acid H-benzoglyoxaline, and illustrated with mouse and test, found that this compounds has bronchiectatic activity.On April 29th, 1980, the United States Patent (USP) disclosed German patent DE 2714437 on May 11st, 4,200,641 and 1989 of bulletin disclosed a series of 1-[3-(4-diphenyl-methyl) piperazine-1-yl] propyl group-2,3-dihydro-1H-benzimidazolyl-2 radicals-ketone compound.With mouse these compounds are tested, found that these compounds have anti-histamine activity.On December 31st, 1991 laid-open U.S. Patents 4,954,503 have disclosed a series of compounds of the indazole derivatives that contains 1-(aryl and heteroaryl) 4-propyl group-piperazine substituted, and illustrated with mouse this compounds is tested, find that these compound exhibits have antipsychotic activity and analgesic activities.
Show on the active structures in the inhomogeneous compound for the CNS system in that preparation is various, benzoglyoxaline and benzimidazolone part are used as always and belong to substituting group together.Concrete example can find in following patent and patent application: on December 18th, 1986 disclosed belgian patent application BE904,945; The U.S. Patent application 4,954,503 that on December 31st, 1991 was announced; February 28 nineteen ninety disclosed European patent application EP 200,322.
The inventor has synthesized multiple 1-[4-(aryl or heteroaryl)-piperazine-1-yl with the active replacement of central dopamine energy so far]-3-(2-propyl group-benzoglyoxaline-1-yl)-propan-2-ol; 1-{3-[4-(aryl or heteroaryl)-piperazine-1-yl]-the 2-hydroxypropyl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone and 1-{3-[4-(aryl or heteroaryl)-piperazine-1-yl]-propyl group]-the 1H-benzimidizole derivatives.These compounds are preferred for the D4 Dopamine Receptors.
Description of the invention
The present invention relates to the compound of following general formula:
Wherein every dotted line is represented the two keys of yes or no;
X is carbon or nitrogen;
R
1Be benzyl, be selected from phenyl, 2, the aryl of 3-indanyl and naphthyl or be selected from the heteroaryl of pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl, wherein above-mentioned each aryl, heteroaryl and (C
1-C
4) phenyl moiety of alkyl and benzyl can be by one or more substituting groups, are preferably by 0 to 2 substituting group to replace or do not replace (the C that described substituting group is selected from halogen (as chlorine, fluorine, bromine or iodine) respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl, wherein said aryl is selected from phenyl, 2, and the aryl of 3-indanyl and naphthyl and said heteroaryl are selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
Or, when X is nitrogen, R
1According to circumstances can with X, R
17And be connected in R
17Carbon atom form the tetrahydroquinoline ring together;
R
2And R
3Be selected from hydrogen, hydroxyl, (C respectively
1-C
6) alkyl, (C
1-C
6) alkoxyl group, cyano group ,-CONH
2With-NHC (=O) R
9, or R
2And R
3Form the oxo base together;
R
4Be hydrogen, sulphur, oxygen, (C
1-C
6) alkyl, amino ,-NHR
10,-SR
10, OR
10Or hydroxyl;
R
5, R
6And R
7(the C that is selected from hydrogen, halogen (as chlorine, fluorine, bromine or iodine), cyano group respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) acyl amino, (phenyl) [(C
1-C
6) acyl group] amino, amino, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, aryl and heteroaryl, wherein said aryl is selected from phenyl, 2, and the aryl of 3-indanyl and naphthyl, said heteroaryl are selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
R
8, R
9And R
10Be selected from hydrogen and (C respectively
1-C
6) alkyl; With
R
11Be hydrogen, (C
1-C
6) alkyl or benzyl, wherein the phenyl moiety of said benzyl can be by 1 to 3 substituting group, be preferably by 0 to 2 substituting group and replace or do not replace, (the C that described substituting group is selected from halogen (as chlorine, fluorine, bromine or iodine) respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, amino, cyano group, (C
1-C
6) alkylamino and two (C
1-C
6) alkylamino;
Each R
15And R
16Be selected from respectively hydrogen, methyl, cyano group ,-(C=O)-NH
2With-CH
2-O-(C
1-C
6) alkyl;
R
17Be hydrogen or, when X is nitrogen, R
17Carbon atom that can be coupled, R according to circumstances
1Form the tetrahydroquinoline ring together with X;
The precondition of above-mentioned definition is: (a) work as R
2, R
3, R
15And R
16When all being hydrogen, R
4Can not be oxygen or hydroxyl; (b) when the five-ring of general formula I contains two key, R
11Do not exist; (c) work as R
4When being sulphur or oxygen, R
4Two bonds are incorporated on the coupled carbon atom and described carbon atom singly-bound is attached on two adjacent theheterocyclic nitrogen atoms; And (d) when X be nitrogen and two bond when being incorporated on the adjacent carbon atom, R
1Do not exist.
The compound that is the general formula I of alkalescence can form multiple salt with various inorganic or organic acids.These acid can be used to prepare be alkalescence compound of Formula I pharmaceutically-acceptable acid addition be those acid that can generate non-toxic acid addition salt, can generate and contain pharmaceutically acceptable anionic salt, example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, saccharic acid salt (glucaronate), saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, the acid of tosilate and embonate [promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)].
The invention still further relates to the pharmaceutically-acceptable acid addition of compound of Formula I.
Term used herein " one or more substituting group " but its implication comprises 1 to being the substituting group quantity that may reach at most of benchmark by the quantity of bonding position.
Except as otherwise noted, term used herein " alkyl " is meant the saturated univalence hydrocarbyl that contains straight chain, side chain or circular part or its various combinations.
Except as otherwise noted, term used herein " alkoxyl group " is meant to have general formula-base of O-alkyl, and wherein " alkyl " definition as mentioned above.
The preferred compound of the present invention comprises compound as described below:
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
1-benzoglyoxaline-1-base-3-[4-(4-fluorophenyl) piperazine-1-yl]-propan-2-ol;
1-(5-chloro-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl]-propan-2-ol;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-5-Trifluoromethyl-1 H-benzoglyoxaline;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 1H-benzoglyoxaline;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 3-methyl isophthalic acid, 3-dihydro-benzimidazolyl-2 radicals-ketone;
1-benzoglyoxaline-1-base-3-(4-o-tolyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-(tolyl-piperazine between 4--1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-(4-p-methylphenyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-chloro-phenyl-) phenyl methyl] piperazine-1-yl } propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(4-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-pyrimidine-2-base-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-naphthalene-1-base-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-trifluoromethyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-(4-benzyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-trifluoromethyl benzyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-ethoxy benzyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-[3-(3-trifluoromethyl) propyl group]-piperazine-1-yl }-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-[2-(3-trifluoromethyl) ethyl]-piperazine-1-yl }-propan-2-ol;
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-2-methyl isophthalic acid H-benzimidazolyl-2 radicals-ketone; With
5-fluoro-1-{3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline;
Other compound of the present invention comprises:
(4-chloro-2-nitrophenyl)-and 3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group } amine;
3-[4-(4-fluorophenyl)-piperazine-1-yl] propyl group }-(2-nitro-4-trifluoromethyl) amine;
4-chloro-N1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group } benzene-1, the 2-diamines;
1-(4,5-two chloro-2-nitrophenyl amino)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-phenyl-benzoglyoxaline-1-yl) propan-2-ol;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-propyl group-benzoglyoxaline-1-yl) propan-2-ol;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-methyl-benzoglyoxaline-1-yl) propan-2-ol;
5-fluoro-1-(3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group)-2-methyl isophthalic acid H-benzoglyoxaline;
5-chloro-1-(3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-hydroxypropyl)-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
5-fluoro-1-(3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-hydroxypropyl)-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
1-benzoglyoxaline-1-base-3-[4-(3-p-methoxy-phenyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(4-p-methoxy-phenyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-(4-phenyl-Piperazine-1-yl)-propan-2-ol;
1-{4-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl] phenyl } ethyl ketone;
1-(4-benzo [1,3] dioxy-5-ylmethyl-piperazine-1-yl)-3-benzoglyoxaline-1-base-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3, the 4-3,5-dimethylphenyl)-piperazine-1-yl]-propan-2-ol;
4-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-phenol;
1-benzoglyoxaline-1-base-3-(4-styroyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-phenyl allyl group)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-chloropropyl)-piperazine-1-yl]-propan-2-ol;
2-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-1-morpholine-4-base ethyl ketone;
1-(4-diphenyl-methyl-piperazine-1-yl)-3-benzoglyoxaline-1-base-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-[two (4-fluorophenyl) methyl]-piperazine-1-yl }-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(4-nitrophenyl)-piperazine-1-yl]-propan-2-ol;
4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-carboxylic acid;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl] propyl group }-the 1H-benzoglyoxaline;
3-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-the 1-yl]-1-phenyl-third-1-ketone;
4-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-1-(4-fluorophenyl) fourth-1-ketone;
1-benzoglyoxaline-1-base-3-[4-(tetrahydrofuran (THF)-2-ylmethyl)-piperazine-1-yl]-propan-2-ol;
[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-(tetrahydrofuran (THF)-2-yl) ketone;
[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-(2,3-dihydro-benzo [1,4] dioxy-2-yl) ketone;
[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-(tetrahydrofuran (THF)-2-yl) ketone;
[[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-2,3-dihydro-benzo [1,4] two English-2-yl) ketone;
1-benzoglyoxaline-1-base-3-[4-(2,3-dihydro-benzo [1,4] two English-2-ylmethyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(4-2-nitro butyl)-piperazine-1-yl]-propan-2-ol;
3-[4-(3-benzoglyoxaline-1-base-2-hydroxypropyl)-piperazine-1-yl]-1-(4-chloro-phenyl-)-third-1-ketone;
1-benzoglyoxaline-1-base-3-[4-(5,5-phenylbenzene-penta-3-phenyl)-piperazine-1-yl]-propan-2-ol;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-phenyl-benzoglyoxaline-1-yl)-propan-2-ol;
5,6-two fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 1H-benzoglyoxaline;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-propyl group-benzoglyoxaline-1-yl)-propan-2-ol;
1-[4-(4-fluorophenyl) piperazine-1-yl]-3-(2-methyl-benzoglyoxaline-1-yl)-propan-2-ol;
1-[3-(4-benzyl-piperazine-1-yl) propyl group]-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
1-[3-(4-benzo [1,3] dioxy-5-ylmethyl-piperazine-1-yl) propyl group]-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
1-{3-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
1-[3-(5-fluoro-2-tolimidazole-1-yl) propyl group]-4-(4-fluorophenyl)-piperidines-4-alcohol;
1-{3-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
1-{3-[4-(3,5-two chloro-pyridine-2-yl)-piperazine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-2-methyl isophthalic acid-[3-(4-phenyl-Piperazine-1-yl) propyl group]-1H-benzoglyoxaline;
2-[3-(5-fluoro-2-tolimidazole-1-yl) propyl group]-2,3,4,9-tetrahydrochysene-1H-arboline;
1-{3-[4-(6-chloro-pyridazine-3-yl)-piperazine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
1-{3-[4-(2-chloro-phenyl-)-piperazine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline;
6,7-two fluoro-1-{3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline;
3-[3-(5-fluoro-2-tolimidazole-1-yl) propyl group]-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline also;
1-{3-[4-(4-chloro-phenyl-)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-6,7-two fluoro-2-methyl isophthalic acid H-benzoglyoxalines;
5-fluoro-1-{3-[4-(5-fluorine pyrimidine-2-base)-piperazine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline;
5,6-two fluoro-1-{3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl]-2, the 2-dimethyl propyl }-2-methyl isophthalic acid H-benzoglyoxaline;
Acetate 2-(5-fluoro-2-tolimidazole-1-yl)-1-[4-(4-fluorophenyl) piperazine-1-ylmethyl] ethyl ester;
1-(5-fluoro-2-tolimidazole-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl]-the 2-methyl-propyl }-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl]-the 2-methoxy-propyl }-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-2-Trifluoromethyl-1 H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl]-the 3-methyl butyl }-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl]-the 2-methyl-propyl }-2-methyl isophthalic acid H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl] propyl group }-2-Trifluoromethyl-1 H-benzoglyoxaline;
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl] butyl }-2-methyl isophthalic acid H-benzoglyoxaline; With
5-fluoro-1-{3-[4-(4-fluorophenyl)-piperazine-1-yl] butyl }-2-methyl isophthalic acid H-benzoglyoxaline;
Other embodiment of the present invention comprises:
(a) compound of general formula I, wherein R
1Be phenyl and be unsubstituted or replaced, (the C that described substituting group is selected from halogen, is replaced by 1 to 3 fluorine atom by 1 or 2 substituting groups
1-C
6) the alkyl, (C that replaced by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl;
(b) compound of general formula I, wherein R
1Be 2, (the C that 3-indanyl and be unsubstituted or replaced by 1 or 2 substituting groups, described substituting group are selected from halogen, are replaced by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl;
(c) compound of general formula I, wherein R
1Be naphthyl and be unsubstituted or replaced, (the C that described substituting group is selected from halogen, is replaced by 1 to 3 fluorine atom by 1 or 2 substituting groups
1-C
6) the alkyl, (C that replaced by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl;
(d) compound of general formula I, wherein R
1Be heteroaryl and be unsubstituted or replaced, (the C that described substituting group is selected from halogen, is replaced by 1 to 3 fluorine atom by 1 or 2 substituting groups
1-C
6) the alkyl, (C that replaced by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl;
(e) compound of general formula I, wherein R
5, R
6And R
7Be selected from respectively by 1 to 3 fluorine atom and replace or unsubstituted (C
1-C
6) alkyl, replaced or unsubstituted (C by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group and halogen;
(f) compound of general formula I, wherein R
4Be hydrogen;
(g) compound of general formula I, wherein R
4Be (C
1-C
6) alkyl;
(h) compound of general formula I, wherein R
4Be amino;
(i) compound of general formula I, wherein R
4Be-NHR
10
(j) compound of general formula I, wherein R
4Be SR
10
(k) compound of general formula I, wherein R
4Be-OR
10
(l) compound of general formula I, wherein R
4It is hydroxyl;
(m) compound of general formula I, wherein R
11Do not exist;
(n) compound of general formula I, wherein R
2And R
3All be hydrogen;
(o) compound of general formula I, wherein R
2And R
3In one or two all be hydroxyl;
(p) compound of general formula I, wherein R
2And R
3Form an oxo base together;
(q) compound of general formula I, wherein R
2And R
3In one be (C
1-C
6) alkyl;
(r) compound of general formula I, wherein X is a carbon;
(s) compound of general formula I, wherein X is a nitrogen;
(t) compound of general formula I, wherein R
4Be oxygen; With
(the v) compound of general formula I, wherein R
4Be sulphur;
The compound of above-mentioned general formula I contains chiral centre, and therefore has different enantiomeric forms.The present invention relates to other steric isomer and these mixture of isomers of the optically active isomer of all compound of Formula I and all.
