CN107793362A - A kind of synthesis and its application of Phenylpyridazinones analog derivative - Google Patents
A kind of synthesis and its application of Phenylpyridazinones analog derivative Download PDFInfo
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- CN107793362A CN107793362A CN201610788072.6A CN201610788072A CN107793362A CN 107793362 A CN107793362 A CN 107793362A CN 201610788072 A CN201610788072 A CN 201610788072A CN 107793362 A CN107793362 A CN 107793362A
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- bases
- propoxyl group
- dichlorophenyls
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- piperidin
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- 0 **1CCN(*OC(C(*)=C2*)=NN(*)C2=O)CC1 Chemical compound **1CCN(*OC(C(*)=C2*)=NN(*)C2=O)CC1 0.000 description 3
- RBNIFKHHHBGFSB-DLFDIDQLSA-N CC(C)C(/C=C\C(\CO/C=C/CCCBr)=N/Nc(cc1Cl)ccc1Cl)=O Chemical compound CC(C)C(/C=C\C(\CO/C=C/CCCBr)=N/Nc(cc1Cl)ccc1Cl)=O RBNIFKHHHBGFSB-DLFDIDQLSA-N 0.000 description 1
- KLCRFDWEEYSMDI-UHFFFAOYSA-N CC1Sc2ccccc2N1 Chemical compound CC1Sc2ccccc2N1 KLCRFDWEEYSMDI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
- C07D237/16—Two oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
The present invention relates to field of medicaments, in particular it relates to be specifically related to a kind of phenyl pyridazine analog derivative and its application.In particular it relates to the purposes of Phenylpyridazinones analog derivative, the pharmaceutical composition comprising the Phenylpyridazinones analog derivative and said composition and the Pyridazinones Derivatives in prevention or treatment Mental disease is prepared.Pyridazinones Derivatives have formula (I) structure.Found through experiment, such compound can be used for prevention or spiritual neural class disease.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of phenyl pyridazine analog derivative and its treatment spirit nerve
Application in disease.
Background technology
Schizophrenia is a kind of disease characterized by cognitive power and emotional depth divide, and shows as the most basic mankind
Behavior is affected, such as language, thought, consciousness and self perception etc..The scope that the symptom of the disease is included is wider, most often
See for spirit in terms of obstacle, for example hallucinate, paranoea and illusion etc..
Schizophrenia is the mental disease of most serious, and the people that 1% is there are about in global range suffers from schizophrenia, and in institute
Have in patient receiving treatment and only have 5% can finally be returned to one's perfect health.Further, since schizophrenia would generally trigger conjunction
And disease, such as anxiety disorder, depression or mental drug abuse etc., according to a Datamonitor investigation display, exceed
1/3 schizophreniac will perplex by the disease such as at least one or multinomial concurrent mental disease or cognitive disorder.
Traditionally it is accustomed to by blocking the antipsychotics of d2 dopamine receptor performance pharmacological action to call the first generation
Antipsychotics, i.e. " typical case " antipsychotics (such as haloperole), their treatment schizophrenia positive symptoms have prominent
Broken property, but fail to treat negative symptoms and cognitive disorder.Classical antipsychotic thing typically has serious EPS side effects, and
It is invalid to 1/3rd schizophrenia patients.
After the 1960s, and a series of antipsychotic drugs of new generation are developed successively, including Ziprasidone
(Ziprasidone), Risperidone (Risperidone) etc., are referred to as second generation antipsychotics, i.e., new antipsychotic
Medicine, although their own pharmacological action is not quite identical, there is common pharmacology, i.e., to serotonin (5-HT)
The affinity of acceptor (5-HT1A, 2A, 2c) and norepinephrine (NA) acceptor (α 1, α 2) is led more than to the high of D2 acceptors
Cause D2/5-HT2A ratio relatively low.Its clinical effectiveness has more advantages compared with first generation antipsychotics, not only to the positive
Symptom is same with traditional antipsychotics effective, and effective to negative symptoms, cognitive defect symptom, and action spectrum is wider, still
These medicines have QT gap extensions, the adverse reaction such as hyperprolactinemia and increased weight.Therefore finding can be to schizophrenia
Positive, negative symptoms and cognitive disorder are effective, and the medicine of Small side effects is the focus studied now.
Aripiprazole is a kind of benzene fourth prazosin class compound, has obtained FDA approval listings in November, 2002.The medical instrument has solely
Special mechanism of action, with dopamine D2、D3、5-HT1AAnd 5-HT2AAcceptor has very high affinity, with D4、5-HT2c、5-HT7、α1、
H1Acceptor and 5-HT reabsorptions site have moderate affinity.Aripiprazole is by the partial agonist to D2 and 5-HT1A acceptors
Act on and to 5-HT2AThe antagonism of acceptor produces antipsychotic, has the function that to stablize dopamine system activity.Face
Bed experimental study shows that Aripiprazole is positive to schizophrenia and negative symptoms is all effective, and prolonged application can also reduce spirit
The recurrence rate of Split disease, improve mood and cognition dysfunction.Its EPS adverse reaction and the effect for raising Serum Prolactin Level
It is all smaller than traditional antipsychotics or foregoing atypical antipsychotic agents.
Serotonin system plays an important role in the function of the prefrontal cortex (PFC) of regulation, including emotion control,
Cognitive behavior and working memory.PFC cone neurone and GABA intrerneurons, which contains, several has special high density hydroxyl
Tryptamines receptor subtype 5-HT1AAnd 5-HT2A.It is 5-HT to be proven PFC and nmda receptor channel recently1AR target, the two
Regulation cerebral cortex excitatory neuron, so as to influence cognitive function.In fact, various preclinical datas show 5-HT1AR
It is probably the fresh target of antipsychotic drug development medicine.Atypia anti-semen antibody (such as olanzapine, aripiprazole
Deng) to 5-HT1AR high-affinity and its low EPS side effects illustrate prefrontal cortex of the serotonin system in regulation
(PFC) played an important role in function, including emotion control, cognitive behavior and working memory.PFC cone neurone and
GABA intrerneurons, which contain, several has special high density 5-hydroxytryptamine receptor hypotype 5-HT1AAnd 5-HT2A.Research recently
Show 5-HT1AActivator is related to atypical antipsychotic treatment, can improve negative symptoms and cognitive disorder.It is non-in application
In classical antipsychotic thing Clozapine in Treating schizophrenia, it has been found that 5-HT2ACritically important effect is played wherein, is related to
And the various aspects to perception, mood regulation and motion control.Block 5-HT2AAcceptor can make the release normalization of dopamine,
And play antipsycholic action.In addition, 5-HT2CAcceptor is closely related with increased weight.
D3Acceptor is distributed in limbic system in the distribution situation substantial selectivity of intracerebral, and intracerebral has two main DA nerves logical
Road, one is nigro-striatal pathway regulation and control motor function, and another is Ventral Midbrain tegmental region nucleus accumbens septi prefrontal cortex DA
Path and learning cognition and affective activity are closely related, and its dysfunction will cause schizophrenia, and the DA paths are also intracerebral
The major avenues of approach of rewarding effect (reward efects), D3R is distributed in two DA nerve pathways, and with other DA by
There is complexity between body hypotype to interact, possibly as a target of antipsychotic medications, selective d3Acceptor
Antagonism can reduce schizoid passive and cognition symptom, and this external enwergy prevents extrapyramidal side effect, including Delayed onset
Dyskinesia, Parkinson's.Therefore, the antipsychotic drug of a polyceptor combination Small side effects is found to clinical treatment
It is significant.
The content of the invention:
It is contemplated that at least solves one of technical problem present in prior art.Therefore, one object of the present invention
It is to propose that one kind can be used in treating schizoid noval chemical compound.
On the one hand, the present invention provides a kind of compound, and it is the pharmacy of compound shown in compound shown in Formulas I or Formulas I
Upper acceptable salt or its prodrug,
Wherein:
Z is substituted or unsubstituted-(CH2)n-, n is 1~6 integer, and the substituent is in hydroxyl or methyl, or Z
Carbochain on contain double bond or oxygen atom;
Q is N or CH;
R1For hydrogen, halogen, C1-5Alkoxy, substituted or unsubstituted C1-5One or more in alkyl;R2For hydrogen, C1-5Alkane
Epoxide, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted aryl, wherein institute
One or more of the substituent stated in alkyl, cyano group, hydroxyl or halogen;Or R1And R2Formed together with coupled carbon
The cyclic alkyl or phenyl of five~heptatomic ring;
R3For hydrogen, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted virtue
Base, wherein one or more of the described substituent in alkyl, cyano group, hydroxyl or halogen;
R4For substitution or unsubstituted phenyl, Formula II compound, formula III compound, formula IV compound or Formula V compound, institute
Substituent is stated as halogen, cyano group, substituted or unsubstituted C1-5Alkyl, formamide or hydroxyl;
Wherein, in Formula II, Y is N or CH, X are O or S;R5For H, halogen or formamide.
In Formulas I, the Z is substituted or unsubstituted-(CH2)n-, n is 1~4 integer, and the substituent is hydroxyl, carbonyl
One or more in base and methyl.
In Formulas I, the halogen is fluorine, chlorine, bromine, iodine.
In Formulas I, described R4For Formula II compound, X O, Y CH, NH, R5Selected from hydrogen, fluorine, chlorine, bromine, iodine or formamide;
X is S, Y CH, NH, R5For hydrogen;R4For substituted phenyl, described substituent is selected from methoxyl group, trifluoromethyl, methyl, ethyl
One or more in fluorine, chlorine, bromine, iodine, cyano group.
In Formulas I, the R1、R2、R3It is separately hydrogen, phenyl, halogenophenyl, C1-5The C of alkyl, halo1-5Alkyl or
C1-5Hydroxyalkyl or R1And R2The cyclic alkyl or phenyl of five~heptatomic ring are formed together with coupled carbon;Further, it is described
R1、R2、R3It is separately hydrogen, fluorine, phenyl, methyl, ethyl, propyl group, trifluoromethyl or methylol or R1And R2Together with
Its carbon that is connected forms hexamethylene or phenyl.
