CN104557726A - Aromatic heterocyclic derivatives and application thereof in medicaments - Google Patents
Aromatic heterocyclic derivatives and application thereof in medicaments Download PDFInfo
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- CN104557726A CN104557726A CN201410557556.0A CN201410557556A CN104557726A CN 104557726 A CN104557726 A CN 104557726A CN 201410557556 A CN201410557556 A CN 201410557556A CN 104557726 A CN104557726 A CN 104557726A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/22—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms directly attached to ring nitrogen atoms
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Abstract
The invention provides aromatic heterocyclic derivatives or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, which are used for treating Alzheimer's disease. The invention also discloses pharmaceutical compositions containing the compounds and a method for treating Alzheimer's disease by using the compounds or the pharmaceutical compositions provided by the invention.
Description
Technical field
The invention belongs to drug world and relate to the compound being used for the treatment of Alzheimer's disease, the composition and use thereof comprising described compound and using method.Especially, compound of the present invention is can as 5-HT
6the fragrant heterocyclic derivative of receptor antagonist.
Background technology
Multiple central nervous system disease such as anxiety, depression etc. are all relevant with the disorder of neurotransmitter serotonin (5-HT) or serotonin.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) is by being called as 5-HT
1, 5-HT
2, 5-HT
3, 5-HT
4, 5-HT
5, 5-HT
6and 5-HT
7a large amount of receptor families mediations.Based on 5-HT high-caliber in brain
6receptor mrna, proposes 5-HT
6receptor may play a role in the pathology of central nervous system disorders and treatment.Specifically, 5-HT is determined
6selective ligands has potential therapeutical effect to some CNS disease, and such as parkinson disease, Huntington Chorea, anxiety neurosis, depression, manic depressive illness, psychosis, epilepsy, obsession, migraine, Alzheimer's disease (cognition and memory enhancing), sleep disorder, eating disorders are as anorexia and bulimia nerovsa, panic attack, ADHD, attention deficit disorder, Drug abuse such as ***e, ethanol, nicotine and benzodiazepine
the de-recessive brain syndrome that class causes, schizophrenia and the disease relevant with spinal trauma or head injury are as hydrocephalus.Estimate that described compound also can be used for treating some stomach intestinal disease as functional intestinal disease.(see such as Roth, B.L. etc., J.Pharmacol.Exp.Ther., 268,1403-14120 page (1994), Sibley, D.R. etc., Mol, Pharmacol., 43,320-327 (1993), A.J.Sleight etc., Neurotransmission, 11,1-5 (1995) and Sleight, A.J. etc., Serotonin ID Research Alert, 1997,2 (3), 115-8).Research finds, known 5-HT
6selective antagonist improves the level of glutamic acid in cortex of frontal lobe and aspartic acid significantly, and does not improve hormone, dopamine or 5-HT on nor-kidney
6level.The selectivity of this specific neurochemical noticed in memory and cognition process raises and indicates 5-HT consumingly
6effect (Dawson, the L.A. of part in cognition; Nguyen, H.Q.; Li, P., British Journal of Pharmacology, 2000,130 (1), 23-26).With known selectivity 5-HT
6effect (Rogers, D.C. that the research that the memory of antagonists in animals and study are carried out has some positive; Hatcher, P.D.; Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).5-HT
6the relevant potential therapeutic use of part is the ADD for the treatment of child and adult.Because 5-HT
6antagonist seems the activity that improve nigrostriatal dopamine approach, and because ADHD (Ernst, M relevant to the exception in caudatum; Zametkin, A.J.; Matochik, J.H.; Jons, P.A.; Cohen, R.M., Journal of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT
6antagonist can treat ADD.Also determine 5-HT
6antagonist is the potentially useful compound for the treatment of of obesity.See such as Bentley etc., Br.J.Pharmac.1999, supplementary issue 126; Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255; Wooley etc., Neuropharmacology 2001,41:210-129 and WO02098878.
Summary of the invention
The present invention relates to the method for new fragrant heterocyclic derivative and treatment Alzheimer's disease.The compounds of this invention or comprise described compound pharmaceutical composition to 5-HT
6receptor has good affinity interaction, particularly has good therapeutic effect to Alzheimer's disease.
On the one hand, the present invention relates to a kind of compound, it is the stereoisomer of structure shown in the structure shown in formula I or formula I, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
Y is CH or N;
When
during for singly-bound, X is CH or N; When
during for double bond, X is C;
R
1for H, D, C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6ar
7n-C
1-6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl-C
1-6alkylidene or C
1-9heteroaryl-C
1-6alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, NO
2, OH, NH
2, R
6ar
6n-,-C (=O) R
6,-C (=O) NR
6r
6a,-N (R
6) C (=O)-R
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6s (=O)
2n (R
6athe C that)-, hydroxyl replaces
1-6alkyl, R
6ar
6n-C
1-
6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, R
6ar
6n-C
1-6alkylene oxide group, R
6s (=O)-C
1-6alkylene oxide group, R
6r
6an-C (=O)-C
1-6alkylene oxide group, C
6-10aryl, C
1-9heteroaryl, C
1-6alkoxyl, C
1-6alkylamino, C
1-6alkyl, C
1-6haloalkyl, C
1-6halogenated alkoxy, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
1-6alkylthio group, C
6-10aryl-C
1-6alkyl or C
1-9heteroaryl-C
1-6alkylidene; Or adjacent two R
2the optional 5-6 replaced former molecular carbocyclic ring, heterocycle, aromatic rings or a fragrant heterocycle is formed with the carbon atom be attached thereto;
Each R
4be H, D, F, Cl, Br, I, CN independently, oxo (=O), C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl, C
1-6halogenated alkoxy or C
6-10aryl-C
1-4alkylidene;
R
5for H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-6alkyl, C
1-6haloalkyl, C
3-8cycloalkyl, C
1-6alkoxyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, C
6-10aryl or C
6-10aryl-C
1-6alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkoxyl or C
6-10aryl.
Wherein in some embodiments, R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, or C
6-10aryl-C
1-4alkylidene.
Wherein in some embodiments, each R
2and R
3be separately H, D, F, Cl, Br, I, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or adjacent two R
2the optional 5-6 replaced a former molecular aromatic rings or fragrant heterocycle is formed with the carbon atom be attached thereto.
Wherein in some embodiments, each R
4be H, D, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl.
Wherein in some embodiments, R
5for H, D, F, Cl, Br, I ,-COOH, C
1-4alkyl, C
3-6cycloalkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene.
Wherein in some embodiments, the present invention has the stereoisomer of structure shown in structure as shown in formula II or formula II, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6aor C
6-10aryl-C
1-4alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or the R that two adjacent
2the optional 5-6 replaced a former molecular aromatic rings or fragrant heterocycle is formed with the carbon atom be attached thereto;
Each R
4be H, D, CN, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl;
R
5for H, D, F, Cl, Br, I, C
1-4alkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-4alkyl, C
1-4assorted alkyl or C
1-4haloalkyl.
Wherein in some embodiments, R
1for H, D, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, cyclopropyl or cyclobutyl.
In other embodiments, each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl or cyclobutyl; Or adjacent two R
2the optional phenyl ring replaced is formed with the carbon atom be attached thereto.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound of the present invention, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or their combination.
Wherein in some embodiments, pharmaceutical composition of the present invention, it further comprises the medicine for the treatment of Alzheimer's disease, for medicine or their combination of nervous disorders.
In other embodiments, the medicine for the treatment of Alzheimer's disease is donepezil, nalmefene, risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, tacrine, Rivastigmine, galantamine, memantine, meter Ta Zhaping, venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination.
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition is preparing the purposes in medicine, described medicine is used for the treatment of or prevents and 5-HT
6relevant disease.
Wherein in some embodiments, the present invention relates to and 5-HT
6relevant CNS disease is: ADHD, anxiety, the disease relevant to psychentonia, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea.
In other embodiments, to the present invention relates to and 5-HT
6relevant disease is disorder of gastrointestinal tract.
In other embodiments, to the present invention relates to and 5-HT
6relevant disease is obesity.
The present invention relates to the preparation of the compound shown in formula I, the method for abstraction and purification on the other hand.
Biological results shows, compound provided by the invention can be used as good 5-HT
6antagonist.Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.These aspects and otherwise content will do more specifically complete description below.
Detailed description of the invention
definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinate, and these may be included in existing invention field as defined by the following claims like that.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the present patent application the scope that controls.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element according to the periodic table of elements, CAS version and Chemical Physics handbook, 75
thed., 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry ", Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged list of references.
As described in the present invention, compound of the present invention can optionally replace by one or more substituent group, as general formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or unsubstituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituent group.Unless other aspects show, an optional substituted radical can have a substituent group to replace in each commutable position of group.Not only one or more substituent groups that position can be selected from concrete group in given structural formula replaced, and so substituent group can replace in each position identical or differently.Wherein said substituent group can be, but be not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano group, azido, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl that hydroxyl replaces, the alkoxyl that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)
2-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces
2-, Carboxyalkoxy etc.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the whole text in this article " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, and all should be interpreted broadly, it both can refer in different group, do not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect, with R mutually between concrete option expressed between same-sign
6for example, structural formula "-N (R
6) C (=O) NR
6r
6a" and structural formula "-OC (=O) OR
6" R between the two
6concrete option mutually between unaffected, meanwhile, at same chemical formula "-N (R
6) C (=O) NR
6r
6a" in, multiple R
6concrete option mutually between unaffected.