The invention still further relates to the pharmaceutical composition that is used for the treatment of and prevents following illness, described illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic (Gilles De LaTourettte) syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that causes by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), said composition comprises treatment and prevents compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of the general formula I of above-mentioned these illness significant quantities.
The invention still further relates to the method for the treatment of and preventing following illness, said illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that is caused by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), this method comprise will treatment and prevent compound or its pharmacy acceptable salt of the general formula I of above-mentioned these illness significant quantities to be applied to said Mammals.
The invention still further relates to the pharmaceutical composition that is used for the treatment of and prevents following illness, said illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that causes by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), said composition comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of the general formula I of dopaminergic activity amount.
The invention still further relates to the method for the treatment of and preventing following illness, said illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that is caused by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), this method comprise the compound of the general formula I of dopaminergic activity amount or its pharmacy acceptable salt are applied to said Mammals.
The invention still further relates to and be used for the treatment of or the pharmaceutical composition of preventing disease or illness, it comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of the general formula I of dopaminergic activity amount, and said disease and treatment of conditions or prevention can be undertaken or promote by changing Dopamine HCL mediates in (promptly increase or reduce) Mammals (comprising the people) body neurotransmission.
The invention still further relates to the method for treatment or preventing disease or illness, it comprises the compound of the general formula I of dopaminergic activity amount or its pharmacy acceptable salt is applied to said Mammals, and said disease and treatment of conditions or prevention can be undertaken or promote by changing Dopamine HCL mediates in (promptly increase or reduce) Mammals (comprising the people) body neurotransmission.
The invention still further relates to the pharmaceutical composition that is used for the treatment of and prevents following illness, said illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that causes by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), said composition comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of the general formula I of D4 receptors bind significant quantity.
The invention still further relates to the method for the treatment of and preventing following illness, said illness is selected from sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and disease that is caused by hyperactive immunity system such as allergy and the inflammation of Mammals (comprising the people), this method comprise the compound of the general formula I of D4 receptors bind significant quantity or its pharmacy acceptable salt are applied to said Mammals.
The invention still further relates to and be used for the treatment of or the pharmaceutical composition of preventing disease or illness, it comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of the general formula I of D4 receptors bind significant quantity, and said disease and treatment of conditions or prevention can be undertaken or promote by changing Dopamine HCL mediates in Mammals (the comprising the people) body neurotransmission.
The invention still further relates to the method for treatment or preventing disease or illness, it comprises the compound of the general formula I of D4 receptors bind significant quantity or its pharmacy acceptable salt is applied to said Mammals, and said disease and treatment of conditions or prevention can be undertaken or promote by changing Dopamine HCL mediates in Mammals (the comprising the people) body neurotransmission.
Term used herein " dopaminergic activity amount " is meant that the amount of compound is enough to suppress that Dopamine HCL combines with Dopamine Receptors and the neurotransmission effect that changes Dopamine HCL mediation in (promptly increase or reduce) Mammals (comprising the people) body.
Detailed description of the invention
The preparation method of compound of Formula I is described below.In these following reaction scheme neutralization discussion hereinafter, the X in all general formulas, R
1To R
11And R
15To R
17With dotted line such as above-mentioned definition.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 2 (continuing)
Reaction scheme 3
Reaction scheme 4
Reaction scheme 5
Reaction scheme 5 (continuing)
Reaction scheme 6
Reaction scheme 6 (continuing)
(R
13And R
14=H)
Referring to reaction scheme 1, wherein L is the compound that the compound reaction of the compound of general formula I I of leavings group and general formula III generates corresponding general formula 1.Suitable leavings group comprise chlorine, bromine, iodine ,-O-(C
1-C
6) alkyl sulphonyl and-the O-aryl sulfonyl (as-O-phenyl sulfonyl ,-O-naphthyl alkylsulfonyl or-O-p-nitrophenyl alkylsulfonyl).In addition, the R of Compound I I
2And R
3In to have one can be oxygen and can form epoxide group together with coupled carbon atom and L, and in the case, R
2And R
3In another then be selected from above-mentioned for the given definition of these substituting groups.Above-mentioned reaction is usually in inert polar solvents, under about 0 ℃-Yue 150 ℃ temperature, carry out, said inert polar solvents can be, for example lower alcohol, cyclic or acyclic alkane ketone (as ethanol or acetone), alkyl ester (as ethyl acetate), cyclic or acyclic one or dialkyl amide (as N-picoline-2-ketone or dimethyl formamide (DMF)), cyclic or acyclic alkyl oxide (as tetrahydrofuran (THF) (THF) or isopropyl ether) or the mixture of two or more aforementioned solvents.Reaction preferably in ethanol, is carried out to about solvent refluxing temperature at about 0 ℃.Having acid acceptor is useful as basic carbonate or tertiary amine.
Referring to reaction scheme 2, the compound of general formula I can also prepare according to following method.The compound of general formula I V and compound of formula III reaction generate the midbody compound of general formula V, among the general formula I V, and R
12Be selected from NO
2, NH
2, urea groups, thioureido and-NH (C=O)-Q, wherein Q is hydrogen, (C
1-C
4) alkyl, aryl or heteroaryl, wherein aryl and heteroaryl such as above-mentioned R
1Definition, Z is that a Sauerstoffatom or two hydrogen atoms (on each carbon atom that all singly-bound is attached to Z links to each other) and L are suitable leavings group as defined above.Reaction is carried out under about 0 ℃-Yue 150 ℃ temperature normally in the inert non-polar solvent described in the above-mentioned reaction scheme 1.Preferred solvent is an ethanol, and preferred temperature of reaction is about 0 ℃ of reflux temperature to about solvent.As the reaction of reaction scheme 1, can in reaction, add sour accepting agent such as basic carbonate and tertiary amine.
Must will be wherein Z be the midbody compound of the general formula V of oxygen change into accordingly wherein that Z is (H, compound H).Can use any standard method of reducing well known in the prior art, as in tetrahydrofuran solvent, be that the general formula V compound of oxygen and the lithium aluminum hydride in the tetrahydrofuran (THF) (preferably containing 5 molar equivalents) react and finish above-mentioned conversion by Z wherein.
Z be (H, general formula V midbody compound H) by itself and L ' be suitable leavings group (as chlorine, bromine, iodine, fluorine, amino ,-O-(C
1-C
6) alkyl sulphonyl or O-aryl sulfonyl, wherein aryl is selected from phenyl, naphthyl and p-nitrophenyl) general formula R
4-C (=O)-reaction of the dewatering agent that L ' compound and selectivity exist, and can be on the spot or behind the segregation, convert it into the compound of corresponding general formula I.The solvent that is applicable to this reaction comprises inert polar solvents such as cyclic or acyclic alkyl oxide (as isopropyl ether and tetrahydrofuran (THF) (THF)), alkyl ester (as ethyl acetate), cyclic or acyclic alkyl ketone (as ethanol and acetone), pyridine derivate (lutidine and trimethylpyridine), halogenated solvent (as methylene dichloride and ethylene dichloride) and cyclic, acyclic N, N-dialkyl amide (as DMF and N-N-methyl-2-2-pyrrolidone N-(NMP)) and acyclic alkylamide (as methane amide or ethanamide).Temperature of reaction can be about 0 ℃-Yue 150 ℃.Reactant (V and R
4-C (=O)-and L ') preferably descend reaction and slowly make temperature of reaction rise to the reflux temperature of reaction mixture at 0 ℃ at first.Can add sour accepting agent such as basic carbonate and tertiary amine in the reaction.Can also add dewatering agent.
Reaction scheme 3 is to illustrate wherein that X is nitrogen and R
1Not the preparation method of the compound of Formula I of hydrogen.These will be referred to as " general formula I A compound " below appearing at the compound of reaction scheme 3.Referring to reaction scheme 3, these compounds can pass through wherein R
1Be the respective compound of hydrogen and R wherein
1Not that hydrogen and L ' are the general formula Rs of suitable leavings group as defined above
1L ' compound reacts and prepares.The solvent that is applicable to this reaction comprises that cyclic and acyclic one and dialkyl amide (as DMF or N-N-methyl-2-2-pyrrolidone N-), lower alcohol and two or more are selected from the mixture of above-mentioned each kind solvent.Ethanol and N-N-methyl-2-2-pyrrolidone N-are preferred solvents.This temperature of reaction can be about 0 ℃-Yue 150 ℃, is preferably about 0 ℃ of reflux temperature to solvent.The sour accepting agent that can add in the reaction such as basic carbonate and tertiary amine.