Compound of the present invention is at least one of following compounds, or at least one of described following compounds
Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or it before
Medicine:
2- (3,4- dichlorophenyls) -6- (3- (4- (4- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -
Ketone;
2- (3,4- dichlorophenyls) -6- (3- (4- (2- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -
Ketone;
2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -
Ketone;
2- (3,4- dichlorophenyls) -6- (3- (4- (pyridine -2- bases) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (base of pyrimidine -2) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;
6- (3- (4- (2- chlorphenyls) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -
Ketone;
2- (3,4- dichlorophenyls) -6- (3- (4- (4- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (2- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (3- trifluoromethyls) phenyl) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one;
4- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) propyl group) piperazine -1-
Base) cyanophenyl;
6- (3- (4- benzyl diethylenediamine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (4- fluoro benzoyls) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -
Ketone;
6- (3- (4- (benzo [b] thiene-3-yl) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3
(2H) -one;
3- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) propyl group) piperazine -1-
Base) benzofuran -5- formamides;
6- (3- (4- (1H- indyl -3- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -
Ketone;
6- (3- (4- (benzo [d] isothiazolyl -3- bases) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -
3 (2H) -one;
6- (3- (4- (benzo [d] thiazolyl -2- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3
(2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) rattle away
Piperazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butoxy) rattle away
Piperazine -3 (2H) -one;
6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butoxy) -2- (4- fluorophenyls) pyridazine -3
(2H) -one;
(E) -2- (3,4- dichlorophenyls) -6- ((4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butyl- 2-
Alkene -1- bases) epoxide) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- ((5- (4- ((6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl)) amyl group) oxygen
Base) pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -4,5-
Diformazan radical pyridazine -3 (2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -5,6,
(2H) -one of 7,8- tetrahydrochysene dais piperazine -1;
2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group)-dai
Piperazine -1 (2H) -one;
6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -2- (4- fluorophenyls) pyridazine -3
(2H) -one;
6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- phenyl pyridazine -3 (2H) -
Ketone;
6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (4- aminomethyl phenyls) rattles away
Piperazine -3 (2H) -one;
6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (naphthalene -2- bases) pyridazine -3
(2H) -one;
2- (4- chlorphenyls) -6- (3- (4- (fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3
(2H) -one;
2- (3- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3
(2H) -one;
2- (2- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3
(2H) -one;
2- (2,3- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (2,4 dichloro benzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (2,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (3,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (2,4 difluorobenzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (2,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (2,6- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (3,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3
(2H) -one;
2- (the chloro- 4- fluorophenyls of 3-) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazine -
3 (2H) -one;
6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) pyridazine -3 (2H) -one;
6- (3- (4- (benzo [d] isothiazole -3- bases) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) pyridazine -3 (2H) -
Ketone.
On the other hand, the invention further relates to a kind of pharmaceutical composition, containing any described compound of the present invention, optionally
Further include pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.
On the other hand, purposes of the pharmaceutical composition of the present invention in medicine is prepared, the medicine be used for prevent or
Mental disorder is treated, optionally described mental disorder is schizophrenia.
Embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair
It is bright, and be not considered as limiting the invention.
Definition and general terms
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with
Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》(the 75th edition, 1994) is consistent.In addition, organic chemistry General Principle can join
Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999,
" March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John
Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.According to the present invention
Some embodiments, " patient " refers to people.
The event or situation that term " optional " or " optionally " refer to then describes can with but not necessarily occur, and this is retouched
State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.For example, " optional key " refers to
The key may have or can be not present, and the description includes singly-bound, double or triple bonds.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise
Content.
One or more degrees of unsaturation are contained in term " unsaturation " or " undersaturated " expression part.
As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as
General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or unsubstituted ".In general, art
Language is " substituted " to represent that institute is substituted to one or more of structure hydrogen atom by specific substituent.Unless other aspect tables
Bright, an optional substituted radical can be substituted in each commutable position of group.When in given structural formula not
Only a position can be substituted by one or more substituents selected from specific group, then substituent can with identical or different
Substitute in each position.
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention
" ... separately for " should be interpreted broadly, and it can both refer in different groups, expressed tool between same-sign
Do not influence mutually, can also be represented in identical group between body option, between same-sign expressed specific option it
Between do not influence mutually.
In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special
Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term
“C1-5Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl and C5Alkyl.
Unless explicitly recited, terminology used in the present invention " alkyl " or " alkyl group ", expression contain 1 to 20 carbon original
Son, the straight or branched univalent hydrocarbyl group of saturation, wherein, the alkyl group can be optionally by one or more present invention
The substituent of description is substituted.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.According to one of the present invention
Embodiment, alkyl group contain 1-12 carbon atom;According to another embodiment of the invention, alkyl group contains 1-6 carbon
Atom;According to one embodiment of present invention, alkyl group contains 1-4 carbon atom;According to another embodiment of the invention,
Alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-
CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-
CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-
Bu、-C(CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH
(CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-
1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (-
CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2-
Methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta
Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH
(CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)
C(CH3)3), n-heptyl, n-octyl, etc..
Term " carbonyl ", no matter it is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", table
Show-(C=O)-.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, for example with oxygen atom phase
Even, oh group is formed.
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has
Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.According to the present invention
One embodiment, alkoxy base contains 1-6 carbon atom;According to one embodiment of present invention, alkoxy base contains
1-4 carbon atom;According to one embodiment of present invention, alkoxy base contains 1-3 carbon atom.The alkoxy base is appointed
Selection of land is substituted by the substituent that one or more present invention describe.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-
OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH
(CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen
Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-
BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3)
CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths
Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (-
OCH2CH(CH3)CH2CH3), etc..
Term " ring " includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, etc., wherein the carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring
Group has implication as described in the present invention.
Term " cycloalkyl " represents that containing 3-12 carbon atom monovalent or multivalence saturation is monocyclic, bicyclic or three ring bodies
System.Bicyclic or three-ring system can include condensed ring, bridged ring and loop coil.According to one embodiment of present invention, cycloalkyl includes 3-
10 carbon atoms;According to one embodiment of present invention, cycloalkyl includes 3-8 carbon atom;According to one of present invention implementation
Example, cycloalkyl include 3-6 carbon atom.The example of group of naphthene base include, but not limited to cyclopropyl, cyclobutyl, cyclopenta,
Cyclohexyl, etc..The group of naphthene base is optionally substituted by one or more substituents described in the invention.
Term " aryl " represents to contain 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double
The carbocyclic ring system of ring and three rings, wherein at least one ring are aromatic.Aromatic yl group is usual, but unnecessarily passes through aryl
The armaticity ring of group is connected with parent molecule.The example of aromatic yl group can include phenyl, naphthyl and anthracene.The aromatic yl group
Optionally substituted by one or more substituents described in the invention.
Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo.
Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.On
Being discussed in detail for pro-drug may be referred to documents below:Higuchi et al.,Pro-drugs as Novel Delivery
Systems,Vol.14,A.C.S.Symposium Series;Roche et al.,ed.,Bioreversible Carriers
in Drug Design,American Pharmaceutical Association and Pergamon Press,1987;
Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug
Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and
This is incorporated herein by reference in Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document.
Term " metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism in vivo
Resulting product.The metabolite of one compound can be identified that it is active by technology known to art
Can experimentally it be characterized by adopting as described in the present invention.Such product can be by administrationization
Compound obtains through the methods of peroxidating, reduction, hydrolysis, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc..Phase
Ying Di, the present invention include the metabolite of compound, including when compound of the invention fully to be contacted with mammal to one section
Between caused metabolite.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine
Acceptable salt is known to us in art on, such as document:S.M.Berge et al.,
J.Pharmaceutical Sciences,66:Described in 1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed
Including, but is not limited to, the inorganic acid salt to be formed is reacted with amino group a hydrochloride, hydrobromate, phosphate, sulfate,
Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid
Salt, or these salt are obtained by other method such as ion-exchange described on books document.Other are pharmaceutically acceptable
Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid
Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid
Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid
Salt, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate,
Malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake
Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate,
Undecylate, valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4
Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble or
Dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy
Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation
Thing, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The advantageous effects of the present invention:
The compound provided by the invention affinity stronger to D2,5HT1A and 5HT2A, there is the potential spirit that improves to divide
Disease positive symptom is split, and has potential improvement result to negative symptoms and cognitive disorder;And to 5HT2C, H1 and α 1 affinity
It is low, the advantages of entering without causing increased weight.Zoopery shows that compound of the invention has small extrapyramidal system is secondary to make
With.
General synthetic schemes
The universal synthesis method of the compound of the present invention is first one pyridazinone parent of synthesis, then reacted with halogenated alkane
A carbochain is linked, then reacts and is made with nitrogen end.Such as:
Embodiment
The following examples are for the purpose of description and not as the limitation of the present invention.
A, the embodiment in terms of synthesis
Embodiment 1,2- (3,4- dichlorophenyls) -6- (3- (4- (4- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -
3 (2H) -one
Reaction equation 1
1) take phenylhydrazine hydrochloride 14.5g, maleic anhydride 9.8g to be dissolved in and add 200ml purified waters.Under stirring, 40ml is slowly added to
Concentrated hydrochloric acid, it is heated to reflux, reacts 6 hours after adding.Reaction finishes, and ice-water bath cooling, separates out yellow solid.Filter, filter cake is used
Washing is twice.Take out filter cake saturation NaHCO3Dissolving, filter off insoluble matter, clear liquid with concentrated hydrochloric acid be transferred to pH value to 2~3 it
Between, white solid is separated out, filters and 17.3g, yield 92.0% is obtained after drying.
2) first step product 9.4g, Anhydrous potassium carbonate 13.8g, 1,3- dibromopropane 18.8g are taken, 100ml acetone is added, adds
Hot back flow reaction 4 hours, is cooled to room temperature, filtering, solvent evaporated, give light yellow oil, white solid is obtained through flash chromatography post
10.5g, 77-79 DEG C of fusing point, yield 68.2%.
3) second step product 1.40g, 4- methoxyphenylpiperazderivatives hydrochloride 1.0g, potassium carbonate 2.0g are taken, adds 50ml second
Nitrile, heating reflux reaction 6 hours, it is cooled to room temperature, solvent evaporated, adds q. s. methylene chloride, washing, branch vibration layer, organic layer
Add anhydrous magnesium sulfate to dry, solvent evaporated, obtain yellow oil, pale yellow oil 1.76g, yield are obtained through flash chromatography post
82.5%.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H), 7.52
(d, J=8.7Hz, 1H), 7.06-6.96 (m, 2H), 6.92-6.90 (m, 2H), 6.89-6.82 (m, 2H), 4.27 (t, J=
6.4Hz,2H),3.78(s,3H),3.29–3.09(m,4H),2.77–2.62(m,4H),2.64–2.51(m,2H),2.19–
1.86(m,2H).MS(ESI)m/z 489.2([M+H]+)
Embodiment 2,2- (3,4- dichlorophenyls) -6- (3- (4- (2- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -
3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2- methoxyphenylpiperazderivatives hydrochlorides, are made as described in Example 1
Standby target compound.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.65 (dd, J=8.7,2.5Hz, 1H), 7.51
(d, J=8.7Hz, 1H), 7.06-6.98 (m, 3H), 6.98-6.89 (m, 2H), 6.87 (dd, J=8.1,1.1Hz, 1H), 4.26
(t, J=6.4Hz, 2H), 3.87 (s, 3H), 3.12 (s, 4H), 2.70 (s, 4H), 2.63-2.51 (m, 2H), 2.09-1.94 (m,
2H).MS(ESI)m/z489.1([M+H]+)
Embodiment 3,2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) propoxyl group) rattle away
Piperazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2,3- dimethylphenylpiperaziniums hydrochloride, as described in Example 1
Prepare target compound.