The term " alkyl " that the present invention uses represents the saturated straight chain of 1-20 carbon atom or the univalence hydrocarbyl of side chain.In certain embodiments, alkyl group comprises 1-6 carbon atom, and in further embodiments, alkyl group comprises 1-4 carbon atom.The example of alkyl comprises, but is not limited to, methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), n-pro-pyl (n-Pr ,-CH
2cH
2cH
3), isopropyl (i-Pr ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2cH
2cH
2cH
3), isobutyl group (i-Bu ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2cH
3), the tert-butyl group (t-Bu ,-C (CH
3)
3), n-pentyl (-CH
2cH
2cH
2cH
2cH
3), 2-amyl group (-CH (CH
3) CH
2cH
2cH
3), 3-amyl group (-CH (CH
2cH
3)
2), 2-methyl-2-butyl (-C (CH
3)
2cH
2cH
3), 3-methyl-2-butyl (-CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (-CH
2cH
2cH (CH
3)
2), 2-methyl-1-butene base (-CH
2cH (CH
3) CH
2cH
3), n-hexyl (-CH
2cH
2cH
2cH
2cH
2cH
3), 2-hexyl (-CH (CH
3) CH
2cH
2cH
2cH
3), 3-hexyl (-CH (CH
2cH
3) (CH
2cH
2cH
3)), 2-methyl-2-amyl group (-C (CH
3)
2cH
2cH
2cH
3), 3-methyl-2-amyl group (-CH (CH
3) CH (CH
3) CH
2cH
3), 4-methyl-2-amyl group (-CH (CH
3) CH
2cH (CH
3)
2), 3-methyl-3-amyl group (-C (CH
3) (CH
2cH
3)
2), 2-methyl-3-amyl group (-CH (CH
2cH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (-C (CH
3)
2cH (CH
3)
2), 3,3-dimethyl-2-butyl (-CH (CH
3) C (CH
3)
3), etc.
Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.
The term " alkylidene " that the present invention uses, can be used alone or as most of " aryl-alkylidene " or " heteroaryl-alkylene ", represent the saturated bivalent hydrocarbon radical obtained from straight or branched saturated hydrocarbon cancellation two hydrogen atoms.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, some of them embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is, alkylidene group contains 1-4 carbon atom, other embodiment is, alkylidene group contains 1-3 carbon atom, and other embodiment is, alkylidene group contains 1-2 carbon atom.The example of alkylidene group comprises, but is not limited to, methylene (-CH
2-), ethylidene (-CH
2cH
2-), propylidene (-CH
2cH
2cH
2-), ethylidine (-CH (CH
3)-), secondary isopropyl (-CH (CH
3) CH
2-) etc.Alkylidene can be further substituted, and this substituent group is selected from, but is not limited to, deuterium, fluorine; chlorine, bromine, iodine, cyano group, nitro; azido, alkyl, haloalkyl, alkenyl, alkynyl; hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl, cyanoalkyl; hydroxyl, alkoxyl, sulfydryl, alkylthio group, amino; alkylamino, aminoacyl, alkylamino acyl group, aryl, heteroaryl etc.
Term " thiazolinyl " represents the monovalent hydrocarbon of the straight or branched of 2-12 carbon atom, and wherein at least one position is undersaturated condition, and namely a C-C is sp
2double bond.In certain embodiments, alkenyl group comprises 2-6 carbon atom, and in further embodiments, alkenyl group comprises 2-4 carbon atom.Wherein alkenyl group can independently and optionally replace by one or more substituent group described in the invention, comprising group has negation, " suitable " or " E ", the location of " Z ", the example that wherein thiazolinyl is concrete comprises, but is not limited to, vinyl (-CH=CH
2), pi-allyl (-CH
2cH=CH
2), etc.
Term " alkynyl " represents the monovalent hydrocarbon of the straight or branched of 2-12 carbon atom, and wherein at least one position is undersaturated condition, and namely a C-C is sp triple bond.In certain embodiments, alkynyl group comprises 2-6 carbon atom, and in further embodiments, alkynyl group comprises 2-4 carbon atom.Wherein alkynyl group can independently and optionally replace by one or more substituent group described in the invention, the example that wherein alkynyl is concrete comprises, but is not limited to, acetenyl (-C ≡ CH), propargyl (-CH
2c ≡ CH), etc.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as is connected with oxygen atom, forms oh group.
Term " D " or "
2h " represent single D-atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (-CDH
2), two D-atoms are connected with a methyl, form two-deuterated methyl (-CD
2h), and three D-atoms are connected with a methyl, form three-deuterated methyl (-CD
3).
Term " hetero atom " represents one or more O, S, N, P and Si atom, comprises N, the form of any oxidation state of S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N in such as 3,4-dihydro-2 h-pyrrole bases), NH (NH in such as pyrrolidinyl) or NR (NR in the pyrrolidinyl that such as N-replaces).
Term " halogen " refers to F, Cl, Br or I.
Term " undersaturated " used in the present invention represents that structure division contains one or more degree of unsaturation.
Term " alkyl that hydroxyl replaces " represents that alkyl group is optionally substituted with one or more hydroxyl group and replaces, and wherein alkyl group has implication of the present invention.Such example comprises, but is not limited to methylol, ethoxy, 1,2-dihydroxy ethyl etc.
The present invention use term " haloalkyl " represent alkyl group replace by one or more identical or different halogen atom, wherein alkyl group has implication as described in the present invention, halogen atom and fluorine, chlorine, bromine or iodine.Some of them embodiment is, C
1-6haloalkyl be the alkyl group of 1-6 carbon atom replace by one or more identical or different halogen atom, other embodiment is, C
1-4haloalkyl be the alkyl group of 1-4 carbon atom replace by one or more identical or different halogen atom, such example comprises, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, methyl fluoride etc.
Term " alkoxyl ", can be used alone or as the part of " halogenated alkoxy " or " alkylene oxide group ", represent that alkyl group is connected with molecule remainder by oxygen atom, wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom, and some of them embodiment is, alkoxy base contains 1-6 carbon atom, and other embodiment is, alkoxy base contains 1-4 carbon atom.The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH
3), ethyoxyl (EtO ,-OCH
2cH
3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH
2cH
2cH
3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH
3)
2), 1-butoxy (n-BuO, n-butoxy ,-OCH
2cH
2cH
2cH
3), 2-methyl-l-propoxyl group (i-BuO, i-butoxy ,-OCH
2cH (CH
3)
2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH
3) CH
2cH
3), 2-methyl-2-propoxyl group (t-BuO, t-butoxy ,-OC (CH
3)
3) etc.And described alkoxyl can be substituted or unsubstituted, and wherein substituent group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfydryl, nitro etc.
The present invention use term " halogenated alkoxy " represent alkoxy base replace by one or more identical or different halogen atom, wherein alkoxy base has implication as described in the present invention, halogen atom and fluorine, chlorine, bromine or iodine.Some of them embodiment is, C
1-6halogenated alkoxy be the alkoxy base of 1-6 carbon atom replace by one or more identical or different halogen atom, such example comprises, but is not limited to trifluoromethoxy, trifluoro ethoxy, chlorine methoxyl group, fluorine methoxyl group etc.
Term " alkylthio group " comprises C
1-6the alkyl of straight or branched is connected on the sulphur atom of bivalence.Some of them embodiment is, alkylthio group is more rudimentary C
1-4alkylthio group, such example comprises, but is not limited to methyl mercapto (CH
3s-).
Term " alkylamino " comprises " N-alkyl amino " and " N, N-dialkyl amido ", wherein amine groups separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C
1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C
1-4more rudimentary alkylamino group.Suitable alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc.
Term " ring " comprises carbocyclic ring, heterocycle, aromatic rings, fragrant heterocycle, volution, spiroheterocyclic, condensed ring, condensed hetero ring etc., wherein said carbocyclic ring, heterocycle, aromatic rings, fragrant heterocycle, volution, spiroheterocyclic, condensed ring, and condensed hetero ring group has implication as described in the present invention.
Term " alicyclic group ", " annular aliphatic base ", " carbocyclic ring ", " carbocylic radical " refers to monovalence or multivalence, non-aromatic, the undersaturated ring of saturated or part, and do not comprise hetero atom, comprising the monocycle of 3-6 carbon atom or the bicyclo-of 7-12 carbon atom.The bicyclic carbocyclic with 7-12 atom can be bicyclo-[4,5], [5,5], and [5,6] or [6,6] system, has the bicyclic carbocyclic of 9 or 10 atoms simultaneously, can be bicyclo-[5,6] or [6,6] system.Suitable annular aliphatic base comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.Some of them embodiment is, " cycloalkyl " is the ring of 3-8 carbon atom composition.The example of " annular aliphatic base " comprises, but is never limited to, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-thiazolinyl, 1-cyclopenta-2-thiazolinyl, 1-cyclopenta-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl etc.And described " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " cycloalkyl " can be substituted or unsubstituted, and wherein substituent group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxyl that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)
2-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces
2-, Carboxyalkoxy etc.
Term " " heterocycle " ", " " heterocyclic radical " ", " " assorted alicyclic " " or " " heterocycle " " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, on its medium ring one or more carbon atom independent and optionally replace by hetero atom, described hetero atom has implication as described in the present invention, and ring can be completely saturated or comprise one or more degree of unsaturation, but be never the fragrant same clan, only have a junction point to be connected to other molecules and get on.One or more ring hydrogen atom independent and optionally replace by one or more substituent group described in the invention.Some of them embodiment is, " " heterocycle " ", " " heterocyclic radical " ", " " assorted alicyclic " or " " heterocycle " " group be 3-8 former molecular monocycle (1-6 carbon atom be selected from N; 1-3 the hetero atom of O, P, S; at this S or P optionally replace by one or more oxygen atom and obtain such as SO, SO
2, PO, PO
2group, when described ring is three-membered ring, wherein only have a hetero atom), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, O, P, 1-3 the hetero atom of S, at this S or P optionally replace by one or more oxygen atom and obtain such as SO, SO
2, PO, PO
2group), other embodiment is, " heterocycle " is 2-10 carbon atom and be selected from N, O, the group of the hetero atom composition of P, S, other embodiment is, " heterocycle " is 4-7 carbon atom and is selected from N, the group of the heteroatomic composition of O, P, S.