Reaction scheme 4 has illustrated the another kind of method for preparing compound of Formula I.Referring to reaction scheme 4, wherein L is the general formula VII compound of leavings group and the compound that the reaction of general formula VIII compound obtains general formula I.The example of suitable leavings group be chlorine, bromine, iodine ,-O-(C
1-C
6) alkyl sulphonyl and-the O-aryl sulfonyl, wherein aryl can be for example phenyl, naphthyl or p-nitrophenyl.In addition, the R of general formula VII
2And R
3In to have one can be oxygen and can form epoxide group together with coupled carbon atom and L, and in the case, R
2And R
3In another then be selected from the above-mentioned definition that provides for these substituting groups.This reaction usually uses that used solvent and reaction conditions carries out in the above-mentioned reaction scheme 3.
The compound of general formula I I both can be purchased also and can have been prepared by general formula I V compound by the known method of those of ordinary skill in the present technique field.In embodiment 2, exemplified from the method for general formula I V compound general formula I I compound.
General formula I V compound can be used similar in appearance to the method described in the following reference and prepare: organic chemistry magazine (J.Org.Chem.), 38,3498-502 (1973) and chemical association magazine (J.Chem.Soc.) (C), 2364-66 (1971).For example, can be by the known R that on the ortho position, contains
12The synthetic of general formula I V compound carried out in the reaction of propyl group transfer agent substituent anils and replacement or unsubstituted.This synthetic method has been described in embodiment 8.
Wherein X is that the compound of the general formula III of nitrogen can prepare by following method, piperazine that promptly is purchased and aryl transfer agent such as 4-nitro fluorobenzene, 2-nitro fluorobenzene or similar agents are reacted, and then make nitro be transformed into other substituting group with currently known methods.Wherein X is that the compound of the general formula III of nitrogen also can prepare by the piperazine that is purchased and the reaction of heteroaryl transfering reagent, and said heteroaryl transfer agent is for example 2-chlorine or 2-S-methyl mercapto pyrimidine derivatives, 2-chlorine or 2-bromopyridine derivative, 2-chlorine or 2-Calmazine derivative, the different benzothiazole derivant of 3-chlorine, 3-chlorine Yi benzoxazole derivative, 3-chlorine indazole derivatives or similar reagents.These reactions are preferred in the solvent of form of mixtures, at about 0 ℃-Yue 150 ℃, preferably to the reflux temperature of reaction mixture, carry out said mixed solvent at about 0 ℃, the mixture that can contain as required, following these materials: cyclic and acyclic one and dialkyl amide and (C
1-C
4) alcohol or inert organic solvents such as cyclic and acyclic alkyl oxide (as ether and tetrahydrofuran (THF)), cyclic and acyclic alkyl ester (as ethyl acetate and gamma-butyrolactone), cyclic and acyclic alkyl ketone (as acetone and pimelinketone), pyridine derivate or halogenated solvent.Can add sour accepting agent such as basic carbonate, tertiary amine or similar agents in the reaction and add dewatering agent.
Wherein X is that the compound of the general formula III of carbon can prepare by such method, and 4-piperidone that promptly is purchased and aryl transfer agent such as aryl Grignard reagent or similar reagents are reacted, and makes corresponding benzylalcohol midbody compound dehydration.Wherein X is that the compound of formula III of CH can prepare by such method, 4-piperidone that promptly is purchased and aryl transfer agent such as aryl Grignard reagent or similar reagents are reacted, and make corresponding benzylalcohol midbody compound hydrogenation with platinum dioxide or palladium-carbon.
General formula VI compound can prepare by the reaction that exemplifies general formula I I compound and piperazine or 1-tert-butoxycarbonyl piperazine among the embodiment 9, this reaction is preferred in containing the mixed solvent of following substances, at about 0 ℃-Yue 150 ℃, preferably carry out to the reflux temperature of reaction mixture at about 0 ℃, said mixed solvent contains the mixture of following these materials: (C
1-C
4) pure and mild cyclic and acyclic one and dialkyl amide or inert organic solvents such as cyclic and acyclic alkyl oxide, cyclic and acyclic alkyl ester, cyclic and acyclic alkyl ketone, pyridine derivate or halogenated solvent.Can add sour accepting agent such as basic carbonate, tertiary amine or similar agents in the reaction.Corresponding piperazine intermediate (having different replacement modes) can generate by such method, be the product of above-mentioned reaction and suitable aryl transfering reagent such as 4-nitro fluorobenzene, 2-nitro fluorobenzene or similar reagents reaction, then make nitro change into other substituting group with known method.This corresponding piperazine intermediate also can prepare by such method, and promptly other intermediate and heteroaryl transfer agent such as 2-chlorine or 2-S-methyl mercapto pyrimidine derivatives, 2-chlorine or 2-bromopyridine derivative, 2-chlorine or 2-Calmazine derivative, the different benzothiazole derivant of 3-chlorine, the different benzoxazole derivative of 3-chlorine, 3-chlorine indazole derivatives or similar reagents are reacted.The optimum condition that carries out these reactions is similar in appearance to the preferred reaction conditions described in the embodiment 11.
Equally, general formula VII compound can prepare by such method, i.e. compound of formula III and general formula L
2-CH
2-CH (R
2) CH (R
3)-CH
2-L
3Compound react each L wherein
2And L
3Be leavings group, for example it is selected from chlorine, bromine, iodine, O-alkyl sulphonyl and O-aryl sulfonyl respectively, and wherein aryl can be for example phenyl, naphthyl or p-nitrophenyl.In addition, the R of above-claimed cpd
2And R
3In one can be oxygen and and coupled carbon atom and L
2Or L
3Form epoxy group(ing) together, and in the case, R
2And R
3In another then be selected from the above-mentioned definition that provides for these substituting groups.Reaction mixture can contain one or more inert organic solvents such as cyclic and acyclic alkyl oxide, cyclic and acyclic alkyl ester, cyclic and acyclic alkyl ketone, pyridine derivate, halogenated solvent or ring-type and acyclic N, N-dialkyl group alkylamide.Temperature of reaction can be 0 ℃-Yue 150 ℃.Reaction is preferably carried out to the reflux temperature of reaction mixture at 0 ℃.Can add acid acceptor such as basic carbonate, tertiary amine or similar agents in the reaction.
General formula VIII compound can be according to existing document as at chemical association magazine., P.1396 (1949), chemosynthesis communication (Synth.Commun.), 5, P461 (1975), Journal of the American Chemical Society (J.Amer.Chem.Soc.), 73., p.4297 (1951) or chemical association magazine (J.chem.Soc.), 39, p.3155 currently known methods of describing in (1951) prepares.
Reaction scheme 5 has illustrated the another kind of diverse ways that is used to prepare compound of Formula I.Referring to reaction scheme 5, general formula I X compound can be according in the existing document as be prepared at the currently known methods described in the following reference: chemical association magazine., P1396 (1949), the chemosynthesis communication., 5, P461 (1975), Journal of the American Chemical Society., 73., p.4297 (1951) or chemical association magazine., 39, p.3155 (1951).These compounds also can be shown in reaction scheme 5, by the replacement of general formula X I or the C that does not replace
3-C
4The reaction of alkyl derivative and compound of formula III prepares.In structural formula XI, L and L ' are as above-mentioned definition and work as R
13And R
14When the both was hydrogen, L ' can be the amino of nitro or protection according to circumstances; R
2And R
3As above-mentioned definition, R
2And R
3In one can be oxygen and can form epoxy group(ing) together with coupled carbon atom and L or L '; R
13And R
14The both is a hydrogen, just-and CL ' R
13R
14Part according to circumstances can (promptly wherein L ' be nitrogen and R for cyano group
13And R
14Represent key rather than group).
Above-mentioned these reactions can be in solvent, at 0 ℃-Yue 150 ℃.Preferably carry out expediently to the reflux temperature of solvent at 0 ℃, said solvent is for example alcohol, ring-type and acyclic alkyl ketone, cyclic and acyclic alkyl ester, cyclic and acyclic one and dialkyl amide, acetonitrile, cyclic and the acyclic alkyl oxide or the mixture of these solvents.Can have sour accepting agent such as basic carbonate, tertiary amine or similar agents in the reaction.
For all structures of describing in reaction scheme 5 and 6, R
13And R
14As above-mentioned definition.Therefore, for wherein not containing-CL ' R
13R
14All this structures of part, R
13And R
14The both is a hydrogen.
In addition, the compound of general formula I X can also prepare by the reaction of general formula X I compound as defined above and general formula X VI compound:
Wherein L such as above-mentioned definition.Solvent that be suitable in this reaction and preferred and reaction conditions are similar in appearance to solvent and reaction conditions recited above or general formula X I and the reaction of III compound.
General formula X VI compound can be used similar in appearance to the method for embodiment 23A and prepare.
Can as follows general formula I X compound be changed into the compound of corresponding general formula X.(for example working as nitrogen-protecting group is benzyl, benzyloxycarbonyl, tert-butoxycarbonyl or trityl) can use hydrogenation or acidity to go protective condition to remove this protecting group when L ' is protect amino.When L ' is during with phthalein imino-protection amino, can use the hydroconversion condition of standard to remove this protecting group.When L ' is nitro, can use method of reducing reduction general formula I X compound commonly used to prepare the compound of general formula X.For example, can use hydride reagent such as lithium aluminum hydride or borine, or in the presence of catalyzer such as Raney nickel, platinum oxide, palladium/carbon or other suitable catalyzer, use hydrogen to carry out reduction reaction.
When-CL ' R
13R
14When part is cyano group, can in the presence of cobalt chloride, use hydride reagent such as lithium aluminum hydride or sodium borohydride, or the common method of using the one of ordinary skilled in the art to know is reduced into it-CH
2NH
2
As shown in the page 2 of reaction scheme 5, the reaction of the compound of the general formula X of gained and general formula X II compound (wherein L " as the definition of L ') has obtained wherein R
12Be the compound (referring to reaction scheme 5 and followingly will be referred to as general formula V ' compound) of nitro, then, can convert it into R wherein by the nitro in this compound of reduction
4It is the corresponding compound of Formula I of methyl or trifluoromethyl.Can carry out above-mentioned reaction as zinc or tin in acetate or trifluoroacetic acid (if desired, can contain corresponding acid anhydrides) by using metal.Contain under the situation of hydroxyl substituent at general formula V ' compound, may generate the ester intermediate, the common method that can use the one of ordinary skilled in the art to know then changes into the compound of Formula I that corresponding hydroxyl replaces with these ester intermediates.For example, can be at about 0 ℃-Yue 150 ℃, preferred about 0 ℃ to reflux temperature, use the alkali metal hydroxide aqueous solution in suitable organic solvent to handle this class ester intermediate, said The suitable solvent is selected from cyclic and acyclic one and dialkyl amide, C
1-C
4The mixture of pure and mild these solvents.Can the compound of the hydroxyl replacement of general formula I be changed into the compound of corresponding alkoxyl group replacement by such method, promptly at first use alkalimetal hydride such as sodium hydride or hydrolith to handle the compound of the hydroxyl replacement of general formula I, use therein solvent and condition are as mentioned above, then, handle with alkylating agent such as methyl-iodide, methyl-sulfate, allyl iodide, iodoethane or similar agents again.Reaction scheme 6 has illustrated the method that is begun to prepare compound of Formula I by the hydroxy derivatives of general formula X III.This raw material i.e. R wherein
12Be nitro general formula X III compound can by general formula X I compound (wherein L is that hydroxyl and L ' they are amino) and definition as above and as above-mentioned reaction scheme 5 described in the reaction of general formula X II compound prepare.This reaction usually uses that used solvent and reaction conditions carries out in the reaction of reaction scheme 1.