1H NMR(600MHz,CDCl3) δ 7.91 (d, J=2.4Hz, 1H), 7.68 (dd, J=8.7,2.5Hz, 1H), 7.53
(d, J=8.7Hz, 1H), 7.10 (t, J=7.7Hz, 1H), 7.06-6.99 (m, 2H), 6.94 (t, J=8.2Hz, 2H), 4.29
(t, J=6.4Hz, 2H), 2.94 (t, J=4.2Hz, 4H), 2.62 (dd, J=26.6,19.3Hz, 6H), 2.29 (s, 3H),
2.25(s,3H),2.14–1.99(m,2H).MS(ESI)m/z487.3([M+H]+)
Embodiment 4,2- (3,4- dichlorophenyls) -6- (3- (4- (pyridine -2- bases) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2- Pyridylpiperazines, prepare target chemical combination as described in Example 1
Thing.
1H NMR(600MHz,CDCl3) δ 8.24-8.14 (m, 1H), 7.88 (d, J=2.5Hz, 1H), 7.64 (dd, J=
8.7,2.5Hz, 1H), 7.56-7.45 (m, 2H), 7.05-6.96 (m, 2H), 6.69-6.60 (m, 2H), 4.26 (t, J=
6.4Hz,2H),3.64–3.43(m,4H),2.67–2.32(m,6H),2.23–1.90(m,2H).MS(ESI)m/z460.3([M+
H]+)
Embodiment 5,2- (3,4- dichlorophenyls) -6- (3- (4- (base of pyrimidine -2) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2- pyrimidylpiperazines, prepare target chemical combination as described in Example 1
Thing.
1H NMR(600MHz,CDCl3) δ 8.30 (d, J=4.7Hz, 2H), 7.88 (d, J=2.5Hz, 1H), 7.64 (dd, J
=8.7,2.5Hz, 1H), 7.50 (d, J=8.7Hz, 1H), 7.08-6.89 (m, 2H), 6.48 (t, J=4.7Hz, 1H), 4.25
(t, J=6.3Hz, 2H), 3.90-3.80 (m, 4H), 2.54 (dt, J=7.2,6.2Hz, 6H), 2.04-1.98 (m, 2H) .MS
(ESI)m/z461.5([M+H]+)
Embodiment 6,6- (3- (4- (2- chlorphenyls) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2- chlorophenylpiperazine hydrochlorides, prepare mesh as described in Example 1
Mark compound.
1H NMR(600MHz,CDCl3) δ 7.90 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H), 7.52
(d, J=8.7Hz, 1H), 7.37 (dd, J=7.9,1.5Hz, 1H), 7.23 (ddd, J=8.9,7.7,1.5Hz, 1H), 7.07-
7.03 (m, 1H), 7.03-6.96 (m, 3H), 4.27 (t, J=6.4Hz, 2H), 3.10 (s, 4H), 2.62 (dd, J=32.5,
25.2Hz,6H),2.11–1.91(m,2H).MS(ESI)m/z493.4([M+H]+)
Embodiment 7,2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) pyridazine -
3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2,3- dichlorophenylpiperazines hydrochloride, are made as described in Example 1
Standby target compound.
1H NMR(600MHz,CDCl3) δ 7.90 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.7,2.5Hz, 1H), 7.53
(d, J=8.7Hz, 1H), 7.22-7.12 (m, 2H), 7.07-7.00 (m, 2H), 7.01-6.94 (m, 1H), 4.28 (t, J=
6.4Hz,2H),3.09(s,4H),2.87–2.44(m,6H),2.18–1.95(m,2H).MS(ESI)m/z527.5([M+H]+)
The 2- of embodiment 8 (3,4- dichlorophenyls) -6- (3- (4- (4- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 4- fluorophenyl piperazine hydrochlorides, prepare mesh as described in Example 1
Mark compound.
1H NMR (600MHz, CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H),
7.52 (d, J=8.7Hz, 1H), 7.06-6.99 (m, 2H), 6.99-6.95 (m, 2H), 6.90-6.88 (m, 2H), 4.27 (t, J
=6.4Hz, 2H), 3.20-3.07 (m, 4H), 2.74-2.63 (m, 4H), 2.61-2.52 (m, 2H), 2.02 (dd, J=14.2,
6.7Hz,2H).
m/z477.6([M+H]+)
The 2- of embodiment 9 (3,4- dichlorophenyls) -6- (3- (4- (2- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 2- fluorophenyl piperazine hydrochlorides, prepare mesh as described in Example 1
Mark compound.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H), 7.52
(d, J=8.7Hz, 1H), 7.11-7.01 (m, 4H), 6.99-6.92 (m, 2H), 4.27 (t, J=6.4Hz, 2H), 3.13 (s,
4H),2.68(s,4H),2.62–2.52(m,2H),2.20–1.94(m,2H).m/z 477.7([M+H]+)
Embodiment 10
2- (3,4- dichlorophenyls) -6- (3- (4- (3- trifluoromethyls) phenyl) piperazine -1- bases) propoxyl group) pyridazine -3
(2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 3- trifluoromethylphenypiperazine piperazine hydrochlorides, as described in Example 1
Prepare target compound.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H),
7.57-7.51 (m, 1H), 7.36 (t, J=8.0Hz, 1H), 7.13 (s, 1H), 7.11-7.05 (m, 2H), 7.04-6.99 (m,
2H), 4.28 (t, J=6.4Hz, 2H), 3.30-3.18 (m, 4H), 2.64 (dd, J=20.9,15.9Hz, 4H), 2.63-2.55
(m,2H),2.17–1.92(m,2H).m/z527.5([M+H]+)
Embodiment 11,4- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) third
Base) piperazine -1- bases) cyanophenyl
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 4- (piperazine -1- bases) cyanophenyl, prepare target as described in Example 1
Compound.
1H NMR(600MHz,CDCl3) δ 7.88 (d, J=2.5Hz, 1H), 7.66 (dd, J=8.7,2.5Hz, 1H),
7.55-7.48 (m, 3H), 7.09-6.96 (m, 2H), 6.87 (t, J=5.8Hz, 2H), 4.27 (t, J=6.4Hz, 2H), 3.43-
3.24 (m, 4H), 2.70-2.53 (m, 6H), 2.01 (dd, J=13.7,6.9Hz, 2H) .MS (ESI) m/z484.6 ([M+H]+)
Embodiment 12,6- (3- (4- benzyl diethylenediamine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 4- benzyl diethylenediamines, prepare target compound as described in Example 1.
1H NMR(600MHz,CDCl3) δ 7.88 (d, J=2.5Hz, 1H), 7.65 (dd, J=8.7,2.5Hz, 1H), 7.52
(d, J=8.7Hz, 1H), 7.33 (d, J=4.4Hz, 4H), 7.27 (dd, J=8.6,4.5Hz, 1H), 7.00 (s, 2H), 4.23
(t, J=6.4Hz, 2H), 3.53 (d, J=6.1Hz, 2H), 2.66-2.37 (m, 8H), 2.10-1.78 (m, 3H) .MS (ESI) m/
z473.6([M+H]+)
Embodiment 13,2- (3,4- dichlorophenyls) -6- (3- (4- (4- fluoro benzoyls) piperidin-1-yl) propoxyl group) rattle away
Piperazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 4- fluorobenzoyl propylpiperidine hydrochlorides, are made as described in Example 1
Standby target compound.
1H NMR(600MHz,CDCl3) δ 7.98 (dd, J=8.7,5.5Hz, 2H), 7.89 (d, J=2.4Hz, 1H), 7.65
(dd, J=8.7,2.4Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.16 (t, J=8.6Hz, 2H), 7.07-6.91 (m, 2H),
4.25 (t, J=6.3Hz, 2H), 3.25-3.22 (m, 1H), 3.04 (d, J=11.5Hz, 2H), 2.55 (t, J=7.2Hz, 2H),
2.17(s,2H),2.03–1.98(m,2H),1.90–1.81(m,4H).MS(ESI)m/z 504.1([M+H]+)
Embodiment 14,6- (3- (4- (benzo [b] thiene-3-yl) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls)
Pyridazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 4- benzos [b] thiene-3-yl piperazine hydrochloride, by embodiment 1
Method prepares target compound.
1H NMR(600MHz,CDCl3) δ 8.00-7.87 (m, 1H), 7.67 (ddd, J=8.8,2.4,0.6Hz, 1H),
7.57 (d, J=8.0Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.42 (q, J=5.5Hz, 2H), 7.33-7.25 (m, 1H),
7.07-7.00 (m, 2H), 6.91 (d, J=7.7Hz, 1H), 4.29 (t, J=6.3Hz, 2H), 3.21 (s, 4H), 2.92-2.53
(m,6H),2.15–1.97(m,2H).MS(ESI)m/z 514.7([M+H]+)
Embodiment 15,3- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) third
Base) piperazine -1- bases) benzofuran -5- formamides
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 3- (piperazine -1- bases) benzofuran -5- formamides, by embodiment 1
Method prepare target compound.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.4Hz, 1H), 7.71-7.64 (m, 1H), 7.56-7.50 (m,
1H), 7.45 (s, 1H), 7.42 (d, J=9.0Hz, 1H), 7.18-7.13 (m, 2H), 7.07-6.98 (m, 2H), 4.29 (t, J=
6.3Hz, 2H), 3.24 (d, J=4.3Hz, 4H), 2.66 (dd, J=35.5,28.3Hz, 6H), 2.07 (t, J=6.9Hz, 2H),
1.90–1.54(m,2H).m/z 542.8([M+H]+)
Embodiment 16,6- (3- (4- (1H- indyl -3- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichlorophenyls) rattle away
Piperazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with 3- (piperidin-4-yl) -1H- indoles, are prepared as described in Example 1
Target compound.