Heterocyclic radical can be carbon back or hetero atom base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.The example of heterocycle comprises, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl ， thioxane base, thiazolidinyl ， oxazolidinyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxepane base, thia suberyl, 4-Methoxy-piperidin-1-base, 1,2,3,6-tetrahydropyridine-1-base, oxygen azepine
base, diaza
base, sulfur azepine
base, pyrrolin-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranose, 4H-pyranose, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 1, 2, 6-thiadiazine alkane 1, 1-dioxo-2-base, 4-hydroxyl-1, 4-azepine phosphine 4-oxide-1-base, 2-hydroxyl-1-(piperazine-1-base) ethyl ketone-4-base, 2-hydroxyl-1-(5, 6-dihydro-1, 2, 4-triazine-1 (4H)-Ji) ethyl ketone-4-base, 5, 6-dihydro-4H-1, 2, 4-oxadiazine-4-base, 2-hydroxyl-1-(5, 6-dihydropyridine-1 (2H)-Ji) ethyl ketone-4-base, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2-methyl-5, 6, 7, 8-tetrahydrochysene-[1, 2, 4] triazole [1, 5-c] pyrimidine-6-base, 4, 5, 6, 7-tetrahydrochysene isoxazole [4, 3-c] pyridine-5-base, 3H-indyl 2-oxygen-5-azabicyclo [2.2.1] heptane-5-base, 2-oxygen-5-azabicyclo [2.2.2] octane-5-base, quinolizinyl and N-pyridine radicals carbamide.The example of heterocyclic group also comprises, 1,1-dioxothiomorpholinyl, and on its medium ring two carbon atoms replace by oxygen atom as hybar X base.And described heterocyclic radical can be substituted or unsubstituted, and wherein substituent group can be, but is not limited to, oxo, hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxyl that hydroxyl replaces, alkyl-the C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-alkyl-S (=O)
2-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces
2-, Carboxyalkoxy etc.
Term " aryl " can be used alone or conduct " aralkyl ", a part for " aralkoxy " or " aryloxy alkyl ", represent the monocycle altogether containing 6-10 ring, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the remainder of molecule.Term " aryl " can exchange with term " aromatic rings " and use, as aromatic rings can comprise phenyl, and naphthyl and anthryl.And described aryl can be optional replacement, and wherein substituent group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxyl that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)
2-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces
2-Carboxyalkoxy, etc.
Term " aralkyl ", " aryl-alkyl " comprises the alkyl group that aryl replaces.Some of them embodiment is, aromatic alkyl group refers to " more rudimentary aralkyl " group, and namely aromatic yl group is connected to C
1-6alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C
1-4" the benzene alkylene " of alkyl.Wherein instantiation comprises benzyl, diphenyl methyl, phenethyl.Aryl on aralkyl can further by halogen, alkyl, alkoxyl, and haloalkyl and halogenated alkoxy replaced.
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", represent the monocycle altogether containing 5-10 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more hetero atom, and wherein hetero atom has implication of the present invention, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule remainder.Some of them embodiment is, " heteroaryl alkyl " is 1-9 carbon atom and is selected from N, the monocycle of the hetero atom composition of O, P, S or dicyclo.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or unsubstituted, and wherein substituent group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxyl that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)
2-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces
2-, Carboxyalkoxy etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, pyrimidine-5-base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazole radical (as 5-tetrazole radical), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, 1, 3, 4-thiadiazoles-2-base, pyrazinyl, pyrazine-2-base, 1, 3, 5-triazine radical, benzo [d] thiazol-2-yl, imidazo [1, 5-a] pyridine-6-base, also following dicyclo is comprised, such example comprises, but is not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
As described in the invention, substituent group is drawn a key and is connected to the member ring systems (as follows) that the ring at center is formed and represents substituent group any commutable position on ring and can replace.Such as, formula e represents any position that may be substituted on A ring, such as formula f
1?f
4shown in.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with geometrical isomerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometric isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatic (C as prodrug
1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphate ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" metabolite " refers to concrete compound or its salt in vivo by product that metabolism obtains.The metabolite of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the metabolite of compound, comprise and compound of the present invention and mammal fully contacted the metabolite that a period of time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994.Compound of the present invention can comprise asymmetric center or chiral centre, therefore there is different stereoisomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound linearly polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific stereoisomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereo selectivity or stereoselectivity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by protolysis, as the isomerization of keto-enol and imine-enamine.Atomicity (quantivalence) tautomer comprises the change reassembling into bonding electron.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmaceutically acceptable salt in affiliated field known by us, as document: S.M.Berge et al., J.Pharmaceutical Sciences, 66:1-19, described in 1977.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate is as acetate, oxalates, maleate, tartrate, citrate, succinate, malonate, or obtain these salt by additive method such as ion exchange described on books document.Other pharmaceutically acceptable salts comprise adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises alkali metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or alkali salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmaceutically acceptable salt comprises suitable, nontoxic ammonium further, the amine cation that quaternary ammonium salt and gegenions are formed, as halogenide, and hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C
1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxine, ethyl acetate, acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " refers to a substituent group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituent group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises acetyl group; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and the sub-methoxycarbonyl group (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituent group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises acetyl group and silicyl." carboxy protective group " refers to that the substituent group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH
2cH
2sO
2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can list of references for the general description of blocking group: T.W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Term " ADHD " is the abbreviation of Attention-deficit hyperactivity disorder, means attention deficit hyperactivity disorder, be a kind of childhood period very common psychataxia.According to " Global Access classification of diseases handbook " the tenth edition (ICD-10 of World Health Organization (WHO), WHO, 1992) claim this disease for " hyperactivity disorder " (Hyperkinetic Disorder), classifying and numbering is F90, is generally commonly called as again as " crossing dynamic youngster ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and psychotic disorder, and wherein term " psychosis " refers to vain hope, significantly hallucination, amorphous language or unorganized behavior or stiffization behavior.See Diagnostic and Statistical Manual of Mental Disorder, the 4th edition, American Psychiatric Association, Washington, D.C..
the description of the compounds of this invention
The fragrant heterocyclic derivative that the present invention relates to, its pharmaceutically acceptable salt, and pharmaceutical preparation, have antagonism 5-HT
6, especially have potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compound, it is the stereoisomer of structure shown in the structure shown in formula I or formula I, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
Y is CH or N;
When
during for singly-bound, X is CH or N; When
during for double bond, X is C;
R
1for H, D, C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6ar
7n-C
1-6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl-C
1-6alkylidene or C
1-9heteroaryl-C
1-6alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, NO
2, OH, NH
2, R
6ar
6n-,-C (=O) R
6,-C (=O) NR
6r
6a,-N (R
6) C (=O)-R
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6s (=O)
2n (R
6athe C that)-, hydroxyl replaces
1-6alkyl, R
6ar
6n-C
1-6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, R
6ar
6n-C
1-6alkylene oxide group, R
6s (=O)-C
1-6alkylene oxide group, R
6r
6an-C (=O)-C
1-6alkylene oxide group, C
6-10aryl, C
1-9heteroaryl, C
1-6alkoxyl, C
1-6alkylamino, C
1-6alkyl, C
1-6haloalkyl, C
1-6halogenated alkoxy, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
1-6alkylthio group, C
6-10aryl-C
1-6alkyl or C
1-9heteroaryl-C
1-6alkylidene; Or adjacent two R
2the optional 5-6 replaced former molecular carbocyclic ring, heterocycle, aromatic rings or a fragrant heterocycle is formed with the carbon atom be attached thereto;
Each R
4be H, D, F, Cl, Br, I, CN independently, oxo (=O), C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl, C
1-6halogenated alkoxy or C
6-10aryl-C
1-4alkylidene;
R
5for H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-6alkyl, C
1-6haloalkyl, C
3-8cycloalkyl, C
1-6alkoxyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, C
6-10aryl or C
6-10aryl-C
1-6alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkoxyl or C
6-10aryl.
Wherein in some embodiments, R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, or C
6-10aryl-C
1-4alkylidene.
Wherein in some embodiments, each R
2and R
3be separately H, D, F, Cl, Br, I, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or adjacent two R
2the optional 5-6 replaced a former molecular aromatic rings is formed with the carbon atom be attached thereto.
Wherein in some embodiments, each R
4be H, D, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl.
Wherein in some embodiments, R
5for H, D, F, Cl, Br, I ,-COOH, C
1-4alkyl, C
3-6cycloalkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene.
Wherein in some embodiments, the present invention has the stereoisomer of structure shown in structure as shown in formula II or formula II, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6aor C
6-10aryl-C
1-4alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or the R that two adjacent
2the optional 5-6 replaced a former molecular aromatic rings is formed with the carbon atom be attached thereto;
Each R
4be H, D, CN, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl;
R
5for H, D, F, Cl, Br, I, C
1-4alkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-4alkyl, C
1-4assorted alkyl or C
1-4haloalkyl.
Wherein in some embodiments, R
1for H, D, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, cyclopropyl or cyclobutyl.
In other embodiments, each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl or cyclobutyl; Or adjacent two R
2the optional phenyl ring replaced is formed with the carbon atom be attached thereto.
Wherein in some embodiments, the present invention comprises one of them structure following:
or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
The present invention also comprises the application of compound of the present invention and pharmaceutically acceptable salt thereof, for the production of medical product treatment Alzheimer's disease, comprises that those are described in the invention.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treatment 5-HT
6the disease mediated, particularly Alzheimer's disease.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula formula I or formula II and the pharmaceutically acceptable carrier of at least one, the effective treatment consumption needed for the combination of adjuvant or diluent.