Can use method of reducing commonly used as mixture with metal (as zinc or tin) and hydrochloric acid, or use for hydride reagent such as lithium aluminum hydride or borine, or in the presence of catalyzer such as Raney nickel, platinum oxide or palladium/carbon, make the reactant hydrogenation of general formula X III, thereby R wherein
12The compound that is the general formula X III of nitro changes into wherein R
12It is amino corresponding general formula X III compound.
Can make nitroreduction as zinc or tin in acetate or trifluoroacetic acid (if desired, can contain corresponding acid anhydrides) by using metal, wherein R
12The compound that is the general formula X III of nitro changes into wherein R
4It is the corresponding general formula X IV compound of methyl or trifluoromethyl.Then, can will react the compound that the ester intermediate that generates changes into general formula X IV with the standard method that the one of ordinary skilled in the art knows.For example, can be at about 0 ℃-Yue 150 ℃, preferred about 0 ℃ to reflux temperature, use the alkali metal hydroxide aqueous solution in suitable organic solvent to handle this class ester intermediate, said The suitable solvent is selected from cyclic and acyclic one and dialkyl amide, C
1-C
4Alcohol.
In addition, R wherein
4The general formula X IV compound that is alkyl can prepare by such method, i.e. R wherein
12Be amino general formula X III compound and acylating agent such as propionyl chloride, different propionyl bromide, acetic/formic acid acid anhydride, ethyl formate or similar agents reaction; then; under about 0 ℃ of extremely sour boiling temperature; with the aqueous solution of sour example hydrochloric acid, trifluoroacetic acid or methylsulfonic acid, the preferably salt aqueous acid is handled the intermediate product of above-mentioned generation.
Can incite somebody to action wherein R by such method
4Be the general formula X IV compound of methyl or trifluoromethyl change into L ' wherein be leavings group such as chlorine, bromine, iodine ,-the O-alkyl sulphonyl and-compound of the general formula X IVA of O-aryl sulfonyl (wherein aryl for example can be phenyl, naphthyl or p-nitrophenyl); promptly at-25 ℃ to about 25 ℃ approximately; preferably under about-25 ℃; in the presence of sour accepting agent such as alkaline carbonate, tertiary amine or similar reagents, R wherein
4Be that the general formula X IV compound of methyl or trifluoromethyl and the alkyl or aryl SULPHURYL CHLORIDE in the suitable solvent are reacted, said The suitable solvent is selected from cyclic and acyclic one and dialkyl amide, chloroform, methylene dichloride and pyridine and its mixture.When the L ' among the required general formula X IVA is chlorine, bromine or iodine, about 0 ℃ to the reflux temperature of about reaction mixture, preferably under reflux temperature, make accordingly wherein R
4Be that the general formula X IV compound of methyl or trifluoromethyl and phosphoryl halogen or thionyl halide in solvent such as chloroform, methylene dichloride, benzene, toluene or its mixture react.
Solvent and reaction conditions that use is used in the reaction shown in the reaction scheme 1, the reaction by said compounds X IVA and compound of formula III can be with R wherein
4Be methyl or trifluoromethyl and L ' be leavings group such as chlorine, bromine, iodine ,-the O-alkyl sulphonyl and-compound of the general formula X IVA of O-aryl sulfonyl (wherein aryl for example can be phenyl, naphthyl or p-nitrophenyl) changes into the compound of general formula I.
Above-mentioned these reactions can solvent as alcohol, cyclic and acyclic alkyl ketone, cyclic and acyclic alkyl ester, cyclic and acyclic one and dialkyl amide, acetonitrile, cyclic and acyclic alkyl oxide in, at about 0 ℃-Yue 150 ℃, preferred about 0 ℃ to the reflux temperature of same solvent, carry out expediently.Also can there be sour accepting agent such as alkaline carbonate, tertiary amine or similar agents to exist in the reaction.
Do not have other compound in the specifically described general formula I to be prepared by the combination of above-mentioned each reaction in above-mentioned experimental section, this point is conspicuous for the one of ordinary skilled in the art.
Each reaction of in above-mentioned reaction scheme 1-4, discussing or illustrate, unless specify in addition, pressure is not crucial reaction conditions.About 0.5-about 4 atmospheric reaction pressures are acceptables, and preferably reaction pressure is promptly about 1 normal atmosphere of normal pressure, because it is convenient to operation.
The new compound of general formula I and its pharmacy acceptable salt (following will being referred to as " treatment compound of the present invention ") can be used as dopaminergic preparation, and promptly they have the neurotransmission of Dopamine HCL mediation in change Mammals (the comprising the people) body.Therefore, they can be used as the therapeutical agent of controlling of treatment Mammals various illnesss, and the treatment of these diseases or prevention can be undertaken or promote by the neurotransmission that increases or reduce the Dopamine HCL mediation.These illnesss comprise sleep disordered, venereal disease (comprising sexual dysfunction), gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS such as leptomenigitis, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, pharmaceutical chemicals dependence syndrome such as drugs addiction and drinking habit, blood vessel and cardiovascular disorder, eye disease (comprising glaucoma), dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, dyskinesia disease is as cathisophobiaing, hypertension and the disease such as allergy and the inflammation that cause by hyperactive immunity system.
The compound of Formula I that is alkalescence can form multiple different salt with various mineral acids and organic acid.Although these salt must be acceptable during to animal-use drug.But, in fact often the Perfected process that uses is at first compound of Formula I to be separated from reaction mixture with the form of non-pharmaceutical salts, then, handle with alkaline reagents, it is changed into free alkali compound simply, then again this free alkali is changed into pharmaceutically-acceptable acid addition.The acid salt of basic cpd of the present invention can easily prepare by such method, promptly in the water-containing solvent medium or in suitable organic solvent such as methyl alcohol or ethanol with the mineral acid of selecting for use or the organic acid of equivalent are handled said basic cpd basically.After the carefulness steaming desolventizes, easily obtain required solid salt.In addition, also can be by in the solution of free alkali in organic solvent, adding suitable mineral acid or organic acid so that required acid salt is precipitated out.
Treatment compound of the present invention can by oral, through the mode administration of epidermis (for example, by use plaster), parenteral or local application.Wherein preferred oral administration.Though using dosage can change to some extent according to patient's the body weight and the state of an illness, particularly administering mode,, the dosage of these compound the bests is about 0.01 milligram-Yue 250 milligrams of every days usually.In some cases, may use the dosage that is lower than above-mentioned scope lower limit just enough, and in other cases, even used bigger dosage also can not have side effects, as long as this heavy dose is divided into the administration in a day of several low doses.
Treatment compound of the present invention can be used or adopt a kind of and pharmaceutically acceptable carrier in the foregoing dual mode or thinner to combine separately and use.Above-mentioned medication can be with single dose or a plurality of dosed administration.More particularly, the new treatment compound of the present invention can be used with various dosage form, and promptly they can combine with various pharmaceutically acceptable inert supports and make tablet, capsule, lozenge, lozenge, hard candy agent, pulvis, sprays, creme, ointment, suppository, lyogel agent, gelifying agent, ointment, lotion, ointment, elixir, syrup etc.Said carrier comprises solid diluent or filler, aseptic water-bearing media and various nontoxic organic solvents etc.In addition, can be with oral pharmaceutical composition sweetening and/or add flavor suitably.
With regard to oral administration, the tablet that contains various vehicle such as microcrystalline cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine can use with various disintegrating agents and granulating tackiness agent, and said disintegrating agent is for example starch (preferred corn, potato or tapioca (flour)), alginic acid and some composition silicate; Said granulating tackiness agent is for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, lubricant often also is very useful for the tablet medication as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum.The solids composition of similar type also can be used as the filler of gelatine capsule; Similarly preferred substance also comprises lactose or nougat and high molecular weight polyethylene glycol.When containing water suspending agent and/or elixir and be used for oral administration, activeconstituents wherein can combine with various sweeting agents or spices, coloring matter or pigment, if desired, also can combine with the mixture of emulsifying agent and/or suspension agent and thinner such as water, ethanol, propylene glycol, glycerol and these materials.
With regard to administered parenterally, can use compound of the present invention at sesame oil or peanut oil or the solution in aqueous propylene glycol.If desired, and liquid diluent at first is isotonicity, then this class aqueous solution suitably should be cushioned.These aqueous solutions are applicable to the intravenous injection medication.Oil solution is applicable to intrinsic articulation, intramuscular and subcutaneous injection administration.Pharmaceutical solutions under above-mentioned all these aseptic conditions can prepare with the standard pharmaceutical technology that the one of ordinary skilled in the art knows.
In addition, when need were treated the inflammation of skin, compound of the present invention can also be with the mode administration of local application, and this administering mode preferably uses creme, lyogel, ointment, ointment etc. according to the method for pharmacy of standard.
The D4 dopaminergic activity of The compounds of this invention can be measured with following method.People such as Van Tol are at nature (Nature), and Vo1.350610 has described the active measuring method of D4 Dopamine HCL in (London, 1991).At first obtain the cloned cell line (clonal cell line) of expression human body dopamine d 4 receptor and it is being contained 5 mmole EDTA, 1.5 mmole calcium chloride (CaCl
2), 5 mmole magnesium chloride (MgCl
2), homogenizing (teflon pestle) in 50 mmole Tris.HCl (PH7.4, the 4 ℃) damping fluid of 5 mmole Repone K (KCl) and 120 mmole sodium-chlor (NaCl).With 39, the speed of 000g is the homogenate centrifugation that obtains 15 minutes, and the pill of the gained concentration with the 150-250 mcg/ml is suspended in the buffered soln.In saturation testing, the aliquots containig of 0.25 milliliter of homogenate is placed high density [3H] spiperone (Spiperone), and (ultimate density is 70.3Ci/mmol; 10-3000pM) in the repeat sample, under 22 ℃, be 1 milliliter with total amount and cultivated 30-120 minute.Competition in conjunction with test in, begin to measure and containing the competitive coordination body (10 of indication concentration from adding 0.25 milliliter of film
-4-10
-3Mole) and in the duplicate of [3H] spiperone, do not exist or having a 200uM GPP (NH)
pCultivate under the condition of (5 '/amidino groups imino-diacetic phosphoric acid ester), wherein under 22 ℃, indicated 60-120 minute.Stop measuring by filtering fast with the Titertek cell harvestor, and then use Sunahara, people such as R.K. are at nature, and 346, the method described in the 76-80 (1990) is carried out the monitoring of tritium to filter.In all tests, special [3H] Spiperone is in conjunction with definition as use 1-10 micromole (+) Butaclamole or the combination of 1 micromole Spiperone inhibition.Analyze saturated combination and competition bonded data by operation nonlinear least square curve fitting procedure Ligand on the described digital Micro-pp-11 of people such as Sunahara.
Use above-mentioned method that nearly 80 compounds of the present invention are tested.All these test compounds are used less than 1 micromolar K
iReplaced the combination of [3H] spiperone.
To the present invention be described with embodiment below.But, should be realized that protection scope of the present invention is not limited in the detail of these embodiment.Wherein said fusing point is not calibrated.
Embodiment 1
1-(4-fluorophenyl)-4-oxiranylmethyl radical-piperazine
The mixture of 2.5 gram 1-(4-fluorophenyl) piperazines, 3.0 gram 3-nitrobenzene-sulfonic acid 2S-(+) glycidyl esters (can buy from Aldrich company) and 15 milliliters of dimethyl formamides (DMF) was at room temperature kept 12 hours.Also use the mixture of dichloromethane extraction gained to wherein adding 30 ml waters.Collect dichloromethane extract, wash and use dried over sodium sulfate with 20 ml waters.Remove the crude product (3.5 gram oily matter) that obtains after desolvating and use chromatographic purification: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 5% methyl alcohol.The back gained material sample of purifying shows that 236 M+/z and specific rotation are [α]
D=-15.54 (c=1.1, CHCl
3).