1H NMR(600MHz,CDCl3) δ 8.22 (s, 1H), 7.91 (t, J=5.4Hz, 2H), 7.66 (dd, J=8.7,
2.5Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 7.40 (d, J=8.1Hz, 1H), 7.26-7.13 (m, 3H), 7.08-6.97
(m, 2H), 4.31 (t, J=6.4Hz, 2H), 3.29 (d, J=2.8Hz, 2H), 2.80 (t, J=5.7Hz, 2H), 2.74-2.59
(m,3H),2.22–1.99(m,2H),1.70(s,4H).MS(ESI)m/z 497.1([M+H]+)
Embodiment 17,6- (3- (4- (benzo [d] isothiazolyl -3- bases) piperazine -1- bases) propoxyl group) -2- (3,4- dichloros
Phenyl) pyridazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with benzo [d] piperazine of isothiazolyl -3, are prepared as described in Example 1
Target compound.
1H NMR(600MHz,CDCl3) δ 7.96-7.88 (m, 2H), 7.82 (d, J=8.1Hz, 1H), 7.70-7.64 (m,
1H), 7.52 (dd, J=9.1,3.5Hz, 1H), 7.50-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.07-6.92 (m, 2H),
4.28 (t, J=6.4Hz, 2H), 3.75-3.54 (m, 4H), 2.76-2.69 (m, 4H), 2.65-2.53 (m, 2H), 2.10-1.95
(m,2H).MS(ESI)m/z 515.5([M+H]+)
Embodiment 18,6- (3- (4- (benzo [d] thiazolyl -2- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichloro-benzenes
Base) pyridazine -3 (2H) -one
4- methoxyphenylpiperazderivatives hydrochlorides are replaced with benzo [d] thiazolyl -2- piperidines, are prepared as described in Example 1
Target compound.
1H NMR(600MHz,CDCl3) δ 7.98 (d, J=8.1Hz, 1H), 7.89 (d, J=2.5Hz, 1H), 7.88-7.84
(m, 1H), 7.65 (dd, J=8.7,2.5Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 7.49-7.42 (m, 1H), 7.38-7.32
(m, 1H), 7.06-6.89 (m, 2H), 4.25 (t, J=6.4Hz, 2H), 3.16-3.09 (m, 3H), 2.62-2.51 (m, 2H),
2.18 (dd, J=20.0,11.1Hz, 4H), 2.02-1.93 (m, 4H) .MS (ESI) m/z515.2 ([M+H]+)
Embodiment 19,2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl)
Propoxyl group) pyridazine -3 (2H) -one
With 6- fluorobenzene, simultaneously [d] isoxazole -3- piperidine hydrochlorates replace 4- methoxyphenylpiperazderivatives hydrochlorides, by embodiment 1
Method prepare target compound.
1H NMR(600MHz,CDCl3) δ 7.88 (d, J=2.4Hz, 1H), 7.73-7.60 (m, 2H), 7.56-7.41 (m,
1H), 7.23 (dd, J=8.5,1.6Hz, 1H), 7.10-6.93 (m, 3H), 4.25 (t, J=6.3Hz, 2H), 3.08 (d, J=
11.8Hz, 3H), 2.57 (t, J=7.3Hz, 2H), 2.25-1.89 (m, 6H), 1.25 (d, J=0.6Hz, 2H) .MS (ESI) m/
z517.6([M+H]+)
The 2- of embodiment 20 (3,4- dichlorophenyls) -6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl)
Butoxy) pyridazine -3 (2H) -one
Reaction equation 2
1) hydrochloric acid 3 is taken, 4- dichloro phenyl hydrazine 21.1g, maleic anhydride 9.8g, which is dissolved in, adds 200ml purified waters.Under stirring, slowly
40ml concentrated hydrochloric acids are added, are heated to reflux after adding, are reacted 6 hours.Reaction finishes, and ice-water bath cooling, separates out yellow solid.Take out
Filter, filter cake are washed with water twice.Take out filter cake saturation NaHCO3Dissolving, insoluble matter is being filtered off, clear liquid is transferred to pH value with concentrated hydrochloric acid
To between 2~3, white solid is separated out, filters and 22.4g, yield 87.8% is obtained after drying.
2) first step product 12.4g is taken, Anhydrous potassium carbonate 13.8g, Isosorbide-5-Nitrae-dibromobutane 18.8g, adds 100ml acetone,
Heating reflux reaction 4 hours, is cooled to room temperature, filtering, solvent evaporated, give light yellow oil, is obtained through flash chromatography post white solid
Body 13.5g, 73-74 DEG C of fusing point, yield 69.4%.
3) second step product 1.60g, 6- fluorobenzene simultaneously [d] isoxazole -3- piperidine hydrochlorate 1.28g are taken, potassium carbonate 2.0g, are added
Enter 50ml acetonitriles, heating reflux reaction 6 hours, be cooled to room temperature, solvent evaporated, add q. s. methylene chloride, washing, divide and remove water
Layer, organic layer add anhydrous magnesium sulfate to dry, solvent evaporated, obtain yellow oil, and pale yellow oil is obtained through flash chromatography post
2.36g, yield 89.1%.
1H NMR(600MHz,CDCl3) δ 7.88 (d, J=2.4Hz, 1H), 7.73-7.60 (m, 2H), 7.56-7.41 (m,
1H), 7.23 (dd, J=8.5,1.6Hz, 1H), 7.10-6.93 (m, 3H), 4.25 (t, J=6.3Hz, 2H), 3.08 (d, J=
11.8Hz, 3H), 2.57 (t, J=7.3Hz, 2H), 2.25-1.89 (m, 6H), 1.25 (d, J=0.6Hz, 2H) .MS (ESI) m/
z531.3([M+H]+)
Embodiment 21,6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butoxy) -2- (4- fluorobenzene
Base) pyridazine -3 (2H) -one
3,4- dichloride phenyl hydrazine hydrochloric acid salts are replaced with 4- fluorophenyl hydrazine hydrochlorides, prepare target chemical combination as described in Example 20
Thing.
1H NMR(600MHz,CDCl3) δ 7.73-7.64 (m, 3H), 7.26 (dd, J=8.5,2.1Hz, 1H), 7.19-
7.13 (m, 2H), 7.07 (td, J=8.8,2.1Hz, 1H), 7.04-6.98 (m, 2H), 4.21 (t, J=6.4Hz, 2H), 3.09
(d, J=10.5Hz, 3H), 2.58-2.42 (m, 2H), 2.21-2.01 (m, 6H), 1.87-1.77 (m, 2H), 1.70 (dt, J=
9.5,7.5Hz, 2H) .MS (ESI) m/z=481.3 ([M+H]+)
Embodiment 22, (E) -2- (3,4- dichlorophenyls) -6- ((4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidines -
Base) but-2-ene -1- bases) epoxide) pyridazine -3 (2H) -one
Isosorbide-5-Nitrae-dibromobutane is replaced with (E)-Isosorbide-5-Nitrae-dibromo but-2-ene, prepares target compound as described in Example 20.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.5Hz, 1H), 7.70 (dd, J=8.7,5.1Hz, 1H), 7.66
(dd, J=8.7,2.5Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 7.25 (dd, J=8.5,2.1Hz, 1H), 7.06 (td, J=
8.8,2.1Hz, 1H), 7.04-6.99 (m, 2H), 6.08-5.79 (m, 2H), 4.72 (d, J=5.6Hz, 2H), 3.11 (dd, J=
33.4,9.0Hz, 5H), 2.19-2.07 (m, 6H) .MS (ESI) m/z=545.3 ([M+H]+)
Embodiment 23,2- (3,4- dichlorophenyls) -6- ((5- (4- ((6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl))
Amyl group) epoxide) pyridazine -3 (2H) -one
With 1, pentamethylene bromide replaces Isosorbide-5-Nitrae-dibromobutane, prepares target compound as described in Example 20.
1H NMR(600MHz,CDCl3) δ 7.89 (d, J=2.1Hz, 1H), 7.73 (dd, J=8.6,5.1Hz, 1H), 7.66
(dd, J=8.7,2.1Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.07 (t, J=8.8Hz,
1H), 7.04-6.99 (m, 2H), 4.20 (t, J=6.5Hz, 2H), 3.11 (d, J=10.4Hz, 3H), 2.57-2.42 (m, 2H),
2.14 (dt, J=47.0,27.2Hz, 4H), 1.89-1.73 (m, 2H), 1.77-1.58 (m, 2H), 1.54-1.47 (m, 2H),
1.34–1.20(m,2H).
M/z=480.2 ([M+H]+)
Embodiment 24,2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide) -4,5- diformazans radical pyridazine -3 (2H) -one
Reaction equation 3
1) hydrochloric acid 3 is taken, 4- dichloro phenyl hydrazines 21.1g, 3,4- dimethyl maleic anhydride 12.6g, which are dissolved in, adds 200ml purified waters.
Under stirring, 40ml concentrated hydrochloric acids are slowly added to, are heated to reflux after adding, are reacted 6 hours.Reaction finishes, and ice-water bath cooling, separates out yellow
Color solid.Filter, filter cake is washed with water twice.Take out filter cake saturation NaHCO3Dissolving, filtering off insoluble matter, clear liquid concentrated hydrochloric acid
PH value is transferred to between 2~3, separates out white solid, filters after drying to obtain 26.3g, yield 92.6%.
2) first step product 14.2g, Anhydrous potassium carbonate 13.8g, 1,3- dibromopropane 18.8g are taken, adds 100ml acetone,
Heating reflux reaction 4 hours, is cooled to room temperature, filtering, solvent evaporated, give light yellow oil, is obtained through flash chromatography post white solid
Body 16.8g, 68-69 DEG C of fusing point, yield 83.3%.
3) second step product 2.1g, 6- fluorobenzene simultaneously [d] isoxazole -3- piperidine hydrochlorate 1.28g are taken, potassium carbonate 2.0g, are added
Enter 50ml acetonitriles, heating reflux reaction 6 hours, be cooled to room temperature, solvent evaporated, add q. s. methylene chloride, washing, divide and remove water
Layer, organic layer add anhydrous magnesium sulfate to dry, solvent evaporated, obtain yellow oil, and pale yellow oil is obtained through flash chromatography post
2.16g, yield 84.4%.