Unless other aspects show, the stereoisomer that compound of the present invention is all, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmaceutically acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or compositions, relevant with other components of composition preparation and the mammal that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purification formula I or formula II shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula I or formula II, but not necessarily pharmaceutically acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartaric acid; Aminoacid, as aspartic acid and glutamic acid; Aromatic acid, as benzoic acid and cinnamic acid; Sulfonic acid, as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses inorganic base or organic base, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxide, etc.Suitable salt comprises, but is not limited to, and from the organic salt that aminoacid obtains, as glycine and arginine, ammonia, as uncle ammonia, parahelium and tertiary ammonia, with ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium obtain inorganic salt.
the compounds of this invention and pharmaceutical composition, preparation and administration
When can be used for treatment, the treatment formula I of effective dose or formula II compound and pharmaceutically acceptable salt thereof can be used as unprocessed chemical drugs and give, and the active component that also can be used as pharmaceutical composition provides.Therefore, present disclosure also provides pharmaceutical composition, and this pharmaceutical composition comprises the formula formula I or formula II compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent or excipient for the treatment of effective dose.
Comprise the Therapeutic Method of the compounds of this invention or pharmaceutical composition administration, comprise administration patient being carried out to other anti-Alzheimer disease drugs (therapeutic alliance) further, wherein the medicine of other anti-Alzheimer diseases is selected from donepezil, nalmefene, risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, tacrine, Rivastigmine, galantamine, memantine, meter Ta Zhaping, venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination.
Term as used herein " treatment effective dose " refers to the total amount of each active component being enough to demonstrate significant patient benefit.When using independent active component individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause the combined amount of the active component of therapeutic effect.(I) or formula II compound and pharmaceutically acceptable salt described above.From compatible with other compositions of preparation and harmless to its receiver meaning, carrier, diluent or excipient must be acceptable.According to the another aspect of present disclosure, also be provided for the method for useful in preparing drug formulations, the method comprises and formula I or formula II compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent or excipient being mixed.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, compositions and/or dosage form, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, zest, allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.
Usually, compound of the present invention is applied to treat effective dose by any conventional method of application of the material for playing similar effectiveness.Suitable dosage range typically is 1-500mg every day, preferred every day 1-100mg, most preferably every day 1-30mg, this depends on many factors, such as the seriousness of institute's disease therapy, the age of subject and relative health, the effect of compound used therefor, the approach used and form, use for indication and the preference of relevant medical practitioner and experience.Treat the those of ordinary skill of described disease areas without the need to too much testing the treatment effective dose relying on the disclosure of personal knowledge and the application can determine the compounds of this invention of given disease.
Usually, compound of the present invention is used with pharmaceutical dosage forms, described pharmaceutical preparation comprise those be suitable for oral (comprising oral cavity and Sublingual), rectum, nose, locally, pharmaceutical preparation that lung, vagina or parenteral (comprise intramuscular, intra-arterial, sheath interior, subcutaneous and intravenous) are used or the pharmaceutical preparation that is suitable for sucking or being blown into administration form.Preferred method of application is generally oral, uses suitable daily dose scheme, can adjust according to disease degree to it.
One or more compounds of the present invention can be placed in pharmaceutical composition and unit dosage form together with one or more conventional adjuvant, carrying agent or diluent.Pharmaceutical composition and unit dosage form can comprise the conventional ingredient of conventional ratio, contain or do not contain other reactive compound or composition, and unit dosage form can contain the active component of any suitable effective dose matched with applied plan daily dose scope.The filling capsule that the application form of pharmaceutical composition can be solid such as tablet or filling capsule, semisolid, powder, slow releasing preparation or liquid such as solution, suspensoid, Emulsion, elixir or orally use; Or for the suppository form of rectum or vaginal application; Or for parenteral use sterile injectable solutions form.Therefore, in every sheet containing having an appointment 1mg active component or more broadly, the preparation containing 0.01 to about 100mg active component of having an appointment is suitable representational unit dosage form.
Compound of the present invention can be mixed with various Orally administered dosage form.Pharmaceutical composition and dosage form can comprise one or more compound or pharmaceutically acceptable salt thereofs of the present invention as active component.Pharmaceutically useful carrying agent can be solid or liquid.The preparation of solid form comprises: tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it also can be used as diluent, correctives, solubilizing agent, lubricant, suspending agent, binding agent, antiseptic, tablet disintegrant or coating material.In powder, carrier is generally the solid of porphyrize, and the active component of itself and porphyrize forms mixture.In tablets, active component usually mixes with the carrying agent with required adhesive power mutually with suitable ratio and is pressed into required shape and size.Powder and tablet are preferably containing the reactive compound of 1% to about 70% of having an appointment.Suitable carrying agent includes but not limited to carbonic acid money, magnesium stearate, Pulvis Talci, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter etc.Terms " formulation " is intended to comprise house has coating material as carrying agent to provide the preparation of the reactive compound of capsule, in described capsule the active component of with or without carrier surround by this carrying agent of combining with it.Similarly, cachet and lozenge is also comprised.Tablet, powder, capsule, pill, cachet and lozenge are all be suitable for Orally administered solid form.
Other is suitable for Orally administered form and comprises the preparation that the preparation (comprising Emulsion, syrup, elixir, aqueous solution agent, aqueous suspension) of liquid form or purport change the solid form of liquid form preparation before use at once into.Emulsion can be prepared in solution such as aqueous solution of propylene glycol maybe can contain emulsifying agent such as lecithin, Arlacel-80 or arabic gum.Aqueous solution agent is by adding suitable coloring agent, correctives, stabilizing agent and thickening agent to prepare in water by solubilize active ingredients.The active component of porphyrize to be dispersed in water by the glue with stickum such as natural or synthesis, resin, methylcellulose, sodium carboxymethyl cellulose and other known suspending agent by aqueous suspension to be prepared.The preparation of liquid form comprises solution, suspensoid and Emulsion, and except active component, it can also contain coloring agent, correctives, stabilizing agent, buffer agent, artificial with natural sweeting agent, dispersant, thickening agent, solubilizing agent etc.
Compound of the present invention can be formulated for parenteral use (such as, being used as bolus injection or continuous infusion by injection) and the syringe of ampoule, in advance fill can be present in a unit, low capacity infuse in or be present in and with the addition of in the multi-dose container of antiseptic.The adoptable form of compositions has suspensoid, solution or Emulsion such as in oiliness or aqueous vehicle, such as, solution in Aqueous Solutions of Polyethylene Glycol.The example of oiliness or non-aqueous carrying agent, diluent, solvent or excipient comprises propylene glycol, Polyethylene Glycol, vegetable oil (such as olive oil) and injection organic ester (such as ethyl oleate), and can containing formulating substances as antiseptic, wetting agent, emulsifying agent or suspending agent, stabilizing agent and/or dispersant.Or active component can be powder type, its preparation method be sterile solid is carried out without mattress subpackage or by by solution lyophilizing to build with suitable excipients such as aseptic, pyrogen-free water before use.
Compound of the present invention can be formulated for and be locally applied to epidermis with ointment, ointment or lotion form or with transdermal patch form.Ointment and ointment can such as be prepared by the aqueous or oleaginous base that with the addition of suitable thickening agent and/or gellant.Lotion can use or oleaginous base preparation and usually also containing one or more emulsifying agents, stabilizing agent, dispersant, suspending agent, thickening agent or coloring agent.Be suitable for the preparation of local application in mouth and comprise the lozenge comprising and be in flavored base, be generally the active component in sucrose and arabic gum or tragakanta; Comprise and be in the lozenge of inert base as the active component in gelatin and glycerol or sucrose and arabic gum; And comprise the collutory of the active component be in appropriate liquid carrying agent.
Compound of the present invention can be formulated for and use with suppository form.Can first by low melt wax as fatty glyceride mixt or cocoa butter fusing, and by active component such as by the dispersion that stirs.Then the homogeneous mixture of melting is poured in the mould of suitable size, make it cool and solidify.
Compound of the present invention can be formulated for vaginal application.Vaginal suppository in addition to the active ingredient (s also containing carrying agent known in this field, tampon, newborn blue or green agent, gel, paste, foam or spray are suitable.
Compound of the present invention can be formulated for nasal administration.Can by solution or suspensoid by conventional method, such as directly apply to nasal cavity with dropper, suction pipe or aerosol apparatus.Preparation can be single dose or multiple dose form.For the multiple dose form of dropper or suction pipe, this can by being used solution that is suitable, predetermined or suspensoid realizes by patient.For aerosol apparatus, this can such as be realized by metering atomising atomizing pump.
Compound of the present invention can be formulated for aerosol and use, and is particularly applied to respiratory tract and comprises intranasal administration.Compound has little granularity usually, the granularity of such as 5 microns or more decimal magnitude.Described granularity is by method well known in the art, such as obtain by micronization.Active component is to provide containing the suitable pressurized package of propellant as chlorofluorocarbon (CFC) such as dichlorodifluoromethane, Arcton 11 or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas.Aerosol also can contain surfactant as lecithin suitably.Drug dose controls by metering valve.Or, active component can with dry powdered form, such as at suitable powder base as lactose, starch, the mixture of powders form of starch derivatives as the compound in hydroxypropyl emthylcellulose and polyvinylpyrrolidone provide.Powder carrying agent will form gel in nasal cavity.Powder composition can such as exist with gelatine capsule agent or cartridge case or bubble Army packaged form in a unit ' by inhaler by wherein using powder.