Embodiment 2
1-oxiranylmethyl radical-1H-benzoglyoxaline
The mixture of 2.7 gram 1-H-benzoglyoxalines and 1 gram sodium hydride (60%) in 30 milliliters of DMF was at room temperature kept 0.3 hour.To wherein adding 6 gram 3-nitre Phenylsulfonic acid 2S-(+) glycidyl esters (can buy) and the mixing of gained being stirred 2 hours from Aldrich company.Pour in 100 milliliters of ice said mixture and water and ethyl acetate extraction.Collect acetic acid ethyl acetate extract, wash and use dried over sodium sulfate with 20 ml waters.Remove the crude product (6.5 gram oily matter) that obtains after desolvating and use chromatographic purification: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 2% methyl alcohol.The back gained material sample of purifying shows that M+/z is 175.
Embodiment 3
1-benzoglyoxaline-1-base-3-[4-(4-fluorophenyl) piperazine-1-yl] propylene glycol (two kinds of enantiomorphs)
With 0.26 gram 1-H-benzoglyoxaline with at 6 milliliters of N, the mixture of the gram sodium hydride of 0.097 in the dinethylformamide (DMF) (60%) kept 0.3 hour under chambers temp.To wherein adding 1-(4-fluorophenyl)-4-oxiranylmethyl radical-piperazine (0.52 gram) and mixture being stirred 12 hours.Said mixture is poured into 10 milliliters of ice and water and used chloroform extraction.Collect chloroform extracted solution, wash and use dried over sodium sulfate with 20 ml waters.Remove the crude product (1.0 gram oily matter) that obtains after desolvating and use chromatographic purification: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 2% methyl alcohol.The back gained material sample of purifying shows 355 M+/z.The alcohol suspension of handling above-mentioned gained material with ether/hydrochloric acid mixture is to convert it into hydrochloride.The fusing point of this salt is 246-247 ℃, and specific rotation is [α]
D=-7.3 (c=0.5, MeOH).
Under 80 ℃, 2.0 gram 1-oxiranylmethyl radical-1H-benzoglyoxalines, 2.37 gram 1-(4-fluorophenyl) piperazines and 25 milliliters of alcoholic acid mixtures were stirred 48 hours.Pour into mixture in 25 milliliters of ice-cold aqueous sodium hydroxide solutions and use dichloromethane extraction.Collect dichloromethane extract, wash and use dried over sodium sulfate with 20 ml waters.Removing the crude product (94.18 gram oily matter) that obtains after desolvating purifies with flash chromatography: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 5% methyl alcohol.Alcohol suspension by handling gained material sample after the above-mentioned purification (2.14 gram) with ether/hydrochloric acid mixture is to convert it into hydrochloride.The fusing point of this salt is 238-240 ℃, and specific rotation is [α]
D=-7.3 (c=0.5, MeOH).
Embodiment 4
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 1H-benzoglyoxaline
5.0 gram { 3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-(4-fluoro-2-aminophenyl) amine, 18 milliliters of formic acid and 75 milliliters of methane amides were kept 12 hours down at 140-145 ℃.To wherein adding entry, and with ammonium hydroxide (NH4OH) so that its be alkalescence and use ethyl acetate extraction.Collect acetic acid ethyl acetate extract, wash and use dried over sodium sulfate with 20 ml waters (2 * 20 milliliters).Remove the crude product (2.14 gram oily matter) that obtains after desolvating and use chromatographic purification: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 2% methyl alcohol.Alcohol suspension by handling gained material sample after the above-mentioned purification (2.2 gram) with ether/hydrochloric acid mixture is to convert it into hydrochloride.It is 356.18 with quality that the fusing point of this salt is 236 ℃.
Embodiment 5
N-(2-nitro-4-fluorophenyl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propionic acid amide
The mixture of 14.8 gram N-(2-nitro-4-fluorophenyl)-3-bromine propionic acid amides, 9.0 gram 1-(4-fluorophenyl) piperazines, 6.46 gram diisopropylethylamine and 150 milliliters of DMF was kept 48 hours down at 150 ℃.Under the room temperature, also use the mixture of chloroform extraction gained to wherein adding entry (300 milliliters).Collect chloroform extracted solution, wash and use dried over sodium sulfate with 20 ml waters.Remove the crude product chromatographic purification that obtains after desolvating: solid phase (SiO
240 μ m; Baker); Elutriant is a chloroform.The back gained material sample (12.7 gram) of purifying shows that M+/z is 405.
Embodiment 6
3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-(2-amino-benzene) amine
With 1.03 gram N-(2-amino-4-fluorophenyl)-3-[4-(4-fluorophenyl) piperazine-1-yls] solution in THF of propionic acid amide and 8.5 milliliters of 1.0 moles of lithium aluminum hydrides (under 9 ℃, with 0.3 hour time added) and 10 milliliters of THF descend maintenance 12 hours at 20-25 ℃.After wherein slowly adding 1.7 milliliter of 10% aqueous sodium hydroxide solution, the THF layer is handled and isolated to mixture with sal epsom.Remove the crude product that obtains after the desolvating chromatographic purification of standard: solid phase (SiO
240 μ m; Baker); Elutriant is 5% alcoholic acid ethyl acetate solution.The material sample of gained after purifying (0.22 gram) shows that M+/z is 361.
Embodiment 7
N-(2-amino-4-fluorophenyl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propionic acid amide
Under 20-25 ℃, with 3.0 gram N-(2-nitro-4-fluorophenyl)-3-[4-(4-fluorophenyl) piperazine-1-yls] palladium, 100 milliliters of ethanol and 10 milliliters of Pa Er wobblers (Parr Shaker) that concentrated hydrochloric acids place 45 pounds of/square inch hydrogen to exist on the propionic acid amide, 1 gram, 5% carbon.After absorption of hydrogen stops, with the nitrogen purging mixture and isolate alcohol layer.Remove the crude product that obtains after the desolvating chromatographic purification of standard: solid phase (SiO
240 μ m; Baker); Elutriant is 5% alcoholic acid ethyl acetate solution.The material sample of gained after purifying (0.22 gram) shows that M+/z is 375.
Embodiment 8
N-(2-nitro-4-fluorophenyl)-3-bromine propionic acid amide
The mixtures of 7.8 gram 4-fluoro-2-N-methyl-p-nitroanilines, 8.57 gram 3-bromo propionyl chloros (under 0 ℃, with the interpolation of 0.3 hour time), 6.5 gram diisopropylethylamine and 150 milliliters of methylene dichloride were kept 48 hours down at 20-25 ℃.To wherein adding entry (300 milliliters) and using the dichloromethane extraction mixture.Collection dichloromethane extract, water (2 * 20 milliliters) wash and use dried over sodium sulfate.Except that need not further purification, can directly use the crude product that obtains after desolvating (14.7 gram).This crude product material sample (14.79 gram) shows that M+/z is 292.
Embodiment 9
4-[3-(2-oxo-2,3-dihydro-benzoglyoxaline-1-yl) propyl group] piperazine-1-carboxylic acid tert-butyl ester
With 5.0 gram 1-tert-butoxycarbonyl piperazines, 6.26 gram 1-(3-chloropropyl)-2,3-dihydro-1H-benzimidazolyl-2 radicals-ketone (can buy from Janssen company) and the mixture of 4.16 gram diisopropylethylamine 150 milliliters of ethanol kept 12 hours down at 80 ℃.After mixture is cooled to room temperature, to wherein adding 100 ml waters and using the chloroform extraction mixture.Collect chloroform extract, wash and use dried over sodium sulfate with 20 ml waters.Except that after desolvating, obtain 10 gram yellow oil products, this product need not further purification and promptly can be used for embodiment 10.
Embodiment 10
1-[4-(3-piperazine-1-yl) propyl group]-2,3-dihydro-1H-benzimidazolyl-2 radicals-ketone
Will be in 2 ml methanol hydrochloric acid with 0.43 gram 1-[4-(3-(tert-butoxycarbonyl) piperazine-1-yl) propyl group]-2, the saturated solution of 3-dihydro-1h-benzimidazolyl-2 radicals-ketone kept 1 hour down at 50 ℃.After being cooled to room temperature, remove and desolvate, the gained residue is suspended in 10 ml waters and with ammonium hydroxide aqueous solution and makes it be alkalescence.Use the chloroform extraction waterbearing stratum.Collect chloroform extract, wash and use dried over sodium sulfate with 20 ml waters.Except that after desolvating, obtain 0.207 gram yellow oil product, this product need not further purification and promptly can be used for embodiment 11.
Embodiment 11
1-{3-[4-(5-trifluoromethyl-pyridine-2-yl) piperazine-1-yl] propyl group }-1,3-dihydro-benzimidazolyl-2 radicals-ketone
With 0.054 gram 2-chlorine 5-5-flumethiazine, 0.115 gram 1-[4-(3-piperazine-1-yl) propyl group]-2, the mixture of 3-dihydro-1H-benzimidazolyl-2 radicals-ketone and 0.194 gram diisopropylethylamine in 1-Methyl-2-Pyrrolidone kept 3 hours down at 150 ℃.After mixture is cooled to room temperature, also use the mixture of concentrated hydrochloric acid acidifying gained to wherein adding 10 ml waters, with 2 * 5 milliliters of ether extraction.Then, the waterbearing stratum neutralizes with ammonium hydroxide aqueous solution and uses ethyl acetate extraction.Collect ethyl acetate extract, wash and use dried over sodium sulfate with 20 ml waters.Remove the crude product (0.085 gram) that obtains after desolvating and use chromatographic purification: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 2% methyl alcohol.Alcohol suspension by handling gained material sample after the above-mentioned purification (0.015 gram) with ether/hydrochloric acid mixture is to convert it into hydrochloride (fusing point: 183 ℃).The M+/z of this sample is 406.
Embodiment 12
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline
5.0 gram (3-[4-4-fluorophenyl) piperazine-1-yls that will be in 20 ml acetic anhydride] propyl group }-(4-fluorine, 2-aminophenyl) amine and 100 milliliters of pyridines refluxed 12 hours.Remove and to desolvate, make residue be alkalescence and use dichloromethane extraction with sodium hydroxide.Collection dichloromethane layer, water (2 * 20 milliliters) wash and use dried over sodium sulfate.Remove the crude product chromatographic purification that obtains after desolvating: solid phase (SiO
240 μ m; Baker); Elutriant is the chloroformic solution of 0.5-2% methyl alcohol.Alcohol suspension by handling gained material sample after the above-mentioned purification with ether/hydrochloric acid mixture is to convert it into hydrochloride.The fusing point of this salt is 238-240, and M+/z is 371.
Embodiment 13
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-2-Trifluoromethyl-1 H-benzoglyoxaline
A.3-(2-amino-4-fluorophenyl amino) third-1-alcohol
Be suspended in the mixtures of palladium on pure and mild 4.0 grams of 9.12 gram 3-(2-nitro-4-fluorophenyl amino)-third-1-10% carbon in 300 ml methanol and at room temperature, (40 pounds/square inch) shook 12 hours under nitrogen atmosphere.Then, with removing by filter insolubles, reaction mixture is condensed into Vandyke brown oil (5.25 gram 3-(2-amino-4-fluorophenyl amino)-third-1-alcohol crude product).