1H NMR(600MHz,CDCl3) δ 7.92 (d, J=2.5Hz, 1H), 7.71 (dd, J=8.7,5.1Hz, 1H), 7.67
(dd, J=8.7,2.5Hz, 1H), 7.54-7.46 (m, 1H), 7.25 (dd, J=8.3,2.1Hz, 1H), 7.06 (td, J=8.8,
2.1Hz, 1H), 4.26 (t, J=6.3Hz, 2H), 3.18-2.93 (m, 3H), 2.65-2.52 (m, 2H), 2.26-2.16 (m,
8H),2.16–1.97(m,6H).MS(ESI)m/z545.3([M+H]+)
Embodiment 25,2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide) -1 (2H) -one of -5,6,7,8- tetrahydrochysene dais piperazine
3,4- dimethyl maleic anhydrides are replaced with 5,6,7,8- THPAs, target chemical combination is prepared by the method for embodiment 24
Thing.
1H NMR(600MHz,CDCl3) δ 8.23 (d, J=4.0Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.58 (t,
J=7.8Hz, 1H), 6.79 (dd, J=6.8,5.2Hz, 1H), 6.71 (d, J=8.5Hz, 1H), 4.26-3.99 (m, 4H),
3.95-3.84 (m, 4H), 3.57 (t, J=6.4Hz, 2H), 3.46-3.26 (m, 4H), 3.05-2.94 (m, 2H), 2.87 (t, J
=6.0Hz, 2H), 2.75-2.65 (m, 2H), 2.03-1.93 (m, 2H) .MS (ESI) m/z405.6 ([M+H]+)
Embodiment 26,2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide)-dai piperazine -1 (2H) -one
3,4- dimethyl maleic anhydrides are replaced with phthalic anhydride, target compound is prepared by the method for embodiment 24.
1H NMR(600MHz,CDCl3) δ 8.54-8.46 (m, 1H), 8.08-8.01 (m, 1H), 8.00 (d, J=2.5Hz,
1H), 7.91-7.81 (m, 2H), 7.77-7.54 (m, 2H), 7.55 (d, J=8.7Hz, 1H), 7.27 (dd, J=8.5,2.1Hz,
1H), 7.08 (td, J=8.8,2.1Hz, 1H), 4.46 (t, J=6.3Hz, 2H), 3.16 (d, J=11.1Hz, 3H), 2.69 (t,
J=6.9Hz, 2H), 2.43-1.94 (m, 8H) .MS (ESI) m/z 567.5 ([M+H]+)
Embodiment 27,6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -2- (4- fluorobenzene
Base) pyridazine -3 (2H) -one
Reaction equation 4
1) hydrochloric acid is taken to fluorine phenylhydrazine 16.2g, and maleic anhydride 9.8g, which is dissolved in, adds 200ml purified waters.Under stirring, it is slowly added to
40ml concentrated hydrochloric acids, it is heated to reflux, reacts 6 hours after adding.Reaction finishes, and ice-water bath cooling, separates out yellow solid.Filter, filter
Cake is washed with water twice.Take out filter cake saturation NaHCO3Dissolving, insoluble matter is being filtered off, clear liquid is transferred to pH value to 2~3 with concentrated hydrochloric acid
Between, white solid is separated out, filters and 15.8g, yield 76.7% is obtained after drying.
2) first step product 10.4g, Anhydrous potassium carbonate 13.8g, 1,3- dibromopropane 18.8g are taken, adds 100ml acetone,
Heating reflux reaction 4 hours, is cooled to room temperature, filtering, solvent evaporated, give light yellow oil, brown oil is obtained through flash chromatography post
Shape thing 9.8g, yield 60.2%.
3) second step product 1.60g, 6- fluorobenzene simultaneously [d] isoxazole -3- piperidine hydrochlorate 1.0g are taken, potassium carbonate 2.0g, are added
Enter 50ml acetonitriles, heating reflux reaction 6 hours, be cooled to room temperature, solvent evaporated, add q. s. methylene chloride, washing, divide and remove water
Layer, organic layer add anhydrous magnesium sulfate to dry, solvent evaporated, obtain yellow oil, and pale yellow oil is obtained through flash chromatography post
1.77g, yield 76.0%.
1H NMR(600MHz,CDCl3) δ 7.70 (dd, J=8.7,5.1Hz, 1H), 7.68-7.65 (m, 2H), 7.27-
7.23 (m, 1H), 7.18-7.12 (m, 2H), 7.09-7.04 (m, 1H), 7.03-6.97 (m, 2H), 4.25 (t, J=6.4Hz,
2H),3.16–2.99(m,3H),2.76–2.48(m,2H),2.29–1.93(m,6H),1.26(s,2H).MS(ESI)
m/z467.3[M+H]+)
Embodiment 28,6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- phenyl rattles away
Piperazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with hydrazinobenzene hydrochloride salt, target compound is prepared by the method for embodiment 28.
1H NMR(600MHz,CDCl3)δ7.75–7.66(m,3H),7.51–7.44(m,2H),7.40–7.33(m,1H),
7.26 (dd, J=8.5,2.1Hz, 1H), 7.11-6.97 (m, 3H), 4.26 (t, J=6.4Hz, 2H), 3.09 (dd, J=13.4,
5.3Hz,3H),2.61–2.47(m,2H),2.24–1.94(m,8H).MS(ESI)m/z 449.4([M+H]+)
Embodiment 29,6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (4- first
Base phenyl) pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 4- hydrazinobenzoic acid hydrochlorides, target compound is prepared by the method for embodiment 28.1H NMR(600MHz,CDCl3) δ 7.71 (dd, J=8.7,5.1Hz, 1H), 7.55 (d, J=8.4Hz, 2H), 7.31-7.19 (m,
3H), 7.07 (td, J=8.8,2.1Hz, 1H), 7.04-6.98 (m, 2H), 4.25 (t, J=6.4Hz, 2H), 3.09 (d, J=
11.2Hz, 3H), 2.65-2.53 (m, 2H), 2.40 (s, 3H), 2.18 (t, J=12.3Hz, 2H), 2.12-2.04 (m, 4H),
2.04–1.97(m,2H).MS(ESI)m/z463.6([M+H]+)
Embodiment 30,6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (naphthalene -2-
Base) pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2- naphthylhydrazine hydrochlorides, target compound is prepared by the method for embodiment 28.
1H NMR(600MHz,CDCl3) δ 8.20 (d, J=1.9Hz, 1H), 7.95-7.84 (m, 3H), 7.79 (dd, J=
8.8,2.1Hz, 1H), 7.68 (dd, J=8.7,5.1Hz, 1H), 7.54-7.48 (m, 2H), 7.25 (dd, J=8.5,2.1Hz,
1H), 7.11-6.99 (m, 3H), 4.30 (t, J=6.4Hz, 2H), 3.23-3.03 (m, 3H), 2.66-2.50 (m, 2H), 2.23-
1.92(m,8H).MS(ESI)m/z499.7([M+H]+)
Embodiment 31,2- (4- chlorphenyls) -6- (3- (4- (fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group)
Pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 4- chlorophenylhydxazine hydrochlorides, target compound is prepared by the method for embodiment 28.1H
NMR(600MHz,CDCl3) δ 7.74-7.64 (m, 3H), 7.46-7.40 (m, 2H), 7.26 (dd, J=8.5,2.0Hz, 1H),
7.07 (td, J=8.9,2.2Hz, 1H), 7.04-6.97 (m, 2H), 4.26 (t, J=6.4Hz, 2H), 3.09 (d, J=
10.7Hz, 3H), 2.57 (t, J=7.4Hz, 2H), 2.34-1.91 (m, 6H), 1.27 (s, 2H) .MS (ESI) m/z483.6 ([M+
H]+)
Embodiment 32,2- (3- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group)
Pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 3- chlorophenylhydxazine hydrochlorides, target compound is prepared by the method for embodiment 28.
1H NMR(600MHz,CDCl3) δ 7.71 (dd, J=8.7,5.1Hz, 1H), 7.57-7.53 (m, 1H), 7.47-
7.43 (m, 1H), 7.43-7.36 (m, 2H), 7.26 (dd, J=8.5,2.1Hz, 1H), 7.09-7.01 (m, 3H), 4.20 (t, J
=6.4Hz, 2H), 3.08 (d, J=11.6Hz, 3H), 2.56 (t, J=7.3Hz, 2H), 2.32-1.88 (m, 8H) .MS (ESI)
m/z483.5([M+H]+)
Embodiment 33,2- (2- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group)
Pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2- chlorophenylhydxazine hydrochlorides, target compound is prepared by the method for embodiment 28.