When needing, preparation can be prepared with the enteric coating being suitable for slow release or controlled release and using active component.Such as, compound of the present invention can be formulated into transdermal or subcutaneous drug delivery device.When necessary slow release compounds and when the compliance of patient for treatment's scheme is most important, these delivery systems are favourable.Compound in transdermal delivery system is often attached on skin-adhesive solid carrying agent.The compound paid close attention to also can combinationally use with penetration enhancer, such as laurocapram (1-12 pit foundation azacyclo--2-in heptan ketone).Hypodermic layer is inserted into by subcutaneous for Sustained release delivery systems by operation or injection.Compound is encapsulated in lipid soluble membrane, such as silicone rubber or Biodegradable polymeric such as polylactic acid by hypodermic implant.
Pharmaceutical preparation is preferably unit dosage form.In this form, preparation is subdivided into the unit dose containing Sq active component.Unit dosage form can be the preparation of packaging kit, containing the preparation of discrete magnitude in packaging, and the tablet of such as packaging kit, capsule and powder in the vial or ampulla agent.In addition, unit dosage form can be capsule, tablet, cachet or lozenge itself, or it can be any one in these forms of suitable number in packaging kit form.
Other suitable medicinal carrying agent and their preparation are at Remington:The Science and Practice of Pharmacy 1995Martin, and E.W edits, Mack Publishing Company, the 19th edition, has description in Easton, Pennsylvania.
the purposes of the compounds of this invention and pharmaceutical composition
The feature of pharmaceutical composition of the present invention comprises the compound listed by the compound shown in formula formula I or formula II or the present invention, and pharmaceutically acceptable carrier, adjuvant or excipient.In compositions of the present invention, the amount of compound can detectably antagonism 5-HT effectively
6with treatment of obesity, gastroenteropathy, CNS disease, wherein said CNS disease is: ADHD, anxiety, the disease relevant to psychentonia, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea etc.
" effective dose " or " effective dose " of compound of the present invention or pharmaceutically acceptable compositions refer to process or alleviate one or more the present invention mention the effective dose of the severity of disease.According to method of the present invention, compound and compositions can be any dosage and any route of administration come effectively for the treatment of or the order of severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the generic condition of patient, the order of severity of infection, special factor, administering mode, etc.Compound or compositions can with one or more other treatment agent administering drug combinations, as discussed in the present invention.
the general synthetic method of the compounds of this invention
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is as shown in formula I or formula II.Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by method of modifying by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction condition is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction condition are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan is through sodium metal backflow drying and obtains.Anhydrous methylene chloride and chloroform are through calcium hydride backflow drying and obtain.Ethyl acetate, petroleum ether, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulfate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the rubber closure that reaction bulb is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1
3, DMSO-d
6, CD
3oD or acetone-d
6for solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25 ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent 6120 level Four bar HPLC-M.Mobile phase: 5%-95% is (containing the CH of 0.1% formic acid
3cN) (containing the H of 0.1% formic acid
2o) ratio in), adopt electron spray ionisation (ESI), under 210nm/254nm, detect with UV.
The use Agilent 1260pre-HPLC of pure compound or Calesep pump 250pre-HPLC (pillar model: NOVASEP 50/80mm DAC), detects at 210nm/254nm UV.
The use of brief word below runs through the present invention:
HOAc acetic acid
NaOAc sodium acetate
MeCN, CH
3cN acetonitrile
Cl
3c
2oCl trichloro-acetic chloride
CHCl
3chloroform
CDC1
3deuterochloroform
ClSO
2oH chlorosulfonic acid
DMF DMF
EtOAc/EA ethyl acetate
HCl hydrochloric acid
MgSO
4magnesium sulfate
MgCl
2magnesium chloride
MeOH, CH
3oH methanol
HCHO formaldehyde
CH
2cl
2, DCM dichloromethane
ML, ml milliliter
PE petroleum ether (60-90 DEG C)
Na
2cO
3sodium carbonate
NaHCO
3sodium bicarbonate
KOH potassium hydroxide
RT rt room temperature
Rt retention time
NaBH
3cN sodium cyanoborohydride
NaCl sodium chloride
NaH sodium hydride
Na
2sO
4sodium sulfate
THF oxolane
C
2h
7.HCl dimethylamine hydrochloride
Et
3n, TEA triethylamine
H
2o water
CH
3cOCH
3acetone
PCl
5phosphorus pentachloride
T
scl paratoluensulfonyl chloride
EDTA ethylenediaminetetraacetic acid
PEI polymine
Pargyline pargyline
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, each k, R
1, R
3and R
5there is definition as described in the present invention.
Synthetic method 1
Have such as formula (
3) and (4) shown in the present invention of structure compound of coming into the open can be prepared by the general synthetic method described by synthetic schemes 1, concrete steps can reference example.In synthetic schemes 1, formula (
1) shown in compound and sulfonic acid chloride obtain under the effect of alkali formula (
2) shown in compound.Formula (
2) shown in Formula obtain under the effect of alkali (potassium hydroxide) formula (
3) shown in remove tribromo-acetyl based products, formula (
3) shown in compound obtain with aldehyde or halohydrocarbons reaction further formula (
4) shown in alkylate.
Synthetic method 2
Have such as formula (
6) and (7) shown in the present invention of structure compound of coming into the open can be prepared by the general synthetic method described by synthetic schemes 1, concrete steps can reference example.In synthetic schemes 2, formula (
1) shown in compound and naphthalene sulfonyl chloride obtain under the effect of alkali formula (
5) shown in compound.Formula (
5) shown in Formula obtain under the effect of alkali (potassium hydroxide) formula (
6) shown in remove tribromo-acetyl based products, formula (
6) shown in compound obtain with aldehyde or halohydrocarbons reaction further formula (
7) shown in alkylate.Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
Embodiment
the synthesis of embodiment 1 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-1H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone
By 1-(2-methoxyphenyl) piperazine hydrochloric acid (1.0g, 4.39mmol) with triethylamine (2.5mL, 17.70mmol) join in dichloromethane (15mL), under 0 DEG C of low temperature bath, slow dropping trichloro-acetic chloride (1.0mL, 8.96mmol), after dripping, react 24 hours at being transferred to 25 DEG C, stopped reaction, add 50mL dichloromethane, wash with saturated sodium bicarbonate solution (40mL), organic facies anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1), and obtaining title compound is faint yellow solid (763mg, 52%).
MS(ESI,pos.ion)m/z:337.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:7.09-7.06(m,1H),6.96-6.91(m,3H),4.03(brs,4H),3.91(s,3H),3.18(t,J＝4.4Hz,4H)。
step 2) synthesis of 4-methoxyl group-3-(4-(2,2,2-tribromo-acetyl base) piperazine-1-base) benzene-1-sulfonic acid chloride
By 2,2, the chloro-1-of 2-tri-(4-(2-methoxyphenyl) piperazine-1-base) ethyl ketone (550mg, 1.63mmol) be dissolved in 5mL dichloromethane, then under 0 DEG C of low temperature bath, be added drop-wise in 3mL chlorosulfonic acid, react after 1 hour, reactant liquor is imported in the mixed liquor of frozen water (30mL) and dichloromethane (50mL), separatory after vigorous stirring, organic facies anhydrous magnesium sulfate drying.Filter, filtrate decompression is spin-dried for, and namely obtaining title compound is faint yellow solid (548mg, 78.5%).
MS(ESI,pos.ion)m/z:435.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:7.75(dd,J＝8.8,2.4Hz,1H),7.47(d,J＝2.4Hz,1H),7.01(d,J＝8.8Hz,1H),4.00(brs,7H),3.21(t,J＝4.8Hz,4H)。
step 3) synthesis of 1-(4-(5-((1H-benzo [d] imidazoles-1-base) sulfonyl)-2-methoxyphenyl) piperazine-1-base)-2,2,2-trichlorine ethyl ketones
By benzo [d] imidazoles (295mg at 0 DEG C; 2.5mmol) with sodium hydride (100mg; 2.5mmol) join in DMF (6mL); then 4-methoxyl group-3-(4-(2 is slowly added; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-sulfonic acid chloride (1.2g, 2.75mmol).React after 10 minutes, be warming up to 25 DEG C, continue reaction 2 hours.Add 100mL ethyl acetate, then wash (30mL x 3) with saturated nacl aqueous solution, organic facies anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography purification (petrol ether/ethyl acetate (v/v)=4/1), and obtaining title compound is white solid (1.08g, 84%).
MS(ESI,pos.ion)m/z:517.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.40(s,1H),7.91-7.85(m,1H),7.82-7.76(m,1H),7.74(dd,J＝8.8,2.4Hz,1H),7.45-7.37(m,3H),6.94(d,J＝8.8Hz,1H),4.00(br,4H),3.93(s,3H),3.14(t,J＝4.8Hz,4H)。
step 4) synthesis of 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-1H-benzo [d] imidazoles
At 25 DEG C; by 1-(4-(5-((1H-benzo [d] imidazoles-1-base) sulfonyl)-2-methoxybenzene) piperazine-1-base)-2; 2; 2-trichlorine ethyl ketone (1.19g; 2.30mmol) be dissolved in oxolane (20mL); then potassium hydroxide (281mg, 5.02mmol are made into 1mmol/ml aqueous solution) is slowly added.Reactant liquor stirring reaction, after 24 hours, adds 60ml dichloromethane; Organic facies saturated nacl aqueous solution is washed (30mL x 3), organic facies anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression be spin-dried for, crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=20/1), obtaining title compound is white solid (291mg, 34%).