B.1-(3-hydroxypropyl)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline
With 5.1 gram 3-(2-amino-4-fluorophenyl the amino)-mixture reflux of third-1-alcohol in 50 milliliters of trifluoroacetic anhydrides (TFAA) 5 hours.Remove excessive TFAA and residue is dissolved in 500 milliliters of ethyl acetate.Collect ethyl acetate layer and wash secondaries with 100 milliliters of sodium hydroxide.Water layer is with 3 * 200 milliliters of ethyl acetate extraction.The combined ethyl acetate layer is also used dried over sodium sulfate.The residue that removes the back gained that desolvates is with the flash chromatography (solid phase: SiO2 of purifying; Elutriant: begin to use hexane, then use 1: 1 mixture of ethyl acetate/hexane to carry out gradient elution).Obtain solid matter by 1-(3-hydroxyl-propyl group)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline is formed.
C.1-(3-mesyloxy propyl group)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline
In the mixture of refrigerative (25 ℃), 1-(3-the hydroxypropyl)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline (2.09 gram), triethylamine (2.22 milliliters) and the methylene dichloride (12 milliliters) that are stirring, drip the solution of methylsulfonic acid acid anhydride (2.78 restrain) in 14 milliliters of methylene dichloride.After adding, to room temperature, water (2 * 20 milliliters) extracts, is condensed into thick brown oil { the methyl sulphonyl ester crude product of above-mentioned 1-(3-hydroxypropyl)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline } with dried over sodium sulfate and with it with mixture heating up.
D.5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-2-Trifluoromethyl-1 H-benzoglyoxaline
Be dissolved in the mixture of methyl sulphonyl ester crude product, triethylamine (2.2 milliliters) and the 4-fluorophenyl piperazine of above-mentioned 1-(3-hydroxypropyl)-2-trifluoromethyl-5-fluoro-1H-benzoglyoxaline (2.87 gram) in 14 milliliters of ethanol and reflux 12 hours.To be dissolved in the ethyl acetate and water (2 * 10 milliliters) washing except that the residue that obtains after desolvating.Concentrate ethyl acetate layer and isolate product (solid phase: SiO with flash chromatography
2Elutriant: begin to use hexane, then use 1: 1 mixture of ethyl acetate/hexane to carry out gradient elution).Obtain by 5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group-solid matter (M+/z is 424) that 2-Trifluoromethyl-1 H-benzoglyoxaline is formed.
Embodiment 14
5-fluoro-1-{3-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-yl] propyl group }-2-Trifluoromethyl-1 H-benzoglyoxaline
Add a small amount of zinc powder in the mixture of 11.5 gram 3-(2-nitro-4-fluorophenyl amino) third-1-alcohol in being in backflow, stirring, 200 milliliters of acetate and 15.1 ml acetic anhydride until observing reaction mixture no longer decolour (about 4 hours).Solids removed by filtration is concentrated into black oil with the acetate washing with the acetate layer that merges.The oily residue is dissolved in the ethyl acetate and washs with 2 * 50 ml waters.Collected organic layer, remove desolvate, residue handles until intermediate product 1-(3-ethoxycarbonyl propyl)-2-methyl-5-fluoro-1H-benzoglyoxaline complete hydrolysis with the mixture (about 150 milliliters) of 1N sodium hydroxide (150 milliliters)/diox.Then, mixture is condensed into Vandyke brown oil.This oily product is with the flash chromatography (solid phase: SiO of purifying
2Elutriant: begin to use hexane, then use 1: 1 mixture of ethyl acetate/hexane to carry out gradient elution).What obtain is 4.67 gram 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H-benzoglyoxalines (M+/z is 421).
Embodiment 15
1-(3-sulfonyloxy methyl oxygen base propyl group)-2-methyl-5-fluoro-1H-benzoglyoxaline
In being in stirring, refrigerative (25 ℃) 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H benzoglyoxaline (1.99 gram), triethylamine (1.47 milliliters) and at 15 milliliters of CH
2Cl
2In the mixture of methylene dichloride (40 milliliters) in drip the methylsulfonic acid acid anhydride at 15 milliliters of CH
2Cl
2In solution.After adding, with mixture heating up to room temperature, water (2 * 20 milliliters) extract, with dried over sodium sulfate and be condensed into thick brown oil by 1-(3-sulfonyloxy methyl oxygen base propyl group)-the 2-methyl-5-fluoro-1H-benzoglyoxaline crude product is formed.
Embodiment 16
5-fluoro-1-{3-[4-(tert-butoxycarbonyl) piperazine-1-yl] propyl group }-2-methyl isophthalic acid H-benzoglyoxaline
In being in stirring, drip the solution of methylsulfonyl chloride (0.24 milliliter) in 1.5 milliliters of methylene dichloride in the mixture of refrigerative (25 ℃) 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H benzoglyoxaline (0.6 gram), triethylamine (0.44 milliliter) and methylene dichloride (10 milliliters).After adding, with mixture heating up to room temperature, water (2 * 20 milliliters) extract, with dried over sodium sulfate and be condensed into thick brown oil by 1-(3-sulfonyloxy methyl oxygen base propyl group)-the 2-methyl-5-fluoro-1H-benzoglyoxaline crude product is formed.Be dissolved in this sulfonyloxy methyl ester and tertiary butyl piperazine carboxylic acid ester (0.7 gram) mixture in 5 milliliters of ethanol and reflux 12 hours.Then, remove and desolvate, be dissolved in residue in the ethyl acetate and water (10 milliliters) washing.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: begin to use hexane, then use 1: 1 mixture of ethyl acetate/hexane to carry out gradient elution) separated product.Obtain by 5-fluoro-1-{3-[4-(tert-butoxycarbonyl) piperazine-1-yl] propyl group }-solid matter that 2-methyl isophthalic acid H-benzoglyoxaline is formed.
Embodiment 17
1-{3-[4-(6-chloro-pyridazine-3-yl) piperazine-1-yl] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline
Be dissolved in the mixture of 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H-benzoglyoxaline (according to method recited above, from 0.68 gram 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H-benzoglyoxaline preparation), 0.68 milliliter of triethylamine and 0.97 gram 4-(6-chloro-pyrazine-3-yl) piperazine 1.4 milliliters of ethanol and reflux 12 hours.Remove and desolvate, be dissolved in residue in the ethyl acetate and water (2 * 10 milliliters) washing.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: begin to use hexane, then use 8: 1 mixture of ethyl acetate/hexane to carry out gradient elution) separated product.Obtain piperazine-1-yl by 1-{3-[4-(6-chloro-pyrazine-3-yl)] propyl group }-5-fluoro-2-methyl isophthalic acid H-benzoglyoxaline (M+/z is 388).
Embodiment 18
3-[3-(5-fluoro-2-methyl-benzoglyoxaline-1-yl) propyl group]-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline also
A.2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline also
Bromo acetyl bromide (1.46 milliliters) added lentamente be in 1,2,3 of stirring, in the mixture of 4-tetrahydroquinoline-2-carboxylate methyl ester (3.2 gram), triethylamine (2.9 milliliters) and 120 milliliters of tetrahydrofuran (THF)s.React after 1 hour, with removing by filter precipitation and filtrate being condensed into dark oil.Be dissolved in described oil in 120 milliliters of ethanol and adding benzene methanamine (3.7 milliliters) afterwards, reflux 18 hours.Then, except that desolvating and residue being distributed between ethyl acetate (200 milliliters) and water (200 milliliters).Ethyl acetate layer water (2 * 20 milliliters), salt solution (1 * 50 milliliter) wash and use dried over mgso.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: begin with 25% ethyl acetate in hexane, then use the mixture of 50% ethyl acetate/hexane to carry out gradient elution) separated product.Obtain 1.9 gram orange solids, this solid is by N-benzyl glycine and 1,2,3, and the Diketopiperazine derivative of 4-tetrahydroquinoline-2-carboxylic acid is formed.(C
19H
18N
2O
2-experimental value: C, 74.45%; H, 5.99%; N, 9.23%)
B.3-[3-(5-fluoro-2-methyl-benzoglyoxaline-1-yl) propyl group]-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline also
With above-mentioned diketopiperazine (C
19H
18N
2O
2) (1.0 gram) solution in 20 milliliters of tetrahydrofuran (THF)s adds in the slurries of 0.225 milligram of lithium aluminum hydride in 25 milliliters of THF lentamente.After adding, under nitrogen atmosphere, mixture was refluxed 12 hours.Make the temperature of mixture reach room temperature, poly-cold and pass through Celite with aqueous sodium persulfate solution
Filter, concentrated filtrate is also used flash chromatography separated product, solid phase: SiO
2, elutriant: the ethyl acetate in 10% hexane.Obtain light orange oil (0.56 gram), this oil is by 3-benzyl-2,3,4,4a, and 5,6-six hydrogen-1H-pyrazine also [1,2-a] quinoline (M+279) is formed.At room temperature, under 50 pounds of/square inch hydrogen atmospheres, under the condition that palladium on 200 milligrams of carbon exists, place 22 milliliters of 2% acetate/methyl alcohol to shake 7 hours this product.Filter (Celite
) remove insolubles, concentrated filtrate also distributes residue between ethyl acetate and 1N sodium hydroxide.Ethyl acetate layer water and salt solution (respectively being 2 * 10 milliliters) washing, also concentrated with dried over sodium sulfate.Obtain 0.134 gram 2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline (M+189) also.
Embodiment 19
3-[3-(5-fluoro-2-methyl-benzoglyoxaline-1-yl) propyl group]-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline also
With 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H-benzoglyoxaline (according to method recited above, from the preparation of 0.72 mmole 1-(3-hydroxypropyl)-2-methyl-5-fluoro-1H-benzoglyoxaline) thick methylsulfonyl ester, triethylamine (0.2 milliliter) and 2,3,4,4a, 5, the 6-six hydrogen-1H-pyrazine also mixture of [1,2-a] quinoline (0.1 gram) is dissolved in 10 milliliters of ethanol/tetrahydrofuran (THF)s (1/1) and reflux 12 hours.Then, remove and desolvate, residue is dissolved in the ethyl acetate, ethyl acetate layer water (2 * 10 milliliters) washing.Concentrate ethyl acetate layer and use the high pressure lipuid chromatography (HPLC) separated product, wherein use Waters C18 Bondapak125A post as stationary phase; Elutriant: 70% methanol, flow velocity 10 ml/min.Obtain 3-[3-(5-fluoro-2-methyl-benzoglyoxaline-1-yl) propyl group]-2,3,4,4a, 5,6-six hydrogen-1H-pyrazine is [1,2-a] quinoline (62 milligrams) also.By handling the solution of above-mentioned gained material in methylene dichloride with methylsulfonic acid so that above-mentioned products therefrom changes into mesylate.C
23H
27FN
4* CH
3O
3S-experimental value: C, 5645%; H, 6.91%; N, 10.97%.
Embodiment 20
1-(5-fluoro-2-methyl-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol
A.1-(4-fluoro-2-nitro-phenyl amino)-3-[4-(4-fluorophenyl) piperazine] propan-2-ol
Under 80 ℃, 2.84 gram 1-(4-fluorophenyl)-4-oxiranylmethyl radical piperazines, 2.6 milliliters of benzene methanamines and 25 milliliters of alcoholic acid mixtures were stirred 6 hours.Add mixture in 25 milliliters of ice-cold aqueous sodium hydroxide solutions and use dichloromethane extraction.Collect dichloromethane extract, wash and use dried over sodium sulfate with 20 ml waters.Removing the crude product (4.18 gram) of the gained that desolvates can purify with flash chromatography: solid phase (SiO
240 μ m; Baker); Elutriant: the dichloromethane solution of 5% methyl alcohol.In the presence of palladium (3.2 gram) on ammonium formiate (3.9 gram) and the carbon, make its debenzylation by the methanol solution (100 milliliters) that stirs above-mentioned gained material (3.23 gram).Remove insoluble substance to isolate corresponding primary amines by filtering (diatomite).Gained be-kind of oil curable after placement.Thick intermediate product sample (1.17 gram) is dissolved in 50 milliliters of toluene, and 2, there are heating down 18 hours in 4-two fluoro-oil of mirbane (0.5 gram) and salt of wormwood (0.7 gram).The residue that removes the back gained that desolvates distributes between ethyl acetate (30 milliliters) and water (10 milliliters).Ethyl acetate layer water and salt solution (respectively being 2 * 5 milliliters) wash and use anhydrous magnesium sulfate drying.Concentrate ethyl acetate layer, residue flash chromatography (solid phase: SiO2; Elutriant is an ethyl acetate) purifying obtains intermediate product (1-(4-fluoro-2-nitro-phenyl amino)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol).