1H NMR(600MHz,CDCl3) δ 7.75-7.69 (m, 2H), 7.68-7.63 (m, 1H), 7.40 (t, J=8.1Hz,
1H), 7.38-7.30 (m, 1H), 7.26 (dd, J=8.5,2.1Hz, 1H), 7.07 (td, J=8.8,2.1Hz, 1H), 7.05-
6.99 (m, 2H), 4.28 (t, J=6.4Hz, 2H), 3.20-3.06 (m, 3H), 2.58 (t, J=7.3Hz, 2H), 2.38-1.86
(m,8H).MS(ESI)m/z483.7([M+H]+)
Embodiment 34,2- (2,3- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,3- dichloride phenyl hydrazine hydrochloric acid salts, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR(600MHz,CDCl3) δ 7.69 (dd, J=8.7,5.1Hz, 1H), 7.53 (dd, J=7.7,1.9Hz,
1H), 7.39-7.31 (m, 2H), 7.24 (dd, J=8.5,2.1Hz, 1H), 7.10-6.99 (m, 3H), 4.30-3.99 (m, 2H),
3.16–2.98(m,3H),2.54–2.44(m,2H),2.20–1.85(m,8H).MS(ESI)m/z 517.5([M+H]+)
Embodiment 35,2- (2,4 dichloro benzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,4- dichloride phenyl hydrazine hydrochloric acid salts, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR (600MHz, CDCl3) δ 7.70 (dd, J=8.7,5.1Hz, 1H), 7.55 (s, 1H), 7.39 (d, J=
1.0Hz, 2H), 7.26 (dd, J=8.5,2.0Hz, 1H), 7.12-6.91 (m, 3H), 4.28-4.11 (m, 2H), 3.24-2.94
(m, 3H), 2.54 (t, J=7.3Hz, 2H), 2.28-1.91 (m, 8H) .MS (ESI) m/z 517.4 ([M+H]+)
Embodiment 36,2- (2,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,5- dichloride phenyl hydrazine hydrochloric acid salts, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR(600MHz,CDCl3) δ 7.69 (dd, J=8.7,5.1Hz, 1H), 7.47 (s, 1H), 7.46-7.43 (m,
2H), 7.35 (dd, J=8.6,2.5Hz, 1H), 7.24 (dd, J=8.5,2.1Hz, 1H), 7.08-6.99 (m, 3H), 4.19 (t,
J=6.4Hz, 2H), 3.17-3.00 (m, 3H), 2.58-2.47 (m, 2H), 2.23-1.87 (m, 8H) .MS (ESI) m/z517.5
([M+H]+)
Embodiment 37,2- (3,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 3,5- dichloride phenyl hydrazine hydrochloric acid salts, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR(600MHz,CDCl3) δ 7.76-7.63 (m, 3H), 7.33 (t, J=1.8Hz, 1H), 7.25 (dd, J=
8.5,2.1Hz, 1H), 7.06 (td, J=8.8,2.1Hz, 1H), 7.04-6.99 (m, 2H), 4.28 (t, J=6.4Hz, 2H),
3.49-2.92 (m, 3H), 2.72-2.48 (m, 2H), 2.20 (dd, J=16.2,9.0Hz, 2H), 2.12-1.94 (m, 6H) .MS
(ESI)m/z517.5([M+H]+)
Embodiment 38,2- (3,4- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 3,4- difluorophenyl hydrazines hydrochloride, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR(600MHz,CDCl3) δ 7.70 (dd, J=8.7,5.1Hz, 1H), 7.64 (ddd, J=11.5,7.2,
2.6Hz, 1H), 7.57-7.51 (m, 1H), 7.27-7.21 (m, 2H), 7.07 (td, J=8.8,2.1Hz, 1H), 7.04-6.97
(m, 2H), 4.27 (t, J=6.4Hz, 2H), 3.27-3.03 (m, 3H), 2.71-2.45 (m, 2H), 2.20 (dd, J=16.1,
9.3Hz,2H),2.14–1.95(m,6H).MS(ESI)m/z485.6([M+H]+)
Embodiment 39,2- (2,4 difluorobenzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,4- difluorophenyl hydrazines hydrochloride, target chemical combination is prepared by the method for embodiment 281H
NMR(600MHz,CDCl3) δ 7.69 (dd, J=8.7,5.1Hz, 1H), 7.44 (td, J=8.5,5.9Hz, 1H), 7.24 (dd, J
=8.5,2.1Hz, 1H), 7.09-6.93 (m, 5H), 4.19 (t, J=6.4Hz, 2H), 3.16-2.90 (m, 3H), 2.59-2.46
(m,2H),2.24–2.13(m,2H),2.09–1.92(m,6H).MS(ESI)m/z485.4([M+H]+)
Embodiment 40,2- (2,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,5- difluorophenyl hydrazines hydrochloride, target chemical combination is prepared by the method for embodiment 281H
NMR(600MHz,CDCl3) δ 7.69 (dd, J=8.7,5.1Hz, 1H), 7.26-7.16 (m, 3H), 7.13-7.08 (m, 1H),
7.07-6.97 (m, 3H), 4.20 (t, J=6.4Hz, 2H), 3.08 (dd, J=17.3,9.5Hz, 3H), 2.58-2.47 (m,
2H),2.25–2.10(m,2H),2.13–1.93(m,6H).MS(ESI)m/z485.6([M+H]+)
Embodiment 41,2- (2,6- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 2,6- difluorophenyl hydrazines hydrochloride, target chemical combination is prepared by the method for embodiment 281H
NMR(600MHz,CDCl3) δ 7.70 (dd, J=8.7,5.1Hz, 1H), 7.40 (tt, J=8.5,6.1Hz, 1H), 7.25 (dd, J
=8.5,2.1Hz, 1H), 7.09-7.00 (m, 5H), 4.19 (t, J=6.4Hz, 2H), 3.15-2.99 (m, 3H), 2.58-2.48
(m, 2H), 2.17 (td, J=11.4,4.7Hz, 2H), 2.13-1.94 (m, 6H) ..MS (ESI) m/z485.5 ([M+H]+)
Embodiment 42,2- (3,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with 3,5- difluorophenyl hydrazines hydrochloride, target chemical combination is prepared by the method for embodiment 281H
NMR(600MHz,CDCl3) δ 7.81 (dd, J=6.6,2.6Hz, 1H), 7.70 (dd, J=8.7,5.1Hz, 1H), 7.65 (ddd,
J=8.9,4.2,2.6Hz, 1H), 7.27-7.19 (m, 2H), 7.07 (td, J=8.8,2.1Hz, 1H), 7.04-6.97 (m,
2H), 4.26 (t, J=6.4Hz, 2H), 3.12-3.03 (m, 3H), 2.66-2.48 (m, 2H), 2.20 (dd, J=16.2,
8.9Hz,2H),2.13–1.93(m,6H).MS(ESI)m/z485.2([M+H]+)
Embodiment 43,2- (the chloro- 4- fluorophenyls of 3-) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) third
Epoxide pyridazine -3 (2H) -one
4- fluorophenyl hydrazine hydrochlorides are replaced with the chloro- 4- fluorophenyl hydrazine hydrochlorides of 3-, target chemical combination is prepared by the method for embodiment 28
Thing.
1H NMR(600MHz,CDCl3) δ 7.70 (dd, J=8.7,5.1Hz, 1H), 7.49-7.41 (m, 2H), 7.25 (dd,
J=8.5,1.9Hz, 1H), 7.07-7.03 (m, 1H), 7.03-6.97 (m, 2H), 6.85-6.74 (m, 1H), 4.29 (t, J=
6.3Hz, 2H), 3.20-2.98 (m, 3H), 2.57 (t, J=7.3Hz, 2H), 2.19 (dd, J=16.3,9.1Hz, 2H), 2.14-
1.98(m,6H).MS(ESI)m/z501.4([M+H]+)
Embodiment 44,6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) pyridazine -3
(2H) -one
6- fluorobenzene [d] isoxazole -3- piperidine hydrochlorates are replaced with 2,3- dichlorophenylpiperazines hydrochloride, by embodiment 28
Method prepares target compound.
1H NMR(600MHz,CDCl3)δ7.69–7.64(m,2H),7.20–7.13(m,4H),7.06–6.98(m,2H),
6.97 (dd, J=7.1,2.4Hz, 1H), 4.26 (t, J=6.4Hz, 2H), 3.08 (s, 4H), 2.67-2.58 (m, 6H), 2.10-
1.94(m,2H).MS(ESI)m/z477.6([M+H]+)
Embodiment 45,6- (3- (4- (benzo [d] isothiazole -3- bases) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) rattle away
Piperazine -3 (2H) -one
With benzo [d] isothiazole -3- piperazines-replace 6- fluorobenzene [d] isoxazole -3- piperidine hydrochlorates, by embodiment 28
Method prepares target compound
1H NMR(600MHz,CDCl3) δ 7.92 (d, J=8.2Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.73-7.63
(m, 2H), 7.48 (ddd, J=8.1,7.0,1.0Hz, 1H), 7.37 (ddd, J=8.0,7.0,0.9Hz, 1H), 7.20-7.12
(m, 2H), 7.06-6.98 (m, 2H), 4.27 (t, J=6.4Hz, 2H), 3.70-3.52 (m, 4H), 2.81-2.67 (m, 4H),
2.63–2.56(m,2H),2.13–1.92(m,2H).MS(ESI)m/z466.6([M+H]+)
Preferred compound numbering and its structural formula prepared by the embodiment of table 1
Pharmacological Examples
In embodiment below, the homogenate of use includes three kinds of A homogenates, B homogenates and C homogenates homogenates,
Collocation method difference is as follows:
A homogenates contain final concentration of 0.01M Tris-HCl buffer solutions and final concentration of 0.32M sucrose solution, pH
It is worth for 7.4.
B homogenates be 0.01M Tris-HCl buffer solutions, pH value 7.4.
C homogenates are 50mM Tris buffer solutions, pH value 7.4.
Embodiment 46
5HT1AThe preparation of film
Rat breaks end, and operates on ice, takes brain striatum rapidly, and 2 corpus straitums are closed into a centrifuge tube, adds
3ml buffer solutions (0.05M Tris-HCl buffer solutions, containing 0.1% ascorbic acid, 10um pargyline and 4mM CaCl2) in 4 grades
3-4s is homogenized, and is homogenized 4 times, then add 5ml buffer solutions (0.05M Tris-HCl buffer solutions, containing 0.1% ascorbic acid,
10um pargyline and 4mM CaCl2), hatching 10min in 37 DEG C, test tube balance adjusts weight after hatch, in 12000r, 4
DEG C centrifugation 20min, abandons supernatant, adds 3ml B liquid, mixed with vortex mixer, add 5ml C liquid, centrifuge, in triplicate
Centrifugation, centrifugation finish, abandon supernatant, will be deposited in -80 DEG C and store for future use.
Receptor Binding Assay material:
Isotope aglucon3H-8-OH-DPAT (67.0Ci/mmol), purchased from PerkinElmer companies;5-HT, purchased from RBI
Company;GF/C glass fiber filter papers, purchased from Whatman companies;Tris imports dispense;PPO, POPOP are purchased from the factory of Shanghai reagent one;
Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counters.
Experimental method:
(1) first by the film prepared with appropriate homogenate, it is uniformly dispersed with refiner, 15 test tubes is mixed into
In 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
(2) each reaction tube is separately added into the μ L of film preparation thing 100, the μ L of homogenate 100.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds 5-HT100 μ L (final concentrations
10-5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10-5M);
(4) each reaction tube is separately added into radioligand3The μ L of H-8-OH-DPAT 10 (each reaction tube is all provided with 2 parallel pipes,
Each pipe is placed on ice during sample-adding).
(5) each 37 DEG C of temperature of reaction tube are incubated into 10min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use is ice-cold
Experiment buffer solution fully wash, by filter disc take out be put into 3ml scintillating discs, add 2ml toluene scintillation solution and mix;
(6) scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
Experimental result is shown in Table 2
Embodiment 47
5HT2AThe preparation of film
Rat breaks end, and operates on ice, takes brain striatum rapidly, and 2 corpus straitums are closed into a centrifuge tube, adds
3ml buffer solutions (0.05M Tris-HCl buffer solutions:Take 6.05gTris to be dissolved in 1000ml distilled waters, be with dense HCl tune PH
7.5) it is homogenized in 4 grades of 3-4s, is homogenized 4 times, then adds 5ml buffer solutions, hatches 10min in 37 DEG C, test tube day after having hatched
Heibei provincial opera bulk wight amount, in 12000r, 4 DEG C of centrifugation 20min, supernatant is abandoned, 3ml A liquid is added, is mixed, added with vortex mixer
5ml buffer solutions, centrifugation, abandon supernatant, will be deposited in -80 DEG C and store for future use.