MS(ESI,pos.ion)m/z:373.2[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.38(s,1H),7.87(d,J＝7.6Hz,1H),7.77(d,J＝7.6Hz,1H),7.67(dd,J＝8.4,1.6Hz,1H),7.44-7.32(m,3H),6.88(d,J＝8.4Hz,1H),3.88(s,3H),3.03(d,J＝6.4Hz,8H),2.65(br,1H)；
13C NMR(100MHz,CDCl
3)δ:157.3,144.0,142.7,141.3,130.9,129.1,124.6,121.0,116.6,112.5,111.2,56.0,51.2,45.8。
the synthesis of embodiment 2 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(2-methoxyl group-5-((2-methyl isophthalic acid H-benzo [d] imidazoles-1-base) sulfonyl) phenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 3; by 2-tolimidazole (290mg; 2.20mmol), sodium hydride (90mg; 2.25mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-sulfonic acid chloride (1.05g; 2.41mmol) reaction preparation in DMF (6mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification; it is white solid (1.02g, 87%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:533.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.05(dd,J＝6.6,2.2Hz,1H),7.68-7.63(m,2H),7.40-7.33(m,3H),6.93(d,J＝8.8Hz,1H),3.93(br,7H),3.09(t,J＝4.8Hz,4H),2.84(s,3H)。
step 2) synthesis of 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2, 2, the chloro-1-of 2-tri-(4-(2-methoxyl group-5-((2-methyl isophthalic acid H-benzo [d] imidazoles-1-base) sulfonyl) phenyl) piperazine-1-base) ethyl ketone (347mg, 0.65mmol), potassium hydroxide (80mg, 1.41mmol, be made into 1mmol/ml aqueous solution) reaction preparation in oxolane (20mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, it is white solid (181mg that concentrate drying obtains title compound, 72%).
MS(ESI,pos.ion)m/z:387.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.05-8.03(m,1H),7.63(dd,J＝6.8,2.4Hz,1H),7.59(dd,J＝8.8,2.4Hz,1H),7.39(d,J＝2.4Hz,1H),7.35-7.32(m,2H),6.87(d,J＝8.8Hz,1H),3.89(s,3H),3.04-3.02(m,4H),2.98-2.96(m,4H),2.83(s,3H),2.12(br,1H)；
13C NMR(100MHz,CDCl
3)δ:157.1,151.4,142.6,142.0,133.3,130.0,124.6,124.5,122.3,119.6,116.2,113.4,111.1,56.0,51.3,45.9,16.9。
the synthesis of embodiment 31-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (386mg, 1mmol) is dissolved in methanol (10mL), adds two acetic acid.At 0 DEG C, sodium cyanoborohydride (188.3mg, 3mmol) and formaldehyde (40%, 225 μ L, 3mmol) are slowly joined in reactant liquor.React after 10 minutes, be warming up to 25 DEG C; Continue reaction after 5 hours, add 10mL water and sodium carbonate (370mg, 3.5mmol) cancellation, then use dichloromethane extraction (50mL x 3).Merge organic facies, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, and obtaining title compound is white solid (328mg, 82%).
MS(ESI,pos.ion)m/z:401.1[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.04(d,J＝7.8Hz,1H),7.63(d,J＝7.2Hz,1H),7.59(d,J＝7.8Hz,1H),7.40(s,1H),7.36-7.31(m,2H),6.87(d,J＝9.0Hz,1H),3.89(s,3H),3.03(s,4H),2.82(s,3H),2.58(s,4H),2.35(s,3H)；
13C NMR(150MHz,CDCl
3)δ:157.1,151.4,142.2,141.9,133.2,129.9,124.6,124.5,122.3,119.6,116.2,113.4,111.1,56.0,54.9,50.1,46.0,17.0。
the synthesis of embodiment 4 1-((3-(4-ethyl piperazidine-1-base)-4-methoxyphenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
By 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (386mg, 1mmol), K
2cO
3(276mg, 2mmol), bromoethane (3mmol, 224 μ L) join in acetone (10mL), continue reaction 20 hours at 25 DEG C; Stopped reaction, adds dichloromethane (40mL), washes with saturated nacl aqueous solution (40mL); Organic facies anhydrous sodium sulfate drying after separatory; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, and obtaining title compound is white solid (360mg, 87%).
MS(ESI,pos.ion)m/z:415.0[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.04(d,J＝7.8Hz,1H),7.63(d,J＝7.2Hz,1H),7.59(d,J＝7.8Hz,1H),7.40(s,1H),7.36-7.31(m,2H),6.87(d,J＝8.4Hz,1H),3.89(s,3H),3.06(s,4H),2.82(s,3H),2.63(s,4H),2.50(q,J＝7.2Hz,2H),1.13(t,J＝7.2Hz,3H)；
13C NMR(150MHz,CDCl
3)δ:157.1,151.4,142.2,141.9,133.2,129.9,124.6,124.5,122.3,119.6,116.1,113.4,111.0,56.0,52.6,52.3,50.0,16.9,17.0。
the synthesis of embodiment 5 1-((3-(4-cyclopropylpiperazin-1-base)-4-methoxyphenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
By 1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (386mg at 25 DEG C, 1mmol) be dissolved in methanol (10mL), add acetic acid (5mmol, 300 μ L), then by sodium cyanoborohydride (188.3mg, 3mmol) slowly join in reactant liquor with 1-ethyoxyl-1-three silyloxy cyclopropane (2mmol, 432 μ L); Continue reaction after 12 hours, add water (10mL) and sodium carbonate (370mg, 3.5mmol) cancellation, then use dichloromethane extraction (50mL x 3).Merge organic facies, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, and obtaining title compound is white solid (128mg, 30%).
MS(ESI,pos.ion)m/z:427.1[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.04(d,J＝7.8Hz,1H),7.64-7.61(m,2H),7.40(d,J＝2.4Hz,1H),7.37(m,1H),7.33(m,1H),6.89(d,J＝8.4Hz,1H),3.91(s,3H),3.14(s,4H),2.96(s,4H),2.83(s,3H),0.90(t,J＝6.6Hz,2H),0.63(s,2H)；
13C NMR(150MHz,CDCl
3)δ:157.1,151.4,142.3,141.9,133.2,130.1,124.6,124.5,122.2,119.6,116.2,113.4,111.1,56.0,53.1,50.7,49.9,38.4,16.9,5.6。
the synthesis of embodiment 6 2-ethyl-1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-1H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(5-((2-ethyl-1H-benzo [d] imidazoles-1-base) sulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 3; by 2-ethyl benzo [d] imidazoles (450mg; 3.1mmol), sodium hydride (128mg; 3.2mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-sulfonic acid chloride (1.48g; 3.4mmol) reaction preparation in DMF (6mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification; it is white solid (1.25g, 74%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:547.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.07-8.05(m,1H),7.71-7.69(m,1H),7.61(dd,J＝8.8,2.0Hz,1H),7.37-7.35(m,3H),6.91(d,J＝8.4Hz,1H),3.98-3.93(m,7H),3.20(q,J＝7.6Hz,2H),3.08(t,J＝4.8Hz,4H),1.48(t,J＝7.6Hz,3H)。
step 2) synthesis of 2-ethyl-1-((4-methoxyl group-3-(piperazine-1-base) phenyl) sulfonyl)-1H-benzo [d] imidazoles
This step title compound prepares, by the chloro-1-of 2,2,2-tri-(4-(5-((2-ethyl-1H-benzo with reference to the method described by embodiment 1 step 4
[d]imidazoles-1-base) sulfonyl)-2-methoxyphenyl) piperazine-1-base) ethyl ketone (600mg; 1.09mmol), potassium hydroxide (130mg; 2.32mmol; be made into 1mmol/ml aqueous solution) reaction preparation in oxolane (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification; it is white solid (380mg, 87%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:401.2[M+H]
+；
1H NMR(CDCl
3,400MHz)δ8.07-8.05(m,1H),7.69-7.67(m,1H),7.57(dd,J＝8.8,2.3Hz,1H),7.37-7.28(m,3H),6.87(d,J＝8.4Hz,1H),3.90(s,3H),3.20(q,J＝7.2Hz,2H),3.03(t,J＝4.8Hz,4H),2.97(t,J＝3.2Hz,4H),1.90(br,1H),1.47(t,J＝7.6Hz,3H)；
13C NMR(CDCl
3,100MHz):δ157.1,156.3,142.5,142.0,133.4,130.2,124.6,124.5,122.2,119.8,116.2,113.6,111.1,56.0,51.3,45.9,23.4,11.9。
the synthesis of embodiment 7 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulfonyl)-1H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(1-methoxynaphthalene-2-base) piperazine-1-base) Acetolon
By 1-(1-methoxynaphthalene-2-base) piperazine (680mg, 2.81mmol) with triethylamine (1.12mL, 8.42mmol) join in dichloromethane (15mL), under 0 DEG C of low temperature bath, slow dropping trichloro-acetic chloride (0.47mL, 4.21mmol), after dripping, react 24 hours at being transferred to 25 DEG C, stopped reaction, add 50mL dichloromethane, wash with saturated sodium bicarbonate solution (40mL), organic facies anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=20/1) purification, and obtaining title compound is faint yellow solid (788mg, 72.3%).
MS(ESI,pos.ion)m/z:387.9[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.14(d,J＝8.5Hz,1H),7.81(d,J＝8.2Hz,1H),7.63(d,J＝8.8Hz,1H),7.51(t,J＝7.5Hz,1H),7.42(t,J＝7.4Hz,1H),7.28(d,J＝8.5Hz,1H),4.13-3.89(m,7H),3.39-3.33(m,4H)。
step 2) synthesis of 4-methoxyl group-3-(4-(2,2,2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-sulfonic acid chloride
By 2,2, the chloro-1-of 2-tri-(4-(1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (782mg, 2.02mmol) be dissolved in dichloromethane (5mL), then under 0 DEG C of low temperature bath, slow dropping chlorosulfonic acid (352.9mg, 3.03mmol), then reaction, after 24 hours, adds phosphorus pentachloride (624mg, 3.0mmol) at 25 DEG C, continue stirring reaction 5 hours, reactant liquor is imported in the mixed liquor of frozen water (30mL) and dichloromethane (50mL), separatory after vigorous stirring, organic facies anhydrous magnesium sulfate drying.Filter, filtrate decompression is spin-dried for, and namely obtaining title compound is faint yellow solid (595mg, 60.7%).