B.1-(5-fluoro-2-methyl-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol
With 3 hour time, to 1-(4-fluoro-2-nitro-phenyl amino)-3-[4-(4-fluorophenyl) piperazine-1-yl of heating] propan-2-ol (0.73 gram) containing in the solution in the acetate (20 milliliters) of diacetyl oxide (0.4 milliliter) and adding a small amount of zinc powder (1.26 gram).Then, make the temperature of mixture reach room temperature, filter (Celite
) remove insolubles and concentrated filtrate.Enriched material is distributed between ethyl acetate (50 milliliters) and sodium bicarbonate aqueous solution (30 milliliters).Ethyl acetate layer water and salt solution (respectively being 2 * 10 milliliters) are also used dried over mgso.Use the flash column chromatography separated product, solid phase: SiO
2(40 μ m, Baker); Elutriant: use hexane earlier, then use the hexane solution of 50% ethyl acetate.Obtain two kinds of products: (1) 1-(5-fluoro-2-methyl-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl] propan-2-ol and (2) acetate 2-(5-fluoro-2-methyl-benzoglyoxaline-1-yl)-1-[4-(4-fluorophenyl) piperazine-1-ylmethyl] ethyl ester.Fusing point: 108-110 ℃.
Embodiment 21
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-methoxy-propyl }-2-methyl isophthalic acid H-benzoglyoxaline
Under nitrogen atmosphere, with 1-(5-fluoro-2-methyl-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl] mixture of propan-2-ol (0.063 gram), the sodium hydride in 10 milliliters of tetrahydrofuran (THF)s (0.015 gram) stirred 20 minutes, during add methyl-iodide (0.18 milliliter).After 12 hours, remove and desolvate, residue is distributed between ethyl acetate (20 milliliters) and water (10 milliliters).Ethyl acetate layer is used dried over sodium sulfate with salt solution (2 * 2 milliliters) washing.Except that after desolvating, use the flash column chromatography separated product; Solid phase: SiO
2Elutriant: use 2% alcoholic acid dichloromethane solution earlier, then use 5% alcoholic acid dichloromethane solution to carry out gradient elution, obtain buttery 5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-methoxy-propyl }-2-methyl isophthalic acid H-benzoglyoxaline.Can handle the ethereal solution of above-mentioned product to convert it into maleate, collecting precipitation with toxilic acid.Fusing point: 70-77 ℃.
Embodiment 22
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-methyl-propyl }-2-methyl isophthalic acid H-benzoglyoxaline
A.3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-third-1-alcohol
2,4-two fluoro-oil of mirbane (3.25 gram) and salt of wormwood (2.1 gram) exist down, will be dissolved in 30 milliliters of 3-amino-2-methyl-third-1-alcohol (5.1 gram) heating in the toluene 18 hours.To between ethyl acetate (300 milliliters) and water (100 milliliters), distribute except that the residue that obtains after desolvating.Ethyl acetate layer water and salt solution (respectively being 2 * 50 milliliters) wash, use anhydrous magnesium sulfate drying.Concentrate ethyl acetate layer and use flash chromatography separated product, solid phase: SiO
2Elutriant: use the hexane solution of 10% ethyl acetate earlier, then use the hexane solution of 20% ethyl acetate to carry out gradient elution, obtain 3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-third-1-alcohol (5.62 gram).C
10H
13FN
2O
3-experimental value: C, 52.46%; H, 5.88%; N, 12.41%.
B. methylsulphonic acid 3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-propyl ester
To cold (25 ℃), be in the mixture of 3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-prop-1-alcohol (2.0 gram), the triethylamine (1.82 milliliters) in methylene dichloride (50 milliliters) of stirring and drip the solution of methylsulphonic acid acid anhydride (1.6 gram) in 50 milliliters of methylene dichloride.After adding, mixture heating up to room temperature, water (2 * 20 milliliters) extracted, is condensed into thick brown buttery methylsulphonic acid 3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-propyl ester crude product (2.74 gram) with dried over sodium sulfate and with it.
C. (4-fluoro-2-nitro-phenyl)-3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-methyl-propyl } amine
The mixture of above-mentioned methylsulphonic acid 3-(4-fluoro-2-nitro-phenyl amino)-2-methyl-propyl ester crude product (2.6 gram), triethylamine (2.5 milliliters) and 4-fluorophenyl piperazine (3.7 gram) was dissolved in 100 milliliters of ethanol also reflux 12 hours.To be dissolved in 400 milliliters of ethyl acetate and water (2 * 100 milliliters) washing except that the residue that obtains after desolvating.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: the ethyl acetate solution of 25% hexane) separated product.Obtain orange solids, this solid is made up of (4-fluoro-2-nitro-phenyl)-{ 3-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-propyl } amine.C
20H
24F
2N
4O
2-experimental value: C, 61.37%; H, 6.21%; N, 14.51%.
D.5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl]-the 2-methyl-propyl }-2-methyl isophthalic acid H-benzoglyoxaline
Add a spot of zinc powder (27 restrain) till observing reaction mixture and no longer decolouring (about 4 hours) to the mixture of 15 grams (4-fluoro-2-nitro-phenyl) that are in heating, reflux and stir-{ 3-[4-(4-fluorophenyl) piperazine-1-yl]-2-methyl-propyl } amine, acetate (45 milliliters) and diacetyl oxide (0.59 milliliter).Then, solids removed by filtration is condensed into black oil with acetate washing insolubles and with the acetate layer of collecting.This buttery residue is dissolved in the ethyl acetate (100 milliliters) and washs with 2 * 20 ml waters.Ethyl acetate layer is with dried over sodium sulfate and be condensed into Vandyke brown oil.With flash chromatography (solid phase: SiO
2Elutriant: use the hexane solution of 25% ethyl acetate earlier, then use the hexane solution of 75% ethyl acetate to carry out gradient elution) separated product.Obtain 20 gram 5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yls]-the 2-methyl-propyl }-2-methyl isophthalic acid H-benzoglyoxaline solid.The solid of above-mentioned gained can be changed into metilsulfate by ethanolic soln with methylsulphonic acid acid treatment free alkali.Concentrate this solution, develop residue and collect solid with ether.Fusing point 84-91 ℃.
Embodiment 23
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-2-methyl isophthalic acid H-benzoglyoxaline
A.2-[4-(4-fluorophenyl) piperazine-1-yl] third-1-alcohol
With methylsulphonic acid 2-[(4-fluorophenyl)-(2-sulfonyloxy methyl oxygen base ethyl) amino] ethyl ester (on the spot from 9.1 gram methylsulphonic acid acid anhydrides preparations), 6.92 gram 2-[(4-fluorophenyls)-(2-hydroxyethyl) amino] the mixture reflux 5 hours of ethanol and 12.1 milliliters of triethylamines and 50 milliliters of methylene dichloride and the amino 1-propyl alcohol of 5.22 gram (R) (-) 2-20 milliliters of ethanol.To be dissolved in the ethyl acetate (100 milliliters) except that the residue of the back gained that desolvates and water (2 * 20 milliliters) washing.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: ethyl acetate) separated product.Obtain by 2-[4-(4-fluorophenyl) piperazine-1-yl] the pure solid product of forming of third-1-(3.3 gram).
B.3-[4-(4-fluorophenyl) piperazine-1-yl] butyronitrile
Under-15 ℃, to 2-[4-(4-fluorophenyl) piperazine-1-yl] add the solution of 1.86 gram methylsulphonic acid acid anhydrides in 5 milliliters of chloroforms in the mixture of third-1-alcohol (1.7 gram) and the 4-methylmorpholine (1.18 milliliters) in 6 milliliters of chloroforms.After 30 minutes, make temperature of reaction reach room temperature and to wherein adding cyaniding tertiary butyl ammonium (9.6 gram).After 12 hours, except that desolvating and residue being distributed between ethyl acetate and water.Ethyl acetate layer water (4 * 20 milliliters), salt solution (2 * 10 milliliters) washing are carried out drying with sodium sulfate.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: the separated product hexane solution of 30% ethyl acetate).Obtain by 3-[4-(4-fluorophenyl) piperazine-1-yl] oily mater formed of butyronitrile (1.2 gram).
C. (4-fluoro-2-nitro-phenyl)-and 3-[4-(4-fluorophenyl) piperazine-1-yl] butyl } amine
3-[4-(4-fluorophenyl) piperazine-1-yl] butylamine.With 3-[4-(4-fluorophenyl) piperazine-1-yl] butyronitrile (0.84 gram), 0.811 gram cobalt chloride (CoCl
2, 0.811 gram) and the mixture stirring of the sodium borohydride in 35 ml methanol (1.29 grams added lentamente with 2 hours) 12 hours.Remove by filter insolubles, concentrated filtrate also distributes residue between ethyl acetate and 1N sodium hydroxide.Ethyl acetate layer water (4 * 20 milliliters), salt solution (2 * 10 milliliters) washing are carried out drying with sodium sulfate.Concentrate ethyl acetate layer and with gained by 3-[4-(4-fluorophenyl) piperazine-1-yl] crude product formed of butylamine is directly used in next step reaction.
2,4-two fluoro-oil of mirbane (0.49 gram) and salt of wormwood (0.43 gram) exist down, will be dissolved in 30 milliliters of 3-[4-(4-fluorophenyl) piperazine-1-yls in the toluene] butylamine (0.65 gram) heated 18 hours.To between ethyl acetate (100 milliliters) and water (50 milliliters), distribute except that the residue of the back gained that desolvates.Anhydrous magnesium sulfate drying is used in ethyl acetate layer water and salt solution (respectively being 2 * 25 milliliters) washing.Concentrate ethyl acetate layer and use flash chromatography (solid phase: SiO
2Elutriant: the hexane solution that uses 10% ethyl acetate earlier, then use the hexane solution of 20% ethyl acetate to carry out gradient elution) separated product, obtain orange red solid (4-fluoro-2-nitro-phenyl)-{ 3-[4-(4-fluorophenyl) piperazine-1-yl] butyl } amine.
D.5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-2-methyl isophthalic acid H-benzoglyoxaline
In the mixture of (the 4-fluoro-2-nitro-phenyl) that be in backflow, stir-{ 3-[4-(4-fluorophenyl) piperazine-1-yl] butyl } amine (0.38 gram), 10 milliliters of acetate, add a spot of zinc powder (excessive) until reaction mixture near colourless (about 4 hours).Remove by filter insolubles, be condensed into black oil with the acetate washing and with the acetate layer of collecting.This black oil is dissolved in the ethyl acetate (50 milliliters) also with 2 * 10 ml waters and salt water washing.Collected organic layer, remove desolvate, residue is with flash chromatography (solid phase: SiO
2Elutriant: use ethyl acetate earlier, then use 8: 2 mixture of ethyl acetate/methanol to carry out gradient elution) purifies.Obtain 0.1 gram 5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-2-methyl isophthalic acid H-benzoglyoxaline.(M+/z385.47)。
Embodiment 24
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone
Use the method described in the reaction scheme 5 to prepare title compound.M+/z386, fusing point: 188-193 ℃.