Receptor Binding Assay material:
Isotope aglucon [3H]-Ketanserin (67.0Ci/mmol), purchased from PerkinElmer companies;
Methysergide, purchased from RBI companies;GF/C glass fiber filter papers, purchased from Whatman companies;Tris imports dispense;PPO、
POPOP is purchased from the factory of Shanghai reagent one;Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counters.
Experimental method:
(1) first by the film prepared with appropriate homogenate, it is uniformly dispersed with refiner, 15 test tubes is mixed into
In 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
(2) each reaction tube is separately added into the μ L of film preparation thing 100, the μ L of buffer solution 100.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds Methysergide 100
μ L (final concentrations 10-5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10-5M);
(4) each reaction tube is separately added into radioligand3The μ L of H-Ketanserin 10 (each reaction tube be all provided with 2 it is parallel
Pipe, each pipe is placed on ice during sample-adding).
(5) each 37 DEG C of temperature of reaction tube are incubated into 15min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use is ice-cold
Experiment buffer solution fully wash, by filter disc take out be put into 3ml scintillating discs, add 2ml toluene scintillation solution and mix;
(6) scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
Experimental result is shown in Table 2
Embodiment 48
D2The preparation of film
Rat breaks end, and operates on ice, takes brain striatum rapidly, and 2 corpus straitums are closed into a centrifuge tube, adds
3ml buffer solutions (0.05M Tris-HCl buffer solutions, 120mM containing NaCl, KCl 5mM, MgCl21mM, CaCl2 1mM), in 4
Shelves 3-4s homogenate, is homogenized 4 times, then adds 5ml buffer solutions, and the test tube being homogenized is adjusted into weight, in 12000r, 4 with balance
DEG C centrifugation 20min, abandons supernatant, adds 3mlB liquid, mixed with vortex mixer, add 5ml B liquid, centrifuge, abandon supernatant,
- 80 DEG C will be deposited in store for future use.
Receptor Binding Assay material:
Isotope aglucon3H-Spiperone (67.0Ci/mmol), purchased from PerkinElmer companies;Butaclamol, purchase
From RBI companies;GF/C glass fiber filter papers, purchased from Whatman companies;Tris imports dispense;PPO, POPOP are purchased from Shanghai reagent
One factory;Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counters.
Experimental method:
(1) first by the film prepared with appropriate homogenate, it is uniformly dispersed with refiner, 15 test tubes is mixed into
In 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
(2) each reaction tube is separately added into the μ L of film preparation thing 100, the μ L of buffer solution 100.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds 100 μ L Butaclamol
(final concentration 10-5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10-5M);
(4) each reaction tube is separately added into radioligand3The μ L of H-Spiperone 10 (each reaction tube is all provided with 2 parallel pipes,
Each pipe is placed on ice during sample-adding).
(5) each 37 DEG C of temperature of reaction tube are incubated into 20min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use is ice-cold
Experiment buffer solution fully wash, by filter disc take out be put into 3ml scintillating discs, add 2ml toluene scintillation solution and mix;
(6) scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
Experimental result is shown in Table 2.
Embodiment 49,5HT2CThe preparation of film
Rat breaks end, and operates on ice, takes brain striatum rapidly, and 2 corpus straitums are closed into a centrifuge tube, adds
3ml buffer solutions (0.05M Tris-HCl buffer solutions:Take 6.05gTris to be dissolved in 1000ml distilled waters, be with dense HCl tune PH
7.5) it is homogenized in 4 grades of 3-4s, is homogenized 4 times, then adds 5ml buffer solutions, hatches 10min in 37 DEG C, test tube day after having hatched
Heibei provincial opera bulk wight amount, in 12000r, 4 DEG C of centrifugation 20min, supernatant is abandoned, 3mlA liquid is added, is mixed, added with vortex mixer
5ml buffer solutions, centrifugation, centrifugation finish, abandon supernatant, will be deposited in -80 DEG C and store for future use.
Receptor Binding Assay material:
Isotope aglucon [3H]-mesulergine (67.0Ci/mmol), purchased from PerkinElmer companies;
Mianserin, purchased from RBI companies;GF/C glass fiber filter papers, purchased from Whatman companies;Tris imports dispense;PPO、POPOP
Purchased from the factory of Shanghai reagent one;Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counters.
Experimental method:
(1) first by the film prepared with appropriate homogenate, it is uniformly dispersed with refiner, 15 test tubes is mixed into
In 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
(2) each reaction tube is separately added into the μ L of film preparation thing 100, the μ L of buffer solution 100.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds mianserin100 μ L
(final concentration 10-5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10-5M);
(4) each reaction tube be separately added into radioligand [3H] 10 μ L of-mesulergine (each reaction tube be all provided with 2 it is flat
Row pipe, each pipe is placed on ice during sample-adding).
(5) each 37 DEG C of temperature of reaction tube are incubated into 15min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use is ice-cold
Experiment buffer solution fully wash, by filter disc take out be put into 3ml scintillating discs, add 2ml toluene scintillation solution and mix;
(6) scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
Embodiment 50, histamine H1The preparation of receptor membrane
Rat breaks end, and operates on ice, takes guinea pig cerebellum rapidly, adds homogenate F, is mixed with vortex mixer,
48000g, 4 DEG C of centrifugation 10min, abandons supernatant, takes precipitation, adds homogenate F washings, centrifuges in triplicate, and centrifugation finishes,
Supernatant is abandoned, -80 DEG C will be deposited in and stored for future use.
H1Experiment that acceptor is affine:
The first step:First the film prepared is uniformly dispersed with refiner, 15 test tubes are mixed into appropriate homogenate F
Into 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
Second step:Each reaction tube is separately added into the μ L of film preparation thing 100.
3rd step:Total binding pipe (TB) adds 100 μ L homogenate F, and non-specific binding pipe (NB) adds 100 μ L
Promethazine (final concentrations 10-5M), it is (dense eventually to add 100 μ L test-compounds for each test-compound specific binding pipe (SB)
Degree 10-5M);
4th step:Each reaction tube is separately added into radioligand3(each reaction tube is all provided with 2 to the μ L of H-pyrilamine 10
Parallel pipe, each pipe is placed on ice during sample-adding).
5th step:Each 30 DEG C of temperature of reaction tube are incubated into 60min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use
Ice-cold experiment buffer solution is fully washed, and filter disc is taken out and is put into 3ml scintillating discs, 2ml toluene scintillation solution is added and mixes;
6th step:Scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
The preparation of embodiment 51, norepinephrine receptor film
Rat breaks end, and operates on ice, takes cortex rapidly, adds homogenate E, is mixed with vortex mixer, in 48000g,
4 DEG C of centrifugation 15min, abandon supernatant, take and irrigate shallow lake, add 0.05M Tris-HCl buffer solutions (PH7.7) washing, in triplicate
Centrifugation, centrifugation finish, abandon supernatant, will be deposited in -80 DEG C and store for future use.
α1Experiment that norepinephrine receptor is affine:
The first step:First the film prepared is uniformly dispersed with refiner, 15 test tubes are mixed into appropriate homogenate E
Into 100ml container, the suspension that appropriate homogenate is in 50ml films is added, it is standby.
Second step:Each reaction tube is separately added into the μ L of film preparation thing 100, the μ L of homogenate 100.
3rd step:Total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds prazosin 100
μ L (final concentrations 10-5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10-5M);
4th step:Each reaction tube, which is separately added into, puts Fair parts3The μ L of H-prazosin 10 (each reaction tube be all provided with 2 it is parallel
Pipe, each pipe is placed on ice during sample-adding).
5th step:Each 25 DEG C of temperature of reaction tube are incubated into 60min, reaction finishes, with reference to aglucon by depressurizing fast filtering, use
Ice-cold experiment buffer solution is fully washed, and filter disc is taken out and is put into 3ml scintillating discs, 2ml toluene scintillation solution is added and mixes;
6th step:Scintillation vial is put into liquid scintillation counter to count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm)
× 100%
Two multiple pipes are done in experiment to compound every time, carry out twice individually experiment.
Experimental result is shown in Table 2
Vitro Experimental Results show three kinds of acceptor (D of compound 5,6,12,13,14,16 and 17 pair2,5HT1A,5HT2A) stronger
Affinity, and to 5HT2C,H1,α1Affinity it is low.
Anti- schizophrenia activity in the high activity compound body that embodiment 52, MK-801 are induced
Experimental animal and reagent
Healthy Kunming mouse, male and female half and half, body weight (20 ± 2) g, provided by Nanjing Qinglongshan animal-breeding center.
Ascorbic acid, Chemical Reagent Co., Ltd., Sinopharm Group;
MK-801, produced by Sigma Co., USA, compound method:1mg/ml solution is made into 0.1% vitamin C;
Tested positive drug:Haloperole, Risperidone, Olanzapine, Aripiprazole, Ziprasidone, kui gentle ziprasidone;
Tween 80, concentration 10%.
Experimental method
The re-qualified mouse of selective body, it is randomly divided into blank group, model group, positive controls (Risperidone group), medicine group.
Blank group, the tween 0.1ml/10g of model group gavage 10%, positive controls gavage give Risperidone 0.1mg/kg, medicine group difference
Gavage gives corresponding dosage medicine.0.1% ascorbic acid 0.1ml/10g, model group, the positive is injected intraperitoneally in 1h blank groups after administration
Control group (30min), medicine group intraperitoneal injection MK-801 solution 0.1mg/kg.Thereafter spontaneous work in each group mouse 90 minutes is determined
It is dynamic.It the results are shown in Table 3.
This test result indicates that:Compared with model group, Risperidone, compound 19 and 23 can be obviously improved MK-801 inductions
High activity, and can effectively improves the climbing symptom of apomorphine induction, and do not cause EPS, table under effective dose
Bright its has obvious anti-schizophrenia effect.
Embodiment 53, the climbing experiment of apomorphine inducing mouse
Experimental animal
Healthy KM mouse, male, 18~22g of body weight, provided by Nanjing Qinglongshan animal-breeding center.
Main agents
Tested positive drug:Risperidone, Olanzapine, Aripiprazole;
Apomorphine, Sigma companies provide, and 0.9%NaCl (containing 0.1% vitamin C) dissolves before use, now with the current;
Vitamin C, F20061113, Chemical Reagent Co., Ltd., Sinopharm Group;
Sodium chloride injection, H32026305, pharmacy Co., Ltd., Factory of Xuzhou City the 5th.