MS(ESI,pos.ion)m/z:486.9[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.69(d,J＝8.5Hz,1H),8.30(d,J＝8.2Hz,1H),8.13(s,1H),7.73-7.64(m,2H),4.10(s,7H),3.38-3.32(m,4H)。
step 3) synthesis of 1-(4-(4-((1H-benzo [d] imidazoles-1-base) sulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base)-2,2,2-trichlorine ethyl ketones
This step title compound prepares with reference to the method described by embodiment 1 step 3; by benzo [d] imidazoles (100mg; 0.85mmol), sodium hydride (36mg; 0.90mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-sulfonic acid chloride (453mg; 0.93mmol) reaction preparation in DMF (5mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification; it is yellow solid (261mg, 54%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:569.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.62(s,1H),8.58(dd,J＝6.4,2.0Hz,1H),8.31(s,1H),8.24-8.22(m,1H),7.78-8.77(m,1H),7.73-7.71(m,1H),7.61-7.57(m,2H),7.39-7.34(m,2H),4.12-4.08(m,4H),4.07(s,3H),3.37-3.34(m,4H)。
step 4) synthesis of 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulfonyl)-1H-benzo [d] imidazoles
This step title compound prepares, by 1-(4-(4-((1H-benzo with reference to the method described by embodiment 1 step 4
[d]imidazoles-1-base) sulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base)-2; 2; 2-tribromo-acetyl (260mg; 0.46mmol), potassium hydroxide (56mg; 1.0mmol; be made into 1mmol/ml aqueous solution) reaction preparation in oxolane (20mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification; it is yellow solid (101mg, 52%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:423.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.58(s,1H),8.54(dd,J＝6.0,1.6Hz,1H),8.35(s,1H),8.19(dd,J＝7.2,3.6Hz,1H),7.72(d,J＝7.2Hz,1H),7.69(d,J＝7.6Hz,1H),7.52(t,J＝4.0Hz,2H),7.35-7.28(m,2H),4.03(s,3H),3.26(m,4H),3.15(m,4H),2.56(br,NH)；
13C NMR(100MHz,CDCl
3)δ:153.2,143.9,141.3,138.5,130.8,130.3,127.8,127.3,127.0,125.7,125.4,125.1,124.6,123.1,122.8,121.1,112.3,59.4,51.1,46.1。
the synthesis of embodiment 8 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(1-methoxyl group-4-((2-methyl isophthalic acid H-benzo [d] imidazoles-1-base) sulfonyl) naphthalene-2-base) piperazine-1-base) ethyl ketonethis step title compound prepares with reference to the method described by embodiment 1 step 3; by 2-methyl benzo [d] imidazoles (500mg; 3.79mmol), sodium hydride (160mg; 4.0mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-sulfonic acid chloride (1.84g; 3.79mmol) reaction preparation in DMF (8mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification; it is yellow solid (1.68g, 76%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:581.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.34(d,J＝8.8Hz,1H),8.22(d,J＝8.4Hz,1H),8.11(d,J＝7.6Hz,1H),8.01(s,1H),7.71(d,J＝7.2Hz,1H),7.54(t,J＝7.2Hz,1H),7.45-7.39(m,3H),4.13-4.07(m,7H),3.25(t,J＝4.8Hz,4H),2.73(s,3H)。
step 2) synthesis of 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2, 2, the chloro-1-of 2-tri-(4-(1-methoxyl group-4-((2-methyl isophthalic acid H-benzo [d] imidazoles-1-base) sulphonyl) naphthalene-2-base) piperazine-1-base) ethyl ketone (1.6g, 2.75mmol), potassium hydroxide (308mg, 5.5mmol, be made into 1mmol/ml aqueous solution) reaction preparation in oxolane (30mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, it is yellow solid (1.07g that concentrate drying obtains title compound, 89%).
MS(ESI,pos.ion)m/z:438.1[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.34(d,J＝8.4Hz,1H),8.19(d,J＝8.4Hz,1H),8.06(d,J＝7.8Hz,1H),8.03(s,1H),7.64(d,J＝7.2Hz,1H),7.50-7.48(m,1H),7.39-7.32(m,3H),4.04(s,3H),3.21-3.16(m,4H),3.14(s,4H),2.67(s,3H),2.21(br,NH)；
13C NMR(100MHz,CDCl
3)δ:152.6,151.3,141.5,138.3,133.9,130.2,128.5,127.6,127.3,125.9,124.8,124.6,124.3,123.0,122.9,119.9,113.7,59.4,51.0,46.1,16.8。
the synthesis of embodiment 9 1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (437mg, 1mmol) is dissolved in methanol (10mL), adds two acetic acid.At 0 DEG C, sodium cyanoborohydride (188.3mg, 3mmol) and formaldehyde (40%, 225 μ L, 3mmol) are slowly joined in reactant liquor.React after 10 minutes, be warming up to 25 DEG C; Continue reaction after 5 hours, add 10mL water and sodium carbonate (370mg, 3.5mmol) cancellation, then use dichloromethane extraction (50mL x 3).Merge organic facies, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography purification (methylene chloride/methanol (v/v)=50/1) purification, and obtaining title compound is yellow solid (436mg, 97%).
MS(ESI,pos.ion)m/z:451.1[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.35(d,J＝9.0Hz,1H),8.19(d,J＝8.4Hz,1H),8.06(d,J＝7.2Hz,1H),8.03(s,1H),7.64(d,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.39-7.31(m,3H),4.02(s,3H),3.23(s,4H),2.67(s,7H),2.42(s,3H)；
13C NMR(150MHz,CDCl
3)δ:152.4,151.3,141.5,137.9,133.9,130.2,128.4,127.5,127.3,125.8,124.8,124.6,124.2,123.0,122.9,119.9,113.7,59.4,55.2,49.8,46.0,16.8。
the synthesis of embodiment 10 1-((3-(4-ethyl piperazidine-1-base)-4-methoxynaphthalene-1-base) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
By 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (437mg, 1mmol), K
2cO
3(276mg, 2mmol), bromoethane (3mmol, 224 μ L) join (10mL) in acetone, continue reaction 20 hours at 25 DEG C; Stopped reaction, adds dichloromethane (40mL), washes with saturated nacl aqueous solution (40mL); Organic facies anhydrous sodium sulfate drying after separatory; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) purification, and obtaining title compound is yellow solid (264mg, 57%).
MS(ESI,pos.ion)m/z:465.0[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.35(d,J＝8.4Hz,1H),8.19(d,J＝8.4Hz,1H),8.06(d,J＝8.4Hz,1H),8.03(s,1H),7.64(d,J＝7.8Hz,1H),7.49(t,J＝7.2Hz,1H),7.39-7.32(m,3H),4.02(s,3H),3.28(s,4H),2.75-2.71(m,4H),2.67(s,3H),2.60-2.59(m,2H),1.21(t,J＝6.6Hz,3H)；
13C NMR(150MHz,CDCl
3)δ:152.4,151.3,141.5,137.8,133.9,130.2,128.5,127.5,127.3,125.9,124.8,124.6,124.2,123.0,122.8,119.9,113.7,59.4,52.9,52.4,49.6,16.8,16.8。
the synthesis of embodiment 11 1-((3-(4-cyclopropylpiperazin-1-base)-4-methoxyphenyl) sulfonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles
By 1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-2-methyl isophthalic acid H-benzo [d] imidazoles (437mg at 25 DEG C, 1mmol) be dissolved in methanol (10mL), add acetic acid (5mmol, 300 μ L), then by sodium cyanoborohydride (188.3mg, 3mmol) and 1
-ethyoxyl
-1
-three silyloxy cyclopropane (2mmol, 432 μ L) slowly join in reactant liquor; Continue reaction after 12 hours, add 10mL water and sodium carbonate (370mg, 3.5mmol) cancellation, then use dichloromethane extraction (50mL x 3).Merge organic facies, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, and obtaining title compound is white solid (233mg, 49%).
MS(ESI,pos.ion)m/z:477.1[M+H]
+；
1H NMR(600MHz,CDCl
3)δ:8.36(d,J＝8.4Hz,1H),8.22(d,J＝9.0Hz,1H),8.08(d,J＝8.4Hz,1H),8.05(s,1H),7.67(d,J＝7.8Hz,1H),7.51(t,J＝7.2Hz,1H),7.421-7.34(m,3H),4.07(s,3H),3.20(s,4H),2.89(s,4H),2.69(s,3H),0.57(d,J＝4.1Hz,4H)；
13C NMR(150MHz,CDCl
3)δ:152.5,151.3,141.5,138.1,133.9,130.2,128.4,127.5,127.3,125.8,124.8,124.5,124.3,123.0,122.9,119.8,113.7,59.3,53.6,52.4,49.9,38.6,16.8,5.8。
the synthesis of embodiment 12 2-ethyl-1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulphonyl)-1H-benzo [d] imidazoles
step 1) synthesis of 2,2,2-tri-chloro-1-(4-(4-((2-ethyl-1H-benzimidazole-1-base) sulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone
This step title compound prepares with reference to the method described by embodiment 1 step 3; by 2-ethyl benzo [d] imidazoles (120mg; 0.82mmol), sodium hydride (36mg; 0.9mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-sulfonic acid chloride (400mg; 0.82mmol) reaction preparation in DMF (4mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification; it is yellow solid (166mg, 34%) that concentrate drying obtains title compound.