Claims (16)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein every dotted line is represented the two keys of yes or no;
X is carbon or nitrogen;
R
1Be benzyl, be selected from phenyl, 2, the aryl of 3-indanyl and naphthyl or be selected from the heteroaryl of pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl, wherein above-mentioned each aryl, heteroaryl and (C
1-C
4) phenyl moiety of alkyl and benzyl can be by one or more substituting groups, are preferably by 0 to 2 substituting group to replace or do not replace (the C that described substituting group is selected from halogen (as chlorine, fluorine, bromine or iodine) respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, cyano group ,-C (=O) R
8, aryl and heteroaryl, wherein said aryl is selected from phenyl, 2, and the aryl of 3-indanyl and naphthyl and said heteroaryl are selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
R
2And R
3Be selected from hydrogen, hydroxyl, (C respectively
1-C
6) alkyl, (C
1-C
6) alkoxyl group, cyano group ,-CONH
2With-NHC (=O) R
9, or R
2And R
3Form the oxo base together;
R
4Be hydrogen, sulphur, oxygen, (C
1-C
6) alkyl, amino ,-NHR
10,-SR
10, OR
10Or hydroxyl;
R
5, R
6And R
7(the C that is selected from hydrogen, halogen (as chlorine, fluorine, bromine or iodine), cyano group respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) acyl amino, (phenyl) [(C
1-C
6) acyl group] amino, amino, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, aryl and heteroaryl, wherein said aryl is selected from phenyl, 2, and the aryl of 3-indanyl and naphthyl, said heteroaryl are selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, azoles base, different azoles base, triazolyl, quinolyl and imidazolyl;
R
8, R
9And R
10Be selected from hydrogen and (C respectively
1-C
6) alkyl; With
R
11Be hydrogen, (C
1-C
6) alkyl or benzyl, wherein the phenyl moiety of said benzyl can be by 1 to 3 substituting group, is preferably by 0 to 2 substituting group to replace or do not replace (the C that described substituting group is selected from halogen respectively, is replaced or do not replace by 1 to 3 fluorine atom
1-C
6) the alkyl, (C that replaced or do not replace by 1 to 3 fluorine atom
1-C
6) alkoxyl group, amino, cyano group, (C
1-C
6) alkylamino and two (C
1-C
6) alkylamino;
Each R
15And R
16Be selected from respectively hydrogen, methyl, cyano group ,-(C=O)-NH
2With-CH
2-O-(C
1-C
6) alkyl;
R
17Be hydrogen or, when X is nitrogen, R
17Carbon atom that can be coupled, R according to circumstances
1Form the tetrahydroquinoline ring together with X;
The precondition of above-mentioned definition is: (a) work as R
2, R
3, R
15And R
16When all being hydrogen, R
4Can not be oxygen or hydroxyl; (b) when the five-ring of general formula I contains two key, R
11Do not exist; (c) work as R
4When being sulphur or oxygen, R
4Two bonds are incorporated on the coupled carbon atom and described carbon atom singly-bound is attached on two adjacent theheterocyclic nitrogen atoms; And (d) when X be nitrogen and two bond when being incorporated on the adjacent carbon atom, R
1Do not exist.
2. according to the compound of claim 1, wherein X is a nitrogen.
3. according to the compound of claim 1, wherein X is a carbon.
4. according to the compound of claim 2, R wherein
1Do not exist.
5. according to the compound of claim 1, R wherein
2And R
3All be hydrogen.
6. according to the compound of claim 1, wherein said compound is selected from:
5-fluoro-1-{3-[4-(4-fluorophenyl) piperazine-1-yl] butyl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone;
1-benzoglyoxaline-1-base-3-[4-(4-fluorophenyl) piperazine-1-yl]-propan-2-ol;
1-(5-chloro-benzoglyoxaline-1-yl)-3-[4-(4-fluorophenyl) piperazine-1-yl]-propan-2-ol;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-5-Trifluoromethyl-1 H-benzoglyoxaline;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 1H-benzoglyoxaline;
1-{3-[4-(4-fluorophenyl) piperazine-1-yl] propyl group }-the 3-methyl isophthalic acid, 3-dihydro-benzimidazolyl-2 radicals-ketone;
1-benzoglyoxaline-1-base-3-(4-o-tolyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-(tolyl-piperazine between 4--1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-(4-p-methylphenyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-chloro-phenyl-) phenyl methyl] piperazine-1-yl } propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(4-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-chloro-phenyl-) piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-pyrimidine-2-base-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-naphthalene-1-base-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(3-trifluoromethyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-(4-benzyl-piperazine-1-yl)-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-trifluoromethyl benzyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-[4-(2-ethoxy benzyl)-piperazine-1-yl]-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-[3-(3-trifluoromethyl) propyl group]-piperazine-1-yl }-propan-2-ol;
1-benzoglyoxaline-1-base-3-{4-[2-(3-trifluoromethyl) ethyl]-piperazine-1-yl }-propan-2-ol.
7. pharmaceutical composition, be used for the treatment of or prevent to be selected from following illness: be sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described composition comprise treatment or prevent the compound and the pharmaceutically acceptable carrier of the claim 1 of above-mentioned these illness significant quantities.
8. treatment or prevention are selected from the method for following illness: sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described method comprise treatment or the compound administration of claim 1 of preventing above-mentioned these illness significant quantities in said Mammals.
9. pharmaceutical composition, be used for the treatment of or prevent to be selected from following illness: be sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 of dopaminergic significant quantity.
10. treatment or prevention are selected from the method for following illness: sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described method comprise that compound administration with the claim 1 of dopaminergic significant quantity is in said Mammals.
11. one kind is used for the treatment of or the pharmaceutical composition of preventing disease or illness, said disease and treatment of conditions or prevention can be undertaken or promote that said composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 of dopaminergic significant quantity by the neurotransmission that changes Dopamine HCL mediation in the mammalian body.
12. the method for a treatment or preventing disease or illness, said disease and treatment of conditions or prevention can be undertaken or promote by the neurotransmission that changes Dopamine HCL mediation in the mammalian body, and said method comprises that compound administration with the claim 1 of dopaminergic significant quantity is in said Mammals.
13. pharmaceutical composition, be used for the treatment of or prevent to be selected from following illness: be sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 of D4 receptors bind significant quantity.
14. method for the treatment of or preventing to be selected from following illness: sleep disordered, venereal disease, gastrointestinal illness, psychosis, the emotion psychosis, nonorganic psychosis, character assassin, emotional disorder, behavior and nerve impulse disease, schizophrenia and emotionality Split disease, polydipsia disease, the existing manic alternating insanity that paralepsy is arranged again, dysphoric mania, anxiety disorder and relevant illness thereof, obesity, vomiting, the bacterial infective diseases of CNS, learning disorder, dysmnesia disease, Parkinson's disease, dysthymia disorders, the outer side effect disease of the pyramidal tract that causes by neuroplegic, anti-spiritual medicine malin syndrome, the hypothalamus disease of pituitary gland, congestive heart failure, the pharmaceutical chemicals dependence syndrome, blood vessel and cardiovascular disorder, eye disease, dystonia, tardive dyskinesia, spasmodic tic syndromes and other hyperkinesis, dull-witted, ischemic disorders, Parkinson's disease, cathisophobia and other dyskinesia disease, hypertension and the disease such as mammiferous allergy and the inflammation that are caused by hyperactive immunity system, described method comprise that compound administration with the claim 1 of D4 receptors bind significant quantity is in said Mammals.
15. one kind is used for the treatment of or the pharmaceutical composition of preventing disease or illness, said disease and treatment of conditions or prevention can be undertaken or promote that said composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 of D4 receptors bind significant quantity by the neurotransmission that changes Dopamine HCL mediation in the mammalian body.
16. the method for a treatment or preventing disease or illness, said disease and treatment of conditions or prevention can be undertaken or promote by the neurotransmission that changes Dopamine HCL mediation in the mammalian body, and said method comprises that compound administration with the claim 1 of D4 receptors bind significant quantity is in said Mammals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95194447 CN1154693A (en) | 1994-08-05 | 1995-05-18 | Benzimidazole derivative having dopaminergic activity |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/286,576 | 1994-08-05 | ||
| US08/298,005 | 1994-08-30 | ||
| CN 95194447 CN1154693A (en) | 1994-08-05 | 1995-05-18 | Benzimidazole derivative having dopaminergic activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1154693A true CN1154693A (en) | 1997-07-16 |
Family
ID=5082719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95194447 Pending CN1154693A (en) | 1994-08-05 | 1995-05-18 | Benzimidazole derivative having dopaminergic activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1154693A (en) |
Cited By (6)
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| CN102149688A (en) * | 2008-09-11 | 2011-08-10 | 霍夫曼-拉罗奇有限公司 | New benzimidazole derivatives |
| WO2014079154A1 (en) * | 2012-11-26 | 2014-05-30 | 辽宁贝雷生物制药有限公司 | Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof |
| WO2014079155A1 (en) * | 2012-11-26 | 2014-05-30 | 辽宁贝雷生物制药有限公司 | Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives |
| CN103833642A (en) * | 2012-11-26 | 2014-06-04 | 辽宁贝雷生物制药有限公司 | Application of benzo five-membered nitrogen-containing heterocycle-based piperazine derivative |
| CN103833643A (en) * | 2012-11-26 | 2014-06-04 | 辽宁贝雷生物制药有限公司 | Benzimidazolyl-piperazine compound and preparation method and pharmaceutical composition thereof |
| CN103073460B (en) * | 2004-10-14 | 2015-09-09 | Abbvie德国有限责任两合公司 | Be applicable to treat the aromatic substance that the arylsulfonyl ylmethyl of the disease responded for the adjustment of dopamine D 3 receptor or aryl sulfonic acid amides replace |
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1995
- 1995-05-18 CN CN 95194447 patent/CN1154693A/en active Pending
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| CN103073460B (en) * | 2004-10-14 | 2015-09-09 | Abbvie德国有限责任两合公司 | Be applicable to treat the aromatic substance that the arylsulfonyl ylmethyl of the disease responded for the adjustment of dopamine D 3 receptor or aryl sulfonic acid amides replace |
| CN102149688A (en) * | 2008-09-11 | 2011-08-10 | 霍夫曼-拉罗奇有限公司 | New benzimidazole derivatives |
| WO2014079154A1 (en) * | 2012-11-26 | 2014-05-30 | 辽宁贝雷生物制药有限公司 | Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof |
| WO2014079155A1 (en) * | 2012-11-26 | 2014-05-30 | 辽宁贝雷生物制药有限公司 | Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives |
| CN103833642A (en) * | 2012-11-26 | 2014-06-04 | 辽宁贝雷生物制药有限公司 | Application of benzo five-membered nitrogen-containing heterocycle-based piperazine derivative |
| CN103833643A (en) * | 2012-11-26 | 2014-06-04 | 辽宁贝雷生物制药有限公司 | Benzimidazolyl-piperazine compound and preparation method and pharmaceutical composition thereof |
| US9415047B2 (en) | 2012-11-26 | 2016-08-16 | Liaoning Emmy Biological Pharmaceutical Co., Ltd. | Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives |
| CN106699670A (en) * | 2012-11-26 | 2017-05-24 | 辽宁艾美生物医药产业有限公司 | Benzimidazolyl piperazine compounds, preparation method thereof and pharmaceutical composition |
| US9802929B2 (en) | 2012-11-26 | 2017-10-31 | Shenyang Haiwang Biotechnology Co., Ltd. | Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof |
| CN103833643B (en) * | 2012-11-26 | 2018-01-02 | 沈阳海王生物技术有限公司 | Benzimidazolyl piperazine compounds and its preparation method and pharmaceutical composition |
| CN106699670B (en) * | 2012-11-26 | 2019-11-19 | 沈阳海王生物技术有限公司 | Benzimidazolyl piperazine compounds and its preparation method and pharmaceutical composition |
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