Instrument:Self-control climbing cage, stopwatch.
Experimental method:The climbing experiment of apomorphine inducing mouse
KM mouse, male, 18~22g of body weight, it is randomly divided into each dosage group of negative control group, model group, positive drug (profit
Train ketone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperole, Clozapine) and each dosage group of compound is (specifically
Dosage see the table below), every group 10.Negative control group and model group gavage give coordinative solvent distilled water, positive drug group
Gavage gives corresponding positive drug (first add micro-acetic acid during dissolving, then add distilled water), and each dosage group gavage of compound gives phase
Doses of compound is answered, gavage volume is 0.1ml/10g.Apomorphine (1mg/kg), volume is subcutaneously injected in gastric infusion after 1 hour
For 0.1ml/10g.After injecting apomorphine, it is immediately placed in climbing cage, adapts to 5 minutes, 10- after observation injection apomorphine
The behavior of 11,20-21,30-31 minute are simultaneously scored, standards of grading:Four-footed is scored at 0 on floor;Two front foots are in cylinder mould
On be scored at 1;Four foots are scored at 2 on cylinder mould.
Embodiment 54, catalepsy experimental method
Experimental animal
Healthy Kunming mouse, male and female half and half, (22 ± 2) g, provided by Nanjing Qinglongshan animal-breeding center.
Main agents:
By reagent, haloperole, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone
Instrument:
Rod equipment is grabbed in self-control:Diameter 0.3cm is placed in mouse box, higher than workbench 5cm stainless steel bar.
Experimental method:
KM mouse, male and female half and half, 20~24g of body weight, it is randomly divided into each dosage of negative control group, model group, positive drug
Group (Risperidone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperole, Clozapine) and each dosage group of compound,
Every group 10.Negative control group and model group gavage give coordinative solvent distilled water, and positive drug group gavage gives the corresponding positive
Medicine (first adds micro-acetic acid, then adds distilled water) during dissolving, each dosage group gavage of compound gives corresponding dosage compound, gavage
Volume is 0.1ml/10g.During gastric infusion 30min, 60min, 90min, two fore paws of mouse are gently placed on long 20cm, directly
Footpath 0.3cm, on the spillikin higher than workbench 5.5cm, then animal hind leg put down gently in cassette bottom face, record two fore paws of mouse are in rod
It is the upper duration for keeping posture, stiff motionless for positive reaction with 30s.It is whole during 60s if mouse fore paw is never put down
Only observe.Count each compound dosage group positive reaction number of animals.
Embodiment 55, studies on acute toxicity
The limit experiment of sequential method takes KM mouse, male and female half and half, is randomly divided into some groups, every group 2-5, respectively eachization
Compound 2000mg/kg groups and solvent group, by 0.2ml/10g gastric infusions.Observe the death condition in animal 3 days.If (animal
There are 3 or more than 3 to survive in three days, during life state Non Apparent Abnormality, continue to observe, terminate until being tested after 7 days.Such as
At dead 3 or more than 3, its LD50 was determined using median lethal dose method in three days for fruit animal.)
Median lethal dose method trial test takes KM mouse, male and female half and half, divides some groups at random, every group 4, respectively each chemical combination
Thing 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, by 0.2ml/10g gastric infusions, observe in animal 1-3 days
Death condition.
As a result:The LD that mouse single gavages50More than 2000mg/kg, significantly larger than Risperidone (82.1mg/kg), have compared with
Small acute toxicity.
Inhibiting rate or IC50 of the compound of table 2 to each acceptor
Animal model test result in the preferred compound body of table 3.
Example of formulations
Embodiment 56, the compound prepared respectively using embodiment 1-45 are as active component, by taking Tabules as an example, according to
Formula as below prepares the pharmaceutical composition of the present invention:
It is standby that supplementary material is crossed into 80 mesh sieves, recipe quantity active component, microcrystalline cellulose, lactose, PVP K30 is weighed, adds
Enter into mixed at high speed preparation machine, stirring at low speed is well mixed, and adds appropriate purified water, stirring at low speed, and high-speed cutting is pelletized, so
Afterwards by wet granular in 60 DEG C of dry 3h, 24 mesh sieve whole grains, and recipe quantity carboxyrnethyl starch sodium, silica and magnesium stearate are added,
Always mix, rotary pelleting machine tabletting, produce the pharmaceutical composition of Tabules.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description
Point is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office
Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area
Art personnel can be tied the different embodiments or example and the feature of different embodiments or example described in this specification
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (10)
- A kind of 1. compound, before it is the pharmaceutically acceptable salt of compound shown in compound shown in Formulas I or Formulas I or it Medicine,Wherein:Z is substituted or unsubstituted-(CH2)n-, n is 1~6 integer, and the substituent is the carbon in hydroxyl or methyl, or Z Contain double bond or oxygen atom on chain;Q is N or CH;R1For hydrogen, halogen, C1-5Alkoxy, substituted or unsubstituted C1-5One or more in alkyl;R2For hydrogen, C1-5Alcoxyl Base, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted aryl, wherein described One or more of the substituent in alkyl, cyano group, hydroxyl or halogen;Or R1And R2Five are formed together with coupled carbon The cyclic alkyl or phenyl of~heptatomic ring;R3For hydrogen, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C3-7Cycloalkyl, substituted or unsubstituted aryl, its Described in one or more of the substituent in alkyl, cyano group, hydroxyl or halogen;R4For substitution or unsubstituted phenyl, Formula II compound, formula III compound, formula IV compound or Formula V compound, the substitution Base is halogen, cyano group, substituted or unsubstituted C1-5Alkyl, formamide or hydroxyl;Wherein, in Formula II, Y is N or CH, X are O or S;R5For H, halogen or formamide.
- 2. compound according to claim 1, it is characterised in that:The Z is substituted or unsubstituted-(CH2)n-, n 1 ~4 integer, the substituent are the one or more in hydroxyl, carbonyl and methyl.
- 3. compound according to claim 1, it is characterised in that:The halogen is fluorine, chlorine, bromine, iodine.
- 4. compound according to claim 1, it is characterised in that described R4For Formula II compound, X O, Y CH, NH, R5Selected from hydrogen, fluorine, chlorine, bromine, iodine or formamide;X is S, Y CH, NH, R5For hydrogen;R4For substituted phenyl, described substituent One or more in methoxyl group, trifluoromethyl, methyl, ethyl fluoride, chlorine, bromine, iodine, cyano group.
- 5. compound according to claim 1, it is characterised in that:The R1、R2、R3It is separately hydrogen, phenyl, halogen For phenyl, C1-5The C of alkyl, halo1-5Alkyl or C1-5Hydroxyalkyl or R1And R2Five~heptatomic ring is formed together with coupled carbon Cyclic alkyl or phenyl.
- 6. compound according to claim 5, it is characterised in that:The R1、R2、R3Separately for hydrogen, fluorine, phenyl, Methyl, ethyl, propyl group, trifluoromethyl or methylol or R1And R2Hexamethylene or phenyl are formed together with coupled carbon.
- 7. according to any described compound of claim 1~6, it is characterised in that the compound be following compounds extremely It is one of few, or the stereoisomer of at least one of described following compounds, dynamic isomer, nitrogen oxides, solvate, Metabolite, pharmaceutically acceptable salt or its prodrug:2- (3,4- dichlorophenyls) -6- (3- (4- (4- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (2- methoxyphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (pyridine -2- bases) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (base of pyrimidine -2) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;6- (3- (4- (2- chlorphenyls) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (4- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (2- fluorophenyls) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (3- trifluoromethyls) phenyl) piperazine -1- bases) propoxyl group) pyridazine -3 (2H) -one;4- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) propyl group) piperazine -1- bases) cyanophenyl;6- (3- (4- benzyl diethylenediamine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (4- fluoro benzoyls) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -one;6- (3- (4- (benzo [b] thiene-3-yl) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;3- (4- (3- ((1- (3,4- dichlorophenyls) -6- oxo -1,6- dihydrogen dazin -3- bases) epoxide) propyl group) piperazine -1- bases) Benzofuran -5- formamides;6- (3- (4- (1H- indyl -3- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;6- (3- (4- (benzo [d] isothiazolyl -3- bases) piperazine -1- bases) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;6- (3- (4- (benzo [d] thiazolyl -2- bases) piperidin-1-yl) propoxyl group) -2- (3,4- dichlorophenyls) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butoxy) pyridazine -3 (2H) -one;6- (4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) butoxy) -2- (4- fluorophenyls) pyridazine -3 (2H) -one;(E) -2- (3,4- dichlorophenyls) -6- ((4- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) but-2-ene -1- Base) epoxide) pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- ((5- (4- ((6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl)) amyl group) epoxide) rattle away Piperazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -4,5- diformazans Radical pyridazine -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -5,6,7,8- Tetrahydrochysene dai piperazine -1 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group)-dai piperazine -1 (2H) -one;6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) -2- (4- fluorophenyls) pyridazine -3 (2H) -one;6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- phenyl pyridazine -3 (2H) -one;6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (4- aminomethyl phenyls) pyridazine -3 (2H) -one;6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazolyl -3- bases) piperidin-1-yl) propoxyl group) -2- (naphthalene -2- bases) pyridazine -3 (2H) -one;2- (4- chlorphenyls) -6- (3- (4- (fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -one;2- (3- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -one;2- (2- chlorphenyls) -6- (3- (4- (6- fluorobenzene simultaneously [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group) pyridazine -3 (2H) -one;2- (2,3- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (2,4 dichloro benzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (2,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (3,5- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (3,4- dichlorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (2,4 difluorobenzene base) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (2,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (2,6- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (3,5- difluorophenyls) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;2- (the chloro- 4- fluorophenyls of 3-) -6- (3- (4- (6- fluorobenzene [d] isoxazole -3- bases) piperidin-1-yl) propoxyl group pyridazines -3 (2H) -one;6- (3- (4- (2,3- dichlorophenyls) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) pyridazine -3 (2H) -one;6- (3- (4- (benzo [d] isothiazole -3- bases) piperazine -1- bases) propoxyl group) -2- (4- fluorophenyls) pyridazine -3 (2H) -one.
- 8. a kind of pharmaceutical composition, it is characterised in that containing the compound described in any one of claim 1~7, optionally enter one Step includes pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.
- 9. the pharmaceutical composition described in compound or claim 8 described in any one of claim 1~7 is preparing treatment god Through the application in mental disorder medicine.
- 10. application according to claim 9, it is characterised in that the Nervous and mental diseases are schizophrenia.
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