MS(ESI,pos.ion)m/z:595.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.29(d,J＝8.4Hz,1H),8.23(d,J＝8.8Hz,1H),8.13(d,J＝7.6Hz,1H),7.99(s,1H),7.84(d,J＝6.4Hz,1H),7.56(t,J＝7.6Hz,1H),7.47-7.42(m,3H),4.10-4.05(m,7H),3.25(s,4H),3.16(s,2H),1.25(s,3H)。
step 2) synthesis of 2-ethyl-1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) sulfonyl)-1H-benzo [d] imidazoles
This step title compound prepares with reference to the method described by embodiment 1 step 4, by 2, 2, the chloro-1-of 2-tri-(4-(4-((2-ethyl-1H-benzo [d] imidazoles-1-base) sulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (310mg, 0.52mmol), potassium hydroxide (64.2mg, 1.15mmol, be made into 1mmol/ml aqueous solution) reaction preparation in oxolane (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, it is yellow solid (166mg that concentrate drying obtains title compound, 71%).
MS(ESI,pos.ion)m/z:451.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:8.34(d,J＝8.8Hz,1H),8.19(d,J＝8.4Hz,1H),8.06-8.04(m,1H),7.90(s,1H),7.70-7.68(m,1H),7.51-7.47(m,1H),7.40-7.32(m,3H),4.03(s,3H),3.18-3.12(m,8H),3.04(q,J＝7.2Hz,2H),2.56(br,NH),1.32(t,J＝7.6Hz,3H)；
13C NMR(100MHz,CDCl
3)δ:156.3,152.5,141.6,138.3,133.9,130.2,129.0,127.5,127.2,125.9,124.7,124.5,123.7,123.1,122.8,120.0,113.8,59.4,51.1,46.2,23.1,11.6。
Biologic test
The present invention adopts following methods to carry out biologic test to the compound shown in formula I or formula II:
1. use radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI
6the affinity of receptor
The expression that 32 μ g prepare there is people source 5-HT
6the compound of the Chinese hamster ovary celI memebrane protein of receptor, 2nM radioactive marker [3H] LSD, different test concentrations and assay buffer mix homogeneously, hatch 120 minutes for 37 DEG C; Assay buffer composition is: 50mM Tris-HCl (pH 7.4), 10mM MgCl
2, 0.5mM EDTA, 10 μMs of pargylines and 20mg/l protease inhibitor.
Add 100 μMs of 5-HT and remove nonspecific binding site.After hatching, above-mentioned mixed liquor is used glass filter under vacuum, filter first uses 0.3%PEI preimpregnation before filtration.Rinse several times with 50mM Tris-HCl again after filtration.After filter drying, with scintillation mixed solution counting radioactivity on scintiloscope.Standard reference compounds is 5-HT, all tests several concentration and obtain its Competitive assays curve and calculate IC in each experiment
50.
The compound provided the embodiment of the present invention according to the method described above carries out radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI
6the affinity of receptor measures, result see table 1, the affinity measurement result that table 1 provides for the embodiment of the present invention.
The affinity measurement result of the compound that table 1 embodiment of the present invention provides
| Embodiment number | IC 50(nM) | Embodiment number | IC 50(nM) |
| Embodiment 1 | B | Embodiment 7 | B |
| Embodiment 2 | B | Embodiment 12 | A |
A：0.1～10nM，B：10nM～50nM。
As shown in Table 1, compound of the present invention at radio ligand binding assay assessing compound to expressing people source 5-HT on Chinese hamster ovary celI
6higher activity is generally demonstrated in the affinity test of receptor.
In the description of this description, reference term " embodiment ", " some embodiments ", " example ", the description of " concrete example " or " some examples " etc. means the specific features described in conjunction with this embodiment or example, structure, material or feature are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this description or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, limitation of the present invention can not be interpreted as, those of ordinary skill in the art can change above-described embodiment within the scope of the invention, amendment, replaces and modification.
Claims (17)
1. a compound, it is the stereoisomer of structure shown in the structure shown in formula I or formula I, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
Y is CH or N;
When
during for singly-bound, X is CH or N; When
during for double bond, X is C;
R
1for H, D, C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6ar
7n-C
1-6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl-C
1-6alkylidene or C
1-9heteroaryl-C
1-6alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, NO
2, OH, NH
2, R
6ar
6n-,-C (=O) R
6,-C (=O) NR
6r
6a,-N (R
6) C (=O)-R
6a, R
6r
6an-S (=O)
2-, R
6s (=O)
2-, R
6s (=O)
2n (R
6athe C that)-, hydroxyl replaces
1-6alkyl, R
6ar
6n-C
1-6alkylidene, R
6s (=O)-C
1-6alkylidene, R
6r
6an-C (=O)-C
1-6alkylidene, R
6ar
6n-C
1-6alkylene oxide group, R
6s (=O)-C
1-6alkylene oxide group, R
6r
6an-C (=O)-C
1-6alkylene oxide group, C
6-10aryl, C
1-9heteroaryl, C
1-6alkoxyl, C
1-6alkylamino, C
1-6alkyl, C
1-6haloalkyl, C
1-6halogenated alkoxy, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
1-6alkylthio group, C
6-10aryl-C
1-6alkyl or C
1-9heteroaryl-C
1-6alkylidene; Or adjacent two R
2the optional 5-6 replaced former molecular carbocyclic ring, heterocycle, aromatic rings or a fragrant heterocycle can be formed with the carbon atom be attached thereto;
Each R
4be H, D, F, Cl, Br, I, CN independently, oxo (=O), C
1-6alkyl, C
3-8cycloalkyl, C
1-6haloalkyl, C
1-6alkoxyl, C
1-6halogenated alkoxy or C
6-10aryl-C
1-4alkylidene;
R
5for H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-6alkyl, C
1-6haloalkyl, C
3-8cycloalkyl, C
1-6alkoxyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6a, C
6-10aryl or C
6-10aryl-C
1-6alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkoxyl or C
6-10aryl.
2. compound according to claim 1, wherein, R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, or C
6-10aryl-C
1-4alkylidene.
3. compound according to claim 1, wherein, each R
2and R
3be separately H, D, F, Cl, Br, I, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or adjacent two R
2the optional 5-6 replaced a former molecular aromatic rings or fragrant heterocycle can be formed with the carbon atom be attached thereto.
4. compound according to claim 1, wherein, each R
4be H, D, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl.
5. compound according to claim 1, wherein, R
5for H, D, F, Cl, Br, I ,-COOH, C
1-4alkyl, C
3-6cycloalkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene.
6. compound according to claim 1, it is the stereoisomer of structure shown in the structure shown in formula II or formula II, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
K is 0,1,2,3 or 4;
M is 0,1,2,3 or 4;
N is 0,1,2,3 or 4;
R
1for H, D, C
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl ,-C (=O) R
6,-C (=O) OR
6,-C (=O) NR
6r
6aor C
6-10aryl-C
1-4alkylidene;
Each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, C
1-4alkyl, C
3-6cycloalkyl, C
1-4alkoxyl, C
2-4thiazolinyl, C
2-4alkynyl or C
6-10aryl; Or the R that two adjacent
2the optional 5-6 replaced a former molecular aromatic rings or fragrant heterocycle can be formed with the carbon atom be attached thereto;
Each R
4be H, D, CN, C independently
1-4alkyl, C
3-6cycloalkyl, C
1-4haloalkyl or C
1-4alkoxyl;
R
5for H, D, F, Cl, Br, I, C
1-4alkyl, C
6-10aryl or C
6-10aryl-C
1-4alkylidene;
Each R
6and R
6abe H, D, OH, NH independently
2, C
1-4alkyl, C
1-4assorted alkyl or C
1-4haloalkyl.
7. compound according to claim 6, wherein, R
1for H, D, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, cyclopropyl or cyclobutyl.
8. compound according to claim 6, wherein, each R
2and R
3be separately H, D, F, Cl, Br, I, CN, OH, NH
2, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl or cyclobutyl; Or adjacent two R
2the optional phenyl ring replaced can be formed with the carbon atom be attached thereto.
9. compound according to claim 1, it has one of them structure following:
or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
10. pharmaceutical composition comprises the compound described in claim 1-9 any one, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or their combination.
11. pharmaceutical compositions according to claim 10, wherein further comprise additional treatment agent, and these additional treatment agent are used for the treatment of the medicine of A Cihaimo disease, for medicine or their combination of nervous disorders.
12. pharmaceutical compositions according to claim 11, wherein said additional treatment agent is: donepezil (donepezil), nalmefene (nalmefene), risperidone (risperidone), vitamin e (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, tacrine (tacrinE), Rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), meter Ta Zhaping (Mirtazapine), venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), nicergoline (nicergoline), piracetam (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their combination.
13. 1 kinds use compound described in claim 1-9 any one or the pharmaceutical composition described in claim 10-12 come for the preparation for the treatment of or prevent and 5-HT
6the purposes of relevant disease.
14. purposes according to claim 13, wherein said and 5-HT
6relevant disease is CNS disease.
15. purposes according to claim 14, wherein said CNS disease comprises: ADHD, anxiety, the disease relevant to psychentonia, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea.
16. purposes according to claim 13, wherein said and 5-HT
6relevant disease is disorder of gastrointestinal tract.
17. purposes according to claim 13, wherein said and 5-HT
6relevant disease is obesity.
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| CN105646330B (en) * | 2016-02-01 | 2020-12-11 | 贵州医科大学 | Aromatic heterocyclic derivative and application thereof in medicine |
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